This is the second half of PiHKAL: A Chemical Love Story, by Alexander Shulgin and Ann Shulgin.

Please forgive any typos or misprints in this file; further, because of ASCII limitations, many of the typographical symbols in the original book could not
be properly represented in this file.
If you are seriously interested in the chemistry contained in these files, you should order a copy of the book PiHA!. "he book may be purchased for
#$$.%& '#().%& * #+.,, postage and handling- from "ransform Press, .o/ (012&, .erkeley, CA %+2,(. California residents please add #(.0) State
sales ta/.n
At the present time, restrictive la3s are in force in the 4nited States and it is very difficult for researchers to abide by the regulations 3hich govern efforts
to obtain legal approval to do 3ork 3ith these compounds in human beings.... 5o one 3ho is lacking legal authori6ation should attempt the synthesis of
any of the compounds described in these files, 3ith the intent to give them to man. "o do so is to risk legal action 3hich might lead to the tragic ruination
of a life. It should also be noted that any person any3here 3ho e/periments on himself, or on another human being, 3ith any of the drugs described
herin, 3ithout being familiar 3ith that drug7s action and a3are of the physical and8or mental disturbance or harm it might cause, is acting irresponsibly
and immorally, 3hether or not he is doing so 3ithin the bounds of the la3.
A SH9:" I5;<= "9 "H< PH<5<"H>!A?I5<S
"his short inde/ to the phenethylamines lists the (2% entries that
follo3 in alphebetical order. "he abbreviation P<A is for
phenethylamine, and A is for amphetamine. "he long inde/ includes all
synonyms and is in Appendi/ A.
Code Compact chemical name
( A<? a@<thyl@0,+,&@trimetho/y@P<A
$ A! +@Allylo/y@0,&@dimetho/y@P<A
0 A!<PH +@?ethylthio@$,&@dimetho/y@A
+ A!<PH@$ +@<thylthio@$,&@dimetho/y@A
& A!<PH@+ +@Isopropylthio@$,&@dimetho/y@A
1 A!<PH@1 +@Phenylthio@$,&@dimetho/y@A
2 A!<PH@2 +@Propylthio@$,&@dimetho/y@A
) A:IA;5< $,&@;imetho/y@a@ethyl@+@methyl@P<A
% AS. 0,+@;ietho/y@&@metho/y@P<A
(, . +@.uto/y@0,&@dimetho/y@P<A
(( .<A":IC< $,&@;imetho/y@+,5@dimethyl@A
($ .IS@"9? $,&@.ismethylthio@+@methyl@A
(0 .9. +@.romo@$,&,beta@trimetho/y@P<A
(+ .9; $,&,beta@"rimetho/y@+@methyl@P<A
(& .9H beta@?etho/y@0,+@methylenedio/y@P<A
(1 .9H; $,&@;imetho/y@beta@hydro/y@+@methyl@P<A
(2 .9? 0,+,&,beta@"etrametho/y@P<A
() +@.r@0,&@;?A +@.romo@0,&@dimetho/y@A
(% $@.r@+,&@?;A $@.romo@+,&@methylenedio/y@A
$, $C@. +@.romo@$,&@dimetho/y@P<A
$( 0C@.A +@.en6ylo/y@0,&@dimetho/y@A
$$ $C@C +@Chloro@$,&@dimetho/y@P<A
$0 $C@; +@?ethyl@$,&@dimetho/y@P<A
$+ $C@< +@<thyl@$,&@dimetho/y@P<A
$& 0C@< +@<tho/y@0,&@dimetho/y@A
$1 $C@B +@Bluoro@$,&@dimetho/y@P<A
$2 $C@C 0,+@;imethyl@$,&@dimetho/y@P<A
$) $C@C@0 0,+@"rimethylene@$,&@dimetho/y@P<A
$% $C@C@+ 0,+@"etramethylene@$,&@dimetho/y@P<A
0, $C@C@& 0,+@5orbornyl@$,&@dimetho/y@P<A
0( $C@C@5 (,+@;imetho/ynaphthyl@$@ethylamine
0$ $C@H $,&@;imetho/y@P<A
00 $C@I +@Iodo@$,&@dimetho/y@P<A
0+ $C@5 +@5itro@$,&@dimetho/y@P<A
0& $C@9@+ +@Isopropo/y@$,&@dimetho/y@P<A
01 $C@P +@Propyl@$,&@dimetho/y@P<A
02 CP? +@Cyclopropylmetho/y@0,&@dimetho/y@P<A
0) $C@S< +@?ethylseleno@$,&@dimetho/y@P<A
0% $C@" +@?ethylthio@$,&@dimetho/y@P<A
+, $C@"@$ +@<thylthio@$,&@dimetho/y@P<A
+( $C@"@+ +@Isopropylthio@$,&@dimetho/y@P<A
+$ gamma@$C@"@+ +@Isopropylthio@$,1@dimetho/y@P<A
+0 $C@"@2 +@Propylthio@$,&@dimetho/y@P<A
++ $C@"@) +@Cyclopropylmethylthio@$,&@dimetho/y@P<A
+& $C@"@% +@'t-@.utylthio@$,&@dimetho/y@P<A
+1 $C@"@(0 +@'$@?etho/yethylthio-@$,&@dimetho/y@P<A
+2 $C@"@(& +@Cyclopropylthio@$,&@dimetho/y@P<A
+) $C@"@(2 +@'s-@.utylthio@$,&@dimetho/y@P<A
+% $C@"@$( +@'$@Bluoroethylthio-@$,&@dimetho/y@P<A
&, +@; +@"rideuteromethyl@0,&@dimetho/y@P<A
&( beta@; beta,beta@;ideutero@0,+,&@trimetho/y@P<A
&$ ;<S9=> +@?ethyl@0,&@;imetho/y@P<A
&0 $,+@;?A $,+@;imetho/y@A
&+ $,&@;?A $,&@;imetho/y@A
&& 0,+@;?A 0,+@;imetho/y@A
&1 ;?CPA $@'$,&@;imetho/y@+@methylphenyl-@cyclopropylamine
&2 ;?< 0,+@;imetho/y@beta@hydro/y@P<A
&) ;??;A $,&@;imetho/y@0,+@methylenedio/y@A
&% ;??;A@$ $,0@;imetho/y@+,&@methylenedio/y@A
1, ;?P<A 0,+@;imetho/y@P<A
1( ;9A? +@Amyl@$,&@dimetho/y@A
1$ ;9. +@.romo@$,&@dimetho/y@A
10 ;9.4 +@.utyl@$,&@dimetho/y@A
1+ ;9C +@Chloro@$,&@dimetho/y@A
1& ;9<B +@'$@Bluoroethyl-@$,&@dimetho/y@A
11 ;9<" +@<thyl@$,&@dimetho/y@A
12 ;9I +@Iodo@$,&@dimetho/y@A
1) ;9? +@?ethyl@$,&@dimetho/y@A
1% gamma@;9? +@?ethyl@$,1@dimetho/y@A
2, ;95 +@5itro@$,&@dimetho/y@A
2( ;9P: +@Propyl@$,&@dimetho/y@A
2$ < +@<tho/y@0,&@dimetho/y@P<A
20 <<< $,+,&@"rietho/y@A
2+ <<? $,+@;ietho/y@&@metho/y@A
2& <?< $,&@;ietho/y@+@metho/y@A
21 <?? $@<tho/y@+,&@dimetho/y@A
22 <"H>!@D 5,a@diethyl@0,+@methylenedio/y@P<A
2) <"H>!@ 5@<thyl@a@propyl@0,+@methylenedio/y@P<A
2% B@$ .en6ofuran@$@methyl@&@metho/y@1@'$@aminopropane-
), B@$$ .en6ofuran@$,$@dimethyl@&@metho/y@1@'$@aminopropane-
)( B!<A 5@Hydro/y@5@methyl@0,+@methylenedio/y@A
)$ C@0 0,+@"rimethylene@$,&@dimetho/y@A
)0 C@+ 0,+@"etramethylene@$,&@dimetho/y@A
)+ C@& 0,+@5orbornyl@$,&@dimetho/y@A
)& CA5<SHA 0,+@;imethyl@$,&@dimetho/y@A
)1 C@5 (,+@;imetho/ynaphthyl@$@isopropylamine
)2 H9"@$ $,&@;imetho/y@5@hydro/y@+@ethylthio@P<A
)) H9"@2 $,&@;imetho/y@5@hydro/y@+@'n-@propylthio@P<A
)% H9"@(2 $,&@;imetho/y@5@hydro/y@+@'s-@butylthio@P<A
%, I;55A $,&@;imetho/y@5,5@dimethyl@+@iodo@A
%( I? $,0,+@"rimetho/y@P<A
%$ IP 0,&@;imetho/y@+@isopropo/y@P<A
%0 I:IS &@<tho/y@$@metho/y@+@methyl@A
%+ D a@<thyl@0,+@methylenedio/y@P<A
%& !9PH9PHI5< 0@?etho/y@+,&@methylenedio/y@P<A
%1 ? 0,+,&@"rimetho/y@P<A
%2 +@?A +@?etho/y@A
%) ?A;A?@1 $,5@;imethyl@+,&@methylenedio/y@A
%% ?A! 0,&@;imetho/y@+@methallylo/y@P<A
(,, ?;A 0,+@?ethylenedio/y@A
(,( ?;A! 5@Allyl@0,+@methylenedio/y@A
(,$ ?;.4 5@.utyl@0,+@methylenedio/y@A
(,0 ?;.A 5@.en6yl@0,+@methylenedio/y@A
(,+ ?;CP? 5@Cyclopropylmethyl@0,+@methylenedio/y@A
(,& ?;;? 5,5@;imethyl@0,+@methylenedio/y@A
(,1 ?;< 5@<thyl@0,+@methylenedio/y@A
(,2 ?;H9<" 5@'$@Hydro/yethyl-@0,+@methylenedio/y@A
(,) ?;IP 5@Isopropyl@0,+@methylenedio/y@A
(,% ?;?A 5@?ethyl@0,+@methylenedio/y@A
((, ?;?C 5@?ethyl@0,+@ethylenedio/y@A
((( ?;?<9 5@?etho/y@0,+@methylenedio/y@A
(($ ?;?<9<" 5@'$@?etho/yethyl-@0,+@methylenedio/y@A
((0 ?;?P a,a,5@"rimethyl@0,+@methylenedio/y@P<A
((+ ?;9H 5@Hydro/y@0,+@methylenedio/y@A
((& ?;P<A 0,+@?ethylenedio/y@P<A
((1 ?;PH a,a@;imethyl@0,+@methylenedio/y@P<A
((2 ?;P! 5@Propargyl@0,+@methylenedio/y@A
(() ?;P: 5@Propyl@0,+@methylenedio/y@A
((% ?< 0,+@;imetho/y@&@etho/y@P<A
($, ?<;A 0,+@<thylenedio/y@&@metho/y@A
($( ?<< $@?etho/y@+,&@dietho/y@A
($$ ?<? $,&@;imetho/y@+@etho/y@A
($0 ?<P<A 0@?etho/y@+@etho/y@P<A
($+ ?<"A@;9. &@.romo@$,+@dimetho/y@A
($& ?<"A@;9" &@?ethylthio@$,+@dimetho/y@A
($1 ?<"H>!@;?A 5@?ethyl@$,&@dimetho/y@A
($2 ?<"H>!@;9. +@.romo@$,&@dimetho/y@5@methyl@A
($) ?<"H>!@D 5@?ethyl@a@ethyl@0,+@methylenedio/y@P<A
($% ?<"H>!@ 5@?ethyl@a@propyl@0,+@methylenedio/y@P<A
(0, ?<"H>!@?A 5@?ethyl@+@metho/y@A
(0( ?<"H>!@??;A@$ 5@?ethyl@$@metho/y@+,&@methylenedio/y@A
(0$ ??;A 0@?etho/y@+,&@methylenedio/y@A
(00 ??;A@$ $@?etho/y@+,&@methylenedio/y@A
(0+ ??;A@0a $@?etho/y@0,+@methylenedio/y@A
(0& ??;A@0b +@?etho/y@$,0@methylenedio/y@A
(01 ??< $,+@;imetho/y@&@etho/y@A
(02 ?P 0,+@;imetho/y@&@propo/y@P<A
(0) ?P? $,&@;imetho/y@+@propo/y@A
(0% 9:"H9@;9" $@?ethylthio@+,&@dimetho/y@A
(+, P 0,&@;imetho/y@+@propo/y@P<A
(+( P< 0,&@;imetho/y@+@phenethylo/y@P<A
(+$ P<A P<A
(+0 P:9P>5>! +@Propynylo/y@0,&@dimetho/y@P<A
(++ S. 0,&@;ietho/y@+@metho/y@P<A
(+& "A $,0,+,&@"etrametho/y@A
(+1 0@"AS. +@<tho/y@0@ethylthio@&@metho/y@P<A
(+2 +@"AS. 0@<tho/y@+@ethylthio@&@metho/y@P<A
(+) &@"AS. 0,+@;ietho/y@&@methylthio@P<A
(+% ". +@"hiobuto/y@0,&@dimetho/y@P<A
(&, 0@"< +@<tho/y@&@metho/y@0@methylthio@P<A
(&( +@"< 0,&@;imetho/y@+@ethylthio@P<A
(&$ $@"I? $@?ethylthio@0,+@dimetho/y@P<A
(&0 0@"I? 0@?ethylthio@$,+@dimetho/y@P<A
(&+ +@"I? +@?ethylthio@$,0@dimetho/y@P<A
(&& 0@"? 0@?ethylthio@+,&@dimetho/y@P<A
(&1 +@"? +@?ethylthio@0,&@dimetho/y@P<A
(&2 "?A 0,+,&@"rimetho/y@A
(&) "?A@$ $,+,&@"rimetho/y@A
(&% "?A@0 $,0,+@"rimetho/y@A
(1, "?A@+ $,0,&@"rimetho/y@A
(1( "?A@& $,0,1@"rimetho/y@A
(1$ "?A@1 $,+,1@"rimetho/y@A
(10 0@"?< +,&@;imetho/y@0@ethylthio@P<A
(1+ +@"?< 0@<tho/y@&@metho/y@+@methylthio@P<A
(1& &@"?< 0@<tho/y@+@metho/y@&@methylthio@P<A
(11 $"@??;A@0a $@?ethylthio@0,+@methylenedio/y@A
(12 +"@??;A@$ +,&@"hiomethyleneo/y@$@metho/y@A
(1) "?P<A $,+,&@"rimetho/y@P<A
(1% $@"9<" +@<thyl@&@metho/y@$@methylthio@A
(2, &@"9<" +@<thyl@$@metho/y@&@methylthio@A
(2( $@"9? &@?etho/y@+@methyl@$@methylthio@A
(2$ &@"9? $@?etho/y@+@methyl@&@methylthio@A
(20 "9?S9 $@?etho/y@+@methyl@&@methylsulfinyl@A
(2+ "P +@Propylthio@0,&@dimetho/y@P<A
(2& ":IS 0,+,&@"rietho/y@P<A
(21 0@"S. 0@<tho/y@&@ethylthio@+@metho/y@P<A
(22 +@"S. 0,&@;ietho/y@+@methylthio@P<A
(2) 0@"@":IS +,&@;ietho/y@0@ethylthio@P<A
(2% +@"@":IS 0,&@;ietho/y@+@ethylthio@P<A
PH<5<"H>!A?I5<S
#1 AEM; a-ETHYMES!A"#E;
$-AM"#%-1-&',(,)-T*"METH%+Y,HE#Y-./TA#E;
1-&',(,)-T*"METH%+Y,HE#Y--$-AM"#%./TA#E
S>5"H<SISE "o a solution of +& g 0,+,&@trimetho/yben6aldehyde in (.$ ! IPA, there 3as added ($& g nitropropane and 12.& g t@butylammonium
acetate and the reaction mi/ture 3as held at reflu/ for (1 h. "his 3as poured into 1 ! H$9, and e/tracted 3ith $/$&, m! he/ane. "he pooled e/tracts
3ere stripped of solvent under vacuum giving a residue that slo3ly set to a crystalline mass. 9n filtering, there 3as obtained %.+ g of a crude yello3
product 3hich, on recrystalli6ation from he/ane provided ).2 g of slightly sticky bright yello3 crystals of $@nitro@(@'0,+,&@trimetho/yphenyl-butene@(, 3ith
a mp of 2(@20 deg C. A second recrystalli6ation from he/ane gave fine yello3 crystals 3ith a mp of 2$@20 deg C. Attempts at the preparation of this
nitrostyrene by the more conventional methods 3ith ammonium acetate in acetic acid led either to the formation of a 3hite product C$0H0,5$9) 3hich
3as composed of a molecule of the nitrostyrene, one of the ben6aldehyde itself, and a molecule of ammonia, or to 0,+,&@trimetho/yben6onitrile, from
reaction 3ith the decomposition products of nitropropane.
A stirred suspension of &.% g !AH in 0(, m! anhydrous <t$9 3as held at a gentle reflu/ in an inert atmosphere. A solution of ).& g $@nitro@(@'0,+,&@
trimetho/yphenyl-butene@( in ($& m! <t$9 is added drop@3ise over the course of ,.& h. "he reaction 3as maintained at reflu/ for 1 h, then cooled, and
the e/cess hydride destroyed by the cautious addition of 0,, m! (.) 5 H$S9+. "he phases 3ere separated, and the aFueous phase brought to a pH of
1 by the addition of a saturated 5a$C90 solution. "he neutral solution 3as brought to a boil, and clarified by filtration through paper. "o the hot filtrate
there 3as added a solution of ).% g picric acid in (,, m! boiling <t9H. "he mi/ture 3as stirred and cooled, 3ith the formation of a heavy yello3
crystalline mass. After standing in the ice tub for several hours the mi/ture 3as filtered, providing )., g of the picrate salt 3ith a mp of (21@()( deg C
from H$9. A solution of this salt in 0,, m! boiling H$9 3as treated 3ith 1, m! concentrated HCl. 9n cooling, there 3as a deposition of picric acid,
3hich 3as removed by filtration. "he aFueous filtrate 3as 3ashed 3ith 0/&, m! nitroben6ene, then 3ith 0/&, m! <t$9. "he pH 3as brought above %
by the addition of aFueous 5a9H, and the filtrate 3as e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent from the pooled e/tracts gave a nearly
colorless oil, 3hich 3as dissolved in 0,, m! anhydrous <t$9 and saturated 3ith hydrogen chloride gas. "he 3hite crystals of $@amino@(@'0,+,&@
trimetho/yphenyl-butane hydrochloride 'A<?- 3ere removed by filtration, <t$93ashed, and air dried. "hey 3eighed +.2$ g.
;9SAC<E greater than $$, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "he e/tension of the t3o@carbon chain of mescaline by alpha@methylation to the three carbon chain of "?A
appro/imately doubled the potency of the compound. And it 3as felt to be a completely logical possibility that, by e/tending it one more carbon atom, to
the four carbon chain of alpha@ethyl@mescaline, it might double again. And follo3ing that logical progression, the doubling of potency 3ith each
additional carbon atom, the factor 3ould be $ to the 2th po3er by the alpha@octyl 'or $&1/ that of mescaline, or a milligram as active dose- and 3ith a
side chain of a 2,@carbon alkyl group 'alpha@heptacontylmescaline- it 3ould take Gust a single molecule to be into/icating. "his 3as rich fantasy stuff. As
an active compound, Gust 3here 3ould it go in the brainH Iith an ),@carbon side@chain, 3ould one@thousandth of a single molecule be enough for a
personH 9r might a single molecule into/icate a thousand peopleH And ho3 long a chain on the alpha@position might be sufficient that, by merely
3riting do3n the structure on a piece of paper, you 3ould get highH ?aybe Gust conceiving the structure in your mind 3ould do it. "hat is, after all, the
3ay of homeopathy.
?aybe it 3as Gust as 3ell that this added t3o@carbon side@chain 3ith lo3ered activity 3as already enough to disprove the doubling pattern. .ut by the
time this non@activity had been learned, the alpha series had already been pushed out Fuite a3ays. "he machinery of making the appropriate
nitroalkane 3as straightfor3ard, by reaction of the alkyl halide 3ith nitrous acid, and separating the un3anted nitrite ester from the 3anted nitroalkane by
fractional distillation. "he nitrostyrenes all formed reasonably although often in terrible yields, and reduced reasonably, and all formed crystalline
picrates for isolation and crystalline hydrochloride salts for pharmacological manipulation. .ut since the first of these, A<?, 3as not active, there 3as no
enthusiasm for tasting anything higher. "his family 3as never published; 3hy publish presumably inactive and thus uninteresting materialH "he "able
presents the properties of the precursor nitrostyrenes, and the product picrate and hydrochloride salts, at least 3hatever information I can still find after
thirty
yearsE
"A.!<. Physical Properties of the a@Alkylmescaline Homologues and their Precursor 5itrostyrenes
Code 5ame 5S mp deg C picrate mp deg C HCl mp deg C
AP? Alpha@propylmescaline )$@)0 $(+@$()
A.? Alpha@butylmescaline 20@2+ (1%@(2+ ()$@()+
AA? Alpha@amylmescaline &+@&& (1$@(10 (&&@(&)
AH? Alpha@he/ylmescaline &(@&$
AS?J Alpha@heptylmescaline +0@++
A9? Alpha@octylmescaline JJ
A5? Alpha@nonylmescaline +1@+2 JJJ
A4? Alpha@undecylmescaline JJJ
J S is for septyl, to distinguish heptyl from he/yl. JJ5ever made, as no nonylbromide could be located to make the needed nitrononane.
JJJ"he synthesis got as far as the nitrostyrene stage 3hen the inactivity of A<? 3as determined, and the proGect 3as dropped.
#$ A; (-AY%+Y-',)-0"METH%+Y,HE#ETHYAM"#E; ',)-0"METH%+Y-(-AY%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of &.) g of homosyringonitrile 'see under < for its preparation-, (,, mg decyltriethylammonium iodide, and (0.1 g allyl iodide in
&, m! anhydrous acetone 3as treated 3ith 1.% g finely po3dered anhydrous $C90 and held at reflu/ for (1 h. "he color changed from a near@black to
a light yello3. "he mi/ture 3as filtered, the solids 3ashed 3ith acetone, and the solvent from the combined filtrate and 3ashes removed under vacuum.
"he residue 3as suspended in acidified H$9, and e/tracted 3ith 0/(,, m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith $/&, m! &K 5a9H, once
3ith dilute HCl '3hich lightened the color of the e/tract- and then stripped of solvent under vacuum giving ($.+ g of an amber@colored oil. "his 3as
distilled at ($&@(02 deg C at ,.( mm8Hg to yield &.2 g of 0,&@dimetho/y@+@allylo/yphenylacetonitrile as a yello3 oil. Anal. 'C(0H(&590S- C,H.
A suspension of +., g !AH in (&, m! anhydrous "HB under 5$ 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, $.) m!
(,,K H$S9+, follo3ed by &.& g 0,&@dimetho/y@+@allylo/yphenylacetonitrile in (, m! anhydrous "HB. "he reaction mi/ture 3as stirred at , deg C for a
fe3 min, then brought to a reflu/ on the steam bath for 0, min. After cooling back to room temperature, there 3as added sufficient IPA to destroy the
e/cess hydride, follo3ed by sufficient (,K 5a9H to form granular solids. "hese 3ere removed by filtration, and 3ashed 3ith $, m! IPA. "he filtrate and
3ashes 3ere stripped of solvent under vacuum and the residue added to (,, m! dilute H$S9+. "his 3as 3ashed 3ith $/&, m! CH$Cl$, made basic
3ith aFueous 5a9H, and e/tracted 3ith $/2& m! CH$Cl$. "hese e/tracts 3ere pooled, the solvent removed under vacuum, and the residue distilled at
((,@($, deg C at ,.+ mm8Hg to give +.% g of a colorless oil. "his 3as dissolved in (& m! IPA, neutrali6ed 3ith concentrated HCl '&& drops reFuired-,
and diluted 3ith &, m! <t$9. "he product 3as removed by filtration, 3ashed 3ith <t$9, and air dried to give +.% g of 0,&@dimetho/y@+@
allylo/yphenethylamine hydrochloride 'A!- as 3hite crystals.
;9SAC<E $, @ 0& mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith $+ mg- I first became a3are of something in about (, minutes, a pleasant increase in energy. .y $, minutes it 3as
getting pronounced and 3as a nice, smooth development. ;uring the ne/t hour positive and negative feelings developed simultaneously. Bollo3ing a
suggestion, I ate a bit of food even though I had not been hungry, and to my surprise all the negative feelings dropped a3ay. I felt free to Goin the others
3herever they 3ere at. I moved into the creative, free@flo3ing kind of repertoire 3hich I dearly love, and found everything enormously funny. ?uch of
the laughter 3as so deep that I felt it 3orking through buried depressions inside me and freeing me. Brom this point on, the e/perience 3as most
enGoyable. "he e/perience 3as characteri6ed by clear@headedness and an abundance of energy 3hich kept on throughout the day and evening. At one
point I 3ent out back and strolled along to find a place to 3orship. I had a profound sense of the Presence and great love and gratitude for the place,
the people, and the activities taking place. "he come@do3n from the e/perience 3as very gradual and smooth. Bood tasted 3onderful. I 3ent to bed
late, and Fuite ready for bed, although the energy 3as still running. Ho3ever, sleep 3as not long in coming. '3ith $+ mg- "he onset 3as e/tremely
gradual and graceful, 3ith the first alert that one could really sense at about &, minutes. "his 3as succeeded by a slo3 gentle climb to the peak at one
hour and fifteen minutes. "he e/perience itself left all of the sensory modalities functional; speech 3as cogent and rather fluid. In fact, there 3as an
unusual ease of free association. All throughout the session, the talk 3as high in spirits and someho3 indicative of an inner e/citement. Affect 3as
entirely pleasant, but not e/alting nor conducive to insight or to problem solving. "here 3ere no reFuirements for 3ithdra3al into the self. "he material
seemed 3holly social in nature. 5o visual, auditory or olfactory sharpening 3as in evidence. "he plateau for this material seemed unusually long. I 3as
unable to sleep for several hours, and took $& mg !ibrium before sleep arrived. "he ne/t day 3as a lethargic and slo3 one, 3ith the inner feeling that
the effects had not 3orn off until the middle of the day follo3ing ingestion.
'3ith 0& mg- I 3as a distinct *( in 0& minutes and a *$ by the end of the hour. ?y head congestion in no 3ay cleared up, absolving the material from
having that particular virtue. "he entire e/perience 3as some3hat dissociated L I could not connect 3ith my feelings. Although my mind remained clear,
there 3as a hangover feeling at the end of the e/periment.
<="<5SI95S A5; C9??<5"A:>E "his compound 3as first e/plored in Prague by !eminger. He provided only the synthetic details and the
statement that it 3as the most active compound that he had studied, 3ith activity at $, milligrams, 3ith perceptual changes, color enhancement, and
difficult dreams during sleep that night. Some effects persisted for more than ($ hours. ;osages above 0& milligrams remain une/plored. As A! is one
of the most potent 0,+,&@trisubstituted phenethylamines yet described, and since the corresponding amphetamines are of yet greater potency, it 3ould be
a good guess that +@allylo/y@0,&@dimetho/yamphetamine '0C@A!- 3ould be an interesting compound to e/plore. It could be made from syringaldehyde
in reaction 3ith allyl iodide, follo3ed by the formation of a nitrostyrene 3ith nitroethane, follo3ed by reduction 3ith aluminum hydride. It is, as of the
present time, both unsynthesi6ed and une/plored.
#' AE,H; 0%T; ,A*A-0%T; $,)-0"METH%+Y-(-METHYTH"%AM,HETAM"#E
S>5"H<SISE A solution of $.0 g $,&@dimetho/y@+@'methylthio-ben6aldehyde 'see under $C@" for its synthesis- in 2.& m! nitroethane 3as treated 3ith
,.+& g anhydrous ammonium acetate and heated on the steam bath for 1 h. "he e/cess solvent8reagent 3as removed under vacuum leaving a mass of
orange crystals as residue. "hese 3ere ground up under (, m! ?e9H, col@lected by filtration, 3ashed 3ith a little ?e9H, and air dried to provide $.1 g
crude (@'$,&@dimetho/y@+@methylthiophenyl-@$@nitropropene. After recrystalli6ation from (+, m! boiling ?e9H, filtering and drying there 3as in hand (.)
g of bright orange crystals 3ith a mp of (02@(0) deg C. Anal. 'C($H(&59+S- C,H,5,S. A suspension of (.+ g !AH in (, m! anhydrous <t$9 and +, m!
anhydrous "HB 3as put under an inert atmosphere and, 3ith good stirring, brought up to a gentle reflu/. A solution of (.) g (@'$,&@dimetho/y@+@
methylthiophenyl-@$@nitropropene in 0, m! anhydrous "HB 3as added drop3ise at a rate that maintained the reflu/. Heating and stirring 3ere
maintained for an additional 2 h, then the reaction mi/ture 3as allo3ed to return to room temperature. "here 3as added
(.1 m! H$9 'dissolved in a little "HB-, follo3ed by (.1 m! (&K 5a9H, and finally another +.) m! H$9. Stirring 3as continued until all the curdy solids
had turned 3hite. "he reaction mi/ture 3as filtered, and the filter cake 3ashed 3ith "HB. "he filtrate and the 3ashings 3ere combined, and the solvent
removed under vacuum. "he residue 3as (.0 g of a colorless oil that solidified. Its mp of %,@%0 deg C 3as improved slightly to %(@%0 deg C 3ith
recrystalli6ation from he/ane. "he product 3as dissolved in $& m! 3arm IPA, neutrali6ed 3ith concentrated HCl ',.&2 m! reFuired- and then diluted 3ith
(,, m! anhydrous <t$9. After a moment7s delay, the 3hite crystalline product appeared. It 3as removed by filtration, 3ashed 3ith <t$9, and air dried
to provide (.$ g $,&@dimetho/y@+@methylthioamphetamine hydrochloride 'A!<PH- 3ith a mp of $,,@$,( deg C. :ecrystalli6ation from IPA gave an
analytical sample 3ith a mp of $,+@$,& deg C. Anal. 'C($H$,Cl59$S- C,H; 5E calcd, &.,+; found, &.&$.
;9SAC<E & @ (, mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith & mg- "he initial hints of action 3ere physical L 3arming of first the legs, and then a comfortable 3armth spread over
the entire body. Intense intellectual stimulation, one that inspired the scribbling of some (+ pages of hand3ritten notes. Ihich is a pretty good record for
an e/perience that is almost entirely non@verbal. "he afterglo3 3as benign and rich in empathy for everything. And by the si/th hour I 3as Fuite hungry.
'3ith (, mg- "here 3as a rapid shift of frame of reference that made simple tasks such as reading and tuning the radio Fuite alien. I happened to catch
the eyes of Pretty .aby, the cat, at the same moment she looked at me, and she turned and fled. I am able to interact 3ith people on the telephone
Fuite 3ell but mechanical things, such as arranging flo3ers or alphabeti6ing names, are beyond me. ;riving 3ould be impossible.
<="<5SI95S A5; C9??<5"A:>E "his specific compound is probably the first sulfur@containing phenethylamine to have been evaluated as a
potentially active C5S stimulant or psychedelic. It 3as a complete, total, absolute unkno3n. "he first trials 3ere made at the sub@microgram level,
specifically at ,.$& micrograms, at ((E0, A? on September 0, (%2&. Part of this e/treme precaution 3as due to the uniFueness of a ne3 heteroatom in
a phenethylamine system. .ut part 3as due to the strange manic e/citement that occurred at the time of the isolation and characteri6ing of the final
product in the laboratory. Although it 3as certainly all placebo response, I 3as Gumpy and unable to stay in the lab for more than a fe3 minutes at a
time. ?aybe dust in the airH ?aybe some skin contact 3ith the free baseH 5o3, I kno3 there 3as nothing, but the possibility of e/traordinary potency
3as real, and I did indeed 3ash everything do3n any3ay. In fact, it took a total of () trials to 3ork the e/perimental dosage up to as much as a single
milligram. In retrospect, overly cautious. .ut retrospection, as they say, is cheap.
"he & milligram e/periment, briefly Fuoted from above, is the stuff of Chapter (+ of this book, important in that it gives an interesting e/ample of some
thought processes associated 3ith psychedelic into/ication, ego@inflation, and 3hat might be thought of as bits of mania. As is al3ays the case 3ith
peak e/periences that happen to be cataly6ed by drugs, this e/traordinary event could not be duplicated. At 2 milligrams there 3as an uneventful *(,
and some (, milligrams 3as needed to generate a full *0 e/perience. "he first clue of the erratic nature of the Aleph family came from an independent
assay by a colleague of mine, one 3ho 3as very familiar 3ith such states of consciousness, but for 3hom this 3as not a time for peak e/periences.
At (, milligrams he told me that he had had only mild effects 3hich he found relatively uninteresting.
As it stands, A!<PH remains relatively une/plored. Its t3o positional isomers are entered here as 9:"H9@;9" and ?<"A@;9". "hree higher
homologues have been more thoroughly looked at, and the generic name A!<PH 'the first letter of the Hebre3 alphabet- 3as given this group
on the basis that they might have e/traordinary properties in common. .ut the real treasure came in the e/ploring of the $@carbon homologues, the
compounds that make up the $C@" family. Here, there proved to be much less uncertainty as to reasonable dosages, and much more richness in the
subGective nature of the e/perience.
#( AE,H-$; $,)-0"METH%+Y-(-ETHYTH"%AM,HETAM"#E
S>5"H<SISE A solution of $., g $,&@dimetho/y@+@'ethylthio-ben6aldehyde 'see under $C@"@$ for its synthesis- in ($ m! nitroethane 3as treated 3ith ,.+
g anhydrous ammonium acetate and heated on the steam bath for 0 h. All volatiles 3ere removed under vacuum, leaving a residue that set up as
brilliant red crystals. "hese 3ere mechanically removed from the evaporation flask, blo3n free of nitroethane vapor, and recrystalli6ed from boiling
<t9H, producing (.) g pale orange crystals, 3ith a mp of ((,@(($ deg C. :ecrystalli6ation from $, m! boiling IPA gave, after filtering and air drying,
(.2, g light orange crystals of (@'$,&@dimetho/y@+@ethylthiophenyl-@$@nitropropene 3ith a mp of (($@((0 deg C. A suspension of (.$ g !AH in 2& m!
anhydrous "HB 3as put under an inert atmosphere and, 3ith good stirring, brought up to a gentle reflu/. A solution of (.& g (@'$,&@dimetho/y@+@
ethylthiophenyl-@$@nitropropene in $, m! anhydrous "HB 3as added drop3ise. Heating and stirring 3ere maintained for an additional $+ h, and then the
reaction mi/ture 3as allo3ed to come back to room temperature 3ith stirring. "here 3as added (.+ m! H$9 'dissolved in a little "HB-, follo3ed by (.+
m! (&K 5a9H and finally another +.$ m! H$9. Stirring 3as continued until all the curdy solids had turned 3hite. "he reaction mi/ture 3as filtered, and
the filter cake 3ashed 3ith "HB. "he filtrate and the 3ashings 3ere combined, and the solvent removed under vacuum. "he residue 3as (.( g of a pale
amber oil. "his 3as dissolved in 1 m! IPA, neutrali6ed 3ith concentrated HCl 'about ) drops 3ere reFuired- and then diluted 3ith (&, m! anhydrous
<t$9. "he slightly cloudy solution 3as stirred for a couple of min, then there 3as the formation of a heavy 3hite crystalline mass. "his 3as removed by
filtration, 3ashed 3ith <t$9, and air dried to provide (.( g $,&@dimetho/y@+@ethylthioamphetamine hydrochloride 'A!<PH@$- 3ith a mp of ($)@(0, deg C
3ith decomposition.
;9SAC<E + @ ) mg
;4:A"I95E ) @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith + mg- "here 3as a 3arm feeling in the total body and a light pressure in the head that changed 3ith time into the
feeling of a balloon 3ithout any anatomical definition. "he usual color perception 3as not very much increased, and my vision 3as not sharpened as it
3as 3ith ;9?. :ather, I noticed 3aves of movement, very smooth and not too busy. .oth my tactile perception and auditory acuity 3ere enhanced.
"he main effect for me 3as, parado/ically, an easier handling of the outer 3orld. 5one of the Gitters of amphetamine. "he body feeling is good, healthy,
and I am at peace 3ith the body@mind dualism. "hese are pretty much personal comments L I 3ill 3rite up the pharmacological points later.
'3ith & mg- "his turned out to be a day of e/traordinary visuals and interpretations. About t3o hours into it, I felt that the effects 3ere still climbing, but
there 3as a marvelous onset of visual distortions and illusions, right at the edge of hallucination. "he logs in the fireplace 3ere in continuous motion.
"he notepaper I 3as 3riting on seemed to scrunch and deform under the pressure of the pen. 5othing 3ould stay still; everything 3as al3ays moving.
"here 3as a phase of unabated inflation. "he intensity 3as noticeably dropping at the five hour point and I observed considerable residual shakes and a
muscular tremor. <ven to3ards midnight there 3as some tooth@rubbiness, but I 3as able to get a some3hat fretful though adeFuate sleep.
'3ith & mg- I 3as e/posed to a number of ne3 environments and it 3as difficult to completely separate the e/perience into 3hat 3as seen
differently and 3hat 3as seen for the first time. "he Santa Cru6 ?ystery Spot should have been bi6arre but it 3as simply hokey. And
yet the board3alk that should have been depressing 3as totally magical. "he day 3as un3orldly and I ended up 3ith considerable muscular 3eakness.
All in all, I handled it 3ell, but I probably 3on7t do it again.
'3ith 2 mg- An ama6ing unification of visual hallucination seen only in the very fine detail of something, and 3hat must be considered retinal
hallucination. "here is no one@to@one correspondence bet3een the many retinal cells of the high@resolution part of the eye. "hus, the mind can pick and
choose, sometimes from the right eye, and sometimes from the left. And so a small curve or bump can become 3hatever you 3ish. Bor a moment. And
then it chooses again, but differently. Is all of our perceived 3orld as subGective as thisH
'3ith ) mg- </treme into/ication, but almost no visual phenomena. <ven 3ell into the evening, I kno3 I absolutely could not drive. IhyH I don7t kno3,
since this e/periment, at least, seemed to be Fuite free of strange colors and 3iggly lines and streaks of light. It7s that I don7t trust that the reality I see is
the same reality that the other driver might see. I am very much the center of the 3orld about me, and I don7t think I could trust anyone else to fully
respect my reality.
<="<5SI95S A5; C9??<5"A:>E As 3ith A!<PH itself, and in most 3ays 3ith the entire A!<PH family, there is no predictability of the dose8response
relationship. 9ne person had e/pressed his psychic isolation by taking and maintaining a fetal position in relative hibernation for several hours and 3ith
substantial amnesia; this at a four milligram dose. >et another person, at fully t3ice this amount, 3as a3are of a slight light@headedness that could in no
3ay be measured as more than a bare threshold. .ut by the time this erratic nature had become apparent, the A!<PHS had been assigned and made,
up to and including A!<PH@2.
A!<PH@0 3as intended to be the methallylthio compound, $,&@dimetho/y@+@'beta@methallylthio-amphetamine. "he thioether '$,&@dimetho/yphenyl beta@
methallyl sulfide- 3as easily made from $,&@dimetho/ythiophenol 'see $C@"@$ for its preparation- 3ith 0.+ g dissolved in a solution of (.2 g 9H in $& m!
boiling <t9H, and $.2$ g methallyl chloride, heated ( h on the steam bath, poured into $&, m! H$9, e/tracted 3ith 0/(,, m! CH$Cl$, and solvent
removal yielding +.+ g of the sulfide as an amber oil. An effort to convert this to $,&@dimetho/y@+@'beta@methallylthio-ben6aldehyde '2.$ g P9Cl0, 1.2 g
5@methylformanilide, +.$ g of the crude sulfide from above, (& min heating on the steam bath, H$9 hydrolysis, he/ane e/traction of the residues from a
CH$Cl$ e/traction- produced 0.( g of a peppermint@smelling oil that distilled at (+,@(1, deg C at ,.0 mm8Hg and 3hich did indeed have an aldehyde
group present 'by proton 5?:- but the rest of the spectrum 3as a mess, and the proGect 3as abandoned.
Several years later, this entire proGect 3as reinitiated, and the aldehyde 3as obtained as a yello3 crystal, but again it 3as not pursued. At that time, the
earlier try had been totally forgotten, and a brand ne3 A!<PH@ 'or $C@"@- number had been assigned; i.e., $,. "hus, the corresponding phenethylamine
'$,&@dimetho/y@+@'beta@methallylthio-phenethylamine-, had it ever been made, 3hich it 3as not, 3ould have been called either $C@"@0 or $C@"@$,, and
the amphetamine homologue 3ould probably have been A!<PH@$,.
A closely related $C@"@= compound 3as also started Fuite a 3hile later L this 3as the allylthio homologue of the methallyl material $C@"@0 or
$C@"@$,. Its place in the flo3 of things is evident from its numbering, $C@"@(1. A mi/ture of $,&@dimetho/ythiophenol and 9H and allyl chloride in
?e9H gave $,&@dimetho/yphenyl allyl sulfide as a 3hite oil 3hich boiled at ((,@($& deg C at ,.$& mm8Hg. "his, 3ith P9Cl0 and 5@methylformanilide
provided $,&@dimetho/y@+@'allylthio-ben6aldehyde 3hich distilled at (+,@(1, deg C at ,.+ mm8Hg and could be recrystalli6ed from ?e9H as a pale
yello3 solid. :eaction of this aldehyde in nitroethane in the presence of ammonium acetate 'steam bath for $.& h- provided $,&@dimetho/y@+@allylthio@
beta@nitrostyrene as red crystals from acetonitrile. Its mp 3as ((+@((& deg C. Anal. 'C(0H(&59+S- C,H. "his has not yet been reduced to the final
amine, $,&@dimetho/y@+@allylthiophenethylamine, $C@"@(1. "he corresponding amphetamine 3ould be, of course, A!<PH@(1.
A!<PH@& 3as to be the cyclohe/ylthio analogue '$,&@dimetho/y@+@cyclohe/ylthioamphetamine-. "he thioether '$,&@dimetho/yphenyl cyclohe/yl sulfide-
3as successfully made from (.2 g )&K 9H pellets in $& m! hot <t9H, 0.+ g $,&@dimetho/ythiophenol 'again, see under $C@"@$ for its preparation-, and
+.% g cyclohe/yl bromide, 0 h on the steam bath, into &,, m! H$9, e/traction 3ith 0/(,, m! CH$Cl$, 3ashing the e/tracts 3ith &K 5a9H, and
evaporation to yield &.$ g of an amber oil. "he aldehyde, 'made from 1.( g P9Cl0 and &.+ g 5@methylformanilide, heated until claret colored, then
treated 3ith &., g of the above crude thioether, heating for $, min on the steam bath, into 0,, m! H$9, and over@night stirring- 3as obtained as 0.( g
of a flesh@colored solid that 3as clearly neither pure nor completely correct. :epeated partitioning 3ith organic solvents and cooling and scratching the
residues finally provided a pale orange crystal '(.0 g, mp ))@%0 deg C- 3hich, after t3ice recrystalli6ing from ?e9H, gave ,.+ g of pale yello3 crystals
3ith a mp %&@%1 deg C and a te/tbook perfect 5?: in C;Cl0 'CH9, (H 's- (,.+(; ArH $H 's- 1.%0, 2.0(; 9CH0, 1H, '$s- at 0.)) and 0.%$; CH, (H br. at
0.0+; and 'CH$-& (,H br. at (.$,@$.0+-. "he nitrostyrene 3as prepared from $,, mg of the above aldehyde in (.$ m! nitroethane and ,.( g ammonium
acetate overnight on the steam bath, the solvent removed to give an orange oil that spontaneously crystalli6ed after a fe3 months7 standing. "his 3as
never characteri6ed, but sits there on the shelf to be reduced to A!<PH@& some inspired day. "he t3o@carbon homo@logue of this '$,&@dimetho/y@+@
cyclohe/ylthiophenethylamine- 3ill someday be called $C@"@& 'if it is ever made-. "he remaining members of this family, A!<PH@+, A!<PH@1, and
A!<PH@2 have actually been prepared and they have all been entered here in .ook II, under their o3n names.
#) AE,H-(; $,)-0"METH%+Y-(-&i--,*%,YTH"%AM,HETAM"#E
S>5"H<SISE A solution of $., g $,&@dimetho/y@+@''i-@propylthio-ben6aldehyde 'see under $C@"@+ for its synthesis- in ($ m! nitroethane 3as treated 3ith
,.+ g anhydrous ammonium acetate and heated on the steam bath for ($ h, then allo3ed to stir for another ($ h at room temperature. "he e/cess
solvent8reagent 3as removed under vacuum leaving a residue as a heavy deep orange t3o@phase oily mass. "his 3as brought into one phase 3ith $
m! ?e9H and then, 3ith continued stirring, everything spontaneously crystalli6ed. "his product 3as removed by filtration and, after 3ashing sparingly
3ith cold ?e9H and air drying, yielded $., g of (@'$,&@dimetho/y@+@'i-@propylthiophenyl-@$@nitropropene as orange crystals 3ith a mp of %1@%) deg C.
After recrystalli6ation from (& m! boiling %&K <t9H, filtering and air drying to constant 3eight, there 3as obtained (.1 g of orange crystals 3ith a mp of
%%@(,, deg C.
A suspension of (., g !AH in (,, m! 3arm "HB 3as stirred under a 5$ atmosphere and heated to a gentle reflu/. "o this there 3as added, drop3ise, a
solution of (.$ g (@'$,&@dimetho/y@+@'i-@propylthiophenyl-@$@nitropropene in $, m! anhydrous "HB. "his mi/ture 3as held at reflu/ for ( day, then stirred
at room temperature for $ days. "here 3as then added, slo3ly and 3ith caution, ( m! of H$9, follo3ed by ( m! of (&K 5a9H, and finally by another 0
m! of H$9. Stirring 3as continued until the reaction mi/ture became 3hite and granular, then all solids 3ere removed by filtration and the filter cake
3as 3ashed 3ith additional "HB. "he filtrate and 3ashings 3ere combined, and the solvent removed under vacuum to give (.( g of residue 3hich 3as
an almost 3hite oil. "his 3as dissolved in 1 m! IPA, neutrali6ed 3ith concentrated HCl '(, drops 3ere reFuired- and then diluted 3ith $,, m! anhydrous
<t$9. "he resulting slightly turbid solution 3as clarified by filtration through a sintered glass filter, and the clear and slightly yello3 filtrate 3as allo3ed to
stand. A fine 3hite crystalline product slo3ly separated over the ne/t fe3 h. "his product, $,&@dimetho/y@+@'i-@propylthioamphetamine hydrochloride
'A!<PH@+- 3as removed by filtration, and after 3ashing 3ith <t$9 and air drying, 3eighed ,.& g and had a mp of (+1@(+2 deg C, 3ith prior sintering at
(++ deg C.
;9SAC<E 2 @ ($ mg.
;4:A"I95E ($ @ $, h
L4A!I"A"IM< C9??<5"SE '3ith 2 mg- "hings started off going do3nhill, initially negative 3ith tension and depression, but as the momentum
developed, so did the positive effect. ?y discomfort continued to develop, but I 3as struck by the visual beauty of the trees and the small stream that
flo3ed off the mountain. ?y e/perience continued to gro3, simultaneously, in both the negative and the positive direction. Physically I 3as
uncomfortable and found my breathing difficult, but I ackno3ledged a rapture in the very act of breathing. All moved over to the plus side 3ith time, and
the evening 3as gorgeous. I have never seen the sky so beautiful. "he only fla3 3as 3hen I choked on some lemonade and it seemed to me I almost
dro3ned. I have been e/tremely conscious of eating, drinking and s3allo3ing ever since. I barely slept the 3hole night and a3oke e/tremely tired. I felt
that the e/perience continued for many days, and I feel that it is one of the most profound and deep learning e/periences I have had. I 3ill try it again,
but 3ill block out more time for it.
'3ith ) mg- "here 3as 3ithout Fuestion a plus t3o, but none of the edges of unreality that are part of !S;. "he sounds that are Gust outside of my
hearing are intriguing, and distract me from the eyes@closed imagery that is Gust barely possible 3ith music 3hile lying do3n. .ut, going outside, there
3ere no obvious sources of the sounds that I heard. Could I driveH I suspect so. I took a sho3er and did Gust that L I drove to San Brancisco 3ithout
incident, and 3alked amongst the many strange faces on the do3nto3n streets.
'3ith ($ mg- "he e/perience 3as very intense but completely under control e/cept for a t3enty minute period right in the middle of it. I had to get a3ay
from everything, from everyone. "here 3as a sense of being surrounded and moved in upon that 3as suffocating. I 3as 3eighed do3n 3ith everything
L physical, psychic, emotional. ?y clothes had to come off, my hair had to be released, my shoes 3ent, I needed to move a3ay from 3here I 3as, to
some3here else, to some ne3 place, any ne3 place, 3ith the hope that my other old place 3ouldn7t follo3 me. Pretty soon I found I 3as myself, I could
breathe again, and I 3as 9. :ather sheepishly, I dressed and reGoined the group. "he rest of the day 3as spectacular, but those fe3 minutes 3ere
scary. Ihat if I couldn7t have escapedH
<="<5SI95S A5; C9??<5"A:>E Again, there are hints and suggestions of comple/ities. "hese, and several other reports, suggest some sensory
confusion, and interpretive aspects that are to some e/tent threatening. "here is an underlying suggestion of body to/icity. I kno3 of no e/periment that
e/ceeded ($ milligrams and I 3ould not be able to predict 3hat might come forth at higher dosages. I personally choose not to try them.
#1 AE,H-1 $,)-0"METH%+Y-(-,HE#YTH"%AM,HETAM"#E
S>5"H<SISE "o a 0,, m! three@neck round@bottom flask set up 3ith a magnetic stirrer and protected 3ith a 5$ atmosphere, there 3as added 2& m!
he/ane, 0.& g tetramethylethylenediamine, and +.$ g p@dimetho/yben6ene. "he reaction mi/ture 3as cooled to , deg C 3ith an e/ternal ice bath, and
there 3as then added (% m! of (.1 ? butyllithium in he/ane. Iith stirring, the reaction 3as brought up to room temperature, and there 3ere produced
loose, creamy solids. "here 3as then added, as a solid and portion3ise, 1.1 g diphenyldisulfide 3hich resulted in an e/othermic reaction and the
production of a nearly clear solution. After stirring an additional (, min, the reaction 3as Fuenched in &,, m! of dilute 5a9H. "he he/ane phase 3as
separated, and the aFueous phase e/tracted 3ith +/(,, m! CH$Cl$ "he organic e/tracts 3ere combined, 3ashed 3ith dilute HCl and the solvents 3ere
removed under vacuum to provide 1., g of $,&@dimetho/yphenyl phenyl sulfide as an impure amber oil. A small sample 3as saved for microanalysis and
5?:, and the re@mainder converted to the corresponding ben6aldehyde.
A mi/ture of 1.( g P9Cl0 and &.+ g 5@methylformanilide 3as heated for 0 min on the steam bath, and then added to the remainder of the above@
described $,&@dimetho/yphenyl phenyl sulfide. "he reaction became immediately a deep red and, after heating on the steam bath for ,.& h, 3as
dumped into a large Fuantity of H$9, producing a granular bro3n solid. "his 3as removed by filtration, and 3ashed sparingly 3ith cold ?e9H 'the
3ashes 3ere saved-. "he resulting pale yello3 solids 3ere recrystalli6ed from $, m! boiling absolute <t9H providing, after cooling, filtration and air
drying, +.+ g of e/tremely pale yello3 crystals of $,&@dimetho/y@+@'phenylthio-ben6aldehyde. "his had a mp of ((%@((%.& deg C. All 3ashes and mother
liFuors 3ere combined, flooded 3ith H$9 and e/tracted 3ith CH$Cl$. "his solvent 3as removed under vacuum, and the residue 'a viscous oil- 3as
dissolved in a little <t9H 3hich, on cooling in dry ice, gave (.$ g of a second crop of the aldehyde, mp ((2@((% deg C. :ecrystalli6ation from & m! %&K
<t9H gave an additional ,.+ g product 3ith a mp of (()@((% deg C. "his mp 3as not improved by recry@stalli6ation from cyclohe/ane. "he 5?:
specrum 3as e/cellent, 3ith 9CH0 singlets '0H- at 0.+& and 0.), ppm; ArH singlets at 1.$) and 2.$1 ppm, the C1H& as a broad peak centered at 2.&,,
and the CH9 proton at (,.02 ppm.
A solution of +.+ g $,&@dimetho/y@+@'phenylthio-ben6aldehyde in 0$ m! nitroethane 3as treated 3ith ,.) g anhydrous ammonium acetate and heated on
the steam bath for $( h. "he e/cess solvent8reagent 3as removed under vacuum, leaving a dark red oil as residue. After much diddling and fiddling
around, this set up as a crystalline mass. "hese solids 3ere ground under $, m! cold ?e9H and filtered, providing &.0 g of the crude nitrostyrene as an
orange crystalline residue product after air@drying. "his 3as ground up under (, m! ?e9H, the insolubles collected by filtration, 3ashed 3ith a little
?e9H, and air dried to provide &.0 g crude (@'$,&@dimetho/y@+@phenylthiophenyl-@$@nitropropene as yello3 crystals, 3ith a mp of (,,@(,$ deg C '3ith
prior sintering at about %) deg C-. "his 3as recrystalli6ed from &, m! boiling %&K <t9H. After cooling in an ice bath, it 3as filtered, 3ashed 3ith <t9H,
and air drying provided gold@yello3 crystals 3ith a mp of (,&@(,1 deg C. "he proton 5?: 3as e/cellent 'in C;Cl0-.
A suspension of $., g !AH in (,, m! reflu/ing "HB, under an inert atmosphere and 3ith good stirring, 3as treated 3ith a solution of 0.& g (@'$,&@
dimetho/y@+@phenylthiophenyl-@$@nitropropene in $, m! anhydrous "HB added drop3ise at a rate that maintained the reflu/. Heating and stirring 3ere
maintained for an additional 01 h, and then the reaction mi/ture 3as stirred at room temperature for an additional $+ h. "here 3as added $., m! H$9
'dissolved in a little "HB-, follo3ed by $., m! (&K 5a9H, and finally another 1., m! H$9. Stirring 3as continued until all formed solids had turned
3hite. "he reaction mi/ture 3as filtered, and the filter cake 3ashed 3ith "HB. "he filtrate and the 3ashings 3ere combined and the solvent removed
under vacuum. "he residue 3as $.) g of an oil that Fuite obviously contained some H$9. "his 3as dissolved in +,, m! CH$Cl$, 3ashed first 3ith
dilute 5a9H and then 3ith +/(&, m! (5 HCl. "he organic phase 3as stripped of solvent under vacuum, yielding a pale amber oil that crystalli6ed. "his
3as ground first under <t$9, giving 0.+ g of a yello3 solid. "his 3as then ground under (, m! of acetone, yielding $.+ g of a 3hite crystalline solid that
darkened at (2, deg C, sintered at ()2 deg C and had a mp of (%(@(%0 deg C. "his 3as dissolved in $, m! hot %&K <t9H, and diluted 3ith +, m!
<t$9 to provide a clear solution 3hich, after a minute7s scratching 3ith a glass rod, deposited $,&@dimetho/y@+@phenylthioamphetamine hydrochloride
'A!<PH@1- as 3hite solids. After filtration and air drying, the 3eight 3as (.) g, 3ith a mp of (%+@(%& deg C. "he dilute HCl 3ashes, after being made
basic 3ith aFueous 5a9H and e/traction 3ith CH$Cl$ gave a trivial Fuantity of additional product.
;9SAC<E greater than +, mg.
;4:A"I95E probably long.
L4A!I"A"IM< C9??<5"SE '3ith 0, mg- I had an alert at the one hour point, and in another hour there 3as a clear (*. "here 3as a not 3ell defined,
gentle un@3orldliness. And it 3as still there Fuite unchanged t3elve hours later. In a group I find that all voices about me are of eFual intensity and
eFual importance. .ut this is not at all distracting. "his 3ill be a long lived thing for sure.
'3ith +, mg- I am into a subtle but real effect, no more than one plus, but real. I feel primed, but nothing more. It is not interfering 3ith 3ork, maybe
even helping 3ith it. After another hour of static one@plusness I decided to use it as a primer to !S;, using the usual 1, microgram Fuantity that is
standard for primer studies. "he combination sho3ed definite synergism, 3ith a rapid sho3 of the !S; effects '3ithin fifteen minutes- and an almost
three plus effect. "his is most unusual for the usual 1, microgram challenge amount. An absolutely delightful into/ication that had sufficiently descended
to3ards baseline that I accepted a ride to a party that evening in ?arin County to attend a poetry reading. "here I felt myself at baseline and accepted
'unusual for me- a little mariGuana. And 3ith the utmost Fuiet and delicacy, a rather incredible change of state took place. "he most memorable event
3as the a3areness of a clarinet playing some3here, and the sneaky sounds from it actually coming along the carpet out of the dining room and into the
hall3ay and through the door and into the room 3here I 3as, and all of them gathering at my feet like docile kittens 3aiting for me to ackno3ledge them.
I did, non@verbally, and I 3as ama6ed at the many additional follo3@up sounds that came from the same clarinet along the same t3isty path along the
floor and through the door and into my space, over 3hat seemed to be the ne/t million hours. I ended up 3ith a marvelous collection of notes and
phrases at my feet, and I felt someho3 honored. ?y speech sounded 9 to me, but I kne3 that it 3ould be odd to the ears of others, so I kept Fuiet. A
final measure of the 3eirdness of the A!<PH@18!S;8Pot combination 3as the vie3ing of the !arkspur ferry at its dock, abandoned for the evening and
3ith no one aboard it, and 3ith all that clean, dry sleeping space going to 3aste 3ith so many people sleeping on the streets these days. 9nce home, I
slept soundly and for a long 3hile. Incredible e/perience.
<="<5SI95S A5; C9??<5"A:>E In a sense, this compound 3as a disappointment. "he beauty of putting a 3hole ne3 ring into an active structure
is that it provides a marvelous vehicle for introducing ne3 substituents in ne3 arrangements. Had Aleph@1 been a cleanly active and potent compound,
then the ne3 phenyl group could have been made electronegative to varying degrees '3ith metho/y substitution for e/ample- or electropositive to
varying degrees '3ith trifluoromethyls or nitros- and this fine@tuning could have been e/tremely re3arding.
.ut this material had the earmarks of one of those forever threshold things. "he +, milligram e/periment 3as hopelessly compromised, and nothing
higher 3as ever scheduled or tried. "he t3o@carbon homologue, $,&@dimetho/y@+@phenylthiophenethylamine, or $C@"@1, has never even been
synthesi6ed, let alone assayed.
#2 AE,H-2; $,)-0"METH%+Y-(-&n--,*%,YTH"%AM,HETAM"#E
S>5"H<SISE A solution of $.1 g $,&@dimetho/y@+@''n-@propylthio-ben6aldehyde 'see under $C@"@2 for its synthesis- in $, m! nitroethane and ,.& g
anhydrous ammonium acetate 3as heated on the steam bath overnight. "he e/cess solvent8reagent 3as removed under vacuum leaving an orange oil
as a residue that cry@stalli6ed spontaneously. "his crude product 3as recrystalli6ed from $, m! boiling ?e9H to give, after cooling, filtering, and air
drying, $.+ g of (@'$,&@dimetho/y@+@'n-@propylthiophenyl-@$@nitropropene as orange crystals. Its mp 3as )0@)+ deg C 3ith prior sintering at )( deg C. A
suspension of (.& g !AH in (&, m! of 3arm anhydrous "HB 3as stirred under an inert atmosphere and brought up to a gentle reflu/. A solution of $.0 g
(@'$,&@dimetho/y@+@'n-@propylthiophenyl-@$@nitropropene in $& m! anhydrous "HB 3as added drop3ise at a rate that maintained the reflu/. Heating and
stirring 3ere continued for $ days, and then the reaction mi/ture 3as allo3ed to stir at room temperature for an additional $ days. "here 3as added (.&
m! H$9 'dissolved in (, m! "HB-, follo3ed by (.& m! (&K 5a9H, and finally another +.& m! H$9. Stirring 3as continued until all the curdy solids had
turned 3hite. "he reaction mi/ture 3as filtered, and the filter cake 3ashed 3ith slightly 3et "HB. "he filtrate and the 3ashings 3ere combined, and the
solvent removed under vacuum. "he residue 3as about $ m! of an amber colored oil that 3as dissolved in $,, m! CH$Cl$. "his solution 3as 3ashed
3ith first dilute 5a9H, and then 3ith saturated brine. :emoval of the solvent gave a pale amber oil that 3as dissolved in (, m! IPA, neutrali6ed 3ith
about (+ drops of concentrated HCl, and diluted 3ith $,, m! anhydrous <t$9. "he clear solution 3as decanted from a little gritty material, and then set
aside to allo3 the formation of $,&@dimetho/y@+@'n-@propylthioamphetamine hydrochloride 'A!<PH@2- as fine 3hite crystals. After filtration and air drying,
there 3as obtained (.) g of an off@3hite po3der.
;9SAC<E + @ 2 mg.
;4:A"I95E (& @ 0, h.
L4A!I"A"IM< C9??<5"SE '3ith + mg- At the second hour I had a paraesthetic t3inge or t3o 'all pins and needles-, and then felt Fuite rela/ed, Fuite
3illing to let this play itself out. In the evening my ears still feel 7popped7 and there is a little bit of physical a3areness. "here is not much fun 3ith this.
"he night follo3ing, I 3as unable to sleep and only do6ed slightly, but I seemed to be 9 the ne/t day.
'3ith 1 mg- "he alert 3as felt 3ithin a half hour, and then nothing more. "hen, over the ne/t t3o hours, there 3as the evolution of an e/tremely neutral
state. I danced 3ildly to a record of eith Darrett, but someho3 didn7t care for his style. I fell apart emotionally, 3ith tears and a feeling of total loss of
everything. <verything 3as visible to me only in some strange 3ide@angle lens vie3ing. I 3ent for a 3alk, a 3aste of time. I tried classical music, but
only Ga66 3as acceptable. It 3as a couple of days before I lost the residual strangeness feeling. 5ever again.
'3ith 2 mg- I did this alone, and in retrospect I 3ish I had not. Some3here bet3een the hours $ and 0, I got to a full ***, and I 3as concerned that I sa3
the effects still developing. Ihere 3ould it go no3H "here 3as no reality loss as 3ith !S;, no shakes or shimmers, but an intense and profound *** of
something characteri6ed only by the absence of e/tremes. And I am frightened because this is still deepening. A couple of calls to friends 3ere not
successful, but I found an ally in the Palo Alto area, and I told him I 3as coming to visit. ?y greater than one hour drive there 3as okay only because I
had programmed every move ahead of time. In retrospect, to drive 3as completely stupid, and I certainly 3ill never do it again, under any
circumstances. .ut, there I 3as. I kne3 3hich lane I 3ould be on, on the S.B. .ay .ridge, at every moment of my travels. "he middle lane through the
tunnel. "he second from the left 3hen descending into San Brancisco. "he 3hite lane@marker stripes 3ere 6ipping up past my lateral field of vision as I
drove, those that 3ere to my right 6ipped past my right eye, those to the left past my left eye. !ike disturbed fruit flies leaving an over@ripe peach. .ut,
as everything had been preprogrammed, there 3ere no surprises. I made it successfully, and my baby@sitting friend probed, 3ith a blend of curiosity,
love, and envy, my uncaring state. And in the course of the ne/t couple of hours, this state evolved into a friendly, familiar place. I 3as still fully ***, but
no3 for the first time I 3as at peace 3ith it. A fruit salad tasted heavenly. .y midnight I 3as able to do6e lightly, and the ne/t day I 3as sure that there
3ere some residual effects. "he second evening7s sleep repaired everything. "he neutralness 3as something ne3 to me. I don7t like not caring. Ias
this the N.ethN state of the strange t3enty minutes seen by S! in the A!<PH@+ e/perienceH
'3ith 2 mg- Strange, pleasant, une/citing, long@lasting. "he induced state 3as characteri6ed byE clear uninto/icated central field of vision, concentration
but 3ith the periphery sensed as being filled 3ith a kind of strangeness, and also something sensed inside, at the back of the head. A feeling of
something 3aiting to erupt, 3hich never does. I had a faint touch of amusement, yet no part of the e/perience had the depth or richness of other
compounds. 5o tremors. Slight visuals, but only 3hen looked for. Hunger not present, but food tasted fine 3hen eaten. ?ildly pleasant but one 3ould
not take it again unless bored stiff.
<="<5SI95S A5; C9??<5"A:>E "his drug 3as the first definition of the term, .eth state.
"here is something of the Bournier "ransform in any and all drug e/periments. A psychedelic drug e/perience is a comple/ combination of many signals
going all at the same time. Something like the sound of an oboe playing the notes of the A@maGor scale. "here are events that occur in seFuence, such
as the initial A, follo3ed by ., follo3ed by C@sharp and on and on. "hat is the chronology of the e/perience, and it can be 3ritten do3n as a series of
perceived phenomena. "he notes of the scale. .lack Fuarter notes, 3ith flags at the tops of their staffs, going up the page of music.
.ut 3ithin each of these single events, during the sounding of the note NA,N for e/ample, there is a comple/ combination of harmonics being produced at
the same time, including all components from the fundamental oscillation on up through all harmonics into the inaudible. "his mi/ture defines the played
instrument as being an oboe. <ach component may be shared by many instruments, but the particular combination is the uniFue signature of the oboe.
"his analogy applies precisely to the study of psychedelic drugs and their actions. <ach drug has a chronology of effect, like the notes of the A@maGor
scale. .ut there are many components of a drug7s action, like the harmonics from the fundamental to the inaudible 3hich, taken in concert, defines the
drug. Iith musical instruments, these components can be sho3n as sine 3aves on an oscilloscope. 9ne component, $$K, 3as a sine 3ave at a
freFuency of ($,& cycles, and a phase angle of *&&O. .ut in psychopharmacologyH "here is no psychic oscillo@scope. "here are no easily defined and
measured harmonics or phase angles. Certainly, any eventual definition of a drug 3ill reFuire some such dissection into components each of 3hich
makes some contribution to the comple/ 3hole. "he mental process may some day be defined by a particular combination of these components. And
one of them is this .eth state. It is a state of uncaring, of anhe@donia, and of emotionlessness.
?any drugs have a touch of this .eth state, A!<PH@2 more than most. If a sufficient alphabet of effects 'I am using the Alephs, .eths, Cimels, and
;aleths of the Hebre3 as token starters only- 3ere to be accumulated and defined, the actions of ne3 materials might someday be more e/actly
documented. Could depression, euphoria, and disinhibition for e/ample, all be eventually seen as being made up of their component parts, each
contributing in some measured 3ay to the sum, to the human e/perienceH "he psychologists of the 3orld 3ould be ecstatic. And drugs such as
A!<PH@2 might be useful in helping to define one of these parts.
#3 A*"A0#E; (!-0%M; .-'41$; 0"M%+AM"#E; 1-&$,)-0"METH%+Y-(-METHY,HE#Y--$-AM"#%./TA#E; $,)-0"METH%+Y-a-ETHY-(-
METHY,HE#ETHYAM"#E
S>5"H<SISE In &, m! of ben6ene there 3as dissolved 0(.1 g $,&@dimetho/y@+@methylben6aldehyde 'see recipe for $C@; for its preparation-, $,.$ m! (@
nitropropane, and 1 m! cyclohe/ylamine. "his solution 3as held at reflu/ in a ;ean Stark apparatus for $+ h, effectively removing the 3ater of reaction.
4pon cooling, there 3as deposited (%.1 g of (@'$,&@dimetho/y@+@methylphenyl-@$@nitro@(@butene as brilliant orange crystals. "he mp, after
recrystalli6ation from ?e9H, 3as ((+@((& deg C and a second recrystalli6ation increased the mp another $ deg C. Anal. 'C(0H(259+- C,H,5.
A suspension of ($.& g !AH in 1,, m! anhydrous "HB 3as stirred magnetically, and brought up to a reflu/. "o this there 3as added, drop3ise, (&., g (@
'$,&@dimetho/y@+@methylphenyl-@$@nitro@(@butene dissolved in (&, m! "HB. :eflu/ing 3as continued for (& h and, after cooling, the e/cess hydride 3as
decomposed by the addition of ($.& m! H$9. "he inorganic salts 3ere made loose and granular by the addition of ($.& m! (&K 5a9H follo3ed by an
additional 02.& m! H$9. "hese solids 3ere removed by filtration, and the filter cake 3as 3ashed 3ith "HB. "he combined filtrate and 3ashings 3ere
stripped of solvent under vacuum. "he residue 3as dissolved in anhydrous <t$9, and treated 3ith hydrogen chloride gas, yielding (@'$,&@dimetho/y@+@
methylphenyl-@$@aminobutane hydrochloride 'A:IA;5<- as 3hite crystals 3hich, after recrystalli6ation from IPA, 3eighed ((.+ g and had a mp of $0$.&@
$0+.& deg C. Anal. 'C(0H$$Cl59$- C,H,5,Cl. "he racemic mi/ture 3as resolved into its optical isomers by the formation of salts 3ith '*-@$beta@
nitrotartranilic acid 'to give the NSN isomer- or 3ith '*-@$beta@chlorotartranilic acid 'to give the N:N isomer-. "he N:N isomer can also be prepared by the
reductive amination of (@'$,&@dimetho/y@+@methylphenyl-@$@butanone 'from the above nitrostyrene and elemental iron- 3ith '*-@a@methyl ben6ylamine
follo3ed by the hydrogenolysis of the ben6yl group.
;9SAC<E as psychedelic, unkno3n.
;4:A"I95E short.
L4A!I"A"IM< C9??<5"SE '3ith ($ mg- I believe that my mood has distinctly improved, and my sleep that evening 3as e/cellent. "his is physically
benign.
'3ith 0$ mg- "here 3as some sort of threshold that lasted for a couple of hours.
'3ith $& mg of the N:N isomer- "here is the alert of a psychedelic, 3ith none of the rest of the package. Perhaps a bit of paranoia. And
by the fifth hour everything is largely gone.
<="<5SI95S A5; C9??<5"A:>E Ho3 does one discover a ne3 drug for a malady that does not e/ist in e/perimental animalsH ;rugs that interfere
3ith sleep, or 3ith appetite, or 3ith some infecting bacterium, are naturals for animal screening, in that animals sleep, eat, and can be easily infected.
.ut there are lots of syndromes that involve a state of mind, and these are uniFuely human. ?any of the psychopharmacological anti@this or anti@that
agents address ailments such as an/iety, psychosis, paranoia, or depression, 3hich are only kno3n in man. So ho3 does one discover a ne3 drug in
areas such as theseH If one has in hand a drug that is kno3n to be effective in one of these human ailments, an animal assay can be set up to give
some measurable response to that specific drug, or a biochemical property can be rationali6ed as being related to a mechanism of action. And 3ith the
kno3n drug as a calibration, and restricting your search to structurally related compounds, you can find structural relatives that give the same responses.
.ut ho3 does one find a ne3 classH 9ne 3ay is to kind of stumble into it as a side@line of human e/perimentation 3ith ne3 psychedelics. .ut it is really
difficult to pick up the clues as to 3hat 3ill be a good anti@depressant if you are not depressed. "his compound, to 3hich I had given the name of
A:IA;5< as the first of my ten Nclassic ladiesN 'I7ll say more about them later-, 3as not really a stimulant of any kind, certainly it 3as not a psychedelic,
and yet there 3as something there. It had been e/plored rather e/tensively as a potential psychotherapeutic ally by a friend of mine. He said that there
seemed to be some value in a fe3 of his patients 3ho had some underlying depression, but not much of anything 3ith the others. So, I decided to call it
an anti@depressant. I had mentioned some of this history one time 3hen I 3as giving an address at a conference on the <ast Coast, and my host '3ho
happened to be the research director at a large pharmaceutical house- asked if I 3ould send him a sample. His company did many animal tests, one of
3hich sho3ed that it 3as not hallucinogenic 'a cat 3hose tail erected dramatically 3ith ;9? did nothing 3ith A:IA;5<- and another that sho3ed re@
motivation 'some old ma6e@running monkeys 3ho had decided not to run any more ma6es changed their minds 3ith A:IA;5<-.
So patents 3ere obtained for the N:N isomer, the more effective isomer, covering its use for such things as the restoring of motivation in senile geriatric
patients. And a tradename of ;imo/amine 3as assigned it, despite several voices that held out for Ariadnamine. .ut it didn7t have 3hat 3as needed to
make it all the 3ay to the commercial market.
?any, many analogues of A:IA;5< have been made, and for a variety of reasons. In the industrial 3orld there is research backup carried out, not only
for the discovery of ne3 things, but also for patent protection of old things. Several do6en analogues of A:IA;5< have been made and
pharmacologically evaluated, and some of them have been put into the published literature. "he maGor points of variation have been t3oE keep the +@
position methyl group intact, and make the variations on the alpha@carbon 'propyl, butyl, dimethyl, phenyl, ben6yl, phenethyl, etc. L an e/tensive etc.- orE
keep the alpha@position ethyl group intact and make the variations on the +@position 'chloro, iodo, methylthio, carbo/y, etc. L again, an e/tensive etc.-.
Some of these analogues I had made, and sent in for animal screening. "he high potency of ;9. suggested the bromo@counterpart of A:IA;5<. "he
making of this entailed the proteo counterpart, (@'$,&@dimetho/yphenyl-@$@aminobutane. :eaction of $,&@dimetho/yben6aldehyde 3ith nitropropane in
ben6ene in a ;ean Stark apparatus 3ith cyclohe/ylamine as a catalyst produced (@'$,&@dimetho/yphenyl-@$@nitrobutene, 3hich crystalli6ed as orange
crystals from ?e9H 3ith a mp of +2@+2.& deg C. Anal. 'C($H(&59+- C,H,5. "his 3as reduced to the amine (@'$,&@dimetho/yphenyl-@$@aminobutane
3ith !AH in ether, and this gave a hydrochloride salt 3ith a mp of (2$@(2+ deg C after recrystalli6ation from acetonitrile. "he free base of this compound
3as brominated in acetic acid to give (@'$,&@dimetho/y@+@bromophenyl-@$@aminobutane 3hich yielded a 3hite hydrochloride salt 3ith a mp of $,+@$,1
deg C follo3ing recrystalli6ation from IPA. "he isomeric non@brominated analogue, (@'0,+@dimetho/yphenyl-@$@aminobutane 3as made and e/plored by
the Chemical Iarfare group at <dge3ood Arsenal; its code number is <A@(0$$.
Several of the alpha@ethyl analogues of A:IA;5< 3ere 5,5@dialkylated, and 3ere target compounds for halogenation 3ith radio@iodine or radio@fluorine,
for evaluation as potential brain blood@flo3 indicators. In these studies. all e/amples follo3ed a common flo3 diagram. "he reaction of the appropriate
ben6aldehyde and nitropropane, using 5,5@dimethylethylenediamine as a catalyst and follo3ing recrystalli6ation from ?e9H, gave the corresponding (@
aromatic@$@nitro@(@butene 'the nitrostyrene- 3hich, by reduction 3ith elemental iron, gave the corresponding $@butanone '3hich 3as distilled at about ,.0
mm8Hg-. "his led, by reductive amination 3ith dimethylamine hydrochloride and sodium cyanoborohydride, to the corresponding 5,5@dimethyl product
3hich 3as distilled at about ,.0 mm8Hg and 3hich, in no case, either formed a solid HCl salt or reacted 3ith carbon dio/ide from the air. Brom $,+@
dimetho/yben6aldehyde, the nitrostyrene appeared as yello3 crystals, the ketone as a 3hite oil, and the product 5,5@dimethyl@(@'$,+@dimetho/yphenyl-@
$@aminobutane as a 3hite oil. Brom $,&@dimetho/yben6aldehyde, the nitrostyrene formed bright yello3 crystal, the ketone 3as an off@3hite oil, and the
product 5,5@dimethyl@(@'$,&@dimetho/yphenyl-@$@aminobutane 3as a 3hite oil. Brom 0,&@dimetho/yben6aldehyde, the nitrostyrene formed pale yello3
crystals that discolored on e/posure to the light, the ketone 3as an off@3hite clear oil, and the product 5,5@dimethyl@(@'0,&@dimetho/yphenyl-@$@
aminobutane 3as a 3hite oil. Brom $,1@dimetho/yben6aldehyde, the nitrostyrene 3as obtained as orange crystals, and 3as not pursued further.
A number of A:IA;5< analogues have been made, or at least started, purely to serve as probes into 3hatever ne3 areas of psychopharmacological
activity might be uncovered. 9ne of these is a H9" compound, and one is a "9? compound, and a couple of them are the pseudo 'or near@pseudo-
orientations. "he H9" analogue 3as made from the nitrostyrene precursor to A:IA;5< itself, reduced not 3ith !AH or AH '3hich 3ould give the
primary amine-, but rather 3ith sodium borohydride and borane dimethylsulfide. "he product, (@'$,&@dimetho/y@+@methylphenyl-@5@hydro/y@$@
aminobutane hydrochloride, 3as a 3hite crystalline material. "he &@"9? analogue got as far as the nitrostyrene. "his 3as made from $@metho/y@+@
methyl@&@'methylthio-ben6aldehyde 'see under the &@"9? recipe for its preparation- and nitropropane in acetic acid, and gave bright yello3 crystals.
"he true pseudo@analogue is the $,+,1@trimetho/y material based on "?A@1, 3hich is the NrealN pseudo@"?A@$. "he nitrostyrene from $,+,1@
trimetho/yben6aldehyde and nitropropane crystalli6ed from ?e9H8CH0C5 as fine yello3 crystals, and this 3as reduced 3ith AH in cold "HB to
(@'$,+,1@trimetho/yphenyl-@$@aminobutane 3hich 3as a bright, 3hite po3der.
And the near@pseudo analogueH
Birst, 3hat is near@pseudoH I have e/plained already that the NnormalN 3orld of substitution patterns is the $,+,&. <veryone kno3s that that is the most
potent pattern. .ut, the $,+,1 is in many 3ays eFuipotent, and has been named the pseudo@stuff. "he Nreal,N or NtrueN pseudo@stuff. So 3hat is the
NnearN pseudo@stuffH I am 3illing to bet that the rather easily obtained $,0,1@trisubstitution pattern, and the much more difficult to obtain $,0,&@substitution
pattern, 3ill produce treasures every bit as une/pected and remarkable as either the $,+,&@ or the $,+,1@ counterparts. "hese are neither NrealN nor
Npseudo,N but something else, and I 3ill find a name for them 3hen the time comes, something 3eird from the Creek alphabet. And this 3ill double again
the range of possible e/ploration. "he "?A@& analogue mentioned came from $,0,1@trimetho/yben6aldehyde and nitropropane using cyclohe/ylamine
as a catalyst 'yello3@orange solids- 3hich 3as reduced to the amine 3ith AH. "his hydrochloride salt is an air@stable 3hite po3der. All of these
materials remain une/plored.
Some3here in the 3ealth of compounds implicit in the many structural variables possible 'the normal versus the pseudo versus the near@pseudo
patterns, coupled 3ith the 3ide variety of promising substituents that can be placed on the +@position, together 3ith the availability of the the une/plored
members of the "en Classic !adies harem-, it 3ould seem inescapable that interesting compounds 3ill emerge.
Dust 3hat is this all about the ten NClassic !adiesHN In the chemical struc@ture of ;9?, there is a total of nineteen hydrogen atoms. Some of these are
indis@tinguishable from others, such as the three hydrogen atoms on a methyl group. .ut there are e/actly ten NtypesN of hydrogen atoms present. And,
not having much, if any, intuition as to Gust 3hy ;9? 3as so po3erful a psychedelic, I decided to systematically replace each of the ten uniFue
hydrogens, one at a time of course, 3ith a methyl group. And I planned to give the resulting materials the names of famous ladies, alphabetically, as you
3alk around the molecule.
A:IA;5< 3as the first of these, the methyl for a hydrogen atom on the methyl group of the amphetamine chain. It 3as Ariadne 3ho gave the long piece
of thread to "heseus to guide him through the ma6es of the !abyrinth so he could escape after killing the ?inotaur. "he record is fu66y as to 3hether,
after the successful killing, she 3ent 3ith him, or let him go on alone. A methyl group on the nitrogen atom produced .<A":IC<. "here is the legendary
.eatriGs of the ;utch religious literature of the (+th century, and there is the .eatrice from .eatrice and .enedict 'of .erlio6 fame-. .ut the one I had in
mind 3as the lady from Blorence 3hom ;ante immortali6ed in the ;ivina Commedia, and she is entered under her o3n name in this footnote. :eplacing
the alpha@hydrogen of ;9? 3ith a methyl group 3ould give the phentermine analogue 3hich is named CHA:?IA5. >ou may be thinking of Cleopatra7s
favorite attendant, but I 3as thinking of the s3eet 3ife of a very dear friend of mine, a lady 3ho has been in a state of gentle schi6ophrenia for some
forty years no3. "he ?;A analogue of CHA:?IA5 has been described in this foornote under the code name of ?;PH. CHA:?IA5, herself, has been
synthesi6ed and is of very much reduced potency in animals, as compared to ;9?. It has not been tried in man as far as I kno3.
"he t3o beta@hydrogen atoms of ;9? are distinct in that, upon being replaced 3ith methyl groups, one 3ould produce a threo@isomer, and the other an
erythro@isomer. I have named them ;APH5< '3ho escaped from Apollo by becoming a laurel tree 3hich 3as, incidentally, named for her- and <!MI:A
'3ho might not be too 3ell kno3n classically, but 3hose name has been attached to ?o6art7s $(st piano concerto as its slo3 movement 3as used as
theme music for the movie <lvira ?adigan-. I don7t kno3 if either of this pair has been made L I started and got as far as the cis@trans mi/ture of adducts
bet3eeen nitroethane and $,&@dimetho/y@+@methylacetophenone. Ihoever finally makes them gets to assign the names. I had made and tested the
corresponding homologues of ;??;A that correspond to these t3o ladies.
And there are five positions '$,0,+,& and 1- around the aromatic ring, each of 3hich either carries a hydrogen atom or a methyl group that has a
hydrogen atom. "here is the $@metho/y group 3hich can become a $@etho/y group to produce a compound called B!9:<5C<. Her name is the
<nglish translation of the Italian Biren6e, a city that, although having a female name, has al3ays seemed thoroughly masculine to me. "here is the 0@
hydrogen atom 3hich can become a 0@methyl group to produce a compound called CA5<SHA. "his is a fine elephant@headed Indian Cod 3ho is the
symbol of 3orldly 3isdom and also has been seen as the creator of obstacles. Here I really ble3 it; the Classic !ady turned out to be a Classic Centle@
man; not even the name is feminine. "here is the +@methyl group 3hich can become a +@ethyl group to produce a compound called H<CA"< 3ho
presided over magic arts and spells. "here is the &@metho/y group 3hich can become a &@etho/y group to produce a compound called I:IS, 3ho is the
Coddess of the rainbo3. And there is the 1@hydrogen atom 3hich can become a 1@methyl group to produce a compound called D459, 3ho is pretty
much a lady7s lady, or should I say a 3oman7s 3oman.
CA5<SHA, $,&@dimetho/y@0,+@dimethylamphetamine has been made, and has proven to be an e/traordinary starting point for a large series of potent
phenethylamines and amphetamines 3hich are described in this book. H<CA"< 3as given a synonym early in this process, and is no3 kno3n as
;9<" '$,&@dimetho/y@+@ethylamphetamine-. I:IS has also been entered under her name, and the other etho/y homologue, B!9:<5C<, 3ould be
easily made based on the preparation of the phenethylamine analogue, $C;@$<"9. Perhaps it has already been made someho3, some3here, as I
have noted that I have claimed its citrate salt as a ne3 compound in a .ritish patent. And, finally, D459 '0,1@dimetho/y@$,+@dimethylamphetamine- has
been made 'from $,&@dimetho/y@m@/ylene, 3hich 3as reacted 3ith P9Cl0 and 5@methylformanilide to the ben6aldehyde, mp &0@&+ deg C, and to the
nitrostyrene 3ith nitroethane, mp 20@2+ deg C from cyclohe/ane, and to the final amine hydrochloride 3ith !AH in "HB-. :ather ama6ingly, I have had
D459 on the shelf for almost (+ years and have not yet gotten around to tasting it.
#4 AS.; ASYM.ES!A"#E; ',(-0"ETH%+Y-)-METH%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0$ g of &@bromobourbonal in (&, m! ;?B there 3as added 0( g ethyl iodide and 0$ g of finely ground )&K 9H pellets.
"here 3as the formation of a purple color and a heavy precipitate. 9n gradual heating to reflu/, the color faded to a pale yello3 and the precipitate
dissolved over the course of ( h. "he heating 3as continued for an additional ( h. "he reaction mi/ture 3as added to ( ! H$9, and e/tracted 3ith
$/(&, m! of petroleum ether. "he e/tracts 3ere pooled, 3ashed 3ith $/$,, m! &K 5a9H and finally 3ith H$9. After drying over anhydrous $C90
the solvents 3ere removed under vacuum to yield 01 g of crude 0@bromo@+,&@dietho/yben6aldehyde as an amber liFuid. "his 3as used 3ithout
purification for the follo3ing step. ;istillation at (,&@((& deg C at ,.0 mm8Hg provided a 3hite sample 3hich did not crystalli6e. Anal. 'C((H(0.r90 -
C,H.
A mi/ture of 01 g 0@bromo@+,&@dietho/yben6aldehyde and (2 m! cyclohe/ylamine 3as heated 3ith an open flame until it appeared to be free of H$9.
"he residue 3as put under a vacuum ',.+ mm8Hg- and distilled at (0&@(+& deg C, yielding +$ g 0@bromo@5@cyclohe/yl@+,&@dietho/yben6ylidenimine as a
viscous light greenish oil. "his slo3ly set to a crystalline glass 3ith a mp of 1,@1( deg C. :ecrystalli6ation from he/ane gave a 3hite crystalline product
3ithout any improvement in the mp. Anal. 'C(2H$+.r59$- C,H. "his is a chemical intermediate to a number of active bases, taking advantage of the
available bromine atom. "his can be e/changed 3ith a sulfur atom 'leading to &@"AS. and 0@"@":IS- or 3ith an o/ygen atom as described belo3.
A solution of () g 0@bromo@5@cyclohe/yl@+,&@dietho/yben6ylidenimine in $&, m! anhydrous <t$9 3as placed in an atmosphere of He, stirred
magnetically, and cooled 3ith an e/ternal dry ice8acetone bath. "hen 01 m! of a (.& ? solution of butyllithium in he/ane 3as added over $ min,
producing a clear yello3 solution. "his 3as stirred for (, min. "here 3as then added 0, m! of butyl borate at one time, the stirring continued for & min.
"he stirred solution 3as allo3ed to return to room temperature. "here 3as added (&, m! of saturated aFueous ammonium sulfate. "he <t$9 layer 3as
separated, and the aFueous phase e/tracted 3ith another 2& m! <t$9. "he combined organic phases 3ere evaporated under vacuum. "he residue
3as dissolved in (,, m! ?e9H, diluted 3ith $, m! H$9, and then treated 3ith (& m! 0&K H$9$ added over the course of $ min. "his mildly
e/othermic reaction 3as allo3ed to stir for (& min, then added to &,, m! H$9. "his 3as e/tracted 3ith $/(,, m! CH$Cl$ and the solvent removed
under vacuum. "he residue 3as suspended in (&, m! dilute HCl and heated on the steam bath for ,.& h. Stirring 3as continued until the reaction 3as
again at room temperature, then it 3as e/tracted 3ith $/2& m! CH$Cl$. "hese e/tracts 3ere pooled and e/tracted 3ith 0/(,, m! dilute aFueous 9H.
"he aFueous e/tracts 3ere 3ashed 3ith CH$Cl$, reacidified 3ith HCl, and ree/tracted 3ith $/2& m! CH$Cl$. "hese e/tracts 3ere pooled, and the
solvent removed under vacuum to yield a bro3n residue. "his 3as distilled at (,2@($2 deg C at ,.+ mm8Hg to yield ).0 g of 0,+@dietho/y@&@
hydro/yben6aldehyde as an oil that set to a tan solid. :ecrystalli6ation from cyclohe/ane gave a 3hite product 3ith a mp of 2,.&@2(.& deg C. Anal.
'C((H(+9+- C,H.
A solution of ).0 g of 0,+@dietho/y@&@hydro/yben6aldehyde and 0., g 9H in 2& m! <t9H 3as treated 3ith & m! methyl iodide and stirred at room
temperature for & days. "he reaction mi/ture 3as added to +,, m! H$9 and e/tracted 3ith $/&, m! CH$Cl$. "he e/tracts 3ere pooled, 3ashed 3ith
$/(&, m! dilute 5a9H, and the solvent removed under vacuum. "he residual oil 3as distilled at %&@((, deg C at ,.0 mm8Hg to yield ).$ g of 0,+@
dietho/y@&@metho/yben6aldehyde as a pale yello3 liFuid. "his product 3as a crystalline solid belo3 $, deg C but melted upon coming to room
temperature. It 3as analy6ed, and used in further reactions as an oil. Anal. 'C($H(19+- C,H.
"o a solution of 1.+ g 0,+@dietho/y@&@metho/yben6aldehyde in +, m! nitromethane there 3as added about ,.& g anhydrous ammonium acetate, and this
3as held at reflu/ for ( h. "he e/cess solvent8reagent 3as removed under vacuum, producing a red oil 3hich set up to crystals. "hese 3ere
recrystalli6ed from +, m! boiling ?e9H to yield 0., g of 0,+@dietho/y@&@metho/y@beta@nitrostyrene as yello3 plates, 3ith a mp of )%@%, deg C. Anal.
'C(0H(259&- C,H.
A solution of 0., g !AH in (&, m! anhydrous "HB under He 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, $.( m! of (,,K
H$S9+, follo3ed by the drop3ise addition of a solution of 0.& g 0,+@dietho/y@&@metho/y@beta@nitrostyrene in 0, m! anhydrous "HB, over the course of (,
min. "he addition 3as e/othermic. "he mi/ture 3as held at reflu/ on the steam bath for 0, min. After cooling again, the e/cess hydride 3as destroyed
3ith IPA, follo3ed by the addition of (,K 5a9H sufficient to covert the aluminum o/ide to a 3hite, granular form. "his 3as removed by filtration, the
filter cake 3ashed 3ith IPA, the mother liFuor and filtrates combined, and the solvents removed under vacuum to provide a yello3 oil. "his residue 3as
added to (,, m! dilute H$S9+ producing a cloudy suspension and some yello3 insoluble gum. "his 3as 3ashed 3ith $/2& m! CH$Cl$. "he aFueous
phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith $/2& m! CH$Cl$. "he solvent 3as removed from these pooled e/tracts and the residue
distilled at ((,@(0& deg C at ,.+ mm8Hg to provide $., g of a colorless liFuid. "his 3as dissolved in 2 m! IPA, neutrali6ed 3ith about +, drops of
concentrated HCl, follo3ed by &, m! anhydrous <t$9 3ith stirring. "he initially clear solution spontaneously deposited a 3hite crystalline solid. "his
3as diluted 3ith an additional 0, m! <t$9, let stand for ( h, and the solids removed by filtration. After <t$9 3ashing, the product 3as air@dried to yield
(.$& g of 0,+@dietho/y@&@metho/yphenethylamine hydrochloride 'AS.- 3ith a mp of (+$@(+0 deg C. Anal. 'C(0H$$Cl590- C,H.
;9SAC<E $,, @ $), mg.
;4:A"I95E (, @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith $+, mg- "here 3as a pleasant and easy flo3 of day@dreaming thoughts, Fuite friendly and some3hat erotic. "here
3as a gentle do3n@drift to my starting baseline mental status by about midnight 'I started at %E,, A?-. I never Fuite made it to a ***, and rather
regretted it.
'3ith $), mg- "he plateau of effect 3as evident by hour t3o, but I found the e/perience lacking the visual and interpretive richness that I had hoped for.
Sleep 3as very fitful after the effects had largely dropped L it 3as hard to simply lie back and rela/ my guard L and even 3hile being up and about the
ne/t day I felt a residual plus one. 9ver all, there 3ere fe3 if any of the open interactions of $C@. or !S;. Some negative side seemed to be present.
'3ith $), mg- "he entire session 3as, in a sort of 3ay, like being in a corridor outside the lighted halls 3here a beautiful mescaline e/perience is taking
place, sensing the light from behind a grey door, and not being able to find my 3ay in from the dusky underside passage3ays. "his is sort of a gentle
sister of mescaline, but 3ith a tendency to emphasi6e 'for me, at this time- the negative, the sad, the struggling. Sleep 3as impossible before the
fifteenth hour. Ihen I tried, I got visions of moonlight in the desert, 3ith figures around me 3hich 3ere the vampire@3ere3olf aspect of the soul, green
colored and evil. I had to sit Fuietly in the living room and 3ait patiently until they settled back to 3herever they belonged and stopped trying to take over
the scene. ;uring the peak of the e/perience, my pulse 3as thready, some3hat slo3ed, and uneven. "here 3as a faint feeling of physical 3eirdness.
<="<5SI95S A5; C9??<5"A:>E "his specific amine 3as a target for a single study in cats many years ago, in Holland, using material obtained from
Hoffman !a :oche in .asel. "heir findings are hard to evaluate, in that $,, milligrams 3as inGected into a 0.2& kilogram cat '&0 mg8g-, or about t3ice
the dosage that they used in their studies 3ith metaescaline. Iithin & minutes there 3ere indications of catatonia, and 3ithin a half hour the animal 3as
unable to 3alk. "his condition persisted for t3o days, at 3hich time the animal died. Although this dose 3as many times that used in man, perhaps hints
of the physical unease and long action are there to be gleaned. "he consensus from over a half do6en e/periments is that there is not enough value to
be had to offset the body load e/perienced.
A comment is needed on the strange name asymbescalineO In the marvelous 3orld of chemical nomenclature, bi@ 'or di@- usually means t3o of
something, and tri@ and tetra@ Fuite reasonably mean three and four of something. .ut occasionally there can be an ambiguity 3ith bi 'or tri or tetra- in
that bi some@thing@or@other might be t3o something@or@others hooked together or it might be t3o things hooked onto a something@or@other. So, the
former is called bi@ and the latter is called bis@. "his compound is not t3o escalines hooked together 'bi@escaline- but is only one of them 3ith t3o ethyl
groups attached 'bis@escaline or bescaline-. And since there are t3o 3ays that this can be done 'either symmetrically or asymmetrically- the symmetric
one is called symbescaline 'or S. for short- and this one is called asymbescaline 'or AS. for short-. "o complete the terminology lecture, the term tri@
becomes tris@ 'the name given for the drug 3ith all three etho/y groups present in place of the metho/ys of mescaline- and the term tetra@ mutates into
the rather incredible tetrakis@O
#15 .; ./S!A"#E; (-&n--./T%+Y-',)-0"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of &.) g of homosyringonitrile 'see under < for preparation-, (,, mg decyltriethylammonium iodide, and (( g n@butyl bromide in
&, m! anhydrous acetone 3as treated 3ith 1.% g finely po3dered anhydrous $C90 and held at reflu/ for (, h. An additional 1 g of n@butyl bromide
3as added to the mi/ture, and the reflu/ing continued for another +) h. "he mi/ture 3as filtered, the solids 3ashed 3ith acetone, and the solvent from
the combined filtrate and 3ashes removed under vacuum. "he residue 3as suspended in acidified H$9, and e/tracted 3ith 0/(2& m! CH$Cl$. "he
pooled e/tracts 3ere 3ashed 3ith $/&, m! &K 5a9H, once 3ith dilute HCl, and then stripped of solvent under vacuum giving (0.$ g of a deep yello3
oil. "his 3as distilled at (0$@(+& deg C at ,.$ mm8Hg to yield &., g of +@'n-@butylo/y@0,&@dimetho/yphenylacetonitrile as a pale yello3 oil 3hich set up to
crystals spontaneously. "he mp 3as +$@+0 deg C. Anal. 'C(+H(%590- C H 5.
A solution of AH 3as prepared by the cautious addition of ,.12 m! of (,,K H$S9+ to $& m! of (., ? !AH in "HB, 3hich 3as being vigorously stirred
under He at ice bath temperature. A total of +.% g of +@'n-@butylo/y@0,&@dimetho/yphenylacetonitrile 3as added as a solid over the course of (, min.
Stirring 3as continued for another & min, then the reaction mi/ture 3as brought to reflu/ on the steam bath for another +& min. After cooling again to
room temperature, IPA 3as added to destroy the e/cess hydride 'about & m!- follo3ed by (, m! of (&K 5a9H 3hich 3as sufficient to make the
aluminum salts loose, 3hite, and filterable. "he reaction mi/ture 3as filtered, the filter cake 3ashed 3ith IPA, and the mother liFuor and 3ashes
combined and the solvent removed under vacuum to yield an amber oil. "his residue 3as treated 3ith dilute H$S9+ 3hich generated copious solids.
Heating this suspension effected solution, and after cooling, all 3as 3ashed 3ith 0/&, m! CH$Cl$. "he aFueous phase 3as made basic 3ith aFueous
5a9H, and the product e/tracted 3ith $/(,, m! CH$Cl$. "he e/tracts 3ere evaporated to a residue under vacuum, and this 3as distilled at ($)@(0)
deg C at ,.& mm8Hg yielding 0.) g of a colorless oil. "his 3as dissolved in +, m! IPA, neutrali6ed 3ith concentrated HCl 'about && drops reFuired- and,
3ith vigorous stirring, ), m! of anhydrous <t$9 3as added 3hich produced fine 3hite plates. After standing for several h, the product 3as filtered,
3ashed 3ith $,K IPA in <t$9, and finally 3ith <t$9. Air drying yielded 0.% g of +@'n-@butylo/y@0,&@dimetho/yphenethylamine hydrochloride '.- 3ith a mp
of (&$@(&0 deg C. An analytical sample melted at (&&@(&2 deg C. Anal. 'C(+H$+Cl590- C,H,5.
;9SAC<E greater than (&, mg.
;4:A"I95E several hours.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- "here is a strange taste, not really bitter, it does not linger. "he slight change of baseline has certainly
disappeared by the eighth hour. 5o noticeable changes in either the visual or the auditory area.
'3ith (&, mg- "hroughout the e/periment it 3as my impression that 3hatever effects 3ere being felt, they 3ere more in body than mind. "he body load
never mello3ed out, as it 3ould have 3ith mescaline, after the first hour or t3o. ?ental effects didn7t develop in any interesting 3ay. I 3as a3are of brief
heart arrhythmia. "ummy 3as uncomfortable, off and on, and there 3as light diarrhea. <ven as late as the fifth hour, my feet 3ere cold, and the 3hole
thing left me 3ith a slightly uncomfortable, 7Ihy did I botherH7 feeling.
<="<5SI95S A5; C9??<5"A:>E "here is a Gingle heard occasionally in chemical circles, concerning the homologues of methyl. It goes, N"here7s
ethyl and propyl, but butyl is futile.N And to a large measure this is true 3ith the +@position homologues of mescaline. "his butyl compound, . or
.uscaline, had originally been patented in <ngland in (%0, 3ithout any physical or pharmacological description, and the fe3 physical studies that had
involved it 'lipophilic this and serotonin that- suggested that it 3as less active than mescaline.
In principle, the &@, the 1@, the 2@ and the on@up homologues might be called amylescaline 'possibly pentescalineH-, he/escaline, heptescaline 'possibly
septescaline-, and Cod@kno3s@3hat@scaline. "hey 3ould certainly be easily makeable, but there 3ould be little value that could be anticipated from
nibbling them. In keeping 3ith the name . 'for buto/y-, these 3ould be kno3n as A 'for amylo/y, as the use of a P could confuse pento/y 3ith propo/y-,
as H 'for he/ylo/y, but careful; this letter has been used occasionally for ;?P<A, 3hich is Homopiperonylamine-, and as S 'the H for heptylo/y has
been consumed by the he/ylo/y, so let7s shift from the Creek hepta to the !atin septum for the number seven-. It seems most likely that the to/ic
symptoms that might 3ell come along 3ith these phenethylamines 3ould discourage the use of the dosage needed to affect the higher centers of the
brain. "he same generally negative feeling applies to the amphetamine counterparts 0C@., 0C@A, 0C@H and 0C@S.
A brief reiteration of the $C@0C nomenclature, to avoid a possible misunderstanding. "he drug $C@. is so named in that it is the t3o@carbon chain
analogue of the three@carbon chain compound ;9.. "he drug 0C@. is so named because it is the three@carbon chain analogue of the t3o@carbon chain
compound .uscaline, or more simply, .. "here is no logical connection 3hatsoever, either structural or pharmacological, bet3een $C@. and 0C@..
#11 .EAT*"!E; #-METHY-0%M; $,)-0"METH%+Y-(,#-0"METHYAM,HETAM"#E
S>5"H<SISE A fused sample of &., g of 3hite, crystalline free base $,&@dimetho/y@+@methylamphetamine, ;9?, 3as treated 3ith (, m! ethyl formate,
and held at reflu/ on the steam bath for several h. :emoval of the solvent gave &.& g of a 3hite solid, 3hich could be recrystalli6ed from (& m! ?e9H to
give 0.) g of fine 3hite crystals of $,&@dimetho/y@5@formyl@+@methylamphetamine. An analytical sample from ethyl formate gave granular 3hite crystals.
"o a stirred suspension of +., g !AH in $&, m! anhydrous <t$9 at reflu/ and under an inert atmosphere, there 3as added, by the shunted So/hlet
techniFue, +.$ g of $,&@dimetho/y@5@formyl@+@methylamphetamine as rapidly as its solubility in hot <t$9 3ould allo3. "he mi/ture 3as held at reflu/ for
$+ h and then stirred at room temperature for several additional days. "he e/cess hydride 3as destroyed 3ith the addition of dilute H$S9+ '$, g in &,,
m! 3ater- follo3ed by the additional dilute H$S9+ needed to effect a clear solution. "he <t$9 3as separated, and the aFueous phase e/tracted 3ith
(,, m! <t$9 and then 3ith $/$&, m! CH$Cl$. Bollo3ing the addition of (,, g potassium sodium tartrate, the mi/ture 3as made basic 3ith $&K 5a9H.
"he clear aFueous phase 3as e/tracted 3ith 0/$&, m! CH$Cl$ "hese e/tracts 3ere pooled, and the solvent removed under vacuum. "he residual
amber oil 3as dissolved in +,, m! anhydrous <t$9, and saturated 3ith hydrogen chloride gas. "he 3hite crystals that formed 3ere removed by
filtration, 3ashed 3ith <t$9, and air dried to constant 3eight. "here 3as obtained +.$ g of product 3ith a mp of (0(.&@(00.& deg C. "his product 3as
recrys@talli6ed from (2& m! boiling ethyl acetate to give 0.& g $,&@dimetho/y@+,5@di@methylamphetamine hydrochloride '.<A":IC<- as pale pink crystals
3ith a mp of (01@(02 deg C. A sample obtained from a preparation that employed the methyl sulfate methylation of the ben6aldehyde adduct of ;9?
had a mp of ($&@($1 deg C and presented a different infra@red spectrum. It 3as, follo3ing recrystalli6ation from ethyl acetate, identical to the higher
melting form in all respects.
;9SAC<E above 0, mg.
;4:A"I95E 1 @ (, h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- "here 3as a gentle and demanding rise from the one to the three hour point that put me into an e/tremely
open, erotic, and responsive place. I had to find a familiar spot to orient myself, and the kitchen served that need. As the e/perience 3ent on, it sho3ed
more and more of a stimulant response, 3ith tremor, restlessness, and a bit of trouble sleeping. .ut there 3as no anore/iaO An 9 e/perience.
'3ith 0, mg- "here is a real physical aspect to this, and I am not completely happy 3ith it. "here is diarrhea, and I am restless, and continuously a3are
of the fact that my body has had an impact from something. "he last fe3 hours 3ere spent in talking, and I found myself still a3ake some $+ hours after
the start of the e/periment. "he mental 3as not up there to a ***, and yet the physical disruption 3as all that I might care to 3eather, and e/ceeds any
mental re3ard. Ihen I did sleep, my dreams 3ere 9, but not rich. Ihy go higherH
<="<5SI95S A5; C9??<5"A:>E "his is another e/ample of the 5@methyl homologues of the psychedelics. 5one of them seem to produce stuff of
elegance. It is clear that the adding of an 5@methyl group onto ;9? certainly cuts do3n the activity by a factor of ten@fold, and even then results in
something that is not completely good. "hree milligrams of ;9? is a 3inner, but even ten times this, thirty milligrams of 5@methyl@;9?, is some3hat
fu66y. In the rabbit hyperthermia studies, this compound 3as some $& times less active than ;9?, so even animal tests say this is 3ay do3n there in
value. "his particular measure suggests that the active level in man might be 2& milligrams. Iell, maybe, but I am not at all comfortable in trying it at
that level. In fact I do not intend to e/plore this any further 3hatsoever, unless there is a compelling reason, and I see no such reason. Bor the moment,
let us leave this one to others, 3ho might be more adventurous but less discriminating.
In bro3sing through my notes I discovered that I had made another 5@substitution product of ;9?. <fforts to fuse free@base ;9? 3ith the ethyl
cyclopropane carbo/ylate failed, but the reaction bet3een it and the acid chloride in pyridine gave the corresponding amide, 3ith a mp of (&1@(&2 deg C
from ?e9H. Anal. 'C(1H$0590- C,H,5. "his reduced smoothly to the corresponding amine, 5@cyclopropyl@$,&@dimetho/y@+@methylamphetamine 3hich
formed a hydrochloride salt melting at (&0@(&1 deg C. I can7t remember the reasoning that led to this line of synthesis, but it must not have been too
e/citing, as I never tasted the stuff.
#1$ ."S-T%M; (-METHY-$,)-bis-&METHYTH"%-AM,HETAM"#E
S>5"H<SISE A solution of %., g $,&@dibromotoluene in &, m! petroleum ether 3as magnetically stirred under a He atmosphere. "o this there 3as
added &, m! of a (.1 ? he/ane solution of butyllithium, and the e/othermic reaction, 3hich produced a granular precipitate, 3as allo3ed to stir for ($ h.
"he mi/ture 3as cooled to , deg C and there 3as then added 2.& g dimethyldisulfide. "here 3as a heavy precipitate formed, 3hich tended to become
lighter as the addition of the disulfide neared completion. After $, min additional stirring, the reaction mi/ture 3as poured into H$9 that contained some
HCl. "he phases 3ere separated and the aFueous phase e/tracted 3ith &, m! <t$9. "he organic phase and e/tract 3ere combined, 3ashed 3ith dilute
5a9H, and then 3ith H$9. After drying over anhydrous $C90, the solvent 3as removed under vacuum and the residue distilled to give a fraction that
boiled at 2&@)& deg C at ,.0 mm8Hg and 3eighed &.0 g. "his 3as about ),K pure $,&@bis@'methylthio-toluene, 3ith the remainder appearing to be the
monothiomethyl analogues. A completely pure product 3as best obtained by a different, but considerably longer, procedure. "his is given here only in
outline. "he phenolic 9H group of 0@methyl@+@'methylthio-phenol 3as converted to an SH group by the thermal rearrangement of the 5,5@
dimethylthioncarbamate. "he impure thiophenol 3as liberated from the product 5,5@dimethylthiolcarbamate 3ith 5a9H treatment. "he separation of
the phenol8thiophenol mi/ture 3as achieved by a H$9$ o/idation to produce the intermediate 0@methyl@+@methylthiophenyldisulfide. "his 3as isolated
as a 3hite crystalline solid from ?e9H, 3ith a mp of 2)@2% deg C. Anal. 'C(1H()S+- C,H. It 3as reduced 3ith 6inc in acetic acid, and the resulting
thiophenol 'a 3ater@3hite liFuid 3hich 3as both spectroscopically and microanalytically correct- 3as methylated 3ith methyl iodide and 9H in ?e9H to
give the desired product, $,&@bis@'methylthio-toluene, free of any contaminating mono@sulfur analogues.
A solution of 0.% g of $,&@bis@'methylthio-toluene in $, m! acetic acid 3as treated 3ith a crystal of iodine follo3ed by the addition of 0.& g elemental
bromine. "his mi/ture 3as heated on the steam bath for ( h, 3hich largely discharged the color and produced a copious evolution of H.r. Cooling in an
ice bath produced solids that 3ere removed by filtration. :ecrystalli6ation from IPA gave (.% g of $,&@bis@'methylthio-@+@bromotoluene as a 3hite
crystalline solid 3ith a mp of (00@(0+ deg C. Anal. 'C%H((.rS$- C,H. An alternate synthesis of this intermediate 3as achieved from (,+@
dibromoben6ene 3hich 3as converted to the (,+@bis@'methylthio-ben6ene '3hite crystals 3ith a mp of )0.&@)+.& deg C- 3ith sodium methylmercaptide in
he/amethylphosphoramide. "his 3as dibrominated to $,&@dibromo@(,+@bis@'methylthio-ben6ene in acetic acid '3hite platelets from he/ane melting at
(%&@(%% deg C-. "his, in <t$9 solution, reacted 3ith .u!i to replace one of the bromine atoms 3ith lithium, and subseFuent treatment 3ith methyl iodide
gave $,&@bis@'methylthio-@+@bromotoluene as an off@3hite solid identical to the above material 'by "!C and I:- but 3ith a broader mp range.
A solution of $.+ g $,&@bis@'methylthio-@+@bromotoluene in (,, m! anhydrous <t$9, stirred magnetically and under a He atmosphere, 3as treated 3ith (,
m! of a (.1 ? solution of butyllithium in he/ane. After stirring for (, min there 3as added $.& m! 5@methylformanilide 3hich led to an e/othermic
reaction. After another (, min stirring, the reaction mi/ture 3as added to (,, m! dilute HCl, the phases 3ere separated, and the aFueous phase
e/tracted 3ith $/&, m! <t$9. "he combined organic phase and e/tracts 3ere dried over anhydrous $C90, and the solvent removed under vacuum.
"he partially solid residue 3as distilled at (+,@(&, deg C at ,.$ mm8Hg to give a crystalline fraction that, after recrystalli6ation from (& m! boiling IPA
gave $,&@bis@'methylthio-@+@methylben6aldehyde as a yello3@bro3n solid 3hich 3eighed (.( g and had a mp of (,2@(,% deg C. An analytical sample
from ?e9H melted at ((,@((( deg C 3ith an e/cellent I: and 5?:. Anal. 'C(,H($9S$- C,H. An alternate synthesis of this aldehyde employs the $,&@
bis@'methylthio-toluene described above. A CH$Cl$ solution of this substituted toluene containing dichloromethyl methyl ether 3as treated 3ith
anhydrous AlCl0, and the usual 3orkup gave a distilled fraction that spontaneously crystalli6ed to the desired aldehyde but in an overall yield of only ((K
of theory.
"o a solution of ,.& g $,&@bis@'methylthio-@+@methylben6aldehyde in (& m! nitroethane there 3as added ,.(& g anhydrous ammonium acetate and the
mi/ture 3as heated on the steam bath for ( h. "he e/cess solvent 3as removed under vacuum and the residue 3as dissolved in (, m! boiling ?e9H.
"his solution 3as decanted from a little insoluble residue, and allo3ed to cool to ice bath temperature yielding, after filtering and drying to constant
3eight, ,.&& g of (@P$,&@bis@'thiomethyl-@+@methylphenylQ@$@nitropropene as pumpkin@colored crystals 3ith a mp of %,@%( deg C. "his 3as not improved
by recrystalli6ation from <t9H. Anal. 'C($H(&59$S$- C,H.
A cooled, stirred solution of ,.& g !AH in +, m! "HB 3as put under an inert atmosphere, cooled to , deg C 3ith an e/ternal ice bath, and treated 3ith
,.+$ m! (,,K H$S9+, added drop3ise. A solution of ,.& g (@P$,&@bis@'thiomethyl-@+@methylphenylQ@$@nitropropene in $, m! anhydrous "HB 3as added
over the course of & min, and the reaction mi/ture held at reflu/ for 0, min on the steam bath. After cooling again to ice temperature, the e/cess hydride
3as destroyed by the addition of IPA and the inorganics 3ere converted to a loose, 3hite filterable form by the addition of (.& m! &K 5a9H. "hese
solids 3ere removed by filtration and the filter cake 3as 3ashed 3ith $/&, m! IPA. "he combined filtrate and 3ashings 3ere stripped of solvent under
vacuum to give a residue that 3as a flocculant solid. "his 3as suspended in dilute H$S9+ and e/tracted 3ith $/&, m! CH$Cl$, and the combined
organics e/tracted 3ith $/&, m! dilute H0P9+. "he aFueous e/tracts 3ere made basic, and the product removed by e/traction 3ith $/2& m! CH$Cl$.
After removal of the solvent under vacuum, the residue 3as distilled at ($1@(+$ deg C at ,.$ mm8Hg to give ,.$ g of product 3hich crystalli6ed in the
receiver. "his 3as dissolved in (.& m! hot IPA, neutrali6ed 3ith + drops of concentrated HCl, and diluted 3ith 0 m! anhydrous <t$9 to give, after
filtering and air drying, ,.$ g. of $,&@bis@'methylthio-@+@methylamphetamine hydrochloride '.IS@"9?- as 3hite crystals 3ith a mp of $$)@$$% deg C. Anal.
'C($H$,Cl5S$- C,H.
;9SAC<E greater than (1, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (1, mg- I 3as vaguely a3are of something in the latter part of the afternoon. A suggestion of darting, physically
'3hen going to sleep-, but nothing at the mental level. "his is as high as I 3ill go.
<="<5SI95S A5; C9??<5"A:>E It is reasonable, in retrospect, to accept that .IS@"9? is not an active compound. "he replacement of the $@
position o/ygen of ;9? 3ith a sulfur atom 'to give $@"9?- dropped the potency by a factor of (&/, and the replacement of the &@position o/ygen 3ith a
sulfur atom 'to give &@"9?- dropped the potency by a factor of about (,/. It 3ould be a logical calculation that the replacement of both o/ygen atoms
3ith sulfur might drop the potency by a factor of (&,/. So, 3ith ;9? being active at maybe & milligrams, a logical prediction of the active level of .IS@
"9? 3ould be 2&, milligrams. And maybe this 3ould be the right level, but 3ith the hints of neurological disturbance that seemed to be there at (1,
mg, there 3as no desire to go up by a factor of five again. "he re3ards 3ould simply not be 3orth the risks.
"he $@carbon analogue, $C@.IS@"9?, 3as prepared from the intermediate aldehyde above, first by reaction 3ith nitromethane to give the nitrostyrene
as tomato@colored crystals from <t9Ac, mp (+&@(+1 deg C. Anal. 'C((H(059$S$- C,H. "his 3as reduced 3ith AH to give $,&@bis@'methylthio-@+@
methylphenethylamine hydrochloride as ivory@colored crystals 3ith a mp of $20@$22 deg C.
Although there are many interesting psychedelic drugs 3ith sulfur atoms in them 'the "9?7s, the "9<"7s, the A!<PH7s and all of the $C@"7s-, there Gust
aren7t many that contain t3o sulfur atoms. .IS@"9? bombed out, and $C@.IS@"9? remains untried, but 3ill probably also fail, as the phenethylamines
are rarely more potent than the corresponding amphetamines. "his leaves $C@"@(+ as the remaining hope, and its synthesis is still under3ay.
#1' .%.; beta-METH%+Y-$!-.; (-.*%M%-$,)-beta-T*"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a vigorously stirred suspension of $.( g +@bromo@$,&@dimetho/y@beta@nitrostyrene Pfrom +@bromo@$,&@dimetho/yben6aldehyde and
nitromethane in acetic acid 3ith ammonium acetate as a catalyst, mp (&2@(&) deg C, anal. 'C(,H(,.r59+- C,HQ in $, m! anhydrous ?e9H, there 3as
added a solution of sodium metho/ide in ?e9H 'generated from ,.& g metallic sodium in $, m! anhydrous ?e9H-. After a fe3 min there 3as added (,
m! acetic acid 'no solids formed- follo3ed by the slo3 addition of &, m! of H$9. A cream@colored solid 3as produced, 3hich 3as removed by filtration
and 3ashed 3ell 3ith H$9. After air drying the product, (@'+@bromo@$,&@dimetho/yphenyl-@(@metho/y@$@nitroethane, 3eighed $., g. An analytical
sample from ?e9H 3as off@3hite in color and had a mp of ((%@($, deg C. Anal. 'C((H(+.r59&- C,H.
A solution of !AH '(& m! of ( ? solution in "HB- 3as diluted 3ith an eFual volume of anhydrous "HB, and cooled 'under He- to , deg C 3ith an e/ternal
ice bath. Iith good stirring there 3as added ,.0) m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of (., g (@'+@
bromo@$,&@dimetho/yphenyl-@(@metho/y@$@nitroethane as a solid over the course of & min. After an hour of stirring at , deg C, the temperature 3as
brought up to a gentle reflu/ on the steam bath for 0, min. "here 3as no vigorous e/othermic reaction seen, unlike that 3ith the syntheses of .9;,
.9H and .9?. "he reaction mi/ture 3as cooled again to , deg C, and the e/cess hydride 3as destroyed by the cautious addition of IPA. "his 3as
follo3ed by sufficent dilute aFueous 5a9H to give a 3hite granular character to the o/ides, and to assure that the reaction mi/ture 3as basic. "he
reaction mi/ture 3as filtered, and the filter cake 3ashed first 3ith "HB fol@lo3ed by IPA. "he combined filtrate and 3ashings 3ere stripped of solvent
under vacuum and dissolved in dilute H$S9+, 3ith the apparent generation of yello3 solids. "his 3as 3ashed 3ith $/&, m! CH$Cl$, and the aFueous
phase made basic 3ith 5a9H. "his 3as e/tracted 3ith $/&, m! CH$Cl$, and the pooled e/tracts 3ere stripped of solvent under vacuum. "he residue
3as distilled at (0,@(&, deg C at ,.$ mm8Hg to give ,.$ g of product as a clear 3hite oil. "his fraction 3as dissolved in (, m! IPA, and neutrali6ed 3ith
+ drops concentrated HCl. "he addition of 0, m! anhydrous <t$9 allo3ed the formation of +@bromo@$,&,beta@trimetho/yphenethylamine hydrochloride
'.9.- as a fine 3hite crystalline product. "his 3as removed by filtration, 3ashed 3ith <t$9, and air dried. "here 3as obtained ,.( g 3hite crystals 3ith
a mp of ()2@()) deg C. Anal. 'C((H(2.rCl590- C,H.
;9SAC<E (, @ $, mg.
;4:A"I95E (, @ $, h.
L4A!I"A"IM< C9??<5"SE '3ith (, mg- I don7t kno3 if it 3as me this day, or if it 3as the chemical, but I got into a granddaddy of a paranoid,
sociopathic snit, 3ithout feeling and 3ithout emotion. I 3as indifferent to everything. !ater on, there 3as some improvement, 3ith body tingling 'good,
I7m pretty sure- and a sense of a3areness 'good, I guess- but I still canceled my evening dinner company. All in all, pretty negative.
'3ith (, mg- I had to get a3ay and into myself, so I 3eeded in the vegetable garden for almost an hour. "hen I lay do3n in the bedroom, and enGoyed a
magnificent vegetable garden, in Southern Brance, in my mind7s eye. An e/traordinary 6ucchini. And the 3eeds had all been magically pulled. In
another couple of hours a neurological over@stimulation became apparent, and I spent the rest of the day defending myself. In the evening, I took (,,
milligrams phenobarbital 3hich seemed to smooth things Gust enough. "oo bad. 5ice material, other3ise.
'3ith (& mg- "he erotic 3as lustful, but at the critical moment of orgasm, the Fuestion of neurological stability became Fuite apparent. ;oes one really let
goH <verything seemed a bit irritable. "he tinnitus 3as Fuite bad, but the e/citement of the rich altered place I 3as in 3as certainly 3orth it all. "hrough
the rest of the day, I became a3are of ho3 tired I 3as, and ho3 much I 3anted to sleep, and yet ho3 scared I 3as to give myself over to sleep. Could I
trust the body to its o3n devices 3ithout me as an overseeing caretakerH !et7s risk it. I slept. "he ne/t day there 3as a memory of this turmoil. Clearly
the first part of the e/perience might have been hard to define, but it 3as Fuite positive. .ut the last part makes it not really 3orth 3hile.
<="<5SI95S A5; C9??<5"A:>E "his compound, .9., is the most potent of the .9= series. And yet, as 3ith all of the members of this family,
there are overtones of physical concern, and of some 3orry as to the integrity of the body. "here may 3ell be a separation of activity 3ith the t3o optical
isomers, but there is not a tremendous push to e/plore this particular family much further. "hey can7t all be 3inners, I guess. Ihat 3ould be the
activities of compounds 3ith a sulfur instead of an o/ygen at the beta@o/ygen positionH Ihat 3ould be the nature of action if there 3ere an alpha@
methyl group, making all of these into amphetamine derivativesH 9r 3hat about both a sulfur and a methyl groupH And 3hat about the isomers that are
intrinsic to all of this, the threo@ and the erythro@ and the N;7sN and the N!7sNH All this is terra incognita, and must someday be looked into. It is chemically
simple, and pharmacologically provocative. Someone, some3here, someday, ans3er these FuestionsO
#1( .%0; beta-METH%+Y-$!-0; (-METHY-$,),beta-T*"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of 0%.1 g (@'$,&@dimetho/y@+@methylphenyl-@$@nitrostyrene 'see recipe for $C@; for its preparation- in 0,, m! 3arm ?e9H 3as
prepared. Separately, a solution of % g elemental sodium in (&, m! ?e9H 3as also prepared. "his sodium metho/ide solution 3as added to the 3ell@
stirred nitrostyrene solution, 3hich resulted in a dramatic loss of color. "here 3as then added 2& m! acetic acid, and all 3as poured into $ ! H$9. "his
3as e/tracted 3ith 0/(,, m! CH$Cl$. "he pooled e/tracts 3ere stripped of solvent, and the 0& g of residue 3as treated 3ith & m! ?e9H, allo3ed to
stand for a short 3hile, decanted from some insoluble residue, and the separated clear solution kept at , deg C overnight. "here 3as the deposition of a
yello3 crystalline product 3hich, after removal by filtration and air drying, 3eighed %.2 g. :ecrystalli6ation from $& m! ?e9H gave, after filtering and
drying, ).+ g of canary@yello3 crystals of (@'$,&@dimetho/y@+@methylphenyl-@(@metho/y@$@nitroethane 3ith a mp of 2)@2% deg C. <vaporation of the
mother liFuors from the filtration of the first crop yielded 0.) g of additional product 3hich, upon recrystalli6ation from (( m! ?e9H, provided another $.2
g 3ith a mp of 22@2) deg C. Burther 3orkup of the mother liFuors yielded only impure starting nitrostyrene.
A solution of !AH '%1 m! of ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added $.+ m!
(,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of (,.) g (@'$,&@dimetho/y@+@methylphenyl-@(@metho/y@$@nitroethane.
"here 3as immediate discoloration. After the addition 3as complete, the reaction mi/ture 3as held at reflu/ on the steam bath for $ h. After cooling
again, the e/cess hydride 3as destroyed 3ith + m! IPA and the reaction mi/ture made basic 3ith (&K 5a9H. "he insoluble inorganic salts 3ere
removed by filtration, and the filter cake 3as 3ashed first 3ith "HB, and then 3ith IPA. "he bright yello3 filtrate and 3ashes 3ere pooled and stripped of
solvent under vacuum, yielding (+ g of a yello3 oil. "his 3as suspended in ( ! dilute H$S9+ to give an ugly, cloudy, yello3@orange mess. </traction
3ith 0/2& m! CH$Cl$ removed much of the color, and the remaining aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/2& m!
CH$Cl$. <vaporation of the solvent under vacuum gave % g of a pale amber oil 3hich 3as distilled at ((&@(0, deg C at ,.+ mm8Hg. "he 3ater@3hite
distillate 3as dissolved in (& m! IPA, neutrali6ed 3ith concentrated HCl, and then diluted 3ith 2, m! anhydrous <t$9. After a fe3 min, 3hite crystals
formed, and these 3ere removed by filtration and <t$9 3ashed. Ihen air@dried to constant 3eight, +.+% g brilliant 3hite crystals of +@methyl@$,&,beta@
trimetho/yphenethylamine hydrochloride '.9;- 3ith a mp of (2(@(2$ deg C 3ith decomposition, 3ere obtained. "he mother liFuors on standing
deposited ,.11 g additional crystals 3hich 3ere impure and 3ere discarded. Anal. 'C($H$,Cl590- C,H.
;9SAC<E (& @ $& mg.
;4:A"I95E ) @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- "here 3ere some very pleasant visuals starting at $@$.& hours and continuing to +@& hours after the beginning
of the e/periment. 9pen eye visuals seem to come on after staring at particular areas, such as the living room ceiling or at trees. "he surroundings
tended to move slightly. "here 3as no flo3ing of the images at all. Ihen looking at the pine trees, the needles appeared crystal clear and sharply
defined, 3ith strong contrasts. "hough the mental effect is difficult to define, I am not sure it 3as all that great. I did become tired of the effect 'along
3ith the confusion- after ) hours, and 3as Fuite happy to note that it did taper off in the early evening. I am not particularly sure I 3ould 3ant to try this
material again.
'3ith $, mg- Bor the first three or so hours, the beauty of the e/perience 3as marred by a strange discomfort. "here 3as some Fueasiness, and I felt a
sluggishness of mind. "hen I began moving in and out of a pleasant place, and finally the discomfort completely dissolved and the e/perience turned full
on. Height of beauty, visual perception. !ights belo3 are ama6ing. 9utside, marvelous sense of Presence. "here is not an elation, as often 3ith other
materials, but a strong, even po3erful sense of goodness, inner strength, solidity.
'3ith $& mg- "his 3as Fuite Fuick. "he onset of the e/perience 3as apparent 3ithin a half hour, and 3e 3ere both at *** 3ithin the hour. .ody load
minimal. "here 3as very little visual, compared 3ith some materials. Mery interesting eyes@closed, but not continually L Gust no3 and then an intense
vision might flash. Mery benign and friendly and pleasant and good@humored feeling. Superb for conversation and conceptuali6ation.
'3ith $& mg- "he body load 3as Fuite noticeable for everyone. .ut the general state of mind 3as e/cellent; everyone 3as e/tremely rela/ed and funny.
Puns, insults, delightful amusement. 5ot very much insight 3ork possible. Duices 3ere needed and tolerated 3ell, but no one 3as particularly hungry.
Sleep 3as difficult for most people, not deep and not too refreshing. </cellent material, but body price a bit too much for the mental effects. Pleasant,
and I 3ouldn7t hesitate to take it again, but nothing very memorable e/cept the tremendous humor and laughter, 3hich 3as truly delightful.
<="<5SI95S A5; C9??<5"A:>E "his compound, .9;, 3as the first e/ploratory member of a ne3 family of phenethylamines. "his family is called
the .9= series because an o/ygen atom has been put on the ben6ylic carbon 'the Nben6yl@o/yN or N.9N- of each of several 3ell studied drugs 3ith
recogni6ed substituent patterns on the aromatic ring. "he N=N 3ould be N;,N as used here 3ith .9;, making reference to $C@;, it 3ould be a N.N in .9.
making reference to $C@., etc. Actually the original thought 3as to make the N9N into an N9?N for metho/y, as this 3ould allo3 more versatility in the
naming of things such as etho/ys 'N9<N- or hydro/ys 'N9HN-, but the metho/ylated $C@. analogue 3ould have come out as .9?., so the idea 3as
dropped.
Actually, the concept of naming of drugs 3ith some acronym that is pronounceable has led into some interesting by3ays. Some e/amples have been
unintended. I have heard ;9? pronounced NdomeN and ;9<" pronounced as Ndo it.N And else3here I have mentioned the embarrassing occasions
3here the "9? and "9<" families 3ere pronounced Nthe toms and t3ats.N Some e/amples have had names that have been contractions of popular
names, such as ="C for ecstasy. And there are instances 3here a name might be proposed simply to irritate the ne3spaper people. An early street
suggestion for PCP 3as B4, and a current name for free@base methamphetamine is S59". And mariGuana is fondly called SHI" by its aficionados.
"he final NAN on government groups such as the CIA or the ;<A or the B;A is strongly reminscent of the final NAN 3hich stands for amphetamine in
things such as "?A and ?;?A. ?ight there someday be a drug such as +@cyclopropylmethyl@5@isopropylamphetamine 'CIA-, or 0,&@dimetho/y@+@
ethylamphetamine ';<A-H It has Gust occurred to me that there is already a +@fluoro@$,&@dimetho/yamphetamine 'B;A-, but I have already named it
;9B. If all drugs 3ere kno3n only by publicly embarrassing names, there might be less publicity given them by the press.
.ack to the commentary on .9;. "he rationale for this inclusion of a beta@o/ygen atom into the structure of a phenethylamine is based directly on the
chemistry that occurs naturally in the brain. "he phenethylamine neurotransmitter, dopamine, is converted both in the brain and in the body to the
eFually important transmitter norepinephrine by Gust this sort of transformation. "here is the en6ymatic addition of an o/ygen atom to the Nben6ylicN
position of dopamine. And identical chemistry goes on 3ith tyramine in a number of plants and animals, 3ith a similar addition of o/ygen to form
octopamine, so@named for its discovered presence in the salivary glands of 9ctopus vulgaris. In the first e/plorations in the N9=N series, this o/ygen
3as intentionally blocked 3ith a methyl group, to ease its entry into the brain, and increase the possibilities of its being active as a psychedelic. As
mentioned above, the N;N in N9;N follo3s from its ring orientation pattern being the same as that of $C@; 'and this, originally from the mimicking of the
pattern of ;9?-. All of these ;@ compounds have the $,&@dimetho/y@+@methyl ring@substitution pattern.
An interesting complication is also part of this structure package. "he added metho/y group 'or hydro/y group, see recipe for .9H;- also adds a ne3
asymmetric center, allo3ing for the eventual separation of the material into t3o optical isomers. And at such time as the corresponding amphetamine
homologues might be made and studied, the presence of yet another chiral center 'under the alpha@methyl group- 3ill demand that there be actually t3o
racemic compounds synthesi6ed, and a total of four isomers to contend 3ith, if really careful and thorough 3ork is to be done.
A parallel chemistry to all of this follo3s the addition of sodium etho/ide 'rather than sodium metho/ide- to the nitrostyrene. "he final product, then, is
the etho/y homologue $,&@dimetho/y@beta@etho/y@+@methylphenethylamine, or .9<;. It is do3n in human potency by a factor of three, 3ith a normal
dosage being 2,@2& milligrams. It has a ten hour duration, and is both anore/ic and diuretic. "here have been no visual effects or insights reported, but
rather simply a highly into/icated state.
"3o synonyms, t3o definitions, and an e/pression of admiration. "he 3ord norepinephrine is synonymous 3ith noradrenalin, and the 3ord epinephrine
is synonymous 3ith adrenalin. "he distinctions are that the first in each case is American and the second .ritish. And the term NchiralN indicates a
potential asymmetry in a molecule that 3ould allo3 eventual separation into t3o optical isomers. "he term NracemicN refers to a mi/ture of these t3o
isomers 3hich has not yet been separated into the individual components. A racemic mi/ture is called a racemate and, from the point of vie3 of the
human animal '3hich is completely asymmetric-, must be considered as a mi/ture of t3o structurally identical but optically mirror@image isomers, 3hich
can be potentially separated and 3hich 3ill certainly have different pharmacologies. And the admirationH "his is directed to the e/plorer 3ho ventured
close enough to an octopus to locate its salivary glands and to discover a phenethylamine thereO
#1) .%H; beta-METH%+Y-',(-METHYE#E0"%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0, g piperonal in (,, m! acetic acid there 3as added $, m! nitromethane and (, m! cyclohe/ylamine. After heating on
the steam bath for (.& h, the reaction mi/ture started to crystalli6e. "he mi/ture 3as cooled in an ice bath, and the heavy mass of deposited crystals
removed by filtration and 3ashed 3ith $, m! acetic acid. All 3as supended in (,, m! 3arm ?e9H, cooled again, and filtered to give $+.& g of 0,+@
methylenedio/y@beta@nitrostyrene as canary@yello3 crystals, 3ith a mp of (&)@(1, deg C. :eduction of this compound 3ith !AH gives rise to ?;P<A,
3hich is a separate entry 3ith a recipe of its o3n.
"o a vigorously stirred suspension of $, g 0,+@methylenedio/y@beta@nitro @styrene in (,, m! anhydrous ?e9H there 3as added a freshly prepared
solution of &.& g elemental sodium in (,, m! ?e9H. "he nitrostyrene goes into solution over the course of & min. "here 3as then added, first, &, m!
acetic acid 3ith the stirring continued for an additional ( min. "here 3as then added 0,, m! H$9. An oil separated and 3as e/tracted into $,, m!
CH$Cl$. "he organic e/tract 3as 3ashed 3ith &,, m! dilute aFueous 5aHC90, follo3ed by &,, m! H$9. :emoval of the solvent gave a residue that
3as distilled at ($)@(+& deg C at ,.+ mm8Hg, providing (1.1 g of a yello3 viscous liFuid 3hich slo3ly crystalli6ed. An analytical sample 3as recrystalli6ed
from four volumes of ?e9H to give (@metho/y@(@'0,+@methylenedio/yphenyl-@$@nitroethane as bright yello3 crystals 3ith a mp of &)@&% deg C. Anal.
'C(,H((59&- C,H.
A solution of !AH '(,, m! of ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added $.&
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of ($ g (@metho/y@(@'0,+@methylenedio/yphenyl-@$@nitroethane over
the course of $ min. "here 3as an immediate loss of color. After a fe3 minutes further stirring, the temperature 3as brought up to a reflu/ 3ith a heating
mantle. "here 3as a gentle gas evolution for a fe3 min, follo3ed by an e/othermic reaction that e/ceeded the capacity of the condenser. 9nce the
reaction had subsided, the unreacted hydride 3as destroyed 3ith a minimum of IPA, and (&K 5a9H 3as added to convert the inorganics to a loose
3hite filterable mass. "he reaction mi/ture 3as filtered, and the filter cake 3ashed thoroughly 3ith "HB. "he combined filtrate and 3ashes 3ere
stripped of solvent under vacuum, providing an orange oil. "his 3as dissolved in +,, m! dilute H$S9+, 3hich 3as 3ashed 3ith 0/2& m! CH$Cl$. After
making the aFueous phase basic, it 3as e/tracted 3ith $/(,, m! CH$Cl$. "he pooled e/tracts 3ere stripped of solvent under vacuum, and the residue
distilled at (,0@(($ deg C at ,.& mm8Hg. "here 3as obtained $.& g of a colorless, viscous oil 3hich 3as dissolved in $& m! IPA, neutrali6ed 3ith +&
drops of concentrated HCl, and finally diluted 3ith 0, m! anhydrous <t$9. "here 3as thus formed beta@metho/y@0,+@methylenedio/yphenethylamine
hydrochloride '.9H- as a fine 3hite crystalline product. "he mp 3as (,&@(,1.& deg C, 3ith bubbling and darkening. "he mp properties proved to be
inconsistent, as the salt 3as a hydrate. :ecrystalli6ation from CH0C5, or simply heating to (,, deg C in toluene, converted the salt to an anhydrous
form, 3ith mp of (&$@(&0 deg C. Anal. 'C(,H(+Cl590- C,H.
;9SAC<E ), @ ($, mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith %, mg- ;istinct body a3areness in an hour. "he threshold is mostly physical. Baint sense of inside 3armth, skin
prickling, cold feet, loose bo3els, anore/ia. .y the fifth hour, I 3as on the do3nslope, and in retrospect I found it good humored but not insightful.
'3ith (,, mg- "here 3as a vague nausea, and a chilling of the feet. It reached a real plus t3o, 3ith dilated pupils and Fuite a thirst. Ho3 can one
describe the stateH "here 3ere no visuals, and I 3as not even stoned. I 3as Gust very turned on. And I 3as completely back to baseline by hour
number si/.
<="<5SI95S A5; C9??<5"A:>E "here are several reports of a nice, mild mood enhancement in the $,@+, milligram dosage area, but searches for
psychedelic effects at higher levels gave a strange mi/ of some sort of an altered state along 3ith bodily discomfort. "he .9H name for this member of
the .9= family follo3s the convention discussed in the .9; recipe L 3ith :HS for homopiperonylamine, the simplest of the muni@metro family, F.v. "he
demethylated homologue of .9H is .9HH, and is the methylenedio/y analogue of norepinephrine. It might 3ell hydrolytically open up in the body to
provide this neurotransmitter, and serve as some sort of transmitter in its o3n right. It is discussed under ;?<.
?aybe there is something to the concept that 3hen you imitate a neurotransmitter too closely, you get a hybrid gemisch of activity. "he term Npro@drugN is
used to identify a compound that may not be intrinsically active, but one 3hich metaboli6es in the body to provide an active drug. I feel the term should
have been pre@drug, but pro@drug 3as the 3ord that caught on. .9H may 3ell act in the body as a pro@drug to norepinephrine, but 3ith the temporary
blocking of the polar functions 3ith ether groups, it can gain access to the brain. And once there, it can be stripped of these shields and play a direct
neurological role. I uncovered a very similar analogy in the tryptamine 3orld some years ago. Dust as norepinephrine is a neurotransmitter, so is
serotonin. And I found that by putting an 9@ether on the indolic phenol 'to hide its polarity- and an alpha@methyl group ne/t to the primary amine 'to
protect it from metabolic deaminase-, it became an e/tremely potent, and most comple/, psychedelic. "his 3as the compound alpha,9@
dimethylserotonin, or a,9@;?S. "here is an uncanny analogy bet3een this tryptamine and the phenethylamine .9H.
Someho3 the Fuiet voice deep inside me says, don7t use too much, too Fuickly. ?aybe one of the optical isomers is the body thing, and the other
isomer is the mind thing. So far, only the racemic mi/ture has been tasted, to the best of my kno3ledge.
#11 .%H0; $,)-0"METH%+Y-beta-HY0*%+Y-(-METHY,HE#ETHYAM"#E
S>5"H<SISE A solution of ,.+ g (@'$,&@dimetho/y@+@methylphenyl-@(@metho/y@$@nitroethane 'see preparation in the recipe for .9;- in 0., m! acetic acid
3as heated to (,, deg C on a steam bath. "here 3as added (., g po3dered 6inc, follo3ed by additional acetic acid as needed to maintain smooth
stirring. After ,.& h there 3as added (., m! concentrated HCl and, follo3ing an additional fe3 minutes heating, the reaction mi/ture 3as poured into 0,,
m! H$9. After 3ashing the aFueous phase 3ith 0/2& m! CH$Cl$, the mi/ture 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/&, m! CH$Cl$.
:emoval of the solvent and distillation of the residue at (0,@(+, deg C ,.$& mm8Hg gave an oil that, on dissolving in IPA, neutrali6ation 3ith
concentrated HCl, and the addition of anhydrous <t$9, gave beautiful 3hite crystals of $,&@dimetho/y@beta@hydro/y@+@methylphenethylamine
hydrochloride '.9H;-. "he yield 3as ,.$ g, and the mp 3as (),@()( deg C. "he infrared spectrum 3as that of an amine salt 3ith a strong 9H group
present. Anal. 'C((H()Cl590- C,H.
;9SAC<E greater than &, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith &, mg- At about the t3o hour point, there 3as a precipitous drop of blood pressure 'from ($,82$ to )+81)- although
the pulse stayed steady at 1,. "his trend had been apparent in earlier trials, and 3as being 3atched carefully. 5o further tests are planned.
<="<5SI95S A5; C9??<5"A:>E "he usual method of making beta@ethanolamine such as this is through the reduction of the cyanohydrin of the
corresponding ben6aldehyde and, in fact, that method is described in the recipe for ;?<. "his above procedure 3as actually part of an e/ploration of
different agents that might be used in the reduction of the intermediate nitroalkane. "his product 3as the une/pected result of trying 6inc.
Ihy the potent cardiovascular effect seen by this compoundH "here are a couple of points that might argue for some adrenolytic to/icity. "his material
is a beta@ethanolamine and, 3ith maybe one or t3o e/ceptions, clinically used beta@receptor blockers are beta@ethanolamines. In fact, a fe3 of these so@
called beta@blockers actually have t3o metho/y groups on the aromatic rings, also a property of .9H;. "he antidiabetic drug .uta/amine '.I 1+@% in
the code of .urroughs Iellcome- is identical to .9H; e/cept that the +@methyl group is on the alpha@carbon instead, and there is a tertiary butyl group
on the nitrogen atom. Another point involves the pro/imity of the beta@hydro/y group and the metho/yl o/ygen atom in the $@position of the ring. "here
is going to be a strong hydrogen@bonding 3ith this orientation, 3ith the formation of a stable si/@membered ring. "his might help obscure the hydrophilic
nature of the free hydro/yl group and allo3 the compound to pass into the brain easily. If this group is masked by an easily removed group such as an
acetate ester, one gets the compound beta@aceto/y@0,+@dimetho/y@+@methylphenethylamine '.9A;- 3hich is similar to .9H; as a hypotensive.
"he code@naming procedure used here 'and else3here here in .ook II- isE '(- to use :.9S as the alert to there being an o/ygen on the ben6yl carbon
of a phenethylamine 'it is a ben6yl alcohol-; '$- if there is Gust one more letter 'a third and last letter- it 3ill identify the $C@= parent from 3hich it has been
derived P:.S comes from $C@., :;S comes from $C@;, :HS comes from homopiperonylamine '?;P<A- rather than from $C@H, :?S comes from
mescaline, and in every case the beta@substituent is a metho/y groupQ; and '0- if there are four letters, then the fourth letter is as above, and the third
letter 'the ne/t to last letter- is the substituent on that ben6ylic o/ygen. Iith a three letter code, the substituent is a methyl group, an :HS for a third
letter of four makes it a hydro/yl group, and an :AS for the third letter is an acetyl group, and an :<S is for an ethyl group. A similar sort of
cryptographic music 3as composed by ;u Pont in their three@number codes for the Breons. "he first number 3as one less than the number of carbons
in the molecule, the second number 3as one more than the number of hydrogens in the molecule, the third number 3as the e/act number of fluorines in
the molecule, and the rest of the bonds 3ere filled 3ith chlorines, "hus Breon (( 'really Breon ,((- 3as trichlorofluoromethane and Breon ((1 3as
he/afluoroethane.
Comple/, yes. .ut both systems are completely straightfor3ard, and fle/ible for future creations. A fe3 additional e/amples of similar beta@
ethanolamines are scattered throughout .ook II and they have, in general, proved to be uninteresting, at least as potential psychedelic compounds.
#12 .%M; beta-METH%+YMES!A"#E; ',(,),beta-TET*AMETH%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a vigorously stirred suspension of %., g beta@nitro@0,+,&@trimetho/ystyrene 'see under the recipe for ? for the preparation of this
intermediate- in &, m! anhydrous ?e9H there 3as added a solution obtained from the addition of $., g metallic sodium to &, m! anhydrous ?e9H.
"he bright orange color faded to a light cream as the nitrostyrene 3ent into solution. After 0 min there 3as added 0, m! acetic acid, 3hich produced
3hite solids, and this 3as follo3ed by further dilution 3ith (&, m! H$9. "he formed solids 3ere removed by filtration, 3ashed 3ell 3ith H$9, and
recrystalli6ed from (&, m! boiling ?e9H. After removal of the product by filtration and air drying to constant 3eight, there 3as obtained 1.% g of (@
metho/y@$@nitro@(@'0,+,&@trimetho/yphenyl-ethane as fine, cream@colored crystals. "he mp 3as (+0@(++ deg C, and the :f by "!C 'silica@gel plates and
CH$Cl$ as moving phase- 3as identical to that of the starting aldehyde. Anal. 'C($H(2591- C,H.
A solution of !AH '&, m! of ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.$&
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of 1 g of solid (@metho/y@$@nitro@(@'0,+,&@trimetho/yphenyl-ethane
over the course of $ min. "here 3as some gas evolution. After & min additional stirring, the temperature 3as brought up to a reflu/ 3ith a heating
mantle. "here 3as a gentle gas evolution for a fe3 minutes, follo3ed by an e/othermic reaction 3ith vigorous gas evolution. 9nce everything had
settled do3n, the reaction mi/ture 3as held at reflu/ temperature for an additional $ h. "he e/cess hydride 3as destroyed by the addition of IPA and
(&K 5a9H 3as added to convert the inorganic salts to a loose 3hite filterable mass. "he reaction mi/ture 3as filtered, and the filter cake 3ashed
thoroughly 3ith "HB. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum 3hich provided a red@bro3n liFuid. "his 3as dissolved in
dilute H$S9+ and 3ashed 3ith 0/2& m! CH$Cl$. After making the aFueous phase basic 3ith 5a9H, it 3as e/tracted 3ith $/(,, m! CH$Cl$. "he
pooled e/tracts 3ere stripped of solvent under vacuum, and the colorless residue distilled at ($,@(&, deg C at ,.0 mm8Hg. "here 3as obtained $.) g of
a colorless oil 3hich 3as dissolved in 0, m! IPA and neutrali6ed 3ith concentrated HCl, allo3ing the spontaneous formation of the hydrochloride salt.
"his 3as diluted 3ith 2& m! anhydrous <t$9, yielding $.) g 0,+,&,beta@tetrametho/yphenethylamine hydrochloride '.9?- as a 3hite crystalline product.
"his had a mp of (%).&@(%%.& deg C. Anal. 'C($H$,Cl59+- C,H.
;9SAC<E greater than $,, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "here are some indicators of central activity 3ith assays involving both the ($, milligram and the (), milligram
levels, but nothing that can be rated as over a plus one. It can be seen 3ith the t3o active members of the .9= series '.9; and .9.- that the potency
is about eFual to, or a little more 'up to a factor of maybe /$-, than the analogue 3ithout the metho/yl group on the aliphatic chain. If this formula 3ere
to hold in the relationship bet3een mescaline and .9?, the active level might 3ell be in the $,,@+,, milligram range. .ut at the moment, it remains
unkno3n. Again, the name of the compound '.9?- is from the :.9@S prefi/ of this family 'from ben6yl * o/y-, plus the :?S of mescaline '3hich has
provided the ring substitution pattern-.
#13 (-.*-',)-0MA; ',)-0"METH%+Y-(-.*%M%AM,HETAM"#E
S>5"H<SISE "he starting material 0,&@dimetho/y@+@bromoben6oic acid 'made from the commercially available resorcinol by the action of methyl sulfate-
3as a 3hite crystalline solid from aFueous <t9H 3ith a mp of $+)@$&, deg C. :eaction 3ith thionyl chloride produced 0,&@dimetho/y@+@bromoben6oyl
chloride 3hich 3as used as the crude solid product, mp ($+@($) deg C. "his 3as reduced 3ith tri@9@'t-@buto/y lithium aluminum hydride to produce 0,&@
dimetho/y@+@bromoben6aldehyde 3hich 3as recrystalli6ed from aFueous ?e9H and had a mp of (($@((+ deg C. Anal. 'C%H%.r90- C,H. "his
aldehyde, 3ith nitroethane and anhydrous ammonium acetate in acetic acid, 3as converted to the nitrostyrene (@'0,&@dimetho/y@+@bromophenyl-@$@
nitropropene, 3ith a mp of ($(@($(.& deg C. Anal. 'C((H($.r59+- C,H,5. "his 3as reduced at lo3 temperature 3ith Gust one eFuivalent of !AH, to
minimi6e reductive removal of the bromine atom. "he product 0,&@dimetho/y@+@bromoamphetamine hydrochloride '+@.:@0,&@;?A- 3as isolated in a
02K yield and had a mp of $$(@$$$ deg C. Anal. 'C((H(2.rCl59$- C,H,5.
;9SAC<E + @ (, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith 0 mg- "his is certainly no placebo. At about $ hours I felt some analgesia and numbing in my e/tremities, but if there
3ere any sensory distortions, they 3ere barely perceptible.
'3ith 1 mg- "here is a very shallo3 threshold, no more.
'3ith (, mg- I can certainly confirm the indications of anesthesia that 3ere hinted at. It 3as for me central in nature, ho3ever. I could 'this at three
hours- pierce a skin pinch on my left arm 3ith no bother e/cept for the emerging of the needle due to skin resistance. "here 3as little bleeding. And
multiple needle prickings into the thumb abductor 3ere not felt. A Fuick plunge of the tip of my little finger into boiling 3ater elicited refle/ response, but
no residual pain. Dudgment 3as 9, so I stayed out of physical trouble, luckilyO "he perhaps ** 3as dropping in the fourth or fifth hour, and by the tenth
hour there 3ere fe3 effects still noted, e/cept for some teeth@rubbiness and a burning irritation at the pin@prick area, so feeling is back. 5o sleep
problems at Gust past midnight.
<="<5SI95S A5; C9??<5"A:>E Here is a comple/ and, at the moment, totally undefined drug. "here 3ere t3o independent reports of analgesia,
yet a thorough screen in e/perimental animals, conducted by a maGor pharmaceutical house, failed to confirm any of it. A ** report does not necessarily
reflect a psychedelic effect, since this Fuantitative measure of the level of activity represents the e/tent of impairment of function, regardless of the
nature of the drug producing it. In other 3ords, if you 3ere e/periencing the effects of a drug that 3ould in your Gudgment interfere 3ith safe and good
driving, this 3ould be a ** 3hether your performance 3as being limited by a psychedelic, a stimulant, a hypnotic or a narcotic. 5one of the Fuantitative
reports ever mentioned any sensory distortion 'analgesia is a loss, not a distortion- or visual effect. Perhaps +@.:@0,&@;?A sho3ed its ** as a narcotic.
.ut then, the rats had said no.
#14 $-.*-(,)-M0A; 1-.*-M0A; $-.*%M%-(,)-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE A solution of 0,+@methylenedio/yamphetamine '?;A- in acetic acid 3as treated 3ith elemental bromine, generating the hydrobromide salt
of $@bromo@+,&@methylenedio/yamphetamine in a yield of 1(K of theory. "he mp 3as $$(@$$$ deg C. Anal. 'C(,H(0.r$59$- C,H,.r.
;9SAC<E 0&, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E .oth the synthetic and the pharmacological details for this compound are sparse. "here has been only a single
report of the human activity of this drug in the literature, and the statement has been offered that the effects are amphetamine@like. 5o other Fualitative
comments have been made available, and neither I nor anyone in my circle has tried it, personally. Someday, perhaps. .ut at that high level, perhaps
not.
#$5 $!-.; (-.*%M%-$,)-0"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of (,, g of $,&@dimetho/yben6aldehyde in $$, g nitromethane 3as treated 3ith (, g anhydrous ammonium acetate, and heated
on a steam bath for $.& h 3ith occasional s3irling. "he deep@red reaction mi/ture 3as stripped of the e/cess nitromethane under vacuum, and the
residue crystalli6ed spontaneously. "his crude nitrostyrene 3as purified by grinding under IPA, filtering, and air@drying, to yield )& g of $,&@dimetho/y@
beta@nitrostyrene as a yello3@orange product of adeFuate purity for the ne/t step. Burther purification can be achieved by recrystalli6ation from boiling
IPA.
In a round@bottomed $ ! flask eFuipped 3ith a magnetic stirrer and placed under an inert atmosphere, there 3as added 2&, m! anhydrous "HB,
containing 0, g !AH. "here 3as then added, in "HB solution, 1, g $,&@dimetho/y@beta@nitrostyrene. "he final solution 3as a dirty yello3@bro3n color,
and it 3as kept at reflu/ temperature for $+ h. After cooling, the e/cess hydride 3as destroyed by the drop3ise addition of IPA. "hen 0, m! (&K 5a9H
3as added to convert the inorganic solids to a filterable mass. "he reaction mi/ture 3as filtered and the filter cake 3ashed first 3ith "HB and then 3ith
?e9H. "he combined mother liFuors and 3ashings 3ere freed of solvent under vacuum and the residue suspended in (.& ! H$9. "his 3as acidified
3ith HCl, 3ashed 3ith 3ith 0/(,, m! CH$Cl$, made strongly basic 3ith $&K 5a9H, and ree/tracted 3ith +/(,, m! CH$Cl$. "he pooled e/tracts 3ere
stripped of solvent under vacuum, yielding $1 g of oily residue, 3hich 3as distilled at ($,@(0, deg C at ,.& mm8Hg to give $( g of a 3hite oil, $,&@
dimetho/y@phenethylamine '$C@H- 3hich picks up carbon dio/ide from the air very Fuickly.
"o a 3ell@stirred solution of $+.) g $,&@dimetho/yphenethylamine in +, m! glacial acetic acid, there 3as added $$ g elemental bromine dissolved in +,
m! acetic acid. After a couple of min, there 3as the formation of solids and the simultaneous evolution of considerable heat. "he reaction mi/ture 3as
allo3ed to return to room temperature, filtered, and the solids 3ashed sparingly 3ith cold acetic acid. "his 3as the hydrobromide salt. "here are many
complicated salt forms, both polymorphs and hydrates, that can make the isolation and characteri6ation of $C@. treacherous. "he happiest route is to
form the insoluble hydrochloride salt by 3ay of the free base. "he entire mass of acetic acid@3et salt 3as dissolved in 3arm H$9, made basic to at least
pH (( 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent gave 00.2 g of residue 3hich 3as distilled at ((&@(0, deg C at ,.+
mm8Hg. "he 3hite oil, $2.1 g, 3as dissolved in &, m! H$9 containing 2., g acetic acid. "his clear solution 3as vigorous stirred, and treated 3ith $, m!
concentrated HCl. "here 3as an immediate formation of the anhydrous salt of $,&@dimetho/y@+@bromophenethylamine hydrochloride '$C@.-. "his mass
of crystals 3as removed by filtration 'it can be loosened considerably by the addition of another 1, m! H$9-, 3ashed 3ith a little H$9, and then 3ith
several &, m! portions of <t$9. Ihen completely air@dry, there 3as obtained 0(.,& g of fine 3hite needles, 3ith a mp of $02@$0% deg C 3ith
decomposition. Ihen there is too much H$9 present at the time of adding the final concentrated HCl, a hydrated form of $C@. is obtained. "he
hydrobromide salt melts at $(+.&@$(& deg C. "he acetate salt 3as reported to have a mp of $,)@$,% deg C.
;9SAC<E ($ @ $+ mg.
;4:A"I95E + @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith (1 mg- A day at the Stanford museum. "hings 3ere visually rich, yet I felt that I 3as reasonably inconspicuous. "he
:odin sculptures 3ere very personal and not terribly subtle. I sa3 <scher things in the ceiling design, 3hen I decided to sit in a foyer some3here and
simply pretend to rest. Ialking back, the displays seen in the bark of the eucalyptus trees, and the torment and fear 'of othersH of themselvesH- in the
faces of those 3ho 3ere 3alking to3ards us, 3ere as dramatic as anything I had seen in the art galleries. 9ur appetites 3ere enormous, and 3e 3ent to
a smorgasbord that evening. A rich e/perience in every possible 3ay.
'3ith $, mg- "he drug effect first became kno3n to me as a shift of colors to3ard golden and rose tones. Pigments in the room became intensified.
Shapes became rounder, more organic. A sensation of lightness and rivulets of 3armth began seeping through my body. .right lights began pulsing and
flashing behind my closed lids. I began to perceive 3aves of energy flo3ing through all of us in unison. I sa3 all of us as a grid3ork of electrical energy
beings, nodes on a bright, pulsating net3ork of light. "hen the interior landscape shifted into broader scenes. ;aliesFue vistas 3ere patterned 3ith
eyes of Horus, brocades of geometric design began shifting and changing through radiant patterns of light. It 3as an artist7s paradise L representing
virtually the full pantheon of the history of art.
'3ith $, mg- "he room 3as cool, and for the first hour I felt cold and chilled. "hat 3as the only mildly unpleasant part. Ie had been hanging crystals
earlier that day, and the visions I had 3ere dominated by prismatic light patterns. It 3as almost as if I became the light. I sa3 kaleidoscopic forms L
similar to, but less intense than, 3hen on acid L and organic forms like Ceorgia 97eefe flo3ers, blossoming and undulating. ?y body 3as flooded 3ith
orgasms L practically from Gust breathing. "he lovemaking 3as phenomenal, passionate, ecstatic, lyric, animal, loving, tender, sublime. "he music 3as
voluptuous, almost three@dimensional. Sometimes the sound seemed distorted to me, under3ater like. "his 3as especially so for the less good
recordings L but I could choose to concentrate on the beauty of the music or the inadeFuacy of the sound7s Fuality, and mostly chose to concentrate on
the beauty.
'3ith $+ mg- I am totally into my body. I am a3are of every muscle and nerve in my body. "he night is e/traordinary L moon full. 4nbelievably erotic,
Fuiet and e/Fuisite, almost unbearable. I cannot begin to unravel the imagery that imposes itself during the finding of an orgasm. "rying to understand
physical8spiritual merging in nature L .
<="<5SI95S A5; C9??<5"A:>E Bour Fuotations 3ere chosen arbitrarily from literally hundreds that have 3orked their 3ays into the files. "he vast
maGority are positive, ranging from the colorful to the ecstatic. .ut not all are. "here are people 3ho choose not to go into the corporeal but, rather,
prefer the out@of@body e/perience. "hey e/press discomfort 3ith $C@., and seem to lean more to the etamine form of altered state, one 3hich
dissociates body from mind.
"here have been reports of several overdoses that prove the intrinsic safety of this compound. Prove is used here in the classic .ritish sense; i.e., to
challenge. N"he proof of the pudding is in the eating,N is not a verification of Fuality, but an inFuiry into the Fuality itself. '"he Brench simplify all this by
using t3o separate verbs for prove.- 9ne overdose 3as intentional, the other accidental.
'3ith 1+ mg- I found only mild visual and emotional effects at the $, milligram dose, so I took the remaining ++ milligrams. I 3as propelled into
something not of my choosing. <verything that 3as alive 3as completely fearsome. I could look at a picture of a bush, and it 3as Gust that, a picture,
and it posed no threat to me. "hen my ga6e moved to the right, and caught a bush gro3ing outside the 3indo3, and I 3as petrified. A life@form I could
not understand, and thus could not control. And I felt that my o3n life@form 3as not a bit more controllable. "his 3as from the comments of a physician
3ho assured me that he sa3 no neurological concerns during this dramatic and frightening e/perience.
'3ith (,, mg- I had 3eighed correctly. I had simply picked up the 3rong vial. And my death 3as to be a conseFuence of a totally stupid mistake. I
3anted to 3alk outside, but there 3as a s3imming pool there and I didn7t dare fall into it. A person may believe that he has prepared himself for his o3n
death, but 3hen the moment comes, he is completely alone, and totally unprepared. Ihy no3H Ihy meH "3o hours later, I kne3 that I 3ould live after
all, and the e/perience became really marvelous. .ut the moment of facing death is a uniFue e/perience. In my case, I 3ill some day meet it again,
and I fear that I 3ill be no more comfortable 3ith it then than I 3as Gust no3. "his 3as from the comments of a psychologist 3ho 3ill, 3ithout doubt, use
psychedelics again in the future, as a probe into the unkno3n.
?any of the reports that have come in over the years have mentioned the combination of ?;?A and $C@.. "he most successful reports have follo3ed
a program in 3hich the t3o drugs are not used at the same time, nor even too closely spaced. It appears that the optimum time for the $C@. is at, or Gust
before, the final baseline recovery of the ?;?A. It is as if the mental and emotional discoveries can be mobili6ed, and something done about them.
"his combination has several enthusiastic advocates in the psychotherapy 3orld, and should be the basis of careful research 3hen these materials
become legal, and accepted by the medical community.
A generali6ed spectrum of $C@. action can be gleaned from the many reports that have been 3ritten describing its effects. '(- "here is a steep dose
response curve. 9ver the ($ to $+ milligram range, every $ milligrams can make a profound increase or change of response. Initially, one should go
lightly, and increase the dosage in subseFuent trials by small increments. A commonly used term for a level that produces a Gust perceptible effect is
Nmuseum level.N "his is a slightly@over@threshold level 3hich allo3s public activities 'such as vie3ing paintings in a museum or scenery 3atching as a
passenger in a car- to be entered into 3ithout attracting attention. "here can be considerable discomfort associated 3ith being in the public eye, 3ith
higher doses. '$- "he $C@. e/perience is one of the shortest of any maGor psychedelic drug. Iherever you might be, hang on. In an hour or so you 3ill
be approaching familiar territory again. '0- If there is anything ever found to be an effective aphrodisiac, it 3ill probably be patterned after $C@. in
structure.
"here are t3o N"3eetiosN kno3n that are related to $C@.. 'See recipe R$0 for the origin of this phrase.- "he $@<t9@ homologue of $C@. is +@bromo@$@
etho/y@&@metho/yphenethylamine, or $C.@$<"9. "he unbrominated ben6aldehyde '$@etho/y@&@metho/yben6aldehyde- had a melting point of +2.&@+).&
deg C, the unbrominated nitrostyrene intermediate a melting point of 21@22 deg C, and the final hydrochloride a melting point of ()&@()1 deg C. "he
hydrobromide salt had a melting point of (1).&@(1%.& deg C. It seems that one gets about as much effect as can be had, 3ith a dosage of about (&
milligrams, and increases above this, to 0, and to &, milligrams merely prolong the activity 'from about 0 hours to perhaps 1 hours-. At no dose 3as
there an intensity that in any 3ay resembled that of $C@..
"he $,&@;i<t9@ homologue of $C@. is +@bromo@$,&@dietho/yphenethylamine, or $C.@$,&@;I<"9. "he unbrominated impure ben6aldehyde '$,&@
dietho/yben6aldehyde- had a melting point of about &2 deg C, the unbrominated impure nitrostyrene intermediate a melting point of about 1, deg C, and
the final hydrochloride a melting point of $0,@$0( deg C. "he hydrobromide salt had a melting point of (%$@(%0 deg C. At levels of && milligrams, there
3as only a restless sleep, and strange dreams. "he active level is not yet kno3n.
I have been told of some studies that have involved a positional rearrangement analogue of $C@.. "his is $@bromo@+,&@dimetho/yphenethylamine 'or 1@
.:@;?P<A-. "his 3ould be the product of the elemental bromination of ;?P<A, and it has been assayed as the hydrobromide salt. Apparently, the
intravenous inGection of 1, milligrams gave a rapid rush, 3ith intense visual effects reported, largely yello3 and black. 9rally, there may be some activity
at the +,, to &,, milligram area, but the reports described mainly sleep disturbance. "his 3ould suggest a stimulant component. "he 5@methyl
homologue of this rearranged compound 3as even less active.
#$1 '!-.6; (-.E#6Y%+Y-',)-0"METH%+YAM,HETAM"#E
S>5"H<SISE A solution of $1) g $,1@dimetho/yphenol and $($ g allyl bromide in 2,, m! dry acetone 3as treated 3ith 0(& g anhydrous $C90 and
held at reflu/ for (1 h. "he solvent 3as removed under vacuum, and the residue dissolved in H$9 and e/tracted 3ith 0/(,, m! CH$Cl$. "he pooled
e/tracts 3ere 3ashed 3ith &K 5a9H, then 3ith H$9, and the solvent removed under vacuum. "he residue, 3hich 3eighed $+& g, 3as stirred and
heated in an oil bath to $0, deg C at 3hich point an e/othermic reaction set in. "he heating 3as maintained at $0, deg C for ,.& h, and then the
reaction mi/ture distilled. "here 3as obtained a total of ($2 g of &@allyl@(,0@dimetho/y@$@hydro/yben6ene as a colorless distillate, that 3as identical in all
respects to natural &@metho/yeugenol obtained from 9il of 5utmeg.
A solution containing +,.+ g &@metho/yeugenol and $1.1 g ben6yl chloride in 1& m! <t9H 3as added, all at once, to a hot and 3ell stirred solution of
((.2 g 9H in &,, m! <t9H. "he potassium salt of the phenol crystalli6ed out immediately. .y maintaining reflu/ conditions, this slo3ly redissolved,
and 3as replaced by the steady deposition of Cl. After 1 h, the reaction mi/ture 3as cooled, and the solids removed by filtration. "he filtrate 3as
stripped of solvent under vacuum to give &2 g of crude &@allyl@$@ben6ylo/y@(,0@dimetho/yben6ene. "his 3as dissolved in a solution of 1, g 9H in ),
m! <t9H and heated on the steam bath for (1 h. "he reaction mi/ture 3as Fuenched in &,, m! H$9, and e/tracted 3ith $/$,, m! CH$Cl$. :emoval
of the solvent under vacuum gave 0&.1 g of crude $@ben6ylo/y@(,0@dimetho/y@&@propenylben6ene.
"o a stirred, ice@cold solution of 00.1 g of the above impure $@ben6ylo/y@(,0@dimetho/y@&@propenylben6ene and (0.1 g pyridine in (+$ m! acetone, there
3as added $+.1 g tetranitromethane. After stirring for 0 min, there 3as added a solution of 2.% g 9H in (0$ m! H$9, follo3ed by additional H$9. "he
oily phase that remained 3as H$9 3ashed, and then diluted 3ith an eFual volume of ?e9H. "his slo3ly set up to yello3 crystals, 3hich 3ere removed
by filtration and 3ashed sparingly 3ith ?e9H. "here 3as obtained %.$ g (@'+@ben6ylo/y@0,&@dimetho/yphenyl-@$@nitropropene 3ith a mp of )+@)& deg C.
An analytical sample, from <t9H, had a mp of )1@)2 deg C.
"o a reflu/ing suspension of &.& g !AH in 01, m! anhydrous <t$9 under an inert atmosphere, there 3as added ).1 g (@'+@ben6ylo/y@0,&@
dimetho/yphenyl-@$@nitropropene by letting the condensing <t$9 leach out a saturated solution from a modified So/hlet condenser. "he addition took
(.& h and the reflu/ing 3as maintained for an additional + h. After cooling, the e/cess hydride 3as destroyed by the cautious addition of 00, m! of (.& 5
H$S9+. "he aFueous phase 3as heated up to ), deg C, filtered through paper to remove a small amount of insoluble material, and treated 3ith a
solution of ) g picric acid in (&, m! boiling <t9H. Cooling in the ice chest overnight gave globs of the amine picrate, but no clear signs of crystalli6ation.
"hese 3ere 3ashed 3ith cold H$9, then dissolved in &K 5a9H to give a bright yello3 solution. "his 3as e/tracted 3ith 0/(&, m! CH$Cl$, the solvent
removed under vacuum, the residue dissolved in 0,, m! anhydrous <t$9, freed from a little particulate material by filtration through paper, and then
saturated 3ith hydrogen chloride gas. "here 3as thus obtained, after filtering, <t$9 3ashing and air drying, $.& g +@ben6ylo/y@0,&@
dimetho/yamphetamine hydrochloride '0C@.A- as a 3hite solid 3ith a mp of (1(@(1+ deg C.
;9SAC<E $& @ $,, mg.
;4:A"I95E () @ $+ h.
L4A5"I"A"IM< C9??<5"SE '3ith $& mg- I 3ent into an emotionally brittle place, and for a 3hile I 3as uncomfortable 3ith childhood reminiscences.
"he seeing of my family7s Christmas tree in my mind 3as almost too much. I cried.
'3ith &, mg- "he action is distinct L 3akeful L alerting and 3ound up. Hypnogogic imagery, and I could not sleep at night 3ith my mind doing many
uncontrolled, tangential, busy things. I had fleeting nausea early in the process.
'3ith (,, mg- I took this in t3o portions. Bollo3ing &, milligrams I 3as a3are of a slight light@headedness at a half@hour, but there 3as little else. At (
(8$ hours, I took the second &, milligrams and the augmentation of effects 3as noted in another half hour. "he e/perience Fuietly built up to about the
fifth hour, 3ith some erotic fantasy and suggestions of changes in the visual field. I could not sleep until the t3elfth hour, and my dreams 3ere 3ild and
not too friendly. "here 3as no body threat from this, but I 3as not completely baseline until the ne/t day. I am not too keen to do this again L it lasts too
long.
'3ith (,, mg- 5o effects.
'3ith (&, mg- "his is in every 3ay identical to (,, micrograms of !S;.
'3ith (), mg- I can compare this directly to "?A 3hich 3as the material I took last 3eek. ?any similarities, but this is unFuestionably more intense than
the "?A 3as at $,, milligrams. It is hard to separate the degree of impact that this drug has, from the simple fact that it lasts forever, and I 3as getting
physically tired but I couldn7t sleep. "here is some amphetamine@like component, more than 3ith "?A.
<="<5SI95S A5; C9??<5"A:>E "3o points are 3orthy of commentary; the potency and the promise of 0C@.A.
As to potency, there is such uncertainty as to the effective dose, that it is for all intents and purposes impossible to predict Gust 3hat dose should be
considered for a person7s first time 3ith this. "he choice of Fuotations 3as made 3ith the intention of giving a picture of this scatter. A total of ten
subGects have e/plored this compound, and the very broad range given above, $& to $,, milligrams, reflects the degree of variation that has been
encountered.
Ihich is a shame, because the concept of a ne3 ring such as is found here on the +@position 3ould have allo3ed an e/tremely 3ide array of
substituents. <lectron@rich things, electron@poor things, heavy things, light things, and on and on. "his could have been a location of much variation, but
it is a possibility that the uncertainties of dosage might e/trapolate to these novel ring substitutions as 3ell. 9nly a single variation 3as made, the +@
fluoroben6yl analogue. "his 3as prepared follo3ing e/actly the procedure given here for 0C@.A, e/cept for the replacement of ben6yl chloride 3ith +@
fluoroben6yl chloride. "he allyl intermediate 3as an oil, but the propenyl isomer gave solids 3ith a melting point of &%@1, deg C from he/ane. "he
nitrostyrene 3as a yello3 crystalline solid from methanol 3ith a melting point of %)@%% deg C. "he end product, 0,&@dimetho/y@+@'+@
fluoroben6ylo/y-amphetamine hydrochloride '0C@B.A- 3as a 3hite solid 3ith a melting point of (+%@(&, deg C. It has been assayed only up to +
milligrams and there 3as absolutely no activity of any kind observed at that level.
#$$ $!-!; $,)-0"METH%+Y-(-!H%*%,HE#ETHYAM"#E
S>5"H<SISE 'from $C@H- "he free base of $,&@dimetho/yphenethylamine 3as generated from its salt 'see recipe for $C@H for the preparation of this
compound- by treating a solution of (1.$ g of the hydrochloride salt in 0,, m! H$9 3ith aFueous 5a9H, e/traction 3ith 0/2& m! CH$Cl$, and removal
of the solvent from the pooled e/tracts under vacuum. "he colorless residue 3as dissolved in 2& m! glacial acetic acid 'the solids that initially formed
redissolved completely- and this 3as cooled to , deg C 3ith an e/ternal ice bath. Iith vigorous stirring, there 3as added +., m! of liFuid chlorine, a
little bit at a time 3ith a Pasteur pipette. "he theoretical volume 3as 0.+ m!, but some 3as lost in pipetting, some on contact 3ith the , deg C acetic
acid, and some 3as lost by chlorination of the acetic acid. "he reaction turned a dark amber color, 3as allo3ed to stir for an additional (, min, then
Fuenched 3ith +,, m! H$9. "his 3as 3ashed 3ith 0/(,, m! CH$Cl$ '3hich removed some of the color- then brought to neutrality 3ith dilute aFueous
5a9H and treated 3ith a small amount of sodium dithionite 3hich discharged most of the color 'from deep bro3n to pale yello3-. "he reaction 3as
made strongly basic 3ith aFueous 9H, and e/tracted 3ith 0/2& m! CH$Cl$. "he pooled e/tracts 3ere 3ashed once 3ith H$9 and the solvent 3as
removed under vacuum leaving about (, m! of a deep amber oil as residue. "his 3as dissolved in 2& m! IPA and neutrali6ed 3ith concentrated HCl
3hich allo3ed spontaneous crystalli6ation. "hese crystals 3ere removed by filtration, 3ashed 3ith an additional $, m! IPA, and air@dried to constant
3eight. "here 3as thus obtained +.$ g $,&@dimetho/y@+@chlorophenethylamine hydrochloride '$C@C- 3ith a mp of $()@$$( deg C. :ecrystalli6ation from
IPA increased this to $$,@$$$ deg C. "he position of chlorination on the aromatic ring 3as verified by the presence of t3o para@protons in the 5?:, at
2.($ and 2.$, ppm from e/ternal "?S, in a ;$9 solution of the hydrochloride salt.
Synthesis from $C@.. "o a solution of 2.$+ g $,&@dimetho/y@+@bromophenethylamine '$C@.- and +.& g phthalic anhydride in (,, m! anhydrous ;?B
there 3as added molecular sieves. After (1 h reflu/, the reaction mi/ture 3as cooled and the sieves removed by filtration. "he addition of a little CH$Cl$
prompted the deposition of yello3 crystals 3hich 3ere recrystalli6ed from <t9H. "he resulting (@'$,&@dimetho/y@+@bromophenyl-@$@'phthalimido-ethane
3eighed 2.&2 g and had a mp of (+(@(+$ deg C. Anal. 'C()H(1.r59+- C,H,5,.r.
A solution of (+.%+ g of (@'$,&@dimetho/y@+@bromophenyl-@$@'phthalimido-ethane and +.& g cuprous chloride in 0,, m! anhydrous ;?B 3as heated for &
h at reflu/. "he cooled mi/ture 3as poured into $, m! H$9 that contained (0 g hydrated ferric chloride and 0 m! concentrated HCl. "he mi/ture 3as
maintained at about 2, deg C for $, min, and then e/tracted 3ith CH$Cl$. After 3ashing the pooled organic e/tracts 3ith dilute HCl and drying 3ith
anhydrous ?gS9+, the volatiles 3ere removed under vacuum to provide a solid residue. "his 3as recrystalli6ed from <t9H to provide ($.() g of (@'$,&@
dimetho/y@+@chlorophenyl-@$@'phthalimido-ethane as yello3 needles that had a mp of (0)@(+, deg C. Anal. 'C()H(1Cl59+- C,H,5,Cl.
"o 1, m! absolute <t9H there 3as added ($.$ g (@'$,&@dimetho/y@+@chlorophenyl-@$@'phthalimido-ethane and $.% m! of (,,K hydra6ine. "he solution
3as held at reflu/ for (& min. After cooling, the cyclic hydra6one by@product 3as removed by filtration, and the alcoholic mother liFuors taken to dryness
under vacuum. "he residue 3as distilled at (+&@(&& deg C at ,.,& mm8Hg to give &.(1 g of a clear, colorless oil. "his 3as dissolved in anhydrous <t$9
and treated 3ith hydrogen chloride gas, producing $,&@dimetho/y@+@chlorophenethylamine hydrochloride '$C@C- as 3hite crystals 3ith a mp of $$,@$$(
deg C. Anal. 'C(,H(&Cl$59$- C,H,5.
;9SAC<E $, @ +, mg.
;4:A"I95E + @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- "his is longer lived than $C@., and there is a longer latency in coming on. It took an hour and a half, or even
t3o hours to get there. It had a slight metallic overtone.
'3ith $+ mg- I 3as at a moderately high and thoroughly favorable place, for several hours. It seemed to be a very sensual place, but 3ithout too much in
the 3ay of visual distraction.
'3ith +, mg- "here 3ere a lot of visuals L something that I had noted at lo3er levels. "here seems to be less stimulation than 3ith $C@., and in some
3ays it is actually sedating. And yet I 3as up all night. It 3as like a very intense form of rela/ation.
<="<5SI95S A5; C9??<5"A:>E 9ther reports mention usage of up to &, milligrams 3hich seems to increase yet further the intensity and the
duration. I have one report of an intravenous administration of $, milligrams, and the response 3as described as over3helming. "he effects peaked at
about & minutes and lasted for perhaps (& minutes.
"he halogens represent a small group of atoms that are uniFue for a couple of reasons. "hey are all located in a single column of the periodic table,
being monovalent and negative. "hat means that they can be reasonably stable things 3hen attached to an aromatic nucleus. .ut, being monovalent,
they cannot be modified or e/tended in any 3ay. "hus, they are kind of a dead end, at least as far as the $C@= series is considered. "he heaviest,
iodine, 3as e/plored as the phen@ethylamine, as $C@I, and as the amphetamine as ;9I. "hese are the most potent. "he ne/t lighter is bromine, 3here
the phenethylamine is $C@. and the amphetamine is ;9.. "hese t3o are a bit less potent, and are by far the most broadly e/plored of all the halides.
Here, in the above recipe, 3e have the chlorine counterpart, $C@C. "here is also the corresponding amphetamine ;9C. "hese are less potent still, and
much less e/plored. IhyH Perhaps because chlorine is a gas and troublesome to handle 'bromine is a liFuid, and iodine is a solid-. "he fluorine
analogue is yet harder to make, and reFuires procedures that are indirect, because fluorine 'the lightest of all the halides- is not only a gas, but is
dangerous to handle and does not react in the usual halogen 3ay. "here 3ill be mention made of $C@B, but ;9B is still une/plored.
"he treatment of the $C@. phthalimide described above, 3ith cuprous cyanide rather than cuprous chloride, gave rise to the cyano analog 3hich, on
hydrolysis 3ith hydra6ine, yielded $,&@dimetho/y@+@cyanophenethylamine '$C@C5-. Hydrolysis of this 3ith hot, strong base gave the corresponding acid,
$,&@dimetho/y@+@carbo/yphenethylamine, $C@C99H. 5o evaluation of either of these compounds has been made in the human animal, as far as I
kno3.
#$' $!-0; E-$); $,)-0"METH%+Y-(-METHY,HE#ETHYAM"#E
S>5"H<SISE Into ( ! H$9 that 3as being stirred magnetically, there 3as added, in seFuence, 1$ g toluhydroFuinone, (1, m! $&K 5a9H, and ($1 g
dimethyl sulfate. After about $ h, the reaction mi/ture 3as no longer basic, and another +, m! of the $&K 5a9H 3as added. <ven 3ith stirring for a fe3
additional days, the reaction mi/ture remained basic. It 3as Fuenched in $.& ! H$9, e/tracted 3ith 0/(,, m! CH$Cl$ and the pooled e/tracts stripped
of solvent under vacuum. "he remaining &1.+ g of amber oil 3as distilled at about 2, deg C at ,.& mm8Hg to yield +%., g of $,&@dimetho/ytoluene as a
3hite liFuid. "he aFueous residues, on acidification, provided a phenolic fraction that distilled at 2&@(,, deg C at ,.+ mm8Hg to give &.) g of a pale
yello3 distillate that partially crystalli6ed. "hese solids '3ith mp of &+@1$ deg C- 3ere removed by filtration, and yielded 0.( g of a solid 3hich 3as
recrystalli6ed from &, m! he/ane containing & m! toluene. "his gave $.&0 g of a 3hite crystalline product 3ith a mp of 11@1) deg C. A second
recrystalli6ation 'from he/ane- raised this mp to 2(@2$ deg C. "he literature value given for the mp of $@methyl@+@metho/yphenol is 2,@2( deg C. "he
literature value given for the mp of the isomeric 0@methyl@+@metho/yphenol is ++@+1 deg C. "his phenol, on ethylation, gives $@etho/y@&@metho/ytoluene,
3hich leads directly to the $@carbon $C;@&<"9 'one of the "3eetios- and the 0@carbon Classic !ady I:IS.
A mi/ture of 0+.& g P9Cl0 and 0(.( g 5@methylformanilide 3as heated for (, min on the steam bath, and then there 3as added 0,.+ g of $,&@
dimetho/ytoluene. Heating 3as continued for $.& h, and the viscous, black, ugly mess 3as poured into 1,, m! of 3arm H$9 and stirred overnight. "he
resulting rubbery miniature@rabbit@droppings product 3as removed by filtration and sucked as free of H$9 as possible. "he 02.$ g of 3et product 3as
e/tracted on the steam@bath 3ith +/(,, m! portions of boiling he/ane 3hich, after decantation and cooling, yielded a total of (&.0 g of yello3 crystalline
product. "his, upon recrystalli6ation from (&, m! boiling he/ane, gave pale yello3 crystals 3hich, 3hen air dried to constant 3eight, represented ).2 g of
$,&@dimetho/y@+@methylben6aldehyde, and had a mp of )0@)+ deg C. Anal. 'C)H($90- C,H,5. "he Cattermann aldehyde synthesis gave a better yield
'1,K of theory- but reFuired the use of hydrogen cyanide gas. "he malononitrile derivative, from &.2 g of the aldehyde and $.0 g malononitrile in
absolute <t9H, treated 3ith a drop of triethylamine, 3as an orange crystalline product. A sample recrystalli6ed from <t9H gave a mp of (0).&@(0% deg
C.
A solution of ).1& g $,&@dimetho/y@+@methylben6aldehyde in 0, g nitromethane 3as treated 3ith (.( g anhydrous ammonium acetate and heated for &,
min on the steam bath. Stripping off the e/cess nitromethane under vacuum yielded orange crystals 3hich 3eighed ($.$ g. "hese 3ere recrystalli6ed
from (,, m! IPA providing yello3 crystals of $,&@dimetho/y@+@methyl@beta@nitrostyrene 3hich 3eighed, 3hen dry, 2.2, g. "he mp 3as ((2@(() deg C,
and this 3as increased to (()@((% deg C upon recrystalli6ation from ben6ene8heptane (E$.
"o a 3ell stirred suspension of 2., g !AH in 0,, m! of 3arm "HB under an inert atmosphere, there 3as added 2.2 g $,&@dimetho/y@+@methyl@beta@
nitrostyrene in 0& m! "HB over the course of ,.& h. "his reaction mi/ture 3as held at reflu/ for $+ h, cooled to room temperature, and the e/cess
hydride destroyed 3ith $& m! IPA. "here 3as then added 2 m! (&K 5a9H, follo3ed by $( m! H$9. "he granular gray mass 3as filtered, and the filter
cake 3ashed 3ith $/&, m! "HB. "he combined filtrate and 3ashes 3ere stripped of their volatiles under vacuum to give a residue 3eighing 2.2 g 3hich
3as distilled at %,@((& deg C at ,.0 mm8Hg to provide +.%, g of a clear, 3hite oil, 3hich crystalli6ed in the receiver. "his 3as dissolved in $& m! IPA, and
neutrali6ed 3ith concentrated HCl 3hich produced immediate crystals of the salt. "hese 3ere dispersed 3ith ), m! anhydrous <t$9, filtered, and
3ashed 3ith <t$9 to give, after air drying to constant 3eight, +.% g of fluffy 3hite crystals of $,&@dimetho/y@+@methylphenethylamine hydrochloride '$C@
;-. "he mp 3as $(0@$(+ deg C 3hich 3as not improved by recrystalli6ation from CH0C58IPA mi/ture, or from <t9H. "he hydrobromide salt had a mp
of ()0@()+ deg C. "he acetamide, from the free base in pyridine treated 3ith acetic anhydride, 3as a 3hite crystalline solid 3hich, 3hen recrystalli6ed
from aFueous ?e9H, had a mp of ((1@((2 deg C.
;9SAC<E $, @ 1, mg.
;4:A"I95E + @ 1 h.
L4A!I"A"IM< C9??<5"SE '3ith (, mg- "here is something going on, but it is subtle. I find that I can Gust slightly redirect my attention so that it applies
more e/actly to 3hat I am doing. I feel that I can learn faster. "his is a Ssmart7 pillO
'3ith $, mg- .utterflies in stomach 3hole time. 9. "his is about the right level. In retrospect, not too interesting. Primarily a stimulant, not entirely
physically pleasant. "he visual is not too e/citing. I am easily distracted. 9ne line of thought to another. I feel that more 3ould be too stimulating.
'3ith 0, mg- I 3as into it Fuite Fuickly 'not much over three@Fuarters of an hour- and got up to a ** by the end of an hour. "here is something
unsatisfactory about trying to classify this level. I had said that I 3as 3illing to increase the dose to a higher level, to break out of this not@Fuite@defined
level into something psychedelic. .ut I may not 3ant to go higher. 4nder different circumstances I 3ould not mind trying it at a considerably lo3er
dosage, perhaps at the (, or (& milligrams. I do not have a comfortable label on this material, yet.
'3ith +& mg- "here 3as a rocket from the half@hour to the one and a half hour, from nothing up to a ***. Someho3 the intimacy and the erotic never
Fuite knit, and I feel that I am al3ays 3aiting for the e/perience to come home. "alking is e/tremely easy, but something is missing. Appetite is good. I
am do3n by the fifth hour, and sleep is comfortable. "his compound 3ill take some learning.
'3ith 2& mg- "his is a ***, but the emphasis is on talking, not on personal interacting. I am putting out, but my boundaries are intact. I 3as able to sleep
at the si/th hour. Communication 3as e/cellent. "his is fast on, but not too long lived. ?aybe a therapy toolH
'3ith (&, mg- A truly remarkable psychedelic, one 3hich could compare favorably 3ith $C@.. "here are intense colors, and I feel that more 3ould be too
much.
<="<5SI95S A5; C9??<5"A:>E Io3O "his particular compound is 3hat I call a pharmacological tofu. It doesn7t seem to do too much by itself,
al3ays teasing, until you get to heroic levels. .ut a goodly number of e/perimental therapists have said that it is e/cellent in e/tending the action of
some other materials. It seems to boost the 3aning action of another drug, 3ithout adding its o3n color to the e/perience. >et, the comment above, on
the high level of (&, milligrams, is a direct Fuote from the use of this compound in Cermany '3here it is called !<@$&- in therapeutic research.
"his is probably the most dramatic e/ample of the loss of potency from an amphetamine ';9?, active at maybe 0 milligrams- to a phenethylamine 'only
one tenth as active-. It is so often the case that the first of a series is not the most interesting nor the most potent member. As intriguing and as difficult@
to@define as the $C@; story might be, the ne/t higher homologue of this set, $C@<, is ma/imally active at the (& to $, milligram level, and is, 3ithout any
Fuestion, a complete psychedelic.
"he 5@monomethyl and the 5,5@dimethyl homologues of $C@; have been synthesi6ed from $C@;. "he 5@monomethyl compound 3as obtained by the
Fuaterni6ation of the Schiff7s base formed bet3een $C@; and ben6aldehyde 3ith methyl sulfate, follo3ed by hydrolysis; the hydrochloride salt had a
melting point of (&,@(&( deg C, from <t9H. "he 5,5@dimethyl compound resulted from the action of formaldehyde@formic acid on $C@;; the
hydrochloride salt had a melting point of (1)@(1% deg C from <t9H8ether. "hese t3o compounds 3ere some ten times less effective in interfering 3ith
conditioned responses in e/perimental rats. "here is no report of their having been e/plored in man.
I have learned of an e/tensive study of etho/y homologues of a number of the phenethylamines in the $C@= series; they have been collectively called
the N"3eetios.N "his Sylvester and "3eety@bird allusion came directly from the compulsive habit of trying to alleviate the boredom of driving long
distances 'not under the influence of anything- by the attempt to pronounce the license plates of cars as they passed. "he first of this series of
compounds had a name that indicated that there 3as an etho/y group at the $@position, or $@<t9, or "3eetio, and the rest is history. In every compound
to be found in the $C@= family, there are t3o metho/y groups, one at the $@position and one at the &@position. "here are thus three possible t3eetio
compounds, a $@<t9@, a &@<t9@ and a $,&@di@<t9@. "hose that have been evaluated in man are included after each of the $C@=7s that has served as the
prototype. In general, the $@<t9@ compounds have a shorter duration and a lo3er potency, the &@<t9@ compounds have a relatively unchanged potency
and a longer time duration; the $,&@di@<t9@ homologues are very 3eak, if active at all.
"he $@<t9@homologue of $C@; is $@etho/y@&@metho/y@+@methylphenethylamine, or $C;@$<"9. "he ben6aldehyde '$@etho/y@&@metho/y@+@tolualdehyde-
had a melting point of 1,.&@1( deg C, the nitrostyrene intermediate a melting point of ((,.&@(((.& deg C, and the final hydrochloride a melting point of
$,2@$,) deg C. "he hydrobromide salt had a melting point of (2(@(20 deg C. At levels of 1, milli@grams, there 3as the feeling of closeness bet3een
couples, 3ithout an appreciable state of into/ication. "he duration 3as about + hours.
"he &@<t9@ homologue of $C@; is &@etho/y@$@metho/y@+@methylphenethylamine, or $C;@&<"9. "he ben6aldehyde '&@etho/y@$@etho/y@+@tolualdehyde-
had a melting point of )(@)$ deg C, and the details of this synthesis are given in the recipe for I:IS. "he nitrostyrene intermediate had a melting point of
(($.&@((0.& deg C and the final hydrochloride salt had a melting point of (%2@(%) deg C. "he hydro@bromide salt had a melting point of (&)@(&% deg C.
At dosage levels of +, to &, milli@grams, there 3as a slo3, gradual climb to the full effects that 3ere noted in about $ hours. "he e/perience 3as largely
free from e/citement, but 3ith a friendly openness and outgoingness that allo3ed easy talk, interaction, humor, and a healthy appetite. "he duration of
effects 3as ($ hours.
"he $,&@di@<t9@ homologue of $C@; is $,&@dietho/y@+@methylphenethylamine, or $C;@$,&@;I<"9. "he ben6aldehyde '$,&@dietho/y@+@tolualdehyde- had
a melting point of (,$@(,0 deg C, the nitrostyrene intermediate a melting point of (,)@(,% deg C, and the final hydrochloride salt a melting point of $&(@
$&$ deg C. At a level of && milligrams, a plus one 3as reached, and 3hat effects there 3ere, 3ere gone after four hours.
#$( $!-E; $,)-0"METH%+Y-(-ETHY,HE#ETHYAM"#E
S>5"H<SISE A suspension of (+, g anhydrous AlCl0 in +,, m! CH$Cl$ 3as treated 3ith (,, g acetyl chloride. "his slurry 3as added to a vigorously
stirred solution of ((, g p@dimetho/yben6ene in 0,, m! CH$Cl$. Stirring 3as continued at ambient temperature for an additional +, min, then all 3as
poured into ( ! 3ater and the phases separated. "he aFueous phase 3as e/tracted 3ith $/(,, m! CH$Cl$ and the combined organic phases 3ashed
3ith 0/(&, m! &K 5a9H. "hese 3ashes, after combination and acidification, 3ere e/tracted 3ith 0/2& m! CH$Cl$ and the e/tracts 3ashed once 3ith
saturated 5aHC90. :e@moval of the solvent under vacuum provided $).0 g of $@hydro/y@&@metho/yaceto@phenone as yello3 crystals 3hich, on
recrystalli6ation from $ volumes of boiling ?e9H and air drying, provided $(.0 g of product 3ith a mp of +%@+%.& deg C. <thyl@ation of this material
serves as the starting point for the synthesis of $C<@&<"9. "he CH$Cl$ fraction from the base 3ash, above, 3as stripped of solvent on the rotary
evaporator to give a residual oil that, on distillation at (+2@(&, deg C at the 3ater pump, provided (((.1 g of $,&@dimetho/yacetophenone as an almost
3hite oil.
In a round bottom flask eFuipped 3ith a reflu/ condenser, a take@off adapter, an immersion thermometer, and a magnetic stirrer, there 3as placed (,, g
$,&@dimetho/yacetophenone, 2( g )&K 9H pellets, &,, m! of triethylene glycol, and ($& m! 1&K hydra6ine. "he mi/ture 3as brought up to a boil by
heating 3ith an electric mantle, and the distillate 3as removed, allo3ing the temperature of the pot contents to continuously increase. Ihen the pot
temperature had reached $(, deg C, reflu/ 3as established and maintained for an additional 0 h. After cooling, the reaction mi/ture and the distillate
3ere combined, poured into 0 ! 3ater, and e/tracted 3ith 0/(,, m! he/ane. After 3ashing the pooled e/tracts 3ith 3ater, the solvent 3as removed
yielding $$., g of a pale stra3@colored liFuid that 3as free of both hydro/y and carbonyl groups by infrared. "his 3as distilled at ($,@(+, deg C at the
3ater pump to give $,&@dimetho/y@(@ethylben6ene as a 3hite fluid product. Acidification of the spent aFueous phase 3ith concentrated HCl produced a
heavy black oil 3hich 3as e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent on the rotary evaporator yielded 2) g.of a black residue that 3as
distilled at %,@(,& deg C at ,.& mm8Hg to provide 12.+ g of an orange@amber oil that 3as largely $@ethyl@+@metho/yphenol. "his material could
eventually be used as a starting material for etho/y homologues. Ho3ever, remethylation '3ith CH0I and 9H in methanol- provided some $) g
additional $,&@dimetho/yethylben6ene.
A solution of ).(1 g of $,&@dimetho/y@(@ethylben6ene in 0, m! CH$Cl$ 3as cooled to , deg C 3ith good stirring and under an inert atmosphere of He.
"here 3as then added ((.2 m! anhydrous stannic chloride, follo3ed by 0.%& m! dichloromethyl methyl ether drop3ise over the course of ,.& h. "he
stirred reaction mi/ture 3as allo3ed to come up to room temperature, then held on the steam bath for ( h. "he reaction mi/ture 3as poured into ( !
3ater, e/tracted 3ith 0/2& m! CH$Cl$, and the pooled e/tracts 3ashed 3ith dilute HCl. "he organic phase 3as stripped under vacuum yielding (,.) g
of a dark viscous oil. "his 3as distilled at %,@((, deg C at ,.$ mm8Hg to yield a colorless oil that, on cooling, set to 3hite crystals. "he yield of $,&@
dimetho/y@+@ethylben6aldehyde 3as &.% g of material that had a mp of +1@+2 deg C. After purification through the bisulfite comple/, the mp increased to
+2@+) deg C. "he use of the Milsmeier aldehyde synthesis '3ith P9Cl0 and 5@methylformanilide- gave results that 3ere totally unpredictable. "he
malononitrile derivative 'from ,.0 g of this aldehyde and ,.0 g malononitrile in & m! <t9H and a drop of triethylamine- formed red crystals 3hich, on
recrystalli6ation from toluene, had a mp of ($0@($+ deg C.
A solution of $(., g of the unrecrystalli6ed $,&@dimetho/y@+@ethylben6aldehyde in 2& g nitromethane 3as treated 3ith + g of anhydrous ammonium
acetate and heated on the steam bath for about $ h. "he progress of the reaction 3as best follo3ed by "!C analysis of the crude reaction mi/ture on
silica gel plates 3ith CH$Cl$ as the developing solvent. "he e/cess solvent8reagent 3as removed under vacuum yielding granular orange solids that
3ere recrystalli6ed from seven volumes of boiling ?e9H. After cooling in e/ternal ice@3ater for ( h, the yello3 crystalline product 3as removed by
filtration, 3ashed 3ith cold ?e9H and air dried to give (0.+ g of $,&@dimetho/y@+@ethyl@beta@nitrostyrene. "he mp 3as %1@%) deg C 3hich improved to
%%@(,, deg C after a second recrystalli6ation from ?e9H.
A total of ($, m! of (., ? solution of !AH in "HB '($, m! of (., ?- 3as transferred to a 0 neck &,, m! flask, under an inert atmosphere 3ith good
magnetic stirring. "his solution 3as cooled to deg C 3ith an e/ternal ice@3ater bath, and there 3as then added 0., m! of (,,K H$S9+ over the course
of ,.& h. "his 3as follo3ed by a solution of &.)& g of $,&@dimetho/y@+@ethyl@beta@nitrostyrene, in +, m! of 3arm "HB. "he reaction mi/ture 3as stirred
for ,.& h, brought to room temperature, heated on the steam bath for ,.& h, and then returned to room temperature. "he addition of IPA drop3ise
destroyed the e/cess hydride, and some +.& m! of &K 5a9H produce a 3hite cottage cheese, in a basic organic medium. "his mi/ture 3as filtered,
3ashed 3ith "HB, and the filtrate evaporated to produce $.) g of an almost 3hite oil. "he filter cake 3as resuspended in "HB, made more basic 3ith
additional (& m! of &K 5a9H, again filtered, and the filtrate removed to provide an additional $.) g of crude product. "hese residues 3ere combined
and distilled at %,@(,, deg C at ,.$& mm8Hg to give a colorless oil. "his 3as dissolved in 0, m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith
&, m! anhydrous <t$9 to provide, after spontaneous crystalli6ation, filtration, 3ashing 3ith <t$9, and air drying, 0.)2 g of $,&@dimetho/y@+@
ethylphenethylamine hydrochloride '$C@<- as magnificent 3hite crystals. A similar yield can be obtained from the reduction of the nitrostyrene in a
suspension of !AH in "HB, 3ithout the use of H$S9+. Iith ((.0 g of !AH in 0,, m! dry "HB, there 3as added, drop3ise, a solution of (0.+ g of $,&@
dimetho/y@+@ethyl@beta@nitrostyrene in 2& m! "HB over the course of $ h. "he mi/ture 3as kept at reflu/ for an additional ) h, and killed by the careful
addition of (( m! H$9, follo3ed 3ith (( m! (&K 5a9H, and finally another 00 m! of H$9. "his mass 3as filtered, 3ashed 3ith "HB, and the combined
filtrates and 3ashes evaporated to a residue under vacuum "he appro/imately (& m! of residue 3as dissolved in 0,, m! CH$Cl$ and treated 3ith $,,
m! H$9 containing $, m! concentrated HCl. 9n shaking the mi/ture, there 3as deposited a mass of the hydrochloride salt 3hich 3as diluted 3ith a
Fuantity of additional H$9. "he organic phase 3as e/tracted 3ith additional dilute HC!, and these aFueous phases 3ere combined. After being made
basic 3ith $&K 5a9H, this phase 3as again e/tracted 3ith 0/2& m! CH$Cl$ and after the removal of the solvent, yielded ($.1 g of a colorless oil. "his
3as dissolved in 2& m! of IPA and neutrali6ed 3ith concentrated HCl. "he solidified mass that formed 3as loosened 3ith another &, m! IPA, and then
filtered. After <t$9 3ashing and air drying there 3as obtained 2.2 g of $,&@dimetho/y@+@ethylphenethylamine hydrochloride '$C@<- as lustrous 3hite
crystals. Anal. 'C($H$,Cl59$- C,H.
;9SAC<E (, @ $& mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith (1 mg- "here 3as a strange devil@angel pairing. As I 3as being told of the ecstatic 3hite@light ascent of my partner
into the Cod@space of an out@of@body e/perience, I 3as fighting my 3ay out of a bro3n oo6e. She sa3 the young Desus at the bottom of a ladder drifting
up3ards step by step to some taking@off place, and I sa3 all the funny gargoyles around the base of the ladder surrounded by picnic bunting. Bor me it
3as the +th of Duly, rather than <asterOS
'3ith $, mg- "he vie3 out of the 3indo3 3as unreal. "he garden 3as painted on the 3indo3, and every petal of flo3er and tuft of grass and leaf of tree
3as carefully sculptured in fine strokes of oil paint on the surface of the glass. It 3as not out there; it 3as right here in front of me. "he 3oman 3ho 3as
3atering the plants 3as completely fro6en, immobili6ed by Mermeer. And 3hen I looked again, she 3as in a different place, but again fro6en. I 3as
destined to become the eternal museum vie3er.
'3ith $& mg- I have a picture in my living room that is a styli6ed Cerman scene 3ith a man on horseback riding through the 3oods, and a young girl
coming out to meet him from the nearby trees. .ut she 3as not Gust 7coming out.7 He 3as not Gust riding through the 3oods. "he 3ind 3as blo3ing, and
his horse 3as at full gallop, and his cape 3as flapping in the storm, and she 3as bearing do3n upon him at full bore. "he action never ceased. I
became e/hausted.
'3ith $& mg- Iithin minutes I 3as an/ious and s3eaty. <ach person has his o3n brand of to/ic psychosis L mine al3ays starts 3ith the voices in my
head talking to me, about all my 3orst fears, a Gumble of 3arnings and deep fears spinning faster. "3enty minutes later this comple/ chaos passed as
Fuickly as it had come. At lo3er dosages $C@< has been a truly enGoyable esthetic enhancer. .ut it really has a steep dose8response curve.
<="<5SI95S A5; C9??<5"A:>E Here is another of the magical half@do6en. "he range is purposefully broad. At (, milligrams there have been
some pretty rich *** e/periences, and yet I have had the report from one young lady of a 0, milligram trial that 3as very frightening. ?y first e/perience
3ith $C@< 3as really profound, and it is the substance of a chapter 3ithin the story. "he amphet@amine homologue is ;9<", 3hich is not only much
longer in action, but considerably more potent. Several people have said, about $C@<, NI don7t think I like it, since it isn7t that much fun. .ut I intend to
e/plore it again.N "here is something here that 3ill re3ard the e/perimenter. Someday, the full character of $C@< 3ill be understood, but for the moment,
let it rest as being a difficult and 3orth@3hile material. A very much 3orth@3hile material. 9ne "3eetio of $C@< is kno3n. "he &@<t9@homologue of $C@<
is &@etho/y@+@ethyl@$@metho/yphenethylamine, or $C<@&<"9. "he nitrostyrene intermediate had a melting point of ((,@((,.& deg C, and the final
hydrochloride a melting point of ()+@()& deg C. "he effective level of $C<@&<"9 is in the (, to (& milligram range. It is gentle, forgiving, and e/tremely
long lived. Some 0 to + hours 3ere needed to achieve plateau, and on occasion e/peri@ments 3ere interrupted 3ith Malium or Halcion at the (1 hour
point. After a night7s sleep, there 3ere still some effects evident the ne/t day. "hus, the dose is comparable to the parent compound $C@<, but the
duration is $ to 0 times longer. It 3as given the nickname N<ternityN by one subGect.
#$) '!-E; ',)-0"METH%+Y-(-ETH%+YAM,HETAM"#E
S>5"H<SISE A solution of 0.1 g syringaldehyde '0,&@dimetho/y@+@ hydro/yben6aldehyde- in &, m! ?e9H 3as combined 3ith a solution of 0.2 g )&K
9H in 2& m! 3arm ?e9H. "his clear solution suddenly set up to crystals of the potassium salt, too thick to stir satisfactorily. "o this suspension there
3as added 2.+ g ethyl iodide 'a large e/cess- and the mi/ture 3as held at reflu/ temperature 3ith a heating mantle. "he solids eventually loosened and
redissolved, giving a clear amber@colored smooth@boiling solution. :eflu/ing 3as maintained for $ days, then all volatiles 3ere removed under vacuum.
"he residue 3as dissolved in +,, m! H$9, made strongly basic 3ith $&K 5a9H, and e/tracted 3ith +/(,, m! CH$Cl$. "he pooled e/tracts 3ere
3ashed 3ith saturated brine, and the solvent removed under vacuum to give 0.0 g of a pale amber oil 3hich set up as crystals of 0,&@dimetho/y@+@
etho/yben6aldehyde 3ith a mp of +2@+) deg C. A small sample recrystalli6ed from methanol had a mp of +)@+% deg C.
A solution of 0.0 g 0,&@dimetho/y@+@etho/yben6aldehyde in $& m! nitroethane 3as treated 3ith ,.& g anhydrous ammonium acetate and heated on the
steam bath for 01 h. "he solvent8reagent 3as removed under vacuum giving a thick yello3@orange oil that 3as dissolved in t3o volumes hot ?e9H. As
this cooled, crystals appeared spontaneously, and after cooling in ice for a short time, these 3ere removed by filtration and 3ashed sparingly 3ith cold
?e9H, Air drying to constant 3eight provided $.$ g (@'0,&@dimetho/y@+@etho/yphenyl-@$@nitropropene 3ith a mp of )+@)& deg C. "he mother liFuors, on
standing overnight, deposited large chunks of crystalline material 3hich 3as isolated by decantation, ground up under a small amount of methanol, then
recrystalli6ed from 1,K <t9H. A second crop of ,.2 g of the nitrostyrene 3as thus obtained, as canary@yello3 crystals 3ith a mp of )0@)& deg C.
A solution of $.2 g (@'0,&@dimetho/y@+@etho/yphenyl-@$@nitropropene in $, m! anhydrous "HB 3as added to a suspension of $., g !AH in (&, m! 3arm
"HB. "he mi/ture 3as held at reflu/ for +) h. After stirring at room temperature for another +) h, the e/cess hydride 3as destroyed by the addition of
$., m! H$9 in (, m! "HB, follo3ed by $., m! (&K 5a9H and then an additional 1., m! H$9. "he inorganic salts 3ere removed by filtration, and the
filter cake 3ashed 3ith "HB. "he combined mother liFuor and 3ashings 3ere stripped of solvent under vacuum leaving a yello3 oil 3ith some inorganic
salts still in it. "his 3as dissolved in 0,, m! CH$Cl$, 3ashed 3ith dilute 5a9H, and e/tracted 3ith 0/(&, m! ( 5 HCl. "he pooled e/tracts 3ere
3ashed once 3ith CH$Cl$ made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. "he combined organics 3ere 3ashed 3ith saturated
brine, and the solvent removed under vacuum to yield about $ m! of a colorless oil. "his 3as dissolved in (, m! IPA, neutrali6ed 3ith concentrated HCl
'(, drops 3ere reFuired-, and diluted 3ith ($& m! anhydrous <t$9. "he slight cloudiness gradually became the formation of fine 3hite crystals. After
standing at room temperature for $ h, these 3ere removed, <t$9 3ashed, and air dried. "here 3as thus obtained (.% g of 0,&@dimetho/y@+@
etho/yamphetamine hydrochloride '0C@<- as brilliant 3hite crystals.
;9SAC<E 0, @ 1, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith +, mg- It developed into a strange and indefinable something. It is un3orldly. I am very much in control, but 3ith an
undertone of unreality that is a little reminiscent of high doses of !S;. If there 3ere a great deal of sensory input, I might not see it. And if I 3ere in
complete sensory Fuiet I 3ould miss it, too. .ut Gust 3here I am, I can see it. <erie state of a3areness. And by the )th hour I am sober, 3ith no residue
e/cept for some slight teeth clenching, and pretty much disbelieving the 3hole thing.
'3ith 1, mg- Misuals very strong, insistent. .ody discomfort remained very heavy for first hour. Sense of implacable imposition of something to/ic for a
3hile. I felt at the mercy of uncomfortable physical effects L faint or pre@nausea, heavy feeling of tremor 'although tremor actually relatively light- and
general dis@ease, un@ease, non@ease. ept lying do3n so as to be as comfortable as possible. Bantasy began to be Fuite strong. At first, no eyes
closed images, and certainly anti@erotic. $nd hour on, bright colors, distinct shapes L Ge3el@like L 3ith eyes closed. Suddenly it became clearly not anti@
erotic. "hat 3as the end of my bad place, and I shot immediately up to a ***. Comple/ fantasy 3hich takes over L hard to kno3 3hat is real, 3hat is
fantasy. Continual erotic. Image of glass@3alled apartment building in mid@desert. </Fuisite sensitivity. ;o3n by H midnight. 5e/t morning, faint
flickering lights on looking out 3indo3s.
<="<5SI95S A5; C9??<5"A:>E "his is an interesting closing of the circle. Although mescaline launched the entire sho3, the first half could be
called the amphetamine period, 3ith variations made on all aspects of the molecule e/cept for that three@carbon chain. And it 3as found that the +@
substitution position 3as of paramount importance in both the potency and the Fuality of action of a compound. "hen, looking at the long@ignored chain,
lengthening it by the addition of a carbon atom eliminated all psychedelic effects and gave materials 3ith reduced action. "he action present 3as that of
an antidepressant. .ut removing a carbon atomH "his returned the search to the 3orld of mescaline, but 3ith the kno3ledge of the strong influence of
the +@position substituent. "he t3o@carbon side@chain 3orld 3as rediscovered, principally 3ith $C@. and $C@;, and the +@etho/y@analogue of mescaline,
<. "his second half of the sho3 could be called the phenethylamine period. And 3ith compounds such as 0C@< 3hich is, Fuite simply, <scaline 'or <-
ree/tended again to a 0@carbon chain amphetamine, there is a kind of satisfying closure. A fascinating compound, but for most subGects a little too heavy
on the body.
#$1 $!-7; $,)-0"METH%+Y-(-7/%*%,HE#ETHYAM"#E
S>5"H<SISE A solution of 21.1 g $,&@dimetho/yaniline in $(, m! H$9 containing $,& m! fluoroboric acid 3as cooled to , deg C. 3ith an e/ternal ice
bath. "here 3as then added, slo3ly, a solution of 0& g sodium nitrite in 2, m! H$9. After an additional ,.& h stirring, the precipitated solids 3ere
removed by filtration, 3ashed first 3ith cold H$9, then 3ith ?e9H and finally <t$9. Air drying yielded about (,, g of the fluoroborate salt of the aniline
as dark purple@bro3n solids. "his salt 3as pyroly6ed 3ith the cautious application of a flame, 3ith the needed attention paid to both an e/plosion risk,
and the evolution of the very corrosive boron trifluoride. "he liFuid that accumulated in the receiver 3as distilled at about ($, deg C at $, mm8Hg, and
3as subseFuently 3ashed 3ith dilute 5a9H to remove dissolved boron trifluoride. "he product, $,&@dimetho/yfluoroben6ene, 3as a fluid, stra3@colored
oil that 3eighed 2., g.
"o a vigorously stirred solution of +,.2 g $,&@dimetho/yfluoroben6ene in $(& m! CH$Cl$ cooled 3ith an e/ternal ice bath, there 3as added (0& g of
anhydrous stannic chloride. "here 3as then added, drop3ise, $1 g of dichloromethyl methyl ether at a rate that precluded e/cessive heating. "he
reaction mi/ture 3as allo3ed to come to room temperature over the course of ,.& h, and then Fuenched by dumping into &,, g shaved ice containing 2&
m! concentrated HCl. "his mi/ture 3as stirred for an additional (.& h. "he separated organic layer 3as 3ashed 3ith $/(,, m! dilute HCl, then 3ith
dilute 5a9H, then 3ith H$9 and finally 3ith saturated brine. :emoval of the solvent under vacuum yielded a solid residue that 3as recrystalli6ed from
aFueous <t9H yielding +(.) g $,&@dimetho/y@+@fluoroben6aldehyde 3ith a mp of %%@(,, deg C.
A solution of $.& g $,&@dimetho/y@+@fluoroben6aldehyde in (& m! acetic acid containing ( g nitromethane 3as treated 3ith ,.$ g anhydrous ammonium
acetate, and heated on the steam bath for + h. After cooling, and follo3ing the Gudicious addition of H$9, crystals separated, and additional H$9 3as
added 3ith good stirring until the first signs of oiling out appeared. "he solids 3ere removed by filtration, and recrystalli6ed from acetone to give $., g of
$,&@dimetho/y@+@fluoro@beta@nitrostyrene 3ith a mp of (&%@(1$ deg C.
"o a suspension of $., g !AH in $,, m! cool anhydrous <t$9 under an inert atmosphere, there 3as added a "HB solution of $., g $,&@dimetho/y@+@
fluoro@beta@nitrostyrene. "he reaction mi/ture 3as stirred at room temperature for $ h and then heated briefly at reflu/. After cooling, the e/cess hydride
3as destroyed by the cautious addition of H$9, and 3hen the reaction 3as finally Fuiet, there 3as added $ m! of (&K 5a9H, follo3ed by another 1 m!
of H$9. "he basic insolubles 3ere removed by filtration, and 3ashed 3ith "HB. "he combined filtrate and 3ashes 3ere stripped of solvent, yielding a
residual oil that 3as taken up in (, m! of IPA, neutrali6ed 3ith concentrated HCl, and the generated solids diluted 3ith anhydrous <t$9. "he 3hite
crystalline $,&@dimetho/y@+@fluorophenethylamine hydrochloride '$C@B- 3as recrystalli6ed from IPA to give an air@dried product of ,.& g 3ith a mp of ()$@
()& deg C.
;9SAC<E greater than $&, mg.
;4:A"I95E unkno3n
L4A!I"A"IM< C9??<5"SE '3ith $&, mg- <ven at $&, milligrams, the effects 3ere slight and uncertain. "here may have been some eyes@closed
imagery above normal, but certainly not profound. At several hours there 3as a pleasant lethargy; sleep 3as completely normal that night.
<="<5SI95S A5; C9??<5"A:>E A number of graded acute dosages 3ere tried, and it 3as only 3ith amounts in e/cess of (,, milligrams that there
3ere any baseline disturbances at all. And at no dose that 3as tried 3as there any convincing indication of believable central effects.
"he three@carbon amphetamine analogue of $C@B 3ould Fuite logically be called ;9B '$,&@dimetho/y@+@fluoroamphetamine-. It has been prepared by
reaction of the above ben6aldehyde 3ith nitroethane 'giving (@'$,&@dimetho/y@+@fluorophenyl-@$@nitropropene, 3ith a melting point of ($)@($% deg C from
ethanol- follo3ed by !AH reduction to ;9B 'the hydrochloride salt has a melting point of (11@(12 deg C, after recrystalli6ation from ether8ethyl
acetate8ethanol-. Animal studies that have compared ;9B to the highly potent ;9I and ;9. imply that the human activity 3ill be some four to si/ times
less than these t3o heavier halide analogues. As of the present time, no human trials of ;9B have been made.

#$2 $!-8; $,)-0"METH%+Y-',(-0"METHY,HE#ETHYAM"#E
S>5"H<SISE "o a clear solution of +,.+ g flake 9H in +,, m! 3arm <t9H there 3as added )1.& g $,0@/ylenol follo3ed by &(.+ g methyl iodide. "his
mi/ture 3as held at reflu/ for $ days, stripped of volatiles under vacuum, the residues dissolved in ( ! of H$9, and e/tracted 3ith +/$,, m! CH$Cl$.
"he pooled e/tracts 3ere 3ashed 3ith &K 5a9H until the 3ashes remained basic. Bollo3ing a single 3ashing 3ith dilute HCl, the solvent 3as removed
under vacuum, and the residue, +(.& g of a pungent smelling amber oil, spontaneously crystalli6ed. "he mp of $,0@dimethylanisole 3as $&@$1 deg C
and it 3as used 3ithout further purification in the ne/t step. Brom the aFueous basic 3ashes, follo3ing acidification, e/traction, and solvent removal,
there 3as obtained +1.& g crude unreacted /ylenol 3hich could be recycled.
A mi/ture of $,& g P9Cl0 and $$) g 5@methylformanilide 3as allo3ed to incubate at room temperature until there 3as the development of a deep claret
color 3ith some spontaneous heating. "o this, there 3as added 2,.) g $,0@dimethylanisole, and the dark reaction mi/ture heated on the steam bath for
$.& h. "he product 3as then poured into (.2 ! H$9, and stirred until there 3as a spontaneous crystalli6ation. "hese solids 3ere removed by filtration,
H$9 3ashed and air dried to give 22.2 g of crude ben6aldehyde as bro3n crystals. "his 3as distilled at 2,@%, deg C at ,.+ mm8Hg to give 1+.) g of $,0@
dimethyl@+@metho/yben6aldehyde as a 3hite crystalline product 3ith a mp of &(@&$ deg C. :ecrystalli6ation from ?e9H produced an analytical sample
3ith a mp of &&@&&.& deg C. Anal. 'C(,H($9$- C,H. "he malononitrile derivative 'from the aldehyde and malononitrile in <t9H 3ith a drop of
triethylamine- had a mp of (00@(00.& deg C from <t9H. Anal. 'C(0H($5$9- C,H,5. :ecently, this aldehyde has become commercially available.
A solution of 0$.+ g $,0@dimethyl@+@metho/yben6aldehyde in ),, m! CH$Cl$ 3as treated 3ith &).1 g )&K m@chloropero/yben6oic acid and held at reflu/
for 0 days. After cooling to room temperature, the 3hite solids 'm@chloroben6oic acid- 3ere removed by filtration 'about +, g 3hen dry-. "he filtrate 3as
e/tracted 3ith several portions of saturated 5aHC90 'on acidification, this aFueous 3ash yielded additional m@chloroben6oic acid- and the organic
solvent removed under vacuum. "he crystalline residue '3eighing 0$ g and deeply colored- 3as dissolved in (&, m! boiling ?e9H to 3hich there 3as
added () g of solid 5a9H and the solution heated on the steam bath for a fe3 min. "he mi/ture 3as added to ),, m! H$9, and a little surface scum
mechanically removed 3ith a piece of filter paper. "he solution 3as acidified 3ith concentrated HCl, depositing 0,.% g of a tan solid. :ecrystalli6ation
from H$9 gave $,0@dimethyl@+@metho/yphenol as 3hite needles, 3ith a mp of %&@%1 deg C. Anal. 'C%H($9$- H; CE calcd, 2(.,1; found 2,.$,. "he 5@
methyl carbamate 3as made by the treatment of a solution of the phenol '( g in 2& m! he/ane 3ith & m! CH$Cl$ added- 3ith $ g methyl isocyanate and
a fe3 drops of triethyl amine. "he pale pink solids that separated 3ere recrystalli6ed from ?e9H to give a product that had a mp of (+(@(+$ deg C.
Anal. 'C((H(&590- C,H,5.
"o a solution of $0.( g flake 9H in $&, m! hot <t9H there 3as added 1(.) g $,0@dimethyl@+@metho/yphenol follo3ed by 1, g methyl iodide. "his 3as
held under reflu/ for ($ h, then stripped of solvent under vacuum. "he residue 3as dissolved in (.$ ! H$9, acidified 3ith HCl, and e/tracted 3ith 0/$,,
m! CH$Cl$. "he combined e/tracts 3ere 3ashed 3ith 0/(,, m! &K 5a9H, and the solvent 3as removed under vacuum. "he residue set up as an off@
3hite mass of leaflets 3eighing 02.2 g after filtering and air drying. :ecrystalli6ation from ?e9H gave $,0@dimethyl@(,+@dimetho/yben6ene as 3hite
solids, 3ith a mp of 2)@2% deg C. Anal. 'C(,H(+9$- C,H. An alternate route leading from $,0@/ylenol to this diether via nitrogen@containing
intermediates 3as e/plored. "he seFuence involved the reaction of $,0@/ylenol 3ith nitrous acid '+@nitroso product, mp ()+ deg C dec.-, reduction 3ith
sodium dithionite '+@amino product, mp about (2& deg C-, o/idation 3ith nitric acid 'ben6oFuinone, mp &) deg C-, reduction 3ith sodium dithionite
'hydro@Fuinone- and final methylation 3ith methyl iodide. "he yields 3ere inferior 3ith this process.
A mi/ture of )) g P9Cl0 and %% g 5@methylformanilide 3as allo3ed to incubate until a deep claret color had formed, then it 3as treated 3ith 01.& g $,0@
dimethyl@(,+@dimetho/yben6ene and heated on the steam bath for 0 h. It 3as then poured into ( ! H$9, and stirred until the formation of a loose,
crumbly, dark crystalline mass 3as complete. "his 3as removed by filtration, and dissolved in 0,, m! CH$Cl$. After 3ashing first 3ith H$9, then 3ith
&K 5a9H, and finally 3ith dilute HCl, the solvent 3as removed under vacuum yielding 0%.& g of a black oil that solidified. "his 3as e/tracted 3ith $/0,,
m! boiling he/ane, the e/tracts 3ere pooled, and the solvent removed under vacuum. "he yello3ish residue crystalli6ed to give 0$.2 g $,&@dimetho/y@
0,+@dimethylben6aldehyde 3ith a mp of +1@+2 deg C. :epeated recrystalli6ation from ?e9H raised the mp to &%@1, deg C. "he malononitrile derivative
3as prepared 'aldehyde and malononitrile in <t9H 3ith a fe3 drops triethyl amine- as yello3 crystals from <t9H, 3ith a mp of (%,@(%( deg C. Anal.
'C(+H(+5$9$- C,H; 5E calcd, ((.&1; found, ((.,1, ((.,+.
"o a solution of (1.0 g $,&@dimetho/y@0,+@dimethylben6aldehyde in &, m! nitromethane there 3as added 0., g anhydrous ammonium acetate, and the
mi/ture 3as heated on the steam bath overnight. "here 3as then added an eFual volume of ?e9H, and 3ith cooling there 3as obtained a fine crop of
yello3 crystals. "hese 3ere removed by filtration, 3ashed 3ith ?e9H, and air dried to provide +.+ g of $,&@dimetho/y@0,+@dimethyl@beta@nitrostyrene
3ith a mp of ($,@($( deg C 3hich 3as not improved by recrystalli6ation from ?e9H '&, m!8g-. "he mother liFuors of the above filtration 3ere diluted
3ith H$9 to the point of permanent turbidity, then set aside in a cold bo/. "here 3as a chunky, granular, tomato@red crystal deposited 3hich 3eighed $.&
g 3hen dry. It had a mp of (()@((%.& deg C, 3hich 3as undepressed in mi/ed mp 3ith the yello3 sample. .oth forms had identical 5?: spectra '$.$,,
$.$& CH0; 0.2$, 0.)+ 9CH0; 1.), ArH; 2.21, ).$) CHTCH, 3ith (+ cycle splitting-, infrared spectra, ultra violet spectra 'ma/. 0$+ nm 3ith shoulder at
011 nm in <t9H, t3o peaks at 0,% and 0&& nm in he/ane-, and microanalyses. Anal. 'C($H(&59+- C,H,5.
A solution of !AH '&1 m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.&$
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of 0.10 g $,&@dimetho/y@0,+@dimethyl@beta@nitrostyrene in 01 m!
anhydrous "HB over the course of ( h. After a fe3 minutes further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath for
about & min, then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of % m! IPA follo3ed by $.& m! (&K
5a9H and finally 2.& m! H$9. "he reaction mi/ture 3as filtered, and the filter cake 3ashed first 3ith "HB and then 3ith IPA. "he filtrate 3as stripped of
solvent under vacuum and the residue 3as distilled at ((,@($, deg C at ,.$ mm8Hg to give $.,2 g of $,&@dimetho/y@0,+@dimethylphenethylamine as a
clear 3hite oil. "his 3as dissolved in (, m! IPA, neutrali6ed 3ith concentrated HCl, and then diluted 3ith $& m! anhydrous <t$9. "he crystals that
formed 3ere filtered, <t$9 3ashed, and air dried to constant 3eight. "here 3as obtained $.(0 g of beautiful 3hite crystals of $,&@dimetho/y@0,+@
dimethylphenethylamine hydrochloride '$C@C- 3ith a mp of $0$@$00 deg C. Anal. 'C($H$,Cl59$- C,H.
;9SAC<E $, @ 0& mg.
;4:A"I95E () @ 0, h.
L4A!I"A"IM< C9??<5"SE '3ith $$ mg- I am completely functional, 3ith 3riting and ans3ering the telephone, but the coffee really tastes most
strange. Ihile the mental effects 'to a ** only- 3ere dispersing, the body still had Fuite a bit of memory of the day. Sleep 3as fine, and desirable, in the
early evening.
'3ith 0$ mg- Superb material, to be classified as a 7true psychedelic7 unless one is publishing, in 3hich case it could be best described as an 7insight@
enhancer7 and obviously of potential value in psychotherapy 'if one 3ould 3ish to spend 0, hours in a therapy sessionO-. I suppose it 3ould be best to
simply stick 3ith the insight@enhancing and skip the psychotherapy. Dust too, too long. "here 3as not any particular visual impact, at least for me. "he
non@se/ual and the anore/ic aspects might indeed change, 3ith increasing familiarity. :emains to be seen. "he length of the e/perience is against its
freFuent use, of course, 3hich is a pity, since this one is 3ell 3orth investigating as often as possible.
'3ith 0$ mg- "here 3as, at the very beginning, a certain feeling of non@physical heat in the upper back 3hich reminded me of the onset of various
indoles, 3hich this ain7t. "he energy tremor 3as Fuite strong throughout, but someho3 the body 3as generally at ease.
'3ith 0$ mg- At a plateau at t3o hours, 3ith Gust a bit of tummy Fueasi@ness. And I am still at the plateau several hours later. Sleep finally at the ()th
hour, but even after getting up and doing all kinds of things the ne/t day, I 3as not completely baseline until that evening. And a couple of days more for
3hat is certainly complete repair. "hat is a lot of mileage for a small amount of material.
<="<5SI95S A5; C9??<5"A:>E Here is the first e/ample, ever, of a phen@ethylamine that is of about the same potency as therelated three@carbon
amphetamine. At first appro/imation, one is hard put to distinguish, from the recorded notes, any maGor differences either in potency, in duration, or in
the nature of activity, bet3een $C@C and CA5<SHA itself.
I had al3ays thought of the phenethylamines as being some3hat 3eaker than the corresponding amphetamines. Sometimes a little 3eaker and
sometimes a lot 3eaker. .ut that is a totally preGudiced point of vie3, an outgro3th of my earliest comparisons of mescaline and "?A. "hat7s the kind of
thing that can color one7s thinking and obscure 3hat may be valuable observations. It is eFually valid to think of the phenethylamines as the prototypes,
and that the amphetamines are some3hat stronger than the corresponding phenethylamines. Sometimes a little stronger and sometimes a lot stronger.
"hen the Fuestion suddenly shifts from asking 3hat is different about the phenethylamines, to 3hat is different about the amphetaminesH It is simply a
historic fact, that in most of my e/ploring, the amphetamine 3as made and evaluated first, and so tended to slip into the role of the prototype. In any
case, here the t3o potencies converge.
#$3 $!-8-'; $,)-0"METH%+Y-',(-&T*"METHYE#E-,HE#ETHYAM"#E;
&@'$@A?I59<"H>!-@+,2@;I?<"H9=>I5;A5<-
S>5"H<SISE "o a solution of $$ g of 9H in $&, m! of hot <t9H, there 3as added &, g of +@indanol and 2& g methyl iodide. "he mi/ture 3as held at
reflu/ for ($ h. "here 3as then added an additional $$ g 9H follo3ed by an additional &, g of methyl iodide. :eflu/ing 3as continued for an additional
($ h. "he mi/ture 3as poured into ( ! H$9, acidified 3ith HCl, and e/tracted 3ith 0/2& m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith &K 5a9H,
then 3ith dilute HCl, and the solvent 3as removed under vacuum. "he residue of crude $,0@'trimethylene-anisole 3eighed &1.& g and 3as used 3ithout
further purification in the follo3ing reaction.
A mi/ture of 0$2 g 5@methylformanilide and $%& g P9Cl0 3as allo3ed to incubate until a deep claret color had formed. "o this there 3as then added
((, g of crude $,0@'trimethylene-anisole, and the mi/ture heated on the steam bath. "here 3as a vigorous evolution of gases, 3hich largely Fuieted
do3n after some + h of heating. "he reaction mi/ture 3as added to + ! H$9 and stirred overnight. "he oily aFueous phase 3as e/tracted 3ith 0/$,,
m! CH$Cl$, and after combining the e/tracts and removal of the solvent there 3as obtained (+2 g of a black, s3eet@smelling oil. "his 3as distilled at
()$@(%+ deg C at the 3ater pump to yield (,%.( g of a pale yello3 oil. At lo3 temperature, this crystalli6ed, but the solids melted again at room
temperature. Cas chromatography of this product on 9M@(2 at ()& deg C sho3ed detectable starting anisole and 5@methylformanilide 'combined,
perhaps &K of the product- and a small but real isomeric peak, 'about &K, slightly faster moving than the title aldehyde, again about &K of the product-
of 3hat 3as tentatively identified as the ortho@aldehyde '$@metho/y@0,+@'trimethylene-@ben6aldehyde-. "he bulk of this crude product '2+ g- 3as
redistilled at ((,@(0, deg C at ,.0 mm8Hg to give 11 g of +@metho/y@$,0@'trimethylene-ben6aldehyde as a nearly colorless oil 3hich set up as a
crystalline solid. A portion on porous plate sho3ed a mp of $)@$% C. A gram of this aldehyde and a gram of malononitrile in $& m! of <t9H 3as treated
3ith a fe3 drops of triethylamine and gave pale yello3 crystals of the malononitrile derivative. "his, upon recrystalli6ation from &, m! boiling <t9H, had
a mp of (21@(21.& deg C. Anal. 'C(+H($5$9- C,H,5. A side path, other than to3ards the intended targets $C@C@0 and C@0, 3as e/plored. :eaction
3ith nitroethane and anhydrous ammonium acetate gave the $@nitropropene analogue 3hich 3as obtained in a pure state 'mp 2+@2& deg C from ?e9H-
only after repeated e/traction of the crude isolate 3ith boiling he/ane. :eduction 3ith elemental iron gave the phenylacetone analogue 3hich 3as
reductively aminated 3ith dimethylamine and sodium cyanoborohydride to give 5,5@dimethyl@+@metho/y@$,0@'trimethylene-amphetamine. "his 3as
designed for brain blood@flo3 volume studies after iodination at the &@position, a concept that has been discussed under I;55A. It has never been
tasted by anyone. "he corresponding primary amine, +@metho/y@$,0@'trimethylene-amphetamine has not yet even been synthesi6ed.
A solution of 0+.) g +@metho/y@$,0@'trimethylene-ben6aldehyde in ),, m! CH$Cl$ 3as treated 3ith &).1 g of )&K m@chloropero/yben6oic acid and held
at reflu/ for 0 days. After cooling and standing for a fe3 days, the solids 3ere removed by filtration and 3ashed sparingly 3ith CH$Cl$. "he combined
filtrate and 3ashings 3ere 3ashed 3ith $,, m! saturated 5aHC90, and the solvent removed, yielding +0.& g of a deeply colored oil. "his 3as dissolved
in (&, m! ?e9H to 3hich 3as added % g 5a9H and all heated to reflu/ on the steam bath. After ( h, a solution of % g 5a9H in $, m! H$9 3as added,
heated further, then follo3ed by yet another treatment 3ith % g 5a9H in $, m! H$9 follo3ed by additional heating. All 3as added to ),, m! H$9,
3ashed once 3ith CH$Cl$ '3hich removed a trivial amount of material- and then acidified 3ith HCl. "he dark crystals that 3ere generated 3ere filtered
and air dried to constant 3eight, yielding $2.& g dark but nice@looking crystals 3ith a mp of )%@%( deg C. .y all counts, this should have been the
product phenol, +@metho/y@$,0@'trimethylene-phenol, but the microanalysis indicated that the formate ester 3as still there. Anal. 'C(,H($9$- reFuires C
T 20.,), H T 2.02. 'C((H($90- reFuires C T 1).20, H T 1.$%. BoundE C T 1%.,+, 1).)+; H T 1.1+, 1.&). Ihatever the e/act chemical status of the
phenolic hydro/yl group might have been, it reacted successfully in the follo3ing methylation step.
"o a solution of (, g 9H in (,, g <t9H 'containing &K IPA- there 3as added $2.& g of the above )%@%( deg C melting material, follo3ed by $& g
methyl iodide. "he mi/ture 3as held at reflu/ overnight. All 3as added to ),, m! H$9, acidified 3ith HCl, and e/tracted 3ith 0/(,, m! CH$Cl$. "he
combined e/tracts 3ere 3ashed 3ith 0/(,, m! &K 5a9H, then once 3ith dilute HCl, and the solvent removed under vacuum yielding $,.+ g of a
fragrant crystalline residue. "his 3as recrystalli6ed from 1, m! boiling ?e9H to give, after filtering and air drying, (1., g of (,+@dimetho/y@$,0@
'trimethylene-ben6ene '+,2@dimetho/yindane- 3ith a mp of )1@)) deg C. Anal. 'C((H(+9$- C,H.
"o a mi/ture of 0%., g of 5@methylformanilide and 0&.% g P9Cl0 that had been allo3ed to stand at ambient temperature until deeply claret 'about +& min-
there 3as added (&.) g of (,+@dimetho/y@$,0@'trimethylene-ben6ene. "he mi/ture 3as heated on the steam bath for + h and then poured into 1,, m!
H$9. After stirring overnight there 3as produced a heavy crystalline mass. "his 3as removed by filtration and, after air drying, 3as e/tracted 3ith
0/(,, m! boiling he/ane. Pooling and cooling these e/tracts yielded %.2 g of salmon@colored crystals 3ith a mp of 12@1) deg C. "his 3as recrystalli6ed
from $& m! boiling <t9H to give, after filtration, <t9H 3ashing, and air drying to constant 3eight, 2.+ g of $,&@dimetho/y@0,+@
'trimethylene-ben6aldehyde, 3ith a mp of 2(@2$ deg C. "he mother liFuors on cautious treatment 3ith H$9, yielded, after <t9H recrystalli6ation, ( g
additional product. Anal. 'C($H(+90- C,H. A solution of (&, mg aldehyde and an eFual 3eight of malononitrile in $.0 m! <t9H treated 3ith 0 drops
triethylamine gave immediate yello3 crystals of the malononitrile derivative, 3ith a mp of (1(@(1$ deg C. Anal. 'C(&H(+5$9$- C,H,5.
A solution 0.2 g $,&@dimetho/y@0,+@'trimethylene-ben6aldehyde in (& g nitromethane 3as treated 3ith ,.2 g anhydrous ammonium acetate and heated
on the steam bath for (+ h. "he volatiles 3ere removed under vacuum, and the residue set up to 0.& g dark crystals, 3hich melted broadly bet3een
($1@(0) deg C. :ecrystalli6ation of the entire mass from 2, m! boiling <t9H gave 0.$ g burnished gold crystals 3ith a mp of ($%@(02 deg C. A further
recrystalli6ation of an analytical sample from ?e9H gave $,&@dimetho/y@0,+@'trimethylene-@beta@nitrostyrene as yello3 crystals 3ith a mp of (+1@(+2 deg
C. Anal. 'C(0H(&59+- C,H.
"o a cold solution of !AH in "HB '+, m! of a ( ? solution- 3ell stirred and under an inert atmosphere, there 3as added drop3ise (.,& m! freshly
prepared (,,K H$S9+. "here 3as then added, drop3ise, a solution of $.0% g $,&@dimetho/y@0,+@'trimethylene-@beta@nitrostyrene in $& m! "HB. "he
bright yello3 color 3as discharged immediately. After the addition 3as complete, stirring 3as continued for an additional $, min, and the reaction
mi/ture brought to a reflu/ on the steam bath for another ,.& h. After cooling, the e/cess hydride 3as destroyed 3ith IPA ') m! reFuired- follo3ed by
sufficient (&K 5a9H to convert the inorganics into a loose, filterable mass. "his 3as removed by filtration, and the filter cake 3ashed 3ith "HB. "he
combined filtrate and 3ashes 3ere stripped of solvent under vacuum, and the residue dissolved in dilute H$S9+. After 3ashing 3ith CH$Cl$, the
aFueous phase 3as made basic 3ith $&K 5a9H and e/tracted 3ith 0/2& m! CH$Cl$. After removal of the solvent under vacuum, the residue 3as
distilled at ($&@(1, deg C at ,.+& mm8Hg to yield ,.), g of a 3hite oil. "his 3as dissolved in ) m! IPA, neutrali6ed 3ith $, drops of concentrated HCl
'the salt crystals started to form before this 3as completed- follo3ed 3ith the addition of 1& m! anhydrous <t$9. "he 3hite crystalline mass 3as filtered,
3ashed 3ith <t$9, and air dried to provide (.(1 g of $,&@dimetho/y@0,+@'trimethylene-phenethylamine hydrochloride '$C@C@0- 3ith a mp of $(+@$(1 deg
C 3ith decomposition. Anal. 'C(0H$,Cl59$- C,H.
;9SAC<E (1 @ $& mg.
;4:A"I95E ($ @ $+ h.
L4A!I"A"IM< C9??<5"SE '3ith (1 mg- It came on in little leaps and bounds. All settled, and then it 3ould take another little Gump up3ards. I am
totally centered, and 3riting is easy. ?y appetite is modest. Iould I drive to to3n to return a book to the libraryH 5o ever@loving 3ayO I am very content
to be right here 3here I am safe, and stay 3ith the 3riting. It does take so much time to say 3hat 3ants to be said, but there is no Fuick 3ay. A 3ord at
a time.
'3ith $$ mg- I 3alked out for the mail at Gust about t3ilight. "hat 3as the most courageous thing that I could possibly have done, Gust for one lousy
postcard and a Gournal. Ihat if I had met someone 3ho had 3anted to talkH "o3ards evening I got a call from Peg 3ho said her bean soup 3as
bubbling in a scary 3ay and 3hat should she do, and I said maybe better make soap. It 3as that kind of an e/perienceO Iay up there, lots of !S;@like
sparkles, and nothing Fuite really making sense. ?arvelous.
'3ith $& mg- "here 3as easy talking, and no hint of any body concern. Sleep that evening 3as easy, and the ne/t day 3as 3ith good energy.
<="<5SI95S A5; C9??<5"A:>E "he positives of a completely intriguing altered state free from apparent physical threats, are here coupled 3ith the
negative of having to invest such a long period of time. "here is a merry nuttiness 3hich can give a Goyous into/ication, but 3ith the underlying paranoia
of ho3 it looks to others. "here is an ease of communication, but only 3ithin surroundings that are 3ell@kno3n and friendly. "his might be a truly
frightening e/perience if it 3ere in an unfamiliar or unstructured environment.
"he numbering of this compound, and all the e/tensions of CA5<SHA, have been made on the basis of the nature of the stuff at the 0,+@position. Here
there are three atoms 'the trimethylene bridge- and so $C@C@0 seems reasonable. Iith this logic, the dimethylene bridge 3ould be $C@C@$ 'and the
corresponding amphetamine 3ould be C@$, of course-. .ut these compounds call upon a common intermediate 3hich is a ben6ocyclobutene, 9 in
principle but not yet 9 in practice. "he right ben6yne reaction 3ill be there someday, and the dimethylene analogues 3ill be made and assayed. .ut,
in the meantime, at least the names have been assigned.
#$4 $!-8-(; $,)-0"METH%+Y-',(-&TET*AMETHYE#E-,HE#ETHYAM"#E;
1@'$@A?I59<"H>!-@&,)@;I?<"H9=>@"<":A!I5
S>5"H<SISE "o a solution of +%.$ g &,1,2,)@tetrahydronaphthol '&@hydro/ytetralin- in (,, m! ?e9H, there 3as added &1 g methyl iodide follo3ed by a
solution of $+.) g 9H pellets ')&K purity- in (,, m! boiling ?e9H. "he mi/ture 3as heated in a && deg C bath for 0 h 'the first 3hite solids of
potassium iodide appeared in about (, min-. "he solvent 3as stripped under vacuum, and the residues dissolved in $ ! H$9. "his 3as acidified 3ith
HCl, and e/tracted 3ith +/2& m! CH$Cl$. After 3ashing the organic phase 3ith 0/2& m! &K 5a9H, the solvent 3as removed under vacuum to give
+).$ g of a black residue. "his 3as distilled at ),@(,, deg C at ,.$& mm8Hg to provide 00.% g &@metho/y@(,$,0,+@tetrahydronaphthalene as a 3hite oil.
"he 5a9H 3ashes, upon acidification and e/traction 3ith CH$Cl$ gave, after removal of the solvent under vacuum and distillation of the residue at ,.0&
mm8Hg, ((.+ g of recovered starting phenol.
A mi/ture of 1(.2 g P9Cl0 and &+.0 g 5@methylformanilide 3as heated on the steam bath for (& min 3hich produced a deep red color. "his 3as added
to &+.0 g of &@metho/y@(,$,0,+@tetrahydronaphthalene, and the mi/ture 3as heated on the steam bath for $ h. "he reaction mi/ture 3as Fuenched in (.$
! H$9 3ith very good stirring. "he oils generated Fuickly turned to bro3n granular solids, 3hich 3ere removed by filtration. "he 2% g of 3et product
3as finely triturated under an eFual 3eight of ?e9H, filtered, 3ashed 3ith $, m! ice@cold ?e9H, and air dried to yield 0$., g of +@metho/y@&,1,2,)@
tetrahydronaphthaldehyde as an ivory@colored solid. "he filtrate, on standing, deposited another +.& g of product 3hich 3as added to the above first
crop. An analytical sample 3as obtained by recrystalli6ation from <t9H, and had a mp of &2@&) deg C. Anal. 'C($H(+9$- C,H.
"o a solution of $&.( g +@metho/y@&,1,2,)@tetrahydronaphthaldehyde in 0,, m! CH$Cl$ there 3as added $& g )&K m@chloropero/yben6oic acid at a rate
that 3as commensurate 3ith the e/othermic reaction. Solids 3ere apparent 3ithin a fe3 min. "he stirred reaction mi/ture 3as heated at reflu/ for ) h.
After cooling to room temperature, the solids 3ere removed by filtration and 3ashed lightly 3ith CH$Cl$. "he pooled filtrate and 3ashes 3ere stripped
of solvent under vacuum and the residue dissolved in (,, m! ?e9H and treated 3ith +, m! $&K 5a9H. "his 3as heated on the steam bath for an
hour, added to ( ! H$9, and acidified 3ith HCl, producing a heavy crystalline mass. "his 3as removed by filtration, air dried, and distilled at up to (2,
deg C at ,.$ mm8Hg. "here 3as thus obtained $(.+ g of +@metho/y@&,1,2,)@tetrahydronaphthol as an off@3hite solid 3ith a mp of (,2@((+ deg C. An
analytical sample 3as obtained by recrystalli6ation from 2,K <t9H, and melted at ((%@($, deg C. He/ane is also an e/cellent recrystalli6ation solvent.
Anal. 'C((H(+9$- C,H. As an alternate method, the o/idation of the naphthaldehyde to the naphthol can be achieved through heating the aldehyde in
acetic acid solution containing hydrogen pero/ide. "he yields using this route are consistently less than +,K of theory.
A solution of $(., g of +@metho/y@&,1,2,)@tetrahydronaphthol in (,, m! acetone in a ( ! round@bottomed flask, 3as treated 3ith $& g finely ground
anhydrous $C90 and $1 g methyl iodide. "he mi/ture 3as held at reflu/ on the steam bath for $ h, cooled, and Fuenched in ( ! H$9. "rial e/traction
evaluations have sho3n that the starting phenol, as 3ell as the product ether, are e/tractable into CH$Cl$ from aFueous base. "he aFueous reaction
mi/ture 3as e/tracted 3ith 0/1, m! CH$Cl$, the solvent removed under vacuum, and the residue '(%.1 g- 3as distilled at %,@(0, deg C at ,.0 mm8Hg
to give (+.( g of an oily 3hite solid mi/ture of starting material and product. "his 3as finely ground under an eFual 3eight of he/ane, and the residual
crystalline solids removed by filtration. "hese proved to be Fuite rich in the desired ether. "his 3as dissolved in a he/ane8CH$Cl$ mi/ture '0E( by
volume- and chromatographed on a silica gel preparative column, 3ith the eluent continuously monitored by "!C '3ith this solvent system, the :f of the
ether product 3as ,.&, of the starting phenol ,.(-. "he fractions containing the desired ether 3ere pooled, the solvent removed under vacuum and the
residue, 3hich 3eighed 0.)1 g, 3as dissolved in (., m! he/ane and cooled 3ith dry ice. Clistening 3hite crystals 3ere obtained by filtration at lo3
temperature. "he 3eight of &,)@dimetho/ytetralin isolated 3as $.+, g and the mp 3as ++@+& deg C. CC?S analysis sho3ed it to be largely one product
'm8s (%$ parent peak and maGor peak-, but the underiviti6ed starting phenol has abysmal CC properties and "!C remains the best measure of chemical
purity.
A 3ell@stirred solution of 0.1% g &,)@dimetho/ytetralin in 0& m! CH$Cl$ 3as placed in an inert atmosphere and cooled to , deg C 3ith an e/ternal ice
bath. "here 3as then added, at a slo3 rate, +.& m! anhydrous stannic chloride, 3hich produced a transient color that Fuickly faded to a residual yello3.
"here 3as then added $., m! dichloromethyl methyl ether, 3hich caused immediate darkening. After a fe3 min stirring, the reaction mi/ture 3as
allo3ed to come to room temperature, and finally to a gentle reflu/ on the steam bath. "he evolution of HCl 3as continuous. "he reaction 3as then
poured into $,, m! H$9, the phases separated, and the aFueous phase e/tracted 3ith $/&, m! CH$Cl$. "he organic phase and e/tracts 3ere pooled,
3ashed 3ith 0/&, m! &K 5a9H, and the solvent removed under vacuum. "he residue 3as distilled at ($,@(+, deg C at ,.0 mm8Hg to give 0.(% g of a
3hite oil that spontaneously crystalli6ed. "he crude mp of (,+@dimetho/y@&,1,2,)@tetrahydro@$@naphthaldehyde 3as 2,@2$ deg C. An analytical sample
from he/ane had the mp 2+@2& deg C. "he CC?S analysis sho3ed only a single material 'm8s $$,, (,,K- 3ith no apparent starting dimetho/ytetralin
present. Attempts to synthesi6e this aldehyde by the Milsmeier procedure 'P9Cl0 and 5@methylformanilide- gave comple/ mi/tures of products.
Synthetic efforts employing butyllithium and ;?B gave only recovered starting material.
"o a solution of (.& g (,+@dimetho/y@&,1,2,)@tetrahydro@$@naphthaldehyde in $, g nitromethane there 3as added ,.(+ g anhydrous ammonium acetate
and the mi/ture heated on the steam bath for &, min. "he rate of the reaction 3as determined by "!C monitoring, on silica gel 3ith CH$Cl$ as the
moving solvent; the :f of the aldehyde 3as ,.2,, and of the product nitrostyrene, ,.%&. :emoval of the volatiles under vacuum gave a residue that
spontaneously crystalli6ed. "he fine yello3 crystals that 3ere obtained 3ere suspended in (., m! of ?e9H, filtered, and air dried to yield (.12 g $,&@
dimetho/y@beta@nitro@0,+@'tetramethylene-styrene 3ith a mp of (&(.&@(&$.& deg C. Anal. 'C(+H(259+- C,H.
;9SAC<E unkno3n.
;4:A"I95E unkno3n
<="<5SI95S A5; C9??<5"A:>E "he road getting to this final product reminded me of the reasons 3hy, during the first fe3 billion years of the
universe follo3ing the big bang, there 3as only hydrogen and helium. 5othing heavier. Ihen everything had e/panded enough to cool things
sufficiently for the first actual matter to form, all 3as simply very energetic protons and neutrons. "hese 3ere banging into one@another, making
deuterium nuclei, and some of these got banged up even all the 3ay to helium, but every time a helium nucleus collided 3ith a particle of mass one, to
try for something 3ith mass five, the products simply couldn7t e/ist. .oth !ithium@& and Helium@& have the impossible half@lives of (, to the minus $(
seconds. Hence, in the primordial soup, the only 3ay to get into something heavier than helium 3as to have a collision bet3een a couple of the
relatively scarcer heavy nuclei, or to have a three body collision. .oth of these 3ould be e/tremely rare events, statistically. And if a fe3 got through,
there 3as another forbidden barrier at mass ), since .eryllium@) has a half life of (, to the minus (1 seconds. So everything had to 3ait for a fe3 suns
to burn do3n so that they could process enough helium into heavy atoms, to achieve some nuclear chemistry that 3as not allo3ed in the early history of
the universe.
And in the same 3ay, there 3ere t3o nearly insurmountable barriers encountered in getting to $C@C@+ and C@+. "he simple act of methylating an
aromatic hydro/yl group provided mi/tures that could only be resolved into components by some pretty intricate maneuvers. And 3hen that product 3as
indeed gotten, the conversion of it into a simple aromatic aldehyde resisted the classic procedures completely, either giving comple/ messes, or nothing.
And even no3, 3ith these t3o hurdles successfully passed, the presumed simple last step has not yet been done. "he product $C@C@+ lies Gust one
synthetic step 'the !AH reduction- a3ay from completion, and the eFually fascinating C@+ also that one last reduction step from being completed.
Having gotten through the 3orst of the s3amp, let7s get into the lab and finish up this challenge. "hey 3ill both be active compounds.
#'5 $!-8-); ',1-0"METH%+Y-(-&$-AM"#%ETHY-.E#6%#%*.%*#A#E
S>5"H<SISE "o a stirred solution of $& g 0,1@dihydro/yben6onorbornane 'from <astman odak Company- in $,, m! acetone there 3as added $,, mg
decyltriethylammonium iodide, +, g of po3dered anhydrous $C90, and && g methyl iodide. "he mi/ture 3as held at reflu/ 3ith a heating mantle
overnight. After re@moval of the solvent under vacuum, the residue 3as added to $ ! of H$9, acidified 3ith concentrated HCl, and e/tracted 3ith 0/(,,
m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith $/(&, m! &K 5a9H and once 3ith dilute HCl, and the solvent 3as removed under vacuum to give
(%., g of a black oil as a residue. "his 3as distilled at %,@((& deg C at ,.0 mm8Hg to yield (&.& g of an orange oil 3hich set up as a crystalline solid.
"he product, 0,1@dimetho/yben6onorbornane, had a mp of 0&@02 deg C from he/ane or +,@+( deg C from ?e9H. Anal. 'C(0H(19$- C,H.
A solution of +.1 g P9Cl0 and +.1 g 5@methylformanilide 3as heated briefly on the steam@bath until the color had become deep claret. "here 3as then
added 0.,& g of 0,1@dimetho/yben6onorbornane and the solution 3as heated on the steam bath for ($ h. "he black, tarry reaction mi/ture 3as poured
into H$9, and after hydrolysis, the H$9 3as decanted and the insoluble residues 3ere 3ashed alternately 3ith H$9 and 3ith CH$Cl$. "he combined
3ashes 3ere separated, and the aFueous phase e/tracted 3ith $/&, m! CH$Cl$. "he combined organic fractions 3ere 3ashed 3ith &K 5a9H, and
the solvent removed under vacuum. "he fluid, black residue 3as distilled at (0,@(+, deg C at ,.0 mm8Hg to give (.(2 g of an almost 3hite oil. "his 3as
dissolved in ( m! ?e9H, and cooled to @&, deg C to give a 3hite crystalline solid that 3as removed by filtration and 3ashed sparingly 3ith @&, deg C
?e9H and air dried. "here 3as obtained ,.)0 g 0,1@dimetho/y@+@formylben6onorbornane 3ith a mp of 02@+, deg C 3hich could be increased, by
3asteful recrystalli6ation from ?e9H, to &0@&+ deg C. An intimate mi/ture of this product 3ith the starting diether 'mp +,@+( deg C- 3as a liFuid at room
temperature. Anal. 'C(+H(190- C,H.
"o a solution of 0.2, g 0,1@dimetho/y@+@formylben6onorbornane in $, g nitromethane, there 3as added (.0 g anhydrous ammonium acetate and the
mi/ture 3as heated on the steam bath for +& min. "he e/cess reagent8solvent 3as removed under vacuum, and the residue 3as dissolved in $, m!
boiling ?e9H. A speck of seed crystal started a heavy crystalli6ation of orange crystals 3hich 3ere removed by filtration and 3ashed 3ith ?e9H. After
drying, the product 0,1@dimetho/y@+@'$@nitrovinyl-ben6onorbornane 3as yello3, 3eighed 0.+2 g, and had a mp of ))@)% deg C. :ecrystalli6ation of an
analytical sample from ?e9H did not improve this mp. Anal. 'C(&H(259+- C,H.
A solution of !AH '+1 m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.$&
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of 0.+ g 0,1@dimetho/y@+@'$@nitrovinyl-ben6onorbornane in 0, m!
anhydrous "HB. After a fe3 min further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath for (, min, and then all 3as cooled
again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of 2 m! IPA, follo3ed by $ m! (&K 5a9H and & m! H$9, 3hich gave an
easily filtered 3hite granular solid. "his 3as removed by filtration, and the filter cake 3as 3ashed 3ith "HB. "he combined filtrate and 3ashes 3ere
stripped of solvent under vacuum providing a pale amber oil 3hich 3as distilled at (&,@(1, deg C at ,.0 mm8Hg to give (.+& g of a 3hite oil. "his 3as
dissolved in 2 m! IPA, and neutrali6ed 3ith (& drops of concentrated HCl. "here 3as then added $& m! anhydrous <t$9 and, after a short delay, 3hite
crystals formed spontaneously. "hese 3ere removed by filtration, <t$9 3ashed, and air dried to constant 3eight, yielding (.(0 g of 0,1@dimetho/y@+@'$@
aminoethyl-ben6onorbornane hydrochloride '$C@C@&-. "he mp 3as (%%@$,, deg C. Anal. 'C(&H$$Cl59$- C,H.
;9SAC<E (, @ (1 mg.
;4:A"I95E 0$ @ +) h.
L4A!I"A"IM< C9??<5"SE '3ith (+ mg- I 3as 3ell a3are of things at the end of t3o hours, and I 3as totally un3illing to drive, or even go out of the
house. I 3as reminded continuously of $C@. 3ith its erotic push, and the benign interplay of colors and other visual effects. .ut it is so much longer
lived. I am a full ***, very stoned, and there is no believable sign of dropping for another several hours. "here is a good appetite 'again, $C@. like-, and
I managed to sleep for a fe3 hours, and all the ne/t day I 3as spacey and probably still a plus one. "he day yet follo3ing, I 3as finally at a believable
baseline. .oth of these days 3ere filled 3ith 3hat might be called micro do6e@offs, almost like narcolepsy. ?aybe I am Gust sleep deprived.
'3ith (1 mg- "he first effects 3ere felt 3ithin one hour, and full effects bet3een $ (8$ and 0 hours. "remendous clarity of thought, cosmic but grounded,
as it 3ere. "his is not at all like !S;, and is a lot mello3er than the $C@" family. Bor the ne/t fe3 hours it 3as delightful and fun and I felt safe and good@
humored. I got to sleep 3ithout much difficulty 3hile still at a plus three, and my dreams 3ere positive and balanced, but I a3oke irritable and
emotionally flattened. I did not 3ant to interact 3ith anyone. "he first (1 hours of this stuff 3ere great, and the second (1 hours 3ere a bit of a drag.
Dust t3ice as long as it ought to be.
'3ith (1 mg- I 3as at full sparkle 3ithin three hours, and I continued to sparkle for the longest time. "he tiredness that comes after a 3hile probably
reflects the inadeFuacy of sleep. I 3as a3are of something still going on some t3o days later.
<="<5SI95S A5; C9??<5"A:>E In the eventual potency assessment of a drug, there must be some consideration of not only the dosage needed,
but the duration of effects. "he area under the curve, so to speak. .y these measures, this phenethylamine is a record breaker, in that it is not only
amongst the most potent, but it goes on and on and on.
"here are a couple of chemical commentaries. 9ne, the miserable phenol@to@ether@to@aldehyde series of steps, so maddeningly unsatisfactory in the
$C@C@+ process, 3as completely comfortable here. "he reactions rolled, and the yields 3ere most satisfactory. Secondly, this is one of the fe3
phenethylamines that is a racemate. "he strange geometry of the norbornane ring carries 3ithin it a chiral character, so this compound is potentially
resolvable into t3o optically active forms. "hat might be Fuite a task, but it 3ould have the value of providing for the first time a pair of isomers that 3ere
asymmetric in the 0,+@aliphatic part of the molecule. "o the e/tent that some insight into the geometry of the receptor site can be gleaned from the
absolute configurations of active agonists, here is a compound 3here the subtle variations are over there at the ring substitution area of the structure,
rather than at the 3ell@e/plored alpha@carbon atom. Some day I might try to resolve this drug into its optical isomers. .ut I suspect that it might be Fuite
difficult.
A number of chemical variations of $C@C@& are obvious. "he dihydro/yben6onorbornane compound that 3as the starting point of all this 3as certainly
the adduct of cyclopentadiene and ben6oFuinone, 3ith the double bond reduced. "he same chemistry 3ith (,0@cyclohe/adiene 3ould give a t3o@carbon
bridge instead of the one@carbon bridge of norbornane and, after hydrogenation, 3ould provide a non@chiral analog 3ith t3o ethylene bridges bet3een
the 0@ and +@position carbons. "his is a cyclohe/ane ring connected, by its (@ and +@positions, to the t3o methyl groups of $C@C. Iith si/ carbons in
this aliphatic mess, the compound is probably best called $C@C@1. It should be easily made, and it is certain to be very potent. And there are potentially
several other ;iels Alder dienes that might serve 3ith ben6oFuinone as the dieneophile. "here are aliphatic things such as he/a@$,+@diene and $,0@
dimethylbutadiene. "he te/tbooks are filled 3ith do6ens of diene candidates, and ben6Fuinone 3ill al3ays provide the t3o o/ygens needed for the
eventual $,&@dimetho/y groups of the phenethylamine.

#'1 $!-8-#; 1,(-0"METH%+Y#A,HTHY-$-ETHYAM"#E
S>5"H<SISE A solution of (2.& g (,+@naphthaFuinone in $,, m! ?e9H 3as heated to the boiling point, and treated 3ith $).& g stannous chloride at a
rate that maintained a continuous rolling boil. At the completion of the addition, the reaction mi/ture 3as saturated 3ith anhydrous hydrogen chloride,
and held at reflu/ on the steam bath for $ h. "he reaction mi/ture 3as poured into 2,, m! H$9 and treated 3ith aFueous 5a9H. ;uring the addition
there 3as transient development of a curdy 3hite solid 3hich redissolved 3hen the system became strongly basic. "his 3as e/tracted 3ith 0/$,, m!
CH$Cl$ and the pooled e/tracts 3ere 3ashed first 3ith H$9, then 3ith dilute HCl, and finally again 3ith H$9. :emoval of the solvent under vacuum
yielded (&.2& g of a lo3 melting black flaky crystalline material 3hich 3as distilled at (1,@(), deg C at ,.,& mm8Hg to give (+.& g of an amber, solid
mass 3ith a mp of 2)@)1 deg C. :ecrystalli6ation from 2& m! boiling ?e9H provided (,+@dimetho/ynaphthalene as 3hite crystals melting at )2@)) deg
C.
A mi/ture of $,., g P9Cl0 and $$.& g 5@methylformanilide 3as allo3ed to stand at room temperature for ,.& h 3hich produced a deep claret color. "o
this there 3as added %.+ g (,+@dimetho/ynaphthalene and the mi/ture 3as heated on the steam bath. "he reaction mi/ture Fuickly became
progressively darker and thicker. After $, min it 3as poured into $&, m! H$9 and stirred for several h. "he solids 3ere removed by filtration, and
3ashed 3ell 3ith H$9. "he 3et crude product 'a dull yello3@orange color- 3as dissolved in ($& m! boiling <t9H to give a deep red solution. 9n
cooling, this deposited a heavy crop of crystals that 3as removed by filtration, and 3ashed 3ith cold <t9H. "here 3as obtained, after air@drying to
constant 3eight, 2.% g (,+@dimetho/y@$@naphthaldehyde as 3hite crystals 3ith a mp of ((%@($( deg C. "his 3as not improved by further
recrystalli6ation. "he malononitrile derivative, from the aldehyde and malononitrile in <t9H 3ith a drop of triethylamine, had a mp of ()2@()) deg C.
A solution of 0.% g (,+@dimetho/y@$@naphthaldehyde in (0.& g nitromethane 3as treated 3ith ,.2 g anhydrous ammonium acetate, and heated on the
steam bath for ( h. "he e/cess reagent8solvent 3as removed under vacuum giving a residue that spontaneously crystalli6ed. "his crude product 3as
removed 3ith the aid of a fe3 m! ?e9H, and pressed on a sintered funnel 3ith modest ?e9H 3ashing. "here 3as obtained 0.1 g '3hen dry- of old@
gold colored crystals 3ith a mp of (+1@(+) deg C. :ecrystalli6ation from (+, m! boiling <t9H gave 0., g (,+@dimetho/y@$@'$@nitro@vinyl-naphthalene as
deep gold@colored crystals 3ith a mp of (+1@(+2 deg C. A small sample, upon recrystali6ation from ?e9H, melted at (+0@(++ deg C. Anal.
'C(+H(059+- C,H.
A solution of !AH '&, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.0$
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of $.), g (,+@dimetho/y@$@'$@nitrovinyl-naphthalene in +, m!
anhydrous "HB. "here 3as an immediate loss of color. After ( h stirring at , deg C, the temperature 3as brought up to a gentle reflu/ on the steam bath
for $, min, then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of 2 m! IPA follo3ed by &.& m! &K 5a9H.
"he reaction mi/ture 3as filtered, and the filter cake 3ashed 3ith several portions of "HB. "he combined filtrate and 3ashings 3ere stripped of solvent
under vacuum providing 0.1 g of a pale amber oil that 3as distilled at (+&@(1, deg C at ,.$ mm8Hg to give (.$& g of product as an absolutely 3hite oil.
"his 3as dissolved in 2 m! IPA, and neutrali6ed 3ith concentrated HCl forming immediate crystals of the hydrochloride salt in the alcohol solvent. "hirty
m! of anhydrous <t$9 3as added, and after complete grinding and mi/ing, the hydrochloride salt 3as removed by filtration, <t$9 3ashed, and air dried
to constant 3eight. "he spectacular 3hite crystals of (,+@dimetho/ynaphthyl@$@ethylamine hydrochloride '$C@C@5- 3eighed (.$0 g and had melting
properties of darkening at (%, deg C, and decomposing in the $0&@$+& deg C area. Anal. 'C(+H()Cl59$- C,H.
;9SAC<E $, @ +, mg.
;4:A"I95E $, @ 0, h.
L4A!I"A"IM< C9??<5"SE '3ith $+ mg- "he effects 3ere interestingly colored by the reading of Alan Iatts7 Doyous Cosmology during the coming@on
period. "he only body negatives 3ere some urinary retention and a feeling of a shallo3 but continuing amphetamine stimulation. .ut not enough to be
actually Gingly, nor to interfere 3ith sleep that evening. "here is not much psychedelic here, but there is something really going on any3ay. "his has
some similarities to the antidepressant 3orld.
'3ith 0& mg- ?uch 3riting, much talking, and there 3as considerable residual a3areness the ne/t day. Someho3 this material is not as friendly as the
other $C@C7s.
'3ith 0& mg- "hinking is clear. 5o fu66iness, no feeling of being pushed. 5one of the 3alking on the fine middle line bet3een light and dark that is the
e/citement and the threat of !S;. "his is Gust a friend, an ally, 3hich invites you to do anything you 3ish to. Pcomment added t3o days laterQ :?y sleep
3as not deep enough, but it 3as pleasant and relatively resting. "he 3hole ne/t day I 3as feeling happy, but 3ith an overlay of irritability. Strange
mi/ture. .y bedtime the irritability had become a mild depression. I feel that there might have been a threshold continuing for a couple of days. "he
character of my dreaming had the stamp of drug on it. "his compound, in retrospect, presents some problems that cause a faint unease.

#'$ $!-H; $,)-0"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of &, g $,&@dimetho/yben6aldehyde in (,, g nitromethane 3as treated 3ith & g of anhydrous ammonium acetate, and heated
on the steam bath for + h. "he solution 3as decanted from a little insoluble material, and the solvent removed under vacuum. "he clear oily residue
3as dissolved in (,, m! boiling IPA 3hich, after standing a moment, set up as dense crystals. After returning to room temperature, these 3ere removed
by filtration, the product 3as 3ashed 3ith IPA and air dried, yielding &1.% g $,&@dimetho/y@beta@nitrostyrene as spectacular yum@yum orange crystals 3ith
a mp of ((%@($, deg C. An analytical sample, from ethyl acetate, melted at ($,@($( deg C.
A suspension of 1, g !AH in &,, m! anhydrous "HB 3as placed under an inert atmosphere, stirred magnetically, and brought up to reflu/ temperature.
"here 3as added, drop3ise, &1 g of $,&@dimetho/y@beta@nitrostyrene dissolved in "HB, and the reaction mi/ture 3as maintained at reflu/ for 01 h. After
being brought to room tem@perature, the e/cess hydride 3as destroyed 3ith +, m! IPA, follo3ed by &, m! of (&K 5a9H. An additional (,, m! "HB
3as reFuired for easy stirring, and an additional (&, m! H$9 3as needed for complete conversion of the aluminum salts to a loose, 3hite, filterable
consistency. "his solid 3as removed by filtration, and the filter cake 3ashed 3ith additional "HB. "he combined filtrate and 3ashes 3ere stripped of
solvent under vacuum, and the residue dissolved in dilute H$S9+. Iashing 3ith 0/2& m! CH$Cl$ removed most of the color, and the aFueous phase
3as made basic 3ith aFueous 5a9H and ree/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent yielded 0%.$ g of a pale amber oil that 3as
distilled. "he fraction boiling at ),@(,, deg C at ,.+ mm8Hg 3eighed $+.) g and 3as 3ater@3hite product amine. As the free base, it 3as suitable for
most of the further synthetic steps that might be 3anted, but in this form it picked up carbon dio/ide rapidly 3hen e/posed to the air. It 3as readily
converted to the hydrochloride salt by dissolution in 1 volumes of IPA, neutrali6ation 3ith concentrated HCl, and addition of sufficient anhydrous <t$9 to
produce a permanent turbidity. Crystals of $,&@dimetho/yphenethylamine hydrochloride '$C@H- spontaneously formed and 3ere removed by filtration,
3ashed 3ith <t$9, and air dried. "he mp 3as (0)@(0% deg C.
;9SAC<E unkno3n.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E I kno3 of no record of $C@H ever having been tried by man. It has been assumed by everyone 'and probably
correctly so- that this amine, being an e/cellent substrate for the amino o/idase systems in man, 3ill be completely destroyed by the body as soon as it
gets into it, and thus be 3ithout action. In virtually all animal assays 3here it has been compared 3ith kno3n psychoactive drugs, it remains at the Nless@
activeN end of the ranking.
It is, ho3ever, one of the most magnificent launching pads for a number of rather unusual and, in a couple of cases, e/traordinary drugs. In the lingo of
the chemist, it is amenable to Nelectrophilic attack at the +@position.N And, in the lingo of the psychopharmacologist, the N+@position is 3here the action is.N
Brom this 'presumably- inactive thing have evolved end products such as $C@., $C@I, $C@C, and $C@5. And in the future, many possible things as might
come from a carbinol group, an amine function, or anything that can stem from a lithium atom.

#'' $!-"; $,)-0"METH%+Y-(-"%0%,HE#ETHYAM"#E
S>5"H<SISE A mi/ture of 2.+ g phthalic anhydride and %.,& g of $,&@dimetho/yphenethylamine 'see the recipe for $C@H for its preparation- 3as heated
3ith an open flame. A single clear phase 3as formed 3ith the loss of H$9. After the hot melt remained Fuiet for a fe3 moments, it 3as poured out into
a crystalli6ing dish yielding (+.) g of a crude solid product. "his 3as recrystalli6ed from $, m! CH0C5, 3ith care taken for an endothermic dissolution,
and an e/othermic crystalli6ation. .oth transitions must be done 3ithout haste. After filtration, the solids 3ere 3ashed 3ith $/$, m! he/ane and air
dried to constant 3eight. A yield of ($.%0 g of 5@'$@'$,&@dimetho/yphenyl-ethyl-phthalimide 3as obtained as electrostatic yello3 crystals, 3ith a mp of
(,%@((( deg C. A sample recrystalli6ed from IPA 3as 3hite, 3ith a mp of ((,@((( deg C. Anal. 'C()H(259+- C,H,5.
"o a solution of ($.% g 5@'$@'$,&@dimetho/yphenyl-ethyl-phthalimide in (0, m! 3arm '0& deg C- acetic acid 3hich 3as being vigorously stirred, there
3as added a solution of (, g iodine monochloride in +, m! acetic acid. "his 3as stirred for ( h, 3hile being held at about 0, deg C. "he reaction
mi/ture 3as poured into (&,, m! H$9 and e/tracted 3ith +/2& m! CH$Cl$. "he e/tracts 3ere pooled, 3ashed once 3ith (&, m! H$9 containing $., g
sodium dithionite, and the solvent removed under vacuum to give (1.$ g of 5@'$@'$,&@dimetho/y@+@iodophenyl-ethyl-phthalimide as yello3 amber solids
3ith a mp of (00@(+( deg C. "his mp 3as improved by recrystalli6ation from 2& m! CH0C5, yielding ($.$ g of a pale yello3 solid 3ith mp (+%@(&( deg
C. A small sample from a large Fuantity of IPA gives a 3hite product melting at (&&.&@(&2 deg C.
A solution of ($.$ g 5@'$@'$,&@dimetho/y@+@iodophenyl-ethyl-phthalimide in (&, m! hot IPA 3as treated 3ith 1., m! of hydra6ine hydrate, and the clear
solution 3as heated on the steam bath. After a fe3 minutes there 3as the generation of a 3hite cottage cheese@like solid '(,+@dihydro/yphthali6ine-.
"he heating 3as continued for several additional h, the reaction mi/ture cooled, and the solids removed by filtration. "hese 3ere 3ashed 3ith $/(, m!
<t9H, and the pooled filtrate and 3ashes stripped of solvent under vacuum giving a residue 3hich, 3hen treated 3ith aFueous hydrochloric acid, gave
0.+0 g of voluminous 3hite crystals. "his, after recrystalli6ation from $ 3eights of H$9, filtering, 3ashing first 3ith IPA and then 3ith <t$9, and air
drying, gave $.(1 g $,&@dimetho/y@+@iodophenethylamine hydrochloride '$C@I- as a 3hite microcrystalline solid, 3ith a mp of $+1@$+2 deg C. Anal.
'C(,H(&ClI59$- C,H,5.
;9SAC<E (+ @ $$ mg.
;4:A"I95E 1 @ (, h.
L4A!I"A"IM< C9??<5"S '3ith , mg- I 3as present at a group meeting, but 3as only an observer. Iith 6ero milligrams of $C@I, I 3as able to get to a
delightful plus $.& in about five minutes after I arrived at your place, and absorbed the ambience of the folks 3ho had actually imbibed the material. ?y
level lasted about four hours and came do3n at about the same time as did the others. "here 3ere no after@effects e/perienced e/cept for a pleasant
languor.
'3ith (& mg- Comfortable onset. ?ost notable are the visuals, patterning like $C@. 'Persian carpet type-, very colorful and active. ?uch more balanced
emotional character, but still no feeling of insight, revelation, or progress to3ard the true meaning of the universe. And at & (8$ hours drop@off very
abrupt, then gentle decline. I 3ould like to investigate museum levels.
'3ith (1 mg- "here 3as an immediate alert 3ithin minutes. As usual, it 3as only an a3areness, then nothing happened for a 3hile. In retrospect, I see
some type of activity or a3areness 3ithin +, minutes, 3hich then builds up over time. "he peak 3as at $ hours and seemed to maintain itself for a
3hile. 5ear the peak, there 3as some hallucinogenic activity, though not a lot. "he pictures in the dining room had color and pattern movement that
3as fairly detailed. Bocusing on other areas, such as 3alls or the outside of the house, produced little activity, though I tried. "here 3as certainly a lot of
color enhancement. "here 3as also that peculiar aspect of the visual field having darkened or shado3ed areas. "hese darker areas seemed to shift
around to some degree. "hat aspect seems to be similar to $C@.. I don7t think I 3as more than *$.& at the peak. Coming do3n 3as uneventful. I 3as
do3n 3ithin 1 hours. I had no problems driving home, nor 3ere there any difficulties 3ith sleep. "here 3ere no body problems 3ith this material. I ate
like a horse.
'3ith (1 mg- "he (1 3as a bit much, I reali6ed, because my body 3as not sure of 3hat to do 3ith all the energy. 5e/t time I7ll try (+ or (&. Ho3ever, my
conversations 3ere e/tremely clear and insightful. "he degree of honesty 3as incredible. I 3as not afraid to say anything to anyone. Belt really good
about myself. Mery centered, in fact. A bit tired at day7s end. <arly bedtime.
'3ith $, mg- I think there is slightly less than full immersion in the sensual, 3ith this material, compared 3ith $C@., but I suspect it7s more a matter of
getting used to the language of $C@I and the feelings L getting tuned to a slightly different freFuency, really L rather than that the material is less sensual
or less easy to use sensually. Dust different freFuency, and 3e are very, very used to $C@.. Cood on the body. "ransition, for me, not as strongly dark
as $C@.. .ut it could certainly take a lot more e/ploring, if 3e 3ere able to give the time 'about % hours- to it. 5e/t dayE sleep e/cellent. <nergy ne/t
day unusually good. Luite tired by evening.
<="<5SI95S A5; C9??<5"A:>E "he freFuent comparisons bet3een $C@I and $C@. stem, 3ithout doubt, from a bit of chemical suggestion. "he
t3o compounds have structures that are truly analogous, in technical terms. In one, there is a strategically located iodine atom, and in the other, an
identically placed bromine atom. "hese are directly above and belo3 one@another in the periodic table. And 3hat is particularly maddening to the
synthetic diddler, is that they cannot be lengthened, or shortened, or sFuooshed around in any 3ay. >ou can7t make a longer and narro3er version of a
bromine atom, as you can do 3ith, say, a butyl group. >ou7ve got 3hat you7ve got, like it or not. 5o subtle variations.
.ut, on the brighter side of the picture, you have a heavy atom here, and this atom is intrinsic to the central activity of the compound. So, these materials
are naturals for radio@labelling e/periments. $C@I has been made radioactive 3ith radio@iodine, but the most impressive findings have been made 3ith
the 0@carbon analog, ;9I.
9ne Fuotation from an observer of a group e/periment is enclosed; an e/periment 3ith 6ero milligrams being taken. "his is a instructive observation of
3hat has been called a :contact high. "here is one Iodot3eetio kno3n. In Scrabble, 3ould you challenge a 3ord that had seven of its eleven letters as
vo3elsH <specially if the vo3els 3ere, specifically, iooeeioH It sounds Gust a little like the noise coming out of 9ld ?c;onald7s farm. .ut a "3eetio there
is, namely, the $@<t9@homologue of $C@I. "his is $@etho/y@+@iodo@&@metho/yphenethylamine, or $CI@$<"9. "he hydrochloride salt 3as a 3hite,
crystalline product 3ith a melting point of (2&@(2&.& deg C. "he threshold level of activity 3as seen at an oral dose of & milligrams, and the generated
effects 3ere completely dispersed in a couple of hours. ?ost interestingly, larger doses, of up to &, milligrams orally, seem to produce no more intense
an effect, but simply to stretch out this threshold for an additional couple of hours. At no level that has been tried, has $CI@$<t9 produced even a plus@
t3o response.
Ihere else can one go, from $C@IH "he iodine is the fourth, and the last of the so@called halogens, at the bottom of the classical periodic table. .ut,
thanks to the miracles that have accompanied us into the nuclear age, there is a fifth halide no3 kno3n, Astatine. All of its isotopes are radioactive,
ho3ever, and it seems unlikely that there 3ill ever be an entry 'other than this one- for $,&@dimetho/y@+@astatophenethylamine. Ihat might be
speculated as to its activityH Probably similar in potency to $C@I, reFuiring maybe (, or $, milligrams. "he duration 3ould be dicey to measure, since
the isotope 3ith the longest kno3n half@life is half decayed in about ) hours, and the longest lived natural isotope 'for those 3ho insist on natural rather
than man@made things- is half decayed in less than a minute. "3o predictions 3ould be pretty solid. >ou might have Fuite a Gob accumulating your (,
milligrams of Astatine, as the most that has so far been made at one time is only about ,.,& micrograms, appro/imately a millionth of the amount
needed. And the second predictionH >ou 3ould not survive the screaming radiation that 3ould bombard you if you could get the needed & or (,
milligrams of radio@astatine onto that magic +@position, and the resulting $C@A into your tummyO

#'( $!-#; $,)-0"METH%+Y-(-#"T*%,HE#ETHYAM"#E
S>5"H<SISE A cooled, stirred solution of (., g $,&@dimetho/yphenethylamine 'see the recipe for $C@H for its preparation- in $, m! glacial acetic acid
3as treated 3ith 0.0 m! 2,K H590 in small portions, 3ith the reaction temperature kept do3n 3ith periodic cooling. After the addition 3as completed,
the stirring 3as continued until there 3as the spontaneous separation of a yello3 solid. "his 3as $,&@dimetho/y@+@nitrophenethylamine nitrate '$C@5-
3hich 3as obtained after removal by filtration, 3ashing 3ith <t$9 and air drying, as a fluffy yello3 solid. "his 3eighed (.,+ g and melted, 3ith
decomposition, in the area of (2,@(), deg C, depending on the rate of heating. A solution of ,.) g of this nitrate salt in &, m! H$9 3as made basic 3ith
aFueous 5a9H. </traction 3ith 0/&, m! CH$Cl$, and removal of the solvent under vacuum gave the free base as a residue. "his 3as distilled at (0,@
(&, deg C at ,.0& mm8Hg to give an orange@red oil that 3eighed ,.& g and set up as crystals. "his 3as dissolved in 0 m! IPA, neutrali6ed 3ith 2 drops
of concentrated HCl 'the color lightened considerably at the titration end point- and diluted 3ith & m! anhydrous <t$9. "here 3as the formation of the
hydrochloride salt 3hich 3as a pumpkin@colored crystalline mass. After removal by filtration, <t$9 3ashing and air drying, these crystals 3eighed ,.++
g. "he mp, (%0@(%& deg C, 3as not improved by recrystalli6ation from any of several solvents '?e9H, IPA, CH0C5-. "he perchlorate salt 3as a yello3
solid from ?e9H, 3ith a mp of $(( deg C, 3ith decomposition. 5itration of $C@H in a mi/ture of acetic acid and acetic anhydride produced the acetamide
derivative of $C@5 as yello3 crystals 3ith a mp (+$.&@(+0 deg C. Bor the nitrate saltE Anal. 'C(,H(&5092- C,H. "his 3as the form used for all human
titrations.
;9SAC<E (,, @ (&, mg.
;4:A"I95E + @ 1 h.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- "his came on very fast L I 3as a3are of it 3ithin a half hour, and it got as far as it 3ould go by an hour.
"here are similarities to ?;?A, but missing is the benign anti@stress component. I am light@headed, and there Gust might be a little eye 3iggling. And
then it dropped right off to nothing 3ithin a couple of hours.
'3ith (&, mg- "here may have been some visual changes, I7m not sure. .ut the talking 3as e/tremely easy. If there 3ere no other things to use, this
3ould be e/cellent, but there are other compounds available. "his doesn7t have too high a priority.
'3ith (&, mg- Am I enGoying itH 5ot e/actly, but I am in a good mood. "here is not the light@filled energy that some other materials can provide. .y si/
hours, pretty much baseline. Strange material, but okay. Binal scoreE body *0, mind *$, barely.
<="<5SI95S A5; C9??<5"A:>E A most consistent feature 3ith $C@5 3as the fact that in every report, some3here, there is the note that it
someho3 came up Gust a little short of e/pectations. Brom the esthetic point of vie3, the pure salt is yello3 rather than the usual 3hite color, so the
solutions that are to be consumed are by definition also yello3 colored. Brom the structural point of vie3, the +@nitro group, like the +@bromo group of
$C@., is a dead@end. It cannot be stretched or compressed or lengthened or shortened. "his uniFue aspect demands that you have to live 3ith 3hat
you have, as there are no subtle 3ays of modifying the molecule. Iith $C@., the end product 3as a total 3inner; there 3as no 3ish to modify it. Iith
$C@5 the end product is something a little less, and there is no 3ay to modify it.

#') $!-%-(; $,)-0"METH%+Y-(-&i--,*%,%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0.(, g )&K 9H pellets in 0, m! 3arm ?e9H there 3as added 1.(1 g $,&@dimetho/yphenol 'there 3as immediate
darkening- follo3ed by ).& g isopropyl iodide. "he reaction mi/ture 3as heated on the steam bath for 0.& h. Ihite crystals of I appeared at the end of
the first h. "he mi/ture 3as poured into ),, m! H$9 'it 3as still basic- and acidified 3ith HCl. "his 3as e/tracted 3ith 0/(,, m! CH$Cl$, and the
combined e/tracts 3ashed 3ith $/(,, m! &K 5a9H. "he organic phase 3as stripped of solvent under vacuum, and the residual dark amber oil '1.+ g-
distilled at ((,@(0, deg C at ,.2 mm8Hg. "here 3as obtained &.2 g of (,+@dimetho/y@$@'i-@propo/yben6ene as a 3hite oil.
A mi/ture of (, g 5@methylformanilide and (, g P9Cl0 3as heated on the steam bath for (, min producing a deep claret color. "o this there 3as added
&.( g of (,+@dimetho/y@$@'i-@propo/yben6ene, and the immediately e/othermic reaction mi/ture 3as heated on the steam bath for +& min. It 3as then
poured into ),, m! H$9 3hich 3as stirred until the dark oil changed into loose, light@colored solids. "hese 3ere removed by filtration giving &.2 g of an
amber crystalline product 3ith a mp of 21@2) deg C. "his 3as dissolved in an eFual 3eight of ?e9H, and heated to a solution 3hich 3as clear at the
boiling point. "his 3as brought to , deg C and held there for several hours, yielding $,&@dimetho/y@+@'i-@propo/yben6aldehyde as a fine, off@3hite
crystalline product 3hich, after filtering and air drying, 3eighed +.,0 g. "he mp 3as 2%@), deg C 3ith prior shrinking at 2( deg C. Anal. 'C($H(19+-
C,H.
A solution of 0.% g $,&@dimetho/y@+@'i-@propo/yben6aldehyde in $, g nitromethane 3as treated 3ith ,.(2 g anhydrous ammonium acetate and heated on
the steam bath for (.$& h. "he progress of the condensation 3as readily follo3ed by a "!C analysis of the reaction mi/ture. Iith silica gel plates, the
starting aldehyde and the product nitrostyrene had :f7s of ,.(1 and ,.&, resp., using CH$Cl$ as a developing solvent. "he e/cess solvent 3as removed
under vacuum to give a red residue that 3as dissolved in (, m! boiling ?e9H. "he solution spontaneously crystalli6ed giving, after filteration and air
drying, +.( g of orange crystals of $,&@dimetho/y@beta@nitro@+@'i-@propo/ystyrene.
A solution of !AH '1, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.1,
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of +., g $,&@dimetho/y@beta@nitro@+@'i-@propo/ystyrene as a solid,
perhaps $,, mg at a time. "here 3as an immediate loss of color after each addition. "he final pale salmon@colored solution 3as stirred for $ h as it
returned to room temperature. "he e/cess hydride 3as destroyed by the cautious addition of ) m! IPA, 3hich 3as follo3ed by & m! (&K 5a9H
follo3ed, in turn, by sufficient additional "HB to make the suspension of inorganic salts loose and filterable. "he reaction mi/ture 3as filtered, and the
filter cake 3ashed 3ith additional "HB. "he filtrate and 3ashings 3ere combined and stripped of solvent under vacuum providing +.1 g of a pale amber
oil. "his 3as dissolved in dilute H$S9+, 3ashed 3ith $/&, m! CH$Cl$, made basic 3ith aFueous 5a9H, and e/tracted 3ith 0/&, m! CH$Cl$.
:emoval of the solvent under vacuum yielded $.0 g of residue 3hich 3as distilled at ((&@($& deg C at ,.0 mm8Hg to give ,.%+ g of a clear 3hite oil. "his
3as dissolved in & m! IPA, neutrali6ed 3ith ($ drops of concentrated HCl, and diluted 3ith (, m! anhydrous <t$9. Ihite crystals of $,&@dimetho/y@+@
'i-@propo/yphenethylamine hydrochloride '$C@9@+- separated, and 3ere removed by filtration, <t$9 3ashed, and air dried. "he final 3eight 3as ,.&) g.
;9SAC<E greater than 1, mg.
;4:A"I95E unkno3n
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- I became a3are of something in the front part of my head, and there 3as a lot of ya3ning. "he body 3as
a3are of the e/periment. .ut also there 3as a general e/hilaration and e/citement, 3hich lasted for a fe3 hours. At best, I am at a plus one.
<="<5SI95S A5; C9??<5"A:>E "he full activity of $C@9@+ is yet to be discovered. It represents an interesting hybrid lying in bet3een several
fascinating compounds.
Birst and foremost, all these carry the $,+,&@trisubstitution 3hich has consistently proven to be the most interesting and the most active of the
phenethylamines. And 3ith very fe3 e/ceptions, the $@ and the &@ are metho/yl groups.
"he sulfur analogues in this area, compounds 3ith an alkylthio group at the +@position of the $,&@dimetho/yphenethylamine backbone, are the $C@"
things. "he replacement of a sulfur 3ith an o/ygen, Fuite rightly, should give rise to the $C@9 counterparts. And they have been given the same
numbering system that 3as besto3ed upon the :"S series. $C@"@+ 3as the +@isopropylthio compound and one of the most interesting of this family.
And so, Fuite reasonably, the o/ygen coun@terpart should be the $C@9@+ analogue, and should be one of the first e/plored.
"he e/tension of the +@alko/y@group led to the discovery of the "?A@$ L ?<? L ?IP? L ?P? L ?.? series of amphetamine analogues. "he $@
carbon counterparts of these 3ould be a fascinating series to e/plore, I thought, if there 3as some encouragement to be had from a preliminary try in
this field.
"his 3as a first shot in the dark, the actual trial e/ample, and it certainly didn7t provide much encouragement. "he three@carbon analogue, ?IP?, 3as
made 'F.v.- but not e/plored, follo3ing the disappointing trials of ?P?. If this area is ever re@opened, the numbering should reasonably follo3 the sulfur
materials. "he +@etho/y material 3ould be $C@9@$, the +@'n-@propo/y compound $C@9@2, and the +@'n-@buto/y compound $C@9@(%. "hese are the e/act
analogues of $C@"@$, $C@"@2, and $C@"@(%, resp., and the $@carbon homologues of ?<?, ?P?, and ?.?. "he simplest member of this series, the
methyl counterpart, is $C@9, and it is the obvious analogue of $C@". "his is also called $,+,&@"?P<A, and its story is presented else3here.
.ut, 3ith the probable lo3 eventual potency of $C@9@+, I feel that the $C@9 series 3ill not be an e/citing one.

#'1 $!-,; $,)-0"METH%+Y-(-&n--,*%,Y,HE#ETHYAM"#E
S>5"H<SISE "o a stirred solution of (0) g p@dimetho/yben6ene in +,, m! CH$Cl$ there 3as added a suspension of (2$ g anhydrous AlCl0 in &,, m!
CH$Cl$ 3hich contained %$.& g propionyl chloride. After stirring for (.& h the reaction mi/ture 3as poured into $ ! H$9 containing ice. "he phases 3ere
separated, and the aFueous fraction 3as e/tracted 3ith $/(,, m! CH$Cl$. "he organic phase and the e/tracts 3ere pooled, 3ashed once 3ith H$9,
and then 3ith $/(,, m! &K 5a9H. "he solvent from the organic phase 3as removed under vacuum, yielding a deeply colored residue. "his 3as
distilled at (&,@(1& deg C at $, mm8Hg yielding (2, g of $,&@dimetho/ypropiophenone as a pale amber@colored oil. Acidification of the sodium hydro/ide
e/tract, e/traction 3ith CH$Cl$, and evaporation of the solvent, yielded 0 g of an oil that slo3ly crystalli6ed. "hese solids, on recrystalli6ation from
?e9H, provided (., g of $@hydro/y@&@metho/ypropiophenone 3ith a mp of +2@+) deg C. "he same Briedel Crafts reaction, conducted on the same
scale in CS$ rather than in CH$Cl$, reFuired reduced temperature '& deg C- and a $+ h reaction period. "his solvent variation, 3ith the same 3orkup
and isolation, gave 21 g of $,&@dimetho/ypropiophenone as a pale amber oil boiling at (0,@(02 deg C at + mm8Hg.
A total of (&, g mossy 6inc 3as amalgamated by treatment 3ith a solution of (& g mercuric chloride in ( ! H$9. After s3irling for ,.& h, the H$9 phase
3as removed by decantation and the 6inc added to a ( ! three neck flask. "o this there 3as added $, m! H$9 and $, m! concentrated HCl, follo3ed
by $, g of $,&@di@metho/ypropiophenone dissolved in &, m! <t9H. "his mi/ture 3as held at reflu/ 3ith a heating mantle overnight, 3ith the occasional
addition of HCl as needed to maintain acidic conditions. After cooling to room temperature, the residual solids 3ere removed by filtration, and the filtrate
e/tracted once 3ith (,, m! CH$Cl$ 'this 3as the upper phase-. Sufficient H$9 3as then added to allo3 e/traction 3ith $/(,, m! additional CH$Cl$
3ith the organic solvent being the lo3er phase. "he combined organic e/tracts 3ere 3ashed t3ice 3ith &K 5a9H, follo3ed by one 3ashing 3ith dilute
acid. :emoval of the solvent under vacuum yielded () g of a dark bro3n oil that 3as distilled at the 3ater pump to yield 2.$ g of $,&@
dimetho/ypropylben6ene as a light yello3 oil boiling at %,@(0, deg C.
A mi/ture of $$ g $,&@dimetho/ypropylben6ene, $0 g P9Cl0 and $$ g 5@methylformanilide 3as heated on the steam bath for (.& h. "he hot, dark
reaction mass 3as poured into ( ! H$9, 3hich allo3ed the eventual separation of $,&@dimetho/y@+@'n-@propylben6aldehyde as a clear yello3 oil
3eighting (+ g. Although the homologous +@ethyl and +@butyl ben6aldehydes 3ere clean crystalline solids, this propyl homologue remained an oil. Cas
chromatographic analysis sho3ed it to be about %,K pure, and it 3as used as obtained in the nitrostyrene steps 3ith either nitromethane 'here- or
nitroethane 'under ;9P:-.
"o a solution of (0 g $,&@dimetho/y@+@'n-@propylben6aldehyde in (,, m! nitromethane, there 3as added (.0 g anhydrous ammonium acetate and the
mi/ture held at reflu/ for ( h. :emoval of the solvent8reactant under vacuum yielded a spontaneously crystalli6ing mass of orange solids that 3as
removed 3ith the help of a little ?e9H. After filtering and air drying there 3as obtained 2.& g $,&@dimetho/y@beta@nitro@+@'n-@propylstyrene 3ith a mp of
(()@($$ deg C. :ecrystalli6ation from CH0C5 gave an analytical sample 3ith a mp ($0@($+ deg C. Anal. 'C(0H(259+- 5.
In a ( ! round bottomed flask 3ith a magnetic stirrer under a He atmosphere there 3as added ($, m! ( ? !AH in tetrahydrofuran. "his stirred solution
3as cooled 3ith an e/ternal ice bath, and there 3as added, drop3ise, 0.$ m! of (,,K H$S9+, freshly made by the addition of (0.& g $,K fuming
H$S9+ to (&., g of ordinary %1K concentrated H$S9+. Ihen the addition 3as complete, a total of 2.$ g of dry $,&@dimetho/y@beta@nitro@+@'n-@
propylstyrene 3as introduced as solids in several batches, against a flo3 of He, over the course of $, min. "he reaction mi/ture 3as allo3ed to come to
room temperature, and stirred for an additional ,.& h, then brought to reflu/ for (, min on the steam bath. "he e/cess hydride 3as destroyed 3ith () m!
IPA, and then sufficient (&K 5a9H 3as added 3hich made the aluminum o/ides distinctly basic and of a filterable te/ture. "he inorganics 3ere
removed by filtration, and the filter cake 3ashed 3ith additional "HB. "he combined filrate and 3ashes 3ere stripped of solvent, yielding several g of a
pale yello3 oil that 3as suspended in a large Fuantity of dilute H$S9+. "he aFueous phase 3as filtered free of insolubles, 3ashed 3ith a little CH$Cl$,
and made basic 3ith aFueous 5a9H. "his 3as e/tracted 3ith 0/+, m! CH$Cl$ and, after the removal of the solvent under vacuum, the residual $ g of
off@3hite oil 3as distilled. A fraction that distilled at (,,@((, deg C at ,.0 mm8Hg 3as 3ater 3hite, 3eighed (.&% g and spontaneously crystalli6ed. "his
fraction 3as dissolved in 2.& m! 3arm IPA and neutrali6ed 3ith ,.1 m! concentrated HCl. "he spontaneous crystals of $,&@di@metho/y@+@'n-@
propylphenethylamine hydrochloride '$C@P- 3ere suspended in $, m! anhydrous <t$9, filtered, <t$9 3ashed, and air dried. "he 3eight 3as (.1& g and
the mp 3as $,2@$,% deg C 3ith prior sintering at ()0 deg C., Anal. 'C(0H$$Cl59$- 5.
;9SAC<E 1 @ (, mg.
;4:A"I95E (, @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith 1 mg- I 3as not feeling so good. Hangover, I guess. "he material 3as so gentle in coming on, and soon my body
became Gangled. "hinking 3as easy. Merbali6ing 3as easy. .eing comfortable 3ith my body 3as not. ?y back hurt and then my legs hurt. ?y lo3er
back 3as in spasm. At first I did not particularly like 3hat this drug 3as doing to my body, but took a good look at it and decided that I 3as the culprit.
"ook a good look at my drinking so much, and decided that I didn7t need it. So much energy 3as going through me I didn7t kno3 3hat to do 3ith it. "he
3hole day 3as spent in physical discomfort. Bood tasted good, and 3e nibbled all day. ?y stomach 3as bloated. 5e/t day I 3as more or less like a
6ombie. I 3as 3iped out.
'3ith ) mg- Comes on slo3ly, not feeling intently until into $nd hour. I feel slight discomfort but override it responding to music. I take in air, directing it
inside to heal uncomfortable places, open up my clogged sinuses. Ionderful e/perience of clean, fresh, healing air. Bind that discomfort 6one is places
3here I think there is something 3rong 3ith me. I dissolve these places 3ith the feeling I7m 9. !ike myself better and better, and find more reasons to
enGoy and appreciate myself. I find this material po3erful, and an e/cellent 3orking material. 4nder other circumstances, 3ould probably spend more
time 3orking alone inside, 3here there 3ere great openings, and some of the most beautiful visuals I have seen for a long time. 4sually I do not get
visuals. I like the long action. I feel that this material 3orked for a good 3eek after the e/perience, 3ith internal processes taking place, many insights,
and energy running. At times the energy 3as a little uncom@fortable, but could al3ays be Fuelled by taking a moment for deep rela/ation or looking
directly at the internal process. I feel that much good internal 3ork has been done, a lot of it unconscious.
'3ith % mg- At the one hour point, I am barely off of baseline. It is not until almost the third hour that the e/perience is fully developed, and once there it
is maintained for another four hours. I 3as 3ell grounded but rather diffuse. I e/plored 3riting '3hich 3ent Fuite 3ell-, interpretation 'pictures and
reading both 9- and talking 'very good-. "his is an e/cellent level, and probably near the ma/.
'3ith ($ mg- Slo3 and even rise. At five minutes to seven 'suddenly the clock time makes no sense at all- I am at a 0* and feel that I have not yet
plateau7d. <rotic 3as e/cellent. ?usic good. <yes@closed imagery very different place than usual e/periences. Slo3, calm, strong images from an area
that has no apparent connection 3ith usual 3aking 3orld, yet underlies all of it. A cool, 3ise place 3hich has its o3n rules. All emotions and feeling
available, but there is a cool perspective 3hich informs all thinking. "alking superb and fun, and it 3as possible to feel our bodies healthy and full of
determination to remain so, despite obvious faults and self@indulgences. Could do a lot of learning 3ith this material, but probably not a group thing. It
3ould lend itself too easily to hypnotic po3er@games, and it 3ould be too easy to open up the shared consciousness level, 3hich 3ould be frightening to
a lot of people and bring about necessary escapes such as sickness. </cellent feeling the ne/t day.
<="<5SI95S A5; C9??<5"A:>E "here is certainly a broad mi/ture of e/periences 3ith $C@P but, on the 3hole, probably more favorable than not.
"here 3as one report of an e/perience in 3hich a single dosage of (1 mg 3as clearly an overdose, 3ith the entire e/periment labeled a physical
disaster, not to be repeated. A consistent observation is that there may not be too much latitude in dosage bet3een that 3hich 3ould be modest, or
adeFuate, and that 3hich 3ould be e/cessive. "he need for individual titration 3ould be most important 3ith this compound.

#'2 !,M; !Y!%,*%,YMES!A"#E;
(-!Y!%,*%,YMETH%+Y-',)-0"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of $.) g homosyringonitrile 'see under < for synthesis- in $, ml acetone containing about &, mg decyltriethylammonium
iodide, there 3as added 0., g cyclopropylmethyl chloride and &., g 5aI. Stirring 3as continued during a color change from pale yello3 to blue. "here
3as then added $.% g of finely po3dered anhydrous $C90, resulting in a beautiful turFuoise color. "he mi/ture 3as held at reflu/ on the steam bath for
0 h, 3hich discharged all color. "he solvent 3as removed under vacuum, and the residues 3ere added to (,, m! H$9. "his solution 3as e/tracted
3ith 0/2& m! CH$Cl$, the e/tracts 3ere pooled, 3ashed 3ith $/&, m! &K 5a9H, and the organic solvent removed under vacuum. "he residual oil
3eighed +.$ g, and 3as distilled at (+,@(&& deg C at ,.+ mm8Hg to yield +@cyclopropylmetho/y@0,&@dimetho/yphenylacetonitrile as a colorless oil
3eighing $.) g 3hich spontaneously crystalli6ed. Its mp 3as ++@++.& deg C after recrystalli6ation from ?e9H8H$9. Anal. 'C(+H(2590- C,H.
A suspension of (.0 g !AH in 1& m! anhydrous "HB under He 3as cooled to , deg C 3ith stirring, and ,.)& m! of (,,K H$S9+ 3as slo3ly added.
"hen, 3ith continued stirring, a "HB solution of $.2 g of +@cyclopropylmetho/y@0,&@dimetho/yphenylacetonitrile in &, m! "HB 3as added drop3ise. After
the addition 3as complete, the mi/ture 3as brought to a boil briefly on the steam bath, cooled, and treated 3ith sufficient IPA to destroy the e/cess
hydride. "hen there 3as added an amount of (&K 5a9H sufficient to produce a loose filterable solid form of aluminum o/ide. "his 3as removed by
filtration, and the filter cake 3ashed 3ith "HB. "he pooled filtrate and 3ashes 3ere stripped of solvent, and the residue 3as dissolved in dilute H$S9+,
3ashed 3ith $/&, m! CH$Cl$, made basic 3ith aFueous 5a9H, and then e/tracted 3ith $/&, m! of CH$Cl$. After removal of the solvent, the residue
3as distilled at ($)@(+, deg C at ,.+ mm8Hg to yield $.& g of a 3hite oil. "his 3as dissolved in (, m! IPA, and treated 3ith 0, drops of concentrated HCl
3hich 3as Gust sufficient to demonstrate acidity as Gudged by e/ternal dampened pH paper. "he addition of $& m! anhydrous <t$9 to the stirred solution
allo3ed, in a fe3 minutes, the product +@cyclopropylmetho/y@0,&@dimetho/yphenethylamine hydrochloride 'CP?- to spontaneously crystalli6e as a fine
3hite solid. "he yield 3as (.) g, and a second crop of ,.) g 3as obtained from the IPA8<t$9 mother liFuors. "he mp 3as (2$@(20 deg C. Anal.
'C(+H$$Cl590- C,H.
;9SAC<E 1, @ ), mg.
;4:A"I95E ($ @ () h.
L4A!I"A"IM< C9??<5"SE '3ith 2, mg- I 3as surprised at the fast development of this drug, 3ith the kno3ledge that it 3as a long@laster. "3enty
minutes into it I 3as a3are of some changes, and by the end of one and a half hours there 3as a complete plus three. "he most remarkable property is
the eyes@closed imagery. 5o, not Gust imagery but fantasy. It is not completely benign, but it locks into music 3ith an e/traordinary fit. I 3as at one
moment keenly a3are of my body touching the rug, the tactile aspects of my surroundings, and then I 3ould find that my 3orld 3as simply my personal
sphere of reality that kept engulfing everything about me, all completely augmented by the music. Constructed by the music. I hoped that I 3ouldn7t
offend anyone else around me 3ith this gro3ing 3orld of mine. <yes open, there 3as not that much of note. 5ot much insight. 5ot much in the 3ay of
visuals. .y the eighth hour an effort to sleep sho3ed me ho3 e/posed and vunerable I 3as, and 3hen I closed my eyes I needed my guards against
this fantasy 3orld. <ven at the t3elth hour there 3as no easy 3ay to rela/ and sleep. 4se higher dosages 3ith caution.
'3ith 2, mg- "here is a goodly amount of eyes@closed patterning but I found e/ternal sounds to be irritating. Moices, and even music, seemed to be
intrusive. I didn7t 3ant to share my space 3ith anyone. I 3as reminded of mescaline, in that I kept losing the a3areness of the drug7s role in my
e/perience. Misual e/aggerations are probably right around the corner. "he residual effects 3ere too much to ignore, but (,, milligrams of phenobarb
at about the t3elth hour allo3ed me to lie do3n Fuietly.
'3ith ), mg- A 3ild day of profound philosophy, 3ith discussions of the art of molecules, the origins of the universe, and similar 3eighty trivia. ?uch day@
dreaming in erotic areas, but by and large, it 3ent on a bit too long. I 3as tired.
<="<5SI95S A5; C9??<5"A:>E In the literary 3orld, the guy 3ho is on your side, your leader, your champion, is the protagonist and the guy he
battles, your enemy, is the antagonist. "hese same roles are played in the 3orld of pharmacology, but the names are slightly changed. A drug 3hich
does the needed or e/pected thing is called the agonist rather than protagonist, but the drug that gets in its 3ay is still called the antagonist.
"he cyclopropylmethyl group plays an interesting role in the 3orld of narcotics. "here are numerous e/amples of opiates 3ith a methyl group attached
to a nitrogen atom 3hich are famous for being valuable in producing analgesia and sedation. "hese run the gamut from natural alkaloids such as
morphine and codeine, to synthetic variants such as ;ilaudid and Percodan. And yet, 3ith most of these narcotics, 3hen the methyl on the nitrogen is
removed, and a cyclopropylmethyl group put into its place, the agonist becomes an antagonist. 9/ycodone 'the active narcotic thing in Percodan-
becomes 5altre/one, a drug that 3ill immediately snap a heroin victim out of his overdose.
Cyclopropylmescaline 'CP?- is a molecule that is very simply mescaline itself, 3ith a methyl group removed from an o/ygen atom and a
cyclopropylmethyl group put on instead. ?ight CP? be not only inactive, but actually block the action of mescalineH Interesting concept. .ut it turned
out to be entirely 3rong.
"he amphetamine analog of CP? should be easily made from the alkyl@ation of syringaldehyde 3ith cyclopropyl chloride, follo3ed by conventional
reaction of the resulting aldehyde 3ith nitroethane, and finally a reduction step. "here is no reason to believe that the resulting compound 0,&@
dimetho/y@+@cyclo@propylo/yamphetamine '0C@CP?- 3ould be any shorter acting than CP?.

#'3 $!-SE; $,)-0"METH%+Y-(-METHYSEE#E%,HE#ETHYAM"#E
S>5"H<SISE A suspension of &.1& g (,+@dimetho/yben6ene in (,, m! petroleum ether containing 1.& m! 5,5,57,57@tetramethylethylenediamine 3as
magnetically stirred, placed in an inert atmosphere, and cooled to , deg C 3ith an e/ternal ice bath. "here 3as then added $2 m! of (.1 ? butyllithium
in he/ane. "he solids present 3ent into solution, and after a fe3 min continued stirring, a fine precipitate appeared. "he reaction 3as allo3ed to stir
3hile coming up to room temperature. "here 3as then added +.) g dimethyl diselenide 3hich led to an e/othermic reaction, bringing the petroleum ether
up to a reflu/ and sho3ing a color change from 3hite to yello3, to light green, to an eventual bro3n, all over the course of 0, min. After $ h additional
stirring, the reaction 3as Fuenched by pouring into dilute 5a9H. "he organic phase 3as separated, and the aFueous phase e/tracted 3ith $/2& m!
<t$9. "he pooled organics 3ere 3ashed first 3ith dilute 5a9H, then 3ith dilute HCl, and then the solvent 3as removed under vacuum. ;istillation of the
residue at ,.+ mm8Hg gave an early fraction '2&@(,, deg C- that solidified in the receiver and 3as largely unreacted dimetho/yben6ene. A pale yello3
oil distilled from (,, to ($, deg C 3hich proved to be largely $,&@dimetho/yphenyl methyl selenide. ?icroanalysis gave C T +%.)1, +%.1%; H T &.0$, &.+2.
As C%H($Se9$ reFuires C T +1.21, H T &.$0, there is appro/imately (0K dimetho/yben6ene present 'C)H(,9$ reFuires C T 1%.&+, H T 2.$%-. "his
mi/ture 3as used as such, 3ithout further purification.
A mi/ture of (.$& g P9Cl0 and (.( g 5@methylformanilide 3as 3armed on the steam bath for several min until the color had become a deep claret.
"here 3as then added (.& g of the )2K pure $,&@dimetho/yphenyl methyl selenide and the steam bath heating continued for an additional $& min. "he
very tarry reaction mi/ture 3as poured into (,, m! H$9, producing fine yello3 solids almost immediately. "hese 3ere removed by filtration and distilled
at ,.$ mm8Hg. A first fraction distilling up to (,, deg C 3as a mi/ture of unreacted ethers and 3hat appeared to be $,&@dimetho/yben6aldehyde. A
second cut distilled at (+,@(&, deg C, solidified to a yello3 solid in the receiver, and 3eighed (.$ g. A small amount of this product '3ith mp %(@%1 deg
C- 3as recrystalli6ed from ?e9H to give an analytic sample of $,&@dimetho/y@+@'methylseleneo-ben6aldehyde 3ith a mp ))@%$ deg C. All efforts to
achieve a tighter melting range 3ere unsuccessful. Anal. 'C(,H($90 Se- C,H. Although this ben6aldehyde migrates normally on a silica gel "!C plate
':f of ,.+ employing CH$Cl$ as a solvent- 3hen it is once completely dried on the plate, there seems to be some irreversible reaction 3ith the silica, and
the spot 3ill no longer move at all.
"o a solution of ,.)& g $,&@dimetho/y@+@'methylseleneo-ben6aldehyde in (, m! nitromethane there 3as added (&, mg anhydrous ammonium acetate,
and the solution 3as heated for 0& min on the steam bath. :emoval of the volatiles under vacuum yielded brick@red solids '(.( g- 3hich 3ere ground
under a small amount of ?e9H, filtered, and air dried. "his yielded ,.)) g of solid $,&@dimetho/y@+@methylseleneo@beta@nitrostyrene 3ith a mp of (2,.&@
(2(.& deg C. :ecrystalli6ation from IPA or from toluene gave no improvement of mp. Anal. 'C((H(059+Se- C,H.
A solution of !AH '$, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added ,.&0
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of ,.)& g $,&@dimetho/y@+@methylseleneo@beta@nitrostyrene in $, m!
hot anhydrous "HB. "here 3as an immediate discoloring. After a fe3 minutes further stirring, the temperature 3as brought up to a gentle reflu/ on the
steam bath for ,.& h, then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of IPA and, 3hen there 3as no
further activity, the reaction mi/ture 3as poured into &,, m! dilute H$S9+. "his 3as 3ashed 3ith $/(,, m! CH$Cl$, and then made basic 3ith &K
5a9H. "he milky aFueous phase 3as e/tracted 3ith $/(,, m! CH$Cl$, and e/tensive centrifuging 3as reFuired to obtain a clear organic phase.
<vaporation of the pooled e/tracts gave (.1 g of an oil that crystalli6ed. "his 3as distilled at (0,@(+, deg C at ,.(& mm8Hg providing ,.1 g of a 3hite oil
that set to a crystalline solid melting at )2@)% deg C. "his 3as dissolved in + m! boiling IPA, neutrali6ed 3ith ) drops of concentrated HCl and the
formed solids further diluted 3ith IPA 3ith a little anhydrous <t$9. "his crystalline product 3as removed by filtration, 3ashed 3ith <t$9, and air dried to
constant 3eight, yielding $,&@dimetho/y@+@methylseleneophenethylamine hydrochloride '$C@S<- 3ith a mp of $+,@$+( deg C.
;9SAC<E perhaps (,, mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith &, mg- ?y tongue feels as if I had eaten hot food. 9verall I got up to a plus (, and found the effects to be completely
benign. I 3andered about 3ithin the Craves e/hibit at the 9akland ?useum but there seemed to be only minor enhancement of the visual input.
'3ith 2, mg- "he 3ater solution of this material has an unspeakable smell. .ut there is no lasting taste, thank heaven. "his is up to a (.& * and
probably half again 3ould be an effective dose. "he first a3areness 3as at +& minutes, and the plateau lasted from (.& hours to about the fourth hour. I
3as at certain baseline at ) hours.
<="<5SI95S A5; C9??<5"A:>E Iith an entirely ne3 hetero atom in the molecule 'the selenium-, and 3ith clear indications that large dosages
3ould be needed '(,, milligrams. or more-, some discretion 3as felt desirable. "here 3as certainly an odd taste and an odd smell. I remember some
early biochemical 3ork 3here selenium replaced sulfur in some amino acid chemistry, and things got pretty to/ic. It might be appropriate to get some
general animal to/icity data before e/ploring those dosages that might get to a ***.
Ihat doors are opened by the observation that the selenium analog of $C@" is an active compoundH "he potency appears to be in the same ball park,
3hether there is a sulfur atom or a selenium atom there.
Brom the point of vie3 of the thing that is hung onto the hetero@atom, the selenium, the most active 'and as first appro/imation the most safe- analogue
3ould be the same ones that are the most potent 3ith sulfur. "hese 3ould probably be the Se@ethyl, the Se@propyl, or the Se@isopropyl, the analogs of
S@ethyl, S@propyl, and S@isopropyl. If one 3ere to be systematic, these 3ould be called $C@S<@$, $C@S<@+, and $C@S<@2. And a very special place
might be held for $C@S<@$(, the analogue of $C@"@$(. 5ot only is this of high potential potency, but it 3ould certainly be the first time that both fluorine
and selenium are in the same centrally active drug. In fact, might not this compound, $C@S<, be the first compound active 3ithin the human C5S 3ith a
selenium atom in itH It is certainly the first psychedelic 3ith this atom in itO
Brom the point of vie3 of the hetero@atom itself, there are t3o more kno3n belo3 selenium in the Periodic "able. <ach deserves some special comment.
"he ne/t atom, directly belo3 selenium, is tellurium. It is more metallic, and its com@pounds have a 3orse smell yet. I heard a story about a Cerman
chemist, many years ago, 3ho 3as carrying a vial of dibutyl telluride in his pocket in a passenger coach from here to there in Cermany, back at about
the turn of the century. It fell to the floor and broke. 5o one could remain in the car, and no amount of decontamination could effectively make the smell
tolerable. Scratch one rail3ay coach. .ut the compound, $C@"<, 3ould be readily makeable. ;imethyl ditelluride is a kno3n thing.
Ho3ever, the atom belo3 tellurium 'and at the bottom of that particular column of the Periodic "able- is the element polonium. Here one must deal in
terms of theory, as far as human activity goes, since there are no non@radioactive isotopes of polonium. "he only readily available isotope is that 3ith
mass $(,, 3hich is also called :adium B, and is an alpha@particle emitter. If this 3ere ever to be put into a living organism, and if it 3ere to seek out and
hang around some particular site of action, that area 3ould be thoroughly and completely cooked by alpha@particle emission. It 3ould be a fun academic
e/ercise to make $C@P9 '$,&@dimetho/y@+@methylpoloneophenethylamine-, but in no 3ay could it ever go into anyone. I kne3 an eminent physiologist
named ;r. Hardin Dones 'no3 dead- 3ho al3ays argued that the continuing use of drugs 3ould burn out the pleasure center of the brain. It is a certainty
that $C@P9 3ould, Fuite literally, do this. If I ever made it, I 3ould call it HA:;I5A?I5< in his honor.
"here 3as an interesting observation associated 3ith the making of $C@S<. In the synthesis of many of the sulfur compounds 'of the $C@" family- is 3as
Fuite common to find, 3hen there 3as a Fuantity of some organic sulfide let go as a by@product of a reaction on a 3arm summer night, a number of flies
coming into the lab to pay a visit. 9n the first synthesis of the starting material for $C@S<, a Fuantity of CH0SeH 3as let go into the environment. Iithin
minutes, there 3ere t3o beautiful dragonflies in the lab. A coincidence certainly, but someho3, it 3as a nice message to receive.
#'4 $!-T ; $,)-0"METH%+Y-(-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of (+% g sodium thiosulfate in 0,, m! H$9 3as vigorously stirred. "o this there 3as added, over the course of (, min, a
solution of +0.$ g ben6oFuinone in $,, m! acetic acid. After an additional ( h stirring at room temperature, all volatiles 3ere removed under vacuum.
"he residual syrup slo3ly set up as crystals 3hich, after grinding under brine, 3ere removed by filtration and 3ashed 3ith additional brine. "hese 3ere
dissolved in ?e9H, clarified by filtration through a Celite bed, and the clear filtrate stripped of solvent under vacuum. "he yello3, po3dery sodium $,&@
hydro/yphenylthiosulfate 3eighed 12 g 3hen dry. "his intermediate 3as dissolved in aFueous HCl '&, g in $,, m! H$9 containing +,, m!
concentrated HCl-, cooled 3ith an e/ternal ice bath, and treated 3ith $&, g 6inc dust added at a rate that kept the temperature belo3 1, deg C. About
(.& h 3ere reFuired, and caution must be taken concerning the poisonous hydrogen sulfide that evolves. An additional &, m! concentrated HCl 3as
added, and the aFueous phase decanted from the unreacted 6inc metal. "his 3as e/tracted 3ith 1/(,, m! <t$9, and these e/tracts 3ere pooled,
3ashed 3ith brine, and the solvent removed under vacuum to yield 00.( g of $,&@dihydro/ythiophenol as pale yello3 needles 3ith a mp of (()@((% deg
C.
A solution of (().1 g 9H pellets in $,, m! H$9 3as placed under 5$, and to it 3as added $+., g $,&@dihydro/ythiophenol. Iith vigorous stirring, there
3as then added (1, g methyl sulfate at a rate that maintained the temperature at about 1, deg C. "his took about $ h. After the addition 3as complete,
the mi/ture 3as held at reflu/ for 0 h, and allo3ed to stir at ambient temperature overnight. It 3as then filtered, and the filtrate e/tracted 3ith 1/(,, m!
<t$9, the e/tracts pooled, 3ashed 3ith $/&, m! brine, dried over anhydrous 5a$S9+, and the solvent removed under vacuum. "he residue 3as
distilled at )1@)) deg C at ,.,+ mm8Hg to provide $&.% g of $,&@dimetho/ythioanisole as a 3hite oil that crystalli6ed on standing. Its mp 3as 00@0+ deg
C. An alternate preparation of this compound follo3s the direct methylation of $,&@dimetho/ythiophenol 'see under $C@"@$ for the preparation of this
common intermediate- 3ith methyl iodide.
"o +, m! dry CH$Cl$ there 3as added 1.,2 g $,&@dimetho/ythioanisole, and this 3as cooled to , deg C under 5$. "o this 3ell stirred solution there 3as
added (0.,$ g stannic chloride over the course of $ min. "his 3as follo3ed by the drop@3ise addition of dichloromethyl methyl ether over & min, and the
reaction mi/ture allo3ed to stir for an additional (& min. After returning to room temperature, it 3as stirred for an additional ( h. "he reaction mi/ture
3as poured over (& g ice, and the organic phase separated, 3ashed 3ith 0/$& m! 0 5 HCl, 3ith 0/&, m! brine and, after drying over anhydrous
5a$S9+, the solvent 3as removed under vacuum. "he residue 3as a solid and, after recrystalli6ation from ?e9H8H$9, gave &.)1 g $,&@dimetho/y@+@
'methylthio-ben6aldehyde 3ith a mp of %&@%2 deg C. Purification via the bisulfite comple/ provided an analytical sample 3ith mp of %%@(,, C. Anal.
'C(,H($90S- C,H,S. "he malononitrile derivative 'from eFual 3eights of the aldehyde and malononitrile in <t9H 3ith a drop of triethylamine as
catalyst- 3as recrystalli6ed from an eFual volume of <t9H to give orange crystals 3ith a mp of ()&@()1 deg C. Anal. 'C(0H($5$9$S- C,H,5,S.
A solution of $.( g $,&@dimetho/y@+@'methylthio-ben6aldehyde in 2.& m! nitromethane 3as treated 3ith ,.+& g anhydrous ammonium acetate and held at
steam bath temperature for 1 h. "he deep red solution 3as stripped of solvent to give a residue that spontaneously crystalli6ed. "his 3as ground up
under ($ m! ?e9H, filtered, and 3ashed 3ith ?e9H to yield, after air@drying, (.2 g of $,&@dimetho/y@+@methylthio@beta@nitrostyrene as orange solids.
:ecrystalli6ation from <t9H provided rust@orange colored crystals 3ith a mp of (1&.&@(11 deg C. Anal. 'C((H(059+S- C,H,5; SE calcd, ($.&1; found,
((.%1.
"o a gently reflu/ing mi/ture of (.+ g !AH in +, m! anhydrous "HB under an inert atmosphere there 3as added, drop3ise, (.2 g $,&@dimetho/y@+@
methylthio@beta@nitrostyrene in $& m! "HB. "he reflu/ing 3as continued for () h, and the stirring continued for another day at room temperature. "here
3as then added (.& m! H$9 'diluted 3ith a little "HB-, (.& m! (&K 5a9H, and finally +.& m! H$9. "he 3hite aluminum o/ide salts 3ere removed by
filtration, and the filter cake 3ashed 3ith "HB. "he filtrate and 3ashings 3ere combined and stripped of solvent under vacuum yielding a stra3@colored
residue that crystalli6ed 'mp )(@%$ deg C 3ithout purification-. "his residue 3as dissolved in $& m! IPA and neutrali6ed 3ith concentrated HCl. "he
slightly pink solution spontaneously crystalli6ed. "here 3as added (,, m! anhydrous <t$9, and the 3hite crystalline mass of $,&@dimetho/y@+@
methylthiophenethylamine hydrochloride '$C@"- 3as removed by filtration, 3ashed 3ith <t$9, and air dried. "he final 3eight 3as (., g, and had a mp of
$0$@$02 deg C. :ecrystalli6ation from <t9H provided an analytical sample 3ith mp $+,@$+( deg C. IPA 3as not a good recrystalli6ation solvent. Anal.
'C((H()Cl59$S- C,H,5,S.
;9SAC<E 1, @ (,, mg.
;4:A"I95E 0 @ & h.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- Poetry 3as an easy and natural thing. .oth the reading of it and the 3riting of it. "his is a potential ?;?A
substitute since it opens things up but it doesn7t do anything to get in the 3ay.
'3ith 2& mg- I am already a3are at a Fuarter of an hour into itO It develops very Fuickly but very Fuietly. "here are no visuals at all but, rather, a tactile
sensitivity, 3ith 3arm close feelings. "his could be very erotic. "here is some fantasy to music, but nothing very demanding. "he vie3ing of pictures
doesn7t do much either. "he drop@off 3as e/tremely rela/ed, 3ith a good body feeling. At the fifth hour I 3as able to drift into an e/cellent, deep sleep
3ith busy dreams. In the morning I felt refreshed and active, 3ithout apparent deficit.
'3ith 2& mg- I got up to a thin and fragile plus t3o, but there 3as a continuing feeling of a hooded cloak brought do3n over my head. 5othing obvious L
it is transparent L but it someho3 separated me from everything around me. I do not think the overall e/periment 3as 3orth it.
'3ith (,, mg- ?aterial all right, but a little bit along the lines of a 7generic7 psychedelic effect. Sharper edges than $C@.. "he one true negative, 3hich
has been pretty consistent 3ith this drug, is that there is a certain emotional removal. 9ne teeny step removed. 9ne is connected 3ith feelings,
certainly, but there is a tendency for the intellect to be more evident, in me, than the heart. All this is moderately so. 5othing e/treme. Pretty good
material, but there are more inter@esting ones. Ho3ever, if you are looking for a really short one, this is one of the ans3ers. Bor most people. Bor me,
it7s still around & to 1 hours long. I 3ish 3e had more shorties, indeed.
'3ith ($& mg- "here 3as some physical tummy uncertainty, but once that 3as past, talking 3as e/tremely easy. "his is probably really psychedelic, but I
am not really sure 3hy, as there is not much in the 3ay of visuals. ;ropping 3as noted Gust after hour number three, and I 3as at baseline three hours
later.
<="<5SI95S A5; C9??<5"A:>E "he earliest 3ork 3ith the sulfur atom 3as 3ith the three@carbon chain materials, the A!<PHs. It 3as only after a
considerable time of 3orking 3ith them, and trying to come to peace 3ith their property of being so different from person to person as to potency, that
the t3o@carbon homologues 3ere looked at. Although the first of these 'this compound, called $C@"- 3as prepared at the same time as A!<PH@(, there
3as a lapse of about four years bet3een their trials. "he relatively lo3 potency of $C@" 3as a bit discouraging. .ut the methodical pursuit of the higher
$C@"7s 'to parallel the higher A!<PHs- proved to be a treasure house, and they have been e/plored much further than any of the A!<PHs.
A note on the :"S in $C@". ?any, in fact most, of the $C7s have their name based on the last letter of the amphetamine prototype. $C@. from ;9., $C@
C from ;9C, $C@I from ;9I, $C@5 from ;95, etc. And since the original name for A!<PH@( 3as ;9" 'the deso/y@ and a thiomethyl group at the +@
position-, the $C@" naming follo3ed this general pattern. And as a note on the subseFuent numbering, they 'both the A!<PHs and the $C@"7s- are
assigned numbers as they are thought up. "here is no structural significance in the number but they have been, like the houses on the streets in
residential "okyo, assigned numbers in strict historical order, documenting the seFuence of construction rather than the relative position do3n the side of
the street.
.oth of the homologous mono@etho/y "3eetios of $C@" have been synthesi6ed and evaluated. "he $@<t9@homologue of $C@" is $@etho/y@&@metho/y@+@
methylthiophenethylamine, or $C"@$<"9. "he ben6aldehyde '$@etho/y@&@metho/y@+@'methylthio-ben6aldehyde- 3as an oil, the nitrostyrene
intermediate had a melting point of (02@(0) deg C, and the final hydrochloride a melting point of $(&@$(1 deg C. "he effects 3ere felt very Fuickly, and
there 3as a blurring of vision. Ho3ever, the highest dose tried, &, milligrams, 3as not able to produce a greater@than@plus one state, and 3hat did occur,
lasted for only + hours.
"he &@<t9@homologue of $C@" is &@etho/y@$@metho/y@+@methylthio@phenethylamine, or $C"@&<"9. "he ben6aldehyde '&@etho/y@$@metho/y@+@'methyl@
thio-ben6aldehyde- 3as impure, and had a melting point of about 11 deg C, the nitrostyrene intermediate a melting point of (00@(0+ deg C, and the final
hydrochloride a melting point of ()+@()& deg C. "here 3as a body a3areness and modest eyes@closed visuals follo3ing the use of 0, milligrams of
$C"@&<"9. "he e/perience 3as Fuiet, peaceful, contemplative, and insightful. "he duration 3as perhaps (& hours and Halcion 3as needed to allo3
sleep. "here 3ere a lot of dreams, and the ne/t day 3as restful.

#(5 $!-T-$; $,)-0"METH%+Y-(-ETHYTH"%,HE#ETHYAM"#E
S>5"H<SISE "o a solution of (1& g (,+@dimetho/yben6ene in ( ! of CH$Cl$, in a 3ell ventilated place and 3ell stirred, there 3as cautiously added 0,,
m! chlorosulfonic acid. Iith about half the acid chloride added, there 3as a vigorous evolution of HCl gas and the generation of a lot of solids. As the
addition 3as continued, these redissolved to form a clear, dark green solution. "o3ards the end of the addition, some solids 3ere again formed. Ihen
everything 3as stable, there 3as added $ ! H$9, a fe3 m! at a time, commensurate 3ith the vigor of the reaction. "he t3o phases 3ere separated, and
the aFueous phase e/tracted 3ith $/2& m! CH$Cl$. "he original organic phase and the e/tracts 3ere combined and the solvent removed under
vacuum. "he residue 3eighed (1$ g and 3as Fuite pure $,&@dimetho/yben6enesulfonyl chloride, a yello3 crystalline solid 3ith a mp of ((&@((2 deg C.
It need not be further purified for the ne/t step, and it appears to be stable on storage. "he sulfonamide, from this acid chloride and ammonium
hydro/ide, gave 3hite crystals from <t9H, 3ith a mp of (+2.&@(+).& deg C.
"he follo3ing reaction is also a very vigorous one and must be performed in a 3ell ventilated place. "o a solution of +,, m! $&K H$S9+ 'M8M- in a
beaker at least $ ! in si6e, there 3as added &+ g of $,&@dimetho/yben6enesulfonyl chloride, and the mi/ture 3as heated on a steam bath. "he yello3
crystals of the acid chloride floated on the surface of the aFueous layer. "here should be ), g of 6inc dust at hand. A small amount of An dust 3as
placed at one spot on the surface of this chapeau. Iith occasional stirring 3ith a glass rod, the temperature 3as allo3ed to rise. At about 1, or 2, deg
C an e/othermic reaction took place at the spot 3here the 6inc 3as placed. Additional dollups of 6inc 3ere added, and each small e/othermic reaction
site 3as spread about 3ith the glass stirring rod. Binally, the reaction spread to the entire solid surface layer, 3ith a melting of the acid chloride and an
apparent boiling at the H$9 surface. "he remainder of the ), g of 6inc dust 3as added as fast as the si6e of the reaction container 3ould allo3. After
things subsided again, the heating 3as continued for ( h on the steam bath. After the reaction mi/ture had cooled to room temperature, it 3as filtered
through paper in a .uchner funnel, and the residual metal 3ashed 3ith (,, m! CH$Cl$. "he t3o@phase filtrate 3as separated, and the lo3er, aFueous
phase 3as e/tracted 3ith $/2& m! CH$Cl$. "he addition of $ ! H$9 to the aFueous phase no3 made it the upper phase in e/traction, and this 3as
again e/tracted 3ith $/2& m! CH$Cl$. "he organic e/tracts 3ere pooled 'H$9 3ashing is more trouble than it is 3orth- and the solvent removed under
vacuum. "he light amber residue '0,., g- 3as distilled at 2,@), deg C at ,.0 mm8Hg to yield $&.0 g $,&@dimetho/ythiophenol as a 3hite oil. "his
chemical is certainly not centrally active, but it is a most valuable precursor to all members of the $C@" family.
"o a solution of 0.+ g of 9H pellets in 2& m! boiling <t9H, there 3as added a solution of (,., g $,&@dimetho/ythiophenol in 1, m! <t9H follo3ed by
(,.% g ethyl bromide. "he reaction 3as e/othermic 3ith the immediate deposition of 3hite solids. "his 3as heated on the steam bath for (.& h, added to
( ! H$9, acidified 3ith HCl, and e/tracted 3ith 0/(,, m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith (,, m! of &K 5a9H, and the solvent
removed under vacuum. "he residue 3as $,&@dimetho/yphenyl ethyl sulfide 3hich 3as a pale amber oil, 3eighed about (, g and 3hich 3as sufficiently
pure for use in the ne/t reaction 3ithout a distillation step.
A mi/ture of (%.$ P9Cl0 and ()., g 5@methylformanilide 3as heated briefly on the steam bath. "o this claret@colored solution there 3as added the
above $,&@dimetho/yphenyl ethyl sulfide, and the mi/ture heated an additional $, min on the steam bath. "his 3as then added to &,, m! of 3ell@stirred
3arm H$9 'pre@heated to && deg C- and the stirring continued for (.& h by 3hich time the oily phase had completely solidified to a bro3n sugar@like
consistency. "he solids 3ere removed by filtration, and 3ashed 3ith additional H$9. After being sucked as dry as possible, these solids 3ere dissolved
in &, m! boiling ?e9H 3hich, after cooling in an ice@bath, deposited almost@3hite crystals of $,&@dimetho/y@+@'ethylthio-@ben6aldehyde. After filtration,
modest 3ashing 3ith cold ?e9H, and air drying to constant 3eight, there 3as obtained ((., g of product 3ith a mp of )1@)) deg C. :ecrystalli6ation of
a small sample again from ?e9H provided an analytical sample 3ith mp )2@)) deg C. Anal. 'C((H(+90S- C,H.
"o a solution of ((., g $,&@dimetho/y@+@'ethylthio-ben6aldehyde in (,, g of nitromethane there 3as added ,.& g of anhydrous ammonium acetate, and
the mi/ture 3as heated on the steam bath for ), min 'this reaction progress must be monitored by "!C, to determine the point at 3hich the starting
aldehyde has been consumed-. "he e/cess nitromethane 3as removed under vacuum leaving a residue that spontaneously set to orange@red crystals.
"hese 3ere scraped out to provide ($.% g crude $,&@dimetho/y@+@ethylthio@beta@nitrostyrene 3ith a mp of (&$@(&+ deg C. A sample recrystalli6ed from
toluene 3as pumpkin colored and had a mp of (+)@(+% deg C. Another sample from acetone melted at (+% deg C sharp, and 3as light orange. Brom
IPA came spectacular fluorescent orange crystals, 3ith a mp (&(@(&$ deg C. Anal. 'C($H(&59+S- C,H.
A suspension of ($.+ g !AH in &,, m! anhydrous "HB 3as stirred under He. "o this there 3as added ($.+ g $,&@dimetho/y@+@ethylthio@beta@nitrostyrene
in a little "HB, and the mi/ture 3as held at reflu/ for $+ h. After the reaction mi/ture had returned to room temperature, the e/cess hydride 3as
destroyed by the cautious addition of 1, m! IPA, follo3ed by $, m! of &K 5a9H follo3ed, in turn, by sufficient H$9 to give a 3hite granular character to
the o/ides. "he reaction mi/ture 3as filtered, and the filter cake 3ashed first 3ith "HB and then 3ith ?e9H. :emoving the solvents from the combined
filtrate and 3ashings under vacuum provided %.& g of a yello3 oil. "his 3as added to ( ! dilute HCl and 3ashed 3ith $/(,, m! CH$Cl$ 3hich removed
all color. After making the aFueous phase basic 3ith $&K 5a9H, it 3as e/tracted 3ith 0/(,, m! CH$Cl$, the e/tracts pooled, and the solvent removed
under vacuum to provide 2.0 g of a pale amber oil. ;istillation at ($,@(0, deg C at ,.0 mm8Hg gave 1.(2 g of a clear 3hite oil. "his 3as dissolved in ),
m! IPA and neutrali6ed 3ith concentrated HCl, forming immediate crystals of $,&@dimetho/y@+@ethylthiophenethylamine hydrochloride '$C@"@$-. An eFual
volume of anhydrous <t$9 3as added and, after complete grinding and mi/ing, the salt 3as removed by filtration, 3ashed 3ith <t$9, and air dried to
constant 3eight. "he resulting 3hite crystals 3eighed 1.$ g.
;9SAC<E ($ @ $& mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith ($ mg- I don7t feel this for fully an hour, but 3hen I do it is Fuite a 3eight. It feels good to 3ork it through. It is 9 to
be 3ith pain. >ou can7t eliminate it. And it is 9 to contact your deep pools of anger. And all of it stems from the lack of ackno3ledgment. All the
macho carrying on, the fights, the 3ars, are 3ays of demanding attention, and getting even for not having had it in one7s life. I am e/periencing more
deeply than ever before the importance of ackno3ledging and deeply honoring each human being. And I 3as able to go through and resolve some
Gudgments 3ith particular persons.
'3ith $, mg- I chose $C@"@$ at this dose level because the lateness of getting started, and I 3anted a shorter e/perience 3ith my daughter and her
family around. I feel, ho3ever, that I have some3hat less of a body load 3ith $C@"@2. "oday I 3as badly in need of the help that might possibly come
from this material, and today it 3as my ally. I sorely needed the type of help that it afforded. "he result 3as to 3ork off the heavy feeling of tiredness
and lack of motivation that had been hounding me. "he ne/t day I felt that I had dropped my burden.
'3ith $, mg- "here is a neutralness to this. I am at the ma/imum,
and I am asking myself, 7Am I enGoying thisH7 And the ans3er is, 75o,
I am e/periencing it.7 <nGoyment seems beside the point. It is a rather intensely matter@of@fact *0. Is it interestingH >es, but mostly in e/pectation of
further developments. Is it inspiringH 5o. Is it negativeH 5o. Am I glad I took itH >es. 5ot glad. Satisfied and contented. "his is a controlled *0. 5o
threat. "he body is all right. 5ot superbly healthy L but 9. 9f no interest, either 3ay. If I 3ere to define the body7s state, I 3ould have to define it in
image. "he image is of a not comfortable state of being clenched. ClenchedH Iell, carefully bound in control.
'3ith $$ mg- A slo3 onset. It took an hour for a plus one, and almost another t3o hours to get to a ***. Mery vivid fantasy images, eyes closed, but no
blurring of lines bet3een NrealityN and fantasy. Some yello3@grey patterns a la psilocybin. Acute diarrhea at about the fourth hour but no other obvious
physical problems. <rotic lovely. Cood material for unkno3n number of possible uses. Can e/plore for a long time. .etter try $, milligrams ne/t time.
'3ith $& mg- I 3as at a *** in an hourO It is most difficult to do even ordinary things. I took notes but no3 I can7t find them. "his is much too high for
anything creative, such as looking at pictures or trying to read. "alking is 9. And to my surprise I 3as able to get to sleep, and a good sleep, at the
seven hour point.
<="<5SI95S A5; C9??<5"A:>E "here is a considerable parallel bet3een $C@"@$ and $C@"@2, and both have proven to be e/cellent tools for
introspection. "he differences are largely physical. Iith $C@"@$, there is more of a tendency to have physical disturbances such as nausea and
diarrhea. And the e/perience is distinctly shorter. Iith $C@"@2, physical disturbances are less common, but you are into the effects for almost t3ice as
long. .oth have been freFuently used in therapy as follo3@ups to ?;?A.
A point of potential misidentification should be mentioned here. $C@"@$ has occasionally been called, simply, "@$. "his abbreviated nickname has also
been used for "@$ "o/in, a mycoto/in of the "ricothecene group, formed mainly by the Busarium spp. "his is the infamous N3arfare agentN in Southeast
Asia, 3hich 3as finally identified as bee feces rather than a Soviet military adventure. "@$ and $C@"@$ are radically different compounds.
All three "3eetios of $C@"@$ have been made and looked at through human eyes. "he $@<t9@homologue of $C@"@$ is $@etho/y@+@ethylthio@&@
metho/yphenethylamine, or $C"$@$<"9. "he ben6aldehyde '$@etho/y@+@ethylthio@&@metho/yben6aldehyde- had a melting point of 20@2& deg C, the
nitrostyrene intermediate a melting point of ($$@($0 deg C, and the final hydrochloride a melting point of $,$@$,+ deg C. Bifty milligrams 3as a
completely effective level. "he effects 3ere felt very Fuickly. Mision 3as blurred, and there 3ere intense eyes@closed visuals and the generation of a
pleasant, contemplative mood. .aseline 3as re@established in five or si/ hours, but sleep 3as restless, 3ith 3eird dreams. 5asal administration
sho3ed considerable variation bet3een individuals, but a typical dose 3as (, milligrams.
"he &@<t9@homologue of $C@"@$ is &@etho/y@+@ethylthio@$@metho/yphenethylamine, or $C"$@&<"9. "he ben6aldehyde '&@etho/y@+@ethylthio@$@
metho/yben6aldehyde- had a melting point of +% deg C, but it 3as impure. "he nitrostyrene intermediate melted at (,2@(,) deg C, and the final
hydrochloride had a melting point of (), deg C. At levels of $, milligrams, there 3as a slo3, gentle climb to a full effect at the third or fourth hour. "he
flooding of thoughts and easy conversation lasted for many hours, and on some occasion a sedative 3as needed at the (1 hour point. "here 3as a
feeling of being drained for the follo3ing day or t3o. Some into/ication 3as still noted in the second day. Again it is true here, as had been stated as a
generality, that the &@"3eetio analogues have potencies similar to that of the parent compound, but sho3 a much longer duration. "he nickname of
Nforever yoursN had been applied. "here may indeed be insight, but $+ hours7 3orth is an a3ful lot of insight.
"he $,&@;i<t9@homologue of $C@"@$ is $,&@dietho/y@+@ethylthiophen@ethylamine, or $C"$@$,&;I<"9. "he ben6aldehyde, $,&@dietho/y@+@
'ethylthio-ben6aldehyde, had a melting point of )+@)& deg C, the nitrostyrene intermediate a melting point of ($0@($+ deg C, and the final hydrochloride
a melting point of $$,@$$( deg C. !evels that 3ere evaluated from (, to &, milligrams 3ere not particularly different in intensity, but 3ere progressively
longer in duration. At &, milligrams there 3as a nervousness and edginess during the early part of the e/perience, but for the ne/t several hours there
3as evident both energy and high attentiveness. "here 3ere fe3 if any sensory alterations. "here 3ere no negatives on the follo3ing day. "he duration
3as perhaps nine hours.

#(1 $!-T-(; $,)-0"METH%+Y-(-&i--,*%,YTH"%,HE#ETHYAM"#E
S>5"H<SISE "o a solution of $.& g of 9H pellets in +, m! hot <t9H, there 3as added &.+ g $,&@dimetho/ythiophenol 'see under $C@"@$ for its
preparation- and ).2 g isopropyliodide. Ihite solids appeared in a fe3 min, and the reaction mi/ture 3as heated on the steam bath overnight. "his
mi/ture 3as added to $,, m! H$9 follo3ed by additional aFueous 5a9H to raise the pH to a deep purple@blue on universal pH paper. "his 3as
e/tracted 3ith 0/2& m! CH$Cl$. "he pooled e/tracts 3ere stripped of solvent under vacuum, and the residue distilled at (,,@((, deg C at ,.$ mm8Hg to
yield 1.% g of $,&@dimetho/yphenyl isopropyl sulfide as a pale yello3 oil. It has a very light, pleasant smell of apples.
A mi/ture of +.) g P9Cl0 and +.& g 5@methylformanilide 3as stirred and allo3ed to stand at room temperature for ( h "o this claret@colored solution 3as
added 0., g of $,&@dimetho/yphenyl isopropyl sulfide, producing an e/othermic reaction and immediate reddening. "his 3as heated for ,.& h on the
steam bath, then Fuenched in $,, m! of 3arm H$9 producing immediate crystals. Stirring 3as continued for a fe3 min, and then the solids 3ere
removed by filtration, 3ashed 3ith H$9 and sucked as dry as possible. Ihen they 3ere ground up under an eFual 3eight of cold ?e9H, refiltered and
air dried, they gave $.0& g of $,&@dimetho/y@+@'i@propylthio-ben6aldehyde as pale yello3 solids 'in some runs this 3as a pale lime@green color- 3ith a mp
of )%@%, deg C. A 3asteful recrystalli6ation from ?e9H gave pale yello3 crystals 3ith a mp of %, deg C sharp.
"o a solution of 1.2 g $,&@dimetho/y@'i@propylthio-ben6aldehyde in +, g of nitromethane there 3as added ,.(, g of anhydrous ammonium acetate, and
the mi/ture 3as heated on the steam bath for $ h. "he e/cess reagent8solvent 3as removed under vacuum yielding ).% g of orange solids. "his 3as
recrystalli6ed from $,, m! boiling ?e9H providing 1.$ g of $,&@dimetho/y@beta@nitro@+@'i@propyl@thio-styrene as lustrous golden orange platelets.
A solution of !AH '), m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added $.(
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of &.2+ g $,&@dimetho/y@beta@nitro@+@'i@propylthio-styrene as a solid,
a bit at a time. After (& min further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath for another (& min, then allo3ed to
stand at room temperature overnight. After cooling again to , deg C, the e/cess hydride 3as destroyed by the addition of 2 m! IPA follo3ed by 1 m!
(&K 5a9H 3hich 3as sufficent to give a 3hite granular character. "he reaction mi/ture 3as filtered and the filter cake 3ashed 3ith "HB. "he filtrate
and 3ashings 3ere pooled, stripped of solvent under vacuum providing 0.% g of a pale amber oil 3hich 3as dissolved in $&, m! dilute H$S9+. "his 3as
3ashed 3ith 0/2& m! CH$Cl$ 3hich removed the residual yello3 color. After making basic 3ith $&K 5a9H, the product 3as e/tracted 3ith 0/2& m!
CH$Cl$ and the solvent removed under vacuum to give $.2$ g of a residue 3hich 3as distilled at (+,@(+& deg C at ,.$ mm8Hg to give $.+$ g of a clear
3hite oil. "his 3as dissolved in $& m! IPA, and neutrali6ed 3ith concentrated HCl. "his gave a clear solution 3hich, 3ith good stirring, 3as diluted 3ith
(,, anhydrous <t$9 to provide $.+, g $,&@dimetho/y@+@'i-@propyl@thiophenethylamine hydrochloride '$C@"@+- as 3hite crystals.
;9SAC<E ) @ $, mg.
;4:A"I95E ($ @ () h.
L4A!I"A"IM< C9??<5"SE '3ith ) mg- Misual effects set in at about t3o hours. "here 3as much color enhancement, particularly of green, and some
flo3ing of colors. "he bright impressionistic picture of the little girl, in the bathroom, 3as particularly good for the visuals to take over, especially 3hen I
3as concentrating on urinating. "he shado3s in the large picture above the fireplace 3ould change constantly. I could not either control or turn off
these effects during the middle period '0@1 hours-. Brom the physical point of vie3, something early in the e/perience simply didn7t feel right. .oth my
lo3er legs tended to fall asleep, and this seemed to spread to my hands and lo3er arms. It 3as uncomfortable and although I 3as apprehensive at first
it didn7t get any 3orse 3ith time so I ignored it. "his is not one my favorite materials, and it takes too long to 3ear off. If I 3ere to do it again I 3ould
settle for + or & milligrams. It may 3ell cut out the e/tremity problem amd still allo3 for a pleasant e/perience.
'3ith % mg- An important characteristic of this e/perience 3as the sense of letting go and flo3ing 3ith it. Dust follo3 3here it leads. "his seemed to lead
to a gro3ing euphoria, a feeling of clearing out of body residues, and the handling of very impressive insights. ?y thinking continued to gro3 in clarity,
visual perception 3as crystal clear, and it 3as a Goy to simply look over the scenery, enGoy the beauty, enGoy the companionship, and ponder 3hatever
came to mind. "his clarity of body and mind lasted the rest of the evening 3ith a 3onderful feeling of peace and centeredness. I still felt a lot of push
from the chemical at bed time, causing some tiredness, and allo3ing very little sleep. I kept 3orking at 3hat had taken place, all night, Gust to release the
e/perience.
'3ith (+ mg- Mery rational, benign, and good humored. "he insight and calm common to the $C@"7s are present, 3ith less of the push of body@energy
3hich makes $C@"@$ difficult for some people. "here are no particular visuals, but then I tend to screen them out consistently, e/cept in cases of
mescaline and !S; and psilocybin, so I can7t Gudge 3hat others 3ould e/perience in the visual area. "he eyes@closed imagery is very good 3ithout
being compelling. "he decline is as gradual and gentle as the onset. I am fully capable of making phone calls and other normal stuff. ?usic is
marvelous, and the body feels comfortable throughout.
'3ith (+ mg- Persistent cold feet, and an uncertain stomach 3hen moving around. .rilliant color trails reminiscent of $C@.. .ut a change is occurring
and I can7t talk myself out of it. "here are dark corners. If I 3ere 3ith other people, this 3ould bring out the 3orst in me, 3hich can be pretty bad.
'3ith (% mg- I 3as caught by the "M. !eonard .ernstein conducting Iest Side Story. I think I kno3 every note. "his 3as a (%)& rehearsal 3ith the
goofs and the s3eat. And no3 Peter, Paul and ?ary, gro3n older along 3ith the songs 3e all sang. Ihere Have All the Blo3ers Cone L and an
audience of gro3n@older people singing Puff the ?agic ;ragon like earnest children and probably crying along 3ith me. It is good to have lived through
the 1,7s and not to be in them no3. 5o3 there7s a ne3 song about <l Salvador and it7s the battle all over again on a different field, but it 3ill al3ays be
so, until and unless. 5o3, in the ),7s, I don7t get really angry anymore. I am more 3arrior than angry protester, and that7s a much better 3ay to be. In
fact, I am Fuite happy to be 3here I am. I kno3 a lot more about the game, and 3hat it is, and 3hy it is played, and I have a good idea about my part in
it, and I like the part I7ve chosen.
'3ith $$ mg- "he transition took place over three hours, an alert in 0, minutes follo3ed by a slo3 and gentle climb. I found it difficult, not physically but
mentally since I 3as for a 3hile locked into the illogical and disconnected aspects of human e/periences and e/pressions, particularly la3s and
pronouncements and unseeing preGudices, most of 3hich I 3as picking up from reading the Sunday paper book revie3s. As time 3ent on, things
became less pushy and I came to be at ease 3ith very positive feelings about everything going on. 5o self@reGecting aspect at all. Sleep 3as e/cellent,
but the ne/t day things 3ent slo3ly and I had to nap a bit. 5e/t time, maybe () milligrams.
<="<5SI95S A5; C9??<5"A:>E "here are shades of the variability of the Alephs. Some observers are over3helmed 3ith colors and visual activity;
others volunteer their absence. And a very 3ide range of dosages represented, from an estimated + or so milligrams for full effects, to something over
$, milligrams 3ithout any loss of control. "hat is an unusually 3ide lattitude of activity. And a rich variety of effects that might be e/perienced. "he same
3ide range of effective dosages 3as also observed 3ith the corresponding "3eetio. "he $@<t9@homologue of $C@"@+ is $@etho/y@&@metho/y@+@'i-@
propylthiophenethylamine, or $C"+@$<"9. "he ben6aldehyde '$@etho/y@&@metho/y@+@'i@propylthio-ben6aldehyde had a melting point of +0@++ deg C,
the nitrostyrene intermediate a melting point of 22@2% deg C, and the final hydrochloride a melting point of (&0.&@(&+ deg C. "here 3ere practically no
differences bet3een trials at & milligram increments 3ithin the (, and $& milligram range. <ach produced a gentle plus t3o level of effect 3hich lasted
for some (, hours. A code name of NtendernessN 3as felt to be appropriate, as there 3as a peaceful meditative inner receptiveness and clarity noted,
3ith an honest connection felt 3ith those 3ho 3ere present during the e/perience. Sleep 3as not comfortable.
I have heard $C@"@+ referred to as "@+. "here is a potent e/plosive used by terrorists called cyclotrimethylenetrinitramine, kno3n by the code name
:;=, or "@+. "here is also a "@+ term that refers to thyro/ine, an amino acid in the body. "he drug $C@"@+ is neither an e/plosive nor an amino acid, I
am happy to say.

#($ ga99a-$!-T-(; $,1-0"METH%+Y-(-&i--,*%,YTH"%,HE#ETHYAM"#E-
S>5"H<SISE A stirred solution of ).0 g 0,&@dimetho/y@(@chloroben6ene and 2.$ g isopropylsulfide in (,, m! anhydrous <t$9 3as cooled 3ith an
e/ternal ice bath, and then treated 3ith 12 m! (.& ? lithium diisopropylamide in he/ane 3hich 3as added over the course of (, min. "he reaction
mi/ture 3as allo3ed to return to room temperature and the stirring 3as continued for ,.& h. "he mi/ture 3as poured into dilute H$S9+, the organic layer
3as separated, and the aFueous phase e/tracted 3ith 0/2& m! <t9Ac. "he organic phases 3ere combined, dried over anhydrous $C90, and the
solvent removed under vacuum. "he resulting +.&+ g of almost colorless oil 3as distilled at )&@%& deg C at ,.( mm8Hg to give +.$ g of 0,&@
dimetho/yphenyl isopropyl sulfide as a colorless oil, sho3ing a single spot on "!C 3ith no indication of starting chloroben6ene. "he product formed a
picrate salt, but this had an unsatisfactory mp character 'partly melting at +&@+2 deg C, and then completely at about ),@%, deg C-. "he microanalysis
for this picrate 3as lo3 in the carbon value, although the hydrogen and nitrogen 3ere e/cellent. Anal. 'C(2H(%509%S- H,5; CE calcd, +1.$&; found,
++.&), ++.+&.
"o a 3ell@stirred solution of +.( g 0,&@dimetho/yphenyl isopropyl sulfide and 0.& m! 5,5,57,57@tetramethylethylenediamine in $& m! anhydrous <t$9 that
had been cooled to @2) deg C 3ith a dry@ice8acetone bath, there 3as added (, m! $.& ? he/ane solution of butyllithium. "he mi/ture 3as allo3ed to
return to room temperature, and there 3as added 0.& m! ;?B 3hich caused the yello3 color to progressively darken. "he reaction mi/ture 3as poured
into dilute H$S9+, the <t$9 layer 3as separated, and the aFueous phase e/tracted 3ith 0/2& m! <t9Ac. "he solvent 3as removed from the combined
organic phases, and the residue distilled at ,.(& mm8Hg to give t3o fractions. 9ne, boiling at ($,@(+, deg C, 3as ,.%) g of a pale yello3 mobile liFuid,
3hich 3as part starting sulfide and part product aldehyde by "!C. "he second cut, boiling at (1,@(), deg C, 3as a viscous liFuid, 3eighed (.11 g, and
3as largely $,1@dimetho/y@+@'i@propylthio-ben6aldehyde. "his formed a crystalline anil 3ith +@metho/yaniline 'by fusing eFuimolar amounts of the t3o
3ith a flame- 3hich, after recrystalli6ation from ?e9H, gave fine yello3 crystals 3ith a mp of )2.&@)% deg C. Anal. 'C(%H$0590S- C,H.
A solution of ,.) g $,1@dimetho/y@+@'i@propylthio-ben6aldehde in (, m! nitromethane 3as treated 3ith ,.$ g anhydrous ammonium acetate and heated
on the steam bath for ( h. "he e/cess reagent8solvent 3as removed under vacuum, and the residue spontaneously solidified. "his 3as recrystalli6ed
from & m! ?e9H to give ,.2, g $,1@dimetho/y@beta@nitro@+@'i-@propylthiostyrene as a pale yello3 fluffy solid, 3ith a mp of )0@)+.& deg C. Anal.
'C(0H(259+S- C,H.
A solution of !AH '$, m! of a ( ? solution in "HB- 3as cooled, under He to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added ,.&+
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of ,.&+ g $,1@dimetho/y@beta@nitro@+@'i-@propylthiostyrene in a small
volume of anhydrous "HB. "he color 3as discharged immediately. After a fe3 minutes further stirring, the temperature 3as brought up to a gentle reflu/
on the steam bath for about (, min, and then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of IPA
follo3ed by sufficent (&K 5a9H to give a 3hite granular character to the o/ides, and to assure that the reaction mi/ture 3as basic. "he reaction
mi/ture 3as filtered, and the filter cake 3ashed 3ell 3ith "HB. "he filtrate 3as stripped of solvent under vacuum and the residue dissolved in (,, m! of
dilute H$S9+. "his 3as 3ashed 3ith $/&, m! CH$Cl$ 'the 3ashes 3ere saved, see belo3-, made basic 3ith aFueous 5a9H, and then e/tracted 3ith
$/&, m! CH$Cl$. "he residue remaining after the removal of the solvent 3as distilled at (0,@(+, deg C at ,.,& mm8Hg to give ,.(( g of a 3hite oil.
"his 3as dissolved in (, m! IPA, neutrali6ed 3ith & drops of concentrated HCl and diluted 3ith &, m! anhydrous <t$9. After filtration of the formed
crystals, <t$9 3ashing, and air drying, there 3as obtained ), mg of $,1@dimetho/y@+@'i-@propylthiophenethylamine hydrochloride 'gamma@$C@"@+- as
fine 3hite crystals. "he removal of the solvent from the CH$Cl$ 3ashes of the dilute H$S9+ solution gave a H$9@soluble 3hite solid that proved to be
the sulfate salt of the product. "his provided, after making the H$9 solution basic, e/traction 3ith CH$Cl$, and solvent removal, the free base that 3as
converted, as described above, to a second crop of the hydrochloride salt.
;9SAC<E above ($ mg.
;4:A"I95E probably short.
L4A!I"A"IM< C9??<5"SE '3ith ) mg- I might actually be up to a plus (, and 3ith a very good feeling. .ut I cannot say ho3 long it lasted, and it 3as
probably pretty short. It Gust sort of faded a3ay.
'3ith ($ mg- At the $& minute point I am reminded of the e/periment, and in another Fuarter hour I am into something. Iill this be another forever
thresholdH I feel very good, but there is no sparkle.
<="<5SI95S A5; C9??<5"A:>E Here is another e/ample of the presentation of a compound for 3hich there has not yet been an effective level
determined. IhyH Bor a very good reason. "his is an e/ample of a 3hole class of compounds that I have called the pseudos, or the gamma@
compounds. Pseudo@ as a prefi/ in the literary 3orld generally stands for Nfalse.N A pseudopod is a thing that looks like a foot, but isn7t one. A
pseudonym is a fictitious name. .ut in chemistry, it has Fuite a different meaning. If something has a common name, and there is a second form 'or
isomer, or shape, or orientation- that is possible and it doesn7t have a common name, it can be given the name of the first form 3ith a :pseudo@S
attached. <phedrine is the erythro@isomer of 5@methyl@beta@hydro/yamphetamine. "here is a second stereoisomer, the threo@ isomer, but it has no
trivial name. So it is called pseudoephedrine, or the NSudafedN of sinus decongestant fame.
"he pseudo@psychedelics are the $,+,1@trisubstituted counterparts of the $,+,&@trisubstituted psychedelics. Almost all of the $,&@dimetho/y@+@something@
or@other compounds are active and interesting 3hether they be phenethylamines or amphetamines, and it is an e/citing fact that the $,1@dimetho/y@+@
something@or@other compounds are going be Gust as active and Gust as interesting. A number of e/amples have already been mentioned. "?A@$ is
$,+,&@trimetho/yamphetamine 'a $,&@dimetho/y@substituted compound 3ith a metho/yl at the +@position-. "he pseudo@ analogue is "?A@1 '$,+,1@
trimetho/yamphetamine- and it is every bit as potent and fascinating. A@2 could be called pseudo@;9?, and although it is Fuite a bit do3n in potency, it
is an active drug and 3ill both demand and receive much more clinical study some day.
Iill the other $,+,&@things spa3n $,+,1@things that are activeH Iithout a shado3 of a doubt. Chemically, they are much more difficult to synthesi6e. "he
$,&@dimetho/y orientation made the +@position a natural and easy target. "he $,1@dimetho/y orientation pushes for 0@substitution, and the +@position is
completely unnatural. "ricks are needed, but tricks have no3 been found. "he above synthesis of pseudo@$C@"@+ sho3s one such trick. "his is, in my
opinion, the e/citing chemistry and psychopharmacology of the ne/t decade. Iell over half of all the psychedelic drugs mentioned in .ook II are $,+,&@
trisubstituted compounds, and every one of them has a 'potentially active- $,+,1@pseudo@counterpart.
It goes yet further. "he antidepressant series of NAriadneN compounds are (@phenyl@$@aminobutanes. .ut the (@phenyl is again a $,+,&@trisubstituted
compound. "he $,+,1@isomer 3ill give rise to a pseudo@Ariadne family, and I 3ill bet that they too 3ill be antidepressants. "he (@phenyl@$@aminobutane
analog of gamma@$C@"@+ is the $,+,1@analogue and it has been prepared as far as the nitrostyrene. It has not yet been reduced, so it is not yet been
evaluated, but it could be a most remarkable psycho@pharmacological probe.
And it goes yet yet further. "hink back to the si/ possible "?A7s. "?A and "?A@0 3ere relatively inactive. And "?A@$ and "?A@1 3ere the interesting
ones. "he first gave rise to the last t3enty years of psychedelic chemistry, and the other 'as speculated upon above- 3ill give rise to the forthcoming ten
years. .ut 3hat of "?A@+ and "?A@&H .oth sho3ed activity that 3as more than "?A but less than that of the @$ or @1 isomers. Could they, some day,
provoke yet other families of psychedelicsH ?aybe the 0@position of these t3o might be focal points of leverage as to psychological activity. Ihat are
the letters that follo3 y in the Creek alphabetH If I remember correctly, the ne/t letter is the last letter, omega. So, I guess that 5ature is trying to tell us
something, that the @+ and @& isomers 3ill not engender interesting families. Ihat a pity. "he chemistry is so unthinkably difficult that it 3ould have been
a true challenge. ?y ne/t incarnation, maybeH
#(' $!-T-2; $,)-0"METH%+Y-(-&n--,*%,YTH"%,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0.+ g of 9H pellets in &, m! hot ?e9H, there 3as added a mi/ture of 1.) g $,&@dimetho/ythiophenol 'see under the
recipe for $C@"@$ for its preparation- and 2.+ g 'n-@propylbromide dissolved in $, m! ?e9H. "he reaction 3as e/othermic, 3ith the deposition of 3hite
solids. "his 3as heated on the steam bath for ,.& h, added to ),, m! H$9, additional aFueous 5a9H added until the pH 3as basic, and e/tracted 3ith
0/2& m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith dilute 5a9H, and the solvent removed under vacuum. "he residue 3as $,&@dimetho/yphenyl
'n-@propyl sulfide 3hich 3as obtained as a pale yello3 oil, and 3hich 3eighed ).% g. It had a light pleasant fruity smell, and 3as sufficiently pure for use
in the ne/t reaction 3ithout distillation.
A mi/ture of (+.+ g P9Cl0 and (0.+ g 5@methylformanilide 3as heated for (, min on the steam bath. "o this claret@colored solution 3as added ).% g of
$,&@dimetho/yphenyl 'n-@propyl sulfide, and the mi/ture heated an additional $& min on the steam bath. "his 3as then added to ),, m! of 3ell@stirred
3arm H$9 'pre@heated to && deg C- and the stirring continued until the oily phase had completely solidified 'about (& minutes-. "he resulting bro3n
sugar@like solids 3ere removed by filtration, and 3ashed 3ith additional H$9. After sucking as dry as possible, they 3ere dissolved in an eFual 3eight of
boiling ?e9H 3hich, after cooling in an ice@bath, deposited pale ivory colored crystals. After filtration, modest 3ashing 3ith cold ?e9H, and air drying to
constant 3eight, there 3as obtained ).0 g of $,&@dimetho/y@+@'n@propyl@thio-ben6aldehyde 3ith a mp of 20@21 deg C. :ecrystalli6ation from $.& volumes
of ?e9H provided a 3hite analytical sample 3ith mp 21@22 deg C. "he 5?: spectrum in C;Cl0 3as te/tbook perfect, 3ith the t3o aromatic protons
sho3ing singlet signals at 1.)( and 2.$2 ppm, giving assurance that the assigned location of the introduced aldehyde group 3as correct.
"o a solution of +., g $,&@dimetho/y@'n@propylthio-ben6aldehyde in $, g of nitromethane there 3as added ,.$0 g of anhydrous ammonium acetate, and
the mi/ture 3as heated on the steam bath for ( h. "he clear orange solution 3as decanted from some insoluble material and the e/cess nitromethane
removed under vacuum. "he orange@yello3 crystalline material that remained 3as crystalli6ed from 2, m! boiling IPA 3hich, on slo3 cooling, deposited
$,&@dimetho/y@beta@nitro@+@'n-@propylthiostyrene as orange crystals. After their removal by filtration and air@drying to constant 3eight, they 3eighed 0.1 g,
and had a mp of ($,@($( deg C. Anal. 'C(0H(259+S- C,H.
A solution of !AH '(0$ m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added 0.&
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of ).+ g $,&@dimetho/y@beta@nitro@+@'n-@propylthiostyrene in &, m!
anhydrous "HB. "here 3as an immediate loss of color. After a fe3 min further stirring, the tem@perature 3as brought up to a gentle reflu/ on the steam
bath, then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of IPA '$( m! reFuired- follo3ed by sufficent &K
5a9H to give a 3hite granular character to the o/ides, and to assure that the reaction mi/ture 3as basic '(& m! 3as used-. "he reaction mi/ture 3as
filtered and the filter cake 3ashed first 3ith "HB and then 3ith IPA. "he filtrate and 3ashes 3ere combined and stripped of solvent under vacuum
providing about 1 g of a pale amber oil. Iithout any further purification, this 3as distilled at (+,@(&, deg C at ,.$& mm8Hg to give +.) g of product as a
clear 3hite oil. "his 3as dissolved in $& m! IPA, and neutrali6ed 3ith concentrated HCl forming immediate crystals of the hydrochloride salt in the
alcohol solvent. An eFual volume of anhydrous <t$9 3as added, and after complete grinding and mi/ing, $,&@dimetho/y@+@'n-@propylthiophenethylamine
hydrochloride '$C@"@2- 3as removed by filtration, <t$9 3ashed, and air dried to constant 3eight. "he resulting spectacular 3hite crystals 3eighed &.$ g.
;9SAC<E (, @ 0, mg.
;4:A"I95E ) @ (& h.
L4A!I"A"IM< C9??<5"S '3ith $, mg- A 3onderful day of integration and 3ork. "ook about $ hours for the onset. Some nausea on and off L that
seemed to cycle periodically throughout the day. Misuals 3ere great, much like mescaline but less sparkly. !ots of movement and aliveness L velvety
appearance and increased depth perception. 5eck and shoulder tension throughout the day along 3ith legs. I 3ould periodically notice e/treme
tightness of muscles, and then rela/. Iorking 3as very integrative. .ack and forth constantly bet3een 3onderful Cod@space L similar to ?;?A but
more grounded L then al3ays back to sadness. I felt that it really sho3ed me 3here I 3as unfinished, but 3ith self@loving and tolerance. "remendous
processing and letting go. Seeing things very clearly and also able to laugh at my trips. !ots of singing. In spite of shoulder tension, vocal freedom and
facility 3ere very high. I felt my voice integrated and dropped in a 3ay it never had before, and that remained for several days. Able to merge body,
voice, psyche and emotions 3ith music and then let go of it as a role. I also reali6ed and gave myself permission to do 3hatever it takes to get free. I let
go of ;ad 3ith tragic arias. "he ne/t day I let go of ?om by singing addish for her, and merging 3ith it.
'3ith $, mg- I lay do3n 3ith music, and become engrossed 3ith being as still as possible. I feel that if I can be totally, completely still, I 3ill hear the
inner voice of the universe. As I do this, the music becomes incredibly beautiful. I see the e/traordinary importance of simply listening, listening to
everything, to people and to nature, 3ith 3ide open receptivity. Something very, very special happens at the still point, so I keep 3orking on it. Ihen I
become totally still, a huge burst of energy is released. And it e/plodes so that it takes enormous effort to Fuiet it all do3n in order to be still again.
Creat fun.
'3ith $& mg- "his 3as a marvelous and strange evening. "his $C@"@2 is good and friendly and 3onderful as I remember it. I think it is going to take the
place of $C@"@$ in my heart. It is a truly good material. I got involved 3ith a documentary on television. It 3as about certain people of .olivia, people
living in the high mountains and about a small village 3hich L perhaps alone among all the places in the country L maintains the old Inca 3ays, the old
traditions, the old language. Ihich is, I gather, against the la3 in .olivia. It sho3ed a yearly meeting of shamans and it 3as Fuite clear that
hallucinogens played a maGor part in this meeting. "he shaman faces, male and female, 3ere startling in their intensity and earthy depth. "he Mirgin
?ary is 3orshipped as another version of the ancient Pacha ?ama, the <arth ?other. Ionderful dark, vivid look at places and people 3ho are not
usually to be seen or even kno3n about.
'3ith 0, mg- "he visuals have an adaptable character to them. I can use them to recreate any hallucinogenic substance I have kno3n and loved. Iith
open eyes, I can go easily into !S; flo3ing visuals, or into the 3arm earth 3orld of Peyote, or I can stop them altogether. Iith closed eyes, there are
<scher@like graphics 3ith a lot of chiaroscuro, geometric patterns 3ith oppositional play of sculptured light and dark values. Creen light.
<="<5SI95S A5; C9??<5"A:>E If all the phenethylamines 3ere to be ranked as to their acceptability and their intrinsic richness, $C@"@2 3ould be
right up there near the top, along 3ith $C@"@$, $C@., mescaline and $C@<. "he range is intentionally e/tended on the lo3er side to include (, milligrams,
as there have been numerous people 3ho have found (, or so milligrams to be Fuite adeFuate for their tastes.
9ne "3eetio related to $C@"@2 has been made and evaluated. "his is the $@<t9@homologue of $C@"@2, $@etho/y@&@metho/y@+@'n-@propylthiophenethyl@
amine, or $C"2@$<"9. "he ben6aldehyde '$@etho/y@&@metho/y@+@'n@propyl@thio-ben6aldehyde had a melting point of 1%@2( deg C, the nitrostyrene
intermediate a melting point of (,1@(,1.& deg C, and the final hydrochloride a melting point of ()2@()% CO. At the $, milligram level, the effects 3ere felt
Fuickly, and the eyes@closed visuals 3ere modest but real. It 3as very short@lived, 3ith baseline recovery at about the fifth hour. "he ne/t day there 3as
an uncomfortable headache 3hich seemed on an intuitive level to be an after@effect of the compound.
"he unusual properties of a number of 5@methyl@5@'i-@propyltryptamines suggested the possibility of something like a similar set of 5@methyl@5@'i-@
propylphenethylamines. Ihy not try one from $C@"@2H "he thought 3as, maybe 5@methylate this compound, then put on an isopropyl group 3ith
reductive alkylation, using acetone as the carbon source and sodium cyanoborohydride. "o3ards this end, the free base of $C@"@2 'from one gram of
the hydrochloride- 3as reflu/ed for $ h in (.0 g butyl formate, and on removing the solvent8reactant the residue spontaneously crystalli6ed. "his
formamide ',.2 g- 3as reduced 3ith lithium hydride in cold "HB to provide $,&@dimetho/y@+@'n-@propyl@5@methyl@phenethylamine, ?<"H>!@$C@"@2,
3hich distilled at (&,@(2, deg C at ,.+ mm8Hg. A very small amount of the hydrochloride salt 3as obtained '1& milligrams- and it had a bro3n color. "oo
small an amount of an impure product; the entire proGect 3as dropped.
#(( $!-T-3; $,)-0"METH%+Y-(-!Y!%,*%,YMETHYTH"%,HE#ETHYAM"#E
S>5"H<SISE "o a solution of $.) g of 9H pellets in $& m! hot ?e9H, there 3as added a mi/ture of &.% g $,&@dimetho/ythiophenol 'see under $C@"@$
for its preparation- and &., g of cyclopropylmethyl bromide. "here 3as an immediate e/othermic reaction 3ith spontaneous boiling and the formation of
3hite crystals. "his 3as heated on the steam bath for + h, and then added to +,, m! of H$9. After e/traction 3ith 0/2& m! CH$Cl$, the pooled
e/tracts 3ere 3ashed first 3ith dilute 5a9H, then 3ith saturated brine, then the solvent 3as removed under vacuum. "he residue, ).+& g of crude $,&@
dimetho/yphenyl cyclopropyl methyl sulfide, 3as distilled at ($,@(+, deg C at ,.0 mm8Hg to give a 3hite oil 3eighing 2.& g.
A mi/ture of (0.& g P9Cl0 and (0.& g 5@methylformanilide 3as heated for (, min on the steam bath. "o this claret@colored solution 3as added 2.$) g of
$,&@dimetho/yphenyl cyclopropylmethyl sulfide, and the spontaneously e/othermic mi/ture 3as heated for an additional (, min on the steam bath, and
then Fuenched in +,, m! of && deg C H$9 3ith good stirring. After a fe3 minutes a reddish solid phase separated. "his 3as removed by filtration, and
3ashed 3ith additional H$9. After sucking as dry as possible, this ).2& g of ochre@colored solid 3as dissolved in (+ m! of boiling ?e9H, and after
cooling, filtering, 3ashing sparsely 3ith ?e9H, and air drying, gave 2.$2 g of 3hite solid crystals of $,&@dimetho/y@+@
'cyclopropylmethylthio-ben6aldehyde. "he proton 5?: spectrum 3as impeccable; CH9 %.0), ArH 2.$2, 1.)( $ s., 9CH0 0.%0, 0.%, $ s., SCH$ t. $.%1,
CH$, m. (.2$, and CH$, t. (.((.
"o a solution of 1.1 g $,&@dimetho/y@+@'cyclopropylthio-ben6aldehyde in )$ g of nitromethane there 3as added ,.($ g of anhydrous ammonium acetate,
and the mi/ture 3as heated on the steam bath for 1 h. "he reaction mi/ture 3as allo3ed to stand overnight producing a heavy crystalli6ation crop.
Biltration, 3ashing lightly 3ith ?e9H, and air drying gave +.2$ g of orange crystals of $,&@dimetho/y@+@cyclopropylmethylthio@beta@nitrostyrene as yello3
crystals. "he evaporation of the mother liFuors and grinding of the resulting solids 3ith ?e9H provided another $., g of the product.
A solution !AH '+, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.,& m!
(,,K H$S9+ drop3ise over (, min, to minimi6e charring. "his 3as follo3ed by the addition of $.%& g $,&@dimetho/y@+@cyclopropylmethylthio@beta@
nitrostyrene as a solid, over the course of (, min. After a fe3 min further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath,
then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of 1 m! IPA follo3ed by 0 m! (&K 5a9H 3hich gave
the aluminum o/ide as a curdy 3hite solid. "he reaction mi/ture 3as filtered, and the filter cake 3ashed 3ith additional "HB. "he filtrate and 3ashes
3ere stripped of solvent under vacuum providing about (.) g of a colorless oil. "he addition of dilute H$S9+ produced a thick mass of 3hite solids. "his
3as 3ashed 3ith CH$Cl$, and the remaining aFueous phase, still containing solids, 3as made basic 3ith $&K 5a9H. "he aFueous phase 3as
e/tracted 3ith 0/2& m! CH$Cl$, and the combined e/tracts stripped of solvent under vacuum. "he result 3as (.+ g of colorless oil. "his 3as distilled at
(&,@(1& deg C at ,.$ mm8Hg to give (.$ g of a 3hite oil. "his 3as dissolved in 1 m! IPA, neutrali6ed 3ith ,.1 m! concentrated HCl producing
spontaneous 3hite crystals. "hese 3ere diluted 3ith ) m! additional IPA, and suspended under 1, m! anhydrous <t$9 to provide, after filtering and air
drying, (.(0 g of $,&@dimetho/y@+@cyclo@propylmethylthiophenethylamine hydrochloride '$C@"@)- as 3hite crystals.
;9SAC<E 0, @ &, mg.
;4:A"I95E (, @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith 0, mg- .ad taste, 3orse smell. .ut I like it. I can paint easily, and 3ouldn7t hesitate to take a little more ne/t time, but
this is enough 3ith no one to talk to. ?anual de/terity good. .ody rather 3arm. Iouldn7t mind fooling around. In retrospect, it has a smooth onset, and
is not too stimulating. "his is a good one.
'3ith +, mg- "his is beginning to develop at one and a half hours into it. High energy, good feeling. I have had a heavy, dense feeling bet3een me and
my 3ork for several days no3, but this is rapidly dissolving, and 3ith this loss, the day continues into one of the most remarkable e/periences I have
ever had. </cellent feelings, tremendous opening of insight and understanding, a real a3akening as if I had never used these materials effectively
before. Bor the ne/t several hours it 3as an internal Gourney for me; I 3ished to interact 3ith myself. I cannot recall all the details, but I did revie3 many
aspects of myself and my personal relations. I kno3 that I am the better for all of this.
'3ith +, mg- I first noted the effects at three Fuarters of an hour, and at t3o hours I have pain in my sinuses. ?y head is split in t3o L this is not being
t3o or three different people L this is one person 3ith a head living in t3o different universes at the same time. 5ot a crisis e/perience, but one of
e/treme and prolonged discomfort. Hypersensitivity to light, noise, motion, 3ith the belief that it 3ould not go a3ay 3hen the chemical 3ore off. ?y
visual and spatial perceptions 3ere divided in t3o along a vertical a/is, 3ith both halves moving in uncoordinated 3ays. A feeling that the eyes 3ere
3orking independently of each other. 5ausea 3ithout vomiting, even 3hen I tried to. Mertigo became intolerable if I closed my eyes or lay do3n, so I felt
that I 3ould never lie do3n or close my eyes again. Problems 3ith 7boundaries.7 "he outside environment seemed to be getting inside my head. "he
parts of myself seemed to either separate uncontrollably or run together into someone I didn7t kno3. A late movie, and "ran/ene, and a little sleep all
helped me out of this. Ho3ever, a bu66ing in the head, an uncertain balance, and an out@of@it feeling lasted for 0 days, and 3as still faintly present after
a 3eek.
'3ith +0 mg- Bor the first t3o hours I rocked in place and felt Fuite happy not trying to 7do7 anything useful or e/pected, but 3atched some e/cellent
programs on "M. !ater I sat at the type3riter and felt the energy and the opening of the particular kind of thinking@connection that I associate 3ith $C@"@
$. I felt this very strongly; I 3as fully into my o3n energy and capable of being aggressive if I decided to. I 3as very good humored and completely
anchored to the earth. In the late evening I 3ent to bed and felt that I 3ould not allo3 myself to sleep, since the tendency to go completely out of
conscious body 3as Fuite strong. Ho3ever, before I could get up and continue happily 3riting, as I intended, I fell asleep. I slept thoroughly, 3ell, and
3oke up the ne/t day 3ith good energy and a 3illingness to get on 3ith the day.
'3ith &, mg- "he 3hole e/perience 3as some3hat negative, self@doubting, paranoid. .asically, I am not in a good place. 5o constructive values ever
knit, and although there 3as a lot of talking, nothing positive developed. I 3as glad of sleep at about t3elve hours into it, and this aspect of it 3as
completely friendly. 5e/t day, no deficit. Strange. ?aybe too much.
<="<5SI95S A5; C9??<5"A:>E Iith $C@"@), there are as many negatives as there are positives, and the particular substitution pattern is not one
to set the 3orld on fire. "he first step 3as made to3ards the synthesis of the 0@carbon counterpart, $,&@dimetho/y@+@cyclopropylmethylthioamphetamine,
A!<PH@). "he above ben6aldehyde '$.$ g- 3as cooked overnight on the steam bath in nitroethane '$, m!- containing ammonium acetate ',.+ g- and
3hen the solvent 3as removed, the residue 3as converted to orange crystals by the addition of a little ?e9H. "his 3as not pursued further. Although
the cyclopropylmethyl group 3as Fuite something on the mescaline o/ygen atom, it is less appealing on the $C@"@= sulfur atom, and there is even less
enthusiasm to put it into an A!<PH. "hat7s the 3ay it is, and 3ho could have guessedO


#() $!-T-4; $,)-0"METH%+Y-(-&t--./TYTH"%,HE#ETHYAM"#E
S>5"H<SISE "o a 3ell@stirred ice@cold suspension of $.) g p@dimetho/yben6ene and 0.$ m! 5,5,57,57@tetramethylethylenediamine in (,, m! petroleum
ether under an inert atmosphere of He, there 3as added (0 m! of a (.1 5 solution of butyllithium in he/ane. "he suspended dimetho/yben6ene
became opaFue and there 3as a pale yello3 color generated. "he reaction mi/ture 3as 3armed to room temperature 3hich converted it to light 3hite
solids. After an additional ,.& h stirring, there 3as added, slo3ly, 0.1 g of di@'t-@butyldisulfide. "he yello3 color deepened, the solids dissolved and, after
( h, the color 3as a clear deep bro3n. "his solution 3as poured into (,, m! dilute HCl and the organic phase 3as separated. "he aFueous fraction
3as e/tracted 3ith 0/2& m! CH$Cl$. "he combined organic phases 3ere 3ashed 3ith dilute aFueous 5a9H, 3ith H$9, and then stripped of solvents
under vacuum. "he residue 3as distilled at %&@(,& deg C at ,.& mm8Hg to provide 0.2 g of $,&@dimetho/yphenyl 't-@butyl sulfide as a 3hite, mobile
liFuid. Anal. 'C($H()9$S- C,H. A solid derivative 3as found in the nitration product, $,&@dimetho/y@+@'t-@butylthio@(@nitroben6ene, 3hich came from the
addition of ,.(( m! of concentrated H590 to a solution of ,.$0 g of the above sulfide in & m! ice cold acetic acid. ;ilution 3ith H$9 provided yello3
solids 3hich, on recrystalli6ation from ?e9H, had a mp of %$@%0 deg C. Anal. 'C($H(259+S- C,H. Attempts to make either the picrate salt or the
sulfonamide derivative 3ere not satisfactory.
A mi/ture of 2$ g P9Cl0 and 12 g 5@methylformanilide 3as heated for (, min on the steam bath. "o this claret@colored solution 3as added $) g of $,&@
dimetho/yphenyl 't-@butyl sulfide, and the mi/ture heated for (, min on the steam bath. "his 3as then added to ( ! of H$9 and stirred overnight. "he
residual bro3n oil 3as separated from the 3ater mechanically, and treated 3ith (&, m! boiling he/ane. "he he/ane solution 3as decanted from some
insoluble tars, and on cooling deposited a dark oil 3hich did not crystalli6e. "he remaining he/ane 3as removed under vacuum and the residue
combined 3ith the above he/ane@insoluble dark oil, and all distilled at ,.$ mm8Hg. An early fraction '2,@((, deg C- 3as largely 5@methyl@formanilide and
3as discarded. Crude $,&@dimetho/y@+@'t@butylthio-ben6aldehyde came over at ($,@(0, deg C and 3eighed ($., g. "his 3as never satisfactorily
crystalli6ed despite the successful formation of seed. It 3as a comple/ mi/ture by "!C, containing several components. It 3as used for the ne/t step as
the crude distilled fraction.
"o a solution of (, g impure $,&@dimetho/y@'t@butylthio-ben6aldehyde in 2& m! of nitromethane there 3as added (., g of anhydrous ammonium acetate,
and the mi/ture 3as heated on the steam bath (.& h. :emoval of the e/cess solvent8reagent under vacuum produced an orange oil that 3as 'not
surprisingly- comple/ by "!C and 3hich 3ould not crystalli6e. A hot he/ane solution of this oil 3as allo3ed to slo3ly cool and stand at room temperature
for several days, yielding a mi/ture of yello3 crystals and a bro3n viscous syrup. "he solids 3ere separated and recrystalli6ed from +, m! ?e9H to
give 0.2 g $,&@dimetho/y@+@'t-@butylthio@beta@nitrostyrene as fine lemon@yello3 crystals, 3ith a mp of %0@%+ deg C. A second crop of (.+ g had a mp of
%(@%$ deg C. Anal. 'C(+H(%59+S- C,H.
A solution of !AH '2, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added $.(
m! (,,K H$S9+ drop3ise, over the course of $, min. "his 3as follo3ed by the addition of +.2 g $,&@dimetho/y@+@'t-@butylthio@beta@nitrostyrene in $,
m! anhydrous "HB. "here 3as an immediate loss of color. After a fe3 min further stirring, the mi/ture 3as allo3ed to come to room temperature, and
the stirring 3as continued for & h. "he e/cess hydride 3as destroyed by the cautious addition of (, m! IPA follo3ed by 1 m! (&K 5a9H and finally 1
m! H$9. "he loose 3hite solids 3ere removed by filtration, and the filter cake 3ashed 3ith "HB. "he filtrate and 3ashes 3ere combined and, after
stripping off the solvent under vacuum, there 3as obtained +.11 g of a pale yello3 oil. Iithout any further purification, this 3as distilled at ,.$ mm8Hg. A
first fraction came over at up to ($, deg C and 3as a light colorless oil that 3as not identified. "he correct product distilled at (0,@(1, deg C as a pale
yello3 viscous oil that 3eighed (.11 g. "his 3as dissolved in (, m! IPA, neutrali6ed 3ith $, drops of concentrated HCl and diluted 3ith ), m!
anhydrous <t$9. After standing a fe3 min there 3as the spontaneous generation of 3hite crystals of $,&@dimetho/y@+@'t-@butylthiophenethylamine
hydrochloride '$C@"@%- 3hich 3ere removed by filtration, and air dried. "he 3eight 3as (.(, g.
;9SAC<E 1, @ (,, mg.
;4:A"I95E ($ @ () h.
L4A!I"A"IM< C9??<5"SE '3ith %, mg- $C@"@% tastes the 3ay that old crank@case motor oil smells. I 3as up to something above a plus t3o at the
third hour. Although there 3ere no visuals noted, I certainly 3ould not choose to drive. Someho3 this does more to the body than to the head. I feel
that the effects are 3aning at maybe the si/th hour, but there is a very strong body memory that makes sleeping difficult. Binally, at sometime after
midnight and 3ith the help of a glass of 3ine, some sleep.
'3ith ($& mg- "here 3as a steady climb to a *** over the first couple of hours. So far, the body has been Fuite peaceful 3ithout any strong energy push
or stomach problems, although my tummy insists on being treated 3ith Fuiet respect, perhaps out of habit, perhaps not. At the fifth hour, the body
energy is Fuite strong, and I have the choice of focusing it into some activity, such as love@making or 3riting, or having to deal 3ith tapping toes and
floor@pacing. Bor a novice this 3ould be a murderously difficult e/perience. "oo much energy, too long a time. I suppose I could get used to it, but let
me Gudge by 3hen I get to sleep, and Gust 3hat kind of sleep it is. It turned out that sleep 3as 9, but for the ne/t couple of days there 3as a continuing
a3areness of some residue in the body L some kind of lo3@level poisoning. I feel in general that there is not the e/citement or creativity to connect 3ith,
certainly not enough to Gustify the cost to the body.
<="<5SI95S A5; C9??<5"A:>E "he three@carbon analog of $C@"@% 'this 3ould be one of the A!<PH series- has never been made and, for that
matter, none of the higher numbered $C@"7s have had the amphetamine counterparts synthesi6ed. "hey are, as of the present time, unkno3n
compounds. "his nifty reaction 3ith di@'t-@butyl disulfide 3orked so 3ell, that three additional disulfides that 3ere at hand 3ere immediately thro3n into
the chemical program, 3ith the Fuick assignment of the names $C@"@(,, $C@"@((, and $C@"@($.
"he lithiated dimetho/yben6ene reaction 3ith $,$@dipyridyl disulfide produced $,&@dimetho/yphenyl $@pyridyl sulfide 3hich distilled at (0&@(&, deg C at
,.+ mm8Hg and could be recrystalli6ed from cyclohe/ane containing $K <t9H to give a product that melted at 11@12.& deg C. Anal. 'C(0H(059$S-
C,H. "his 3ould have produced $,&@dimetho/y@+@'$@pyridylthio-phenethylamine '$C@"@(,- but it 3as never pursued.
"he same reaction 3ith di@'+@bromophenyl- disulfide produced $,&@dimetho/yphenyl +@bromophenyl sulfide 3hich distilled at (&,@(2, deg C at ,.&
mm8Hg and could be recrystalli6ed from ?e9H to give a product that melted at 2$@20 deg C. Anal. 'C(+H(0.r9$S- C,H. "his 3as being directed
to3ards $,&@dimetho/y@+@'+@bromophenylthio-phenethylamine '$C@"@((- but it also 3as abandoned.
"he same reaction 3ith 5,5@dimorpholinyl disulfide produced virtually no product at all, completely defusing any plans for the synthesis of a novel sulfur@
nitrogen bonded base $,&@dimetho/y@+@'(@morpholinothio-phenethylamine '$C@"@($-. 9ne additional effort 3as made to prepare a $C@"@= thing 3ith a
sulfur@nitrogen bond. "he acid chloride intermediate in the preparation of $,&@dimetho/ythiophenol 'as described in the recipe for $C@"@$- is $,&@
dimetho/yben6enesulfonyl chloride. It reacted smoothly 3ith an e/cess of diethylamine to produce $,&@dimetho/y@5,5@diethylben6enesulfonamide
3hich distilled at (&& deg C at ,.(0 mm8Hg and 3hich could be recrystalli6ed from a +E( mi/ture of cyclohe/ane8ben6ene to give a product 3ith a melting
point of +(@+$ deg C and an e/cellent proton 5?:. "his amide proved totally refractory to all efforts at reduction, so the target compound, $,&@
dimetho/y@+@diethylaminothiophenethylamine, has not been made. It has not even been given a $C@"@= number.

#(1 $!-T-1'; $,)-0"METH%+Y-(-&$-METH%+YETHYTH"%-,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0.$& g of 9H pellets in $& m! hot ?e9H, there 3as added 1.) g of $,&@dimetho/ythiophenol 'see under $C@"@$ for its
preparation- follo3ed by +.20 g of $@metho/yethylchloride. "his mi/ture 3as heated on the steam bath for ,.& h, then added to &,, m! H$9. "his very
basic aFueous phase 3as e/tracted 3ith 0/(,, m! CH$Cl$, the e/tracts pooled, and back@3ashed 3ith &K 5a9H. "he solvent 3as removed under
vacuum to give ).)$ g of a 3hite oil. ;istillation gave $,&@dimetho/yphenyl $@metho/yethyl sulfide 3ith a bp ((&@($& deg C at ,.0 mm8Hg, and a 3eight
of 1.1& g.
A mi/ture of (, g P9Cl0 and (, g 5@methylformanilide 3as heated for (, min on the steam bath. "o this claret@colored solution 3as added 1.(1 g of
$,&@ dimetho/yphenyl $@metho/yethyl sulfide. "here 3as an immediate e/othermic reaction and gas evolution. "he mi/ture 3as heated for (& min on
the steam bath, at 3hich time there 3as no starting sulfide present by "!C. "his 3as then added to &,, m! of 3ell@stirred 3arm H$9 'pre@heated to &&
deg C- and the stirring continued until only a thin oily phase remained. "his 3as e/tracted 3ith CH$Cl$, the e/tracts 3ere combined, and the solvent
removed under vacuum. "he residue 3as e/tracted 3ith & seFuential $, m! portions of boiling he/ane 3hich deposited crystals on cooling. Biltering
gave a total of +.($ g crystalline solids. :ecrystalli6ation from ?e9H gave a poor yield of a cream@colored crystal 3ith a mp of 1)@1% deg C. A more
efficient purification 3as achieved by distillation '(&&@(1) deg C at ,.0 mm8Hg- yielding 0.&, g of $,&@dimetho/y@+@'$@metho/yethylthio-ben6aldehyde as
a pale yello3 solid, 3ith a mp of 12@1) deg C. A faster moving 'by "!C- trace component 3ith an intense fluo@rescence persisted throughout the entire
purification scheme, and 3as still present in the analytical sample. Anal. 'C($H(19+S- C,H.
"o a solution of 0.+( g $,&@dimetho/y@+@'$@metho/yethylthio-ben6aldehyde in &, g of nitromethane there 3as added ,.(( g of anhydrous ammonium
acetate, and the mi/ture 3as heated on the steam bath for $ h, at 3hich time the starting aldehyde had largely disappeared by "!C 'silica gel plates 3ith
CH$Cl$ as the developing solvent- and a faster moving nitrostyrene product 3as clearly visible. "he clear orange solution 3as stripped of the e/cess
nitromethane under vacuum producing a yello3 oil that crystalli6ed yielding 0.%2 g of a yello3 solid 3ith a mp of %%@(,+ deg C. :ecrystalli6ation of a
small sample from ?e9H produced '3hen dry- yello3 electrostatic crystals of $,&@dimetho/y@+@'$@metho/yethylthio-@beta@nitrostyrene 3ith a mp of (,2
deg C sharp. Brom IPA the product is a burnished gold color 3ith the mp (,1@(,2 deg C. Anal. 'C(0H(259&S- C,H.
A solution of !AH '+, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.,&
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of 0.,2 g $,&@dimetho/y@+@'$@metho/yethylthio-@beta@nitrostyrene in
small portions, as a solid, over the course of (, min. "here 3as a considerable amount of gas evolved, and a little bit of charring. After a fe3 min further
stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath, and then all 3as cooled again to , deg C. "he e/cess hydride 3as
destroyed by the cautious addition of ) m! IPA follo3ed by 0 m! (&K 5a9H 3hich gave the reaction mi/ture a curdy 3hite granular character. "he
reaction mi/ture 3as filtered, the filter cake 3ashed 3ith "HB, and filtrate and 3ashes 3ere stripped of solvent under vacuum providing about 0 g of a
pale amber oil. "his 3as dissolved in about +, m! CH$Cl$ and e/tracted 3ith $,, m! dilute H$S9+ in three portions. All of the color remained in the
organic phase. "he pooled aFueous e/tracts 3ere 3ashed 3ith CH$Cl$, then made basic 3ith $&K 5a9H, e/tracted 3ith 0/2& m! CH$Cl$, and the
combined e/tracts pooled and stripped of solvent under vacuum. "he $ g pale yello3 oily residue 3as distilled at (&&@(1& deg C at ,.$ mm8Hg to give
(.$0 g of a clear 3hite oil. "his 3as dissolved in IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith anhydrous <t$9 to produce crystals of $,&@
dimetho/y@+@'$@metho/yethylthio-phenethylamine hydrochloride '$C@"@(0-. After filtration, 3ashing 3ith <t$9, and air drying, this 3hite crystalline
product 3eighed ,.)% g.
;9SAC<E $& @ +, mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith $& mg- I felt it 3as some3hat noisy as 3e 3ent into the e/perience. "his noisiness lasted only about an hour, then
stopped. At the peak, 3hich seemed to be at about ( to maybe (.& hours, some eyes@closed visuals appeared. "here 3as a 3hite field 3ith colored
visuals, at times geometric in shape. "hese eye@closed images 3ere pleasant and I enGoyed them 3hen I did not concern myself 3ith, or listen to, the
conversation. "here 3as an eyes@open change in color, the ivy became a little lighter or maybe a little stronger in color. I7m not sure 3hich. I felt there
3as a gradual diminishing of activity '3hatever that undefined activity 3as- starting at $ to $.& hours, and coming close to baseline at 1 P?. "he
descent 3as pleasant and I 3ould say pleasurable. "he e/perience did not lead to any confusion 3hich I sometimes notice in other e/periences. "here
3as no problem 3ith anore/ia. Ie ate constantly during the e/perience. "he grapes and other fruit 3ere lovely. "his is one of the fe3 times I 3ould
say that I 3ould try a higher dose. ?aybe 0, or 00 milligrams. I suspect the e/perience 3ould be similar, 3ith Gust a heightened peak at ( hour and
perhaps a little more body effect. It may 3ell be one to try 3ith one7s 3ife.
'3ith $) mg- "here 3as a strange, disturbing t3inge e/actly eight minutes after starting this, that asked me, SShould I have done thisH7 I ans3ered, S>es7
and the t3inge disappeared. And then there 3as nothing until the e/pected time of development, at a half hour 3hen I felt a light head and slight
di66iness. "here 3as a solid plus t3o for a couple of hours. I paid careful attention for auditory oddities that I had noted before, but they 3ere not there.
In an earlier trial '3ith $, milligrams- the radio had the sound of being located in the outdoors 3ith the sounds coming through the 3all and into the room
3here I 3as. I 3as at a neutral baseline at about seven hours.
'3ith 0& mg- "here 3as a Fuiet climb, but it 3as marred 3ith some tummy unFuiet, and an annoying persistence of diarrhea. I 3as very impressed 3ith
eyes@closed patterning, 3hich seemed to do its o3n thing independently of the music. I 3as clearly up to a ***, but there 3as a feeling that as soon as
it got there it started to go a3ay again. "here 3as no there, there. >et there 3ere a couple of touches of introspection, of seriousness 3hich I had to
respect.
'3ith +, mg- "here 3ere four of us, and the entry 3as individual for each of us. "3o of us 3ere nauseous. 9ne volunteered a statement, almost a
confession, of too much food and drink in the immediate past. 9ne of us needed his cigarette right no3, and then he sa3 that he 3as killing himself, and
he s3ore off. ;on7t kno3 if it 3ill last, ho3ever. At the t3o and a half hour point there is a consensus that this has gone its route and 3ill lose its impact,
so three of us decided to supplement on $C@"@$. Si/ milligrams proves to be a little light so, some four hours later, 3e each took another si/ milligrams.
</cellent. In a 3hile 3e discoved that 3e 3ere very hungry, and food tasted marvelous. Headaches ackno3ledged in the early evening, but the
e/tension from "@(0 to "@$ seemed to be absolutely correct. And as of the ne/t day, the non@smoker 3as still a non@smoker.
<="<5SI95S A5; C9??<5"A:>E ?ost of the synthetic adventures of putting a basic something a3ays out from the ben6ene ring, at the four@
position, have involved subtle things such as unsaturated bonds or three@membered rings. "his 3as the first try 3ith the actual use of a different atom
'an o/ygen-. Ihat about other heteroatoms such as sulfur or nitrogen or silicon or phosphorus, or some@suchH
"he sulfur counterpart of $C@"@(0 3as named $C@"@(+, and 3as immediately launched. "he reaction of $,&@dimetho/ythiophenol and 9H 3ith $@
methyl@thioethyl chloride in hot ?e9H gave $,&@dimetho/yphenyl $@methylthioethyl sulfide as a 3hite oil 'boiling point of (+,@(1, deg C at ,.0 mm8Hg-.
"his under3ent a normal Milsmeier reaction 'phosphorous o/ychloride and 5@methylformanilide- to give $,&@dimetho/y@+@'$@
methylthioethylthio-ben6aldehyde 3ith a melting point of 1+@1+.& deg C from ?e9H. "his, in nitromethane containing a little ammonium acetate, 3as
heated on the steam bath for (, hours and 3orked up to give an e/cellent yield of $,&@dimetho/y@+@'$@methylthioethylthio--@beta@nitrostyrene as garish
orange@red N!as MegasN colored crystals from acetonitrile, 3ith a melting point of ($1@($2 deg C. And as of the moment, this is sitting on the shelf
3aiting to be reduced to the target compound $,&@dimetho/y@+@'$@methylthioethylthio-phenethylamine hydrochloride, or $C@"@(+. Iill it be activeH I
rather suspect that it 3ill be, and I7ll bet it 3ill be longer@lived than the o/ygen model, $C@"@(0.

#(2 $!-T-1); SES:/"; $,)-0"METH%+Y-(-!Y!%,*%,YTH"%,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0.0 g of 9H pellets in (&, m! hot ?e9H, there 3as added (, g $,&@dimetho/ythiophenol 'see recipe for $C@"@$ for its
preparation- follo3ed by (, g (@bromo@0@chloropropane. "he reaction 3as e/othermic, and immediately deposited 3hite solids of Cl. "he reaction
mi/ture 3as 3armed for a fe3 min on the steam bath, and then Fuenched in H$9. "he basic reaction mi/ture 3as e/tracted 3ith 0/2& m! CH$Cl$. "he
pooled e/tracts 3ere stripped of solvent under vacuum. "he residual oil 3as distilled at (+&@(&& deg C at ,.$ mm8Hg to give (1.& g of $,&@
dimetho/yphenyl 0@chloropropyl sulfide as a clear, colorless oil.
A solution of the lithium amide of $,$,1,1@tetramethylpiperidine 3as prepared by the addition of $, m! of $.1 ? butyllithium in he/ane to a 3ell stirred
he/ane solution of the piperidine in (,, m! he/ane, under an atmosphere of He. "he reaction 3as e/othermic, formed a 3hite solid precipitate, and
3as allo3ed to continue stirring for a fe3 min. "here 3as then added 1.& g $,&@dimetho/phenyl 0@chloropropyl sulfide, and a strongly e/othermic
reaction ensued. "his 3as stirred for 0, min and then poured into dilute H$S9+ 'the progress of the reaction must be follo3ed by "!C, silica gel plates,
CH$Cl$Epetroleum ether &,E&, to determine 3hen it is done; in one run over $ h 3ere reFuired for completion of the reaction-. "he organic phase 3as
separated, and the aFueous phase e/tracted 3ith 0/2& m! <t9Ac. "he combined organic phases 3ere 3ashed first 3ith dilute 5a9H, then 3ith dilute
HCl, then the solvents 3ere removed under vacuum. "he residue 3as distilled to provide $,&@dimetho/yphenyl cyclopropyl sulfide as a pale yello3 liFuid
that boiled at (,,@((& deg C at ,.( mm8Hg. "he use of other bases to achieve this cycli6ation 3ere less successful. Incomplete cycli6ation resulted
from the use of lithium diisopropyl amide and, if the conditions 3ere made more vigorous, there 3as dehydrohalogenation to the allyl sulfide. An
une/pected difficulty 3as that the allyl sulfide 'from elimination- and the 0@chloropropyl sulfide 'starting material- behaved in an identical manner on "!C
analysis. "hey 3ere easily separated, ho3ever, by CC analysis.
A completely different approach to the synthesis of this sulfide 3as e/plored through the reaction of cyclopropyllithium 3ith an aromatic disulfide, thus
avoiding the base@promoted cycli6ation step. A solution of $.1 g di@'$,&@dimetho/yphenyl-disulfide 'from $,&@dimetho/ythiophenol and hydrogen
pero/ide, bp $$,@$0, deg C at ,.0 mm8Hg- 3as made in anhydrous <t$9, and 3ell stirred. In a separate flask, under an atmosphere of He, + m! of $.1
? butyllithium 3as added to a solution of (.$ g cyclopropyl bromide in $, m! anhydrous <t$9. "his mildly e/othermic combination turned a bit cloudy,
3as stirred for ( h, then trans@ferred 3ith an air@tight syringe to the above@described <t$9 solution of the aromatic disulfide. A heavy precipitate formed,
and stirring 3as continued for an additional ,.& h. "he reaction mi/ture 3as then poured into H$9, the layers separated, and the aFueous phase
e/tracted 3ith CH$Cl$. "he e/tracts 3ere pooled, 3ashed 3ith dilute aFueous 9H, and the solvents removed under vacuum. ;istillation gave ,.2 g of
$,&@dimetho/yphenyl cyclopropyl sulfide 3ith identical gas chromatographic behavior to the sample prepared by the cycli6ation of the chloropropylthio
compound.
A mi/ture of 2.$ g P9Cl0 and 1.2 g 5@methylformanilide 3as heated on the steam bath until it 3as claret red. "o this there 3as added +.& g of $,&@di@
metho/yphenyl cyclopropyl sulfide, and the e/othermic combination heated on the steam bath for about & min. "he deep red, bubbling reaction mi/ture
3as added to (&, m! H$9 and stirred until all oils had been converted into loose solids. "hese 3ere then removed by filtration, 3ashed 3ith H$9, and
sucked as dry as possible. "hey 3ere dissolved in boiling ?e9H 3hich, after cooling in an ice@bath, deposited yello3 crystals of $,&@dimetho/y@+@
'cyclopropylthio-ben6aldehyde that 3eighed 0.+0 g after air drying, and had a mp of %2@%% deg C. Anal. 'C($H(+90S- C,H.
"o a solution of 0., g $,&@dimetho/y@+@'cyclopropylthio-ben6aldehyde in +, g of nitromethane there 3as added ,.$ g of anhydrous ammonium acetate,
and the mi/ture 3as heated on the steam bath for 0 h. "he e/cess nitromethane 3as removed under vacuum yielding 0.+ g orange crystals. "hese
3ere recrystalli6ed from (&, m! boiling IPA containing a little toluene. After cooling, filtering, and air drying there 3ere obtained $.2& g of $,&@dimetho/y@
+@cyclopropylthio@beta@nitro@styrene as pumpkin@colored crystals 3ith a mp of (&%@(1, deg C. Anal. 'C(0H(&59+S- C,H.
A solution of !AH '+, m! of a ( ?. solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.,&
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of $.& g $,&@dimetho/y@+@cyclopropylthio@beta@nitrostyrene in +, m!
anhydrous "HB over the course of (& min. "here 3as an immediate loss of color. After a fe3 min further stirring, the temperature 3as brought up to a
gentle reflu/ on the steam bath and held there for $ h. After recooling, there 3as added IPA 'to destroy the e/cess hydride- follo3ed by sufficent (&K
5a9H to give a 3hite granular character to the o/ides, and to assure that the reaction mi/ture 3as basic. "he reaction mi/ture 3as filtered, and the filter
cake 3ashed 3ith "HB. "he filtrate and 3ashes 3ere stripped of solvent under vacuum providing a yello3 oil that 3as treated 3ith dilute H$S9+. "his
produced a flocculant 3hite solid, apparently the sulfate salt of the product. "his 3as 3ashed 3ith +/2& m! CH$Cl$ 3hich removed most of the yello3
color. "he aFueous phase 3as made basic 3ith aFueous 5a9H and e/tracted 3ith 0/2& m! CH$Cl$. :emoval of the solvent under vacuum gave a
light yello3 colored oil that 3as distilled at ,.0 mm8Hg. "he fraction boiling at (+,@(&, deg C 3as a colorless, viscous oil that 3eighed (.%2 g. "his 3as
dissolved in a fe3 m! IPA, and neut@rali6ed 3ith concentrated HCl forming immediate cottage cheese@like crystals of the hydrochloride salt. "his 3as
diluted by suspension in anhydrous <t$9, removed by filtration, and air dried to give (.%+ g of $,&@dimetho/y@+@cyclopropylthiophenethylamine
hydrochloride '$C@ "@(&- that had a mp of $,0@&@$,+.& deg C. Anal. 'C(0H$,Cl59$S- C,H.
;9SAC<E greater than 0, mg.
;4:A"I95E several hours.
L4A!I"A"IM< C9??<5"SE 'at 0, mg- I 3as some3here bet3een a threshold and a plus one for several hours, and appeared to be Fuite talkative in
the evening.
<="<5SI95S A5; C9??<5"A:>E "he commonly used name for $C@"@(&, during its synthesis, 3as S<SL4I. "he general name for a (&@carbon
terpene is sesFuiterpene, from the !atin prefi/ for one and a half. "he active level of $C@"@(& is not kno3n. "he highest level yet tried 3as 0, milligrams
orally, and there had been threshold reports pretty regularly all the 3ay up from 1 milligrams. .ut no definite activity yet. "his compound is isosteric 3ith
the isopropyl group as seen in the analogous compound $C@"@+ 'the three carbons are in e/actly the same positions, only the electrons are located
differently- and it is a little surprising that the potency appears to be considerably less. Dust over $, milligrams of the latter compound 3as
over3helmingly psychedelic.
"he entire mini@proGect of hanging cyclic things onto the sulfur atom 3as an interesting problem. "his is the three carbon ring. "he si/ carbon ring 'the
cyclohe/yl homologue- 3as discussed as $C@"@& in the recipe for of A!<PH@$. "he cyclobutyl and cyclopentyl homologs 3ere assigned the names of
$C@"@() and $C@"@$0, respectively, and their preparations taken as far as the nitrostyrene and the aldehyde stages, respectively, before the proGect ran
out of steam.
"o3ards the cyclobutyl homologue, a solution of $,&@dimetho/ythiophenol and cyclobutyl bromide in ;?S9 containing anhydrous potassium carbonate
3as stirred for several hours at room temperature and yielded $,&@dimetho/yphenyl cyclobutyl sulfide as a 3hite oil that boiled at (0&@(+, deg C at ,.0
mm8Hg. Anal. 'C($H(19$S- C,H. "his 3as brought to react 3ith a mi/ture of phosphorus o/y@chloride and 5@methylformanilide producing $,&@
dimetho/y@+@'cyclobutylthio-ben6aldehyde that had a melting point of (,)@(,%.& deg C from ?e9H. Anal. 'C(0H(190S- C,H. Coupling 3ith
nitromethane in the presence of ammonium acetate produced $,&@dimetho/y@+@cyclobutylthio@beta@nitrostyrene as lustrous orange crystals from boiling
acetonitrile, melting point (1,@(1( deg C. Anal, 'C(+H(259+S- C,H. "his 3ill some day be reduced to $,&@dimetho/y@+@cyclobutylthiophenethylamine
hydrochloride, $C@"@().
"o3ards the cyclopentyl homologue, a solution of $,&@dimetho/ythiophenol and cyclopentyl bromide in ;?S9 containing anhydrous potassium
carbonate 3as stirred for several hours at room temperature and yielded $,&@dimetho/yphenyl cyclopentyl sulfide as a 3hite oil that boiled at (0&@(+&
deg C at ,.0 mm8Hg. "his 3as brought to react 3ith a mi/ture of phosphorus o/ychloride and 5@methylformanilide producing $,&@dimetho/y@+@
'cyclopentylthio-ben6aldehyde as yello3 crystals from ?e9H. "his 3ill some day be converted to the nitrostyrene and then reduced to $,&@dimetho/y@+@
cyclopentylthiophenethylamine hydrochloride, $C@"@$0.

#(3 $!-T-12; #"M"T6; $,)-0"METH%+Y-(-&s--./TYTH"%,HE#ETHYAM"#E
S>5"H<SISE "o a solution of $.1 g of 9H pellets in &, m! hot ?e9H, there 3as added a mi/ture of 1.) g $,&@dimetho/ythiophenol 'see under $C@"@$
for its preparation- and &.) g 's-@butyl bromide. "he reaction 3as e/othermic, 3ith the deposition of 3hite solids. "his 3as heated on the steam bath for
a fe3 h, the solvent removed under vacuum, and the resulting solids dissolved in $&, m! H$9. Additional aFueous 5a9H 3as added to bring universal
pH paper to a full blue color. "his 3as e/tracted 3ith 0/+, m! CH$Cl$, the e/tracts pooled, and the solvent removed under vacuum. "he residue 3as
$,&@dimetho/yphenyl 's-@butyl sulfide 3hich 3as a pale yello3 oil, 3eighing (,.($ g. It 3as sufficiently pure for use in the ne/t reaction 3ithout a
distillation step.
A mi/ture of (&.( g P9Cl0 and (+.( g 5@methylformanilide 3as heated for (, min on the steam bath. "o this claret@colored solution 3as added %.+ g of
$,&@dimetho/yphenyl 's-@butyl sulfide, and the mi/ture heated for 0& min on the steam bath. "his 3as then added to $,, m! of 3ell@stirred 3arm H$9
'pre@heated to && deg C- and the stirring continued until the oily phase had completely solidified 'about (& min-. "hese light bro3n solids 3ere removed
by filtration, and 3ashed 3ith additional H$9. After sucking as dry as possible, these solids '($.(+ g 3et- 3ere ground under an eFual 3eight of ?e9H
3hich produced a yello3ish crystalline solid 3ith a mp of 21@)( deg C. :ecrystalli6ation of a ,.+ g sample from an eFual 3eight of boiling ?e9H
provided ,.$2 g of $,&@dimetho/y@+@'s@butylthio-ben6aldehyde as a pale cream@colored crystalline material 3ith a mp of )1@)2 deg C.
"o a solution of )., g of the crude $,&@dimetho/y@+@'s@butylthio-ben6aldehyde in +, g of nitromethane there 3as added ,.0) g of anhydrous ammonium
acetate, and the mi/ture 3as heated on the steam bath for ( h. "he reddish colored solution 3as decanted from some insoluble tan material and the
e/cess nitromethane removed under vacuum. "he heavy red oil that remained 3as diluted 3ith an eFual volume of boiling ?e9H, and allo3ed to return
to room temperature. "he orange@colored crystals that slo3ly formed 3ere removed by filtration and, after air drying, 3eighted 1.$+ g. "his 3as again
recrystalli6ed from an eFual volume of ?e9H, yielding $,&@dimetho/y@+@'s@butylthio-@beta@nitrostyrene as yello3, some3hat beady crystals that 3eighed
'3hen dry- 0.&, g and 3hich had a mp of 1$@1& deg C. A small portion of this fraction 3as crystalli6ed yet again from ?e9H to provide an analytical
sample that 3as yello3@orange in color, and had an mp of 1)@1% deg C. Anal. 'C(0H(259+S- C,H.
A solution of !AH '($, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added 0.0
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of ).)0 g $,&@dimetho/y@+@'s@butylthio-@beta@nitrostyrene in ), m!
anhydrous "HB drop3ise over the course of $ h. After a fe3 min further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath,
and then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of () m! IPA follo3ed first by & m! of (&K 5a9H
and then by (& m! of H$9. "he reaction mi/ture 3as filtered, and the filter cake 3ashed 3ith "HB. "he filtrate and 3ashing 3ere combined and
stripped of solvent under vacuum providing about ).& g of a pale amber oil. Iithout any further purification, this 3as distilled at (0&@(&, deg C at ,.+
mm8Hg to give 1.($ g of a clear 3hite oil. "his 3as dissolved in 0, m! IPA, and neutrali6ed 3ith $.( m! of concentrated HCl forming crystals
immediately. Another (, m! of IPA 3as added to allo3 the solids to be finely dispersed, and then about (,, m! of anhydrous <t$9 3ere added. "he
solids 3ere removed by filtration, <t$9 3ashed, and air dried to constant 3eight. "he product, $,&@dimetho/y@+@'s-@butylthiophenethylamine
hydrochloride '$C@"@(2- 3as obtained as spectacular 3hite crystals, 3eighing &.12 g.
;9SAC<E 1, @ (,, mg.
;4:A"I95E (, @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- "his material took fully three hours to get into its ma/imum effect. I never 3as at a ***, Fuite, and I am not
sure 3hy it is really active, but I kno3 it is. "here does not seem to be any interference 3ith my concentration or mental coordination, but I 3ouldn7t 3ant
to drive right no3. Cood appetite in the evening, for a Chicago@style pi66a, and there 3as no "omso effects 'the rekindling of a psychedelic effect 3ith
alcohol- 3ith a glass of 3ine. An over@all good and instructive **, no visuals, totally benign. "here is no hesitation in doing it again some day. '3ith (,,
mg- A small fragment hadn7t dissolved 3hen I drank the solution, and it must have stuck to the back of my mouth, because it made a searing spot that
burned for & minutes. "he first central effects 3ere noted at an hour. "he plateau stretched from the 0rd to the 2th hour, then tapered off Fuite Fuickly.
?y sleep 3as fitful, 3ith some hints of nervous sensitivity. I felt that there 3ere some residuals even into the ne/t morning. A truly heavy psychedelic,
but 3ith very fe3 e/plicit sensual changes or unusual perceptions to Gustify that comment. Ihy is it heavyH It Gust is. "his dosage is high enough.
<="<5SI95S A5; C9??<5"A:>E An interesting, and Fuite logical, habit that seems to al3ays pop up 3hen a lot of talk and energy become directed
at a specific compound, is the habit of using a nickname for it. "he "3eetios are an e/ample, and in the $C@"@= family I had mentioned the term
S<SL4I. Here, this compound 3as called 5I?I"A, for the obvious reason that the maGor free3ay from 9akland to San Dose, the 5imit6 free3ay, 3as
also called State High3ay (2. Its name has been changed to Interstate )),, and I guess it could no3 only be used as a reference point if efforts 3ere
being made for a $C@"@)),.
"he reason that $C@"@(2 is of special theoretic interest is that it is one of the very first of the active psychedelic compounds 'along 3ith $C@C@&- to have
a potential optically active center on the side of the ring a3ay from the nitrogen atom. 9ne of the oldest and best studied variants of the phenethylamine
chain are the alpha@methyl homologues, the substituted amphetamines. Here there is an asymmetric carbon atom right ne/t to the amine group,
allo3ing the molecule to be prepared in either a right@hand 3ay or a left@hand 3ay. "he N:N or the NSN isomer. And in the several studies that have
looked at such isomers separately, it has al3ays been the N:N isomer that has carried the psychedelic effects. "his probably says something about the
nitrogen end, the metabolic end, the NnorthN end of the receptor site that recogni6es these compounds, and suggests that there is some intrinsic
asymmetry in the area that binds near to the basic nitrogen atom.
.ut very little is kno3n of the receptor7s NsouthN end, so to speak, the geometry of the area 3here the opposite end of the molecule has to fit. Here, 3ith
$@C@(2, there is a secondary butyl group, and this contains an asymmetric carbon atom. .ut no3 this center of asymmetry is clear across the ben6ene
ring from the nitrogen, and should certainly be in some entirely ne3 part of the receptor site. Ihy not make this compound 3ith the N:N and the NSN
forms in this ne3 and unusual locationH Ihy not, indeedO Ihy not call them the right@lane and the left lane of the 5imit6H Bortunately, both N:N and NSN
secondary butyl alcohols 3ere easily obtained, and the synthesis given above for the racemic compound 3as paralleled for each of these isomers,
separately. Is there any chemistry that is different 3ith the specific optical isomers from that 3hich has been reported 3ith the racemicH "here certainly
is for the first step, since the butyl alcohols rather than the butyl bromides must be used, and this first step must go by inversion, and it cannot be
allo3ed any racemi6ation 'loss of the optical purity of the chiral center-.
"he synthesis of $C@"@(2 N:N reFuired starting 3ith the NSN isomer of secondary butanol. "he NSN $@butanol in petroleum ether gave the lithium salt 3ith
butyllithium 3hich 3as treated 3ith tosyl chloride 'freshly crystalli6ed from naphtha, he/ane 3ashed, used in toluene solution- and the solvent 3as
removed. "he addition of $,&@dimetho/ythiophenol, anhydrous potassium carbonate, and ;?B produced NSN@$,&@dimetho/yphenyl s@butyl sulfide. "he
conversion to N:N@$,&@dimetho/y@+@'s@butyl@thio-ben6aldehyde '3hich melted at 2)@2% deg C compared to )1@)2 deg C for the racemic counterpart- and
its conversion in turn to the nitrostyrene, NSN@$,&@dimetho/y@+@'s-@butylthio@beta@nitrostyrene 3hich melted at 2,@2( deg C compared to 1)@1% deg C for
the racemic counterpart, follo3ed the specific recipes above. "he preparation of the intermediates to $C@"@(2 NSN follo3s the above precisely, but
starting 3ith N:N $@butanol instead. And it is at these nitrostyrene stages that this proGect stands at the moment.
It 3ould be fascinating if one of the t3o optically active $C@"@(27s carried all of the central activity, and the other, none of it. Ihat is more likely is that the
spectrum of effects 3ill be teased apart, 3ith one isomer responsible for some of them and the other isomer responsible for the others. "hen, again,
maybe the south end of the receptor site in the brain is totally symmetric, and the t3o optical antipodes 3ill be indistinguishable.
An incidental bit of trivia L yet another bit of evidence that 3e are all totally asymmetric in our personal body chemistry. N:N and NSN secondary butanols
smell different. "he N:N has a subtle smell, 3hich is rather fragrant . "he NSN is stronger, hits the nasal passages harder, and reminds one of
isopropanol more than does the NSN isomer.
#(4 $!-T-$1; $,)-0"METH%+Y-(-&$-7/%*%ETHYTH"%-,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 1.% g of 9H pellets in (,, m! hot ?e9H, there 3as added (0., g $,&@dimetho/ythiophenol 'see under $C@"@$ for its
preparation- follo3ed by %.1 g $@fluoroethyl bromide. "he reaction 3as e/othermic, 3ith the immediate deposition of 3hite solids. "his 3as allo3ed to
stand for $ h, added to ( ! H$9, and e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere pooled and the solvent removed under vacuum. "he residue
3as $,&@dimetho/yphenyl $@fluoroethyl sulfide 3hich 3as a colorless oil and 3eighed (2.$ g. It 3as sufficiently pure for use in the ne/t reaction 3ithout a
distillation step.
A mi/ture of $1.) g P9Cl0 and $+.) g 5@methylformanilide 3as heated for (, min on the steam bath. "o this claret@colored solution 3as added (2., g of
$,&@ dimetho/yphenyl $@fluoroethyl sulfide, and the mi/ture heated an additional $& min on the steam bath. "his 3as then added to (.& ! of 3ell@stirred
3arm H$9 'pre@heated to && deg C- and the oily phase that formed solidified almost immediately. "his bro3n sugar@like product 3as removed by
filtration, and 3ashed 3ith additional H$9. After sucking as dry as possible, the residual solids '3eighing (%., g 3et- 3ere dissolved in an eFual 3eight
of boiling ?e9H 3hich, after cooling in an ice@bath, deposited pale ivory colored crystals of $,&@dimetho/y@+@'$@fluoroethylthio-ben6aldehyde. "his 3as
air dried to constant 3eight, 3hich 3as (&.( g.
"o a solution of (&., g $,&@dimetho/y@'$@fluoroethylthio-ben6aldehyde in 2& m! nitromethane there 3as added (.0& g of anhydrous ammonium acetate,
and the mi/ture 3as heated on the steam bath for 2, min 'the progress of the reaction must be follo3ed by continuous "!C monitoring-. "he clear
deeply@colored solution 3as decanted from some insoluble material and the e/cess nitromethane removed under vacuum. "here resulted (2.2) g of
almost dry brick@red crystals 3hich 3ere dissolved in ((, m! boiling <t9Ac. After cooling overnight in the refrigerator, the crystalline product 3as
removed, 3ashed 3ith <t9Ac, and air dried. "here 3as obtained (+.00 g of $,&@dimetho/y@+@'$@fluoroethylthio-@beta@nitro@styrene as bright orange
crystals.
A solution of !AH '(+, m! of a ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added 0.2
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of ).% g $,&@dimetho/y@+@'$@fluoroethylthio-@beta@nitrostyrene in +,
m! of hot anhydrous "HB 'a heat lamp 3as needed to keep the nitrostyrene in solution-. As the nitrostyrene entered the hydride solution, there 3as an
immediate loss of color. After ( h stirring at room temperature, the temperature 3as brought up to a gentle reflu/ on the steam bath, then all 3as cooled
again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of (& m! IPA and the inorganic solids 3ere made 3hite and filterable by
the addition of (& ml (&K 5a9H. "he loose cottage@cheesy solids 3ere removed by filtration, and 3ashed 3ith additional "HB. "he filtrate and 3ashes
3ere pooled and stripped of solvent under vacuum providing 2.0% g of a pale amber oil. "his 3as dissolved in 1,, m! dilute H$S9+, and 3ashed 3ith
0/&, m! CH$Cl$ '3hich removed the light yello3 color-. "he aFueous phase 3as made strongly basic 3ith $&K 5a9H, e/tracted 3ith 0/2& m! CH$Cl$
and, after pooling, the solvent 3as removed under vacuum leaving +.%( g of product as an oil. "his 3as distilled at (+&@(1, deg C at ,.+ mm8Hg giving
0.%( g of a 3hite oil. "his 3as dissolved in +, m! IPA and neutrali6ed 3ith 0& drops of concentrated HCl. "he beautiful 3hite solids that formed 3ere
removed by filtration, and 3ashed 3ith IPA. All 3ere suspended in, and ground under, +, m! anhydrous <t$9, refiltered and air dried. "he final 3eight
of $,&@dimetho/y@+@'$@fluoroethylthio-phenethylamine hydrochloride '$C@"@$(- 3as +.,2 g of glistening 3hite crystals.
;9SAC< ) @ ($ mg.
;4:A"I95E 2 @ (, h.
L4A!I"A"IM< C9??<5"SE '3ith 1 mg- I noticed something undefined 3ithin five minutes 3hich 3ent a3ay. Iithin (& minutes I noticed a definite
a3areness of activity. "here 3as a progressive increase in a3areness of something happening over the ne/t t3o hours 3ith a plateau of perhaps an
hour then occurring. "he nature of the happening, as usual, 3as not clear. ;uring the e/perience I 3as more talkative than I usually am. I seemed to
be interacting 3ith all others. "here 3as no euphoria but, then, there 3as no body load or nausea, nor 3as there any nystagmus. I found a little mental
confusion at the peak and there 3as some searching in my memory bank for the right chips at times. I lost the entire line of one of my conversations at
one point during the plateau and had to ask 3hat I 3as talking about. I tested my visual field on a painting and 3ith sufficient concentration I could get
the center part to 3iggle a little. I didn7t try to observe anything 3ith my eyes closed. I feel that there 3as something physical about the eyes. In the
evening, after@images 3ere Fuite intense, and the ne/t day my eyes seemed tired or bothered. Ihat can I sayH "he material 3as pleasant and I
certainly got the feeling of being high but not getting too much out of it. "here 3ere no insights or Nah@hahs.N I 3onder if periodic and freFuent use 'say
t3ice a day- at the one or t3o milligram level 3ould be a positive mood enhancerH
'3ith ) mg- Comes on very gradually and slo3ly. "akes about an hour to feel. :easonably intense in t3o hours, **. Mery pleasant material, enhancing
communication, clear thinking, good feeling. "here is a feeling of closeness; the bondedness 3ith the group gro3s steadily during the day, reaching a
highly re3arding level. Bor me a couple of firsts regarding food. I 3as hungry only t3o hours into it. I usually don7t 3ant food 7til 3ell do3n as I usually
feel that it interferes 3ith the e/perience. And, also, I nibbled constantly as I felt that there 3as nothing in my body. And I enGoyed it thoroughly, feeling
only the 3armth and energy, 3ith no contrary developments. "here 3as a nice feeling of inner strength and peace.
'3ith ) mg- It 3as very difficult to fi/ the times of ascent or descent. Some chilling during onset but not later. And there 3as some ya3ning and ear@
popping. It is easy on the body, in no 3ay threatening. "his time I am very rela/ed and some3hat lethargic; the visuals are not too pronounced.
</cellent sleep.
'3ith (, mg- I find I can use it if I set my energy in a direction I really 3ant to go in. 9ther3ise I can Gust be stoned and self@indulgent. 5ot out@of@body
cosmic at all. .ut it7s good material, an ally, not presenting hidden negatives.
'3ith ($ mg- Iell ... ($ milligrams is Fuite enough for a *0, 3hich 3as established 3ithin the first hour and plateau7d by the end of the second. .ody felt
Fuite safe, again, but there 3as considerable push of energy. I did not feel par@ticularly interested in doing anything like 3riting and in fact preferred to
3atch television 3hile rocking a bit on the couch, to ease the push. ?ood 3as faintly grim, but not more than faintly. I noted something that I hadn7t
seen before 3ith this materialE time slo3ing. "he first t3o hours seemed to last a very long time. "here 3as no anore/ia. It 3asn7t until (, P? Pfifth
hourQ that the idea of 3riting had any appeal at all. .y then, I 3as still *0 but a lot more at ease. I 3rote t3o letters and enGoyed the process. Sleep 3as
fine. ?y mood ne/t day 3as slightly introverted, not very spontaneous for a 3hile. !ate in the afternoon, it 3as a lot better.
<="<5SI95S A5; C9??<5"A:>E "his is about as potent a phenethylamine as they come. "here are a couple in the $C@C family that are similar in
potency, but they are much longer lived. "he motivation for the use of the beta@fluoroethyl group can be seen under the discussion of ;9<B, 3here
there 3as an amalgamation of t3o lines of reasoningE the imitation of potent serotonin agonists 3ith a need of including an atom 'the fluorine- that is
potentially labelable 3ith a positron emitter. And the mass@() isotope of fluorine, 3ith a half@life of Gust under $ hours, is ideal for many biological studies.
In fact, much of the research 3ork being carried out by the 5uclear ?edicine group in .erkeley is based on the analogy bet3een a halogen atom and a
beta@fluoroethyl group. "here are some similarities in pharmacology so that if there is a bromine or an iodo atom present in a drug, it is a fair guess that
the corresponding beta@fluoroethyl 3ould also be active. In a sense, the cute 'and chemically impossible- idea of putting a bromo atom on the sulfur of
the $C@" family is nicely satisfied by using the beta@fluoroethyl group instead '3hich is chemically completely possible-.
A logical e/tension of $C@"@$( is the three carbon amphetamine analogue 3hich should be, by comparing structures and activities, a very potent and in@
teresting material in its o3n rights. "his 3ould be $,&@dimetho/y@+@'$@fluoroethylthio-amphetamine or, follo3ing the nomenclature used 3ith the earlier
members of this series, A!<PH@$(. A solution of $,&@dimetho/y@+@'$@fluoroethylthio-ben6aldehyde 'see earlier in this recipe- in nitroethane 3ith
ammonium acetate gave (@'$,&@dimetho/y@+@'$@fluoroethylthio-phenyl-@$@nitropropene as yello3@orange crystals from ?e9H 3ith a melting point of (,$@
(,+ deg C. And that is 3here the proGect no3 stands. It has not yet been reduced to the amine.
"his phenethylamine, $C@"@$(, 3as the last of the $C@"7s to be completed. A couple of other sulfur analogues have been given numbers, and have been
started, but the syntheses are still at some intermediate state.
"he 'n-@butyl compound, named $C@"@(%, has been taken to the nitrostyrene stage. :eaction bet3een $,&@dimetho/ythiophenol and 'n-@butylbromide
3ith 9H gave $,&@dimetho/yphenyl 'n-@butyl sulfide as a colorless oil. "his, 3ith phosphorus o/ychloride and 5@methylformanilide, provided $,&@
dimetho/y@+@'n@butylthio-ben6aldehyde as pale orange solids from ?e9H, 3ith a melting point of 2)@2% deg C. "his, 3ith nitromethane and ammonium
acetate, gave $,&@dimetho/y@+@'n@butylthio-@beta@nitrostyrene, 3ith a melting point of (00@(0+ deg C from either IPA or acetonitrile.
"he $,$,$@trifluoroethyl compound, 3hich I have named $C@"@$$, has been taken to the ben6aldehyde stage. :eaction bet3een $,&@
dimetho/ythiophenol and $,$,$@trifluoroethyliodide 3ith 9H gives $,&@dimetho/yphenyl $,$,$@trifluoroethyl sulfide as a very pale amber oil. "his, 3ith
phosphorus o/ychloride and 5@methylformanilide provided $,&@dimetho/y@+@'$,$,$@trifluoroethyl-ben6aldehyde as crystals that proved to be e/ceedingly
difficult to purify. >ello3 solids can be obtained from several solvents, and they melt in the 2, deg C area. "he initially isolated fraction melted at 1%@2$
deg C and sho3ed three maGor spots by both "!C and CC?S. "he largest CC peak 3as the correct product 3ith a parent peak of $), m8e, and
cracking fragments at (&+ and $0+ m8e. A small sample 3as finally obtained from he/ane 3ith a melting point of 2)@2% deg C but I am not sure that
even it is particularly pure. 5ot surprisingly, the reaction of this crude ben6@aldehyde 3ith nitromethane and ammonium acetate gave a nitrostyrene
product that 3as a comple/ mi/ture. And there that proGect also rests.
A couple of additional efforts 3arrant comment. "he reaction bet3een trifluoromethyliodide and $,&@dimetho/ythiophenol should have produced $,&@
dimetho/yphenyl trifluoromethyl sulfide, but it didn7t produce anything. And one more. Ihat about a bare thio group at the +@position in this $C@"@
familyH ?aybe this can be protected through everything as the disulfide, and be reduced at the last stepO "he disulfide, $,&@dimetho/yphenyl disulfide
'see under $C@"@(&- 3as aimed to3ards the needed bis@aldehyde 3ith phosphorus o/ychloride and 5@methylformanilide, but all that came out of this
3ere black oils and tars. "his has also been abandoned for no3.
And it has Gust occurred to me that there is yet another effort that is certain@ly 3orth making, inspired by the observation that $,$@difluoroethyl iodide is
commercially available and not prohibitively e/pensive. It, 3ith $,&@dimetho/ythiophenol, and follo3ing the obvious steps to the aldehyde, the
nitrostyrene, and the final amine, 3ould produce $,&@dimetho/y@+@'$,$@difluoroethylthio-phenethylamine hydrochloride. It lies e/actly half 3ay bet3een
the highly potent $C@"@$( 'the mono@fluoro-, and the yet to be finished $C@"@$$ 'the trifluoro-. !et7s be 3eird, and call it $C@"@$(.&. I 3ill 3ager mucho
that it 3ill be very potent.

#)5 (-0; ',)-0"METH%+Y-(-T*"0E/TE*%METH%+Y-,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0+., g homosyringonitrile '0,&@dimetho/y@+@hydro/yphenylacetonitrile, see under <SCA!I5< for its preparation- in 0&, m!
acetone containing ,.& g decyltriethylammonium iodide, there 3as added $& g trideuteromethyl iodide follo3ed by &, g of finely po3dered anhydrous
$C90. "his mi/ture 3as held at reflu/ on a steam bath for ($ h, added to $ ! of dilute HCl, and e/tracted 3ith 0/(,, m! of CH$Cl$. "he e/tracts 3ere
3ashed 3ith &K 5a9H, and the solvent removed under vacuum, yielding $)., g yello3 solids. "hese 3ere distilled at (0&@(&, deg C at ,.& mm8Hg
providing (%.+ g 0,&@dimetho/y@+@trideuterometho/yphenylacetonitrile 3hich melted at 21.&@22.& deg C after crystalli6ation from toluene, or 22@2) deg C
from methylcyclohe/ane8CHCl0 0E(. "he mp of the proteo@reference compound, from toluene, 3as 22@2).& deg C. "he 9C;0 stretch in the infra@red
occured at $,2$ cm@(.
A solution of $2& m! of (., ? !AH in "HB 3as cooled under He to , deg C and treated 3ith 2.$& m! (,,K H$S9+ added very slo3ly 3ith vigorous
stirring. A solution of (%.0 g 0,&@dimetho/y@+@trideuterometho/yphenylacetonitrile in $,, m! anhydrous "HB 3as added slo3ly, and follo3ing the
addition stirring 3as continued for $, min. "he reaction mi/ture 3as brought to a reflu/ for 0, min on a steam bath, cooled again to , deg C, and the
e/cess hydride destroyed 3ith $& m! IPA. About (& m! of (&K 5a9H 3as reFuired to convert the solids to a filterable 3hite consistency. "hese 3ere
removed by filtration, the cake 3ashed 3ith IPA, the filtrates and 3ashes 3ere combined, and the solvent removed under vacuum leaving a 3hite oil as
residue. "his 3as dissolved in (.& ! dilute H$S9+, 3ashed 3ith 0/2& m! CH$Cl$, made basic 3ith aFueous 5a9H, and then e/tracted 3ith 0/2& m!
CH$Cl$. :emoval of the solvent from these e/tracts under vacuum yielded ().& g of a colorless oil 3hich 3as distilled at ($,@(&, deg C at ,.& mm8Hg
to provide (0.& g of a 3hite oil. "his 3as dissolved in 2, ml IPA and neutrali6ed 3ith concentrated HCl, producing spontaneous crystals. "hese 3ere
removed by filtration, 3ashed first 3ith IPA then 3ith anhydrous <t$9. After air drying, the final yield of 0,&@dimetho/y@+@
trideuterometho/yphenethylamine hydrochloride '+@;- 3as (0.&, g.
;9SAC<E $,, @ +,, mg 'as the sulfate salt-; (2) @ 0&1 mg 'as the
hydrochloride salt-.
;4:A"I95E ($ h.
L4A!I"A"IM< C9??<5"SE '3ith $2& mg- "he onset 3as smooth and gradual. Iithin the hour, the slight Fueasiness I e/perienced 'not as much as
3ith mescaline- completely disappeared. Some visual enhancement, good energy, good communication. It 3as a very special day for me as I 3as in a
good place pretty much the 3hole day, and able to communicate clearly 3ithout deeper feelings getting in the 3ay. Ihile most enGoyable, and at times
remarkable fun, I did not e/perience the intensity I am familiar 3ith, 3ith mescaline.
'3ith 0,, mg- "he taste 3as bitter to a moderate degree but faded fast. About +, minutes later the first stirrings of pleasurable e/perience came on. It
3as very mild. "3enty minutes after that an unease of the stomach 3as apparent, and it stayed 3ith me until I ate some crackers an hour or so later. I
got no sharpened visual reactions and no physical instability at any time. I did feel a Fuickening of thought and verbal flo3; again, this 3as mild and
unlike my earlier mescaline patter.
'3ith 0&, mg- A rapid onset L alert in $, minutes. Climbed to a plus t3o in about one hour and stayed there. ;uring the first t3o hours had a slight
Fueasiness or pre@nausea, and cold hands and feet, but this all disappeared completely and I became very hungry during the 3hole latter half of the
e/perience. I did not eat much at any one time, but did a lot of snacking and everything tasted good. Mery pleasant after the plateau 3as reached.
Pretty good visuals 3ith eyes closed, but not as bright as $C@.. Mery little visuals 3ith eyes open L some movement and flo3 of obGects L pupils
dilated. Spent most of the day lying do3n L had no aversion to conversation but it felt good Gust to be still. I 3as in a funny place I can7t Fuite describe
L I 3as in an 7alert lassitude,7 a state of 7interested detachment,7 or a place of 7vibrating eFuanimity7 or 3hatever. Ihile trying to recapture the day, it
seemed to me that it 3as a good day, but that nothing much had really transpired. Ho3ever, upon reflection, I am startled to find that several important
shifts took place. It 3as a day that allo3ed some peaceful gear@shifting in the mind.
'3ith +,, mg- 5ot a great taste. Some type of a3areness at appro/. $, minutes. Considerable nausea peaking at about ( hr. Some nausea continued
through the e/perience but became Fuite lo3. I enGoyed the color sho3 considerably. "rees outside 3ould change color in a 3ave@like manner. "he
book@covers upstairs 3ould also change colors and become distorted. .rightly lighted items 3ould undergo the same thing. .elieved I could suppress
the vision, but concentrating on something 3ould cause it to easily undergo the color and visual changes. <vidently I had little problem follo3ing the
conversation do3nstairs, but I remained some3hat Fuiet. Had an element of confusion that seemed to last for some + or & hours. Had no problems
dropping off to sleep that evening.
<="<5SI95S A5; C9??<5"A:>E "he effects of +@; and beta@; are similar to one@another, both as to dosage and effect. And 3ith both, there is a
close parallel to those reported from mescaline. It is reasonable to assume that the human body handles these materials in the same manner, although
no metabolic studies have ever been published.
A similar deuterium substitution pattern is of course completely feasible 3ith "?A and related 0,+,&@trimetho/y@substituted analogues. Some studies
have supported the idea that the ability to remove methyl groups from such aromatic ethers might be correlated to endogenous schi6ophrenia. It is
possible to imagine that, in such individuals, the effects of substituting trideuteromethyl groups for normal methyl groups might result in
psychopharmacological differences of action. "3o reports e/ist that describe metabolic products of mescaline that have lost this methyl group on the +@
position o/ygen. It is possible that these might be produced in abnormal Fuantities in mentally ill subGects. "here are also similar reports of the 0@
metho/yl group being demethylated in man. Here, studies 3ith 0,&@; '0,&@bis@trideuterometho/y@+@metho/yphenethylamine- might reveal some
differences in Fuantitative responses in man. "hese are e/tremely minor metabolites, ho3ever. I suspect that more e/tensive studies 3ill establish that
+@;, 0,&@; and beta@; all have properties indistinguishable from one@another, at least in healthy subGects.

#)1 beta-0; ',(,)-T*"METH%+Y-beta,beta-0"0E/TE*%,HE#ETHYAM"#E
S>5"H<SISE "o a solution of (0.1 g homosyringonitrile 'see under <SCA!I5< for its preparation- in (&, m! acetone containing $,, mg
decyltriethylammonium iodide and 0, g of finely po3dered anhydrous $C90, there 3as added $, g methyl iodide. "he mi/ture 3as held at reflu/ for
() h in a heating mantle 3ith effective stirring. "his 3as added to ( ! H$9, acidified 3ith concentrated HCl, and e/tracted 3ith 0/2& m! CH$Cl$. "he
e/tracts 3ere pooled, 3ashed 3ith $/(,, m! &K 5a9H, once 3ith dilute HCl, once 3ith saturated brine, and the solvent 3as removed under vacuum.
"he pale yello3 residue 3as distilled at (0,@(&, deg C at ,.0 mm8Hg to yield ($.% g of 0,+,&@trimetho/yphenylacetonitrile as an off@3hite solid. 4pon
crystalli6ation from methylcyclohe/ane8CHCl0 it 3as 3hite and had a mp of 22@2) deg C. Attempts to prepare this compound by the theoretically
appealing route from 0,+,&@trimetho/yben6aldehyde to 5,5@dimethyl@0,+,&@tri@metho/yben6ylamine 'reductive amination 3ith dimethylamine-, to 0,+,&@
trimetho/y@5,5,5@trimethylben6ylammonium iodide 'methylation 3ith methyl iodide-, and then to 0,+,&@ trimetho/yphenylacetonitrile '3ith some source of
cyanide ion- gave e/cellent yields in the first t3o steps, and no product at all in the last step.
A solution of $,.1 g of 0,+,&@trimetho/phenylacetonitrile in 2, g pyridine 3as treated 3ith (& m! %%*K ;$9 and held at reflu/ for $+ h. All volatiles 3ere
stripped first under vacuum and finally 3ith a hard vacuum at room temperature in a ugelrohr apparatus. "he dark residue 3as treated again 3ith
another 0, m! pyridine and another (& m! %%*K ;$9. "he flask 3as protected 3ith a drying tube and held at reflu/ for another $+ h. Again, all
volatiles 3ere stripped, and the residue distilled at ((,@(0, deg C at ,.$& mm8Hg to yield (1.22 g of an almost 3hite solid. "he CC?S verified this
chemical to be 0,+,&@trimetho/y@beta,beta@dideuterophenylacetonitrile, 3ith a parent peak at m8e $,% and no visible peak at m8e $,2.
A solution of $&, m! of ( ? !AH in "HB 3as cooled under He to , deg C and treated 3ith 1.) m! (,,K H$S9+ added very slo3ly 3ith vigorous stirring.
A solution of ().$0 g 0,+,&@trimetho/y@beta,beta@dideuterophenyl@acetonitrile in $,, m! anhydrous "HB 3as added slo3ly, and follo3ing the addition
stirring 3as continued for $, min. "he reaction mi/ture 3as brought to a reflu/ for 0, min on a steam bath, cooled again to , deg C, and the e/cess
hydride destroyed 3ith (& m! IPA. About (, m! of (&K 5a9H 3as reFuired to convert the solids to a filterable 3hite consistency. "hese 3ere removed
by filtration, the cake 3ashed 3ith IPA, the filtrates and 3ashes 3ere combined, and the solvent removed under vacuum leaving (2 g of a 3hite oil as
residue. "his 3as dissolved in $ ! dilute H$S9+, 3ashed 3ith 0/2& m! CH$Cl$, made basic 3ith aFueous 5a9H, and then e/tracted 3ith 0/2& m!
CH$Cl$. :emoval of the solvent from these e/tracts under vacuum yielded (,.0 g of a colorless oil 3hich 3as distilled at ($,@(0, deg C at ,.0 mm8Hg
to provide %.$ g of a 3hite oil. "his 3as dissolved in &, ml IPA and neutrali6ed 3ith concentrated HCl, producing spontaneous crystals. "hese 3ere
diluted 3ith &, m! anhydrous <t$9, removed by filtration, 3ashed first 3ith <t$98IPA, and then 3ith anhydrous <t$9. After air drying, the final yield of
0,+,&@trimetho/y@beta,beta@dideuterophenethylamine hydrochloride 'beta@;- 3as (,., g of 3hite needles.
;9SAC<E $,, @ +,, mg 'as the sulfate salt-; (2) @ 0&1 mg 'as the
hydrochloride salt-.
;4:A"I95E ($ h.
L4A!I"A"IM< C9??<5"SE '3ith $,, mg- "he onset 3as very gradual and very gentle. At about an hour and a half I 3as rather out of my body 'at least
I 3asn7t a3are of my body, it felt so light-. I 3as listening to .erlio6 :eFuiem, and it took me to the highest realm. I 3as totally caught up in the
magnificence of the music, of the genius it took to compose it, the love it took to complete it, and the devotion of the composer. I felt as though this
music had been 3ritten for me. Ihat came ne/t is hard to remember because I 3as so taken 3ith this e/perience 3hich came only ( (8$ hours after
ingestion. I 3ondered 3hat time it 3as and ho3 come I 3as having a peak e/perience so soon, because this material 3as supposed to reach its peak
after t3o hours. Iell, no3 3e can revise the records, hehH Incidentally this material is really good for interior 3ork. It 3as a magnificent e/perience L
one of the best.
'3ith $2& mg- I begin to feel it in (& minutes, stomach getting sFueamish. !ooking up into the clouds, becoming absorbed in them, 3atching light gro3
in intensity, stomach feelings disappeared. .ecame totally absorbed by the music. !istening to .oito7s Prologue to ?ephistopheles L e/Fuisitely
beautiful, dramatic. !ying on the couch, the music continuing, I 3as suddenly filled 3ith enormous po3er. I reali6ed that ra3, male po3er 3as pouring
through me as I had never before e/perienced it. I 3as 3ild, totally self satisfied, and completely oblivious of others and their needs. I 3anted to strike
out, to 3in, to conFuer. I felt 3hat conFuerers have felt in the past, the unbridled passion to vanFuish everything. I could see ho3 such misguided po3er
could lead nations to 3ar. Ianting still more po3er, I 3as about to find out if Cod 3ould grant me the po3er to destroy the 3orld if I 3ished it, 3hen I felt
a gentle kiss on my bro3. ?y 3ife had leaned over Gust in time to save the 3orld.
'3ith $2& mg- 5ever had I had such a magnificent appreciation of Cod. It 3as clear that if I minded my business and turned to Him to learn as I had
been doing today, then I could continue to gro3 and learn in a most 3onderful 3ay. It became crystal clear to me that I didn7t have to help anybody or
heal anybody, as everyone can turn directly to the source for their needs. An earth@shaking e/perience.
'3ith 0,, mg- I had e/treme nausea, and vomited. "his had a very hard impact on me, and I had to retreat 3ith a paranoia that s3ept over me 3ithout
3arning. I lay do3n and let it s3eep on, and through this came several very important insights. At least they 3ere important to me. It 3as about the
fourth hour before I could emerge from my retreat, and at that time I kne3 that I had ans3ered some troublesome personal problems. It 3as a
satisfactory day, but I probably shall not repeat it.
'3ith 0&, mg- Strong body a3areness started 3ithin (& minutes. Misual activity started 3ithin half an hour. Misuals 3ere typical kinds, but seemed to
arrive earlier. A strong e/perience of pleasantness started and continued throughout the e/perience. I tended to internali6e to some e/tent. <nded on a
3ater bed at maybe an hour and a half, pulled covers over me, and 3ent in3ard 3ith considerable visuals but not much insight. I felt good about 3here I
3as. I 3ould not mind being there again, so something 3as going 3ell. I am not sure ho3 long this continued. "he visuals decreased some3here
around the &th or 1th hour. After ) or % hours, activity considerably decreased. I felt Fuite clear and reasonably centered. Iould I do this againH "he
ans3er is yes.
'3ith &,, mg- I consumed the material over a period of t3enty minutes, and at the ( hour +& minute point, haven7t had any nausea, but I am still careful
not to bounce around. Am absolutely grounded even though I am completely into the e/perience. 5o more that state in 3hich it is possible to seriously
consider trying to rise t3o inches above the floor and skim, as I do so e/pertly in dreams. As a matter of fact I haven7t had those dreams for some time
no3. "his material doesn7t allo3 the straddling of realities as does ordinary mescaline. I kno3 3here my realities are, and reality is, basically, 3here my
center is. "hus I am grounded in the physical reality even 3hen the doors are open to non@physical levels.
<="<5SI95S A5; C9??<5"A:>E "he +@; and the beta@; are t3o of five obvious deuterium isomer derivatives of mescaline. "he three remaining
areE '(- 0,&@; '+@metho/y@0,&@bis@trideuterometho/yphenethylamine-; '$- $,1@; '$,1@di@deutero@0,+,&@trimetho/yphenethylamine-; and '0- a@; 'a.a@
dideutero@0,+,&@tri@metho/yphenethylamine-. I fully e/pect both 0,&@; and $,1@; to be indistinguishable from mescaline in effect, since it is kno3n that
not much metabolism takes place in man at these locations of the molecule.
"he last compound, a@;, could be Fuite a different matter. "he principal metabolite of mescaline is 0,+,&@trimetho/yphenylacetic acid, and this product
reFuires en6ymatic attack at the e/act position 3here the deuteriums 3ill be located. "o the e/tent that they are harder to remove 'come off more slo3ly
or to a lesser degree-, to that e/tent the molecule 3ill be more potent in man, and the dosage reFuired for effects 3ill be less. "he compound 3ill be
easily made by the reduction of 0,+,&@trimetho/yphenylacetonitrile 3ith lithium aluminum deuteride. And if there is a believable difference bet3een a@;
and mescaline, it 3ill be necessary to synthesi6e each of the t3o optically active a@mono@deutero analogs. "hat 3ill be Fuite a challenge.
Some years ago I performed a fascinating series of e/periments 3ith another isotopically labeled mescaline derivative. "his 3as beta@(+C labeled
material, 3hich I self@administered on three occasions, at three different levels. 9ne dosage 3as 3ith 0&, milligrams, a second a fe3 3eeks later 3as
3ith + milligrams, and a third 3as a fe3 3eeks later yet, 3ith about 1, micrograms. In each case, e/actly the same absolute Fuantity of radioactivity 3as
administered, so the metabolic distribution 3as eFually visible. 9nly the 3eight dosage 3as different. 4rinary analysis 3as run for each e/periment for
the presence of unchanged mescaline, and for the primary metabolite, 0,+,&@trimetho/yphenylacetic acid. "he smaller the dosage, the proportionately
larger amount of mescaline 3as o/idi6ed to the inactive acetic acid, and the smaller amount 3as e/creted in an unchanged state. It seemed to me that
there might be a finite capacity of the body to o/idatively deaminate mescaline, and at larger and larger dosages, this capacity became increasingly
depleted. Perhaps this is 3hy mescaline reFuires such a large dosage to be effective in man.
#)$ 0ES%+Y; ',)-0"METH%+Y-(-METHY,HE#ETHYAM"#E
S>5"H<SISE "o a 3ell@stirred solution of 0( g $,1@dimetho/ytoluene in $,, m! CH$Cl$ there 3as added (( m! elemental bromine, a portion at a time.
"here 3as a copious evolution of H.r and the color gradually faded from deep red to stra3. "he reaction mi/ture 3as poured into &,, m! H$9, and the
organic layer separated, 3ashed first 3ith dillute 5a9H and finally 3ith dilute HCl. "he solvent 3as removed under vacuum, and the residue distilled at
)&@%, deg C at ,.+ mm8Hg to provide ++ g of 0@bromo@$,1@dimetho/ytoluene as a 3hite oil.
A 3ell@stirred solution of +$ m! diisopropylamine in (,, m! petroleum ether 3as placed in a He atmosphere and cooled to , deg C 3ith an e/ternal ice@
3ater bath. "here 3as then added ($, m! of a $.& ? solution of n@butyllithium in he/ane, producing a clear but viscous solution of the lithium amide.
?aintaining this temperature, there 3as added (,, m! of anhydrous "HB, follo3ed by (, m! dry CH0C5, 3hich produced an immediate 3hite
precipitate. A solution of $0 g of 0@bromo@$,1@dimetho/ytoluene in 2& m! anhydrous "HB 3as then added 3hich produced a light red color. "he reaction
mi/ture 3as allo3ed to come to room temperature. "he color became progressively darkened, eventually becoming a deep red@bro3n. After ,.& h, the
reaction mi/ture 3as poured into &,, m! of dilute H$S9+, the layers 3ere separated, and the aFueous layer e/tracted 3ith $/2& m! CH$Cl$. "he
organics 3ere combined, the solvent removed under vacuum, and the residue distilled. ;iscarding a first fraction, the cut boiling at ($&@(1& deg C at ,.0
mm8Hg 3as collected. "his light yello3 fraction spontaneously crystalli6ed and 3eighed ((., g. "rituration under $, m! petroleum ether provided (.2$ g
of 0,&@dimetho/y@+@methylphenylacetonitrile as a yello3ish solid.
A solution of !AH in anhydrous "HB under nitrogen '$, m! of a (., ? solution- 3as cooled to , deg C and vigorously stirred. "here 3as added,
drop3ise, ,.&+ m! (,,K H$S9+, follo3ed by (.& g 0,&@dimetho/y@+@methylphenylacetonitrile as a solid. "he reaction mi/ture 3as stirred at , deg C for
a fe3 min, then brought to room temperature for ( h, and finally to a reflu/ on the steam bath for 0, min. After cooling back to , deg C there 3as added
IPA until no more hydrogen 3as evolved, follo3ed by sufficient (&K 5a9H to produce a granular te/ture. "he 3hite solids 3ere removed by filtration,
and 3ashed 3ith "HB. "he filtrate and 3ashes 3ere stripped of solvent under vacuum, the residue added to (&, m! dilute H$S9+ and 3ashed 3ith
$/&, m! CH$Cl$. "he aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. "hese e/tracts 3ere pooled, the
solvent removed under vacuum, and the residue distilled at ((,@($, deg C at ,.+& mm8Hg to give a colorless viscous oil. "his 3as dissolved in (, m! of
IPA, neutrali6ed 3ith (, drops of concentrated HCl and diluted 3ith $, m! anhydrous <t$9. "he product 3as removed by filtration, 3ashed 3ith <t$9,
and air dried to give ,.&& g 0,&@dimetho/y@+@methylphenethylamine ';<S9=>- as 3hite crystals.
;9SAC<E +, @ ($, mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith +, mg- Initially I felt very chilled, so I lay do3n under a blanket. <yes@closed imagery became very dream@like and
my general state 3as felt as having lost my center. Also, not much in touch 3ith feelings, sense of strangeness, almost alien vie3 of the 3orld. 5ot
through recog@ni6able eyes. 5either pleasant nor unpleasant, Gust strange. Ias able to drift into sleep very easily, or sleep@like trance state, 3ith
disconnected, far@out imagery. After 0 hours the nausea 3as gone, I 3as able to get up and e/plore. A little food 3ent do3n 3ell. 5o drive, no strong
focus in any direction. Beel this 3as a Fuite fascinating e/perience. Completely do3n by si/ hours. Iould go a bit slo3ly because of slight hints of
neurological sensitivity L the instant chilling and a tendency to dart on going to sleep. "he nervous system does not feel over@e/posed, but all of a
sudden there 3ill be a millisecond of auditory hallucination, or an out@of@the@blue startle. So take it easy going up. PSome $+ hours after this e/periment
had been completed, and a normal baseline re@established, a comple/ and psycho@logically disruptive syndrome occurred, that lasted for the better part
of a 3eek. "he temporal Gu/taposition bet3een the use of deso/y and the subseFuent Nspiritual crisisN initially suggested some possible connection, but
in retrospect the events seem to be unrelatedQ.
'3ith +, mg- I have offered to be a control on an e/periment 3here there had been a close relationship bet3een a trial 3ith deso/y and 3hat might have
been a psychotic break, or some kind of so@called spiritual emergency. "hese t3o events lay 3ithin a day of one another. I 3as a3are of my +,
milligram dosage at about three@Fuarters of an hour into the e/periment, and felt that there 3as no more in@tensification at the t3o@hour point. At that
time I felt distinctly spaced but 3ith a very good feeling, and I could see no reason not to increase the dosage at some future time. "here 3as a good
and mello3 mood, and enGoyment in escapist reading. "he only physical oddity that I noted 3as that there had been no urge to urinate, and only a small
amount of Fuite concentrated urine 3as passed rather late in the e/periment. I 3as at baseline at the fifth hour, and there 3as nothing unusual at any
time during the follo3ing 3eek.
'3ith (,, mg- "he stuff has a s3eet tasteO "here 3as a slight heart@push in the early a3areness period, 3ith a pulse up to (,, and a feeling of pressure
in the chest. "here 3ere no apparent visual enhancements, but the eyes@closed imagery to music 3as note3orthy. "hinking skills and conversation
seemed to be fully under control, if not enhanced. "here 3as none of the colorful psychedelic 3orld of mescaline, but this might be Gust around the
corner; perhaps 3ith a larger dose. "his is a comfortable in@bet3een level. Sleep 3as not possible at the si/th hour, but t3o hours later, it 3as easy and
very restful. "here 3as no negative price to pay the ne/t day.
<="<5SI95S A5; C9??<5"A:>E All substituents that are involved 3ith the several drugs being discussed in this 3riting are really things that are
stuck like 3arts on the ben6ene ring that is central to every phenethylamine. Some of these 3arts are things attached 3ith a o/ygen atom; there are
some of these in every single compound in this story. 5o o/ygen atom, no psychedelic effect. Iithout them, one has stimulants or, more freFuently, no
effects at all.
.ut the removal of an o/ygen atom 'in those cases 3here there is more than one- can radically change the nature of the effects seen. "his is the e/act
meaning of the term Ndeso/y.N N;esN, 3ithout, and No/yN, the o/ygen. Since this drug is simply the structure of mescaline 3ith the o/ygen at the +@
position plucked out of the picture, the first impulse 3as to abbreviate this compound as ;9? for des@o/ymescaline. Ho3ever, a long, long time ago, in a
universe far, far a3ay, a compound 3as synthesi6ed that had a metho/y group replaced by a methyl, and it 3as already named ;9?. "his 3as the first
of the S"P analogs, and the initials stood for deso/y ';9, losing an o/ygen- and methyl '?, having it replaced 3ith a methyl group-. "hese are t3o
different 3orlds. 9ne ? stands for ?escaline, and the other ? stands for ?ethyl. !et7s call it +@deso/ymescaline, or simply ;<S9=>, and be e/act.
"his drug is a prime e/ample of a pharmacological challenge directed to the metabolic attack at the +@position as a mechanism for the e/pression of
biological activity. A metho/y group there 3ould allo3 easy removal of the methyl group from the o/ygen by some demethylation process, but a bare
methyl group there cannot be removed by any simple process. It must be removed by a very difficult o/idation.
"his is not the first time that o/ygen atoms have been removed from the mescaline molecule. .oth the 0,&@dideo/ymescaline '0,&@dimethyl@+@
metho/yphenethylamine- and 0,+,&@trideo/ymescaline 'also called deso/ymescaline in the literature, but really tri@deso/ymescaline or 0,+,&@
trimethylphenethylamine- have been studied in the cat, and have sho3n e/traordinary pharmacological profiles of C5S action. "he trimethyl compound
sho3ed behavior that 3as interpreted as being intense mental turmoil, accompanied by a startling rise in body temperature. "he significance is hard to
determine, in that !S; gave similar responses in the cat, but mescaline 3as 3ithout effects at all. 5o human studies have been made on these
compounds, Gust animal studies. .ut they might prove upon trial in man to be most revealing. "hey 3ould have to be performed 3ith e/ceptional care.
"he 0@carbon chain amphetamines that correspond to these mescaline look@alikes 3ith one or more metho/y groups replaced 3ith methyl groups, are
largely untested and 3ould reFuire independent and novel syntheses. "he 0,+,&@trimethylamphetamine is kno3n, and is kno3n to be very hard on
e/perimental cats.
A mescaline analogue 3ith a bromo atom in place of the +@metho/yl group is an analogue of mescaline in e/actly the same 3ay that ;9. 'a very potent
am@phetamine- is an analog of "?A@$ 'the original trisubstituted amphetamine-. "his analogue, 0,&@dimetho/y@+@bromoamphetamine, has been found
to be a most effective serotonin agonist, and it is a possibility that it could be a most potent phenethylamine. .ut, as of the present time, it has never
been assayed in man.

#)' $,(-0MA; $,(-0"METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of (, g $,+@dimetho/yben6aldehyde in &, m! nitroethane there 3as added ,.& g anhydrous ammonium acetate, and the
mi/ture 3as heated on the steam bath for $ h. "he e/cess solvent8reagent 3as removed under vacuum, and the residue oil dissolved in $& m! boiling
?e9H. 9n cooling, this deposited yello3 crystals of (@'$,+@dimetho/yphenyl-@$@nitropropene that, after filtering, ?e9H 3ashing, and air drying, 3eighed
(,.$ g and had a mp of 2)@2% deg C.
A magnetically stirred suspension of 1., g !AH in 0,, m! anhydrous <t$9 3as brought up to a gentle reflu/ under a He atmosphere. A total of ).& g (@
'$,+@dimetho/yphenyl-@$@nitropropene 3as introduced into the reaction mi/ture by allo3ing the condensed <t$9 to leach it from a modified So/hlet
condenser. After the addition 3as complete, the reaction 3as held at reflu/ for an additional $+ h. After cooling 3ith an e/ternal ice bath, the e/cess
hydride 3as destroyed by the cautious addition of H$9. Ihen the e/othermic reaction had subsided, there 3as added &,, m! H$9, (&, g potassium
sodium tartrate, and sufficient base to bring the pH above %. "he phases 3ere separated, the organic phase dried over anhydrous ?gS9+, the drying
agent removed by filtration, and the clear filtrate then saturated 3ith anhydrous HCl gas to produce 3hite crystals of $,+@dimetho/yamphetamine
hydrochloride '$,+@;?A- 3ith a mp of (+1@(+2 deg C.
;9SAC<E greater than 1, mg.
;4:A"I95E short.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- "his is definitely threshold, or even a bit more. "here is a lot of amphetamine@like component, and a certain
blush of euphoria. "here is also a diffusion of association, so it7s more than Gust amphetamine, no Fuestion about it. At the three@hour point, it is
definitely Fuieting do3n.
<="<5SI95S A5; C9??<5"A:>E Ihat can one say as to the active dosage of $,+@;?AH 5othing. Ihat can one say as to the durationH Probably
short. "he 1, milligram report given above is the highest level that I personally kno3 of having been tried in man, and there is no hint as to 3hat might
be found at a fully active dose, or Gust 3here that dose might be. It might be fully speedy. It might be fully psychedelic. It might give a cardiovascular
push that 3ould be scary. Studies of $,+@;?A on vascular strips 'associated 3ith serotonin action- 3ere not impressive in comparison 3ith structurally
related psychedelics, and it seems as if its action might involve norepinephrine release. It is a reasonable guess that there 3ould be cardio@vascular
activity at higher levels. .ut it 3ill only be 3ith human trials, someday, that the ans3er 3ill be kno3n for sure.
"he meta@orientation of the t3o metho/yl groups does, ho3ever, greatly increase the susceptibility of the aromatic ring to electrophilic attack. "his is
one of the three possible meta@dimetho/y substituted amphetamines, and it is the best studied one in the pursuit of potential radio@halogen substituted
brain blood@flo3 agents. "his strategy is discussed under I;55A; the other t3o meta@compounds are discussed under 0,+@;?A.
"he homologues of $,+@;?A that 3ere iodinated 'or occasionally fluor@inated- 3ere mono@ or di@alkylated on the nitrogen, and the precursor that 3as
common to all 3as the corresponding acetone. "he above nitrostyrene, (@'$,+@dimetho/yphenyl-@$@nitropropene, 3as reduced in acetic acid 3ith
elemental iron, and the base@3ashed e/tracts stripped of solvent and distilled '($&@(+& deg C at ,.& mm8Hg- to give $,+@dimetho/yphenylacetone as a
3ater@3hite oil. "he principal reductive amination product of this, the one that 3as most thoroughly e/plored 3ith various halogenation schemes, 3as
obtained by the reaction of $,+@dimetho/yphenylacetone 3ith dimethylamine and sodium cyanoborohydride. "his product, $,+@dimetho/y@5,5@
dimethylamphetamine or $,+@;55A, distilled at (,&@((& deg C at ,.+ mm8Hg and formed a perchlorate salt that melted at %)@%).& deg C. "his could be
iodinated 3ith the radio@iodide anion, 3hen o/idi6ed 3ith chloramine@" in buffered sulfuric acid, to give the iodinated analogue '$,+@dimetho/y@5,5@
dimethyl@&@iodoamphetamine- in an e/cellent yield. :adio@fluorination 3ith acetyl hypofluorite gave the &@fluoroanalogue '$,+@dimetho/y@5,5@dimethyl@&@
fluoroamphetamine- in an acceptable yield. .oth compounds 3ent into a rat7s brain to a pretty good e/tent, but both of them 3ashed out too rapidly to
be clinically interesting.
A large family of other 5@substituted homologues of $,+@;?A 3ere similarly prepared from the above ketone and sodium cyanoborohydride.
?ethylamine, ethylamine, propylamine, isopropylamine and he/ylamine gave the corresponding 5@alkyl homologues. "he 5,5@diethyl homologue 3as
made from the primary amine, $,+@;?A itself, 3ith acetaldehyde and sodium cyanoborohydride but the product, 5,5@diethyl@$,+@dimetho/yamphetamine,
could not be converted into a crystalline hydrochloride salt.
>et another variation on these structures 3as launched, again 3ith the design of making radio@iodination targets 3hich are not psychedelic and thus
might be useful clinically. In this variation, the nitrogen atom substitution pattern 3as held constant, 3ith t3o methyl groups, as 3ere the ring locations of
the t3o o/ygen atoms. .ut the identities of the alkyl groups on these o/ygen atoms 3ere varied. "he synthetic procedure follo3ed 3as to make the
appropriate $,+@dialko/yben6aldehyde, convert it to the nitrostyrene 3ith nitroethane, reduce this to the phenylacetone 3ith elemental iron, and then
reductively aminate this ketone 3ith dimethylamine. Bollo3ing this reaction scheme, five amphetamine homologues of $,+@;?A 3ere made, three 3ith
the +@metho/y group maintained but the $@position e/tended, and t3o 3ith both groups e/tended symmetrically. "hese areE '(- 5,5@dimethyl@$@etho/y@
+@metho/yamphetamine; '$- $@'n-@butylo/y@5,5@dimethyl@+@metho/y@amphetamine; '0- $@'n-@decylo/y@5,5@dimethylamphetamine; '+- $,+@dietho/y@5,5@
dimethylamphetamine; and '&- 5,5@dimethyl@$,+@di@'i-@propo/yamphetamine. I believe that most of these have been iodinated and assayed in rats, and
several of them appear Fuite promising. .ut none of them have been assayed in man, yet. "he bromination product of $,+@;?A '&@bromo@$,+@
dimetho/yamphetamine, &@.r@$,+@;?A- is 3ay do3n in activity 'see its recipe, separately-. Since all iodo analogues are of about the same potency as
the bromo counterparts, and since the addition of t3o methyl groups on the nitrogen does not appear to enhance central activity, I feel the iodination
products of these 5,5@dialkyl@dialko/yamphetamines 3ould not have any interesting psychopharmacology.
"here is something vaguely counterproductive, in my evaluation of things, 3hen the goal of a research proGect is to avoid activity rather than to create it.
Although this chemistry 3as completely fascinating and could have produced the 3orld7s best positron@emitting, brain@scanning diagnostic compound, I
feel it Fuite unlikely that it 3ould have produced the 3orld7s best insight@revealing, empathy@enhancing psychedelic, so this research direction never
totally caught my fancy. I 3ent on to other things.

#)( $,)-0MA; 0MA; $,)-0"METH%+YAM,HETAM"#E
S>5"H<SISE A solution of (,., g $,&@dimetho/yben6aldehyde in &, m! glacial acetic acid 3as treated 3ith 1.) g of nitroethane and +., g of anhydrous
ammonium acetate. "his mi/ture 3as heated on the steam bath for 0 h and then the reagent8solvent 3as removed under vacuum. "he residue 3as
suspended in H$9 and e/tracted 3ith CHCl0. :emoval of the solvent from the pooled e/tracts yielded ((.$ g of an impure (@'$,&@dimetho/yphenyl-@$@
nitropropene 3hich, on recrystalli6ation from 2& m! boiling ?e9H, gave 1.2 g of product 3ith a mp of 20@2& deg C. Anal. 'C((H(059+- C,H,5. "his
nitrostyrene has been periodically available commercially from a number of sources.
A solution of (2., g of (@'$,&@dimetho/yphenyl-@$@nitropropene 3as prepared in &,, m! anhydrous <t$9. "his solution 3as added slo3ly to a 3ell@
stirred suspension of ($., g !AH in 2,, m! anhydrous <t$9. "he mi/ture 3as then brought up to a reflu/ and maintained there for $, h, cooled 3ith an
e/ternal ice bath, and the e/cess hydride destroyed by the cautious addition of H$9. Binally, a total of &,, m! H$9 3as added, follo3ed by the addition
of 0,, g potassium sodium tartrate, and sufficient aFueous 5a9H to bring the pH above %. "he t3o phases 3ere separated, and the ether phase dried
by the addition of anhydrous ?gS9+. "he drying agent 3as removed by filtration, and the clear filtrate saturated 3ith a stream of anhydrous HCl gas.
"he formed crystals of $,&@dimetho/yamphetamine hydrochloride '$,&@;?A- 3ere removed by filtration, 3ashed 3ith anhydrous <t$9, and dried to
constant 3eight of (1.0 g. :ecrystalli6ation from <t9H gave an analytical sample 3ith a mp of ((+@((1 deg C. "he hydrobromide salt is reported to melt
at ($%@(0( deg C.
;9SAC<E ), @ (1, mg.
;4:A"I95E 1 @ ) h.
<="<5SI95S A5; C9??<5"A:>E "he Fualitative information on $,&@;?A is very sparse. I 3as up to a (* 3ith ), milligrams of the hydrochloride,
and since it appeared to be totally a physical trip 3ith tremors and some cardiovascular push and nothing of a sensory nature, I chose to e/plore it no
further. A report from South America found the into/ication to be largely pleasant 'this, at 2& milligrams-, 3ith an enhanced interest in one7s
surroundings, but no perceptual changes, no overt stimulation, and no gross physiological effects other than a slight mydriasis 'dilation of the pupils-. I
have also been told of a single trial of $&, milligrams of the tartrate 'this is eFuivalent to some3here in the (&,@$,, milligram range of the hydrochloride
salt, depending upon the acid8base ratio of the tartrate salt- 3ith some NspeedyN effects but still no sensory changes. A sei6ure of capsules reported by
the drug la3 enforcement authorities some $, years ago found that each contained some $,, milligrams of the hydrobromide salt. "his is eFuivalent to
(2, milligrams of the hydrochloride salt, and suggests that level may be an effective dosage.
An intriguing, but little studied, analogue of $,&@;?A is the compound 3ith methyls in place of the metho/yls. $,&@;imethylamphetamine has been
looked at, in man, as a potential anore/ic, but there is little effect even at (&, milligrams. "he 0,+@isomer, 0,+@dimethylamphetamine or /ylopropamine,
is an adrenergic agent and it has been found to be an analgesic in man at as little as (, milligrams. "his 3as assayed, rather remarkably, by attaching
electrodes to the tooth fillings of the e/perimental subGects. .ut 3ith this base, cardiovascular effects 3ere not observed until doses of about (,,
milligrams 3ere administered, and to/ic effects 'nausea and vomiting- 3ere reported at (&, milligrams. "here 3as no suggestion of anything
psychedelic.
All three isomers of monomethylamphetamine have also been looked at in man. "he ortho@ and meta@isomers, $@methyl@ 'and 0@methyl@ - amphetamine
are 3eak anore/ics. At doses of up to (&, milligrams orally, there 3ere signs of stimulation noted L talkativeness and loss of appetite. "he para@
isomer, +@methyl@amphetamine or Aptrol, is more potent. At 2& milligrams 'orally, in man- there is clear adrenergic stimulation, and at t3ice this dosage
there are signs of mild to/icity such as salivation, coughing and vomiting.
"here is a mystery, at least to me, concerning the commercial production of $,&@;?A. At regular intervals, there is a public announcement of the
production Fuotas that are reFuested or allo3ed by the ;rug <nforcement Administration, for drugs that have been placed in Schedules I or II. In the
Schedule I category there are usually listed amounts such as a gram of this, and a fe3 grams of that. "hese are probably for analytical purposes, since
there are no medical uses, by definition, for drugs in this Schedule. .ut there is a staggering Fuantity of $,&@;?A reFuested, regularly. Luantities in the
many tens of millions of grams, Fuantities that vie 3ith medical mainstays such as codeine and morphine. I have heard that this material is used in the
photographic industry, but I have no facts. Some3here I am sure that there is someone 3ho has to keep a lot of very careful booksO
In the area of psychedelic drugs, the value of $,&@;?A is mainly in its role as a precursor to the preparation of materials that can come from a direct
electrophilic attack on the activated +@position. "hese uses can be found under things such as ;9. and ;9I and ;95. "he radio@halogenation of 5@
substituted homologues of $,&@;?A 3ith hypoiodite or hypofluorite is part of an e/tensive study under3ay in the search for radio@labeled brain blood flo3
agents. "he rationale for this 3ork is to be found in the commentary under I;55A. In essence it has been found that the 5@substitution or 5,5@
disubstitution of $,&@;?A 3here the +@position is unsubstituted and thus available for the introduction of a radioactive nucleus can give rise to potentially
useful drugs. ?ost of these $,&@dimetho/y e/ploratory compounds 3ere made by the reductive alkylation of $,&@dimetho/y@+@'radio-iodophenylacetone,
using various mono or dialkyl amines. "his, too, is described under I;55A.
Ho3ever, the study of various direct iodinations and fluoridations that 3ould have the 5,5@dimethyl substitution on the amphetamine nitrogen atom,
3ould reFuire the +@proteo@ analogue, and this 3as made from the above nitrostyrene. A solution of the above nitrostyrene, $$.0 g (@'$,&@
dimetho/yphenyl-@$@nitropropene in (,, m! acetic acid 3as added to a suspension of elemental iron in acetic acid '+& g in $&, m!- and 3orked up 3ith
3ater and base 3ashing to give, after distillation at %$@(,1 deg C at ,.0& mm8Hg, (0.) g $,&@dimetho/yphenylacetone as a pale yello3 oil. "his
under3ent reductive amination 3ith dimethylamine hydrochloride in ?e9H solution, using sodium cyanoborohydride, to give the target compound $,&@
dimetho/y@5,5@dimethylamphetamine o/alate 3ith a melting point of (00@(0+ deg C '+.1 g ketone gave (.0) g of salt-. Anal. 'C(&H$0591- C,H. It has
also been prepared by the 5,5@dimethylation of $,&@;?A directly, 3ith formaldehyde and formic acid. "his has been called $,&@;55A, or I;55A 3ithout
the NI.N "his intermediate, $,&@;55A, under3ent direct radioiodination 3ith labeled iodine monochloride in the presence of perchloric acid to give I;55A
3ith a +,K incorporation of isotope. :eaction 3ith labeled acetyl hypofluorite, on the other hand, gave only a $K in@corporation of the radio@isotope.
"his latter compound is, chemically, +@fluoro@$,&@dimetho/y@5,5@dimethylamphetamine and, using the reasoning suggested above and 3ith I;55A,
might best be encoded B;55A.
"he $,&@dimethylamphetamine analogue mentioned above 3as also e/plored in this I;55A concept. "he commercially available $,&@
dimethylben6aldehyde 3as converted to the nitrostyrene 3ith nitroethane '(@'$,&@dimethylphenyl-@$@nitropropene, yello3 crystals 3ith a melting point of
$+.&@$&.& deg C- 3hich reacted 3ith elemental iron in acetic acid to give the ketone $,&@dimethylphenylacetone 'boiling at (+,@(&, deg C at ,.+ mm8Hg-.
:eductive amination 3ith dimethylamine and sodium cyanoborohydride gave $,&@;?55A '$,&,5,5@tetramethylamphetamine- as a clear oil 3ith a boiling
point of ((&@($& deg C at ,.0& mm8Hg. It gave poor yields of the +@fluoro analogue 3ith acetyl hypofluorite.
All of these latter materials remain unevaluated in man.
#)) ',(-0MA; ',(-0"METH%+YAM,HETAM"#E
S>5"H<SISE A solution of 00.$ g of veratraldehyde in (&., g nitroethane 3as treated 3ith ,.% g of n@amylamine and placed in a dark place at room
temperature. In a day or so, separated H$9 3as apparent and, after a couple of 3eeks, the mi/ture completely solidified. "he addition of &, m! <t9H
and heating effected complete solution and, on cooling, this provided (@'0,+@dimetho/yphenyl-@$@nitropropene as yello3 crystals, $%., g, 3ith mp of 2,@
2( deg C. "he more conventional reaction scheme, 1 h heating of a solution of the aldehyde and nitroethane in acetic acid 3ith ammonium acetate as
catalyst, gave a much inferior yield of product '00.$ g gave (+.) g- of the same purity. :ecrystalli6ation from ?e9H increased the mp to 2$@20 deg C.
"o a reflu/ing suspension of 2 g !AH in 1,, m! anhydrous <t$9, stirred and under an inert atmosphere, there 3as added 2.& g (@'0,+@
dimetho/yphenyl-@$@nitropropene by allo3ing the returning condensed ether to leach out the material as a 3arm solution from a So/hlet thimble.
Bollo3ing the completion of the addition of the nitrostyrene, reflu/ing 3as maintained for $+ h, and the reaction mi/ture allo3ed to stand several days at
room temperature. "he e/cess hydride 3as destroyed by the cautious addition of &,, m! H$9 containing +, g H$S9+, and the phases 3ere separated.
"he aFueous phase 3as 3ashed 3ith both <t$9 and CH$Cl$. "here 3as then added $,, g potassium sodium tartrate, and the pH brought above % by
the addition of aFueous 5a9H. "his clear solution 3as e/tracted 3ith 0/(&, m! CH$Cl$, the e/tracts 3ere pooled, and the solvent removed under
vacuum to give a residual oil. "his 3as dissolved in <t$9, saturated 3ith anhydrous HCl gas, and the resulting solids removed by filtration.
:ecrystalli6ation from (, m! acetone gave (.0& g 0,+@dimetho/yamphetamine hydrochloride '0,+@;?A- as beautiful 3hite crystals 3ith a mp of (++@(+&
deg C.
;9SAC<E a fe3 hundred milligrams.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith 2, mg i.v.- P9ne patient received ,.,,+ m?8g of the hydrochloride salt intravenously and e/hibited only slight
increase in psychiatric symptoms; a comparable dosage in a second individual also elicited only insignificant changes.Q
'3ith 2,, mg i.v.- PIhen one of these patients 3as reinGected at a later date 3ith appro/imately ,.,+ m?8g of 0,+@;?A a definite Smescaline@like7 state
3as induced. "he symptoms included colored hallucinations of geometric figures and occasional structured forms. "he other individual e/perienced
visual distortions, notable after@imagery, feelings of unreality, and paranoid ideas. ?arked mydriasis and gross body tremors also occurred but
apparently no hallucinations 3ere e/perienced.Q
<="<5SI95S A5; C9??<5"A:>E "hese NLualitative CommentsN are not e/plicit Fuotations from people 3ho had taken 0,+@;?A. "hey are 3ritten
descriptions by the observers 3ho had given 0,+@;?A to psychiatric patients. "his is one of the most outrageous chapters in the books on military
medicine. "he chemical 3arfare group 3ithin the 4.S. Army e/plored many potential psychedelics by administering them to innocent patients 3ith not
even a thought of obtaining informed consent. "hese e/periments took place at the 5e3 >ork State Psychiatric Institute 'amongst other places- in the
early (%1,7s. "he <dge3ood Arsenal code name for 0,+@;?A 3as <A@(0(1. A fe3 non@military studies have indicated that 0,+@;?A is orally active at
(1, milligrams, and so probably its potency by this more conventional route 3ould fall mid3ay bet3een that of mescaline and of ?;A. "he 0@metho/y@
+@other@than@metho/y things 'such as hydro/y, etho/y, allylo/y and methyl- are mentioned in the recipe for ?<P<A. "he alpha@ethyl homologue of 0,+@
;?A, $@amino@(@'0,+@dimetho/yphenyl-butane, and of other ;?A7s are discussed under the recipe for A:IA;5<.
"here are a total of si/ possible amphetamine molecules 3ith t3o metho/yl groups attached. "he 0,+@orientation has al3ays been the most appealing to
the life scientists as this is the positional substitution pattern found in the natural neuro@chemicals dopamine, norepinephrine and epinephrine. "hese
latter t3o are called noradrenalin and adrenalin in <ngland. "3o adGacent hydro/y groups represent the catechol in the 3ell kno3n 3ord
catecholamines. >ou might read in a te/tbook, N"his is 3here nature placed the groups 3hen she put the compounds in our brains. So that is 3here the
groups might be the most interesting in a psychedelic.N IhyH I have never understood this kind of reasoning. If a possible psychedelic has Gust the
e/act o/ygen positioning of a neurotransmitter, then, voila, that7s 3hy it is active. And if a possible psychedelic has some positioning of these o/ygen
atoms that is different than that of a neurotransmitterH "hen voila again. "hat7s 3hy it is active. .oth sound eFually reasonable to me, and neither one
even begins to address the fundamental Fuestion, ho3 do the psychedelic drugs do 3hat they doH A study in the human animal of the intimate effects of
one of these neurotransmitter analogues might bring us a little bit closer to ans3ering this fundamental Fuestion. .ut maybe it 3ouldn7t, after all.
5othing has made much sense so farO Any3ay, 0,+@;?A is one of the ten essential amphetamines that can, in theory, arise from the ten essential oils of
the spice and herb trade. In this case, the origins are methyl eugenol and methyl isoeugenol.
"3o of these NdifferentN isomers, $,+@;?A and $,&@;?A, have already been discussed in their o3n separate recipes. And the remaining three of the si/
possible ;?A7s that are NdifferentN have been made and studied pharmacologically in animals but not in man. "hese are the $,0@;?A, $,1@;?A and the
0,&@;?A isomers. "he products of their reaction 3ith elemental bromine are discussed under ?<"A@;9..
.oth the $,1@ and the 0,&@isomers, as the 5,5@dimethyl homologues, have been looked at as potential radio@halogen recipients in the search for positron@
emitting brain blood@flo3 indicators, as discussed in the recipe for I;55A. .oth 3ere made from the appropriate nitrostyrene via the corresponding
phenylacetone.
"he $,1@isomer 3as derived from $,1@dimetho/yben6aldehyde. "his, in nitroethane and ammonium acetate, gave the nitrostyrene as canary@yello3
crystals from ?e9H that melted at (,(.&@(,$.& deg C. <lemental iron in acetic acid converted this nitrostyrene to $,1@dimetho/yphenylacetone 'a 3ater@
3hite oil 3ith boiling point of %&@(,& deg C at ,.+ mm8Hg. Anal. 'C((H(+90- C,H- and reductive amination 3ith dimethylamine and sodium
cyanoborohydride gave $,1@dimetho/y@5,5@di@methylamphetamine perchlorate '$,1@;55A- 3ith a melting point of (,%@((, deg C. "his base 3as readily
fluorinated 3ith ()B acetylhypofluorite and iodinated 3ith chloramine@"@o/idi6ed ($$I iodide ion. It 3as also halogenated 3ith 'non@radioactive- bromine
and iodine monochloride to give the corresponding 0@bromo@'and 0@iodo-@$,1@dimetho/y@5,5@dimethylamphetamines but these, in turn, did not react 3ith
radioactive acetyl hypofluorite.
"he 0,&@isomer follo3ed precisely the same flo3 sheet. 0,&@;imetho/yben6aldehyde gave the nitrostyrene '3ith a melting point of )2@)) deg C-, the
phenylacetone '3ith a boiling point of ((,@(0, deg C at ,.0 mm8Hg- and the product 0,&@dimetho/y@5,5@dimethylamphetamine perchlorate '0,&@;55A-
3ith a melting point of (,,@(,( deg C. "his also reacted readily 3ith ()B acetylhypofluorite and ($$I@hypoiodite. Several alpha@ethyl homologues of
these compounds have also been discussed in the recipe for A:IA;5<.
#)1 0M!,A; $-&$,)-0"METH%+Y-(-METHY,HE#Y-!Y!%,*%,YAM"#E
S>5"H<SISE "o a solution of $& g $,&@dimetho/y@+@methylben6aldehyde 'see the recipe for $C@; for the preparation- and $%.$ g malonic acid in &, m!
anhydrous pyridine, there 3as added $ m! piperidine and this 3as heated on the steam bath for several h. "he mi/ture 3as added to a solution of ($&
m! concentrated HCl in &,, m! H$9 at , deg C, and the solid product that 3as formed 3as removed by filtration, and 3ashed 3ith H$9.
:ecrystalli6ation from aFueous <t9H yielded 0( g $,&@dimetho/y@+@methylcinnamic acid 3ith a mp of (10@(11 deg C. Anal. 'C($H(+9+- C,H.
In a cooled high@pressure reaction vessel there 3as placed a suspension of 0, g $,&@dimetho/y@+@methylcinnamic acid in (&, m! liFuid isobutene. "his
3as treated drop3ise 3ith ,.1 m! concentrated H$S9+, then sealed and brought to room temperature. After +) h shaking, the vessel 3as cooled again
to @(, deg C, opened, and poured into $,, m! of (,K 5a$C90. "his 3as e/tracted 3ith he/ane, the pooled e/tracts 3ashed 3ith H$9, and the solvent
removed to yield (2., g of 't-@butyl $,&@dimetho/y@+@methylcinnamate as an amber oil. Anal. 'C(1H$$9+- C,H.
"he cyclopropane ester 3as prepared by the reaction bet3een (1 g 't-@butyl $,&@dimetho/y@+@methylcinnamate and dimethylsulfo/onium methylide,
prepared as described in the aiser reference in the ackno3ledgements. Hydrolysis of this ester gave &0K trans@$@'$,&@dimetho/y@+@
methylphenyl-cyclopropanecarbo/ylic acid 3hich, after recrystalli6ation from a ?e9H8H$9 mi/ture, had a mp of (01 deg C. Anal. 'C(0H(19+- C,H.
A suspension of + g of trans@$@'$,&@dimetho/y@+@methylphenyl-cyclopropanecarbo/ylic acid in an eFual volume of H$9, 3as treated 3ith sufficient
acetone to effect complete solution. "his 3as cooled to , deg C and there 3as added, first, $., g triethylamine in 0& m! acetone, follo3ed by the slo3
addition of $.& g ethyl chloroformate in (, m! acetone. "his 3as stirred for ,.& h, and then there 3as added a solution of (.2 g 5a50 in 1 m! H$9,
drop3ise. After ( h stirring at , deg C, the mi/ture 3as Fuenched by pouring into H$9 at , deg C. "he separated oil 3as e/tracted 3ith <t$9, and
e/tracts dried 3ith anhydrous ?gS9+. :emoval of the solvent under vacuum gave a residue of the a6ide, 3hich 3as dissolved in (, m! anhydrous
toluene. "his solution 3as heated on the steam bath until the nitrogen evolution 3as complete, and the removal of the solvent under vacuum gave a
residue of crude isocyanate as an amber oil. "his intermediate isocyanate 3as dissolved in &.+ g ben6yl alcohol and the reaction mi/ture 3as heated on
the steam bath for 1 h. "he e/cess ben6yl alcohol 3as removed by distillation, yielding trans@$@'$,&@dimetho/y@+@
methylphenyl-carboben6o/yamidocyclopropane as a crystalline residue. "his 3as recrystalli6ed from an <t9Ac8he/ane mi/ture to give 1.(0 g of a
crystalline product 3ith a mp of (,2@(,) deg C. Anal. 'C$,H$059+- C,H,5.
A solution of (.& g trans@$@'$,&@dimetho/y@+@methylphenyl-carboben6o/yamidocyclopropane in ($, m! ?e9H containing $,, mg (,K Pd8C 3as shaken
under hydrogen gas at 0& psig for +& min. "he solution 3as filtered through celite, and a sufficient amount of a solution of &K HCl in <t9H 3as added to
the filtrate to make it acidic. :emoval of all volatiles under vacuum gave a solid residue that 3as recrystalli6ed from an <t9H8ether mi/ture to give ,.%)
g of trans@$@'$,&@dimetho/y@+@methylphenyl-cyclopropylamine hydrochloride ';?CPA- as 3hite crystals 3ith a mp of $(,@$(( deg C.
;9SAC<E (& @ $, mg.
;4:A"I95E + @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith (, mg- "he effects 3ere Fuite real at an hour, but very hard to define. 5othing left at four hours, but my sleep 3as
filled 3ith bi6arre and colorful dreams. Something 3as still 3orking some3here, at some level.
'3ith $, mg- I found myself lightheaded, and the thinness seemed to be, rather remarkably, on the left side of my brain. "he e/perience 3as flighty. I
3as reminded of the aura that has been described preceding a convulsion. I 3as decoupled from my e/perience and from my environment. 5ot all of
the control is there, and I am uncomfortable. .ut in an hour, there is complete control again, and I can rela/ my conscious guard 3hich allo3s an easy
plus three. Iith this, there 3as easy fantasy, erotic, Fuite a bit of movement in the visual field, and mild anore/ia. "he residual hyperrefle/ive thinness
is largely gone, and not at all 3orrisome. "his stuff is complicated, 3ith a little too much of the physical. "he ne/t day 3as 3ithout any residues at all.
<="<5SI95S A5; C9??<5"A:>E ?ost of the human trials took place in the fifteen to t3enty milligram range. Several reports describe some
muscular tremor, especially in the earliest part of the e/perience, but this never seemed to be a concern. "he efforts to lock imagery to music 3ere not
too successful. All of these clinical studies 3ere conducted on the trans@compound, but on the racemic mi/ture. "his has been resolved into the t3o
optical isomers, but they have not been compared in man. "he cis@mi/ture is unkno3n.
"his material is intimately related to tranylcypromine, a clinically proven antidepressant. "his drug is a kno3n monoamine o/idase inhibitor, and it is
certainly possible that some of this pharmacological property might be found in ;?CPA if it 3ere to be looked for. "he hints of physical to/icity at the
higher doses assayed might suggest some such activity.
"his compound, ;?CPA, 3as modeled directly after the structure of ;9?, 3ith the $,&@dimetho/y@+@methyl substitution pattern. Another analogue of
tranylcypromine, similarly modeled, is 0,+,&@trimetho/ytranylcypromine, or trans@$@'0,+,&@trimetho/yphenyl-cyclopropylamine '"?"-. It has been
evaluated at levels of only (0 milligrams orally, and at this dose there 3ere no hints of central activity.

#)2 0ME; ',(-0"METH%+Y-beta-HY0*%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of (,.$ g 0,+@dimetho/yben6aldehyde in (, m! <t9H, cooled to , deg C, there 3as added a solution of +.$ g C5 in +, m!
H$9. Iith good stirring, there 3as slo3ly added (, m! concentrated HCl 'cautionE HC5 is evolved- and the t3o@phase reaction mi/ture 3as allo3ed to
continue stirring until there 3as the spontaneous formation of crystals. After a fe3 days standing, these 3ere removed by filtration and 3ell 3ashed 3ith
H$9. All 3as recrystalli6ed from 2& m! of &,K ?e9H and air dried to provide 1.%& g of the cyanohydrin 0,+@dimetho/y@a@hydro/yphenylacetonitrile.
"he mp 3as (,+@(,1 deg C, 3hich can be increased to (,% deg C by recrystalli6ation from ben6ene.
A 3ell@stirred suspension of +.2 g !AH in &,, m! anhydrous <t$9 3as brought up to a gentle reflu/, and +.2 g 0,+@dimetho/y@a@
hydro/yphenylacetonitrile 3as leached in from a So/hlet thimble, over the course of 0 h. "he color of the ether solution progressed from yello3 to
green, to an eventual blue. "he reflu/ 3as maintained for (1 h. After cooling again, there 3as added 'carefully- a solution of $2 g H$S9+ in &,, m!
H$9. "he completely clear t3o@phase mi/ture 3as separated, and the aFueous phase treated 3ith )2 g potassium sodium tartrate. "he addition of
$&K 5a9H brought the pH U%, and this phase 3as e/tracted 3ith +/(,, m! CH$Cl$. :emoval of all the organic solvents under vacuum gave a residue
that 3as part oil and part solid. "his 3as e/tracted 3ith +/&, m! boiling <t$9, the e/tracts pooled, and saturated 3ith anhydrous HCl gas. "he ,.%& g
of pale@yello3 crystals that formed 3ere removed by filtration, and finely ground under & m! CH0C5. "here remained, after refiltration and air drying,
,.)& g of 0,+@dimetho/y@beta@hydro/yphenethylamine hydrochloride, ;?<, 3ith a mp of (2,@(2$ deg C.
;9SAC<E greater than ((& mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith ((& mg- I 3as faintly nauseous about an hour after taking the compound, and perhaps I 3as more alert than usual in
the evening. Substantially no effects.
<="<5SI95S A5; C9??<5"A:>E "he rationale for e/ploring the beta@hydro/ylated phenethylamines, especially those 3ith o/ygens at the
biologically important 0@ and +@positions, has already been presented. 5orepinephrine is a beta@hydro/ylated phenethylamine 3ith o/ygens at these t3o
ring positions. Iith ;?<, these are masked as t3o methyl ethers, and the initials ;?< stand for 0,+@dimetho/yphenyl@beta@ethanolamine. "his is an
alternate name for 0,+@dimetho/y@beta@hydro/yphenethylamine.
An e/actly analogous compound is 0,+@methylenedio/y@beta@ethanolamine, 3here the masking is done 3ith the biologically more fragile methylenedio/y
ether. 9riginally I had called this compound ?;< 'methylenedio/yethanolamine- but that code has been, since (%2&, used e/clusively for 0,+@
methylenedio/y@5@ethylamphetamine, 3hich is a recipe all by itself. 4nder the discussion of members of the .9= series, there is a
methylenedio/yphenethylamine 3ith a metho/yl group at the beta@position, and it is called .9H 'F.v.-. "here, a reasonable code name for this specific
compound is given, namely .9HH. :.9S stands for the beta@o/ygen function on a phenethylamine; this is the heart of the .9= family. "he :HS
3hich is the third letter of .9HH stands for the free hydro/yl group. And the final :HS is for homopiperonylamine '3hich is the trivial name for the
compound 3ithout the hydro/yl group-. .9HH, or 0,+@methylenedio/y@beta@hydro/yphenethylamine, or 0,+@methylenedio/y@beta@ethanolamine, has
also be assayed in man at up to (,, milligrams 3ithout any effects, and must be considered, as of no3, to be inactive centrally. "he possible to/ic roles
of beta@ethanolamines as potential adrenolytic agents, have been discussed in the .9H; recipe. And be3are of the use of the code name ?;< in the
very old literature. It might be this .9HH compound.
#)3 0MM0A; $,)-0"METH%+Y-',(-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE Apiole, as the crystalline essential oil (@allyl@$,&@dimetho/y@0,+@methylenedio/yben6ene, is isolated directly from commercial 9il of Parsley,
by careful fractional distillation. It is the fraction that boils at (1&@(12 deg C at $2 mm8Hg. A solution of (%.) g apiole in a mi/ture of +0 g 9H and 1, m!
hot <t9H 3as heated in the steam bath for $+ h. Iith vigorous stirring, it 3as diluted 3ith H$9, at a rate 3hich the crystals that formed spontaneously
could accumulate from the turbidity that 3as generated. Ihen no more H$9 could be added 'there 3as persistent oiling out of material- the reaction
mi/ture 3as filtered to give ($.( g of an amber solid material. "his 3as recrystalli6ed from $, m! boiling he/ane, 3hich 3as filtered 3hile hot to remove
insolubles. Brom the cooled filtrate, there 3as obtained %.0 g of $,&@dimetho/y@0,+@methylenedio/y@(@propenylben6ene, isoapiole, as pale cream@
colored solids.
A stirred solution of ).) g $,&@dimetho/y@0,+@methylenedio/y@(@propenylben6ene and 0.% g pyridine in +& m! acetone 3as cooled to ice@bath
temperatures, and treated 3ith 2.% g tetranitromethane. "his e/tremely dark reac@tion 3as stirred at , deg C for & min, then Fuenched 3ith a solution of
$.1 g 9H in +& m! H$9. Iith continued stirring, there appeared yello3 crystals of (@'$,&@dimetho/y@0,+@methylenedio/yphenyl-@$@nitropropene 3hich,
after filtering, 3ashing 3ith &,K acetone and air drying, 3eighed )., g and had a mp of ((,@((( deg C.
"o a 3ell@stirred and gently reflu/ing suspension of 1.0 g !AH in &,, m! anhydrous <t$9, under an inert atmosphere, there 3as added 2.& g (@'$,&@
dimetho/y@0,+@methylenedio/yphenyl-@$@nitropropene by leaching out the nitrostyrene from a thimble in a modified So/hlet condenser apparatus. "he
addition took (.& h, and the reflu/ing 3as maintained for an additional 0 h. After cooling, the e/cess hydride 3as destroyed by the cautious addition of
0,, m! of (.& 5 H$S9+. "he aFueous phase 3as brought to a pH of 1 3ith 5a$C90. "his 3as heated to ), deg C and clarified by filtration though
paper. "he addition of a stochiometric amount of picric acid in boiling <t9H gave rise to precipitation of the product picrate as globs that did not
crystalli6e. "hese 3ere 3ashed 3ith cold H$9, then dissolved in 0, m! &K 5a9H. </traction 3ith $/2& m! <t$9, and the stripping of the solvent from
the pooled e/tracts, gave 0.( g of an oily residue 3hich, upon dissolving in $&, m! <t$9 and saturation 3ith anhydrous HCl gas, gave 3hite crystals.
"hese 3ere removed by filtration, <t$9@3ashed, and air dried, to give $.% g of $,&@dimetho/y@0,+@methylenedio/yamphetamine hydrochloride ';??;A-
that melted in the (1&@(2& deg C range.
;9SAC<E 0, @ 2& mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith $& mg- "he into/ication 3as there at an hour and a Fuarter, and I 3as hit 3ith nausea 3ith no particular 3arning. I
am shaky, a little dilated in the eyes, and there is a modest depersonali6ation 'reminding me of !S;-. "ime might be slightly slo3ed, and there is a mild
ata/ia in the legs. A couple of hours later, all effects are going a3ay fast. I ate an apple, but maybe my mouth didn7t 3ork Fuite right. "he apple 3as
incredibly noisy.
'3ith 0$ mg- I am up to a $ (8$ plus at something after t3o hours, 3ith no apparent visuals, no push, no erotic. And a fe3 hours later it is Fuietly slipping
a3ay. It felt completely safe, and 3ithout any conspicuous psychedelic action, at least at this level.
'3ith &, mg- I took graded doses of (, milligrams every thirty minutes for a total of &, milligrams, and there 3ere no effects at all.
'3ith &, mg- In the middle of this all, I found myself getting into abstract thinking, and maybe some imagery as 3ell. "he effects 3ere disappointingly
light.
'3ith 2& mg- "his 3as eFual to some3here bet3een 2& and (,, micrograms of !S;. I 3as caught up 3ith the imagery, and there 3as an overriding
religious aspect to the day. "he e/perience had an esthetic value. I liked it.
<="<5SI95S A5; C9??<5"A:>E ;??;A 3as the first of the tetrao/ygenated amphetamine derivatives that 3as ever e/plored in man, back in
(%1$. And it is not easy to find an acceptable single phrase to describe its action or an acceptable number to describe its potency. I have put the value
of (, mescaline units '?.4.- into the literature and this 3ould imply that maybe 0, milligrams 3as an active dose. "his is probably too lo3, and some
day I 3ould like to run an e/periment 3ith the entire research group 3ith this compound to see Gust 3hat it really does.
"he essential oil that corresponds to ;??;A is, of course, apiole from the 9il of Parsley, 3hich again ties together the spice 3orld and the
amphetamine 3orld. And there is isoapiole, also a natural thing. "his pair represents the ring@substitution pattern of one of the ten essential oils and
;??;A is one of the ten essential amphetamines.
Several people have asked me 3hat I thought about the potential activity of a compound 3ith a methyl group added to ;??;A. 9ne of these
possibilities 3ould be the 5@methylated derivative, $,&@dimetho/y@5@methyl@0,+@methylenedio/yamphetamine, or ?<"H>!@;??;A 'or ;??;?A for the
dimetho/y@methylenedio/y@methamphetamine nomenclature-. It is a ?;?A analogue, and is described in the recipe for ?<"H>!@??;A@$.
"he placement of an added methyl group onto the beta@position of ;??;A, rather than on the nitrogen atom, produces a pair of stereoisomeric
homologues. "hese are the threo@ 'or@trans@- and erythro@ 'or cis-@$,&@dimetho/y@beta@methyl@0,+@methylenedio/yamphetamines. "hey have never
been assigned trivial names 'my original codes for them 3ere S@(+%& and S@(+%1 3hich is not too intuitively informative-. "heir chemically proper
names 3ould have the $@amino@0@substituted phenylbutane form. "he synthesis of these ;??;A homologues started 3ith the reduction of the
nitrosyrene to the ketone 'see under ?<"H>!@??;A@$ for this preparation-, follo3ed by methylation 3ith fresh sodium isopropo/ide and methyl iodide,
to give the beta@methyl product. "his formed the t3o possible o/imes, one 3ith a mp of ($, deg C, and the other from ?e9H 3ith a mp of (+1 deg C.
"he ($, deg C o/ime, 3ith fresh sodium etho/ide gave threo@$@amino@0@'$,&@dimetho/y@0,+@methylenedio/yphenyl-butane hydrochloride. "his salt had
a mp of $+2@$+% deg C. "he (+1 deg C o/ime gave erythro@$@amino@0@'$,&@dimetho/y@0,+@methylenedio/yphenyl-butane hydrochloride 3ith a mp of
())@()% deg C. "he threo@isomer sho3ed a possible threshold effect at ), milligrams, 3ith hyperventilation and perhaps some mental muddiness. "he
erythro@isomer sho3ed no effects, but it had been taken up only to (, milligrams.
"he only other beta@methyl homologue of an active material that 3as e/plored chemically, 3as related to ?;A. "he ketone '0,+@piperonylacetone, see
under ?;?A- 3as methylated 3ith sodium isopropo/ide and methyl iodide, and a crystalline o/ime 3as obtained. :eduction 3ith An dust gave 3hat
appeared to be $@amino@0@'0,+@methylenedio/yphenyl-butane hydrochloride, but there 3ere sufficient uncertainties 'possible dimethylation, only one
o/ime isolated, the need of strong reducing conditions- that the entire proGect 3as placed in, and still is in, an indefinite holding pattern. "he similar
analogues for ;9? are the t3o Classic !adies, ;APH5< and <!MI:A, and they, too, are for some time in the future.
#)4 0MM0A-$; $,'-0"METH%+Y-(,)-METHYE#E0"%+YAM,HETAM"#E
;9SAC<E about &, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith &, mg- I am into it; it is much like ?;A.
<="<5SI95S A5; C9??<5"A:>E "his is pretty sparse information upon 3hich to build a picture of biological activity. Birst, the synthesis 3as done
by someone else and, as I have not been able to find 3here the notes are, this 3ill be the one recipe in the footnote 3ithout e/plicit directions
incorporated. "he procedure used 3as e/actly the same as that described for ;??;A, e/cept that the starting material 3as dillapiole rather than
apiole. "he dillapiole 3as obtained by the careful fractionation of 9il of ;ill 'as opposed to the isolation of apiole from the careful fractionation of 9il of
Parsley-. Isomeri6ation to isodillapiole, nitration 3ith tetra@nitromethane to give (@'$,0@dimetho/y@+,&@methylenedio/yphenyl-@$@nitropropene, and its
reduction 3ith !AH in ether to give $,0@dimetho/y@+,&@methylenedio/yamphetamine hydrochloride ';??;A@$- proceeded in a precisely analogous
manner to the preparation of ;??;A.
And the pharmacological part is rather thin as 3ell. I 3as not the taster, and can only Fuote 3hat I had been given. "his same observer found a
threshold at $) milligrams. 4nder other circumstances, this comment on ;??;A@$ 3ould have been tucked into the commentary on ;??;A 3here it
belongs, but the activity level 3as called for in a large revie3 article, and on the basis of the above, both its initials and the value of &/ the potency of
mescaline 3ere permanently enshrined in the published literature. Ihat is it really likeH I don7t kno3. Its structure is an appealing amalgamation of that
of ??;A and ??;A@$, and it might be Fuite a 3inner if the dosage and the duration 3ere kno3n. It is, after all, one of the ten essential amphetamines,
since dillapiole is one of the ten essential oils.
At the time that ;??;A and ;??;A@$ 3ere synthesi6ed, I had visions of doing the same thorough study 3ith these as I had set up 3ith the "?A7s 'si/
possible, si/ done- and the ??;A7s 'si/ possible, five done-. Here, too, 3ith a pair of metho/y groups on an amphetamine skeleton, 3ith a
methylenedio/y ring thro3n in, si/ isomers are possible but only these t3o have been prepared. "he unkno3n ones 3ill certainly be called ;??;A@0,
@+, @& and @1, but the assignments of code to structure haven7t even been thought out yet. "he remarkable and totally une/pected activity of ;9? 3as
discovered at about this time and it 3as a much more tempting direction to follo3. "he remaining four possible ;??;A7s have been left to that famous
time, a future :rainy day.

#15 0M,EA; ',(-0"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of 00 g 0,+@dimetho/yben6aldehyde in (+, m! acetic acid 3as treated 3ith $0 m! nitromethane and ($.& g anhydrous
ammonium acetate, and heated on the steam bath for +& min. "o this there 3as slo3ly added, 3ith good stirring, 0,, m! H$9, and the resulting solids
3ere removed by filtration. "he product 3as finely ground under a small amount of ?e9H, filtered again, and air dried to give (0.& g 0,+@dimetho/y@
beta@nitrostyrene 3ith a mp of (+$@(+0 deg C.
"o a stirred suspension of ($., g !AH in &,, m! anhydrous <t$9 that 3as at a gentle reflu/ and under an inert atmosphere, there 3as added ((.+& g
0,+@dimetho/y@beta@nitrostyrene by leaching it from a thimble in a modified So/hlet condenser. "he addition took $ h and the reflu/ing 3as maintained
for another (1 h. After cool@ing to room temperature, the e/cess hydride 3as destroyed by the cautious addition of &,, m! (.& 5 H$S9+. "he phases
3ere separated, and to the aFueous phase there 3as added $&, g potassium sodium tartrate. "he pH 3as brought to U%, and the clear solution 3as
e/tracted 3ith 0/(,, m! CH$Cl$. :emo@val of the solvent from the combined e/tracts under vacuum gave &.$ g of a pale yello3 oil. "his 3as dissolved
in 0,, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas, giving &., g of a slightly sticky off@3hite solid. "his 3as recrystalli6ed from 2& m! of
boiling CH0C5 to give 0.0 g 0,+@dimetho/yphenethylamine hydrochloride ';?P<A- as beautiful 3hite crystals.
;9SAC<E greater than (,,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith &,, mg- 5othing.
'3ith (,,, mg- 5othing.
'3ith (, mg i.v.- :5othing.
'3ith (,,, mg of 0,+@dimetho/yphenylacetic acid, a maGor human metabolite of ;?P<A- :5othing.
'3ith &,, mg of 5@acetyl@0,+@dimetho/yphenethylamine, a maGor human metabolite of ;?P<A- :5othing.
<="<5SI95S A5; C9??<5"A:>E Ihy all the interestH Ihy keep pursuing a compound that is so obviously 3ithout activityH 9r a metabolite that is
also 3ithout activityH "he ans3er is that these are totally fascinating compounds Gust because they have no activityO .y the 3ay, in this instance, I
actually made up most of the Fuotations. I am not sure that the subGects actually said, N5othing,N but they did report that there 3ere no effects. In my
o3n e/periments, my notes record the phrase, N5o effects 3hatsoever.N
A little backgroundE one of the transmitter heavy3eights in the brain is dopamine. ;opamine is called dopamine because it is an amine that comes from
an amino acid that is 0,+@dihydro/yphenylalanine and this, in Cerman, is ;i@9/o@Phenyl@Alanine, or ;9PA. "he levo@optical 'or !@- isomer of ;9PA has
rather cutely been called the punch@drunk Spanish matador, or <l ;opa. .ut that is not part of the story.
"he story is really about the NPink Spot of Schi6ophrenia.N ?any years ago, an observation 3as made in a biochemical laboratory on the <ast Coast that
stirred up a rolling controversy. It had been found that if the urines of schi6ophrenic patients 'sloppily called Nschi6ophrenic urinesN- 3ere e/tracted in
such and such a 3ay, and the e/tracts chromatographed, a pink spot 3ould develop at a particular place on the chromatogram. Iell, if this proved to be
true 3ith urines of a sick population, and 3ere this proved to be different from the urines of a healthy population, it 3ould constitute an obGective
diagnosis of schi6ophrenia. A simple chemical test to confirm a pathology that had defied all efforts to achieve consensus amongst the psychiatrists of
the 3orld.
"he literature 3as suddenly filled 3ith do6ens of papers. :esearcher A confirmed that the pink spot 3as found 3ith schi6ophrenics, and not 3ith normal
controls. :esearcher . found the pink spot in all urines, regardless of pathology. :esearcher C found it in no urines at all. :esearcher ; argued that it
3as a factor from the hospital diet. :esearcher < found that the pink spot reflected the time of day that the urine sample 3as collected. :esearcher B
dre3 a conclusion about 3here truth might lie by tallying the number of papers that supported argument A, ., C, ;, or <.
"he only confirmable fact that endured 3as that the pink spot 3as due to ;?P<A. So a bright spotlight 3as directed to3ards its possible role in mental
illness. And this e/pressed itself in the simple FuestionE 3ould it produce schi6ophrenia in a normal subGectH 5o. And in a 3ay I am comforted that that
did not evolve into a simple litmus test for a schi6ophrenic diagnosis. "here are so many cultural, political, and social factors that come to bear on the
assignment of a diagnosis of mental illness, that I 3ould have been forever skeptical of a neat biochemical marker.
A chemical modification of ;?P<A that has been e/plored in this Fuestion of pink spots, mental pathology, and diagnostic markers, is the corresponding
acetamide. 9ne of the metabolites of ;?P<A 3as found to be the 5@acetyl deriva@tive, 5@acetyl@0,+@ dimetho/yphenethylamine. It 3as found to be
demethylated in man, and to have pharmacological activity in animals. ?aybe this 3as the active compound that could be involved in the schi6ophrenic
process. .ut human trials 3ith it, as 3ith the principal metabolite 0,+@dimetho/yphenylacetic acid, sho3ed nothing at all in man.
Another chemical modification is the beta@hydro/y analogue of ;?P<A. It has been e/plored separately, and is the subGect of its o3n recipe, in its o3n
rights. See ;?<.
Pink 3as not the only colorful spot associated 3ith schi6ophrenia. Some3here at about this same time, a research paper from Canada reported the
observation of a mauve spot in the chromatographic analysis of urines of schi6ophrenic patients. "his had nothing to do 3ith ;?P<A. I 3as 3orking
closely 3ith a researcher at the psychiatric institute and 3e 3ere fascinated by, again, a possible diagnostic marker. Ie assayed the urines of the ne/t
(, patients being admitted as acute schi6ophrenics. 5o trace of mauve. Ie 3rote to Canada, and verified the analytical procedure. Ie 3ere told that
the 3hat6is should have been added after, rather than before, the 3hosey, and that 3e should have heated for 0,, not (, minutes. 9kay. Ie assayed
the urines of the ne/t (, patients being admitted using these ne3 directions. 5o trace of mauve. Another call to Canada, and 3e 3ere informed that 3e
still 3eren7t doing it right. "hey 3ere consistently batting a (,,K positive correlation bet3een mauve spots and schi6ophrenics, and ,K 3ith healthy
controls. In fact, they actually gave this positive test the name of a disease, ?alvaria.
"hen, that little burst of insightO AhaO Ihat if, Gust 3hat if, they had been seeing something given to their schi6ophrenicsH Chlorproma6ine 3as the
popular treatment of the day. Ie took a 3hopping dose of chlorproma6ine, and over the ne/t couple of days did manage 'barely- to collect our urine
samples. .oth of us 3ere positive ?alvariansO And three days later, 3e 3ere again negative. Ie 3ere most likely seeing a metabolite of
chlorproma6ine. 9ne last call to Canada 3ith the ultimate Fuestion L had you given any medication to your schi6ophrenics before your urine analysisH
9f course 'came the ans3er- L it 3ould not be ethical to leave them untreated. Another color do3n the drain, and still no obGective measure for mental
illness.
.y the 3ay, I cannot say I like the chlorproma6ine trip. "here is no real communication either 3ith others or 3ith yourself, 3ith that stuff. >ou are a
6ombie, but if you are both schi6ophrenic and a 6ombie, you cannot possibly be troublesome for anybody in the emergency room.

#11 0%AM; $,)-0"METH%+Y-(-&n--AMYAM,HETAM"#E
S>5"H<SISE A solution of ((, g p@dimetho/yben6ene and (,$ g valeric acid in (1) g polyphosphoric acid 3as heated on the steam bath for 0 h, giving
a deep red homogeneous solution. "his 3as poured into ( ! H$9 3ith good stirring. "he strongly acidic, cloudy suspension 3as e/tracted 3ith 0/$,,
m! CH$Cl$, the e/tracts pooled, 3ashed 3ith +/(&, m! &K 5a9H, and finally once 3ith dilute HCl. "he solvent 3as removed under vacuum, and the
residual amber oil cooled overnight at , deg C. Some 0, g of crystalline, unreacted dimetho/yben6ene 3ere removed by filtration, and the )& g of
residual oil distilled at the 3ater pump. Another (& g of di@metho/yben6ene came over as an early cut, but the fraction boil@ing at ()+@(%$ deg C 'mostly
())@(%$ deg C- 3eighed &0., g and 3as reasonably pure $,&@dimetho/yamylophenone. "he reaction of the acid chloride of valeric acid 3ith p@
dimetho/yben6ene and anhydrous AlCl0 in CH$Cl$ 'parallel to the preparation of the butyrophenone analog, see ;9.4- gave an inferior yield '$0.$ g
from %$ g dimetho/yben6ene-, but did provide a si6eable sample '($.$ g- of $@hydro/y@&@metho/yamylophenone from the basic 3ashes of the crude
reaction mi/ture. "his pale yello3 solid, after recrystalli6ation from ?e9H, had a mp of 1$@1$.& deg C. Anal. 'C($H(190- C,H.
"o 01, g mossy 6inc there 3as added a solution of 2.$ g mercuric chloride in $,, m! 3arm H$9, and this 3as s3irled periodically for $ h. "he H$9 3as
drained off, and the amalgamated 6inc added to a $ ! three@neck round@bottomed flask, treated 3ith $,, m! concentrated HCl, and heated 3ith an
electric mantle. A solution of &0., g of $,&@dimetho/yamylophenone in (,2 m! <t9H containing 0, m! concentrated HCl 3as added drop@3ise over the
course of + h accompanied by 00, m! of concentrated HCl added batch3ise over this same period. "he mi/ture 3as held at reflu/ overnight and, after
cooling, diluted 3ith sufficient H$9 to allo3ed CH$Cl$ to be the lo3er phase. "he phases 3ere separated, and the aFueous phase 3as e/tracted 3ith
$/$,, m! additional CH$Cl$. "hese organic phases 3ere combined, 3ashed first 3ith &K 5a9H and then 3ith H$9, and the solvent removed under
vacuum. ;istillation at the 3ater pump yielded t3o fractions. "he first distilled from about (,,@(0, deg C, 3eighed ).) g, had a faint smell of apples and
fennel, and 3as free of a carbonyl group in the infra@red. It proved to be only &,K pure by CC, ho3ever, and 3as discarded. "he maGor fraction 3as a
pale amber oil distilling bet3een (&$@(2, deg C and 3as substantially free of smell. It 3eighed ().% g, and 3as 'by CC- %,K pure $,&@dimetho/y@'n-@
amylben6ene.
A mi/ture of 01.0 g P9Cl0 and +,.% g 5@methylformanilide 3as allo3ed to incubate for ,.& h. "o this there 3as then added ().& g of $,&@dimetho/y@'n-@
amylben6ene and the mi/ture heated on the steam bath for $ h. "his mi/ture 3as poured into a large Fuantity of H$9 and stirred overnight. "he black
oily product 3as e/tracted 3ith 0/(,, m! CH$Cl$, and the e/tracts combined and stripped of solvent under vacuum. "he black residue 3as distilled at
(),@$,& deg C at $, mm8Hg to give ($.& g of a pale amber oil that slo3ly set up to a crystalline mass. An analytical sample 3as recrystalli6ed from
?e9H to provide $,&@dimetho/y@+@'n-@amylben6aldehyde 3ith a mp of $&@$1 deg C. Anal. 'C(+H$,90- H; CE calcd, 2(.(1E found, 2(.%$, 2(.2+.
A solution of ($.0 g $,&@dimetho/y@+@'n-@amylben6aldehyde in &, m! acetic acid 3as treated 3ith +., g anhydrous ammonium acetate and ($ m!
nitroethane. "his mi/ture 3as heated on the steam bath for + h, then poured into a large Fuantity of H$9. "his 3as e/tracted 3ith 0/$,, m! CH$Cl$,
the e/tracts 3ashed 3ith H$9, and the solvent removed to give a deep red oil that, on standing in the refrigerator, slo3ly set to a crystalline mass
3eighing (0.& g. An analytical sample 3as recrystalli6ed from ?e9H to provide (@'$,&@dimetho/y@+@'n-@amylphenyl-@$@nitropropene as fine yello3
microcrystals 3ith a mp of ++ deg C sharp. Anal. 'C(1H$059+- C,H,5.
"o a gently reflu/ing suspension of (, g !AH in &,, m! anhydrous <t$9 under a He atmosphere, there 3as added by (0.$ g (@'$,&@dimetho/y@+@'n-@
butyl@phenyl-@$@nitropropene by allo3ing the condensing ether drip into a So/hlet thimble containing the nitrostyrene 3hich effectively added a 3arm
saturated solution of it drop3ise to the reaction mi/ture. :eflu/ing 3as maintained for () h, and the cooled reaction flask stirred for several additional
days. "he e/cess hydride 3as destroyed by the cautious addition of ( ! )K H$S9+. Ihen the aFueous and <t$9 layers 3ere finally clear, they 3ere
separated, and the aFueous layer 3as 3ashed 3ith an additional $/(,, m! <t$9. :emoval of the solvent from the organic phase and 3ashings
provided +.2 g of a thick red oil that 3as discarded. "he aFueous phase 3as then e/tracted 3ith $/$,, m! CH$Cl$ 3hich actually removed the product
as the sulfate salt. "his organic phase 3as 3ashed 3ith $/(,, m! &K $C90 'removing the H$S9+- and 3ith the evaporation of the solvent there 3as
obtained 1.$ g of an oily amber residue. "his 3as dissolved in $,, m! <t$9 and saturated 3ith anhydrous HCl gas. Bine 3hite crystals of $,&@
dimetho/y@+@'n-@amylamphetamine hydrochloride ';9A?- separated, 3ere removed by filtration, <t$9@3ashed and air dried, and 3eighed &.$ g. "he
mp of (01@(0% deg C 3as increased to (+&@(+1 deg C by recrystalli6ation from CH0C5. Anal. 'C(1H$)Cl59$- C,H,5.
;9SAC<E greater than (, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (, mg- "here 3as a clear threshold that in no 3ay interfered 3ith my day7s activities. I 3as Fuite gay and voluble at
lunch and bubbled on into the afternoon 3ith puns and high spirits. "here may have been a little motor incoordination as noted in hand3riting, and there
3as a strange tenseness during driving. "here 3ere no seFuelae, there 3as no trouble sleeping, and 3ith this potency 3ay do3n from the lo3er
homologues, I have no pressing desire to take this compound to a higher dose.
<="<5SI95S A5; C9??<5"A:>E "he actual procedure that 3as published for the isolation of this final amine 3as a different one, one that 3ould
certainly 3ork, but 3hich 3as based on the procedures tried and proven 3ith the lo3er homologues. "he process described above is Gust a bit bi6arre 'a
sulfate salt e/tracting into methylene chloride- but it 3as the actual thing that 3as done. "he 3ork 3as started to3ards t3o additional compounds but
these never got past the first Nketone and phenolN stage. p@;imetho/yben6ene 3as brought into reaction 3ith n@caproic acid 3ith polyphosphoric acid
'aiming to3ards $,&@dimetho/y@+@'n-@he/ylamphetamine, ;9H<- but this 3as dropped 3hen ;9A? proved to be do3n in potency. And the reaction
bet3een p@dimetho/yben6ene and ben6oyl chloride 3ith anh. aluminum chloride 3ent 3ell 'aiming to3ards $,&@dimetho/y@+@ben6ylamphetamine,
;9.A-. A goodly amount of the phenol '$@hydro/y@&@metho/yben6ophenone- 3as obtained as fine yello3 crystals, but this line of inFuiry 3as also
dropped.
"he preparation of ;9A? 3as, as a matter of fact, the last of the homol@ogous series of compounds actually completed, 3hich stemmed from the
original discovery of ;9?. "he N"en Classic !adiesN concept 3as mentioned under A:IA;5<, and the adding of a methyl group in the place of a
hydrogen atom at the +@position@methyl led to the synthesis of ?s. H<CA"< and gave rise to ;9<". "he 3hole series of methyl@ethyl@propyl@butyl@amyl
compounds 3as appealing to me, in that the potency seemed to increase initially as the chain got longer, and then it abruptly dropped off. Iouldn7t it be
nice, I thought, if I could interest some pharmacologist in looking at this tight set of drugs 3ith some animal model, to see if there is some
neurotransmitter activity that 3ould sho3 a parallel action.
I learned of a curious young researcher in Iashington 3ho had an elegant procedure for measuring serotonin agonist action using the 'other3ise-
discarded sheep umbilical artery strips. "hese become available each year at lambing time, do not cost the life of anything, and reFuire very little
compound. He assayed my compounds and, lo and behold, the serotonin activity also 3ent through a ma/imum in the middle of this series. Ie
published a short paper to this effect, 3hich served as a e/cellent vehicle to get the cogent human data into the scientific literature.
I have never understood the reasons that there might be connection bet3een the t3itching of a umbilical artery in a sheep and the appearance of an
insight in the mind of man. And, I have never personally met this pharmacologist. Some day, I hope to do both.
#1$ 0%.; $,)-0"METH%+Y-(-.*%M%AM,HETAM"#E
S>5"H<SISE "o a 3ell@stirred solution of (.%& g of the free base of $,&@dimetho/yamphetamine '$,&@;?A- in ($ m! glacial acetic acid, there 3as added
(.) g elemental bromine dissolved in + m! acetic acid over the course of & min. "he slightly e/othermic reaction 3as allo3ed to stir for 0 h, and then
added to about $,, m! H$9. "he cloudy solution 3as 3ashed 3ith $/(,, <t$9, made basic 3ith aFueous 5a9H, and e/tracted 3ith 0/(,, m!
CH$Cl$. <vaporation of the solvent from the pooled e/tracts gave about 0 m! of a pale amber oil 3hich 3as dissolved in $&, m! anhydrous <t$9 and
saturated 3ith anhydrous HCl gas. "he fine 3hite crystals of $,&@dimetho/y@+@bromoamphetamine hydrochloride, ;9., 3ere removed by filtration, <t$9
3ashed, and air dried. "hese 3eighed (.2 g and had a mp of (%&@(%1 deg C. :ecrystalli6ation from IPA brought this up to $,2@$,) deg C. Proton 5?:
spectroscopy of the hydrochloride salt in ;$9 gave confidence that the bromine atom had uniFuely entered the +@position, in that there 3ere only t3o
unsplit aromatic hydrogen atoms present, at 1.%2 and at 2.$, ppm do3nfield from e/ternal "?S.
;9SAC<E (., @ 0., mg.
;4:A"I95E () @ 0, h.
L4A!I"A"IM< C9??<5"SE '3ith ,.+ mg- "here 3as a distinct enhancement of visual perception, and some strengthening of colors. A clean, cold
feeling of 3ind on the skin. I felt an enriched emotional affect, a comfortable and good feeling, and easy sleeping 3ith colorful and important dreams.
'3ith $., mg- "here 3as a continuous tremor at the physical level, and an incredible ?oebius strip representation of reality at the intellectual level. I 3as
able to enter into personal problems easily, and get out again 3hen I chose to. ;uring the ne/t day, there 3ere brief lapses of attention, or little fugue
states, and it 3as not until the follo3ing evening that I 3as completely myself again.
'3ith $.) mg- About three hours into this I had a severe cramp, and had a near fainting response to the pain, and yet there 3as no painO I felt that I 3as
very near a loss of consciousness, and this 3as most disturbing. "here 3ere flashes of depersonali6ation. I sa3 rings around the moon 3ith prismatic
colors, and there 3ere long@lasting Nafter@imagesN follo3ing any vie3ings of points of light. I 3as still a good plus ( at (+ hours, but did manage to sleep.
It 3as the ne/t day before I 3as again at baseline.
'3ith 0., mg- "his 3as a comple/, but a very good day. It involved making a large pot of chicken@vegetable soup, and listening to H.!., my favorite
Saturday morning fundamentalist Christian radio preacher, bless "im. "he ;emocrats are not e/actly all anti@American dupes of ?osco3 'or the ;evil-,
but to H.!., they are practically, almost, ne/t@door to it. "he :apture is supposed to happen tomorro3 according to a certain book, ne3ly published 'Gust
in time, looks like- and he is busy softening the possible disappointment of those 3ho may find themselves unchanged ?onday morning. Iunnerful. It7s
been one heck of a good e/periment, and I can7t understand 3hy 3e 3aited nine years to try this gorgeous stuff. Iithout going into the cosmic and
delicious details, let7s Gust say it7s a great material and a good level.
'3ith ,.& mg of the N:N isomer- I am under3ay, and this is a smooth into/ication. I am completely functional, but still really a plus t3o. I 3ould not
choose to drive a car. 5ot very far. I felt a rather Fuick dropping to a plus@one at the fifth hour, but there is a residual stimulation still the follo3ing
morning.
'3ith (., mg of the N:N isomer- .y the fourth hour I am absolutely a *** and am searching the kitchen for food. .ut 3hat I eat is only so@so. "here is
not the introspection or intensity of $., milligrams of the racemate material, but this is a re3arding place nonethless. At the ()th hour, there 3as some
fitful sleep, 3ith bi6arre dreams. "he ne/t day I 3as still hungry for altered spaces, and successfully challenged the residual plus one 3ith !S; and, as is
usually the case, acid cut right through the detritus and allo3ed a direct shot up to a *** again.
'3ith (.& mg of the N:N isomer- "his is a *** but it is vaguely irrational. I feel a heavy body load, but then the temperature outside is over a hundred
degrees and I may not be in the best of all physical environments. I 3ould not 3ish any higher dosage. "here 3ere cat@naps at the t3elth hour, but
most symptoms 3ere still there at the ()th hour. A good e/perience. It 3ould be interesting to compare this, some day, 3ith 0., milligrams of the
racemate.
'3ith ,.& mg of the NSN isomer- "here are no effects at all.
'3ith (., mg of the NSN isomer- "here is something 3arm and nice at a couple of hours into this, but I am no more than threshold, and the effects are
very slight. .y the fifth hour there are no longer any effects.
<="<5SI95S A5; C9??<5"A:>E "he stars had clearly lined up in favor of making ;9. and e/ploring its biological activity. "his preparation had
been completed in (%12 and the report of this compound and its unprecedently high potency published in (%2(. And very shortly, t3o additional papers
appeared completely independently. 9ne described ;9. made via a different route, and describing high activity in rats. "he other described ;9. and a
couple of closely related brominated amphetamines and their action in man.
"his is one of the last of the e/perimental compounds 3ithin the phenethylamine family on 3hich any animal to/icity studies 3ere performed by me prior
to human studies. A mouse inGected 3ith &, mg8g 'ip- sho3ed considerable t3itching and 3as irritable. Another, at (,, mg8g 'ip-, had overt shaking
at $, minutes, 3hich evolved into persistent hyperactivity that lasted several hours. >et another, at ($& mg8g 'ip-, lost much of her righting refle/ 3ithin
(& minutes, entered into convulsions at &, minutes, and 3as dead a half hour later. A fourth mouse, at (&, mg8g 'ip-, entered into spontaneous
convulsions 3ithin (, minutes, and e/pired in 3hat looked like an uncomfortable death at $$ minutes follo3ing inGection. Ihat 3as learnedH "hat the
!;8&, 3as some3here bet3een (,, and ($& mg8g for the mouse. And an effective dose in man of maybe $ mg 'for an ), g man- is eFuivalent to $&
ug8g. "herefore the inde/ of safety 'the therapeutic inde/, the lethal dose divided by the effective dose- is 3ell over a thousand. I feel that t3o mice
3ere killed 3ithout anything of value having been received in return.
Actually, it is very likely that the damaging, if not lethal, level of ;9. in man is a lot lo3er than this ratio 3ould imply. "here 3as a report of a death of a
young lady follo3ing the snorting of an amount of ;9. so massive, there 3as the actual recovery of over nine milligrams of the drug from her body
tissues in the post@mortem e/amination. It 3as said that she and her companion had thought that the drug they 3ere using 3as ?;A and, taking a
dosage appropriate for this, effectively overdosed themselves. He survived, follo3ing convulsions and an e/tended period 'several 3eeks- of being in a
comatose state. "ragic e/amples have been reported that involve arterial vascular spasm. .ut in most overdose cases ascribed to ;9., the identity of
the drug has remained unestablished.
As 3ith ;9I, the presence of a heavy atom, the bromine atom, in ;9. makes the radioactive isotope labelled material a po3erful research tool. Studies
3ith ;9. labelled 3ith either )$.r or 22.r have been used in human subGects to follo3 the distribution of the drug. "he use of a 3hole body scanner
permits the imaging of the intact body, 3ith the travelings of the radioactivity easily follo3ed from outside. A fascinating finding is that ;9. goes first and
foremost to the human lung 3here it accumulates for a couple of hours. It is only after3ards that the brain level builds up. "here is a strong implication
that some metabolic conversion occurs in the lung, and it is only after this that the truly active metabolite is available for central action. "his is consistent
3ith the relatively slo3 onset of effect, and the very long duration of action.
As 3ith all the other psychedelics 3hich can and have been studied as their optical isomers, it is the N:N isomer of ;9. that is the more active than the
racemic mi/ture, and the NSN is certainly much less active, but it has never been run up to fully active levels. "he alpha@ethyl homologue of ;9. is
mentioned under A:IA;5<. "he positionally rearranged isomers of ;9. are discussed under ?<"A@;9..

#1' 0%./; $,)-0"METH%+Y-(-&n--./TYAM,HETAM"#E
S>5"H<SISE A 3ell stirred suspension of (+, g anhydrous AlCl0 in +,, m! CH$Cl$ 3as treated 3ith (,$ g butyryl chloride. "his mi/ture 3as added in
small portions, over the course of $, min, to a 3ell@stirred solution of ((,.+ g p@dimetho/yben6ene in 0,, m! CH$Cl$. After an additional ( h stirring, the
mi/ture 3as poured into ( ! H$9, and the t3o phases separated. "he aFueous phase 3as e/tracted 3ith $/(,, m! CH$Cl$, and the organic fractions
pooled. "hese 3ere 3ashed 3ith +/($& m! &K 5a9H 3hich removed both unreacted butyric acid as 3ell as a small amount of $@hydro/y@+@
metho/ybutyrophenone. :emoval of the CH$Cl$ under vacuum gave (&1.2 g of a residue that 3as distilled at (2,@(2) deg C at the 3ater pump. "he
isolated $,&@dimetho/ybutyrophenone 3as a pale yello3 oil that 3eighed (+1 g and 3as about )&K pure by CC analysis. "he principal impurity 3as
unreacted dimetho/yben6ene. "he identical preparation 3ith CS$ as a solvent, rather than CH$Cl$ gave a some3hat smaller yield of product.
"o (&, g mossy 6inc there 3as added a solution of 0 g mercuric chloride in 1, m! H$9, and this 3as s3irled periodically for $ h. "he H$9 3as drained
off, and the amalgamated 6inc added to a ( ! three@neck round@bottomed flask, treated 3ith ), m! concentrated HCl, and heated on the steam bath. A
solution of $,.) g of $,&@dimetho/ybutyrophenone in +& m! <t9H containing (, m! concentrated HCl 3as added in increments over a + h period.
;uring this period an additional (+, m! of concentrated HCl 3as added periodically to the ketone solution. Heating 3as maintained for an additional +
h. After cooling, the aFueous filtrate 3as e/tracted 3ith 0/(,, m! CH$Cl$ and these pooled e/tracts 3ashed 3ith $/$,, m! &K 5a9H to remove a
small amount of phenolic impurity. After removal of the solvent under vacuum, the residual (1.( g of clear oil 3as distilled over the (,,@(1, deg C range
'largely at (+(@(+& deg C- at the 3ater pump to give (, g of $,&@dimetho/y@'n-@butylben6ene as a 3hite oil. "his 3as about %,K pure by CC analysis,
and 3as used 3ithout further purification in the ne/t step.
A mi/ture of %) m! P9Cl0 and (,) m! 5@methylformanilide 3as allo3ed to incubate for ,.& h. "o this there 3as then added +2.0 g of $,&@dimetho/y@'n-@
butylben6ene and the mi/ture heated on the steam bath for (.& h. "his mi/ture 3as poured into ( ! H$9 and stirred overnight. "he H$9 3as drained
from the e/tremely gooey black crystals that 3ere formed, and e/tracted 3ith $/(,, m! portions of he/ane. "he black residue 3as diluted 3ith these
e/tracts and, on slo3 evaporation there 3as deposited $1.+ g of oily amber crystals. Biltering these through a medium porous funnel and sucking the oily
phase a3ay from the solids yielded (+.) g of yello3 crystals that could be recrystalli6ed from &, m! ?e9H to give, after filtration and air drying to
constant 3eight, 1.+ g of $,&@dimetho/y@+@'n-@butylben6aldehyde as pale yello3 crystals 3ith a mp of +2@+) deg C. "he recovery of all organic soluble
things from the above process gave, after removal of the e/traction solvents and making boiling he/ane e/tractions of the residues, a second crop of
aldehyde of eFual 3eight and of identical mp. An analytical sample, from he/ane, had the same mp. Anal. 'C(0H()90- C,H.
A solution of (0.$ g $,&@dimetho/y@+@'n-@butylben6aldehyde in &, m! acetic acid 3as treated 3ith +., g anhydrous ammonium acetate and (, m!
nitroethane. "his mi/ture 3as heated on the steam bath for + h, then poured into a large Fuantity of H$9. "his 3as e/tracted 3ith $/$,, m! CH$Cl$,
the e/tracts 3ashed 3ith H$9, and the solvent removed to give (% g of a deep red oil. "his 3as dissolved in 0& m! hot ?e9H and slo3ly cooled,
depositing yello3@orange crystals. "hese 3ere removed by filtration, 3ashed 3ith cold ?e9H, and air@dried to constant 3eight. "hus there 3as
obtained ((.) g of (@'$,&@dimetho/y@+@'n-@butylphenyl-@$@nitropropene 3ith a mp of &+@&1 deg C. :ecrystalli6ation of an analytical sample from ?e9H
tightened the mp to &&@&1 deg C. Anal. 'C(&H$(59+- C,H,5.
"o a gently reflu/ing suspension of ).& g !AH in 0,, m! anhydrous <t$9 under a He atmosphere, there 3as added ((., g (@'$,&@dimetho/y@+@'n-@
butylphenyl-@$@nitropropene by allo3ing the condensing ether to drip into a So/hlet thimble containing the nitrostyrene, thus effectively adding a 3arm
saturated solution of it drop3ise. :eflu/ing 3as maintained overnight, and the cooled reaction flask stirred for several additional days. "he e/cess
hydride 3as destroyed by the cautious addition of 1,, m! H$9 containing && g H$S9+. Ihen the aFueous and <t$9 layers 3ere finally clear, they
3ere separated, and $&, g of potassium sodium tartrate 3as dissolved in the aFueous fraction. AFueous 5a9H 3as then added until the pH 3as above
%, and this 3as then e/tracted 3ith 0/$,, m! CH$Cl$. <vaporation of the solvent produced ($ g of an amber oil that gelatini6ed to a 3a/y, amorphous
mass. "his 3as leached as thoroughly as possible 3ith anhydrous <t$9 3hich 3as clarified by filtration, then saturated 3ith anhydrous HCl gas. After a
fe3 minutes delay, there commenced the separation of fine 3hite crystals of $,&@dimetho/y@+@'n-@butylamphetamine hydrochloride ';9.4-. "hese
3eighed, after filtration, <t$9 3ashing, and air drying to constant 3eight, &.) g. :ecrystalli6ation from boiling CH0C5 'this is an unusually e/othermic
crystalli6ation- yielded &.+ g of a fluffy 3hite product 3ith mp (&(@(&$ deg C. Anal. 'C(&H$1Cl59$- C,H,5.
;9SAC<E uncertain.
;4:A"I95E very long.
L4A!I"A"IM< C9??<5"SE '3ith $.$ mg- It 3as almost the fourth hour before I noticed something. "hen I felt an increasing manic into/ication, 3inding
up tighter and tighter. Sleep 3as impossible until some () hours after the start of the trial. "here 3as some paresthesia, but no mydriasis. "his might
be a stimulant, but it is not a psychedelic, at least at this level. Co up slo3ly.
'3ith $.) mg- 5othing for over seven hours. "hen there 3as 3hat seemed to be an irritability and shortness of temper. ?entally I am completely clear,
but no more alert than usual. "here 3as no sleep that evening, and the ne/t day there 3as a feeling of overall depression. Perhaps that 3as due to the
lack of sleep, but there 3ere no signs of residual sleepiness.
<="<5SI95S A5; C9??<5"A:>E It is not possible to give a dosage range for ;9.4. "here is no Fuestion but that 3hatever is occurring is slo3 of
onset, and very long lived. In general, the effects resemble stimulation more that anything else.
A butyl group has four carbons, and they can be interconnected in four 3ays 'as long as you don7t connect them in rings-. If all four of them are in a
straight chain, you have the so@called normal butyl 'or n@butyl- group, and this is the e/act arrangement that is found in the ;9.4. "he atoms can be
numbered R( through R+, going out3ards from the point of attachment. "he chain can, ho3ever, be only three carbons long, and the fourth or e/tra
carbon attached on the R$ carbon atom; this is called the iso@butyl 'or i@butyl- group. 9r the e/tra left@over carbon can be attached to the R( carbon
atom; this is called the secondary butyl 'or sec@butyl or s@butyl- group. 9r lastly, the atoms can be all scrunched up, 3ith the chain only t3o carbons
long, and the other t3o left@over methyl carbons attached to the R( carbon atom. "his isomer is called the tertiary butyl 'or tert@butyl or t@butyl- group. In
animal studies, and in preliminary human studies, the activity of these compounds drops as the butyl group gets more and more scrunched.
"he isomer 3ith the iso@butyl group has been synthesi6ed by the Briedel@ Crafts reaction of isobutyryl chloride 3ith p@dimetho/yben6ene, follo3ed by
reduction of the ketone to an alcohol, dehydration to a dimethylstyrene, and final hydrogenation to a hydrocarbon. "he formation of the ben6aldehyde,
reaction 3ith nitroethane, and final lithium aluminum hydride reduction to $,&@dimetho/y@+@'$@methylpropyl-@amphetamine hydrochloride ';9I., mp (1+@
(11 deg C- 3ere completely conventional. In drug discrimination studies in rats, ;9I. 3as only a third as active as ;9?, and in humans the activity
falls in the (, to (& milligram area. "he isomer 3ith the sec@butyl group 3as made in a some3hat similar manner, from $,&@dimeth@o/yacetophenone.
"he addition of ethyl magnesium bromide gave an alcohol 3hich 3ith dehydration yielded a pair of dimethylstyrenes isomeric to the compound
mentioned above. Brom there an identical seFuence of steps 'hydrogenation, ben6aldehyde synthesis, nitrostyrene, and lithium aluminum hydride
reduction- produced $,&@dimetho/y@+@'(@methylpropyl-amphetamine hydrochloride ';9S., mp (1)@(2, deg C.-. In the rat studies it 3as only a t3elfth
the potency of ;9?, and in man the active dose is in the $& to 0, milligram area. As 3ith the normal butyl compound, there is a strong stimulation
factor, 3ith real and long@lasting sleep disturbance.
"he last of the butyl isomers, the tert@butyl compound, 3as made from a much more obvious starting material. "his is the commercially available tert@
butyl hydroFuinone. It 3as methylated in sodium hydro/ide 3ith methyl iodide, and then carried through the above seFuence 'ben6aldehyde. mp ($+
deg C from cyclohe/ane, nitrostyrene, yello3 crystals from methanol, mp %&@%1.& deg C, and lithium aluminum hydride reduction- to give $,&@dimetho/y@
+@'(,(@dimethylethyl-amphetamine hydrochloride ';9"., mp (1) deg C-. :ats trained in a process called the Sidman Avoidance Schedule gave
behavior that suggested that ;9". had no activity at all, and in human trials, doses of up to $& milligrams 3ere totally 3ithout effect.
An effort 3as made to prepare a butyl analogue containing a ring, but it 3as never completed. "his 3as the cyclopropylmethyl isomer, $,&@dimetho/y@+@
cyclo@propylmethylamphetamine hydrochloride, ;9CP?. 9nly the first step of its synthesis 3as complete 'the reaction of cyclopropylcarbo/ylic acid
chloride 3ith p@dimetho/yben6ene- and even it 3ent badly. "he desired ketone '$,&@dimetho/yphenyl cyclopropyl ketone- 3as most difficult to separate
from the recovered starting ether. A promising approach 3ould be the isolation of the phenol '$@hydro/y@&@metho/yphenyl cyclopropyl ketone- 3hich is a
beautiful yello3 solid 3ith a melting point of %%@(,, deg C from methanol. Anal. 'C((H($90- C,H. It then could be methylated to the 3anted
intermediate. It is the maGor product 3hen the reaction is conducted 3ith anhydrous aluminum chloride in methylene chloride.
"he $@carbon phenethylamine homologues of these compounds could all, in principle be easily made by using nitromethane instead of nitroethane 3ith
the intermediary ben6aldehydes. .ut, as of the present time, none of them have been made, so their pharmacology remains completely unkno3n.

#1( 0%!; $,)-0"METH%+Y-(-!H%*%AM,HETAM"#E
S>5"H<SISE A solution of 1.%1 g $,&@dimetho/yamphetamine hydrochloride '$,&@;?A- in $&, m! H$9 3as made basic 3ith aFueous 5a9H and
e/tracted 3ith 0/2& m! CH$Cl$. After removal of the solvent from the pooled e/tracts under vacuum, the residual free base 3as dissolved in 01 g
glacial acetic acid and, 3ith good stirring, cooled to , deg C 3ith an e/ternal ice bath. "here 3as then added, 3ith a Pasteur pipette, 0 m! of liFuid
chlorine. "he generation of HCl 3as evident, and the reaction 3as allo3ed to stir for an additional 0 h. "he mi/ture 3as then poured into 0,, m! H$9
and 3ashed 3ith 0/(,, m! <t$9. "he aFueous phase 3as made basic 3ith 5a9H and e/tracted 3ith 0/(&, m! CH$Cl$. After removal of the solvent
from the pooled e/tracts, the residue 3as dissolved in <t$9 and saturated 3ith anhydrous HCl gas. "here 3as the formation of a heavy oily precipitate.
"he ether supernatent 3as decanted, and the residue 3as intimately mi/ed 3ith $,, m! of fresh anhydrous <t$9. <verything set up as an off@3hite
crystalline mass 3eighing $.0 g. "his 3as dissolved in ($ m! of boiling ?e9H and diluted 3ith $0, m! boiling <t$9. "he clear solution 3as Fuickly
filtered to give a clear, pale amber mother liFuor, 3hich soon started depositing lustrous 3hite crystals. After filtering, <t$9 3ashing, and air drying to
constant 3eight, there 3as obtained (.+ g of $,&@dimetho/y@+@chloroamphetamine hydrochloride ';9C- Brom the mother liFuors 'from the original HCl
saturation- an eFual amount of product could be obtained by e/ploiting the acetone insolubility of the hydrochloride salt of the product. "he published
mp of this salt, from acetone8<t9H, is ()2@()) deg C. A sample of this hydrochloride salt, prepared from the amino analogue via dia6oti6ation and
eventual hydrolysis of an acetylated precursor, 3as recrystalli6ed from <t9H8ether and had a mp of (%0@(%+.& deg C.
;9SAC<E (.& @ 0., mg.
;4:A"I95E ($ @ $+ h.
L4A!I"A"IM< C9??<5"SE '3ith (.1 mg- I 3as hit 3ith a slightly light head; the effects 3ere Fuite real. I 3as disconnected, and someho3 spacey, but
this 3as a favorable spacey 3hich 3as kind of fun. Some3here at about the si/th hour I reali6ed that I 3as beginning to drop off a bit, but si/ hours later
yet, there 3as still a lot of memory. "his is a long thing.
'3ith $.+ mg- "his is 3hat I might call an archetypical psychedelic. <verything is there in spades, 3ith fe3 if any of the subtle graces, the Sgentle images7
and Sgentle fantasies7 of the $@carbon phenethylamines. "his is the 3orks. "here are visuals, and there are interpretive problems 3ith kno3ing Gust
3here you really are. "he place 3here nothing makes sense, and yet everything makes sense. I have Gust slept for a fe3 hours, and no3 I am a3ake
and it has been eighteen hours, and there is a lot still going on, although I have a rela/ed, good feeling. Anyone 3ho uses this had better have $+ hours
at their disposal.
'3ith $.+ mg- Here I am at the si/th hour, and I am still roaring along at a full plus three. I have established that this material is neither anti@erotic nor
anore/ic. "he body is very comfortable, and so is the mind. "here is an interesting aspect, perhaps peculiar only to this e/periment and under these
conditions. Iith my eyes closed the fantasy is a completely dark screen, lovely and seductive, subtle, and yet light must be deliberately brought in. "his
is not in any 3ay negative for being in the dark, but is Gust unusual. I 3ill have to try this in the daylight ne/t time, to see 3hat the eyes@closed brings to
the mind@screen. At $+ hours, I have found that my sleep 3as not too great. ?y dreams 3ere tight, and I kept defending against trouble; the nervous
system 3as too alert. I 3as in a good humor, though, and I still am. "his is e/cellent stuff, but start early in the day.
<="<5SI95S A5; C9??<5"A:>E It is clear that the three halo@amphetamine derivatives, ;9I, ;9. and ;9C, are all pretty much of the same
potency. And all of them very long lived. "he difference bet3een the various halogen atoms 3as brought up under the $C@C discussion. ;9C is clearly
a long@lasting, dyed@in@the@3ool psychedelic.
In the making of this, by the procedures that have been follo3ed in Canada, there are t3o chemical intermediates 3hich might, some day, be looked at
as potential psychedelics under their o3n colors. :eduction of the compound that is called ;95 in this .ook II '$,&@dimetho/y@+@nitroamphetamine
hydrochloride- 3ith Pd8charcoal and hydrogen, gives the +@amino derivative. "his is $,&@dimetho/y@+@aminoamphetamine dihydrochloride, ;9A, 3hich
melts at $+)@$&, deg C. And the reduction of an o/ime intermediate gives rise to the acetamido analogue, $,&@dimetho/y@+@acetamidoamphetamine
hydrochloride, ;9AA, 3ith a mp of $+%@$&, deg C. 5either compound has been tasted, but someday this omission 3ill be corrected. ;9A and ;9AA
have a sinister ring to them, ho3ever, and some changes of terminology might be needed. ;9A, in the coroner7s vocabulary, means ;ead@9n@Arrival.
.ut then, A?A 'the American ?edical Association- Gust happens to also mean 'in the Gargon of emergency medicine- Against@?edical@Advice. <verything
averages out, someho3. :emember that the amyl homolog 'amyl at the +@position- follo3s the +@letter convention of all of the ;9? homo@logues, and
has the code name of ;9A?. "hus, ;9A, amino; ;9AA, acetamido, and ;9A?, amyl.
9ne must learn to keep one7s sense of humor. "he immortal humorist Iavy Cravy once said, NIf you can7t laugh at life, it Gust isn7t funny anymore.N "he
code name of this compound, $,&@dimetho/y@+@chloroamphetamine is, after, all, ;9C. "his should certainly appeal to some physicians.

#1) 0%E7; $,)-0"METH%+Y-(-&$-7/%*%ETHY--
A?PH<"A?I5<
S>5"H<SISE A 3ell@stirred solution of ,.+& g free base ;9. in $ m! CH$Cl$ 3as treated 3ith ,.02 g triethylamine, cooled to , deg C, and there 3as
then added a solution of ,.0% g (,(,+,+@tetramethyl@(,+@dichlorodisilylethylene in $ m! CH$Cl$. "he reaction mi/ture 3as allo3ed to return to room
temperature, 3ith stirring continued for $ h. "he solvent 3as removed under vacuum, the residue suspended in he/ane, and the insoluble by@products
removed by filtration through celite. :emoval of the solvent under vacuum gave ,.1, g (@'+@bromo@$,&@dimetho/yphenyl-@$@'(@a6a@$,&@disila@$,$,&,&@
tetramethylcyclopentyl-propane as a gold@colored impure semi@solid mass 3hich 3as used 3ithout further purification.
"o a solution of ,.1, g (@'+@bromo@$,&@dimetho/yphenyl-@$@'(@a6a@$,&@disila@$,$,&,&@tetramethylcyclopentyl-propane in (, m! anhydrous <t$9 under an
inert atmosphere and cooled to @2) deg C there 3as added (.) m! of a (.2 ? solution of t@butyl lithium in he/ane. "he resulting yello3 solution 3as
stirred for $, min, and then treated 3ith (.1& m! of a (.+ ? solution of ethylene o/ide in <t$9, the stirring 3as continued for +, min, then the reaction
mi/ture allo3ed to come to room temperature over an additional +, min. "here 3as added $, m! he/ane, and the temperature increased to &, deg C
for an additional $ h. "he reaction mi/ture 3as treated 3ith 0 m! H$9 and diluted 3ith 1, m! <t$9. "he organic phase 3as 3ashed 3ith saturated
5H+Cl, dried over anhydrous ?gS9+, and after filtering off the inorganic drying agent, the organic solvents 3ere removed under vacuum. "he gold@
colored residual oil 3as dissolved in (, m! ?e9H and treated 3ith a (,K 9H. "his mi/ture 3as heated for 0, min on the steam bath, returned to
room temperature, and the volatiles removed under vacuum. "he residue 3as dissolved in 0K H$S9+, 3ashed t3ice 3ith CH$Cl$, brought to pH ($
3ith $&K 5a9H, and e/tracted 3ith 0/&, m! CH$Cl$. "he pooled e/tracts 3ere combined, dried 3ith anhydrous 5a$S9+, and the solvent removed
under vacuum to give ,.$+ g of $,&@dimetho/y@+@'$@hydro/yethyl-amphetamine ';9<H- as a 3hite solid 3ith a mp of (,$@(,+ deg C.
"o a suspension of ,.%+ g ;9<H in ice@cold anhydrous <t$9 containing (.+ g triethylamine, there 3as added $.+ g trifluoroacetic anhydride drop3ise
over the course of (, min. "he reaction mi/ture 3as brought to reflu/ temperature, and held there 3ith stirring for ( h. After cooling, 1, m! of CH$Cl$
3as added, and the organic phase 3ashed 3ith saturated 5aHC90. "he solvent 3as removed under vacuum, providing a gold@colored solid as a
residue. "his 3as dissolved in &, m! ?e9H, diluted 3ith 0, m! H$9 and, follo3ing the addition of ,.21 g solid 5aHC90 the reaction mi/ture 3as
stirred at room temperature for 0 h. "he e/cess ?e9H 3as removed under vacuum, and the remaining solids 3ere suspended in CH$Cl$ and 3ashed
3ith H$9. After drying the organic phase 3ith anhydrous 5a$S9+ and removal of the solvent under vacuum, there 3as obtained (.0+ g (@'$,&@
dimetho/y@+@'$@hydro/yethyl-phenyl-@$@'$,$,$@trifluoroacetamido-propane as 3hite solid 3ith a mp of ($%@(0( deg C. Anal. 'C(&H$,B059+- C,H.
A 3ell@stirred solution of ,.,% g (@'$,&@dimetho/y@+@'$@hydro/yethyl-phenyl-@$@'$,$,$@trifluoroacetamido-propane in (& m! CH$Cl$ 3as cooled to @2) deg
C and treated 3ith ,.,& g diethylaminosulfur trifluoride ';AS"- added drop3ise. "he pale yello3 reaction solution 3as stirred an additional & min and
then brought up to room temperature and stirred for ( h. "here 3as then added 'cautiously- 0 m! H$9 follo3ed by additional CH$Cl$. "he phases
3ere separated, the organic phase 3ashed 3ith H$9, dried 3ith anhydrous 5a$S9+ and, after filtering off the drying agent, stripped of solvent under
vacuum. "here 3as thus obtained ,.,)) g of (@P$,&@dimetho/y@+@'$@fluoroethyl-phenylQ@$@'$,$,$@trifluoroacetamido-propane as a 3hite solid 3ith a mp of
(,$@(,+ deg C.
A solution of ,.($ g (@P$,&@dimetho/y@+@'$@hydro/yethyl-phenylQ@$@'$,$,$@trifluoroacetamido-propane in a mi/ture of & m! CH$Cl$ and & m! IPA 3as
treated 3ith ,.$ m! $ 5 9H, heated on the steam bath for 0, min, and then stripped of solvents under vacuum. "he residue 3as suspended in
CH$Cl$ and 3ashed 3ith $,K 5a9H. "he organic phase 3as dried 3ith anhydrous 5a$S9+ 3hich 3as removed by filtration, and the combined filtrate
and 3ashings stripped of solvent under vacuum. "he residual glass ',.,) g- 3as dissolved in IPA, neutrali6ed 3ith concentrated HCl and diluted 3ith
anhydrous <t$9 to provide $,&@dimetho/y@+@'$@fluoroethyl-amphetamine hydrochloride ';9<B- as a 3hite crystalline solid 3ith a mp of $,&@$,) deg C.
Anal. 'C(0H$(ClB59$- C,H.
;9SAC<E $ @ 0.& mg.
;4:A"I95E ($ @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith $.$ mg- Some3here bet3een the first and second hour, I gre3 into a 3orld that 3as slightly un3orldly. IhyH "hat is
hard to say, as there 3as no appreciable visual component. I Gust kne3 that the place I 3as in 3as not completely familiar, and it 3as not necessarily
friendly. .ut it 3as fascinating, and the music around me 3as magical. "ime 3as moving slo3ly. I had to drive across the bay at about ten hours into
this, and I 3as comfortable. "hat evening I slept 3ell, but my dreams 3ere pointless.
'3ith 0., mg- It took almost three hours to full activity. "he first signs of effects 3ere felt 3ithin a half hour, but from then on the progress 3as slo3 and
easy, 3ithout any discernible Gumps. "here 3as absolutely no body discomfort at all. Completely comfortable. "here 3as a general humorousness
about my state of mind 3hich is al3ays a good sign. Ie 3ent to the bedroom at the t3o and a half hour point, and proceeded to establish that the
material is far from anti@erotic. .eautiful response, 3ithout a mention of any feeling of risk at orgasm. I myself 3as not able to reach orgasm until about
&th to 1th hour, and then it 3as full and e/ceptionally delicious. So 3as the second one, a couple of hours later, if I remember correctly. All systems
intact, body, mind and emotion. Centle. Cood for 3riting. 5o dark corners apparent at all. Bor me, not highly visual. Iould take again, higher.
'3ith 0., mg- "here 3as no body threat at any time L very comfortable. Cood eyes closed, 3ith comple/ imagery to music, but not too much 3ith eyes@
open. ?y attention span is relatively short, and easily diverted into ne3 directions L all Fuite reminiscent of ;9I both as to dosage and effect. At (0
hours, I am still too alert to sleep, but a couple of hours later, 9. In the morning there is still a trace of something going on. "his 3as a valid ***.
<="<5SI95S A5; C9??<5"A:>E I 3as asked by a student of mine a 3hile ago, 3hen I told him of this material, Gust 3hy 3ould anyone Gust happen
to place a fluorine atom at the end of the +@ethyl group of ;9<"H It 3asn7t the sort of thing that someone 3ould Gust happen to do. If there 3ere a
rationale, then that7s fine. .ut by capricious impulse, no. .ut there is a rationale of sorts, 3hich I Gust hinted at in the discussion under $C@"@$(.
"his argument of reason goes as follo3s. Assume that I 3ould like to put a fluorine atom into a drug that does not normally have one. Ihy 3ould I 3ant
toH .ecause I 3ant to have the molecule carry a radioactive fluorine atom into some inner recess of the brain. IhyH .ecause by using a positron@
emitting fluorine I could possibly visuali6e the area of the brain that the drug 3ent to. And if it 3ent there in some abnormal 3ay, the e/act measure of
that abnormality might give some clue as to potential brain misfunctioning.
.ut, if you put a fluorine atom on a drug, it becomes a totally ne3 drug and, Fuite reasonably, a pharmacologically different drug. Ho3ever, a body of
evidence is being accumulated that if a halogen, such as a bromine or an iodine atom, is replaced by a beta@fluoroethyl group, the electronic and polar
properties of the drug can be pretty much the same. So, 3hat psychedelics have a bromo or an iodo groupH 9bviously, ;9. and ;9I. "hus, ;9<B is a
natural candidate for fluorine@() positron emission tomography, and also a natural candidate for clinical trials. And, voila, it is an active material.
And I7ll bet you dollars to doughnuts, that if one 3ere to make the t3o@carbon analog $,&@dimetho/y@+@'$@fluoroethyl-@phenethylamine, it 3ould be every
bit as much a treasure and ally as is $C@. or $C@I. In fact, I am sure enough about this prediction that I am 3illing to name the stuff $C@<B. It 3ill be
easily made from $C@. by the same reaction scheme that 3as used above for ;9<B. And I 3ill even guess that its activity level 3ill be in the $,@0,
milligram area.

#11 0%ET; HE!ATE; $,)-0"METH%+Y-(-ETHYAM,HETAM"#E
S>5"H<SISE "o a solution of (%.2 g $,&@dimetho/y@+@ethylben6aldehyde 'see the recipe for $C@< for its preparation- in 2$ g glacial acetic acid there 3as
added 1.& g anhydrous ammonium acetate and (,.$ g nitroethane. After heating for (.2& h on the steam bath, the reaction mi/ture 3as cooled in a 3et
ice bath, diluted 3ith (, m! H$9, and seeded 3ith a small crystal of product. "he yello3 crystals 3ere removed by filtration '2.1 g 3et 3ith acetic acid-
and another $.$& g 3as obtained from the mother liFuors 3ith additional H$9. "he combined fractions 3ere recrystalli6ed from $& m! boiling ?e9H, to
give 1.& g fine yello3 crystals of (@'$,&@dimetho/y@+@ethyl-@$@nitropropene, 3ith a mp of 12.&@1).& deg C. Anal. 'C(0H(259+- C,H,5.
A suspension of 1.& g !AH in &,, m! 3ell stirred anhydrous <t$9 3as held at reflu/ under an inert atmosphere, 3ith the return of the condensed solvent
passing through a So/hlet thimble containing 1.& g (@'$,&@dimetho/y@+@ethylphenyl-@$@nitropropene. After the addition of the nitrostyrene 3as complete,
the stirred suspension 3as maintained at reflu/ for an additional () h, then cooled to room temperature. "he e/cess hydride 3as destroyed 3ith &,, m!
)K H$S9+, added cautiously until the hydrogen evolution ceased, then at a speed that allo3ed the formed solids to disperse. "he phases 3ere
separated, the aFueous phase 3ashed once 3ith <t$9, treated 3ith (&, g potassium sodium tartrate, and finally made basic 'pH U%- 3ith &K 5a9H.
"his 3as e/tracted 3ith 0/(,, m! CH$Cl$, the e/tracts pooled, and the solvent removed under vacuum. "he residue, 2.% g of a clear oil, 3as dissolved
in (,, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas. After standing at room temperature for $ h, the crystalline $,&@dimetho/y@+@
ethylamphetamine hydrochloride ';9<"- 3as removed by filtration, 3ashed 3ith <t$9, and air dried to constant 3eight. "here 3as obtained &.% g of
lustrous 3hite crystal 3ith a mp of (%,@(%( deg C. :ecrystalli6ation from CH0C5 or <t9Ac increased the mp to (%+@(%& deg C. Anal. 'C(0H$$Cl59$-
C,H,5.
;9SAC<E $ @ 1 mg.
;4:A"I95E (+ @ $, h.
L4A!I"A"IM< C9??<5"SE '3ith (., mg- "his 3as a very gentle, rela/ing level, but there 3ere no psychedelic effects that 3ere apparent. <asy, and
rela/ed, and I am in no 3ay into/icated or turned on. .ut I 3as in the throes of my menstrual period, and the cramps 'and the accompanying irritability-
3ere completely knocked out. Perhaps this is 3hy I felt so rela/ed and at peace.
'3ith $.& mg- "here is much, too much, movement 3ith my eyes closed. And an a3ful lot there 3ith my eyes open. "he movement on the concrete floor
in the basement 3hen I 3ent do3nstairs for 3ood for the fireplace, 3as too much. I felt almost sea@sick. And I am having reality problems L I cannot
seem to find my centering point of reference. "here has to be a place to pin myself do3n to, and it is not findable any3here I look. And my legs are
t3itching, and feeling as if they are falling asleep, and I had a cra3ling sensation on my body, so the body is not at peace either. In the morning I 3as
still **, but there is a clear indication that I am repairing. Any3ay, I survived the e/perience. "his is definitely not my thing.
'3ith + mg- Dust after an hour into the e/periment, I 3as surprised by the a3areness of some effects L I had forgotten that I had taken something. At the
second hour, it 3as real, but subtle. As a psychotomimetic or S"P@like thing, there is very little there. .ut as a mood energi6er, it is really a ** or more.
"he clinical literature is right L none of the hallucinogenic effects, but one brings into play 3hatever one 3ants to. Iorked at cleaning up the office until
(( P?. I slept 3ell. "his has none of the !S; or S"P seriousness.
'3ith 1 mg- "he onset 3as slo3, and subtle. .ut the effects are fully there in about three or so hours. <verything I smelled 3as vivid, as are all the
colors and shapes; they are clean, beautiful, serenely self@contained. 5o visual movement. "he eyes@closed fantasy images tend to take off on their
o3n, ho3ever, and they are e/tremely rich. I don7t see any dark corners. I believe it might 3ell be possible to be creative 3ith this, and there is no
suggestion of body depletion, of body load.
'3ith 2 mg- A hot day. 4nbelievably lovely erotic@to@divine, deep loving, open, not much visual, eyes@closed form@image@symbol. Sleep attempts very
shallo3, slight Sthinness7, 3ith an anticipation of darts. Intellect and feeling@emotion area intact and functioning at all times. 5e/t morning still at a plus
one. Incredible material. Perhaps best at 1 to 2 milligrams, no higher due to body load.
<="<5SI95S A5; C9??<5"A:>E "he original code for this compound 3as ;9<, 3hich 3as completely logical based on ;9? being the methyl
member of this series ';9 for the removal of the o/ygen, deso/y, and ? for putting a methyl in its place-. And the putting of the ethyl thence should be
;9<. "his 3as fine until it 3as pointed out to me by a close colleague that ;9< 3as a classic abbreviation for deso/yephedrine, a synonym for
methamphetamine. "he pressure to add the :"S of the :<"S of the ethyl 3as heightened by looking ahead to other members of the series. ;9A
became ;9A?, ;9< became ;9<", but ;9? 3as already too firmly set in popular usage. And, any3ay, ;9?< really looked strange.
"he original publications of the action of ;9? clearly documented the compound as being a psychedelic and one 3ith a si6eable measure of potential
abuse. And, it is not a surprise that it 3as Fuickly shuffled into a legal classification that effectively precluded any further study of it. So, 3hen this
immediate homologue of ;9? 3as studied and discussed in the literature, all reported dosages 3ere those that 3ere at the lo3est levels, and no
disturbing hints of abusability 3ere mentioned. And this particular homologue has so far escaped the attention and restrictive action of the drug
enforcement agencies, although the specific 3ording of the Controlled Substance Analogue <nforcement Act of (%)1 might make this point moot, at
least as far as human trials are concerned. At modest levels, ;9<" has the reputation of being a cognitive enhancer and is largely free of those sensory
distortions that 3ould catch the attention of the authorities 3ho cannot tolerate drugs that distort the senses. "he higher levels mentioned here have
never been put into the published literature. It must be noted that there is a considerable variation of individual responses to this material. "he effective
dose range stated is Fuite broad. Some people are Fuite sensitive. "his is, after all, one of the Classic !adies, namely H<CA"<.
"he young e/perimental subGect 3ho had the dramatic relief from menstrual cramps at the one milligram dose tried the compound again the follo3ing
month, and again had complete relief. .ut another volunteer, also plagued 3ith severe cramping at that particular time of month, found no relief at all. A
&,K success rate. 5o one else has, to my kno3ledge, e/plored this particular property.

#12 0%"; $,)-0"METH%+Y-(-"%0%AM,HETAM"#E
S>5"H<SISE A mi/ture of (+.) g phthalic anhydride and (%.& g of $,&@dimetho/yamphetamine '$,&@;?A- as the free base 3as heated gradually to
about (&, deg C 3ith an open flame. A single clear phase 3as formed 3ith the loss of H$9. After the hot melt remained Fuiet for a fe3 moments, it 3as
allo3ed to cool to about &, deg C and then diluted 3ith (,, m! of hot ?e9H. "he solution 3as stirred until homogenous, seeded 3ith product, and then
cooled in an ice bath to complete the crystalli6ation. After removal of the product by filtration, 3ashing sparingly 3ith ?e9H, and air drying, there 3as
obtained $+.1 g of 5@'(@'$,&@dimetho/yphenyl-@$@propyl-phthalimide as off@3hite crystals, 3ith a mp of (,&@(,1 deg C. Anal. 'C(%H(%59+- C,H,5.
"o a solution of $., g 5@'(@'$,&@dimetho/yphenyl-@$@propyl-phthalimide in (& m! 3arm acetic acid 3hich 3as being vigorously stirred, there 3as added a
solution of (.$ g iodine monochloride in 0 m! acetic acid. "his 3as stirred for $ h at about +, deg C during 3hich time there 3as a definite lightening of
color, but no solids formed. "he reaction mi/ture 3as poured into 1,, m! H$9 3hich produced a reddish glob floating in a yello3@orange opaFue
aFueous phase. "he glob 3as physically removed, dissolved in 0, m! boiling ?e9H 3hich, on cooling in an ice bath, deposited off@3hite crystals.
"hese 3ere removed by filtration, 3ashed 3ith ?e9H, and air dried to give (.& g of 5@P(@'$,&@dimetho/y@+@iodophenyl-@$@propylQphthalimide as fine 3hite
crystals 3ith a slight purple cast. "he mp 3as (,0@(,&.& deg C and the mi/ed mp 3ith the starting non@iodinated phthalimide 'mp (,&@(,1 deg C- 3as
depressed ')&@%) deg C-. </traction of the aFueous phase, after alkalinification, provided an additional ,.(& g product. Anal. 'C(%H()59+- C,H,5.
A solution of ,.2& g 5@'(@'$,&@dimetho/y@+@iodophenyl-@$@propyl-phthalimide in (, m! <t9H 3as treated 3ith ,.0 m! of hydra6ine hydrate, and the clear
solution 3as held at reflu/ on the steam bath overnight. After cooling, there 3as a crystalli6ation of (,+@dihydro/yphthali6ine that started as small beads
but finally became e/tensive and Fuite curdy. "hese solids 3ere removed by filtration and had a mp of about 0+, deg C 'reference samples melted over
a five to ten degree range in the area of 00&@0&, deg C-. "he filtrate 3as dissolved in (,, m! CH$Cl$ and e/tracted 3ith $/(&, m! ,.( 5 HCl. "he
aFueous e/tracts 3ere 3ashed once 3ith CH$Cl$, made basic 3ith &K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent under
vacuum gave ,.& g of a colorless oil 3hich 3as dissolved in 0,, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas. "here 3as obtained, after
filtration, and air drying, ,.0& g of $,&@dimetho/y@+@iodoamphetamine hydrochloride ';9I- as 3hite crystals that melted at $,,.&@$,(.& deg C. "his value
did not improved 3ith recrystalli6ation. Anal. 'C((H(2ClI59$- C,H,5.
;9SAC<E (.& @ 0., mg.
;4:A"I95E (1 @ 0, h.
L4A!I"A"IM< C9??<5"SE '3ith ,.1 mg- "here 3as a nice spacey light@headedness for a fe3 hours, and time seemed to move Fuite slo3ly. "hen a
generic sadness came over me, as I reminisced about earlier days 'recalling pleasures no3 gone- and 3ondered if I 3ould be allo3ed to be here on the
Barm 3hen I am old and not important. "here is so much to be done, and I cannot do it all, and no one else cares. ?y mood became present@day and
healthy by about the seventh hour.
'3ith (.1 mg- "he general nature of the e/perience 3as depressing, 3ith a sad vie3 of life. "here 3as no 3ay I could connect 3ith my emotions. <ven
my sadness 3as vague. At about the ninth hour I decided that enough 3as enough, and this strangely disappointing about@plus@t3o 3as aborted 3ith
($& micrograms of !S;. "he emotions became present and living 3ithin a half hour. I 3as greatly relieved. "he erotic 3as not a mechanical attempt
but a deeply involved feeling 3ith an archetype of orgasm easily available. It 3as shaped like a flo3er, richly colored, 3ith an unusual NSN shape to it.
"his 3as a lovely end to a difficult day.
'3ith 0., mg- "his is a clear, clean psychedelic. "he eyes@closed imagery is e/cellent, 3ith clearly delineated patterns, pictures, and colors. Perfect for
an artist, and ne/t time I7ll devote some time to painting. "otal ease for the body, but no help for my smoking problem. I still 3ant to smoke. And at
si/teen hours into this I am still at (.&* but I7ll try to go to bed any3ay, and sleep.
'3ith 0.& mg- I 3as at a full crashing *** for about three or four hours. "here 3as none of the !S; sparkle, but there 3ere moments of Slight@
headedness7 3here one could move side3ays 3ith reality. I could leave 3here I 3as right over there, and come over here and get a strange but
authentic vie3 of 3here the Sthere7 3as that I had left. It 3ould be out@of@body, e/cept that the body came over here 3ith me rather than staying there.
"his doesn7t make sense no3, but it sure did then. "here 3as no trace of body impact, and I slept late that evening, but 3ith some guardedness due to
the intense imagery. "his 3as no more intense than 3ith 0., milligrams, but it 3as a little bit more to the unreal side.
'3ith (., mg of the N:N isomer- "here 3as a clear ** from the second to the eighth hour, but someho3 there 3as not Fuite the elegance or the push of
the racemate. I 3as sensible, and managed to do several technical chores in a reasonable 3ay. <asy sleep at (& hours into it.
'3ith $.0 mg of the N:N isomer- "he 3ater solution of the hydrochloride salt has a slightly s3eetish tasteO I 3as at a *** 3ithout Fuestion, but there 3as
a slight do3n mood to3ards the end. And it lasted a really long time; I 3as distinctly a3are of residual stuff going on, 3ell into the ne/t day.
'3ith 1.0 mg of the NSN isomer- I 3as at a benign one@and@a@half plus at about t3o hours, and finally flattened out at a **. Iould I double this doseH
Probably not, but half again 'to % or (, milligrams- 3ould feel safe for a plus 0. .y evening I 3as near enough baseline to drive into to3n for a social
obligation, but even 3hen trying to sleep later that night there 3as some residue of imagery; remarkably, it 3as all in slo3 motion. "he fantasies 3ere
slo3@paced and sluggish. It 3ould have been interesting to have e/plored eyes@closed during the day.
<="<5SI95S A5; C9??<5"A:>E Again, as 3ith every other psychedelic amphetamine analogue 3hich has a chiral center and has been e/plored as
the individual optical isomers, it is the N:N isomer that is the more potent. And again, the other isomer, the NSN isomer, still sho3s some activity. "he
same 3as true 3ith ;9., and ;9?, and ?;A. "he only e/ception 3as ?;?A, but then that is more of a stimulant, and there is virtually no psychedelic
component to its action. :at studies, 3here there is a measure of the discrimination of a test compound from saline, have sho3n the N:N isomer to have
about t3ice the potency of the NSN isomer. "hat the N:N is more potent is certain, but the above reports 3ould suggest that the factor 3ould be closer to
times@four rather than times@t3o.
A number of studies 3ith ;9I in animal models have sho3n it to have an e/tremely high binding capacity to 3hat are called the &@H"$ receptors.
Serotonin is a vital neurotransmitter in the brain, and is strongly implicated in the action of all of the phenethylamine psychedelics. "he place 3here it
acts, at the molecular level, is called its receptor site. As an outgro3th of the cooperative studies of the medicinal chemists 3orking closely 3ith the
neuropharmacologists, a number of compounds have emerged that interact 3ith these sites. .ut this one interacts 3ith these sites and not those, and
that one interacts 3ith those sites and not these. So, there has developed a collection of sub@divisions and sub@subdivisions of receptor sites, all related
to serotonin, but each defined by the particular compound that interacts most tightly 3ith it.
"hus, there 3ere serotonin N(N receptors, and then there 3ere N(N and N$N receptors, and then N(aN and N(bN and N$aN and N$bN receptors, and on and on.
"hese are called &@H" receptors, since the chemical name for serotonin is &@hydro/ytryptamine, and the scientist 3ould never 3ant to let the layman
kno3 Gust 3hat he is talking about. ;9I has been synthesi6ed 3ith a variety of radioactive iodine isotopes in it, and these tools have been of
considerable value in mapping out its brain distribution. And by e/trapolation, the possible locali6ation of other psychedelic compounds that cannot be
so easily labelled. A small neurochemical research company on the <ast Coast picked up on these properties of ;9I, and offered it as a commercial
item for research e/periments. .ut I doubt that they are completely innocent of the fact that ;9I is an e/tremely potent psychedelic and that it is still
unrecogni6ed by the Bederal drug la3s since, in their most recent catalog, the price had almost doubled and a note had been added to the effect that
telephone orders cannot be accepted for this compound.
"he four@carbon butylamine homologue 'the A:IA;5< analogue- of ;9I has been synthesi6ed. A mi/ture of the free base of (@'$,&@dimetho/yphenyl-@
$@aminobutane 'see preparation under ;9.- and phthalic anhydride 3as fused, cooled, and recrystalli6ed from either methanol or cyclohe/ane to give
crystals of 5@P(@'$,&@dimetho/yphenyl-@$@butylQphthalimide 3ith a melting point of 21@22 deg C and an analysis 'C$,H$(59+- C,H,5. "his 3as iodinated
3ith iodine monochloride in acetic acid to give 5@P(@'$,&@dimetho/y@+@iodophenyl-@$@butylQphthalimide 3hich 3as chromatographically distinct from the
uniodinated starting material 'silica gel, CH$Cl$ -, but 3hich did not crystalli6e. "his 3as treated 3ith hydra6ine hydrate in ethanol to provide (@'$,&@
dimetho/y@+@iodophenyl-@$@aminobutane hydrochloride 3hich 3as crystalli6ed from CH0C58<t9H to give 3hite crystals 3ith a mp of $(2@$().& deg C
and an analysis 'C($H(%CI59$- C,H,5. "his butyl homolog of ;9I has been assayed at up to four milligrams, and is 3ithout any central effects
3hatsoever. An e/periment 3ith ($.+ microcuries of (0(I labelled material 3ith the 3hole body scanner sho3ed most of it accumulating in the gut and
liver, 3ith almost none to the brain.
Bor those 3ho find such statistics interesting, the parent compound ;9I vies 3ith ;9. as probably the most potent of the phenethylamine psychedelics
as of the moment, and certainly one of the most long lived.
A very important, centrally pivotal, and completely parado/ical compound in this area, is the 5,5@dimethyl homologue of ;9I, or $,&@dimetho/y@5,5@
dimethyl@+@iodoamphetamine 'I;55A-. "his compound 3as the starting point of the study of a large number of homologues and it deserves, and has
received, a separate recipe.

#13 0%M; ST,; $,)-0"METH%+Y-(-METHYAM,HETAM"#E
S>5"H<SISE "o a solution of &+.% g $,&@dimetho/y@+@methylben6aldehyde 'see the recipe for $C@; for its preparation- in $(& g glacial acetic acid there
3as added (%.& g anhydrous ammonium acetate and 0,.1 g nitroethane. "his mi/ture 3as heated for 0 h on the steam bath, the reaction mi/ture 3as
cooled in a 3et ice bath, allo3ing the spontaneous formation of yello3 crystals. As much H$9 as possible 3as added 'Gust short of a persistant cloudy
oily character- and after a fe3 additional h standing, the crystalline (@'$,&@dimetho/y@+@methylphenyl-@$@nitropropene 3as removed by filtration and
recrystalli6ed from boiling acetic acid. "he yield, after drying to constant 3eight, 3as $).0 g and the mp 3as )2@)) deg C. Anal. 'C($H(&59+- C,H,5.
A suspension of %.& g !AH in 2&, m! 3ell stirred anhydrous <t$9 3as held at reflu/ under an inert atmosphere, 3ith the return of the condensed solvent
passing through a So/hlet thimble containing %.& g (@'$,&@dimetho/y@+@methylphenyl-@$@nitropropene. After the addition of the nitrostyrene 3as
complete, the stirred suspension 3as maintained at reflu/ for an additional + h, then cooled to room temperature and allo3ed to continue stirring
overnight. "he e/cess hydride 3as destroyed by the addition of 2&, m! )K H$S9+, cautiously, until the hydrogen evolution ceased, then at a speed
that allo3ed the formed solids to disperse. "he phases 3ere separated, the aFueous phase 3ashed once 3ith <t$9, treated 3ith $$& g potassium
sodium tartrate, and finally made basic 'pH U%- 3ith &K 5a9H. "his 3as e/tracted 3ith 0/(&, m! CH$Cl$, the e/tracts pooled, and the solvent
removed under vacuum. "he residue 3as %.1 g of a clear oil 3hich spontaneously formed crystals 3ith a mp of 1,.&@1( deg C from he/ane. "hese
solids 3ere dissolved in (&, m! anhydrous <t$9, and saturated 3ith anhydrous HCl gas. After standing at room temperature for $ h, the crystalline $,&@
dimetho/y@+@methylamphetamine hydrochloride ';9?- 3as removed by filtration, 3ashed 3ith <t$9, and air dried to constant 3eight. "here 3as
obtained ).$& g of glistening 3hite crystals that had a mp of (%,.&@(%(.& deg C. "he sulfate had a mp of (0( deg C. Anal. 'C($H$,Cl59$- C,H,5.
"he above nitrostyrene may also be converted to the final amine product through the intermediary of the corresponding phenylacetone. "o a 3ell stirred
suspension of (,.+ g po3dered iron in $, m! glacial acetic acid held at reflu/ temperature, there 3as added +.% g (@'$,&@dimetho/y@+@methylphenyl-@$@
nitropropene as a solid. :eflu/ing 3as continued for $ h and then all 3as filtered through 3et Celite. After 3ashing 3ith 0,, m! H$9 follo3ed by 0,, m!
<t$9, the combined filtrate and 3ashes 3ere separated, and the aFueous phase e/tracted 3ith $/(,, m! <t$9. "he organic phase and e/tracts 3ere
combined and 3ashed 3ith $/(,, m! saturated $C90 and the solvent 3as removed under vacuum yielding a reddish oil 3eighing 0.0 g. "his 3as
distilled at (((@((& deg C at ,.& mm8Hg to give a pale green solid. After recrystalli6ation from ben6ene, there 3as obtained $.) g (@'$,&@dimetho/y@+@
methylphenyl-@$@propanone as 3hite crystals 3ith a mp of &2@&% deg C. "his ketone has also been described as a pale@yello3 oil 3ith a bp of ((&@(()
deg C at ,.+ mm8Hg. A solution of ,.2 g (@'$,&@dimetho/yphenyl@+@methyl-@$@propanone in $, m! ?e9H 3as treated 3ith 1., g ammonium acetate, ,.0
g sodium cyanoborohydride, and 0 g !inde 0 A molecular sieves. "he mi/ture 3as stirred overnight, the solids removed by filtration, and the filtrate
dissolved in (,, m! H$9. "he solution 3as acidified 3ith dilute H$S9+, and 3ashed 3ith $/$& m! CH$Cl$. "he aFueous phase 3as made basic 3ith
aFueous 5a9H, and the product e/tracted 3ith $/$& m! CH$Cl$. "he solvent 3as removed under vacuum, and the residue distilled 'at (1, deg C at
,.$ mm8Hg- to give colorless product 3hich 3as dissolved in 0 m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith &, m! anhydrous <t$9.
"here 3as obtained ,.() g of $,&@dimetho/y@+@methylamphetamine hydrochloride ';9?- as a 3hite solid 3ith a mp of ()2@()) deg C.
"he optical isomers of ;9? have been prepared in t3o 3ays. "he racemic base has been resolved as the ortho@nitrotartranilic acid salt by
recrystalli6ation from <t9H. "he '*- acid provides the '*- or NSN isomer of ;9? preferentially. Also, the above@mentioned (@'$,&@dimetho/y@+@
methylphenyl-@$@propanone can be reductively aminated 3ith optically active alpha@methyl ben6ylamine 3ith :aney 5ickel. "his amine is isolated and
purified by recrystalli6ation of the hydrochloride salt. Ihen optically pure, the ben6yl group 3as removed by hydrogenolysis 3ith palladium on carbon.
"he mp of either of the optical isomers, as the hydrochloride salts, 3as $,+@$,& deg C.
;9SAC<E 0 @ (, mg.
;4:A"I95E (+ @ $, h.
L4A!I"A"IM< C9??<5"SE '3ith (., mg- "here is almost certainly an effect. Physically there is a slight dryness in the mouth, and my eyes are
noticeably dilated. "here is an eerie feeling overall.
'3ith $.0 mg- ?ood elevation at $@0 hrs. After 0 hours, emotional effects become more pronounced, enhancement of color also. Mery little distortion of
perception, no disorientation, no creeping or flo3ing, but color enhancement considerable. "he emotional content and empathy for others 3as closer to
mescaline than to amphetamine, a 3elcome change. 5o suggestion of nausea at any time. 4nable to sleep at ten hours, so I took 08+ grain Seconal.
Headache and listlessness ne/t morning, probably due to the Seconal.
'3ith 0 mg- In the middle of the e/perience I found that I 3as able to separate components of comple/ things so as to evaluate them separately. "here
is no need to respect their normal purpose. "he sharpness of observation is enhanced, but one can focus at every different depth of a thing or a
concept. Colors are not Gust brighter; there are more of them. "here is a profoundness of meaning inherent in anything that moves. A line of thought or
a bit of personal history ties the thinker to the obGects that had been thought of, or once e/perienced. It is this relationship that 3ill prove productive. 5ot
like in a movie 3hich is circular in its totalness, but as in true life 3here the future is the result of your o3n involvement 3ith everything about you.
'3ith + mg- "he first four hours 3ere largely directed to the body. "here 3as a shuddering, and a tight Ga3, and I am not particularly motivated to talk to
anyone. It is more arousing 'like amphetamine- than depressing 'like phenobarb-. I am feeling Gust a little sick at the three hour point, but a bit of
regurgitation clears this up. "hen at the fourth hour, it 3ent totally outside of me. I sa3 the clouds to3ards the 3est. "H< C!94;SOOO 5o visual
e/perience has ever been like this. "he meaning of color has Gust changed completely, there are pulsations, and pastels are e/tremely pastel. And no3
the oranges are coming into play. It is a beautiful e/perience. 9f all past Goys, !S;, mescaline, cannabis, peyote, this ranks number one. 5ormally I
have no color effects 3ith mescaline. A dynamic e/perience. Beels good, too.
'3ith & mg- "here 3as the magnification of light, color and odors. It 3as all very pleasant and beautiful, e/cept that I had an over3helmingly negative
feeling. "his at times gre3 to considerable intensity, and I feel it 3as clearly due to anger. At times the negativity disappeared completely, and I broke
into the most enGoyable, even hilarious e/periences. I alternated about &,@&, bet3een Goy and discomfort. As the evening dre3 on, I became 3ithdra3n
and pensive. It seemed clear that I had made all the 3rong decisions L choice of partner, place to live, isolation, no meaningful activity. "he greatest
shocker 3as that my practice of meditation, 3hich is one of my central focuses, and 3hich I thought had brought me much peace and understanding,
seemed to be a delusional solution to my unhappiness and isolation. "he e/perience continued unabated throughout the night 3ith much tension and
discomfort. I 3as unable to get any sleep. I hallucinated Fuite freely during the night, but could stop them at 3ill. Ihile I never felt threatened, I felt I
kne3 3hat it 3as like to look across the brink to insanity.
'3ith ) mg- "he very Fuiet development picks up speed bet3eeen the first and second hour. "here is a rich curly@imaged eyes@closed sho3 that
interlocks closely 3ith music. It is occasionally an off@beat fantasy and not directly knit together, and even occasionally unenGoyable. .ut al3ays intense
and completely appropriate to the music. "here is a continuous thirst, and little urine. 5apping seems 9 at (1 hours, but real sleep must 3ait until the
$, hour point. 9verall a rolling ***, and I am looking for3ard to a repeat some day.
'3ith (, mg- If on this page I shall have e/pressed it to you then it is true that ;9? has the glory and the doom sealed up in it. All that7s needed to
unseal it is to surround it 3ith a 3arm living human for a fe3 hours. Bor that human for those hours all the dark things are made clear.
'3ith ($ mg- "he first a3areness 3as at 0, minutes and it 3as in the tummy. "he development 3as e/tremely rapid, something more like !S; than
previously remembered. "he body tremor feels like poisoning, there is no escaping the feeling of being disabilitated, but at least there is no nausea.
"his transition ended and the trauma cleared completely at about the second hour. "he music 3as e/ceptional, the erotic 3as e/ceptional, the fantasy
3as e/ceptional. !ist67s NA Christmas Cantata R(,N part (, 3ith eyes closed 3as an e/perience 3ithout precedent. "here 3ere some residual effects still
noted the ne/t day. "his may be a bit much for me.
'3ith ,.0 mg of the N:N isomer- ?aybe slightly 3iryH 5o effects.
'3ith ,.& mg of the N:N isomer- "here is a real effect, and it is significant that the first effects of the racemate 3ere noted at (., milligram. "here is a
trace of time slo3ing and in general a pretty full manic state. "here is some mydriasis. <verything had pretty much cleared up by evening.
'3ith $., mg of the NSN isomer- 5o effects. "here 3as an une/pected slight tachycardia at the t3o hour point, but nothing suggesting psychotropic
action.
'3ith $.1 mg of the NSN isomer- "here are signs of both pulse increase and blood pressure increase. "here is some teeth@rubbiness, but still no
psychological turn on at all.
<="<5SI95S A5; C9??<5"A:>E "he rationale for the design and making of ;9? has already been discussed. 9ne could predict that it could have
been, theoretically, a totally inactive compound and maybe an effective blocker for 3hatever receptor sites are being occupied by other psychoactive
drugs and even for strange things that some unbalanced people might actually make 3ithin their bodies, using their o3n personal chemistry. 9n the
other hand, it could have been a potent psychedelic in its o3n rights, and if so, probably long lived. "he latter Ncould have beenN proved to be so.
"he very modest amount of study of the individual optical isomers clearly indicates that the N:N isomer is the more active. "he sparse comments
suggest that some of the heavier physical aspects of the racemate might be due to contributions from the NinactiveN NSN isomer. It is, after all, the NSN
isomer of amphetamine that carries the maGor punch of that stimulant. ?aybe if that isomer 3ere removed, and one 3ere to e/plore the pure N:N isomer
of ;9?, the dramatic visual aspects of the larger dosages might not be complicated 3ith a troublesome physical component.
"his compound, unbekno3nst to me, 3as scattered 3idely and plentifully in the heyday of the Haight@Ashbury in San Brancisco, in mid@(%12. It 3as
distributed under the name S"P, 3hich 3as said to stand for Serenity, "ranFuility, and Peace. It 3as also claimed to represent Super "errific
Psychedelic, or Stop "he Police. "he police called itE "oo Stupid to Puke. Actually, the name 3as taken from the initials of a motor additive 3hich 3as
completely unrelated chemically. Incredibly, and sadly, one of the avo3ed e/perts in the area of the Nsensuous drugsN actually stated that S"P, the motor
oil additive, 3as really one and the same as S"P, the highly dangerous psychedelic. "he motor oil additive, he 3rote in a book of his, had properties
some3hat related to those of !S;, mescaline, and the amphetamines. Ho3 fortunate that the love children of the time didn7t do much reading, for they
might have gotten into yet deeper pharmacological troubles 3ith drug raids on the local gasoline stations.
"3o complications became apparent during this first appearance and they led to serious difficulties. 9ne, there 3as no eFuation made bet3een S"P
and ;9?. 5o one kne3 3hat this drug 3as 3hich had been distributed in a cavalier 3ay throughout the city. "here could be no educated guess as to
the best treatment of overdose emergencies. And secondly, the initial tablets that had been distributed apparently contained $, milligrams of ;9? per
tablet; later, it 3as dropped to (, milligrams. <ither of these, in retrospect, is no3 kno3n to be a thoroughly 3hopping dose. "he overdose situation 3as
aggravated by the slo3 onset of ;9?. "he user may be a3are of some initial effects at the half@hour point, there 3ill be 3hat might be called a * or **
at the end of the first hour, and the full impact of the drug is not appreciated until some t3o hours have elapsed. .ut many of the recipients of the free
handouts of ;9? 3ere familiar 3ith !S; 3hich can sho3 its alert in (& to $, minutes, or even sooner 3ith a large dose, and there is already a deep and
compelling into/ication felt at the half@hour point. "hey, Fuite reasonably, e/pected this familiar activity pattern 3ith S"P and assumed, 3hen there 3as
little if any activity noted at the half@hour point, that the potency 3as less than e/pected. "hey took one or even t3o additional dosage units. "hus,
some of the overdose victims of that period may 3ell have taken as much as 0, mg of ;9?. "he slo3 onset of action, coupled 3ith the remarkably long
duration, caught many innocent users unprepared.
Clinical studies have documented the rapid tolerance development from repeated e/posures to ;9?. Bive volunteers 3ere given 1 milligrams daily for
three days. 9bGectively, psychological tests sho3ed a decrease in responses. SubGectively, all found e/tremely intense effects on the first day, and all
but one found it unpleasant. .y the third e/posure on the third day, all had diminished responses, ranging from only Nmoderately strongN to Nfelt
absolutely nothing.N 9ne actually slept during the e/perience on the third day.
"he he/adeutero@analogue 'deuterium atoms on the t3o metho/yl groups- has been prepared as an internal standard for analytical 3ork, but there are
no reports of its human pharmacology. A study 3ith this sort of derivative 3ould be a fine companion to the studies already under3ay 3ith the mescaline
analogues that are similarly substituted. A difference e/ists, ho3ever. Iith mescaline, it is believed that the loss of a metho/yl group is a step to3ards
the inactivation of the compound, 3hereas 3ith ;9? this loss may be associated 3ith the formation of an active metabolite. "he several fascinating
Fuestions raised by possible differences in both the rates and the degree of demethylation of these t3o compounds are 3ell 3orth trying to ans3er.
A number of compounds related to ;9? had been synthesi6ed and studied at the 4niversity of California at San Brancisco, at about this time. "3o of
these 3ere simply the Guggling of the t3o metho/yl groups and the methyl group on the ring, still maintaining the $,+,&@ness relative to the amphetamine
chain. "hese are $,+@dimetho/y@&@methylamphetamine and +,&@dimetho/y@$@methylamphetamine. Since the slang name for ;9? in and about the
medical center 3as S"P, and since S"P 3as the name of a motor oil additive, it is not unreasonable that the first of these to be synthesi6ed, the $,+@
dimetho/y@&@methyl isomer, 3as referred to by the name of another motor oil additive popular at that time, B@0(,. "he Milsmeier reaction bet3een $,+@
dimetho/ytoluene and the Milsmeier comple/ of P9Cl0 and 5@methylformanilide gave the ben6aldehyde 'mp ((2@(() deg C- 3ith a yello3 malononitrile
derivative from <t9H 3ith a mp of (%0@(%+ deg C. "he nitrostyrene from this and nitroethane formed yello3 crystals from CH0C5, 3ith a mp (0)@(0%
deg C. "he amine formed easily 3ith !AH in ether, and the product B@0(, 'or &@;9?- gave 3hite crystals from CH0C5 3ith a mp of ()$@()0 deg C.
And the other isomer, the +,&@dimetho/y@$@methyl counterpart, became kno3n familiarly as B@0$,, or sometimes simply $@;9?. Its preparation follo3ed
an identical procedure, starting from 0,+@dimetho/ytoluene. I have been told that B@0(, is not active even at $, milligrams in man, 3hich 3ould make it
several times less potent than ;9? 'S"P-. I kno3 of no trials 3ith B@0$,. "he use of the letter :BS does not imply any relationship bet3een these t3o
compounds and the series described else3here 3ith the :BS code follo3ed by other numbers, such as B@$ and B@$$. "hese latter are B7s because they
are furans, not motor oil additives. And yet another oil additive, 3ell kno3n at the time as A@2, became associated 3ith the synthesis of the ;9? 'S"P-
isomer 3ith its groups in the $,+,1@positions. "his is entered separately under gamma@;9?.

#14 ga99a-0%M; 6-2; $,1-0"METH%+Y-(-METHYAM,HETAM"#E
S>5"H<SISE "o a solution of $,1@dimetho/y@+@methylben6aldehyde 'mp %$@%0 deg C from the lithiation of 0,&@dimetho/ytoluene follo3ed by reaction
3ith 5@methylformanilide- in (, m! nitroethane, there 3as added ,.( g anhydrous am@monium acetate and the mi/ture 3as heated on the steam bath for
(1 h. :emoval of the solvent under vacuum gave a slightly oily red@orange crystalline mass 3hich 3as finely ground under ( m! of ?e9H. Biltration
and a sparing 3ash 3ith ?e9H gave, after air drying, ,.) g of a light yello3 crystalline solid 3ith a mp of ($(@($$.& deg C. :ecrystalli6ation from + m!
boiling absolute <t9H gave ,.1 g of (@'$,1@dimetho/y@+@methylphenyl-@$@nitropropene as very light yello3 platelets, 3hich melted at ($0@($+ deg C.
"o a solution of ,.$& g !AH in $& m! reflu/ing "HB, 3ell stirred and under He, there 3as added a solution of ,.0 g (@'$,1@dimetho/y@+@methylphenyl-@$@
nitropropene in & m! dry "HB. 4pon the completion of the addition, the reaction mi/ture 3as held at reflu/ for +) h. After cooling 3ith an e/ternal ice
bath there 3as added, in seFuence, ,.& m! H$9, ,.& m! (&K 5a9H, and finally (.& m! H$9. "he inorganic solids 3ere removed by filtration, and the
filter cake 3ashed 3ith "HB. "he solvent from the combined filtrate and 3ashings 3as removed under vacuum, and the residue ',.0 g- 3as a crystal
clear colorless oil 3ith a high refractive inde/. "his 3as dissolved in $ m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith 0& m! of anhydrous
<t$9. After a minute7s standing, the solution became turbid, follo3ed by the slo3 deposition of very fine 3hite crystals. After standing ( h at room
temperature, these 3ere removed by filtration, <t$9 3ashed, and air dried to constant 3eight. "here 3as thus obtained ,.0 g $,1@dimetho/y@+@
methylamphetamine hydrochloride 'gamma@;9?- 3ith a mp of $,0 deg C. sharp.
;9SAC<E (& @ $& mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith (+ mg- I am really Fuite spacey. I can go from a train of thought straight up into thin air. "hen, to get to another one
there must be a careful choice of 3ords. !ogic has nothing to do 3ith any of it. "here is no trace of the ?;?A@like magic. "his is an interpretive drug,
not simply an ASC Paltered state of consciousnessQ opening.
'3ith () mg- "here is a light@headedness, and a some3hat starry@eyed stoned state. 5othing visual, and no body concern e/cept for 3hat seems to be
a very fine inner tremor. I think that 3ith a little more, things might very 3ell begin to move in the visual field. .ut I have no feeling of great concern
about taking a some3hat higher dosage.
'3ith $& mg- I 3as at a *** for about three hours, and it 3as a very 3eird place. "here 3ere some visuals, but they 3ere not at all commensurate 3ith
the degree to 3hich I 3as simply stoned. "he erotic does not knit, and it7s hard to get involved 3ith music. It is as if you 3ere going do3n some totally
unkno3n street in a completely familiar city. >ou kno3 the territory, but yet it is strangely all ne3. <yes closed fantasy and shaped imagery 3as Fuite
remarkable. .ut some heart arrhythmias and a pretty constant diarrhea made the e/perience less than totally ideal. ?y sleep 3as good and 3ith good
dreams.
<="<5SI95S A5; C9??<5"A:>E I can7t remember the e/act names of the companies that 3ent 3ith the oil additives. S"P 3as, I believe, it7s o3n
thing, and originally stood for Scientifically "reated Petroleum. And B@0(, 3as, I believe, a Chevron 9il product. B@0$, 3as, of course, the product of the
3ild and happy chemists at the Pharmaceutical Chemistry ;epartment at the 4niversity of California in San Brancisco, playing 3ith 3hat they fondly
called Nfunny drugs.N And 3hen the $,+,1@orientation became an obvious positional isomer, the Penn6oil 9il Company7s additive, A@2, 3as a natural to
have its name volunteered to the cause. "here 3as one additional isomer possible, 3ith the methyl in the $@position and the metho/yl groups at the +@
and 1@positions. "his follo3ed the more conventional aldehyde made from 0,&@dimetho/ytoluene via the Milsmeier process, 3ith P9Cl0 and 5@
methylformanilide. "his material '$,+@dimetho/y@1@methylben6aldehyde 3ith mp 1+@1& deg C from cyclohe/ane or from ?e9H- is completely distinct
from the isomer used above '$,1@dimetho/y@+@methylben6aldehyde 3ith a mp of %$@%0 deg C from ?e9H-. "he amphetamine from this isomer is $,+@
dimetho/y@1@methylamphetamine, and had been christened by the chemistry cro3d as A@2.(.
?uch effort had been put forth in research by this medical school group of graduate students and graduate advisors, to try to e/plain the biological
activity of the $,+,&@things such as "?A@$ and ;9? 'S"P-. And a considerable investment had been made in the attempt to tie together the
amphetamine 3orld of psychedelics 3ith the indole 3orld of psychedelics. "he convenience of having t3o metho/y groups para to one another 3as a
clear invitation to speculate upon the formation of a ben6oFuinone intermediate of some kind, and this 3ould reFuire the loss of the methyl groups 3hich
3ere already kno3n to be metabolically labile. "his NFuinone@likeN intermediate 3as the cornerstone of a NhydroFuinone hypothesis,N as it allo3ed
further condensation 3ithin the molecule itself involving the primary amine group, to form something called an indolene 3hich, 3ith some arcane electron
pushing and removal, could eventually become an indole. "here. Ie no3 have a tie@in to the tryptamine 3orld, and to serotonin, and that entire
neurotransmitter magic.
"here 3as only one small fly in the ointment. 5o matter ho3 the $,+,&@things 3ere e/plained, none of the proposed mechanisms could allo3 for the
$,+,1@things to also be active.
Ho3 can one accommodate such blasphemyH "he first and obvious approach 3as the simplest. ;enial. "he $,+,1@things aren7t really active at all.
Placebo stuff. "here is a commonly used phrase, Nbad scienceN 3hich is an in@famous term used to belittle findings that do not fit 3ith one7s theories or
purposes. .ut that simply didn7t 3ash, because I kne3, as did a fe3 others 3ho chose not to identify themselves too publicly, that "?A@$ and "?A@1
3ere both fully active in the +, to &, milligram area. And although not as potent as ;9?, the compound of this recipe, gamma@;9? or A@2, 3as
certainly an active one. So, since approach number one didn7t 3ork, try approach number t3o. ?ake the shoe fit the 3earer, 3ithout respect to the si6e
of his foot. 9ne single si6e shoe fits all. 9ne single mechanistic hypothesis e/plains all. It 3as obvious that for the NhydroFuinoneN hypothesis to
survive, A@2 3ould have to undergo some metabolic o/idation L phenol formation L in the 0@position.
And guess 3ho 3as actually euchred into embarking onto the synthesis of this hypothetical metabolic !ucy Pthat7s the anthropological@type, not the !S;@
type !ucyQH ?oiO 9n to a ne3 metho/ylated amphetamine 3hich 3ould be called A@2.$. 9/idation of the above $,+@dimetho/y@1@methylben6aldehyde
3ith metachloropero/yben6oic acid gave $,+@dimetho/y@1@methylphenol 3hich smoothly methylated '9H, CH0I- to give $,0,&@trimetho/ytoluene as a
3hite oil, bp &%@1$ deg C at ,.( mm8Hg. "his formed the anion bet3een the meta@metho/y groups 3ith butyllithium, and 5@methylformanilide gave the
ne3 compound $,0,1@trimetho/y@+@methylben6aldehyde, also an oil 'bp (0,@(+, deg C at ,.2 mm8Hg- 3ith an e/cellent 5?: spectrum. "his formed the
0@carbon nitrostyrene 3ith nitroethane, as bright yello3 crystals from methanol 3ith a mp 12@1).& deg C 'and e/cellent 5?: and microanalysis, C,H,5-.
!ithium aluminum hydride reduction gave rise to 3hat I 3as assuming 3ould be the target amphetamine, +@methyl@$,0,1@trimetho/yamphetamine or A@
2.$. "his formed a hydrochloride salt 3hich, although analytically e/cellent, insisted in remaining as an ether and chloroform@soluble oil 3hich had an
e/cellent 5?: spectrum. "his 3as certainly ?> target compound, but it 3as not "H<I: target compound. "he upper echelons 3ho 3ere running the
sho3 3ere serious about this hydroFuinone thing. "herefore, this product A@2.$, that should have been entered into human evaluation, 3as instead
processed further by the substitution of a t@.9C on the amine group, o/idation to the Fuinone 3ith ceric ammonium nitrate, reduction to the
hydroFuinone 3ith dithionite, and finally deprotection of the blocking t@.9C group by hydrochloric acid. "he final product, $,&@dihydro/y@1@metho/y@+@
methylamphetamine hydrochloride, 3as an e/tremely light@sensitive solid 3hich 3as looked at by 5?: 'e/cellent spectrum in ;$9- and by cyclic
voltimetry 'destructive and uninformative- but 3hich 3ould have been totally 3orthless to have tasted.
In fact, the 3hole $,+,1 substitution concept is Gust no3 beginning to e/plode. Bully half of the drugs described in this .ook II are of the classical $,+,&@
trisubstitution pattern, and it is becoming evident that every one of them 3ill have a $,+,1@trisubstituted counterpart that bids fair to be an active
psychedelic. ;iligence could thus easily double the number of kno3n psychedelics. "he nickname NpseudoN is really the Creek letter NpsiN 3hich looks
like a candelabrum standing on the table holding up three candles. If I can find the type in some font, I 3ill simply precede each kno3n drug 3ith this
letter, to indicate that the $,+,&@ness has become a $,+,1@ness. "herefore, A@2 is also pseudo@;9?.
A@2.$ might have been an interesting compound to taste. .ut the academic climate 3as not appropriate at that time 'early (%22- for such honesty. "he
Nhydro@Fuinone hypothesisN is no3 not much more than a minor bit of history. And anyho3, it 3as Gust about this time that I had uncovered a slick 3ay of
getting a sulfur atom into the amphetamine molecule. I Fuickly lost interest in the pursuit of other people7s hypotheses that didn7t seem to lead
any3here. ?aybe, someday, some single earth@shaking mechanism 3ill emerge to e/plain everything. .ut in the meantime, the best contribution I can
make to this Ngrand unified theory of psychedelic activityN is to continue to make ne3 and une/pected things 3hich, if they are active, 3ill effectively
destroy any hypothesis that Gust happens to be popular at the moment. It is a lot more e/citing, too.
#25 0%#; $,)-0"METH%+Y-(-#"T*%AM,HETAM"#E
S>5"H<SISE A solution of ).+ g $,&@dimetho/yamphetamine base in +, m! acetic acid 3as added drop3ise over the course of ,.& h to +0 m! of &,K
nitric acid 3hich 3as 3ell stirred and cooled 3ith an e/ternal ice bath. "he resulting solution 3as Fuenched 3ith ice 3ater, made basic 3ith aFueous
5a9H, and e/tracted 3ith a ben6ene@ether mi/ture. "he residue that remained after the removal of the solvent 3as dissolved in dilute HCl 3hich, upon
evaporation of the H$9, yielded a nearly colorless residue. :ecrystalli6ation from an ethanol8ether mi/ture gave, after drying, (,.& g of $,&@dimetho/y@+@
nitroamphetamine hydrochloride ';95- 3ith a mp of $,1@$,2 deg C. "he acetamide derivative melted at (11@(1) deg C. "he formamide derivative 3as
easily hydroly6ed 3ith 05 HCl. And the :@isomer of ;95 hydrochloride had a mp of $0(@$0$ deg C.
;9SAC<E 0., @ +.& mg.
;4:A"I95E ) @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith 0., mg- "here 3as an amphetamine@like stimulation that 3as apparent an hour into it, and considerable an/iety. I
had stomach cramps, but there 3ere indications that there might be something hallucinogenic at a higher dose.
'3ith +.& mg- An enhancement of color perception, and some auditory distortion, that 3as still noticeable some eight hours into the e/perience. "he
visual changes 3ere intense. I felt I 3as running a slight fever, and 3as restless, but there 3as almost no physical malaise. I 3as still some3hat 3ound
up even at the (+th hour.
<="<5SI95S A5; C9??<5"A:>E "hese Fualitative comments are not true Fuotations, but have been reconstructed from the published summaries of
the human trials reported by several South American researchers. I have personally never tasted ;95 and have only these fragments from 3hich to
create a portrait of activity. A brief Fuotation, from a note published by these researchers in a bulletin that is restricted to forensic scientists serving la3
enforcement agencies, is certainly subGect to a number of interpretations. It reads as follo3sE N"his action Pa strong stimulant action reminiscent of
amphetamineQ seems to reduce the incidence of insightful, and therefore potentially unpleasant e/periences, and thus P;95 seems likelyQ to appear on
the market as an illicit recreational drug.N I must admit that I have tried, and I am still not able, to interpret this Fuotation.
#21 0%,*; $,)-0"METH%+Y-(-&n--,*%,YAM,HETAM"#E
S>5"H<SISE A suspension of $)& g mossy 6inc in $)& m! H$9 containing &.2 g mercuric chloride 3as treated 3ith $)& m! concentrated HCl and
shaken as needed to effect amalgamation. "he H$9 3as then drained off, the 6inc 3ashed 3ith fresh 3ater and drained again. "here 3as added a
solution of 2+ g $,&@dimetho/ypropiophenone 'from the reaction of propionic acid and p@dimetho/yben6ene in the presence of polyphosphoric acid, see
under ;9A? for an effective general procedure- in (+, g <t9H. "he reaction mi/ture 3as held at reflu/ for $+ h 3ith the periodic addition of
concentrated HCl. It 3as then cooled, diluted 3ith H$9 and CH$Cl$, and the organic phase separated. "he aFueous phase 3as e/tracted 3ith $/(,,
m! additional CH$Cl$. "he combined organic phases 3ere 3ashed 3ith &K 5a9H until the 3ashes remained basic, once 3ith H$9, and then the
solvent 3as removed under vacuum. "he residue 3as distilled at the 3ater pump, giving an early fraction Fuite rich in starting p@dimetho/yben6ene, and
a second fraction '1( g, bp (+,@(1, deg C- 3hich 3as free of carbonyl group by infra@red, and 3hich 3as largely $,&@dimetho/ypropylben6ene. It 3as
used 3ithout further purification in the follo3ing aldehyde synthetic step.
A mi/ture of ($+ g 5@methylformanilide and (+, g P9Cl0 3as allo3ed to stand until there 3as the development of a strong red color. "here 3as then
added 1, g of the above $,&@dimetho/ypropylben6ene and the mi/ture 3as held on the steam bath for $ h. "he mi/ture 3as added to $ ! H$9 and
stirred until the e/cess acid chloride had completely decomposed. "he mi/ture 3as e/tracted 3ith 0/(,, m! CH$Cl$ and, after the removal of the
solvent from the combined e/tracts, the residue 3as e/tracted 3ith 0/(,, m! boiling he/ane. :emoval of the solvent gave the product $,&@dimetho/y@+@
propylben6aldehyde as an oil, $0 g, 3hich 3as characteri6ed as its malononitrile derivative. <Fual 3eights of the product and malononitrile in <t9H 3ith
a catalytic amount of triethylamine gave yello3 crystals 3hich, on recrystalli6ation from toluene, had a mp of ((0@((+ deg C.
A solution of $(.& g of the above crude $,&@dimetho/y@+@propylben6aldehyde in 2& g acetic acid, 3as treated 3ith (,.+ g nitroethane and 1.1 g
anhydrous ammonium acetate. "his 3as heated on the steam bath for (.2& h, then cooled and diluted 3ith H$9 to the point of turbidity. Iith long
standing and scratching, there finally 3as the deposition of crystals 3hich 3ere removed by filtration and sucked as dry as possible. "his $0 g of crude
product cake 3as triturated under ?e9H, filtered again, and air dried to give (( g of dull orange crystals. :ecrystalli6ation from boiling ?e9H gave (@
'$,&@dimetho/y@+@'n-@propylphenyl-@$@nitropropene as fine orange crystals 3hich 3eighed, after filtering, 3ashing, and drying, 2.+ g, and 3hich had a mp
of %+@%1 deg C.
"o a suspension of 1., g !AH in &,, m! anhydrous <t$9, 3hich 3as being stirred and also held as a gentle reflu/, there 3as added a saturated solution
of '$,&@dimetho/y@+@'n-@propylphenyl-@$@nitropropene in 3arm "HB. "he reaction mi/ture 3as held at reflu/ for $+ h, then cooled to room temperature.
"he e/cess hydride 3as destroyed by the cautious addition of &,, m! dilute H$S9+. "he phases 3ere separated, and the aFueous phase 3ashed 3ith
additional <t$9. "here 3as then added (&, g potassium sodium tartrate, and the pH 3as brought to U% 3ith aFueous 5a9H. "he product 3as
e/tracted 3ith <t$9 and, after removal of the solvent, the residue 3as dissolved in $,, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas. "he
solids that formed 3ere removed by filtration, giving 1.(& g $,&@dimetho/y@+@'n-@propylamphetamine hydrochloride ';9P:- as an electrostatic, 3hite
crystalline po3der, 3ith a mp of ()$.&@()0 deg C. "his 3as not improved by recrystalli6ation from either IPA or CH0C5.
;9SAC<E $.& @ &., mg.
;4:A"I95E $, @ 0, h.
L4A!I"A"IM< C9??<5"SE '3ith $., mg- "he onset is slo3er than any other thing I can think of. "here 3as nothing at all at the end of an hour, and
only a threshold a half hour later. .y the middle of the third hour, I 3as up to (*, and that seemed to be about as high as it intended to take me.
Attempts to sleep at the ninth hour 3ere not successful, as there 3ere strange patterns of not@Fuite logical thinking going on. Stuff likeE S"he block
events 'like a baby7s rectangular building blocks- that 3ere gotten, along 3ith other things, from the full octaves of the left hand in !ist67s Hungarian
:hapsody, events that allo3ed an easy recognition of the odds of achieving successful re@entry from any of several erotic codes.7 Clearly this 3as not a
baseline state. After si/ hours of successful sleep, I 3as still off@baseline , and on into the follo3ing day. Co on up 3ith curiosity but 3ith caution.
'3ith 0.1 mg- Imagery that 3as constructed in response to the music turned out to be necessary to organi6e and contain it. "he trio is the nucleus that
transforms the 3ritten to the heard, but it has created its o3n bubble 3ithout connections to the real 3orld, and must play on and on and on to keep itself
afloat and never touching the stage again.
'3ith &., mg- I am no3 at midnight, and still strongly ***. "his is certainly ma/imum dosage, at least for a long time. "here are faint intimations of
nervous system scrungies. >ou kno3, the kind of thing that makes you figure it7s going to be a 3hile before you7ll try to rela/ into sleep. "his material,
like all the other ;97s, is a heavy duty psychedelic, the kind that says to you, 7Borget all that stuff about screening out visuals,7 and then proceeds to
prove it. Sort of indole@like in that 3ay. >our body as 3ell as your mind tells you you7re into it, baby, and better rela/ and enGoy the trip, because you7ve
left the shore 3ay behind. Ihen it 3as time for bed, I got to sleep 3ith surprising ease, and slept for only about si/ hours. ?y dreams 3ere e/cellent,
balancing, and good humored. .ut the ne/t day I reali6ed I 3as still carrying the ;9P: in me, and that baseline 3as definitely not there. .ut it 3as 9.
5o problems e/cept for sleepiness. "he ne/t evening I 3ent to bed at unheard@of hour of % P? and slept for (0 hours, give or take. Bascinating
compound, but I 3on7t go out of my 3ay to take it again soon.
<="<5SI95S A5; C9??<5"A:>E "here is a thread of disconnection and of inconsistent reference that pervades most of the reports that I have
received concerning the use of ;9P:. "he 3ord that comes to mind is hypnogogic. "here is a drifting into that place that lies bet3een a not@Fuite@
a3ake and a not@Fuite@asleep state seems to characteri6e this compound. "here is no Fuestion but that it is very potent, and that it is very long@lived.
.ut there is a nagging suggestion of the out@of@body, out@of@center character that is the hallmark of the anesthetic and delusional drugs such as
scopolamine or ketamine. Iith them, the psychedelic effects become clouded 3ith touches of amnesia. If ;9P: sho3s this 3ith it7s three carbon alkyl
group, thereis every reason to pay close attention as the chain becomes longer.
"here had been Fuite a bit of speculation in the literature that the metabolic attack on ;9? 3as at the +@position, and this 3as an o/idation process. In
a moment of inspiration, I decided to e/plore a similar o/idation step in ;9P:, since it is probably the most potent of the ;9@series. Ihy not make the
compound 3hich 3ould be the first step in this o/idation, the (@hydro/ypropyl analogueH "his I did, by using the phthalimide derivative of $,&@
dimetho/yamphetamine 'described in the synthesis of ;9I- and making the propiophenone using propionic acid as both reagent and solvent, and
polyphosphoric acid as the condensing agent. "he ketone product 'a 3hite crystalline solid from methanol- 3as dissolved in 3arm methanol and
reduced to the alcohol 3ith sodium borohydride. "his product, also a 3hite crystalline solid, 3as stripped of the phthalimide blocking group 3ith
overnight reflu/ing 3ith hydra6ine in ethanol. "he product, $,&@dimetho/y@+@'(@hydro/ypropyl-@amphetamine 'hydro/y@;9P:- had a mp of (+)@(&, deg
C from IPA. Its activity is not yet kno3n, but there 3ere no effects at all at trials, orally, of up to $,, micrograms.
.ut this is all 3ith the normal@propyl compound. "here is a rich collection of misinformation and potential discovery that is associated 3ith the isopropyl
isomer. "his structural isomer, $,&@dimetho/yl@+@'i-@propylamphetamine is properly called ;9IP for des@o/y@iso@propyl. It has been synthesi6ed and
e/plored in animals and, to a modest e/tent, in man. "he synthesis has proceeded from $,&@dimetho/yacetophenone by the addition of a methyl group
to the carbonyl follo3ed by reduction to the hydrocarbon. Aldehyde formation, nitropropene synthesis 3ith nitroethane, and lithium aluminum hydride
reduction are uneventful, providing the hydrochloride salt ;9IP, 3hich has a mp of ()0@()+ deg C as an analytical sample. Animal tests 'such as rabbit
hyperthermia assays-, have indicated that the isopropyl compound ;9IP is less potent than the propyl prototype, ;9P:, by bet3een one and t3o
orders of magnitude. In man, a dose of four milligrams, a rousing dose of ;9P:, is 3ithout any effects. At (, milligrams, there is some disturbance but
substantially no effects. I have been told that 3ith doses in the $, to 0, milligram range there are valid changes in mental state, but I have not been told
the nature of these changes.
A fascinating red herring had been dra3n across all of these e/acting lines by a strange visitor to this research proGect. An olive@faced ?.;., Ph.;.,
passed through this confusing scene briefly, and 3hen he left, a small supply of ;9P: left 3ith him. He promptly published in an obscure Gournal some
animal behavioral responses 3hich he ascribed to the isopropyl analogue, ;9IP. .ut 3hat he had studied could only have been ;9P: since ;9IP, at
that time, had not yet been synthesi6ed either by me, or by either of the other t3o active synthesists of that moment. It 3as not yet a kno3n material.
Ie all made it some time later, but by that time our olive@face had disappeared. "here is a magnificent Brench phrase that applies here as no3here
else; Il a foutu le camp. Its idiomatic meaning is eFuivalent to our, NHe took off,N or NHe split the scene,N but the literal translation is, NHe fucked the
camp.N
#2$ E; ES!A"#E; ',)-0"METH%+Y-(-ETH%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 2$.0 g $,1@dimetho/yphenol in +,, m! ?e9H, there 3as added &0.0 g of a +,K solution of aFueous dimethylamine
folo3ed by +, g of a +,K aFueous solution of formaldehyde. "he dark solution 3as heated under reflu/ for (.& h on a steambath. "he volatiles 3ere
then removed under vacuum yielding a dark oily residue of $,1@dimetho/y@+@dimethylaminomethylphenol. "his residue 3as dissolved in +,, m! of IPA,
to 3hich there 3as added &, m! of methyl iodide. "he spontaneously e/othermic reaction deposited crystals 3ithin 0 min, and 3as allo3ed to return to
room temperature and occasionally stirred over the course of + h. "he solids 3ere removed by filtration, 3ashed 3ith cold IPA, and allo3ed to air dry
yielding (1, g of the methiodide of $,1@dimetho/y@+@dimethylaminomethylphenol as a cream@colored crystalline solid.
A suspension of (&& g of the above methiodide of $,1@dimetho/y@+@dimethylaminophenol in 1,, m! H$9 3as treated 3ith a solution of (0, g C5 in 0,,
m! H$9. "he reaction mi/ture 3as heated on a steam bath for 1 h during 3hich time there 3as a complete dissolving, the development of a bro3nish
color 3ith a bright blue film on the surface and the 3alls of the flask, and the gentle evolution of fine gas bubbles. "he hot reaction mi/ture 3as poured
into (.$ ! H$9 and acidified 3ith concentrated HCl 'careful, HC5 evolution-. "he aFueous solution 3as e/tracted 3ith 0/(&, m! CH$Cl$, the e/tracts
pooled, 3ashed 3ith saturated 5aHC90 3hich removed much of the color. "he solvent 3as removed under vacuum yielding about 2, g of a viscous
black oil. "his 3as distilled at ,.+ mm8Hg at (&,@(1, deg C to provide &$.+ g of homosyringonitrile '0,&@dimetho/y@+@hydro/yphenylacetonitrile- as a
3hite oil that spontaneously crystalli6ed to lustrous 3hite crystals that melted at &2@&) deg C.
A solution of &.2& g of homosyringonitrile and ($.( g ethyl iodide in &, m! dry acetone 3as treated 3ith 1.% g finely po3dered anhydrous $C90 and
held at reflu/ for () h. "he mi/ture 3as diluted 3ith (,, m! <t$9, filtered, and the filtrate solvent removed under vacuum "he residue 3as recrystalli6ed
from <t$98he/ane to yield &.2 g 0,&@dimetho/y@+@etho/yphenylacetonitrile 3ith a mp &2@&) deg C. Anal. 'C($H(&590- C,H,5.
A solution of $.$( g 0,&@dimetho/y@+@etho/yphenylacetonitrile in $& m! <t9H containing $.& m! concentrated HCl and +,, mg (,K palladium on
charcoal, 3as shaken in a &, lb8sF.in. atmosphere of hydrogen for $+ h. Celite 3as added to the reaction suspension and, follo3ing filtration, the
solvents 3ere removed under vacuum. "he residue 3as recrystalli6ed from IPA8<t$9 to yield $.(+ g 0,&@dimetho/y@+@etho/yphenethylamine
hydrochloride '<- 3ith a mp of (11@(12 deg C.
Synthesis from syringaldehydeE A 3ell@stirred suspension of $(.% g syringaldehyde in +& m! H$9 3as heated to reflu/ in a heating mantle. "here 3as
then added a solution of (& g 5a9H in 1, m! H$9. "he heating and stirring 3as continued until the generated solids redissolved. 9ver a period of (,
min, there 3as added $0 g diethyl sulfate, then reflu/ing 3as continued for ( h. Bour additional portions each of & g diethyl sulfate and of 1 m! $,K
5a9H 3ere alternately added to the boiling solution over the course of $ h. "he cooled reaction mi/ture 3as e/tracted 3ith <t$9, the e/tracts pooled
and dried over anhydrous ?gS9+, decolori6ed 3ith 5orite, and stripped of solvent. "he crude 0,&@dimetho/y@+@etho/y@ben6aldehyde 3eighed $(.) g
and melted at &(@&$ deg C.
A solution of (+.2 g 0,&@dimetho/y@+@etho/yben6aldehyde and 2.$ m! nitromethane in &, m! glacial acetic acid 3as treated 3ith +.+ g anhydrous am@
monium acetate and held at reflu/ for 0, min. Cooling the reaction allo3ed the formation of yello3 crystals 3hich 3ere removed by filtration and 3ashed
sparingly 3ith cold acetic acid. "he dried 0,&@dimetho/y@+@etho/y@beta@nitrostyrene 3eighed ((.& g and melted at (,)@(,% deg C after recrystalli6ation
from <t9H Anal. 'C($H(&59&- C,H. Alternately, this product may be prepared from 0.% g. 0,&@dimetho/y@+@etho/yben6aldehyde in 1, m! nitromethane
containing ,.2 g ammonium acetate and heated on a steam bath for ( h. "he solvent 3as removed under vacuum, and the residue dissolved in a
minimum of hot ?e9H. Cooling provided, after filtration and air drying, $.0 g of bright yello3 crystals of 0,&@dimetho/y@+@etho/y@beta@nitrostyrene, 3ith a
mp of (,&@(,2 deg C.
A solution of $.$& g !AH in +& m! anhydrous "HB 3as vigorously stirred and cooled to , deg C under He. "here 3as added (.& m! (,,K H$S9+
drop3ise, follo3ed by $.0 g 0,&@dimetho/y@+@etho/y@beta@nitrostyrene in anhydrous "HB. After the addition 3as complete, the mi/ture 3as allo3ed to stir
for 0, min, and then brought to room temperature. "he unreacted hydride 3as decomposed 3ith $.0 m! H$9 in "HB, follo3ed by the addition of %.$ m!
of (&K 5a9H. "he 3hite suspension 3as filtered, the filter cake 3as 3ashed 3ith "HB, the filtrate and 3ashings combined, and the solvent removed
under vacuum. "he residue 3as dissolved in 0,, m! dilute H$S9+, 3ashed 3ith $/2& m! CH$Cl$, made basic 3ith $&K 5a9H, and the product
e/tracted 3ith 0/2& m! CH$Cl$. After removal of the solvent, the residue 3as distilled at ((,@($, deg C at ,.0 mm8Hg yielding (.+ g of a colorless oil. A
solution of this oil in $, m! IPA 3as neutrali6ed 3ith (2 drops of concentrated HCl and diluted 3ith (,, m! anhydrous <t$9. After a fe3 minutes there
3as the spontaneous formation of 3hite crystals of 0,&@dimetho/y@+@etho/yphenethylamine hydrochloride '<- 3hich 3as recrystalli6ed from +, m!
boiling <t9Ac containing ( m! ?e9H. "he mp 3as (1&@(11 deg C.
;9SAC<E +, @ 1, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith +, mg- "his is a po3erful and comple/ into/icant L I could not have coordinated any rational muscular activity. I
could not 3alk; I could not tie my shoe@laces. "here is analgesia and an incoordination that I cannot shake. ?y menstrual flo3 started a bit ahead of
time, but it 3as light.
'3ith &, mg- I felt that the body tensions out3eighed the psychological and sensory re3ards, in that I had a lot of dehydration and my sleep had a
nightmare Fuality. "his pretty much offset the fe3 virtues that I felt I had obtained.
'3ith 1, mg- "here is a Fuality of rational analysis and insight that is totally impressive. ?any subtle factors in my life can be vie3ed 3ith insight, and
usefully dissected. I got into a deep discussion, but I 3as not argumentative or even defensive and I remained detached and kept a tone of cool
impersonality. I had a good appetite. .ut I also had some tachycardia and muscular tension. "here 3as unFuestionable sensory enhancement, but
3ithout an intellectual component. 9verall it 3as most pleasant.
<="<5SI95S A5; C9??<5"A:>E In an isolated situation, there is easy fantasy, but little synthesis of e/ternal sensory inputs such as music or visual
stimulae. A gradual decline brings the subGect back to a restful baseline some3here before the ($th hour. "he follo3ing day is often seen as one of
tiredness and lo3 energy. An anonymous flyer appeared in the California drug community in (%)+ stating an effective range to be &, to (,, milligrams,
but it described the drug as the sulfate. "he above data all pertain to the hydrochloride salt.
"he replacement of that one methyl group 3ith an ethyl group leads to a nice Geu de mots. "he play on 3ords depends on a remarkable coincidence.
"he name of the alkaloid mescaline stems from an ancient 5ahuatl 3ord for a drink '?e/calli- 3hich also provided the source of the term ?escal 'an
Agave of entirely different pharmacology-. "he prefi/ for the simplest, the one carbon organic radical, is methyl. "his is from the Creek 3ord NmethyN
and represents 3ine from 3ood. Such is, indeed, methyl alcohol, or methanol, or 3ood alcohol, the simplest one@carbon drink and a rather dangerous
one for the human animal. And this is the group that is on the central o/ygen of mescaline.
It is customary to refer to homologs 'bigger@by@one- of methanol by their classical chemical names, so the natural e/tension of methyl is ethyl, and that
of mescaline 3ould be escaline. 9ne carbon@chain on the +@position o/ygen becoming a t3o@carbon chain. "his is all entymologically appealing, but
there is no botanical support for any of it. "he ethyl group is much more rare in nature. It is Gust a happy coincidence that mescaline 'the plant-, and
methyl 'the alkyl group involved-, and metho/y 'the group on the +@position of the aromatic ring- all happen to start 3ith the letter :?S.
Mery fe3 of the homomescaline phenethylamines have been synthesi6ed as their three@carbon chain counterparts, the corresponding analogues of
amphetamine. And only three of them have been e/plored in man 'four, if you count the amphetamine analogue of mescaline itself, "?A-. "he obvious
names for these compounds have, unfortunately, already been used. It 3ould be logical to use the letter ? for a metho/y, and the letter < for etho/y,
etc. and simply read the groups from around the ring. .ut this is the naming system for the $,+,&@trisubstituted amphetamines. ?<? is, for e/ample,
$,&@dimetho/y@+@etho/yamphetamine 'in seFuence, metho/y, etho/y, metho/y reading around the ring, and a fascinating compound talked about at
length in this book-, so this term cannot represent 0,&@dimetho/y@+@etho/yamphetamine.
A truly simple code employs the length of the carbon chain. "he phenethylamine chain is t3o carbons long, and the amphetamine chain is three
carbons long.
If a drug has been initially developed 'and initially named- as an amphetamine derivative 'three carbon chain- then the t3o@carbon chain analogue 3ill
use the original name 'or a symbolic part of it- 3ith the term $C ahead of it. "he t3o@carbon analogue of ;9. 'a three@carbon chain compound- 3ill
become $C@.. ;9I becomes $C@I, ;95 becomes $C@5, and ;9<" becomes $C@<. <ach of these is a substituted amphetamine derivative lacking one
carbon atom, thus becoming a phenethylamine derivative. ?ost of these have $,+,&@substitution patterns.
And if a drug has been initially developed 'and initially named- as a phenethylamine derivative 't3o carbon chain- then the three@carbon chain analogue
3ill use the original name 3ith the term 0C ahead of it. "he three carbon analogue of < 'escaline, a t3o@carbon chain compound- 3ill become 0C@<. P
becomes 0C@P and CP? becomes 0C@CP?. ?ost of these have 0,+,&@substitution patterns.
"hus, :$@CS implies that a kno3n amphetamine drug has been shortened to a phenethylamine, and :0@CS inplies that a kno3n phenethylamine has
been lengthened to an amphetamine. A great number of the former have been made and have proven to be most re3arding. 9nly a fe3 of the latter
are kno3n, but most of them 3ill eventually prove to be potent psychedelics.

#2' EEE; $,(,)-T*"ETH%+YAM,HETAM"#E
S>5"H<SISE A solution of (0.0 g 0,+@dietho/yphenol 'see the recipe for ?<< for its preparation- in $, m! ?e9H, and a solution of +.) g 9H in (,, m!
hot ?e9H 3ere combined. "here 3as added ).$ g ethyl bromide and the mi/ture 3as held at reflu/ on the steam bath for $ h. "he reaction 3as
Fuenched by the addition of three volumes H$9, made strongly basic by the addition of (,K 5a9H, and e/tracted 3ith 0/(&, m! CH$Cl$. "he solvent
3as removed from the pooled e/tracts under vacuum giving a residue of %.( g (,$,+@trietho/yben6ene that solidified to a crystalline mass. "he mp 3as
$).&@$%.& deg C, but the infra@red analysis sho3ed the presence of unreacted phenol. "he CH$Cl$ solution 3as again 3ashed thoroughly 3ith (,K
5a9H and, after removal of the solvent, the solidified residue 3eighed 1., g and appeared free of impurities. "he mp of this sample 3as 00@0+ deg C.
"o a mi/ture of (,.& g 5@methyl formanilide and ((.% g P9Cl0 that had incubated at room temperature for ,.& h 'it had become Fuite red in color- there
3as added 1.+ g of the solid ether, (,$,+@trietho/yben6ene. "he mi/ture 3as heated on the steam bath for $.& h, then poured into &,, m! of shaved ice.
After a fe3 minutes stirring, crystals appeared. "he reaction 3as allo3ed to stand for a fe3 h, then filtered and sucked as dry as possible. "he damp
(+.+ g of slate@green crude solids 3ere dissolved in 0, m! boiling ?e9H, and allo3ed to cool to room temperature overnight. Biltration of the cream@
colored product, and air drying, gave 1.( g of $,+,&@trietho/yben6aldehyde 3ith a mp of %+@%& deg C. A solution containing ,.& g of this aldehyde and
,.+ g malononitrile in 2 m! absolute <t9H 3as treated 3ith three drops of triethylamine. "here 3as an immediate formation of granular yello3 crystals of
$,+,&@trietho/yben6almalononitrile 3hich, on filtering and air drying, 3eighed ,.+ g and had a mp of (1%@(2, deg C.
A solution of &., g $,+,&@trietho/yben6aldehyde and $.1 g nitroethane in (+.) g glacial acetic acid 3as treated 3ith (.1 g anhydrous ammonium acetate
and heated on the steam bath for $ h. "he addition of an eFual volume of H$9 gave a slightly turbid solution 3hich, upon the administration of a small
amount of e/ternally developed seed, smoothly set up as orange crystals as the reaction mi/ returned to room temperature. "he product 3as removed
by filtration, 3ashed 3ith a little &,K acetic acid, and allo3ed to air dry to constant 3eight. "here 3as thus obtained $.& g of fluffy yello3@orange 'almost
yello3- crystals of $@nitro@(@'$,+,&@trietho/yphenyl-propene 3ith a mp of %(@%$.& deg C. Anal. 'C(&H$(59&- C,H.
"o a gently reflu/ing suspension of (.2 g !AH in $,, m! anhydrous <t$9 under a He atmosphere, there 3as added $.& g $@nitro@(@'$,+,&@
trietho/yphenyl-propene by allo3ing the condensing <t$9 to drip into a shunted So/hlet thimble containing the nitrostyrene, thus effectively adding a
3arm saturated solution of the nitrostyrene drop3ise. :eflu/ing 3as maintained for & h, and then the reaction mi/ture 3as cooled 3ith an e/ternal ice
bath. "he e/cess hydride 3as destroyed by the cautious addition of 0,, m! (.& 5 H$S9+. Ihen the aFueous and <t$9 layers 3ere finally clear, they
3ere separated, and &, g of potassium sodium tartrate 3ere dissolved in the aFueous fraction. AFueous 5a9H 3as then added until the pH 3as above
%, and this 3as e/tracted 3ith 0/$,, m! CH$Cl$. :emoval of the solvent under vacuum produced an amber oil that 3as dissolved in anhydrous <t$9
and saturated 3ith anhydrous HCl gas. After a fe3 min delay, there com@menced the separation of fine 3hite crystals of $,+,&@trietho/yamphetamine
hydro@chloride, '<<<-. "hese 3eighed, after filtration, <t$9 3ashing, and air drying to constant 3eight, (.2& g and had a mp of (12@(1) deg C, 3ith
prior softening at (1$ deg C. Anal. 'C(&H$1Cl590- C,H,5.
;9SAC<E unkno3n.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "his amphetamine, the final item on the etho/y homologue of "?A@$ proGect, has never been tried in man. I do not
kno3 ho3 it tastes, but I suspect that it is probably bitter. An interesting sidelight concerning this proGect, and one 3hich can serve as a measure of the
enthusiasm that 3ent into it, is that 'e/cept for the $@etho/y homologue <??- all of the possible etho/y homologues of "?A@$, including ?<?, ??<,
<<?, <?<, ?<< and <<<, their precursor nitrostyrenes, the precursor aldehydes 'and their malononitrile derivatives-, the precursor ethers, and the
precursor phenols, for a total of 00 compounds, 3ere all synthesi6ed, purified, and characteri6ed 3ithin a period of Gust over three 3eeks. Actually it 3as
$0 days, and that 3as a magically e/citing time.
And there 3ere t3o true treasures that came out of it all. "he compound ?<?, and the kno3ledge that the +@position 3as 3here the action is.

#2( EEM; $,(-0"ETH%+Y-)-METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of ($.0 g 0@etho/y@+@metho/yphenol 'see recipe for ?<? for the preparation of this phenol- in $, m! ?e9H, there 3as
added a 3arm solution of +.) g 9H in (,, m! ?e9H. "here 3as then added ).$ g ethyl bromide, and the mi/ture held at reflu/ on the steam bath.
Iithin ,.& h, severe bumping ensued. An additional 0 g ethyl bromide 3ere added, reflu/ing continued for another ,.& h, then the reaction mi/ture 3as
allo3ed to come to room temperature and to stand overnight. It 3as poured into 0 volumes H$9 3hich produced crystals spontaneously. "here 3as
added additional base, and the mi/ture 3as e/tracted 3ith 0/(&, m! CH$Cl$. :emoval of the solvent from the pooled e/tracts under vacuum gave 1.+
g of $,+@dietho/yanisole as tan crystals 3ith a mp of +)@+).& deg C.
A mi/ture of (,.% g 5@methylformanilide and ($.0 g P9Cl0 3as allo3ed to stand at room temperature for ,.& h producing a deep red claret color. "here
3as then added 1.$ g $,+@dietho/yanisole and the mi/ture 3as heated on the steam bath for $ h. All 3as poured into $,, g chipped ice, and stirred
mechanically. "he dark viscous gummy oil gradually became increasingly granular and finally appeared as Gade@green solids. "hese 3ere removed by
filtration and 3ashed 3ith H$9, giving a 3et cake 3eighing () g and having a mp 'from a porous plate- of %&.&@%1.& deg C. "he entire crop 3as
recrystalli6ed from 2& m! boiling ?e9H 3hich gave, after filtering, 3ashing lightly 3ith cold ?e9H, and air drying, &.+ g of $,+@dietho/y@&@
metho/yben6aldehyde 3ith a mp of %)@%% deg C. A solution of ,.$ g of this aldehyde, and ,.0 g malononitrile in $., m! 3arm <t9H 3as treated 3ith a
drop of triethyl@amine. "here 3as an immediate generation of crystals 3hich 3ere removed by filtration, <t9H@3ashed, and dried to constant 3eight.
"he bright yello3 needles of $,+@dietho/y@&@metho/yben6almalononitrile 3eighed ,.(& g and had a mp of (2$@(2$.& deg C.
A solution of &., g $,+@dietho/y@&@metho/yben6aldehyde in (1 g glacial acetic acid 3as treated 3ith $.2 g nitroethane follo3ed by (.2 g anhydrous
ammonium acetate. "he mi/ture 3as heated for $.& h on the steam bath, then removed and diluted 3ith a eFual volume of H$9. Iith cooling there
3as the generation of a heavy crop of orange crystals 3hich 3as removed, 3ashed 3ith &,K acetic acid, and sucked as dry as possible. "he product
had a mp of %2@(,+ deg C, and there 3as spectrographic evidence of some unreacted starting aldehyde. A small sample 3as recrystalli6ed from boiling
?e9H, 3ith considerable loss, to give an analytical sample of (@'$,+@dietho/y@&@metho/yphenyl-@$@nitropropene as orange@yello3 crystals 3ith a mp of
(($@((0 deg C. Anal. 'C(+H(%59&- C,H. "he unpurified first crop 3as employed in the follo3ing synthesis of the corresponding amphetamine.
"o a gently reflu/ing suspension of $.% g !AH in +,, m! anhydrous <t$9 under a He atmosphere, there 3as added +., g of impure (@'$,+@dietho/y@&@
metho/yphenyl-@$@nitropropene by allo3ing the condensing ether to drip into a shunted So/hlet thimble apparatus containing the nitrostyrene. "his
effectively added a 3arm saturated solution of the nitrostyrene drop3ise over the course of ( h. :eflu/ing 3as maintained for & h and the reaction
mi/ture 3as cooled 3ith an e/ternal ice bath 3ith the stirring continued. "he e/cess hydride 3as destroyed by the cautious addition of +,, m! of (.& 5
H$S9+. Ihen the aFueous and <t$9 layers 3ere finally clear, they 3ere separated, and (,, g of potassium sodium tartrate 3as dissolved in the
aFueous fraction. AFueous 5a9H 3as then added until the pH 3as above %, and this 3as then e/tracted 3ith 0/(&, m! CH$Cl$. :emoval of the
solvent under vacuum produced $.2 g of a pale amber oil that 3as dissolved in 0,, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas. After a
fe3 minutes delay, there commenced the separation of fine 3hite crystals of $,+@dietho/y@&@metho/yamphetamine hydrochloride '<<?-. After the
crystalli6ation 3as complete, these 3ere removed by filtration, 3ashed 3ith <t$9 and air dried, providing $.&& g of a fine 3hite crystalline solid 3ith mp
(&)@(&% deg C. Anal. 'C(+H$+Cl590- C,H,5.
;9SAC<E unkno3n.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "his particular identity and arrangement of the alko/y groups on the amphetamine molecule, <<?, is a totally
une/plored molecule. It is reasonable to assume that it 3ould be 3ay do3n in potency, but there is no 3ay of guessing 3hat the nature of its activity
might be at the dosage that 3ould be active.

#2) EME; $,)-0"ETH%+Y-(-METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of (+., g +@etho/y@0@metho/yphenol 'see the recipe for ??< for the preparation of this starting material- in an eFual volume
of <t9H, there 3as added a solution of &.0 g 9H in (,, m! hot ?e9H. "his 3as follo3ed 3ith %.( g ethyl bromide, and the mi/ture 3as held at reflu/
for $ h. "he first deposition of .r 3as apparent in & min, and there 3as rather severe bumping by the end of the reaction. "he mi/ture 3as diluted 3ith
0 volumes H$9 and ( volume &K 5a9H, and e/tracted 3ith $/$,, m! <t$9. "he e/tracts 3ere pooled, and the solvent removed under vacuum,
yielding (+.0 g of a pale amber oil that set to crystals of $,&@dietho/yanisole 3ith a mp of ++@+& deg C. "he compound had been reported in the literature
from the action of diethyl sulfate on metho/yhydroFuinone.
"o a mi/ture of $+.( g 5@methylformanilide and $2.0 g P9Cl0 that had been allo3ed to stand at room temperature until strongly red@colored 'about ,.& h-
there 3as added (0.) g solid $,&@dietho/yanisole and the mi/ture 3as heated on the steam bath for $ h. "he black, thick reaction product 3as poured
over chipped ice and, 3ith continuous stirring, the color lightened and there 3as the formation of a yello3ish po3der. After a fe3 h standing, this 3as
removed by filtration and sucked as dry as possible. "he 0$ g of damp product sho3ed the presence of isomeric contaminatiion by CC, and the
aFueous mother liFuor, upon e/traction 3ith CH$Cl$ and concentration, sho3ed yet more aldehyde@like impurities. "he isolated solids 3ere
recrystalli6ed from ($& m! boiling ?e9H giving (&.) g yello3ish crystals '3et 3eight- that still sho3ed detectable impurities by CC. A second
recrystalli6ation from (,, m! boiling ?e9H gave off@3hite fluffy crystals of $,&@dietho/y@+@metho/yben6aldehyde 3hich 3eighed, after air drying, ).& g.
"he mp 3as (,%@((, deg C. "he combined mother liFuors from the t3o ?e9H crystalli6ations 3ere stripped of solvent, and the resulting solid mass
crystalli6ed again from ?e9H to give a second crop of aldehyde, &.2 g, 3ith a mp of ((,@((( deg C. A solution of (., g of this aldehyde and ,.2 g
malononitrile in +, m! 3arm absolute <t9H 3as treated 3ith a fe3 drops of triethylamine. In a minute or so, there 3as the formation of crystals. "hese
3ere removed by filtration, 3ashed 3ith <t9H, and air dried, giving ,.1 g of $,&@dietho/y@+@metho/yben6almalononitrile as brilliant yello3 crystals 3ith a
mp of (&1.&@(&) deg C.
A solution of 1.2 g $,&@dietho/y@+@metho/yben6aldehyde in $( g glacial acetic acid 3as treated 3ith 0.( g nitroethane and (.%0 g anhydrous ammonium
acetate, and heated on the steam bath for $.& h. "he addition of a small amount of H$9 to the hot reaction mi/ture instituted crystalli6ation of an orange
product 3hich, after the mi/ture had come to room temperature and stood for several h, 3as removed by filtration, H$9 3ashed, and air dried. "he
product, (@'$,&@dietho/y@+@metho/yphenyl-@$@nitropropene, 3as dull orange in color, 3eighed 0., g and had a mp of )+@)1 deg C. An analytical sample
from toluene had a mp of )&@)1 deg C. Anal. 'C(+H(%59&- C,H.
"o a gently reflu/ing suspension of $., g !AH in $&, m! anhydrous <t$9 under a He atmosphere, there 3as added $.) g (@'$,&@dietho/y@+@
metho/yphenyl-@$@nitropropene by allo3ing the condensing <t$9 to drip into a shunted So/hlet thimble containing the nitrostyrene. "his effectively
added a 3arm saturated solution of the nitrostyrene drop3ise. "he addition took ( h and the reflu/ing 3as continued for an additional 1 h. "he reaction
mi/ture 3as brought do3n to ice@bath temperature, and the e/cess hydride 3as destroyed by the cautious addition of (&, m! (.& 5 H$S9+. Ihen the
aFueous and <t$9 layers 3ere finally clear, they 3ere separated and &, g of potassium sodium tartrate 3ere dissolved in the aFueous fraction. AFueous
5a9H 3as then added until the pH 3as U%, and this 3as then e/tracted 3ith 0/(&, m! CH$Cl$. :emoval of the solvent under vacuum produced $.0 g
of a clear 3hite oil that 3as dissolved in 0,, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas. At first the solution remained completely clear,
and finally there 3as the start of the formation of fine 3hite crystals. Ihen the crystalli6ation 3as complete, these solids 3ere removed by filtration,
<t$9 3ashed, and air dried. "here 3as thus obtained $.$ g of $,&@dietho/y@+@metho/yamphetamine hydrochloride '<?<- 3ith a mp of (1$@(1+ deg C
3ith prior softening at (&+ deg C. Anal. 'C(+H$+Cl590- C,H,5.
;9SAC<E unkno3n.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "his is another of the collection of all possible etho/y homologues of "?A@$. "he latter and heavier members of
this series 3ere synthesi6ed and completed before the directions of biological activity had become evident from the earlier ones. "his compound has
never been assayed, and it is a reasonable guess that it 3ill have a very lo3 potency, 3ith hints of to/icity at higher dose levels. I suspect that it 3ill
never be assayed, certainly not by me.

#21 EMM; (,)-0"METH%+Y-$-ETH%+YAM,HETAM"#E
S>5"H<SISE A solution of (11 g 0,+@dimetho/yben6aldehyde in 1,, m! acetic acid 3as 3ell stirred, and brought up to an internal temperature of e/actly
$& deg C. "here 3as added, in very small portions, a +,K solution of peracetic acid in acetic acid. "he evolved heat 3as removed 3ith an e/ternal ice
bath, and the rate of addition 3as dictated by the reFuirement that the internal temperature should not e/ceed $& deg C. A total of $(, g of the +,K
peracetic acid 3as used. "he reaction mi/ture 3as poured into 0 ! H$9, and the acetic acid neutrali6ed by the addition of solid $C90. "he neutral
aFueousphase 3as e/tracted 3ith &/(&, m! <t$9, and the solvent from the pooled e/tracts 3as removed under vacuum. "o the red@colored residue
there 3as added 0,, m! (,K 5a9H, and the mi/ture 3as heated for ( h on the steam bath. "his 3as cooled, 3ashed once 3ith CH$Cl$, acidified 3ith
HCl, and e/tracted 3ith &/(&, m! <t$9. "he pooled e/tracts 3ere 3ashed once 3ith saturated 5aHC90 '3hich removed most of the color- and the
removal of the solvent under vacuum gave (,& g of 0,+@dimetho/yphenol as an amber oil that slo3ly set up to crystals.
"he above crude 0,+@dimetho/yphenol 3as dissolved in $,, m! <t9H, and treated 3ith a solution of 0).( g 9H in 0,, m! hot <t9H. "he clear
solution of the potassium salt 3as a deep red color, and 3as promptly treated 3ith %+.0 g allyl bromide, at a rate commensurate 3ith the e/othermic
reaction. "he mi/ture 3as held at reflu/ for $ h. "his 3as then added to ( ! H$9 and e/tracted 3ith &/(,, m! <t$9. "he e/tracts 3ere pooled, and
removal of the solvent under vacuum gave a residue of %) g of a black oil. "his 3as distilled at (,+@(,) deg C at ,.2@(., mm8Hg to give &%.0 g (@
allylo/y@0,+@dimetho/yben6ene as a pale yello3 oil 3ith a greenish cast.
A total of &% g of the neat (@allylo/y@0,+@dimetho/yben6ene 3as provided 3ith an internal thermometer, and heated 3ith an open flame. "he color Fuickly
became purple, then lightened to a red at 2, deg C, and finally to a pale pink by $(, deg C. At $+, deg C an e/othermic reaction set in 3ith the
temperature going up to almost $%, deg C. It 3as held in the $2,@$), deg C range for several min, then allo3ed to return to room temperature. CC
analysis sho3ed t3o peaks, the second and maGor one being the desired (,$,+,&@isomer. A small sample 3as caught by prep@CC, and it successfully
seeded the crude Claissen rearrangement product. "he isolated $@allyl@+,&@dimetho/yphenol, pressed on a porous plate, had a mp of 0%.&@+,.& deg C
3hich 3as improved to +(.&@+$ deg C by recrystalli6ation from he/ane.
"o a solution of %.2 g $@allyl@+,&@dimetho/yphenol in a fe3 m! <t9H, there 3as added a solution of $.) g 9H in $& m! boiling <t9H follo3ed by &.& g
ethyl bromide. "he mi/ture 3as held at reflu/ for 0.& h and then poured into $,, m! H$9 and e/tracted 3ith 0/(,, m! CH$Cl$. Pooling the e/tracts
and removal of the solvent under vacuum gave a residue of (,.+ g of +,&@dimetho/y@$@etho/y@(@allylben6ene as a clear, mobile oil. It 3as substantially a
single component by CC and 3as used in the follo3ing isomeri6ation step 3ithout further purification.
A solution of %.+ g +,&@dimetho/y@$@etho/y@(@allylben6ene in (, m! <t9H 3as treated 3ith $, g flaked 9H, and heated on the steam bath. "he
progress of the isomeri6ation 3as follo3ed by the assay of isolates by CC. After & h, the reaction mi/ture 3as poured into $&, m! H$9 3hich
immediately generated a pasty solid. "his 3as sucked free of solvent and other liFuids on a sintered funnel, giving &.& g of trans@+,&@dimetho/y@$@
etho/y@(@propenylben6ene as an amber solid 3ith a mp of 1&@12 deg C. A small analytical sample from he/ane had a mp of 1) deg C.
A solution of &., g trans@+,&@dimetho/y@$@etho/y@(@propenylben6ene in $2 g acetone that contained $.$ g pyridine 3as magnetically stirred and cooled to
, deg C. "here 3as then added +.& g tetranitromethane and, after $ minutes stirring at this temperature, the reaction mi/ture 3as Fuenched 3ith a
solution of (.& g 9H in $1 m! H$9. "he reaction mi/ture remained a clear deep orange color, and additional H$9 3as reFuired to institute
crystalli6ation. "here 3as the slo3 deposition of bright yello3 crystals of (@'+,&@dimetho/y@$@etho/yphenyl-@$@nitro@propene 3hich 3eighed, after <t9H
3ashing and air drying to constant 3eight of +.+ g. "he mp 3as 2&@21 deg C.
"o a gently reflu/ing suspension of 0.& g !AH in $&, m! anhydrous <t$9 under a He atmosphere, there 3as added 0.% g (@'+,&@dimetho/y@$@
etho/yphenyl-@$@nitropropene by allo3ing the condensing <t$9 to drip into a shunted So/hlet apparatus 3ith the thimble containing the nitrostyrene.
"his effectively added a 3arm saturated solution of the nitrostyrene drop3ise; the nitrostyrene 3as very soluble in <t$9. :eflu/ing 3as maintained for
$.& h and the reaction continued to stir at room temperature for an additional 0.& h. "he e/cess hydride 3as destroyed by the cautious addition of $$&
m! (.& 5 H$S9+. Ihen the aFeous and <t$9 layers 3ere finally clear, they 3ere separated, and 2& g of potassium sodium tartrate 3as dissolved in
the aFueous fraction. AFueous 5a9H 3as then added until the pH 3as U%, and this 3as then e/tracted 3ith 0/(,, m! CH$Cl$. <vaporation of the
solvent under vacuum produced $.) g of a clear, almost colorless oil that 3as dissolved in anhydrous <t$9 and saturated 3ith anhydrous HCl gas. "his
initially generated a solid that then oiled out. After a fe3 minutes stirring, this began to solidify again and it finally transformed into a loose fine 3hite
solid. "his 3as recrystalli6ed by dissolution in &, m! 3arm IPA follo3ed by dilution 3ith 0,, m! <t$9. After a fe3 minutes, crystals of +,&@dimetho/y@$@
etho/yamphetamine hydrochloride '<??- formed 3hich 3ere removed by filtration, <t$9 3ashed, and air dried. "hese 3eighed $.2 g and had a mp of
(2(@(2$ deg C. Anal. 'C(0H$$Cl590- C,H,5.
;9SAC<E greater than &, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith &, mg- "here 3ere no effects.
<="<5SI95S A5; C9??<5"A:>E "his 3as the first of the etho/y homologues of "?A@$, and it 3as immediately '3ell, 3ithin a couple of months- run
up from an initial dab to $& milligrams. "his 3as in early (%10, and the lack of activity of <?? 3as keenly disappointing. "his 3as a level at 3hich the
prototype, "?A@$, 3as very active, and the conclusion 3as that maybe any change on the molecule 3ould result in a loss of activity. So this approach
3as shelved for a 3hile, and all efforts 3ere directed into the relocation, rather than the elongation, of the metho/y groups. A fe3 months later, the
etho/y Fuestion 3as addressed again, and the discovery of ?<? rekindled full interest in this etho/y Fuestion.

#22 ETHY-;; $-ETHYAM"#%-1-&',(-METHYE#E0"%+Y,HE#Y-./TA#E; #-ETHY-1-&1,'-.E#6%0"%+%-)-Y--$-./TA#AM"#E
S>5"H<SISE A stirred solution of %., g (@'0,+@methylenedio/yphenyl-@$@butanone 'see the recipe for D for its preparation- in (&, m! ?e9H 3as treated
3ith %., g ethylamine hydrochloride, +., g anhydrous 5a9Ac, and 0., g sodium cyanoborohydride. "he pH 3as maintained bet3een 1 and 2 by the
periodic addition of HCl. After the base formation had stabili6ed, there 3as added an additional %., g ethylamine hydrochloride, %., g 5a9Ac and $., g
sodium cyanoborohydride. Iith continuous stirring, there 3as HCl added over the course of ( h until the final pH 3as appro/imately $. "he reaction
mi/ture 3as poured into 2,, m! dilute 5a9H, and e/tracted 3ith 0/2& m! CH$Cl$. "hese e/tracts 3ere pooled, and back@e/tracted 3ith dilute H$S9+.
"his 3as 3ashed 3ith $/&, m! CH$Cl$, then made basic 3ith dilute 5a9H and e/tracted 3ith $/2& m! CH$Cl$. :emoval of the solvent under vacuum
gave a ,.)( g residue 3hich 3as dissolved in (, m! IPA. 5eutrali6ation 3ith concntrated HCl formed 3hite crystals spontaneously. "hese 3ere diluted
3ith <t$9, filtered, <t$9 3ashed and air dried to provide ,.)& g $@ethylamino@(@'0,+@methylenedio/y@phenyl-butane hydrochloride '<"H>!@D-, 3ith mp of
(21@(22 deg C. Anal. 'C(0H$,Cl59$- C,H. "he neutral fraction that remained in the organic phase follo3ing the dilute sulfuric acid e/traction, 3as
recovered by removal of the solvent under vacuum. "here 3as obtained about & g of an amber liFuid that 3as largely $@hydro/y@(@'0,+@
methylenedio/yphenyl-butane.
;9SAC<E greater than %, mg.
;4:A"I95E probably short.
L4A!I"A"IM< C9??<5"SE '3ith 1& mg- Perhaps a3are at $, minutes. ;efinitely a3are at +& minutes. ;iffusing to nothing at 0@+ hours.
'3ith %, mg- I am some3here bet3een ( and *. And everything became lost in the evening 3ith a couple of glasses of 3ine and talk that 3ent on to 0
A?.
<="<5SI95S A5; C9??<5"A:>E And nothing higher has ever been looked at. If the analogy 3ith the amphetamine counterparts 'D 3ith ?;A,
?<"H>!@D 3ith ?;?A, and this, 3ith ?;<- 3ere to hold up 'a drop of about a third in potency 3ith the lengthening of the chain by a carbon atom-, one
might guess that this compound 3ould be an interesting into/icant, but probably not until you got up into the area at or above a $,, milligram dose. And
that is a lot of chemical for the body to have to handle. Some day, maybe.
#23 ETHY-<; $-ETHYAM"#%-1-&',(-METHYE#E0"%+Y,HE#Y-,E#TA#E;
#-ETHY-1-&1,'-.E#6%0"%+%-)-Y--$-,E#TYAM"#E
S>5"H<SISE A solution of ($, mg mercuric chloride in (1, m! H$9 3as poured over +.2 g aluminum foil ':eynolds Irap, regular 3eight, cut into ( inch
sFuares- and allo3ed to stand until the amalgamation 3as 3ell under3ay 'about 0, min-. "he H$9 3as then drained and the foil 3ashed 3ith $/$,, m!
H$9 3ith thorough draining. "here 3as then added, in seFuence and 3ith good s3irling and agitation bet3een each addition, ).& g ethylamine
hydrochloride dissolved in 2 m! H$9, $( m! IPA, (2 m! $&K 5a9H, 2.( g (@'0,+@methylenedio/yphenyl-@$@pentanone 'see the recipe for ?<"H>!@ for
its preparation-, and finally +, m! IPA. "he reaction mi/ture 3as periodically heated on the steam bath to keep the reaction moving and active. After all
the metal had been consumed, the mi/ture 3as filtered, and the filter cake 3ashed 3ith ?e9H. "he solvent 3as removed from the combined filtrate and
3ashings, and the residue suspended in ),, m! dilute HCl. "his 3as 3ashed 3ith 0/(,, m! <t$9, made basic 3ith $&K 5a9H, and e/tracted 3ith
0/(,, m! CH$Cl$. "he pooled e/tracts 3ere stripped of solvent under vacuum yielding a residue of 1.0 g of an amber oil. "his 3as distilled at ((&@($&
deg C at ,.+ mm8Hg to give &.1( g of an almost 3hite liFuid 3hich 3as dissolved in $) m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith (,,
m! anhydrous <t$9. "he resulting clear solution became cloudy, then set up in a cottage cheese te/ture, and then all broke up to a beautiful loose
solid. "his 3as filtered, <t$9 3ashed and air dried to give &.%% g $@ethylamino@(@'0,+@methylenedio/yphenyl-pentane hydrochloride '<"H>!@- 3ith a
mp of (&2@(&) deg C. Anal. 'C(+H$$Cl59$- C,H.
;9SAC<E 'greater than +, mg-.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith +, mg- "here 3as a paresthetic t3inge in my shoulder area at about an hour L other than that, absolutely nothing.
<="<5SI95S A5; C9??<5"A:>E And that is as high a dose as has apparently ever been tried 3ith <"H>!@. "he compounds 3ith the he/ane
chain '!@series- rather than the pentane chain of the @series have been made, but they have been spun into the recipe for ?<"H>!@.

#24 7-$; $-M; 1-&$-AM"#%,*%,Y--)-METH%+Y-$-METHY-$,'-0"HY0*%.E#6%7/*A#
S>5"H<SISE "o a solution of +0.$ g 9H pellets in $&, boiling <t9H there 3as added %1 g +@metho/yphenol follo3ed by the slo3 addition of (0(.$ g
allyl bromide, and the mi/ture 3as held under reflu/ing conditions for (1 h. After cooling, the reaction 3as added to (.1 ! H$9, and made strongly basic
3ith $&K 5a9H. "his 3as e/tracted 3ith 0/(,, m! CH$Cl$, the e/tracts pooled, 3ashed once 3ith dilute 5a9H and then once 3ith dilute HCl.
:emoval of the solvent under vacuum gave %0.) g of +@allylo/yanisole as a pale amber oil, 3hich 3as used in the follo3ing reaction 3ithout further
purification.
A round@bottomed flask containing %0 g crude +@allylo/yanisole 3as eFuipped 3ith an immersed thermometer and heated 3ith an e/ternal flame until an
e/othermic reaction set in at $0, deg C. "he temperature rose to $2, deg C and it 3as maintained there 3ith the flame for five minutes. After cooling to
room temperature, the reaction mi/ 3as poured into $ ! H$9 and made strongly basic 3ith the addition of $&K 5a9H. "his dark aFueous phase 3as
3ashed 3ith $/$,, m! CH$Cl$, and then acidified 3ith HCl. "his 3as then e/tracted 3ith $/$,, m! CH$Cl$, and the pooled e/tracts 3ashed first 3ith
saturated 5aHC90 and then 3ith H$9. :emoval of the solvent under vacuum gave 1&.1 g of $@allyl@+@metho/yphenol as a clear, amber oil. "o a
solution of (.11 g of this crude phenol in & m! he/ane 3ith Gust enough CH$Cl$ added to effect a clear solution, there 3as added (.0 g phenyl
isocyanate follo3ed 3ith three drops of triethylamine. An e/othermic reaction ensued 3hich spontaneously deposited 3hite crystals. "hese 3as
removed and he/ane 3ashed to give $@allyl@+@metho/yphenyl 5@phenyl carbamate, 3ith a mp of ))@)% deg C. "he acetate ester, from the phenol and
acetic anhydride in pyridine, did not crystalli6e.
"o a solution of 02.2 g $@allyl@+@metho/yphenol in ($& m! glacial acetic acid there 3as added (% g 6inc chloride follo3ed 3ith 10 m! concentrated HCl.
"he mi/ture 3as held at reflu/ temperature for +, min, then cooled to room temperature, diluted 3ith 0,, m! H$9, and e/tracted 3ith $/$,, m!
CH$Cl$. "he pooled e/tracts 3ere 3ashed repeatedly 3ith )K 5a9H until the 3ashings remained basic. :emoval of the solvent under vacuum gave a
clear pale yello3 oil that 3as distilled at the 3ater pump. A fraction boiling at (&,@(1& deg C 3as &@metho/y@$@methyl@$,0@dihydroben6ofuran 3hich
3eighed $& g and 3hich 3as a highly refractive colorless oil. "he infra@red spectrum indicated that some small amount of hydro/y group 3as present,
but the 5?: spectrum 3as in complete accord 3ith the ben6ofuran structure. A higher cut in this distillation gave +.& g of a phenolic product tentatively
assigned the structure of +@metho/y@$@propenylphenol. "he target dihydroben6o@furan has also been synthesi6ed from the open@ring o@allyl phenol in
acetic acid solution 3ith the addition of a catalytic amount of concentrated H$S9+.
"o a half@hour pre@incubated mi/ture of 1% g P9Cl0 and 1, g 5@methylformanilide there 3as added $%., g &@metho/y@$@methyl@$,0@dihydroben6ofuran
and the mi/ture 3as heated on the steam bath for $ h. "he reaction mi/ture 3as poured into ( ! H$9, and allo3ed to stir overnight. "he bro3n gummy
solids 3ere removed by filtration, and air dried as completely as possible. "hese 3eighed 0$ g and 3ere sho3n by CC on 9M@(2 to consist of t3o
ben6aldehyde isomers in a ratio of 2E$. "his 3as triturated under () m! ?e9H, and the undissolved solids removed by filtration and 3ashed 3ith 1 m!
additional ?e9H. "he mother liFuor and 3ashings 3ere saved. "he (2.)g of dull yello3 solids that 3ere obtained 3ere repeatedly e/tracted 3ith 2& m!
portions of boiling he/ane '+ e/tracts 3ere reFuired- and each e/tract, on cooling, deposited yello3 crystals of the maGor aldehyde. "he dried crystals of
1@formyl@&@metho/y@$@methyl@$,0@dihydroben6ofuran 3ere combined '%.& g- and had a mp of ),@)$ deg C. "he methanol 3ashes saved from above
3ere stripped of solvent, and the sticky, orange solids that remained 3ere enriched in the minor aldehyde isomer '0E$ ratio-. Several inGections of this
crude material into a preparative CC 9M@(2 column gave sufficient Fuantities of the N3rongN isomer for 5?: characteri6ation. "he $@methyl group 3as
intact 'eliminating the possibility of a dihydroben6opyran isomer- and the ring meta@proton splitting reFuired that the formyl group be in the ben6ofuran 2@
position. "his crystalline solid 3as, therefore, 2@formyl@&@metho/y@$@methyl@$,0@dihydroben6ofuran.
A solution of % g of 1@formyl@&@metho/y@$@methyl@$,0@dihydroben6ofuran in 0& m! glacial acetic acid 3as treated 3ith 1 m! of nitroethane follo3ed 3ith
0.( g anhydrous ammonium acetate. "his mi/ture 3as heated on the steam bath for + h, diluted 3ith half its volume 3ith 3arm H$9, and seeded 3ith a
bit of product that had been obtained separately. "he slightly turbid solution slo3ly crystalli6ed as it cooled, and 3as finally held at , deg C for several h.
"he deep orange product 3as removed by filtration, 3ashed 3ith &,K acetic acid, and air dried to constant 3eight. "here 3as thus obtained 2., g &@
metho/y@$@methyl@1@'$@nitro@(@propenyl-@$,0@dihydroben6ofuran 3ith a mp of )%@%, deg C from ?e9H.
A suspension of &., g !AH in &,, m! of 3ell stirred anhydrous <t$9 at a gentle reflu/, 3as treated 3ith a 3arm, saturated solution of 2., g &@metho/y@$@
methyl@1@'$@nitro@(@propenyl-@$,0@dihydroben6ofuran in <t$9 added drop3ise. "he mi/ture 3as kept at reflu/ temperature for 01 h, allo3ed to stand $
days, and then the e/cess hydride destroyed by the cautious addition of &,, m! 1K H$S9+. "he phases 3ere separated, and the aFueous phase
3ashed 3ith $/$,, m! CH$Cl$. A total of ($& g potassium sodium tartrate 3as added to the aFueous phase, and sufficient $&K 5a9H added to bring
the pH to about (,. "his phase 3as e/tracted 3ith 0/(&, m! CH$Cl$, and the pooled e/tracts 3ere stripped of solvent under vacuum. "he residual oil
'+.) g, amber in color- 3as dissolved in 0,, m! anhydrous <t$9 3hich, upon saturation 3ith anhydrous HCl gas gave a clear solution that suddenly
deposited 3hite crystals. "he hydrochloride salt of 1@'$@aminopropyl-@&@metho/y@$@methyl@$,0@dihydroben6ofuran 3eighed $.0 g and 3as not
satisfactory as a solid derivative, but it appears that the o/alate salt is both nonhygroscopic and Fuite stable. It 'B@$- had a mp of $(1@$() deg C and it
displayed a te/tbook 5?:.
;9SAC<E greater than (& mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "his material, 3hich is certainly a mi/ture of t3o diastereoisomeric pairs of racemates since there are t3o chiral
centers present, sho3ed no effects at levels of up to (& milligrams orally. ;oses of (,, mg8g 3ere 3ithout effects in mice follo3ing i.p. inGections,
although half again this amount proved to be lethal. In rats trained to discriminate !S; from saline, B@$ proved to be about +, times less potent than the
reference compound ;9?, reFuiring some & mg8g for positive responses. .ut the human trials 3ere only up to about ,.$ mg8g.
"his 3as the prototype compound that 3as originally put together to Gustify giving a paper at a mariGuana conference in S3eden, in (%1). Although I had
never done much 3ith mariGuana or 3ith its principal ingredients, I thought maybe I could bend the topic a bit to embrace some potentially active
phenethylamines. "here is a story of an international conference held in Ceneva a fe3 years earlier to discuss the 3orrisome decrease in the elephant
population. A Cerman 6oologist invested a full eight@hour day in a summary of his $( volume treatise on the anatomy and the physiology of the
elephant. A Brench sociologist presented a lively slide sho3 on the mating rituals and rutting behavior of the elephant. And a rabbi from "el Aviv entitled
his talkE N<lephants and the De3ish Problem.N ?y S3edish talk should have been named N?ariGuana and the Psychedelic Amphetamines.N "he
memorable story of meeting the chief of the S3edish eFuivalent of the .ureau of 5arcotics, and ending up playing ?o6art sonatas in the attic of his
home, has been spun out else3here in the book.
"he original concept 3as a grand plan to imitate t3o of the three rings of tetrahydrocannabinol. "here is an aromatic ring '3ith an alkyl group and t3o
o/ygens on it- and it is fused to a pyran ring 3ith a couple of methyl groups on it. So, if one 3ere to tie the methyl group at the +@position of ;9?
around 3ith a short carbon chain into the o/ygen atom at the five position, one could sFuint and say that the resulting amphetamine 3as kinda
something like an analogue of "HC. "hus, the resulting si/@membered ring 'a pyran- or five@membered ring 'a furan- could be peppered 3ith methyl
groups at different locations 'and up to t3o per location-. If the ring 3as a five@membered structure, then the parent system 3ould be a ben6ofuran, and
the location of methyl groups on the ring 3ould be indicated by the appropriate numbers follo3ing the letter :BS 3hich 3ould stand for NfuranN. And if it
3ere to be a si/@membered ring, the resulting ben6opyran 3ould be indicated 3ith a :PS for pyran, and again the methyl group or groups 3ould be
indicated by the substitution position. "his code 3ould cover all polymethylated homologues 3ith codes that 3ould look like B@$$ and P@$$0+. If any of
them sho3ed up 3ith fascinating activities, I 3ould e/tend methyls to ethyls, and 3ork out some 3hole ne3 naming code at some future time. An early
system, naming this compound $@? for a methyl group on the $@position of the furan ring, 3as abandoned 3hen it became apparent that the pyran 3orld
3ould scre3 everything up.
"he isolation of characteri6able Fuantities of 2@formyl@&@metho/y@$@methyl@$,0@dihydroben6ofuran from the ben6aldehyde recipe above gave a fleeting
fantasy of a 3hole ne3 direction that this little proGect might go. If this une/pected ben6aldehyde 3ere to be converted to the corresponding
amphetamine, one 3ould have 2@'$@aminopropyl-@&@metho/y@$@methyl@$,0@dihydroben6ofuran. Suddenly here 3ould be a $,0,&@trisubstituted thing 3ith
a ring at the $,0@position, similar to the still unmade ??;A@+. "he temptation to be diverted in this 3ay lasted, fortunately, only a fe3 minutes, and the
proGect 3as shelved. Someday, 3hen there are buckets of spare time or hosts of eager graduate students, some fascinating chemistry might lie this
3ay, and maybe some fascinating pharmacology, even.
"he plain furan analogue, 3ithout any methyl groups on it, has been made. Bive@metho/yben6ofuran formed the 1@formyl derivative 'the aldehyde- 3ith
a mp of 2%@), deg C and from it the nitrostyrene 'orange needles, mp )%@%( deg C- and the final amphetamine '3hite solids, as the methane sulfonate,
mp (+(@(++ deg C- 3ere prepared in a manner similar to the preparation of B@$ above. In the rat studies, it 3as three times more potent than B@$, but
still some (& times less potent than ;9?. And in initial human trials 'of up to 0, milligrams- there 3ere again no effects noted. 5aming of this material is
easy chemically '1@'$@aminopropyl-@&@metho/y@$,0@dihydroben6ofuran- but tricky as to code. If the numbers that follo3 the :BS give the location of the
methyl groups, then this material, 3ithout any such groups, can have no numbers follo3ing, and should properly be simply NB.N 9, it is NB.N "he
preparation or the attempted preparations of other homologues such as B@$0 and B@$00 are outlined under the recipe for B@$$.
#35 7-$$; 1-&$-AM"#%,*%,Y--$,$-0"METHY-)-METH%+Y-$,'-0"HY0*%.E#6%7/*A#
S>5"H<SISE "o a solution of +0.$ g flaked 9H in $&, m! hot <t9H there 3as added %1 g +@metho/yphenol follo3ed by %, g $@methylallyl chloride
over the course of $ h. "he mi/ture 3as held at reflu/ for $+ h, then added to (.1 ! H$9. "here 3as sufficient $&K 5a9H added to make the phase
strongly basic, and this 3as then e/tracted 3ith 0/$,, m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith H$9, and the solvent removed under
vacuum. "he residue, ($& g of a pale amber oil, 3as crude +@'$@methylallylo/y-anisole and 3as used 3ithout further purification in the follo3ing
reaction.
In a round@bottomed flask containing an internal thermometer, there 3as placed ($& g of unpurified +@'$@methylallylo/y-anisole, and this 3as heated 3ith
an open flame. At an internal temperature of (%, deg C an e/othermic reaction set in, raising the temperature to $&, deg C, 3here it 3as held for an
additional $ min. After the reaction mi/ture had cooled to room temperature, it 3as poured into &,, m! H$9, made strongly basic 3ith $&K 5a9H, and
e/tracted repeatedly 3ith (,, m! portions of CH$Cl$ until the e/tracts 3ere essentially colorless. "hese e/tracts 3ere pooled and the solvent removed
to provide ),., g of a deeply colored oil that proved to be largely the appropriately substituted dihydroben6ofuran. "he aFueous residue from above 3as
acidified 3ith concentrated HCl, and again e/tracted 3ith CH$Cl$. :emoval of the solvent gave (2.2 g of +@metho/y@$@'$@methylallyl-phenol as an amber
oil 3hich eventually set do3n as 3hite crystals 3ith a mp of &$.&@&+ deg C.
A solution of (2 g of +@metho/y@$@'$@methylallyl-phenol in &1 g acetic acid 3as treated 3ith ).+ g 6inc chloride follo3ed 3ith $) m! concentrated HCl.
"his mi/ture 3as heated at reflu/ temperature 3ith a mantle for ( h. After cooling, this 3as poured into H$9 and e/tracted 3ith $/(&, m! CH$Cl$. "he
pooled e/tracts 3ere 3ashed 3ith several portions of )K 5a9H, until the e/tracts 3ere colorless. "he organic fraction 3as then 3ashed 3ith H$9, and
the solvent removed to yield &.) g of $,$@dimethyl@&@metho/y@$,0@dihydroben6ofuran as a pale amber oil 3ith a pungent smell. "his 3as purified by
distillation, giving a fraction of an off@3hite oil 3ith a bp of (01@(0) deg C at 00 mm8Hg.
"o a mi/ture of )., g 5@methylformanilide and %.$ g P9Cl0 3hich had been allo3ed to stand for ,.& h, there 3as added +., g $,$@dimethyl@&@metho/y@
$,0@dihydroben6ofuran, and the mi/ture held at the steam bath temperature for $.& h. "his 3as then poured into $,, m! H$9 3hich produced a black
oily phase that gave no hint of crystalli6ation. "his mi/ture 3as e/tracted 3ith 0/(&, m! CH$Cl$ and the solvent 3as removed from the pooled e/tracts
under vacuum. "he residual oil '3hich 3as sho3n by CC to contain appro/imately eFual Fuantities of t3o isomeric ben6aldehydes A and .- 3as
e/tracted 3ith three 2& m! portions of boiling he/ane, each of 3hich on cooling deposited a reddish oil that partially crystalli6ed. A fourth he/ane e/tract
gave nothing more. "he solvent 3as decanted from these three e/tracts, and the semi@solid residues 3ere ground under 0., m! ?e9H giving (.+ g of
pale yello3 crystals of $,$@dimethyl@1@formyl@&@metho/y@$,0@dihydroben6o@furan, isomer :.S. After recrystalli6ation from ?e9H, the color 3as almost
3hite, and the mp 3as 2%.&@),.& deg C. "he combined mother liFuors 3ere enriched in isomer :AS 3hich proved, follo3ing preparative CC separation
and 5?: analysis, to be the 2@formyl isomer. "he ), g of impure dihydroben6ofuran isolated from the Claisen rearrangement above 3as distilled and a
fraction '+0.) g- that boiled from (0)@(&0 deg C at 0, mm8Hg 3as processed as described here to the aldehyde mi/ture. Bollo3ing similar he/ane
e/tractions, a yield of +., g of a %&K pure isomer :.S 3as finally obtained. "he remaining components of this fraction 3ere not determined, but it is
possible that there 3ere some that contained the si/@membered ben6opyran ring system.
"o a solution of &.$ g of $,$@dimethyl@1@formyl@&@metho/y@$,0@dihydro@ben6ofuran in $, m! glacial acetic acid there 3as added 0 m! nitroethane follo3ed
by (.1 g anhydrous ammonium acetate. "his mi/ture 3as heated for + h on the steam bath, and then a small amount of H$9 3as added to the hot
solution. "his instigated the formation of a copious deposition of brick@red crystals 3hich 3ere, after cooling, removed by filtration, and recrystalli6ed
from &, m! boiling ?e9H. After air drying there 3as thus obtained $.2 g of day@glo yum@yum orange crystals of $,$@dimethyl@&@metho/y@1@'$@nitro@(@
propenyl-@$,0@dihydroben6ofuran. An additional ,.1 g of product 3as obtained by 3orking the mother liFuors.
A suspension of $.& g !AH in 0,, m! reflu/ing anhydrous <t$9 3as treated 3ith a solution of 0.( g $,$@dimethyl@&@metho/y@1@'$@nitro@(@propenyl-@$,0@
dihydroben6ofuran in <t$9. "he mi/ture 3as held at reflu/ temperature for () h. After cooling, the e/cess hydride 3as destroyed by the cautious
addition of +,, m! H$9 3hich contained (& g H$S9+. "he aFueous phase 3as separated, 3ashed once 3ith <t$9, and then once 3ith CH$Cl$. "here
3as then added 1, g potassium sodium tartrate, and the pH 3as brought to above (, by the addition of $&K 5a9H. "his 3as e/tracted 3ith 0/$&, m!
CH$Cl$, the e/tracts pooled, and the solvent removed under vacuum. "here remained $.) g of an amber oil 3ith an ammoniacal smell. "his 3as
dissolved in $,, m! anhydrous <t$9, and saturated 3ith anhydrous HCl gas. "here 3as the immediate formation of an oil, from 3hich the supernatent
<t$9 3as decanted. "he residual oil 3as resuspended in a second $,, m! anhydrous <t$9, again decanted, and finally a third $,, m! <t$9 effected
the dissolving of the remaining oil to give a clear solution. All three solutions became gelatinous over the follo3ing fe3 h, and each deposited a crop of
3hite crystals over the follo3ing fe3 days. Brom the first there 3as obtained (.+ g of product 3ith a mp of (&0@(&+ deg C; from the second, ,.$ g 3ith a
mp of (&0@(&+ deg C; and from the third, (.$ g 3ith a mp of (&&@(&1 deg C. "hese crops 3ere combined, and recrystalli6ed from (, m! of boiling
CH0C5 to give (.2 g 1@'$@aminopropyl-@$,$@dimethyl@&@metho/y@$,0@dihydroben6ofuran hydrochloride 'B@$$- as a 3hite crystalline solid 3hich had a mp
of (&+@(&& deg C. "his material, even 3hen dry, sho3ed a tendency to discolor 3ith time.
;9SAC<E greater than (& mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E And here is yet another dihydroben6ofuran 3hich is not of a very high potency if, indeed, it is active at all. "his
particular dihydroben6ofuran analogue, B@$$, had sort of tickled my fancy as being an especially good candidate for activity. It had a certain s3ing to it.
B@$$, like !S;@$&. And here it 3as finished, Gust five days before I had to deliver a paper concerning the syntheses 'and activitiesO- of all these
dihydroben6ofurans to the mariGuana congress. Could this possibly be another !S;H I 3as sufficiently convinced that the possibility 3as real, that I
actually started the screening process at a most unusually lo3 level of (, micrograms. "3o days later, I upped this to a dose of $& micrograms 'no
activity again- and three days after that, at ( A? on the polar flight to Copenhagen, I s3allo3ed the NmonstrousN dose of &, micrograms. Shoot the
3orks. If I 3ere to blossom all over the tourist section of the SAS plane, 3ell, it 3ould be Fuite a paper to give. If not, I could al3ays say something like,
N"he active level has not yet been found.N 5o activity. Another Ialter ?itty fantasy do3n the tubes.
And, as it turned out, the entire proGect pretty much ran out of steam. A number of clever analogs had been started, and 3ould have been pursued if
there had been any activity promised of any kind 3ith any of these dihydroben6ofurans. "he NotherN ben6aldehyde described above, could have been
run in a manner parallel to that proposed for the counterpart 3ith B@$, to make the eventual amphetamine, 2@'$@aminopropyl-@$,$@dimethyl@&@metho/y@
$,0@dihydroben6ofuran. Creat strides had been made to3ards B@$00 'I have discussed the naming system under B@$, 3ith the B standing for the furan
of ben6ofuran and the $ and 0 and 0 being the positions of the methyl groups on it-. "he reaction of +@metho/yphenol 3ith (@chloro@0@methyl@$@butene
gave the ether 3hich under3ent the thermal Claisen rearrangement to $@'(,(@dimethylallyl-@+@metho/yphenol 3ith a bp of (+)@(&2 deg C at 0, mm8Hg.
"his 3as cycli6ed to the intermediate cycle $,0,0@trimethyl@$,0@dihydroben6ofuran 3hich, after distillation, 3as sho3n to be only ),K pure by CC
analysis. "his 3as, nonetheless, 'and 3ith the hope that is in the very fiber of a young innocent chemist-, pushed on to the ben6aldehyde stage 'and
there 3ere a not@too@surprising four ben6aldehydes to be found in the oil that 3as produced, 3hich refused to crystalli6e-. And then '3hen sheer
desperation replaced hope- these 3ere condensed 3ith nitroethane to form an even 3orse mi/ture. ?aybe something might crystalli6e from itH 5othing
ever did. Dunk. <verything 3as simply put on the shelf 3here it still rests today, and B@$00, 1@'$@aminopropyl-@&@metho/y@$,0,0@trimethyl@$,0@
dihydroben6ofuran, remains the stuff of speculation.
And a start to3ards B@$0, 1@'$@aminopropyl-@$,0@dimethyl@&@metho/y@$,0@dihydroben6ofuran, got Gust as far as the starting ether, 3hen it occurred to me
that the final product 3ould have an unprecedented three chiral centers, and so a total of four racemic pairs of diastereoisomers. And then I discovered
that the starting allyl halide, crotyl chloride, 3as only ),K pure, 3ith the remaining $,K being 0@chloro@(@butene. "his 3ould have eventually produced
a $@ethyl@analogue, 1@'$@aminopropyl-@$@ethyl@&@metho/y@$,0@dihydroben6ofuran, 3ith its t3o chiral centers and t3o more pairs of stereoisomers 'not to
speak of the need to devise an entirely ne3 coding system-. 4nless something 3ere to fall into my lap as a crystalline intermediate, the final mess could
have had at least si/ discreet compounds in it, not even considering optical isomers. And I haven7t even begun to think of making the si/@membered
dihydroben6opyrans 3hich 3ere the "HC analogues that presented the rationale that started the 3hole proGect in the first place. A recent issue of the
Dournal of ?edicinal Chemistry has Gust presented an article describing the reaction of 1@metho/ytetrahydroben6opyran 3ith dichloromethyl methyl ether,
and appro/imately eFual amounts of all three of the possible isomers 3ere obtained. "hat 3ould have been the first step to3ards making the prototypic
compound 2@'$@aminopropyl- 1@metho/y@(,$,0,+@tetrahydroben6opyran. Dust as the ben6ofurans 3ere all named as B@compounds, this, as a
ben6opyran, 3ould have been a P compound, but P also is used for proscaline, and there 3ould have been some repair@3ork needed for these codes.
"ime to abandon ship. "he fact that I had Gust synthesi6ed and discovered the strange activity of A:IA;5< at about this time, made the ship
abandonment Fuite a bit easier to accept.

#31 7EA; #-HY0*%+Y-#-METHY-',(-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE 'from 0,+@methylenedio/yphenylacetone- A solution of $.( g 5@methylhydro/ylamine hydrochloride and +.+ g 0,+@
methylenedio/yphenylacetone in &.& m! ?e9H 3as added to a suspension of +.& g 5aHC90 in 0, m! boiling ?e9H. "here 3as added about & m!
H$9 '3hich gave a clear solution- follo3ed by another &, m! H$9 3hich produced a pale yello3 color. "o this solution of the unisolated nitrone there
3as added (.2 g sodium cyanoborohydride, 3hich generated a goodly amount of foaming. "here 3as HCl added as needed to maintain the pH at about
neutrality. "he reaction appeared to have stopped after a day or t3o, so all 3as poured into &,, m! H$9, acidified 3ith HCl, and 3ashed 3ith $/2& m!
CH$Cl$. "he addition of base brought the pH U%, and this 3as then e/tracted 3ith 0/2& m! CH$Cl$. :emoval of the solvent from the pooled e/tracts
gave a residue of (.1& g of crude 5@hydro/y@5@methyl@0,+@methylenedio/yamphetamine. <fforts to obtain solid seed samples of the salts 3ith
hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, and 3ith a number of organic acids, all failed. "he salt formation from this free@base 3ill
be discussed belo3.
'from ?;9H- A solution of ,.2& g crystalline free@base ?;9H in a fe3 m! ?e9H 3as treated 3ith a solution of ,.+ g sodium cyanoborohydride in (,
m! ?e9H, and there 3as then added $ m! of 0&K formaldehyde. "he stirred reaction mi/ture 3as kept at a neutral pH 3ith the occasional addition of
HCl. After several days '3hen additional acid 3as no longer reFuired- the e/cess solvent 3as removed under vacuum, and the residue poured into
dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$ and then, follo3ing the addition of base, this 3as e/tracted 3ith 0/2& m! CH$Cl$. :emoval of
the solvent from the pooled e/tracts gave a viscous oil residue of ,.&0 g. "he free@base product from these preparations 3as distilled at ((,@($, deg C
at ,.$ mm8Hg to give the 5@hydro/y@5@methyl product as a 3hite oil. An alternate methylation procedure used a solution of ?;9H in a +E( ?e9H8acetic
acid solution containing formaldehyde 3hich 3as reduced 3ith sodium borohydride at dry ice temperatures. Its 3ork@up is identical to that involving
sodium cyanoborohydride.
"he distilled product 3as dissolved in an eFual volume of ?e9H, and treated 3ith a half@eFuivalent of o/alic acid dihydrate, dissolved in (, volumes of
?e9H. "his combination gave the slo3 deposition of crystals of the full o/alate salt 'one acid, t3o bases- as a 3hite crystalline product. "he mp of the
crude salt 3as in the (0,@(&, deg C range, and after recrystalli6ation from CH0C5, 5@hydro/y@5@methyl@0,+@methylenedio/yamphetamine o/alate
'B!<A- had a mp of (+1@(+2 deg C.
;9SAC<E (,, @ (1, mg.
;4:A"I95E + @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith %, mg- "he material tastes terrible, like grapefruit Guice that has stayed in the can too long. "here 3as no nausea, no
feeling of difficulty in s3allo3ing at any time during the day. I felt a dry mouth and 3as thirsty L sipped 3ater throughout the day. At the beginning of the
e/periment, there 3as a glimmer of the ?;?A 3armth, but later I felt separated and a bit isolated. I 3as Gust floating around, seeing the beauty of colors
and obGects in the house and outdoors and listening first to this conversation, then to that one. All senses seemed enhanced. I found the material
pleasant. I 3as happy 3ith the amount I took but 3ould not be afraid to take more or to take a supplement. I found it similar to, but not the same as,
?;?A.
'3ith ((, mg- Ie found this very similar to ?;?A, but perhaps slightly slo3er. I plateau7d at $E0, hours and had a very gradual descent. ?y friend had
a marvelous and private 7cone of silence7 that 3as to him uniFue to ?;?A or to $C@"@). "eeth problems 3ere minor, and the descent from the top of the
e/perience sho3ed less interactive, and more contemplative action, than 3ith ?;?A. Mery similar to ?;?A, but 3ith its o3n character.
'3ith ((, mg- "he onset 3as at about a half@hour. "he come@on 3as more gradual and much easier than 3ith ?;?A, and it seemed to be more head
than body oriented. I had about t3o hours of very comple/ and personal self@evaluation, and I am not at peace in putting all of it do3n here in 3riting.
9verall I like it, and I 3ould be interested to see if there7s a difference in conGunction 3ith ?;?A. "hanks very much.
'3ith ((, mg * 0& mg- I sa3 my onset at $, minutes, and it 3as subtle, and very pleasant, and had a mild amphetamine@like elevation for me 'body
lightness, cognitive functions seemed clear and clean, heightened visual a3areness and 3ith some enhancement of color-. It seemed as if I 3ere on the
fringe of !S;@like visual changes, but that never materiali6ed. "he affect 3as very good, communicative, friendly, accepting, but 3ithout the profound
emotional bonding of ?;?A. "he follo3ing day felt very much like a post@!S; day; 3e felt great. "he body 3as light, energy good, emotions high,
several insights throughout the day, interactions clear and open L a magnificent gift of a day. I started a menstrual period the day of the e/perience and
it lasted 1 to 2 days; all of this 3as a couple of 3eeks early. I have a very favorable impression of B!<A although the body penalty seems high.
<="<5SI95S A5; C9??<5"A:>E ?ost people 3ho 3ere involved 3ith the evaluation of B!<A Fuite logically compared it 3ith ?;?A, as it 3as
presented as being a very close analogue 3hich might share some of the latter7s properties. And to a large measure, the comparison 3as favorable.
"he dosages are almost identical, the chronological course of action is almost identical, and there are distinct similarities in the effects that are produced.
If there is a consensus of similarities and differences it 3ould be that it is not Fuite as enabling in allo3ing a closeness to be established 3ith others. And
perhaps there is more of a move to3ards introspection. And perhaps a slightly increased degree of discoordination in the thought processes. .ut also,
part of this same consensus 3as that, 3ere ?;?A unkno3n, this material 3ould have played its role completely.
And from the scientific point of vie3, it lends more 3eight to a hypothesis that Gust might be a tremendous research tool in pharmacology. I first observed
the intimate connection bet3een an amine and a hydro/ylamine 3ith the discovery that 5@hydro/y@?;A '?;9H- 3as eFuipotent and of virtually identical
activity to the non@hydro/ylated counterpart '?;A-. And I have speculated in the recipe for ?;9H about the possible biological interconversions of
these kinds of compounds. And here, the simple addition of a hydro/yl group to the amine nitrogen atom of ?;?A produces a ne3 drug that is in most
of its properties identical to ?;?A. "he concept has been e/tended to $C@"@$, $C@"@2, and $C@"@(2, 3here each of these three active compounds 3as
structurally modified in e/actly this 3ay, by the addition of a hydro/yl group to the amine nitrogen atom. "he results, H9"@$, H9"@2 and H9"@(2 3ere
themselves all active, and compared very closely 3ith their non@hydro/ylated prototypes.
Dust ho3 general might this concept be, that an 5@hydro/yl analog of an active amine shall be of similar action and duration as the parent drugH Ihat if
it really 3ere a generalityO Ihat havoc it 3ould 3reak in the pharmaceutical industryO If I could patent the concept, then I 3ould be able to make parallel
best sellers to all of the primary and secondary amines out there in the industry. Perhaps %,K of all the commercially available drugs that are concerned
3ith the human mental state are amines. And a goodly number of these are primary or secondary amines. And each and every one of these could be
converted to its 5@hydro/yl analogue, effectively by@passing the patent protection that the originating corporation so carefully crafted. An e/ample, Gust
for fun. A run@a3ay best seller right no3 is an antidepressant called fluo/etine, 3ith the trade name Pro6ac. I 3ill make a small 3ager that if I 3ere to
synthesi6e and taste 5@hydro/y@5@methyl@0@phenyl@0@''a,a,a@trifluoro@p@tolyl-o/y-propylamine, I 3ould find it to be an active antidepressant. :emember,
?r. <li !illy and Company; you read about it first, right hereO
9f course, I 3as asked, 3hy call it B!<AH "he origin 3as in a classic bit of poetry. A commonly used code name for ?;?A 3as A;A?, and I had tried
making several modest modifications of the ?;?A structure in the search for another compound that 3ould maintain its particular music 3ithout the
annoying tooth@grinding and occasional nystagmus, or eye@3iggle, that some users have mentioned. 9ne of these 3as the 1@methyl homologue 3hich
3as, 3ith some perverse logic, called ?A;A?. And, follo3ing this pattern, the 1@fluoroanalogue 3as to be B!A;A?. So, 3ith the 5@hydro/y analogue,
3hat about HA;A?H Ihich brought to mind the classic description of Adam7s earliest complaint, an infestation of fleas. "he poem 3as short and
direct. NAdam had 7em.N So, in place of HA; 7<?, the term B!<A Gumped into being.

#3$ 8-'; $,)-0"METH%+Y-',(-&T*"METHYE#E-AM,HETAM"#E;
)-&$-AM"#%,*%,Y--(,2-0"METH%+Y"#0A#E
S>5"H<SISE A solution of 0.2 g of $,&@dimetho/y@0,+@'trimethylene-ben6aldehyde 'see preparation under $C@C@0- in (& m! nitroethane 3as treated 3ith
,.2 g anhydrous ammonium acetate and heated on the steam bath for $.& h. "he e/cess solvent 3as removed under vacuum leaving some & m! of a
deep orange@red oil 3hich on cooling, spontaneously crystalli6ed. "his 3as finely ground under (, m! ?e9H, filtered, 3ashed sparingly 3ith ?e9H,
and air dried to give 0.1 g of orange crystals 3ith a strong smell of old acetamide. "he mp 3as %$@%0 deg C. All 3as recrystalli6ed from 0, m! boiling
?e9H to give, after filtering and drying, $.% g of (@'$,&@dimetho/y@0,+@'trimethylene-phenyl-@$@nitropropene as yello3 crystals 3ith a mp of %0@%+ deg C.
Anal. 'C(+H(259+- C,H,5.
Bifty milliliters of ( ? !AH in "HB 3as placed in an inert atmosphere, 3ell stirred, and cooled to , deg C 3ith an e/ternal ice@bath. "here 3as added,
drop3ise, (.0& m! of (,,K H$S9+ at a rate slo3 enough to minimi6e charring. "here 3as then added, drop3ise, $.) g (@'$,&@dimetho/y@0,+@
'trimethylene-phenyl-@$@nitropropene in (& m! "HB. At the end of the addition, the stirring 3as continued for an additional ,.& h, and then the reaction
mi/ture 3as held at reflu/ on the steam bath for another ,.& h. After cooling again to ice@bath temperature, the e/cess hydride 3as destroyed 3ith the
addition of (( m! IPA, follo3ed by &.& m! &K 5a9H 3hich converted the inorganic mass through a cottage cheese stage into a loose, filterable te/ture.
"he solids 3ere removed by filtration, 3ashed 3ith additional "HB, and the combined filtrates and 3ashes stripped of solvent under vacuum. "here 3as
obtained $.&( g of a 3hite oil that 3as distilled at ((&@(0& deg C at ,.$ mm8Hg to give (.)0 g of a clear colorless oil. "his 3as dissolved in ) m! IPA,
neutrali6ed 3ith $) drops of concentrated HCl, and diluted 3ith (+, m! anhydrous <t$9. In about ,.& h there started a slo3 sno3fall of fine fluffy 3hite
crystals 3hich 3as allo3ed to continue until no additional crystals appeared. After filtering, <t$9 3ashing and air drying, there 3as obtained (.)( g of
$,&@dimetho/y@0,+@'trimethylene-amphetamine hydrochloride 'C@0- 3ith a mp of (&2@(&% deg C. Anal. 'C(+H$$Cl59$- C,H.
;9SAC<E ($ @ () mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith ($ mg- "here 3as a 3armth, a mello3ness, as things developed. 5o body disturbance at all, but then there 3ere no
visuals either 3hich, for me on this particular occasion, 3as disappointing. "he day 3as consumed in reading, and I identified completely 3ith the
character of my fictional hero. It 3as a different form of fantasy. I think I prefer music as a structural basis for fantasy.
'3ith () mg- I am at a plus three, but I am not at all sure of 3hy it is a plus three. Iith my eyes closed, there are puffy clouds, but no drama at all.
?usic 3as not e/citing. "here could 3ell have been easy eroticism, but there 3as no push in that direction. 5o great amount of appetite. 5ot much of
anything, and still a plus three. Simply lying still and surveying the body rather than the visual scene gave some suggestions of neurological sensitivity,
but 3ith getting up and moving about and doing things, all 3as fine. "he ne/t morning I 3as perhaps moving a bit more slo3ly than usual. I am not sure
that there 3ould be re3ard in going higher.
<="<5SI95S A5; C9??<5"A:>E In a comparison bet3een the $@carbon compound '$C@C@0- and the 0@carbon compound 'C@0- the vote goes
to3ards the phenethylamine 'the $@carbon compound-. Iith the first member of this series '$C@C versus CA5<SHA- this 3as a stand@off, both as to
Fuantitative effects 'potency- and Fualitative effects 'nature of activity-. Here, 3ith the some3hat bulkier group located at the definitive 0,+@positions, the
nod is to the shorter chain, for the first time ever. "he potency differences are small, and maybe the amphetamine is still a bit more potent. .ut there
are hints of discomfort 3ith this latter compound that seem to be absent 3ith the phenethylamine. "he more highly substituted compounds 'F.v.- more
clearly define these differences.

#3' 8-(; $,)-0"METH%+Y-',(-&TET*AMETHYE#E-AM,HETAM"#E;
1-&$-AM"#%,*%,Y--),3-0"METH%+YTET*A"#
S>5"H<SISE A solution of (,+@dimetho/y@&,1,2,)@tetrahydro@beta@naphthaldehyde 'see preparation under $C@C@+- in $, m! nitroethane 3as treated 3ith
,.(0 g anhydrous ammonium acetate and heated on the steam bath overnight. "he volatiles 3ere removed under vacuum and the residue, on cooling,
spontaneously crystalli6ed. "his crude rust@colored product '(.%) g- 3as recrystalli6ed from (& m! boiling ?e9H yielding, after filtering and air drying to
constant 3eight, (.00 g of (@'$,&@dimetho/y@0,+@'tetramethylene-phenyl-@$@nitropropene as dull gold@colored crystals. "he mp 3as %+@%+.& deg C. Anal.
'C(&H(%59+- C,H.
;9SAC<E unkno3n.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "he discussion that appeared in the commentary section under $C@C@+ applies here as 3ell. "he maGor struggles
3ere in the preparation of the aldehyde itself. And although the final product has not yet been made, this last synthetic step should be, as .obby Bischer
once said in his analysis of a master7s chess game follo3ing a blunder by his opponent, simply a matter of techniFue.
As 3ith the phenethylamine counterpart, C@+ has a structure that lies intermediate bet3een C@0 and C@&, both potent compounds. It is a/iomatic that it
too 3ill be a potent thing, and all that no3 needs be done is to complete its synthesis and taste it.

#3( 8-); ',1-0"METH%+Y-(-&$-AM"#%,*%,Y-.E#6%#%*.%*#A#E
S>5"H<SISE A solution of 0.2, g 0,1@dimetho/y@+@formylben6onorbornane 'see under $C@C@& for its preparation- in $, g nitroethane 3as treated 3ith
,.)) g anhydrous ammonium acetate and held at steam bath temperature overnight. "he e/cess solvent and reagent 3as removed under vacuum to
yield a residual yello3 oil. "his 3as allo3ed to stand at ambient temperature for a period of time 'about 0 years- by 3hich time there 3as a spontaneous
crystalli6ation. "he dull yello3 crystals 3ere removed by filtration and, after air drying, 3eighed +.$) g. A small sample 3as recrystalli6ed repeatedly
from ?e9H to provide a pale yello3 analytical sample of 0,1@dimetho/y@+@'$@nitropropenyl-ben6onorbornane 3ith a mp of %,@%( deg C. Anal.
'C(1H(%59+- C,H.
A solution of !AH '&, m! of ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.0$
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of +.( g 0,1@dimetho/y@+@'$@nitropropenyl-ben6onorbornane in $,
m! anhydrous "HB over the course of (, min. "he reaction mi/ture 3as stirred and brought to room temperature over the course of ( h. "his 3as then
brought to a gentle reflu/ on the steam bath for ,.& h, and then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious
addition of (, m! IPA follo3ed by & m! &K 5a9H and sufficient H$9 to give a 3hite granular character to the o/ides. "he reaction mi/ture 3as filtered,
and the filter cake 3ashed 3ith "HB. "he filtrate 3as stripped of solvent under vacuum providing a pale amber oil that 3as distilled at ($&@(+, deg C at
,.$ mm8Hg to give $.& g of an almost 3hite oil. "his 3as dissolved in (, m! IPA, neutrali6ed 3ith $& drops of concentrated HCl, and then diluted 3ith
(+, m! anhydrous <t$9. "here appeared, after about t3o minutes, 3hite crystals of 0,1@dimetho/y@+@'$@aminopropyl-ben6onorbornane hydrochloride
'C@&- 3hich, after filtration and air drying, 3eighed $.+2 g.
;9SAC<E (+ @ $, mg.
;4:A"I95E (1 @ 0, h.
L4A!I"A"IM< C9??<5"SE '3ith (& mg- As part of the audience at the San Brancisco conference, Angels, Aliens and Archtypes, I could simply listen
and observe 3ithout having to participate. <ach speaker stood in a cone of light that 3as beautifully bright and colorful, casting everything else on the
stage into obscurity. ?aybe angels really are illuminated from above, and the aliens lurk out of sight until it is their turn. Ihere does one look for the
archetypesH A half of a cream cheese sand3ich 3as all I could eat, and even at dinner that evening I 3as not hungry. Sleep that evening 3as difficult.
'3ith $, mg- Mery slo3 to come on, but then it 3as up there all of a sudden. "here is an une/pected absence of visual activity despite being at a full **
*. "he mental activity is e/cellent, 3ith easy 3riting and a positive flo3 of ideas. .ut an absence of the bells and 3histles that are e/pected 3ith a
psychedelic in full bloom. "here is a real drop by the (1th hour and the ne/t day 3as free of effect e/cept for occasional cat@naps.
'3ith $, mg- "he transition period, 3hich usually lasts for most compounds for the first hour or t3o, 3ith this seems to be much longer. "his presages a
long@acting material, as usually the slo3@in slo3@out rule applies. .ut there are e/ceptions. "here is an indifference to3ards the erotic, but no
separation at all from personal interactions and emotions. I believe in integration, not separation of all parts of ourselves, distrusting any drug states
'particularly those that have the reputation of being strongly Scosmic7- 3hich divorce the consciousness from the body. And 3ith this material there is no
separation from feelings, only from my particular color language.
<="<5SI95S A5; C9??<5"A:>E "his is as potent as any of the three@carbon Canesha compounds, but it someho3 lacks a little something that
3ould have made it a completely favorite 3inner. Perhaps it is the generally commented upon absence of visual and related sensory entertainment.
"here seems to be no bodily threat to discourage further e/ploration, but there simply 3as not the drive to e/plore it much. "he comments concerning
the enlargement of the ring system 'mentioned under $C@C@&- are eFually valid here. "he NshrubberyN that is the hallmark of the Canesha family is, 3ith
C@&, about as bulky as has ever been put onto a centrally active molecule. "he norbornane group has a one carbon bridge and a t3o carbon bridge
sticking out of it at odd angles. "he replacement of the one@carbon bridge 3ith a second t3o@carbon bridge 3ould make the compound C@1. It 3ould be
makeable, but is there really a driving reason to do soH "here is a simplification intrinsic in this, in that C@& actually has t3o centers of asymmetry 'the a@
carbon atom on the amphetamine chain, and the norbornyl area itself- and so it is really a mi/ture of t3o racemic diastereoisomers. C@1 3ould still be a
racemate, but it 3ould be only a single compound, as are all the other substituted amphetamine derivatives.
Someday I may try making C@1, but it7s not a high priority right no3.
#3) 8A#ESHA; 8; $,)-0"METH%+Y-',(-0"METHYAM,HETAM"#E
S>5"H<SISE A solution of (&.+ g $,&@dimetho/y@0,+@dimethylben6aldehyde 'see under $C@C for the preparation- in &, m! nitroethane 3as treated 3ith 0
g anhydrous ammonium acetate and heated on the steam bath for ($ h. "he e/cess nitroethane 3as removed under vacuum, and the residual oil 3as
diluted 3ith a eFual volume of ?e9H. "here 3as the slo3 generation of deep red cottage@cheese@like crystals 3hich 3ere removed by filtration and air@
dried to constant 3eight '%.0 g- 3ith a mp 2(@2+ deg C. :ecrystal@li6ation from ?e9H '(, ml8g- gave an analytical sample of (@'$,&@dimetho/y@0,+@
dimethylphenyl-@$@nitropropene 3ith a mp of )$ deg C sharp. Anal. 'C(0H(259+- C,H,5. "he 5?: spectra 'in C;Cl0- and CI mass spectrograph
'?H* T $&$- 3ere proper.
"o a suspension of 0.0 g !AH in $,, m! reflu/ing "HB, 3ell stirred and maintained under an inert atmosphere, there 3as added +.$ g (@'$,&@dimetho/y@
0,+@dimethylphenyl-@$@nitropropene in $& m! "HB. "he mi/ture 3as held at reflu/ for +) h. After cooling, 0.0 m! H$9 3as added cautiously to
decompose the e/cess hydride, follo3ed by 0.0 m! (&K 5a9H and finally another (, m! H$9. "he inorganic solids 3ere removed by filtration, and
3ashed 3ith additional "HB. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum, and the residue '+.2 g of a deep amber oil-
dissolved in dilute HCl. "his 3as 3ashed 3ith CH$Cl$ '0/2& m!-, then made basic 3ith &K 5a9H and e/tracted 3ith CH$Cl$. :emoval of the solvent
under vacuum yielded an amber oil that 3as distilled '(,&@((& deg C at ,.+ mm8Hg- to give (.$ g of a 3hite oil. "his 3as dissolved in ) m! IPA,
neutrali6ed 3ith (& drops of concentrated HCl, and diluted 3ith $&, m! anhydrous <t$9. After a period of time, there 3as a spontaneous appearance of
3hite crystals 3hich 3ere removed by filtration, <t$9 3ashed, and air dried. "hus 3as obtained (., g of $,&@dimetho/y@0,+@dimethylamphetamine
hydrochloride 'CA5<SHA- 3ith a mp of (1)@(1% deg C. "his 3as not improved by recrystalli6ation from either <t9Ac or nitroethane. Anal.
'C(0H$$Cl59$- 5.
;9SAC<E $, @ 0$ mg.
;4:A"I95E () @ $+ h.
L4A!I"A"IM< C9??<5"SE '3ith $+ mg- "here 3as a slo3 buildup to a ** or more over the course of about three hours. </tremely tranFuil, and no
hint of any body to/icity 3hatsoever. ?ore than tranFuil, I 3as completely at peace, in a beautiful, benign, and placid place. "here 3as something
residual that e/tended into the sleep period, and 3as possibly still there in the morning. Probably I 3as simply tired from an inadeFuate sleep.
'3ith 0$ mg- A rapid and full development. !ying do3n 3ith music, the eyes@closed visuals 3ere Fuite something. "here 3as sudden a3areness of a
potential toe cramp 3hich I possibly e/aggerated, but it kept spinning itself into my a3areness, and someho3 locked in 3ith my visual imagery. It 3as
not easy to keep the visual8somatic8 cognitive 3orlds in their proper places. "he almost@cramp 3ent a3ay and I forgot about it. "here 3as a back
spasm some3here in this drama, and it really didn7t matter either. "his dosage may be a bit much for good housekeeping, thoughO "o3ards the end of
the e/periment, I looked at a collection of photos from a recent trip to <urope, and the visual enhancement 3as 3onderful. A rolling ***.
<="<5SI95S A5; C9??<5"A:>E "his compound 3as the seventh of the ten possible Classic !adies. I have mentioned the concept already under
the discussions on A:IA;5<. "his is the teutonic replacement of each of the distinguishable hydrogen atoms of ;9? 3ith a methyl group. "he findings
3ith CA5<SHA 3ere a total surprise. "he e/tension of a hydrogen in the 0@position of ;9? 3ith a methyl group should have a minor influence on its
steric association 3ith 3hatever receptor site might be involved. A much greater impact might come not from the si6e of the group but from its location.
"his, coupled 3ith a full order of magnitude of decrease in potency, seemed to call for an involvement of that particular position as being one that is
affected by metabolism. And since the activity is decreased, the obvious role is in the blocking of the metabolic promotion of ;9?@like things to active
intermediates.
"he remarkable point being emphasi6ed here is that the placement of a dull methyl group at a dull position of the ;9? molecule actually inactivated 'for
all intents and purposes- the activity of ;9?. It is not the presence of the methyl that has decimated the potency, but the removal of the hydrogen atom.
Ho3 can such a hypothesis be e/ploredH A historic premise of the medicinal chemist is that if a structure gives an unusual response in a receptor, vary
it slightly and see ho3 the response varies. "his is e/actly the principle that led to the ten Classic !adies, and 3ith this particular !ady '3ho actually
turned out to be a gentleman-, the same concept should hold. "here are t3o involved methyl groups in CA5<SHA, one at the 0@position and one at the
+@position. Ihy not homologate each to an ethyl group, and as a 3rap up make both of them into ethyl groups. !ook at the differences along t3o lines
of variation; the effects of the homologation of the 0@ and +@positions, coupled 3ith the effects of the homologation intrinsic in the comparison of the t3o@
carbon chain of the phenethylamine 3ith the three@carbon chain of the amphetamine.
"here are thus si/ compounds involved in such a study. And they have been named 'as have all the other CA5<SHA analogues- in accordance 3ith the
collective carbon inventory in and about these t3o ring positions. "he first t3o compounds are related to ;9<" and to $C@<. ?aintain the methyl group
at the 0@position but homologate the +@position to an ethyl. "he ring pattern 3ould become $,&@dimetho/y@+@ethyl@0@methyl, and the phenethylamine and
amphetamine 3ould be called $C@C@($ and C@($ respectively 'a one carbon thing, the methyl, at position@0 and a t3o carbon thing, an ethyl, at position@
+-. :eversal of these groups, the 0@ethyl homologues of $C@; and ;9? 3ould thus become $C@C@$( and C@$(. And, finally, the diethyl homologues
3ould be $C@C@$$ and C@$$. In each of these cases, the paired numbers give the lengths of the chains at the t3o positions, the 0@ and the +@positions
that are part of the CA5<SHA concept. And this code is easily e/pandable to longer things such as $C@C@0( and $C@C@+(, 3hich 3ould be the 0@propyl@
+@methyl, and the 0@butyl@+@methyl homologues, resp.
4nfortunately, these si/ initially proposed compounds have so far resisted all logical approaches to synthesis, and are at present still unkno3n. Ihat
has been successfully achieved, the building up of a big bulky hydrocarbon glob at these positions, has rather une/pectedly led to a remarkable
enhancement of potency. As 3ith all true e/ploration into areas of the unkno3n, the deeper you get, the less you understand.

#31 8-#; 1,(-0"METH%+Y#A,HTHY-$-"S%,*%,YAM"#E
S>5"H<SISE "o a solution of 0.% g (,+@dimetho/y@$@naphthaldehyde 'see under $C@C@5 for the preparation- in (0.& m! nitroethane there 3as added ,.2
g anhydrous ammonium acetate, and the mi/ture heated on the steam bath for & h. "he deep orange reaction mi/ture 3as stripped of e/cess solvent
under vacuum. "he residue 3as a red oil that, upon dilution 3ith t3o volumes ?e9H, immediately set to orange crystals. "his crude product 'mp ((&@
(() deg C- 3as recrystalli6ed from 2, m! <t9H to yield, after filtering and air drying, 0.0 g of (@'(,+@dimetho/y@$@naphthyl-@$@nitropropene as gold@
orange crystals, 3ith a mp of ($(@($0 deg C. :ecrystalli6ation from ?e9H gave a gold@colored product 3ith a mp of ((%@($, deg C. Anal.
'C(&H(&59+- C,H,5.
A solution of !AH '&, m! of ( ? solution in "HB- 3as cooled, under He, to , deg C 3ith an e/ternal ice@bath. Iith good stirring there 3as added (.0$
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of 0.($ g (@'(,+@dimetho/y@$@naphthyl-@$@nitropropene in +, m!
anhydrous "HB. After stirring for ( h, the temperature 3as brought up to a gentle reflu/ on the steam bath for ,.& h, and then all 3as cooled again to ,
deg C. "he e/cess hydride 3as destroyed by the cautious addition of (1 m! IPA follo3ed by 1 m! &K 5a9H to give a 3hite, filterable, granular
character to the o/ides, and to assure that the reaction mi/ture 3as basic. "he reaction mi/ture 3as filtered, and the filter cake 3ashed 3ith additional
"HB. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum providing 0.(2 g of a deep amber oil. Iithout any further purification,
this 3as distilled at (+,@(1, deg C at ,.0 mm8Hg to give (.$& g of a pale yello3 oil. "his 3as dissolved in ) m! IPA, neutrali6ed 3ith $, drops of
concentrated HCl, and diluted 3ith 1, m! anhydrous <t$9 3hich 3as the point at 3hich the solution became slightly turbid. After a fe3 min, fine 3hite
crystals began to form, and these 3ere eventually removed, 3ashed 3ith <t$9, and air dried to provide (.$) g (,+@dimetho/ynaphthyl@$@isopropylamine
hydrochloride 'C@5- as the monohydrate salt. "he mp 3as $,&@$,1 deg C. <ven after $+ h drying at (,, deg C under vacuum, the hydrate salt
remained intact. Anal. 'C(&H$,Cl59$aH$9- C,H.
;9SAC<E unkno3n.
;4:A"I95E unkno3n,
<="<5"I95S A5; C9??<5"A:>E "he evaluation of this compound is not yet complete. An initial trial at the $ milligram level sho3ed neither central
action, nor to/icity. It could be guessed from the activity of the t3o@carbon counterpart, that an active level 3ill be found in the tens of milligrams area.
.ut, as of the moment, this level is not kno3n to anyone, any3here, because no one has yet defined it. And 3hen the potency is finally found out, the
nature of the activity 3ill also have been found out, all the result of a magical interaction of a virgin compound 3ith a virgin psyche. At the immediate
moment, the nature of C@5 is not only unkno3n, it has not yet even been sculpted. "here can be no more e/citing area of research than this, any3here
in the sentient 3orld.

#32 H%T-$; $,)-0"METH%+Y-(-ETHYTH"%-#-HY0*%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of &.&, g $,&@dimetho/y@+@ethylthio@beta@nitrostyrene 'see under $C@"@$ for its preparation- 3as made in ), m! boiling
anhydrous "HB. 9n cooling, there 3as some separation of a fine crystalline phase, 3hich 3as kept dispersed by continuous stirring. 4nder an inert
atmosphere there 3as added 0.& m! of a (, ? borane dimethylsulfide comple/, follo3ed by ,.& g sodium borohydride as a solid. "here 3as a slight
e/othermic response, and the color slo3ly faded. Stirring 3as continued for a 3eek. "here 3as then added +, m! H$9 and $, m! concentrated HCl,
and the reaction mi/ture heated on the steam bath for (& minutes, 3ith the "HB at reflu/. After cooling again to room temperature, all 3as poured into (
! H$9 and 3ashed 3ith 0/2& m! CH$Cl$, 3hich removed all of the color but little of the product. "he aFueous phase 3as made basic 3ith $&K 5a9H,
and e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere pooled and the solvent removed under vacuum to give a residue of 0.)) g of an amber oil. "his
3as dissolved in 0, m! IPA, acidified 3ith concentrated HC! to a bright red on universal pH paper, and then diluted 3ith $,, m! anhydrous <t$9. After
a short period of time, crystals started to form. "hese 3ere removed by filtration, 3ashed 3ith <t$9, and air dried to constant 3eight. "hus 3as
obtained $.)1 g $,&@dimetho/y@+@ethylthio@5@hydro/yphenethylamine hydrochloride 'H9"@$- as off@3hite crystals, 3ith a melting point of ($$ deg C 3ith
decomposition. Anal. 'C($H$,Cl590 S- H; CE calcd, +%.,&; found, &,.(&, +%.%,.
;9SAC<E (, @ () mg.
;4:A"I95E 1 @ (, h.
L4A!I"A"IM< C9??<5"SE '3ith ($ mg- "astes 9. Some activity noticed in 0, minutes. Mery smooth rise 3ith no body load for ne/t t3o hours. At
that time I noted some visuals. Mery pleasant. "he bright spots in the painting over the fireplace seemed to be moving back3ards 'as if the clouds 3ere
moving in the painting-. 4pon concentrating on any item, there 3as perceptual movement 3ith a little flo3ing aspect. "he visuals 3ere never all that
strong, but could not be turned off during the peak. At hour three there 3as still some shimmering, and it 3as hard to focus 3hen reading. Additionally,
there 3as difficulty concentrating 'some mental confusion-. "he material seemed to allo3 erotic actions; there 3as no problem about obtaining an
erection. I ate very 3ell, some cra6y dips, as 3ell as a fabulous cake. A very gentle do3n trend and I became close to baseline by 1 or 2 P?. I had no
trouble driving. "he dosage 3as good for me. I did not 3ant more or less.
'3ith ($ mg- Comes on smoothly, nicely. In +, minutes I feel nice euphoria, feel home again. "hen I begin to get uncomfortable feelings. Cets more
and more uncomfortable, feel I am sitting on a big problem. .lood pressure, pulse, go up considerably. Have hard time communicating, lie do3n for a
3hile, get insight that most important thing for me to do is learn to listen, pay attention to 3hat is going on. I do this the rest of the day, at first 3ith
considerable difficulty, then easier and easier. ;iscomfort stays 3ith me for several hours, and although I get more comfortable to3ards the end of the
day, I am never animated or euphoric. I feel very humbled, that I have a great deal to 3ork out in my life. "he ne/t day I find myself very strong and
empo3ered. I see that all I have to do is let things be as they areO "his feels marvelous, and a 3hole ne3 3ay to be L much more rela/ed, accepting,
being in the moment. 5o more a/es to grind. I can be free.
'3ith () mg- I found myself 3ith complete energy. I 3as completely centered 3ith an absolute minimum of the dark edges that so often appear as
components of these e/periences. "he ease of talking 3as remarkable. "here 3as some blood@pressure run@up in the early part of the day, but that
Fuickly returned to normal. I 3ould repeat 3ithout hesitation.
<="<5SI95S A5; C9??<5"A:>E Again, a case of 3here the potency range of the Nhot,N or hydro/ylated compound 'H9"@$, (, to () milligrams- is
very similar to that of the non@hydro/ylated prototype '$C@"@$, ($@$& milligrams-. It seems to be a 3ell tolerated, and generally pleasant material, 3ith a
mi/ture of sensory as 3ell as insightful aspects. Something for everyone.

#33 H%T-2; $,)-0"METH%+Y-#-HY0*%+Y-(-&n--,*%,YTH"%,HE#ETHYAM"#E
S>5"H<SISE A 3ell@stirred solution of (.22 g $,&@dimetho/y@beta@nitro@+@'n@propylthio-styrene 'see under $C@"@2 for its preparation- in $, m! anhydrous
"HB 3as placed in an He atmosphere and treated 3ith (.& m! of (, ? borane@dimethyl sulfide comple/. "his 3as follo3ed by the addition of ,.$ g
sodium borohydride, and the stirring 3as continued at room temperature for a 3eek. "he volatiles 3ere removed under vacuum, and the residue 3as
treated 3ith $, m! dilute HCl and heated on the steam bath for 0, min. "he cooled yello3 solution set up as solids. "he addition of H$9 3as follo3ed
by sufficient $C90 to make the aFueous phase basic. All efforts to 3ork 3ith an acidified aFueous phase resulted in terrible emulsions. "he basic
phase 3as e/tracted 3ith 0/2& m! CH$Cl$, and the pooled e/tracts 3ashed 3ith H$9, then stripped of solvent under vacuum. "he residual yello3 oil
3as dissolved in $, m! IPA, neutrali6ed 3ith (& drops of concentrated HCl, and then diluted 3ith &, m! anhydrous <t$9. After a fe3 minutes stirring, a
3hite crystalline solid separated. "his 3as removed by filtration, 3ashed 3ith <t$9, and air dried to constant 3eight to provide ,.)0 g of $,&@dimetho/y@
5@hydro/y@+@'n-@propylthiophenethylamine hydrochloride 'H9"@2-.
;9SAC<E (& @ $& mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith (& mg- I am lightheaded, and maybe a little tipsy. I am 3ell centered, but I don7t 3ant to go outside and meet people.
Shades of alcohol 3oo6y. "he effects 3ere going already by the fifth hour and 3ere gone by the seventh hour. I 3ould call it smoothly stoning.
'3ith $$ mg- "he transition into the effects 3as a bit difficult, 3ith a faint a3areness in the tummy. .ut by the second hour it 3as Fuite psychedelic, and
the body 3as not thought of again, e/cept in terms of se/ual fooling around. Mery rich in eyes@closed imagery, and very good for interpretive and
conceptual thinking. .ut the eyes@open visuals 3ere not as much as they might have been. At the seventh hour, drifted into an easy sleep.
'3ith $$ mg- "he e/perience 3as very positive, but at each turn there seemed to be a bit of sadness. Ias it a complete plus three e/perienceH 5ot
Fuite. .ut it didn7t miss by much. "he erotic e/plorations someho3 Gust failed to knit by the thinnest of margins. It 3as a truly almost@magnificent
e/perience.
<="<5SI95S A5; C9??<5"A:>E "here is a 3orking hypothesis that has been gro3ing in substance over the last fe3 years in this strange and
marvelous area of psychedelic drugs. It all 3as an outgro3th of the rather remarkable coincidence that I had mentioned in the discussion that follo3ed
?;9H. "here, an assay of 3hat 3as thought to be ?;9H gave a measure of activity that 3as substantially identical to ?;A, and it 3as later found out
that the material had decomposed to form ?;A. So, ?;A 3as in essence rediscovered. .ut 3hen the true, valid, and undecomposed sample of ?;9H
3as actually in hand, and assayed in its o3n rights, it 3as found to have a potency that really 3as the same as ?;A. So, the 3orking hypothesis goes
something like thisE
A5 5@H>;:9=> A?I5< HAS APP:9=I?A"<!> "H< SA?< P9"<5C> A5; "H< SA?< AC"I95 AS I"S 5@H>;:9C<5 C945"<:PA:".
?aybe the 5@hydro/y compound reduces to the 5@H material in the body, and the latter is the intrinsically active agent. ?aybe the 5@H material o/idi6es
to the 5@hydro/y material in the body, and the latter is the intrinsically active agent. <ither direction is reasonable, and there is precedent for each. "he
eFuivalence of ?;A and ?;9H 3as the first suggestion of this. And I have made a number of 5H vs. 59H challenges of this hypothesis. "he
interesting $C@"@= series has provided a number of amines that are amenable to 5@hydro/ylation, and this is the first of them. And, after all, if you put a
hydro/y 'H9- group on a thio material '"-, you have a H9" compound.
So, as far as nomenclature is concerned, the family of 5@hydro/y analogues of 5@H amines is kno3n as the H9" family.
Ho3 does H9"@2 compare 3ith $C@"@2H "hey are almost identical. "he same range of dose 'centering on $, milligrams- and if anything, perhaps
slightly less long lived. !ets try some other 5@hydro/ysO
#34 H%T-12; $,)-0"METH%+Y-(-&s--./TYTH"%-#-HY0*%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a 3ell@stirred solution of 1.,) g $,&@dimetho/y@+@'s-@butylthio@beta@nitrostyrene 'see under $C@"@(2 for its preparation- in ), m!
anhydrous "HB under a He atmosphere, there 3as added 0.& m! (, ? borane dimethylsulfide comple/, follo3ed by ,.& g of sodium borohydride. As
the stirring continued, the slightly e/othermic reaction slo3ly faded from bright yello3 to pale yello3, and eventually 'after three days stirring- it 3as
substantially colorless. "here 3as then added ), m! of 0 5 HCl and the mi/ture heated on the steam bath for ( h, and then allo3ed to return to room
temperature. An additional 1,, m! H$9 3as added 'there 3as a combination of crystals and globby chunks in the aFueous phase- and this 3as then
e/tracted 3ith 0/2& m! CH$Cl$. "he color 3ent completely into the organic phase. "his 3as 3ashed 3ith $/&, m! aFueous $C90, yielding a rusty@
red colored CH$Cl$ solution, 3hich on removal of the solvent, yielded +.& g of a red oil. A side effort to make the sulfate salt at this stage 3ith H$9 and
a little H$S9+, indeed gave solids, but all of the color remained in the sulfate salt. "he red oil 3as dissolved in +& m! IPA and neutrali6ed 3ith
concentrated HCl to bright red, not yello3, on universal pH paper. "he addition of 0&, m! anhydrous <t$9 instituted the slo3 precipitation of 3hite
crystals. After filtering and air drying, there 3as obtained (.0$ g $,&@dimetho/y@+@'s-@butylthio@5@hydro/yphenethylamine hydrochloride 'H9"@(2-. "he
aFueous phase from above 3as Gust neutrali6ed 3ith $&K 5a9H 'cloudy, slightly pink color- and then made basic 3ith $C90 'the color becomes
green-. "his 3as e/tracted 3ith 0/2& m! CH$Cl$, the e/tracts pooled, and the solvent removed to yield ,.& g of a 3hite oil. "his 3as dissolved in & m!
IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith a eFual volume of <t$9. An additional ,.01 g of product 3as thus obtained.
;9SAC<E 2, @ ($, mg.
;4:A"I95 E ($ @ () h.
L4A!I"A"IM< C9??<5"SE '3ith 2, mg- "here 3as a light feeling, a little off@the@ground feeling, 3hich made 3alking about a most pleasant
e/perience. 5o distortion of the senses. And there 3as no sense of the beginning of a drop of any kind until about the eighth hour. Sleeping 3as a bit
tricky but it 3orked out 9 'at the t3elfth hour of the e/perience-. A completely valid **.
'3ith ($, mg- H9"@(2 has an unbelievably C:I? taste L not bitter, but
simply evil. "here is a steady and ine/orable climb for three hours to a sound and rolling plus three. "here 3as absolutely no body difficulty, but there
3as still something going on upstairs 3ell into the ne/t day. Iriting 3as surprisingly easy; I 3as completely content 3ith the day, and 3ould be
interested in e/ploring it under a variety of circumstances.
'3ith ($, mg- "his is my first time 3ith this material. It is +E+& P?. Small nudge at 0, minutes, but not too real. At one hour, threshold, Fuite real. 1E(&
to a *(. .y 2E$&, *0 about. 2E+&, no doubt *0. Possibly still climbing; I hope so. 5o body discomfort at all, no apparent body push. "his aspect of it is
similar to the easy body of the H9"@$. Ho3ever, it7s at times like these that I reflect on Gust e/actly ho3 hard@headed 3e t3o are. I mean, *0 is no
longer the out@of@body, nearly loss of center state it used to be, four years ago. "he Fuestion intrudesE 3ould a novice e/perience this as a very scary,
ego@disintegrating kind of e/periment, or notH Silly Fuestion 3hich ans3ers itself. >es, of course. At 0 hours, a3are of some mild time@distortion. ?ore
a tendency to not think in terms of clock@time, than actual distortion. "he mind la6y 3hen attempting to keep track of clock time. Beel it 3ould be Fuite
easy and pleasant to continue 3riting. "he energy could very 3ell go in that direction. Ho3ever, the idea of the erotic is also Fuite agreeable. "his is,
so far, a good@humored .uddha area of the self.
<="<5SI95S A5; C9??<5"A:>E "3o virtues sought by some users of psychedelic drugs are high intensity and brief action. "hey 3ant a Fuicky.
Something that is really effective for a short period of time, then lets you Fuickly return to baseline, and presumably back to the real 3orld out there.
Intensity is often 'but not al3ays- regulated by dose. "he pharmacological property of dose@dependency applies to many of these drugs, in that the
more you take, the more you get. If you 3ant more intensity, take a second pill. And often, you get a longer duration as an added property. .ut it is
instructive to inFuire into the rationale that promotes brevity as a virtue. I believe that it says something concerning the reasons for using a psychedelic
drug. A trade off bet3een learning and entertainment. 9r bet3een the achieving of something and the appearance of achieving something. 9r, in the
concepts of the classics, bet3een substance and image.
In a 3ord, many people truly believe that they cannot afford the time or energy reFuired for a deep search into themselves. 9ne has to make a living,
one has to maintain a social life, one has a multitude of obligations that truly consume the oh@so@fe3 hours in the day. I simply cannot afford to take a
day off Gust to indulge myself in such@and@such 'choose oneE digging to the bottom of a comple/ concept, giving my energies to those 3hom I can help,
to search out my inner strengths and 3eaknesses- so instead I shall simply do such@and@such 'choose oneE read the book revie3, go to church on
Sunday morning, use a short@acting psychedelic-. "he 3orld is too much 3ith us. "his may be a bit harsh, but there is some merit to it.
H9"@(2 is by no means a particularly potent compound. "he hundred milligram area actually has been the kiss of death to several materials, as it is
often at these levels that some physical concerns become evident. And it certainly is not a short lived compound. .ut, as has been so often the case,
the long lived materials have proven to be the most memorable, in that once the entertainment aspect of the e/perience is past you, there is time for
dipping deeply into the rich areas of the thought process, and the 3orking through of ideas and concepts that are easily available. And 3hen this access
is coupled to the capability of talking and 3riting, then a re3arding e/perience is often the result.
As 3ith the parent compound, $C@"@(2 itself, the presence of an asym@metric carbon atom out there on the 's-@butyl side chain 3ill allo3 the separation
of H9"@(2 into t3o components 3hich 3ill be different and distinct in their actions. "he activity of the racemic mi/ture often is an amalgamation of both
sets of properties, and the separate assay of each component can often result in a fascinating and une/pected fractionation of these properties.
#45 "0##A; $,)-0"METH%+Y-#,#-0"METHY-(-"%0%AM,HETAM"#E
S>5"H<SISE "o a stirred solution of ,.+ g $,&@dimetho/y@+@iodoamphetamine hydrochloride ';9I- in ($ m! ?e9H containing + m! of a +,K
formaldehyde solution there 3as added ( g sodium cyanoborohydride. "he pH 3as kept at about 1 by the occasional addition of HCl. Ihen the pH 3as
stable 'about +) h- the reaction mi/ture 3as poured into $&, m! H$9 and made strongly basic by the addition of aFueous 5a9H. "his 3as e/tracted
3ith 0/2& m! CH$Cl$, the e/tracts pooled, and e/tracted 3ith $/2& m! dilute H$S9+, and the pooled acidic e/tracts again made basic and again
e/tracted 3ith CH$Cl$. "he solvent 3as removed under vacuum to give ,.0) g of a colorless oil. "his 3as dissolved in $ m! IPA and treated 3ith a
solution of ,.(0 g o/alic acid dihydrate in (.& m! 3arm IPA, and then anhydrous <t$9 3as added drop3ise until a turbidity persisted. Slo3ly a granular
3hite solid appeared, 3hich 3as filtered off, <t$9 3ashed, and air dried to give ,.0) g of $,&@dimetho/y@5,5@dimethyl@+@iodoamphetamine o/alate
'I;55A- 3ith a mp of (+&@(+1 deg C. Anal. 'C(&H$$I591- C,H. "he hydrochloride salt of this base proved to be hygroscopic.
;9SAC<E greater than $.1 mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "his base, if it 3ere given a code name based upon its substituents arranged in their proper alphabetical order,
3ould have to be called something like ;5;IA, 3hich is Fuite unpronounceable. .ut by a rearrangement of these terms, one can achieve I;55A 'Iodo@
;imetho/y@5,5@dimethyl@Amphetamine- 3hich has a nice lilt to it.
9ne of the maGor goals of research in nuclear medicine is a drug that can be used to demonstrate the brain blood flo3 pattern. "o do this Gob, a drug
should demonstrate four properties. Birst, it must carry a radioactive isotope that is a positron emitter 'best, a fluorine or an iodine atom, for use 3ith the
positron camera- that can be put onto the molecule Fuickly, synthetically, and 3hich 3ill stay on the molecule, metabolically. Second, as to brain entry,
the drug should be rapidly and e/tensively taken up by brain tissue, 3ithout being selectively absorbed or concentrated at any specific sites. In other
3ords, it should go 3here the blood goes. "hirdly, the absorption should be strong enough that it 3ill stay in the brain, and not be 3ashed out Fuickly.
"his allo3s time to both locate and count the radioactivity that 3as carried in there. And lastly, the drug must be 3ithout pharmacological action.
I;55A looked like a promising candidate 3hen tried 3ith a radioactive iodine label, and there 3as Fuite a flurry of interest in using it both as an e/@
perimental drug, and as a prototype material for the synthesis of structural variants. It 3ent in Fuickly, e/tensively and Fuite diffusely, and it stayed in for
a long time.
.ut 3as it pharmacologically activeH Here one finds a tricky road to 3alk. "he animal to/icity and behavioral properties can be determined in a
straightfor3ard manner. InGect increasing amounts into an e/perimental animal and observe him closely. I;55A 3as Fuite inert. .ut, it is a very close
analogue to the e/tremely potent psychedelic ;9I, and it is 3idely admitted that animal assays are of no use in trying to determine this specific
pharmacological property. So, a Fuiet human assay 3as called for. Since it did indeed go into the brain of e/perimental animals, it could Fuite likely go
into the brain of man. In fact, that 3ould be a needed property if the drug 3ere to ever become useful as a diagnostic tool.
It 3as assayed up to levels 3here ;9I 3ould have been active, and no activity 3as found. So one could state that it had none of the psychedelic
properties of ;9I at levels 3here ;9I 3ould be active 'this, at $.1 milligrams orally-. .ut you don7t assay much higher, because sooner or later,
something might indeed sho3 up. So it can be honestly said, I;55A is less active than ;9I itself, in man. !et7s 3ave our hands a bit, and make our
statement 3ith aggressive confidence. I;55A has sho3n no activity in the human C5S at any level that has been evaluated. "his sounds pretty good.
Dust don7t go too far up there, and don7t look too carefully. "his is not as unscrupulous as it might sound since, in practical terms, the e/tremely high
specific activities of the radioactive ($$I that 3ould be used, 3ould dictate that only an e/tremely small amount of the drug 3ould be reFuired. 9ne
3ould be dealing, not 3ith milligram Fuantities, but 3ith microgram Fuantities, or less.
Some fifteen close analogues of I;55A 3ere prepared, to see if any had a better balance of biological properties. A valuable intermediate 3as an
iodinated ketone that could be used either to synthesi6e I;55A itself or, if it 3ere to be made radio@labelled, it 3ould allo3 the preparation of any desired
radioactive analogue in a single synthetic step. "he iodination of p@dimetho/yben6ene 3ith iodine monochloride in acetic acid gave $,&@diiodo@(,+@
dimetho/yben6ene as 3hite crystals from acetonitrile, 3ith a mp of (12@(1) deg C. Anal. 'C)H)I$9$- C,H. "reatment of this 3ith an eFuivalent of
butyllithium in ether, follo3ed 3ith 5@methyl formanilide, gave $,&@dimetho/y@+@iodoben6aldehyde as pale yello3 crystals from ethanol, 3ith a mp of (01@
(02 deg C. Anal. 'C%H%I90- C,H. "his, in solution in nitroethane 3ith a small amount of anhydrous ammonium acetate, gave the nitrostyrene (@'$,&@
dimetho/y@+@iodophenyl-@$@nitropropene as gold@colored crystals from methanol, mp ((%@($, deg C. Anal. 'C((H($I59+- C,H. "his 3as smoothly
reduced 3ith ele@mental iron in acetic acid to give $,&@dimetho/y@+@iodophenylacetone as 3hite crystals from methylcyclopentane. "hese melted at 1$@
10 deg C and 3ere both spec@troscopically and analytically correct. Anal. 'C((H(0I90- C,H.
"his intermediate, 3hen reductively aminated 3ith dimethylamine, gives I;55A identical in all respects to the product from the dimethylation of ;9I
above. .ut it has also been reacted 3ith (0(I 5aI in acetic acid at (+, deg C for (, min, giving the radioactive compound by e/change, and this 3as
reductively aminated 3ith over a do6en amines to give radioactive products for animal assay. "here 3as produced in this 3ay, $,&@dimetho/y@+@iodo@5@
alkyl@amphetamine 3here the alkyl group 3as methyl, isopropyl, cyclopropylmethyl, he/yl, dodecyl, ben6yl, cyanomethyl, and 0@'dimethylaminopropyl-.
Several dialkyl homologue 3ere made, 3ith the alkyl groups being dimethyl 'I;55A itself-, diethyl, isopropyl@methyl, and ben6yl@methyl. "hese specific
homologues and analogues are tallied in the inde/, but a number of other things, such as hydra6ine or hydro/ylamine derivatives, 3ere either too impure
or made in amounts too small to be valid, and they are ignored.
"he diethyl compound 3ithout the iodine is $,&@dimetho/y@5,5@diethylamphetamine, 3hich 3as prepared by the reductive alkylation of ;?A 3ith
acetaldehyde and sodium cyanoborohydride. "his product, ;<;?A, 3as a clear 3hite oil, bp )$@%$ deg C at ,.(& mm8Hg 3hich did not form a
crystalline hydrochloride. An interesting measure of Gust ho3 different these 5,5@dialkylated homologues can be from the psychedelic primary amines,
pharmacologically, can be seen in the published report that the beta@hydro/y derivative of ;<;?A is an antitussive, 3ith a potency the same as codeine.
5one of these many iodinated I;55A analogues sho3ed themselves to be superior to I;55A itself, in the rat model, and none of them have been tasted
for their psychedelic potential in man.

#41 "M; "S%MES!A"#E; $,',(-T*"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of )., g $,0,+@trimetho/yben6aldehyde in ($& m! nitromethane containing (.+ g anhydrous ammonium acetate 3as held at
reflu/ for (.& h. "he conversion of the aldehyde to the nitrostyrene 3as optimum at this time, 3ith a minimum development of a slo3@moving spot as
seen by thin layer chromatography on silica gel plates using CHCl0 as a developing solvent; the :f of the aldehyde 3as ,.0( and the :f of the
nitrostyrene 3as ,.1(. "he e/cess nitromethane 3as removed under vacuum, and the residue 3as dissolved in $, m! hot ?e9H. 9n cooling, the
yello3 crystals that formed 3ere removed by filtration, 3ashed 3ith cold ?e9H and air dried yielding +.2 g yello3 crystals of $,0,+@trimetho/y@beta@
nitrostyrene, 3ith a mp of 20@2+ deg C. Brom the mother liFuors, a second crop of (.$ g 3as obtained.
A solution of +., g !AH in ), m! "HB under He 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, $.2 m! of (,,K H$S9+,
follo3ed by a solution of +.2 g $,0,+@trimetho/y@beta@nitrostyrene in +, m! anhydrous "HB. "he mi/ture 3as stirred at , deg C for ( h, at room
temperature for ( h, and then brought briefly to a reflu/ on the steam bath. After cooling again, the e/cess hydride 3as destroyed 3ith +.2 m! H$9 in
"HB, follo3ed by the addition of ().) m! (&K 5a9H 3hich 3as sufficient to convert the solids to a 3hite and granular form. "hese 3ere removed by
filtration, the filter cake 3ashed 3ith "HB, the mother liFuor and filtrates combined, and the solvent removed under vacuum. "he residue 3as added to
dilute H$S9+, and 3ashed 3ith $/2& m! CH$Cl$. "he aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith $/&, m! CH$Cl$. "he
solvent 3as removed from these pooled e/tracts and the amber@colored residue distilled at %&@(,, deg C at ,.0 mm8Hg to provide $.) g of $,0,+@
trimetho/yphenethylamine as a 3hite oil. "his 3as dissolved in $, m! IPA, neutrali6ed 3ith about ( m! concentrated HCl, and diluted 3ith 1, m!
anhydrous <t$9. After filtering, <t$9@3ashing, and air drying, there 3as obtained 0.$ g of $,0,+@trimetho/yphenethylamine hydrochloride 'I?- as a 3hite
crystalline product.
;9SAC<E greater than +,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith 0,, mg- 5o effects 3hatsoever.
'3ith +,, mg- ?aybe a slight tingle at the hour@and@a@half point. ?aybe not. Certainly nothing an hour later. Put this do3n as being 3ithout action.
<="<5SI95S A5; C9??<5"A:>E Some fifty years ago this material 3as given the name Nreciprocal mescalineN in that it 3as believed to e/acerbate
the clinical symptoms in schi6ophrenic patients. In the original report, one findsE :"hus 3e have discovered an e/tremely remarkable dependency of the
into/icating action upon the position of the three metho/y groups. ?escaline, the 0,+,&@trimetho/y@beta@phenethylamine, produces in the normal subGect
a much stronger over@all into/ication than in the schi6ophrenic patient, 3hereas $,0,+@trimetho/y@beta@phenethylamine has Fuite the opposite effect. It
has little action in healthy individuals, being almost 3ithout into/icating properties, but it is very potent in the schi6ophrenic. "he metabolic conversion
products of the NreciprocalN mescaline 3ill be further studied as soon as the study of the metabolism of the proper mescaline is complete.
"his is a pretty rich offering, and one that the present medical community has no Fualms about discarding. At the bookkeeping level, the promised
further studies have never appeared, so all may be forgotten as far as potential ne3 discoveries might be concerned.
9ne recent related study has been reported, tying together isomescaline and schi6ophrenia. "hrough the use of radioactive labelling, the e/tent of
demethylation 'the metabolic removal of the methyl groups from the metho/yls- 3as determined in both schi6ophrenic patients and normal subGects.
Ihen there 3as a loading of the person 3ith methionine 'an amino acid that is the principal source of the body7s methyl groups-, the schi6ophrenics
appeared to sho3 a lesser amount of demethylation.
.ut might either of these t3o observations lead to a diagnostic test for schi6ophreniaH At the present time, the conventional thinking is that this probably
cannot be. "he illness has such social and genetic contributions, that no simple measure of a response to an almost@psychedelic, or minor shift of some
urinary metabolite pattern could possibly be believed. 5o independent confirmation of these properties has been reported. .ut maybe these findings
are valid. A maGor problem in follo3ing these leads does not involve any comple/ research protocols. Ihat must be addressed are the present
regulatory restrictions and the Bederal la3 structure. And these are formidable obstacles.
#4$ ",; "S%,*%S!A"#E; ',)-0"METH%+Y-(-&i--,*%,%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of &.) g of homosyringonitrile 'see under <SCA!I5< for its preparation- and (0.1 g isopropyl iodide in &, m! dry acetone 3as
treated 3ith 1.% g finely po3dered anhydrous $C90 and held at reflu/ on the steam bath. After 1 h another & m! of isopropyl iodide 3as added, and
reflu/ing continued for an additional ($ h. "he mi/ture 3as filtered and the solids 3ashed 3ith acetone. "he mother liFuor and 3ashes 3ere stripped of
solvent under vacuum, "he residue 3as taken up in dilute HCl, and e/tracted 3ith 0/(,, m! CH$Cl$. "he pooled e/tracts 'they 3ere Fuite deeply
yello3 colored- 3ere 3ashed 3ith $/2& m! &K 5a9H, and finally once 3ith dilute HCl. :emoval of the solvent under vacuum yielded %.) g of an amber
oil, 3hich on distillation at ($&@(0& deg C at ,.0 mm8Hg provided 1., g of 0,&@dimetho/y@+@'i-@propo/yphenylacetonitrile as a pale yello3 oil. A pure
reference sample is a 3hite solid 3ith a mp of 00@0+ deg C. Anal. 'C(0H(2590- C,H,5.
A solution of AH 3as prepared by the cautious addition of ,.)+ m! of (,,K H$S9+ to 0$ m! of (., ? !AH in "HB, 3hich 3as being vigorously stirred
under He at ice@bath temperature. A solution of &.%0 g of 0,&@dimetho/y@+@'i-@propo/yphenylacetonitrile in (, m! anhydrous "HB 3as added drop3ise.
Stirring 3as continued for 0, min, then the reaction mi/ture 3as brought up to reflu/ on the steam bath for another 0, min. After cooling again to room
temperature, & m! IPA 3as added to destroy the e/cess hydride, follo3ed by about (, m! of (&K 5a9H, sufficient to make the aluminum salts loose,
3hite, and filterable. "he reaction mi/ture 3as filtered, the filter cake 3ashed 3ith IPA, the mother liFuor and 3ashes combined, and the solvent
removed under vacuum. "he residue '2., g of an amber oil- 3as dissolved in dilute H$S9+ and 3ashed 3ith 0/2& m! CH$Cl$. "he aFueous phase
3as made basic 3ith aFueous 5a9H, and the product e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere evaporated to a residue under vacuum, and
this 3as distilled at ($&@(+, deg C at ,.0 mm8Hg yielding 0.2 g of a colorless oil. "his 3as dissolved in (& m! IPA, neutrali6ed 3ith &, drops of
concentrated HCl 3hich allo3ed the deposition of a 3hite crystalline product. ;ilution 3ith anhydrous <t$9 and filtration gave 0.2 g. of 0,&@dimetho/y@+@
'i-@propo/yphenethylamine hydrochloride 'IP- 3ith a mp of (10@(1+ deg C. Anal. 'C(0H$$Cl590- C,H,5. "he catalytic hydrogenation process for
reducing the nitrile that gives rise to escaline, also 3orks 3ith this material.
;9SAC<E +, @ ), mg.
;4:A"I95E (, @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith 2& mg- Starts slo3ly. I develop some Fueasiness, turning into nausea. Beels good to lie do3n and let go, but the
uneasiness remains. Dust beginning to break through in $ hours. .ut the occasional sense of relief, the breaking into the open, 3ere transient as ne3
sources of discomfort 3ere al3ays being dredged up. "hen for some reason I chose to dance. !etting go to dancing, a marvelous ecstatic e/perience,
flo3ing 3ith and being the energy, body feeling completely free. 5oticing ho3 this letting go got one completely out of the feeling of unease, as though
attention simply needs to be put else3here. Comedo3n 3as very slo3, gentle, euphoric; a very signicant e/perience. Sleep that night 3as impossible,
but felt good to simply release to the feelings. eeping mind still, no thinking, Gust allo3ing feelings to go 3here they 3ished, became more and more
ecstatic. "remendous feeling of confidence in life and the life process. Complete sense of resolution.
'3ith ), mg- It took about t3o hours for the body to settle do3n. <motions 3ere true and 3ell felt, a fact that is an all@important thing to me as it probably
is to everyone else I kno3 in this kind of e/ploration. Any sense that there is a dulling of the feeling and emotional area of the self is a negative, to be
3atched and noted as are other things such as disturbed sleep, unpleasant dreams, or irritability or depression the ne/t day. I 3as interacting 3ith
others 3ith a great deal of intensity. People found themselves 3andering inside and out, listening to music, stirring soup, eating a bit and enGoying
eating, talking, laughing a great deal, and being silent in great contentment. It7s not a very silent material, though. "alking is too enGoyable. "here 3as a
slight descent noted at 1@2 hours, but very gentle and smooth. Slo3 and pleasant descent until about ($th hour, 3hen sleep 3as attempted. 5e/t day,
everyone slightly irritable but good mood any3ay. "he ne/t night I slept deeply and 3ell, and a3oke 3hole and in e/cellent mood.
<="<5SI95S A5; C9??<5"A:>E "hese t3o e/cerpts give the color and comple/ity of IP. It has proven to be a completely fascinating
phenethylamine. And, as 3ith all the phenethylamines, there is an amphetamine that corresponds to it. "his 3ould be 0,&@dimetho/y@+@
isopropo/yamphetamine, or 0C@IP. "he prepa@ration of it 3ould reFuire access through the 9@isopropo/ylation product 3ith syringaldehyde, follo3ed by
nitrostyrene formation 3ith nitroethane, follo3ed by reduction probably 3ith lithium aluminum hydride. It has not been synthesi6ed, as far as I kno3, and
so it has probably not been evaluated in man. Ihat 3ould be the active levelH It 3ould probably be more potent than IP, but I 3ould guess not by
much. ?aybe in the 0, milligram area.
A moment7s aside for a couple of the 3ords that are so much a part of the chemist7s Gargon. :oom temperature, as used above, means the natural
temperature that something comes to if it is put on the table and is neither heated nor cooled. "he phrase, I discovered during my year at Cif, is
completely un@understandable in Brench. A room has no temperature. 9nly things in rooms have temperatures. "heir e/pression is more e/act. "he
obGect achieves, in the Brench terminology, a temperature normale d7interieur, or about (& to (1 deg C. .ut in common laboratory parlance it has
become the temperature d7ambiance.
And one finds the prefi/ NisoN used every3here. Considerable care should be taken in the t3o different uses of the prefi/ NisoN in the nomenclature 3ith
the mescaline analogues. In general, the term NisoN means the other one of t3o possibilities. If you are allo3ed to paint a house only 3ith green paint or
red paint, and green is the color you actually use, then red could be called iso@green. Iith isoproscaline 'here- there is a rearranging of the propyl group
on the +@o/ygen of mescaline. It has been replaced 3ith its branched analogue, the other of t3o possibilities, the isopropyl group. <verything is still 3ith
the 0,+,&@orientation on the ben6ene ring. Ho3ever, 3ith I? 'isomescaline- there is a rearrangement of substitution pattern on the ben6ene ring, 3ith the
repositioning of the trimetho/yl substitution pattern from the 0,+,&@ arrangement to the $,0,+@ arrangement. It has been the side@chain that has taken the
other of t3o possible positions. "he term NisoN must al3ays be interpreted in precise conte/t.

#4' "*"S; )-ETH%+Y-$-METH%+Y-(-METHYAM,HETAM"#E
S>5"H<SISE "o a solution of %.& g flaked 9H '(,K e/cess- in &,, m! %&K <t9H there 3as added $,.+ g +@metho/y@$@methylphenol 'see under $C@;
for its preparation-. "his 3as follo3ed 3ith $0.& g ethyl iodide, and the mi/ture 3as held at reflu/ overnight. "he solvent 3as removed under vacuum
and the residue suspended in $&, m! H$9. "his 3as made strongly basic 3ith 5a9H and e/tracted 3ith 0/&, m! CH$Cl$. :emoval of the solvent
gave (&.2& g of $@etho/y@&@metho/ytoluene as an amber oil, 3hich 3as used in the follo3ing step 3ithout further purification. Acidification of the
aFueous phase follo3ed by CH$Cl$ e/traction gave, after removal of the solvent, crude recovered starting phenol as a dark bro3n crystalline solid. "he
reasonably pure phenol 3as best isolated by seFuential e/tractions 3ith portions of ), deg C H$9 3hich, on cooling, deposited the phenol as 3hite
crystals.
A mi/ture of 0) m! P9Cl0 and +0 m! 5@methylformanilide 3as allo3ed to incubate for ( h and then there 3as added to it (&.2 g $@etho/y@&@
metho/ytoluene. "his 3as heated in the steam bath for $ h, then poured into ( ! H$9 and allo3ed to stir overnight. "he solids that formed 3ere
removed by filtration and H$9 3ashed, giving $,.2 g of a crude, amber product. "his 3as e/tracted 3ith $/(&, m! boiling he/ane 3hich gave crystals
on cooling. "hese 3ere filtered and he/ane 3ashed, giving ($.)& g of &@etho/y@$@metho/y@+@methylben6aldehyde as pale cream@colored solids 3ith a
mp of 2&@21 deg C. :ecrystalli6ation of an analytical sample from <t9H t3o times gave a product 3ith a 3hite color, and a mp of )(@)$ deg C.
"o a solution of ((.0& g &@etho/y@$@metho/y@+@methylben6aldehyde in +) m! glacial acetic acid containing + g anhydrous ammonium acetate there 3as
added (, m! nitroethane, and the mi/ture heated on the steam bath for $ h. Standing at room temperature overnight allo3ed a heavy crop of brilliant
crystals to deposit. "hese 3ere removed by filtration, 3ashed cautiously 3ith acetic acid, and air dried to give ).1 g (@'&@etho/y@$@metho/y@+@
methylphenyl-@$@nitropropene 3ith a mp of (()@($, deg C. :ecrystalli6ation of all from $,, m! boiling ?e9H gave ).0 g of lustrous crystals 3ith a mp of
($(@($$ deg C.
"o a gently reflu/ing suspension of 1.+ g !AH in &,, m! anhydrous <t$9 under a He atmosphere, there 3as added ).( g (@'&@etho/y@$@metho/y@+@
methylphenyl-@$@nitropropene by allo3ing the condensing ether to drip into a shunted So/hlet thimble containing the nitrostyrene. "his effectively added
a 3arm saturated solution of the nitrostyrene drop3ise. :eflu/ing 3as maintained overnight, and the cooled reaction flask stirred for several additional
days. "he e/cess hydride 3as destroyed by the cautious addition of +,, m! H$9 containing +, g H$S9+. Ihen the aFueous and <t$9 layers 3ere
finally clear, they 3ere separated, and (1, g of potassium sodium tartrate 3as dissolved in the aFueous fraction. AFueous 5a9H 3as then added until
the pH 3as U%, and this 3as then e/tracted 3ith 0/&, m! CH$Cl$. <vaporation of the solvent under vacuum produced an oil that 3as dissolved in
anhydrous <t$9 and saturated 3ith anhydrous HCl gas. "here appeared &@etho/y@$@metho/y@+@methylamphetamine hydrochloride 'I:IS- as fine 3hite
crystals. "hese 3eighed, after filtration, <t$9 3ashing, and air drying to constant 3eight, &.0 g and had a mp of (%$@(%0 deg C. :ecrystalli6ation of an
analytical sample from boiling CH0C5 gave lustrous crystals 3ith a mp of (%1@(%2 deg C 3ith decomposition.
;9SAC<E greater than % mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith 2.& mg- At about three hours I felt that I 3as at threshold, but an hour later there 3as nothing.
'3ith % mg- ?aybe a little light headedH ?aybe not. !ittle effect if any.
<="<5SI95S A5; C9??<5"A:>E "his is one of the ten Classic !adies, the ten possible homologues of ;9?, 3hich I had discussed under
A:IA;5< 'the first of the !adies-. "he active level is unkno3n, but it is higher than % milligrams 'the highest dose tried- and since ;9? itself 3ould
have been smashingly active at this level, it is obvious that I:IS is a homologue 3ith decreased potency.
"his lack of activity brings up a fascinating point. I have referred to a drug7s action on the mind, Fuite freFuently in these notes, 3ith the phrase
Nreasonably comple/.N .y that, I do not mean that a drug7s action simply sho3s many facets, and if these 3ere to be tallied, the drug@mind interaction
3ould become clear. "here is Fuite a bit of importance intrinsically implied by the term, comple/. Simple things, as 3e have come to appreciate and
depend upon them in our day@to@day living, can have simple e/planations. .y this, I mean e/planations that are both completely satisfactory and
satisfactorily complete. Ans3ers that have all the earmarks of being correct. Ihat is the sum of t3o plus three, you askH !et7s try five. And for most of
our needs, five is both factual and complete.
.ut some years ago, a mathematician named CVouml;del devised a proof for a theorem that anything that is reasonably comple/ cannot enGoy this
lu/ury 'I believe he used the 3ord NinterestingN rather than reasonably comple/-. If your collection of information is factual, it cannot be entirely
complete. And if it is complete, it cannot be entirely factual. In short, 3e 3ill never kno3, 3e cannot ever kno3, every fact that constitutes an
e/planation of something. A complete book of kno3ledge must contain errors, and an error@free book of kno3ledge must be incomplete.
"here is a small 3arning light deep inside me that starts flashing any time I hear someone begin to advance an e/planation of some reasonably comple/
phenomenon 3ith an air of confidence that implies, NHere is ho3 it 3orks.N Ihat the speaker usually has is an intense familiarity 3ith one particular
discipline or specialty and the phenomenon is vie3ed through those eyes, often 3ith the assurance that looking at it that 3ay, intently enough and long
enough, 3ill reveal the complete e/planation. And be attentive to the phrase, NIe are not yet com@pletely sure of e/actly ho3 it 3orks.N Ihat is really
meant is, NIe haven7t the slightest idea of ho3 it really 3orks.N
I must admit to some guilt in this matter, certainly as much as the ne/t person. I am a chemist and I suspect that the 3ay that the psychedelic drugs do
their thing can eventually be understood through a comparison of the structures of the molecules that are active and those that are inactive. I put those
that have metho/yl groups in pigeon hole R(, and those that are bicyclic into pigeon hole R$. And then, if pigeon hole R$ becomes more and more
cluttered, I 3ill subdivide the contents into pigeon hole R$A for bicyclics 3ith heteroatoms and pigeon hole R$. for bicyclics 3ithout heteroatoms. "he
more information I can accumulate, the more pigeon holes I need.
.ut in the adGoining lab, there is a molecular biologist 3ho feels that the eventual e/planation for the action of the psychedelic drug 3ill come from the
analysis and understanding of the intimate geometry of the places in the brain 3here they act. "hese classification pigeon holes are called receptor
sites. .ut they, too, can become more and more subdivided as they become cluttered. 9ne reads of a ne3 sub@sub type Fuite regularly in the literature.
"he favorite neurotransmitter of the moment, as far as the current thinking of ho3 these marvelous drugs 3ork, is serotonin, or &@H" 'for &@
hydro/ytryptamine-. "here are &@H"( and &@H"$A and &@H"$. and 'for all I kno3 right no3- &@H"$C and &@H"$; receptors, and I don7t really think that
either he or I have come much closer to understanding the mechanism of action.
And, since the mind is a reasonably comple/ system, CVouml;del has already informed us both that neither of us 3ill be completely successful.
Sometimes I feel that the pigeon hole approach to the classification of kno3ledge might actually limit our vie3s of the problem. A Harvard Professor of
?edicine recently notedE :Ie must recogni6e for 3hat it is, man7s predilection for dividing things into tidy categories, irrespective of 3hether clarity is
gained or lost thereby.
5o. 5o one 3ill ever have it all together. It is like sitting do3n in front of a Gigsa3 3ith a 6illion 6illion pieces spread all over the kitchen table. Iith
diligent searching you 3ill occasionally find a piece that matches another, but it rarely provides any insight into the final picture. "hat 3ill remain a
mystery, unless you had the chance to see the cover of the bo/ in some other incarnation. .ut 9h my, 3hat fun it is, 3henever you do happen to find a
ne3 piece that fitsO
"his harangue is really a lengthy prelude to the story of putting an etho/y group in place of a metho/y on the $,&@dimetho/y skeleton of these
psychedelic families. "he making of I:IS 3as the first move in this direction, done back in (%21. 9ne can have a pigeon hole that is named N<tho/y In
Place of ?etho/yN and toss in there the names of perhaps t3enty pairs of compounds, 3hich differ from one another by Gust this feature. >et 3hen they
are looked at from the potency point of vie3, there are some 3hich sho3 a decrease in potency '3hich is the case 3ith I:IS and most of the "3eetios-
and there are some 3hich seem to maintain their potency 'such as the "?A@$8?<? pair- and there are some 3here there is a distinct potency increase
'the mescaline8escaline pair, for e/ample-.
Ihat does one do to clarify the contents of this particular pigeon holeH "he current fad 3ould be to subdivide it into three subdivisions, maybe
something like N<tho/y in Place of ?etho/y if $@ or &@locatedN and N<tho/y in Place of ?etho/y if +@located and other things $,&N and N<tho/y in Place of
?etho/y if +@located, and other things 0,&.N "he end point that soon becomes apparent, do3n the line, 3ill be to have as many pigeon holes as
compoundsO And at the moment, this particular piece of the Gigsa3 pu66le doesn7t seem to fit any3here at all.
Perhaps both my neighboring molecular biologist and I are asking the 3rong Fuestions. I am looking at the molecules and asking, NIhat are theyHN And
he is follo3ing them and asking, NIhere do they goHN And neither of us is fully attentive to the Fuestion, NIhat do they doHN It is so easy to replace the
3ord Nmind,N in our inFuiries, 3ith the 3ord Nbrain.N
>up. "he operation of the mind can certainly be classified as a Nreasonably comple/N phenomenon. I prefer CVouml;del7s term. "he mind is 3ithout
Fuestion an NinterestingN phenomenon.

#4( ;; .0.; $-AM"#%-1-&',(-METHYE#E0"%+Y,HE#Y-./TA#E;
1-&1,'-.E#6%0"%+%-)-Y--$-./TA#AM"#E
S>5"H<SISE "he Crignard reagent of propyl bromide 3as made by the drop3ise addition of &$ g (@bromopropane to a stirred suspension of (+ g
magnesium turnings in &, m! anhydrous <t$9. After the addition, stirring 3as continued for (, min, and then a solution of &, g piperonal in $,, m!
anhydrous <t$9 3as added over the course of 0, min. "he reaction mi/ture 3as heated at reflu/ for ) h, then cooled 3ith an e/ternal ice bath. It 3as
Fuenched 3ith the addition of a solution of 2& m! cold, saturated aFueous ammonium chloride. "he formed solids 3ere removed by filtration, and the
t3o@phase filtrate separated. "he organic phase 3as 3ashed 3ith 0/$,, m! dilute HCl, dried over anhydrous ?gS9+, and the solvent removed under
vacuum. "he crude 1$.$ g of (@'0,+@methylenedio/yphenyl-@$@butanol, 3hich contained a small amount of the olefin that formed by dehydration, 3as
distilled at %) deg C at ,.,2 mm8Hg to give an analytical sample, but the crude isolate served 3ell in the ne/t reaction. Anal. 'C((H(+90- C,H.
A mi/ture of 1& g crude (@'0,+@methylenedio/yphenyl-@$@butanol and ( g finely po3dered potassium bisulfate 3as heated 3ith a soft flame until the
internal temperature reached (2, deg C and H$9 3as no longer evolved. "he entire reaction mi/ture 3as then distilled at (,,@((, deg C at ,.) mm8Hg
to give && g of (@'0,+@methylenedio/yphenyl-@(@butene as a colorless oil. Anal. 'C((H($9$- C,H.
"o $+, m! of stirred and cooled formic acid there 3as added 0, m! H$9 follo3ed, slo3ly, by +& m! of 0&K hydrogen pero/ide. "here 3as then added a
solution of +) g (@'0,+@methylenedio/yphenyl-@(@butene in $+, m! acetone at a rate that maintained the internal temperature at less than +, deg C.
After the addition, the reaction mi/ture 3as allo3ed to stand and stir for several additional days. "he e/cess volatiles 3ere removed under vacuum 3ith
the temperature never allo3ed to e/ceed +, deg C. "he residue 3as dissolved in %, m! ?e9H and diluted 3ith +&, m! (&K H$S9+. "his mi/ture 3as
heated on the steam bath for $.& h, cooled, and then e/tracted 3ith 0/(,, m! <t$9. "he e/tracts 3ere pooled, 3ashed 3ith $/$,, m! H$9, $/$,, m!
&K 5a9H, $/$,, m! brine, and then dried over anhydrous ?gS9+. After removal of the solvent under vacuum, the residue 3as distilled at (,&@(0& deg
C at ,.0 mm8Hg to give $).$ g (@'0,+@methylenedio/yphenyl-@$@butanone as an amber oil. :edistillation gave a colorless oil, 3ith a bp of %) deg C at
,.(( mm8Hg. Anal. 'C((H($90- C,H. "his intermediate ketone could be prepared by the Iittig reaction bet3een piperonal and the derivative of
triphenylphosphonium propyl bromide and dibutyldisulfide, follo3ed by hydrolysis in a HCl8acetic acid mi/ture, but the yields 3ere no better, <fforts to
prepare this ketone by the iron and acid reduction of the appropriate nitrostyrene '(@'0,+@methylenedio/yphenyl-@$@nitro@(@butene, mp 1+@1& deg C- 3ere
th3arted by the consistently unsatisfactory yield of the precursor from the reaction bet3een piperonal and (@nitropropane.
A stirred solution of $, g anhydrous ammonium acetate and +.1 g (@'0,+@methylenedio/yphenyl-@$@butanone in &, m! ?e9H 3as treated 3ith (.&2 g
sodium cyanoborohydride. ;roplets of HCl 3ere added as needed to maintain the pH at appro/imately 1. "he reaction mi/ture 3as made basic 3ith the
addition of $&, m! dilute 5a9H and e/tracted 3ith 0/(,, m! CH$Cl$. "he pooled organic e/tracts 3ere e/tracted 3ith $/(,, m! dilute H$S9+, the
pooled aFueous e/tracts made basic again, and e/tracted again 3ith $/(,, m! CH$Cl$. :emoval of the solvent gave a residue 3hich 3as distilled to
give $.1 g of a colorless oil 3hich 3as dissolved in (& m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith an eFual volume of anhydrous <t$9.
Crystals of $@amino@(@'0,+@methylenedio/yphenyl-butane hydrochloride 'D- separated slo3ly. After filtering, <t$9 3ashing, and air drying there 3as
obtained $.) g of 3hite crystals that melted at (&%@(1( deg C. Anal. 'C((H(1Cl59$- C,H,5.
;9SAC<E (&, @ $0, mg.
;4:A"I95E + @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith (2& mg- "he first stirrings 3ere evident in a half hour, pleasant feelings, and 3ithout any unto3ard body effects.
Iithin another half hour I 3as at a plus $ and there it leveled off. I 3ould be reluctant to drive a car, but I could 3ere it necessary. "here 3ere no visual
distortions, no giddiness, no introspective urges, and no rise to a psychedelic into/ication of any significance. After about an hour and a half at this level,
I gradually dropped back over another t3o hours. After3ards I 3as Fuite fatigued and languorous.
'3ith $,, mg and a 2& mg supplement- :A very strong climb, and a very good, interior feeling. It has some of the ?;?A properties, but it is difficult to
concentrate on any one point. "here is a tendency to slide off. </cellent emotional affect; music is fine but not gripping. Someone had used the
phrase, mental nystagmus, and there is something valid there. "he supplement 3as taken at the $ hour point 3hen I 3as already a3are of some
dropping, and its action 3as noticed in about a half hour.
'3ith $0, mg- Physically, there 3as a bit of dry mouth but no teeth clenching, some nystagmus, maybe the slightest bit of di66iness, very anore/ic, and it
is not a decongestant. ?entally, it is e/tremely benign and pleasant, funny and good@humored. 5o visuals. Peaceful. <asy silences, easy talking. ?ore
stoning than ?;?A.
<="<5SI95S A5; C9??<5"A:>E In general, all subGects 3ho have e/plored D have accepted it and commented favorably. Perhaps those 3ho have
used supplements 'in an imitation of the common ?;?A procedure- achieved an additional period of effect, but also tended to drop to baseline
after3ards more rapidly. "he physical side effects, such as teeth clench and nystagmus, 3ere infreFuent. "he consensus is that D is a bit more
NstoningN than ?;?A, more like ?;A, but 3ith a chronology that is very much the same.
"3o nomenclature problems have to be faced in the naming of these compounds. 9ne deals 3ith the Chemical Abstracts terminology as contrasted
3ith the logical and intuitive terminology. "he other invokes the concept of the ?uni@?etro, delightfully simple, but neither Chemical Abstracts@approved
nor intuitive in form. "he first problem is addressed here; the second is discussed 3here it better belongs, under the 5@methyl homologue of D 'see
under ?<"H>!@D-.
In short, the t3o@ring system of D, or of any of the ?;A@?;?A family of drugs, can be named as one ring being attached to the other, or by a single term
that encompasses both. "he first procedure, an old friend 3ith chemists and the one that had been used for years in the abstracting services, calls the
combination methylenedio/yben6ene and, as a prefi/, it becomes methylenedio/yphenyl@something. "he ben6ene or the phenyl@something is the
foundation of the name, and there happens to be a methylenedio/y@ring attached to it. 9n this basis, this compound D should be named as if it had no
methylenedio/y ring any3here, and then simply attach the ne3 ring as an afterthought. So, the one@ring parent of D is (@phenyl@$@aminobutane, and D is
(@'0,+@methylenedio/yphenyl-@$@aminobutane 'or, to be a purist, the amino should alphabetically come first, to give $@amino@(@'0,+@methylene@
dio/yphenyl-butane-. "he synthesis of the chemical intermediates given above uses this old@fashioned nomenclature.
.ut the name currently in vogue for this t3o@ring system is (,0@ben6odio/ole. As a prefi/ it becomes (,0@ben6odio/ol@&@yl@something, and so D 3ould be
called (@'(,0@ben6odio/ol@&@yl-@$@aminobutane. "his is the source of the code name .;.. And the 5@methyl homologue, the alpha@ethyl analogue of
?;?A, is named ?.;., or ?<"H>!@D, and is 3ith its o3n separate entry in this footnote.
"here is a psychological nuance to this ne3 nomenclature. "he virtues and potential medical value of ?;?A lie in its most remarkable property of
facilitating communication and introspective states 3ithout an overlay of psychedelic action. "his property has prompted the coining of a ne3
pharmacological class name, <ntactogen, 3hich comes from the Creek roots for Ntouching 3ithin.N .ut ?;?A has been badly smeared in both the public
and the scientific vie3, by its 3ide popular misuse, its precipitous placement into a Schedule I category of the Bederal ;rug !a3, and a flood of negative
neuroto/icological findings in animal studies. "here are some properties of both this compound and its methyl@homologue that suggest this NentactogenN
3orld, so 3hy not avoid the N?;N prefi/ that, in many eyes, is peGorativeH Stick 3ith the totally obscure chemical names, and call them .;. and ?.;..
9r, even more simply, D and ?<"H>!@D.

#4) %,H%,H"#E; '-METH%+Y-(,)-METHYE#E0"%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of &, g myristicinaldehyde '0@metho/y@+,&@methylenedio/yben6aldehyde, see under ??;A for its preparation- in $,, m! acetic
acid 3as treated 3ith 00 m! nitromethane and (2.+ g anhydrous ammonium acetate and held on the steam bath for & h. "he reaction mi/ture 3as
diluted 3ith a little H$9 and cooled in an e/ternal ice@acetone bath. A heavy crop of yello3 crystals formed, 3hich 3ere removed by filtration, 3ashed
3ith cold acetic acid, and dried to constant 3eight. "here 3as thus obtained (%.0 g 0@metho/y@+,&@methylenedio/y@beta@nitrostyrene 3ith a mp of $(,@
$($ deg C. "he mother liFuors 3ere diluted 3ith H$9, and e/tracted 3ith 0/(,, m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith &K 5a9H, and the
solvent removed under vacuum yielding 0+ g of a dark residue that 3as largely unreacted aldehyde. "his residue 3as reprocessed in acetic acid 3ith
nitromethane and ammonium acetate, as described above, and provided an additional ).( g of the nitrostyrene 3ith the same mp.
A suspension of $& g !AH in (.& ! anhydrous <t$9 in an inert atmosphere 3as stirred magnetically, and brought up to a gentle reflu/. "hrough a
So/hlet condenser modified to allo3 <t$9 to return continuously to the reaction mi/ture, there 3as added $2., g of 0@metho/y@+,&@methylenedio/y@beta@
nitrostyrene. "he addition reFuire many h, and 3hen it 3as completed, the reaction 3as held at reflu/ for an additional % days. After cooling the reaction
mi/ture in an e/ternal ice bath, the e/cess hydride 3as destroyed by the cautious addition of dilute H$S9+. "he final amount used 3as (),, m! H$9
containing (00 g H$S9+. "he phases 3ere separated, and the aFueous phase 3as 3ashed 3ith $/(,, m! <t$9. "o it 3as then added 1$& g
potassium sodium tartrate, and sufficient base to bring the pH to U%. "his 3as e/tracted 3ith 0/$&, m! CH$Cl$, and the pooled e/tracts stripped of
solvent under vacuum. "he residue 3as dissolved in anhydrous <t$9 and saturated 3ith anhydrous HCl gas, giving a heavy crystalli6ation of salts.
"hese 3ere removed by filtration, <t$9 3ashed, and air dried, to give (2.2 g 0@metho/y@+,&@methylenedio/yphenethylamine '!9PH9PHI5<- as an off@
3hite solid 3ith a mp of (1,@(1( deg C. "his 3as dissolved in CH0C5 containing &K <t9H, decolori6ed 3ith activated charcoal, filtered, and the
removed charcoal 3ashed 3ith boiling CH0C5. Slo3 cooling of the solution provided ((.2 g of a 3hite product 3hich melted at (1+@(1+.& deg C.
;9SAC<E greater than $,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (&, mg- .et3een t3o and five hours, very peaceful and euphoric mood elevation, similar to mescaline, but 3ithout
any visual distortion. ?ild enhancement of color perception, possibly a function of mood elevation. "here 3as no nausea, no eyes@closed vision. Slept
easily that evening.
'3ith $&, mg- Possibly something of a threshold effect from $E0, to +E0, of the e/periment. Intangible, and certainly there is nothing an hour later.
<="<5SI95S A5; C9??<5"A:>E It looks as if this compound is not active. "here is an e/cellent argument as to 3hy it really should be, and the fact
that it is not active is completely une/pected. !et me try to e/plain.
Luite simply, mescaline is a maGor component and a centrally active alkaloid of the Peyote plant. It is a phenethylamine, 3hich can undergo a
cycli6ation 3ithin the plant to produce a pile of derivatives 'tetrahydroisoFuinolines- such as anhalonine and 9@methylanhalonidine that are marvelously
comple/ alkaloids, all natural components of this magical cactus. .ut there is another pile of derivatives 'tetrahydroisoFuinolines- such as anhalonine,
and lophophorine, and peyophorine 3hich are the logical cycli6ation products of another phenethylamine 3hich does not e/ist in the cactus. It should be
there, but it is not. If it 3ere there it 3ould be the natural precursor to a host of bicyclic alkaloids, but it is absent. "his is 0@metho/y@+,&@
methylenedio/yphenethylamine. I feel that some day it 3ill be discovered as a plant component, and 3hen it is it can be given a name that reflects the
generic binomial of the plant. And since the plant has been kno3n as !ophophora 3illiamsii, 3hy not give a name to this compound '3hich should be in
the plant-, one derived from the !atin name, but one that has never before been usedH Ihat about !9PH9PHI5<H And so, I have named it, but I have
not found it, nor has anyone else. >et.
It is inevitable that this simple and most appealing precursor 3ill be found to be present in the cactus, at some future time 3hen 3e 3ill have tools of
sufficient sensitivity to detect it. And certainly, it 3ould be reasonable to e/pect it to be an active psychedelic, and to be as interesting in man as its close
cousin, mescaline. .ut, at the present time, !9PH9PHI5< is not kno3n to be present in the plant, and it is not kno3n to be active in man. I am
confident that both statuses 3ill change in the future.

#41 M; MES!A"#E; ',(,)-T*"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of $, g 0,+,&@trimetho/yben6aldehyde, +, m! nitromethane, and $, m! cyclohe/ylamine in $,, m! of acetic acid 3as heated on
the steam bath for ( h. "he reaction mi/ture 3as then diluted slo3ly and 3ith good stirring, 3ith +,, m! H$9, 3hich allo3ed the formation of a heavy
yello3 crystalline mass. "his 3as removed by filtration, 3ashed 3ith H$9, and sucked as dry as possible.
:ecrystalli6ation from boiling ?e9H '(& m!8g- yielded, after filtration and air drying, beta@nitro@0,+,&@trimetho/ystyrene as bright yello3 crystals 3eighing
().& g. An alternate synthesis 3as effective, using an e/cess of nitromethane as solvent as 3ell as reagent, if the amount of ammonium acetate
catalysis 3as kept small. A solution of $, g 0,+,&@trimetho/yben6aldehyde in +, m! nitromethane containing ( g anhydrous ammonium acetate 3as
heated on the steam bath for + h. "he solvent 3as stripped under vacuum and the residual yello3 oil 3as dissolved in t3o volumes of hot ?e9H,
decanted from some insolubles, and allo3ed to cool. "he crystals formed are removed by filtration, 3ashed 3ith ?e9H and air dried yielding (+.$ g. of
bright yello3 crystals of beta@nitro@0,+,&@trimetho/ystyrene. "he use of these proportions but 3ith 0.& g ammonium acetate gave e/tensive side@reaction
products even 3hen 3orked up after only (.& h heating. "he yield of nitrostyrene 3as, in this latter case, unsatisfactory.
"o a gently reflu/ing suspension of $ g !AH in $,, m! <t$9, there 3as added $.+ g beta@nitro@0,+,&@trimetho/ystyrene as a saturated <t$9 solution by
use of a So/hlet e/traction condenser modified to allo3 the continuous return of condensed solvent through the thimble. After the addition 3as
complete, the reflu/ing conditions 3ere maintained for another +) h. After cooling the reaction mi/ture, a total of (&, m! of (.& 5 H$S9+ 3as cautiously
added, destroying the e/cess hydride and untimately providing t3o clear phases. "hese 3ere separated, and the aFueous phase 3as 3ashed once
3ith &, m! <t$9. "here 3as then added &, g potassium sodium tartrate, follo3ed by sufficient 5a9H to bring the pH U%. "his 3as then e/tracted 3ith
0/2& m! CH$Cl$, and the solvent from the pooled e/tracts 3as removed under vacuum. "he residue 3as distilled at ($,@(0, deg C at ,.0 mm8Hg
giving a 3hite oil that 3as dissolved in (, m! IPA and neutrali6ed 3ith concentrated HCl. "he 3hite crystals that formed 3ere diluted 3ith $& m! <t$9,
removed by filtration, and air dried to provide $.( g 0,+,&@trimetho/yphenethylamine hydrochloride '?- as glistening 3hite crystals. "he sulfate salt
formed spectacular crystals from 3ater, but had a broad and uncharacteristic mp. An alternate synthesis can employ 0,+,&@trimetho/yphenylacetonitrile,
as described under beta@;.
;9SAC<E $,,@+,, mg 'as the sulfate salt-, (2)@$&1 mg 'as the hydrochloride salt-.
;4:A"I95E (,@($ h
L4A!I"A"IM< C9??<5"SE '3ith 0,, mg- I 3ould have liked to, and 3as e/pecting to, have an e/citing visual day, but I seemed to be unable to
escape self@analysis. At the peak of the e/perience I 3as Fuite into/icated and hyper 3ith energy, so that it 3as not hard to move around. I 3as Fuite
restless. .ut I spent most of the day in considerable agony, attempting to break through 3ithout success. I learned a great deal about myself and my
inner 3orkings. <verything almost 3as, but in the final analysis, 3asn7t. I began to become a3are of a point, a brilliant 3hite light, that seemed to be
3here Cod 3as entering, and it 3as inconceivably 3onderful to perceive it and to be close to it. 9ne 3ished for it to approach 3ith all one7s heart. I
could see that people 3ould sit and meditate for hours on end Gust in the hope that this little bit of light 3ould contact them. I begged for it to continue
and come closer but it did not. It faded a3ay not to return in that particular guise the rest of the day. !istening to ?o6art7s :eFuiem, there 3ere
magnificent heights of beauty and glory. "he 3orld 3as so far a3ay from Cod, and nothing 3as more important than getting back in touch 3ith Him. .ut
I sa3 ho3 3e created the nuclear fiasco to threaten the e/istence of the planet, as if it 3ould be only through the threat of complete annihilation that
people might 3ake up and begin to become concerned about each other. And so also 3ith the famines in Africa. ?any similar scenes of Goy and despair
kept me in balance. I ended up the e/perience in a very peaceful space, feeling that though I had been through a lot, I had accomplished a great deal. I
felt 3onderful, free, and clear.
'3ith 0&, mg- 9nce I got through the nausea stage, I ventured out@of@doors and I 3as a3are of an intensification of color and a considerable change in
the te/ture of the cloth of my skirt and in the concrete of the side3alk, and in the flo3ers and leaves that 3ere handed me by an observer. I e/perienced
the desire to laugh hysterically at 3hat I could only describe as the completely ridiculous state of the entire 3orld. Although I 3as afraid of motion, I 3as
persuaded to take a ride in a car. "he driver turned on the radio and suddenly the music 7"he ?arch of the Siamese Children7 from 7"he ing and I7
became the most perfect background music for the parody of real life 3hich 3as indeed the normal activity of "elegraph Avenue on any Saturday
morning. "he perfectly ordinary people on their perfectly ordinary errands 3ere clearly the most cleverly contrived set of characters all performing all
manners of eccentric activities for our particular hilarity and enGoyment. I felt that I 3as at the same time both observing and performing in an
outrageous moving picture. I e/perienced one moment of transcendant happiness 3hen, 3hile passing <p3orth Hall, I looked out of the 3indo3 of the
car and up at the building and I 3as suddenly in Italy looking up at a gay apartment building 3ith its shutters flung open in sunshine, and 3ith its 3indo3
bo/es 3ith flo3ers. Ie stopped at a spot overlooking the bay, but I found the vie3 uninteresting and the sun uncomfortable. I sat there on the seat of
the car looking do3n at the ground, and the earth became a mosaic of beautiful stones 3hich had been placed in an intricate design 3hich soon all
began to move in a serpentine manner. "hen I became a3are that I 3as looking at the skin of a beautiful snake L all the ground around me 3as this
same huge creature and 3e 3ere all standing on the back of this gigantic and beautiful reptile. "he e/perience 3as very pleasing and I felt no revulsion.
Dust then, another automobile stopped to look at the vie3 and I e/perienced my first real feeling of persecution and I 3anted very much to leave.
'3ith +,, mg- ;uring the initial phase of the into/ication 'bet3een $ and 0 hours- everything seemed to have a humorous interpretation. People7s faces
are in caricature, small cars seem to be chasing big cars, and all cars coming to3ards me seem to have faces. "his one is a duchess moving in regal
pomp, that one is a 3i6ened old man running a3ay from someone. A remarkable effect of this drug is the e/treme empathy felt for all small things; a
stone, a flo3er, an insect. I believe that it 3ould be impossible to harm anything L to commit an overt harmful or painful act on anyone or anything is
beyond one7s capabilities. 9ne cannot pluck a flo3er L and even to 3alk upon a gravel path reFuires one to pick his footing carefully, to avoid hurting or
disturbing the stones. I found the color perception to be the most striking aspect of the e/perience. "he slightest difference of shade could be amplified
to e/treme contrast. ?any subtle hues became phosphorescent in intensity. Saturated colors 3ere often unchanged, but they 3ere surrounded by
cascades of ne3 colors tumbling over the edges.
'3ith +,, mg- It took a long time to come on and I 3as afraid that I had done it 3rong but my concerns 3ere soon ended. "he 3orld soon became
transformed 3here obGects glo3ed as if from an inner illumination and my body sprang to life. "he sense of my body, being alive in my muscles and
sine3s, filled me 3ith enormous Goy. I 3atched <rmina fill to brimming 3ith animal spirit, her features tranformed, her body cat@like in her graceful natural
movement. I 3as stopped in my tracks. "he 3orld seemed to hold its breath as the cat changed again into the Coddess. As she shed her clothes, she
shed her ego and 3hen the dance began, <rmina 3as no more. "here 3as only the dance 3ithout the slightest self@consconciousness. Ho3 can
anything so beautiful be chained and changed by other7s e/pectationsH I became a3are of myself in her and as 3e looked deeply into one another my
boundaries disappeared and I became her looking at me.
<="<5SI95S A5; C9??<5"A:>E ?escaline is one of the oldest psychedelics kno3n to man. It is the maGor active component of the small dumpling
cactus kno3n as Peyote. It gro3s 3ild in the South3estern 4nited States and in 5orthern ?e/ico, and has been used as an intimate component of a
number of religious traditions amongst the native Indians of these areas. "he cactus has the botanical name of !ophophora 3illiamsii or Anhalonium
le3inii and is immediately recogni6able by its small round shape and the appearance of tufts of soft fu66 in place of the more conventional spines. "he
dried plant material has been classically used 3ith any3here from a fe3 to a couple of do6en of the hard tops, called buttons, being consumed in the
course of a ceremony.
"hroughout the more recently published record of clinical human studies 3ith mescaline, it has been used in the form of the synthetic material, and has
usually been administered as the sulfate salt. Although this form has a miserable melting point 'it contains 3ater of crystalli6ation, and the e/act melting
point depends on the rate of heating of the sample- it nonetheless forms magnificent crystals from 3ater. !ong, glistening needles that are, in a sense,
its signature and its mark of purity. "he dosages associated 3ith the above NFualitative commentsN are given as if measured as the sulfate, although the
actual form used 3as usually the hydrochloride salt. "he conversion factor is given under NdosageN above.
?escaline has al3ays been the central standard against 3hich all other compounds are vie3ed. <ven the 4nited States Chemical Iarfare group, in
their human studies of a number of substituted phenethylamines, used mescaline as the reference material for both Fuantitative and Fualitative
comparisons. "he <dge3ood Arsenal code number for it 3as <A@(0,1. All psychedelics are given properties that are something like Nt3ice the potency
of mescalineN or Nt3ice as long@lived as mescaline.N "his simple drug is truly the central prototype against 3hich everything else is measured. "he
earliest studies 3ith the Npsychotomimetic amphetaminesN had Fuantitative psychological numbers attached that read as Nmescaline units.N ?escaline
3as cast in concrete as being active at the 0.2& mg8kg level. "hat means for a ), kilogram person 'a (2, pound person- a dose of 0,, milligrams. If a
ne3 compound proved to be active at 0, milligrams, there 3as a ?.4. level of (, put into the published literature. "he behavioral biologists 3ere happy,
because no3 they had numbers to represent psychological properties. .ut in truth, none of this represented the magic of this material, the nature of the
e/perience itself. "hat is 3hy, in this .ook II, there is only one line given to Ndosage,N but a full page given to NFualitative commentsN.
Bour simple 5@modified mescaline analogues are of interest in that they are natural and have been e/plored in man.
"he 5@acetyl analogue has been found in the peyote plant, and it is also a maGor metabolite of mescaline in man. It is made by the gentle reaction of
mescaline 3ith acetic anhydride 'a bit too much heat, and the product 5@acetyl mescaline 3ill cycli6e to a dihydroisoFuinoline, itself a fine 3hite
crystalline solid, mp (1,@(1( deg C- and can be recrystalli6ed from boiling toluene. A number of human trials 3ith this amide at levels in the 0,, to 2&,
milligrams range have sho3n it to be 3ith very little activity. At the highest levels there have been suggestions of dro3siness. Certainly there 3ere none
of the classic mescaline psychedelic effects.
If free base mescaline is brought into reaction 3ith ethyl formate 'to produce the amide, 5@formylmescaline- and subseFuently reduced '3ith lithium
aluminum hydride- it is converted to the 5@methyl homologue. "his base has also been found as a trace component in the Peyote cactus. And the
effects of 5@methylation of other psychedelic drugs have been commented upon else3here in these recipes, all 3ith consistently negative results '3ith
the note3orthy e/ception of the conversion of ?;A to ?;?A-. Here, too, there is no obvious activity in man, although the levels assayed 3ere only up
to $& milligrams.
5,5@;imethylmescaline has been given the trivial name of "richocerine as it has been found as a natural product in several cacti of the "richocereus
Cenus but, interestingly, never in any Peyote variant. It also has proven inactive in man in dosages in e/cess of &,, milligrams, administered
parenterally. "his observation, the absence of activity of a simple tertiary amine, has been e/ploited in the development of several iodinated
radiopharmaceuticals that are mentioned else3here in this book.
"he fourth modification is the compound 3ith the nitrogen atom o/idatively removed from the scene. "his is the mescaline metabolite, 0,+,&@
trimetho/yphenylacetic acid, or "?P<A. Human dosages up to 2&, milligrams orally failed to produce either physiological or psychological changes.
9ne additional manipulation 3ith some of these structures has been made and should be mentioned. "hese are the analogues 3ith an o/ygen atom
inserted bet3een the aromatic ring and the aliphatic chain. "hey are, in essence, aminoethyl phenyl ethers. "he first is related to mescaline itself, $@
'0,+,&@trimetho/ypheno/y-ethylamine. Human trials 3ere conducted over the dose range of (, to 0,, milligrams and there 3ere no effects observed.
"he second is related to trichocerine, 5,5@dimethyl@$@'0,+,&@trimetho/ypheno/y-ethylamine. It 3as inactive in man over the range of (, to +,,
milligrams. ?escaline, at a dose of +$, milligrams, served as the control in these studies.

#42 (-MA; ,MA; (-METH%+YAM,HETAM"#E
S>5"H<SISE A solution of $2.$ g anisaldehyde and ()., g nitroethane in 0,, m! ben6ene 3as treated 3ith $., m! cyclohe/ane and reflu/ed using a
;ean Stark trap until H$9 ceased to accumulate. A total of 0.) m! 3as generated over about & days. After the removal of the solvent under vacuum,
the viscous red oily residue 3as cooled and it spontaneously crystalli6ed. "his 3as ground under an eFual volume of ?e9H, producing lemon@yello3
crystals of (@'+@metho/yphenyl-@$@nitropropene. "he final yield 3as $2.+ g of product 3ith a mp of +&@+1 deg C. :ecrystalli6ation from + volumes ?e9H
did not improve the mp. An e/cellent alternate synthesis 3ith a comparable yield involved letting a solution of eFuimolar amounts of the aldehyde and
nitro@ethane and a tenth mole of n@amylamine stand in the dark at room temperature for a couple of 3eeks. "he product spontaneously crystal@li6ed,
and could be recrystalli6ed from ?e9H. "he more conventional synthesis involving acetic acid as a solvent and ammonium acetate as a catalyst,
produced a poor yield of the nitrostyrene and it 3as difficult to separate from the 3hite diacetate of the starting anisaldehyde, mp &%@1, deg C.
A suspension of 0$ g !AH in ( ! anhydrous <t$9 3as 3ell stirred and 0$.1 g (@'+@metho/yphenyl-@$@nitropropene in <t$9 3as added at a rate that
maintained a reflu/. After the addition 3as complete, reflu/ 3as continued for +) h. "he reaction mi/ture 3as cooled, and the e/cess hydride 3as
destroyed by the cautious addition of dilute H$S9+. "he <t$9 3as separated, and e/tracted 3ith additional aFueous H$S9+. A solution of 2,, g
potassium sodium tartrate in 1,, m! H$9 3as added, and the pH brought to U% 3ith $&K 5a9H. "his aFueous phase 3as e/tracted 3ith 0/$,, m!
CH$Cl$ 3hich provided, after removal of the solvent, 0$.& g of a clear amber oil. "his 3as dissolved in (,, m! IPA, neutrali6ed 3ith concentrated HCl,
and then diluted 3ith 0,, m! anhydrous <t$9. "here 3as obtained 3hite crystals of +@metho/yamphetamine hydrochloride '+@?A- that 3eighed, after
filtering, <t$9 3ashing and air drying, $$.$ g and had a mp of $,)@$,% deg C. "he amphetamine metabolite, +@hydro/yamphetamine hydrochloride '+@
HA-, 3as prepared by heating &., g +@?A in $, m! concentrated HCl at (& lbs8in. After recrystal@li6ation from aFueous <t9H, the product 3eighed 0.) g
and had a mp of (2(@(2$ deg C.
;9SAC<E &, @ ), mg.
;4:A"I95E short.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- At Gust over an hour, there 3as a sudden blood pressure rise, 3ith the systolic going up && mm. "his 3as
maintained for another hour. I found the effects reminiscent of ;<", distinct after@images, and some parasthesia. I 3as 3ithout any residue by early
evening 'after & hours-.
'3ith 2, mg- It hit Fuite suddenly. I had a feeling of druggedness, almost an alcohol@like into/ication, and I never 3as really high in the psychedelic
sense.
<="<5SI95S A5; C9??<5"A:>E "his is another of the essential amphetamines, because of the appearance of the +@metho/y group in t3o most
important essential oils. "hese are the allylben6ene 'estragole or esdragol- and the propenyl isomer 'anethole-. "heir natural sources have been
discussed under "?A.
"3o comments are 3arranted concerning +@?A, one of scientific interest, and the other about a social tragedy.
A maGor metabolites of amphetamine is +@hydro/yamphetamine, from o/idation at the +@position. It has been long kno3n that 3ith chronic amphetamine
usage there is the generation of tolerance, 3hich encourages ever@increasing doses to be used. Ihen the daily load gets up around one or t3o
hundred milligrams, the subGect can become Fuite psychotic. "he Fuestion 3as askedE might the chronic amphetamine user be methylating his
endogenously produced +@hydro/yamphet@amine to produce +@metho/yamphetamine '+@?A-, and maybe this is the agent that promotes the psychosisH
"o address this Fuestion, several studies 3ere done 3ith normal subGects, about $, years ago, to see if +@?A might produce a psychotic state 'it didn7t at
the highest levels tried, 2& milligrams- and to see if it 3as e/creted to some e/tent unchanged in the urines of these normal subGects 'it 3as seen even at
the lo3est dosage tried, (, milligrams-. It produced e/citation and other central effects, it produced adrenergic pressor effects, and it consistently
produced measur@able Fuantities of +@?A in the urine, but it produced no amphetamine@like cra6ies. And since the administration of up to 1,, milligrams
of amphetamine produced no detectable +@?A in the urine, this theory of psychotomimesis is not valid.
9n the tragic side, a fe3 years later, +@?A became 3idely distributed in both the 4S 'as the sulfate salt- and in Canada 'as the hydrochloride-, perhaps
in@spired by some studies in rats that had reported that it 3as second only to !S; in potency as a hallucinogen. "he several deaths that occurred
probably follo3ed overdose, and it 3as clear that +@?A 3as involved as it had been isolated from both urine and tissue during post mortems. It had
been sold under the names of Chicken Po3er and Chicken >ello3, and 3as promoted as being ?;A. I could find no record of a typical street dosage,
but comments collected in association 3ith the deaths implied that the ingested Fuantites 3ere in the hundreds of milligrams. :recently, the etho/y
homologue, +@<A, appeared on the streets of Canada. "he dosage, again, 3as not reported. It 3as promptly illegali6ed there.
"he t3o positional analogues of +@?A are kno3n; vis., $@?A and 0@?A. "heir synthesis is straightfor3ard, in imitation of that for +@?A above. "he meta@
compound, 0@?A, has been metabolically e/plored in man, but no central effects 3ere noted at a &, milligram dose '$/$& milligrams, separated by three
hours-. "here appears to be no report of any human trial of $@?A. "he 5@methyl homologue of $@?A is a commercial adrenergic bronchodilator called
?etho/yphenamine, or 9rtho/ine. It has been used in the prevention of acute asthma attacks in doses of up to $,, milligrams, 3ith only slight central
stimulation. "he 5@methyl homologues of 0@?A and +@?A are kno3n, and the latter compound is the stuff of a separate entry in this book.
#43 MA0AM-1; $,#-0"METHY-(,)-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE A mi/ture of (,$ g P9Cl0 and ((& g 5@methylformanilide 3as allo3ed to stand for ,.& h at room temperature during 3hich time it turned a
deep claret color. "o this there 3as added +& g 0,+@methylenedio/ytoluene and the mi/ture 3as held on the steam bath for 0 h. It 3as then added to 0 !
H$9. Stirring 3as continued until the oil 3hich had separated had become Fuite firm. "his 3as removed by filtration to give a greenish, some3hat
gummy, crystalline solid, 3hich 3as finely ground under +, m! ?e9H and again filtered giving, 3hen air dried, $& g of an almost 3hite solid.
:ecrystalli6ation of a small sample from methylcyclopentane gave ivory@colored glistening crystals of $@methyl@+,&@methylenedio/yben6aldehyde 3ith a
mp of )).&@)%.& deg C. In the infra@red, the carbonyl 3as identical to that of the starting piperonal '(1%, cm@(- but the fingerprint 3as different and
uniFue, 3ith bands at )1), %$%, (,+, and (,&$ cm@(.
A solution of $0 g $@methyl@+,&@methylenedio/yben6aldehyde in (&, m! nitroethane 3as treated 3ith $., g anhydrous ammonium acetate and heated on
the steam bath for % h. "he e/cess solvent 3as removed under vacuum to give a dark yello3 oil 3hich 3as dissolved in +, m! hot ?e9H and allo3ed
to crystalli6e. "he solids 3ere removed by filtration, 3ashed modestly 3ith ?e9H and air dried, to give $(.$ g of (@'$@methyl@+,&@
methylenedio/yphenyl-@$@nitropropene as beautiful yello3 crystals 3ith a mp of ((1@(() deg C. :ecrystalli6ation of an analytical sample from ?e9H
gave lustrous bright yello3 crystals 3ith a mp of ($,@($( deg C. Anal. 'C((H((59+- C,H,5.
A suspension of &+ g electrolytic elemental iron in $+, g glacial acetic acid 3as 3armed on the steam bath, 3ith freFuent stirring. Ihen the reaction
bet3een them started, there 3as added, a portion at a time, a solution of ().$ g (@'$@methyl@+,&@methylenedio/yphenyl-@$@nitropropene in ($& m! 3arm
acetic acid. "he orange color of the nitrostyrene solution became Fuite reddish, 3hite solids of iron acetate appeared, and a dark tomato@colored crust
formed 3hich 3as continuously broken back into the reaction mi/ture. Heating 3as continued for (.& h, and then all 3as poured into $ ! H$9. All the
insolubles 3ere removed by filtration, and these 3ere 3ashed 3ell 3ith CH$Cl$. "he filtrate and 3ashes 3ere combined, the phases separated, and the
aFueous phase e/tracted 3ith $/(,, m! additional CH$Cl$. "he combined organics 3ere 3ashed 3ith &K 5a9H, and the solvent removed under
vacuum. "he residue 3eighed (&.% g, and 3as distilled at %,@((, deg C at ,.+ mm8Hg to give (0.% g of $@methyl@+,&@methylenedio/yphenylacetone that
spontaneously crystalli6ed. A small sample from methylcyclopentane had a mp of &$@&0 deg C, another from he/ane a mp of &0@&+ deg C, and another
from ?e9H a mp of &+@&& deg C. Anal. 'C((H($90- H; C calcd, 1).20; found 12.)2, 12.)+.
"o a stirred solution of 0, g methylamine hydrochloride in $,, m! 3arm ?e9H there 3as added (0.& g $@methyl@+,&@methylenedio/yphenylacetone
follo3ed, after returning to room temperature, by 2 g sodium cyanoborohydride. "here 3as added HCl as needed to maintain the pH at appro/imately
orange on e/ternal damp universal pH paper. After a fe3 days, the reaction ceased generating base, and all 3as poured into $ ! dilute H$S9+ 'caution,
HC5 evolved-. "his 3as 3ashed 3ith 0/2& m! CH$Cl$, made basic 3ith $&K 5a9H, and the resulting mi/ture e/tracted 3ith 0/(,, CH$Cl$. "he
pooled e/tracts 3ere stripped of solvent under vacuum and the residue, (& g of a pale amber oil, 3as distilled at %&@((, deg C at ,.+ mm8Hg. "here
3as obtained ($.0 g of a 3hite oil that 3as dissolved in 1, m! IPA, neutrali6ed 3ith appro/imately &.& m! concentrated HCl, and crystals of the salt
formed spontaneously. "hese 3ere loosened 3ith the addition of another (, m! IPA, and then all 3as diluted by the addition of an eFual volume of
anhydrous <t$9. "he 3hite crystals 3ere separated by filtration, <t$9 3ashed, and air dried to give (+.( g of $,5@dimethyl@+,&@
methylenedio/yamphetamine hydrochloride '?A;A?@1- as a brilliant 3hite po3der 3ith a mp of $,1@$,2 deg C. Anal. 'C($H()Cl59$- C,H.
;9SAC<E greater than $), mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (), mg- "here is a hint of good things there, but nothing more than a hint. At four hours, there is no longer even a
hint.
'3ith $), mg- I took (&, milligrams, 3aited an hour for results, 3hich 3as niente, nada, nothing. "ook supplements of 1& milligrams t3ice, an hour
apart. 5o effect. >es, 3e giveth up.
<="<5SI95S A5; C9??<5"A:>E "he structure of ?A;A?@1 3as designed to be that of ?;?A, 3ith a methyl group attached at 3hat should be a
reasonably indifferent position. In fact, that is the genesis of the name. ?;?A has been called A;A?, and 3ith a methyl group in the 1@position,
?A;A?@1 is Fuite understandable. And the other ortho@position is, using this nomenclature, the $@position, and 3ith a methyl group there, one 3ould
have ?A;A?@$. I should make a small apology for the choice of numbers. ?;?A is a 0,+@methylenedio/y compound, and the least ambiguous
numbering scheme 3ould be to lock the methylenedio/y group inescapably at the 0,+@place, letting the other ring position numbers fall 3here they may.
"he rules of chemistry ask that if something is really a 0,+,1@orientation it should be renumbered as a $,+,&@orientation. !et7s Fuietly ignore that reFuest
here.
Ho3 fascinating it is, that a small methyl group, something that is little more than one more minor bump on the surface of a molecule that is lumpy and
bumpy any3ay, can so effectively change the action of a compound. A big activity change from a small structure change usually implies that the bump is
at a vital point, such as a target of metabolism or a point of critical fit in some receptor site. And since 1@?A;A? can be looked upon as 1@bump@?;?A,
and since it is at least 0/ less potent than ?;?A, the implication is that the action of ?;?A reFuires some unbumpiness at this position for its particular
action. "here are suggestions that the body may 3ant to put a hydro/yl group right there 'a 1@hydro/y@dopamine act-, and it couldn7t if there 3as a
methyl group right there. "he isopropylamine side chain may 3ant a certain degree of s3ing@around freedom, and this 3ould be restricted by a methyl
bump right ne/t to it. And there are all kinds of other speculations possible as to 3hy that position should be open.
Any3ay, ?A;A?@1 is not active. And the eFually intriguing positional isomer, the easily made ?A;A?@$, 3ill certainly contribute to these speculations.
A Fui6 for the readerO Iill $,5@dimethyl@0,+@methylenedio/yamphetamine '?A;A?@$- beE '(- 9f much reduced activity, akin to ?A;A?@1, or '$- 9f
potency and action similar to that of ?;?A, or '0- Something une/pected and unanticipatedH I kno3 only one 3ay of finding out. ?ake the Schiffs7
base bet3een piperonal and cyclohe/ylamine, treat this 3ith butyl lithium in he/ane 3ith some "?<;A present, add some 5@methylformanilide, convert
the formed ben6aldehyde to a nitrostyrene 3ith nitroethane, reduce this 3ith elemental iron to the phenylacetone, reduce this in the presence of
methylamine 3ith sodium cyanoborohydride, then taste the result.

#44 MA; METHAYES!A"#E;
',)-0"METH%+Y-(-METHAY%+Y,HE#ETHYAM"#E-
S>5"H<SISE "o a solution of &.) g of homosyringonitrile 'see under <SCA!I5< for its preparation- in &, m! of acetone containing (,, mg of
decyltriethylammonium iodide there 3as added 2.) m! methallyl chloride follo3ed by 1.% g of finely po3dered anhydrous $C90. "he suspension 3as
kept at reflu/ by a heating mantle, 3ith effective stirring. After 1 h an additional +., m! of methallyl chloride 3as added, and the reflu/ing 3as continued
for an additional 01 h. "he solvent and e/cess methallyl chloride 3as removed under vacuum and the residue 3as added to +,, m! H$9. "his solution
3as e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere pooled, 3ashed 3ith $/&, m! &K 5a9H, and the solvent removed to provide a dark bro3n oil.
"his 3as distilled at ($,@(0, deg C at ,.+ mm8Hg to provide 1.( g of 0,&@dimetho/y@+@methyallylo/yphenylacetonitrile as a lemon@colored viscous oil.
Anal. 'C(+H(2590- C,H.
A suspension of +.$ g !AH in (1, m! anhydrous "HB under He 3as stirred, cooled to , deg C, and treated 3ith $.%& ml of (,,K H$S9+ added
drop3ise. "his 3as follo3ed by the addition of 1., g of 0,&@dimetho/y@+@methallylo/y@phenylacetonitrile dissolved in (, m! anhydrous "HB, at a slo3
rate 3ith vigorous stirring. "he reaction mi/ture 3as held at reflu/ on the steam bath for ,.& h, brought back to room temperature, and the e/cess
hydride destroyed 3ith IPA. Sufficient (&K 5a9H 3as added to convert the formed solids to a loose, granular te/ture, and the entire mi/ture filtered and
3ashed 3ith "HB. "he filtrate and 3ashings 3ere pooled, the solvent removed under vacuum, and the residue added to &,, m! dilute HCl. "his solution
3as 3ashed 3ith $/&, m! CH$Cl$, made basic 3ith aFueous 5a9H, and e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere pooled, the solvent
removed under vacuum, and the residual pale amber oil distilled at ($,@(0, deg C at ,.0 mm8Hg to provide (.& g of a 3hite oil. "his 3as dissolved in
)., m! of IPA and neutrali6ed 3ith $& drops of concentrated HCl. "he addition of +, ml of anhydrous <t$9 3ith stirring produced, after a fe3 moments
delay, a spontaneous crystalli6ation of 0,&@dimetho/y@+@methallylo/yphenethylamine hydrochloride '?A!- as fine 3hite needles. After standing overnight
these 3ere removed by filtration, 3ashed 3ith an IPA8<t$9 mi/ture, then 3ith <t$9, and allo3ed to air dry to constant 3eight. "he product 3eighed (.(
g, and had a mp of (&0@(&+ deg C. Anal. 'C(+H$$Cl590- C,H.
;9SAC<E +, @ 1& mg.
;4:A"I95E ($ @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith +& mg- "oo much overload. I am sur@rounded 3ith unreality. I do not choose to repeat the e/periment.
'3ith +& mg- I am basically favorably impressed. I believe the initial discomfort 3ould be alleviated by taking t3o 0, milligram doses separated by an
hour.
'3ith +& mg- ?uch too much too much. "here are shades of 3hat might become amnesia. I am losing immediate contact. I 3ill not repeat.
'3ith &, mg- A good level. I found myself totally caught up in the visual theater. Although I had trouble sleeping, I 3ould 3illingly repeat the e/periment
at the same level.
'3ith 1, mg- </tremely restless. Am very impressed 3ith all the activity. .ut if I repeated it 3ould be at a lo3er dose.
'3ith 1, mg- Briendly territory. "here is much kaleidoscopic Sneon7 colors. <yes closed very active. <yes open there is considerable visual distortions
seen in melted 3a/. Baces are distorted 'friendly- but the sinister is not far a3ay.
'3ith 1& mg- Completely involved L good psychedelic state L visual entertainment 3ith alternation 'i.e., depth and movement- at the
retinal level L detail in 3atercolors. !ater in the e/perience 'the ) hour point- easy childhood memory recall.
'3ith 1& mg- .eautiful. "o a *$ by the (st hr and continued climbing. Intense *0 3ithin $ hrs. Luite strong body. ;iuretic. Bantasy, imagery, erotic.
Iay up, good connections bet3een parts of self. Slight slo3ing of pulse in 2th to )th hour. </cellent solid sleep 3ith strong, clear, balancing dreams.
.ut not until after ($ hrs.
<="<5SI95S A5; C9??<5"A:>E "his testimony can be accurately described as a mi/ed bagO
"his base, ?A!, lies as a hybrid of t3o other compounds, A! and CP?. It is an olefin 'as is A!- 3hich means that it has a place of unsaturation in its
structure. And it is an isostere of CP? 3hich means that the carbon atoms are all in the same location, but Gust the connecting electrons 'called the
chemical bonds- are in different places. Actually there is yet a third compound in this same picture, called P:9P>5>!. And yet, although all of them
have e/tremely close structural similarities, there are such great differences in action that one does not dare to generali6e. CP? leads largely to fantasy,
?A! largely to visual imagery, A! is t3ice as potent as either of these but it doesn7t sho3 either effect, and P:9P>5>! is almost 3ithout any action at
all.
Speaking of generali6ation, I am glad that there are al3ays e/ceptions. Some years ago, I had a most difficult e/perience 3ith a strain of mariGuana that
3as kno3n by the name of ;:<;. "he only 3ord that I can use to describe my response to it is to say that I felt I had been poisoned. Brom this I
3arned myself to be3are 'and to believe in- 3hatever common name a drug might have been given. Bortunately, ?A! did not live up to its name 'at
least for me-, although some of the e/perimental subGects might disagreeO
9ne additional compound 3as suggested by these parallels. <ach of these three drugs can be vie3ed as having a negative something hanging out a@
3ays from the molecular center. Iith A! and ?A!, this is the olefin double bond. Iith CP? this is a very strained three@member ring. Ihat about an
o/ygenH "he reaction bet3een homosyringonitrile and metho/yethyl chloride produced the precursor to such a product '0,&@dimetho/y@+@'$@
metho/yetho/y-@phenethylamine- but the yield 3as so bad that the proGect 3as abandoned. "his same grouping has successfully been put into the +@
position of the sulfur@containing analog, and the result '$C@"@(0- has proved to be Fuite a potent and interesting material. ?aybe someday hang a sulfur
atom out there at the end of that chain.
"he name methallylescaline actually is completely unsound. "here is no union of a methallyl 3ith an escaline. Ihat is really there is not an escaline at
all, but rather a mescaline 3ith a $@propene attached to the methyl of the metho/y on the +@position. "here is no 3ay of naming the thing in that manner,
so the only logical solution is to take off the methyl entirely, and then put the methallyl on in its place. "he name of this 3ould then be +@
methylallyldesmethylmescaline. "hat 3ould have received the abbreviation ?A; 3hich 3ould have been even more difficult to deal 3ith. ?A! is
preferable.

#155 M0A; ',(-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE 'from piperonal- "o a solution of (&., g piperonal in ), m! glacial acetic acid there 3as added (& m! nitroethane follo3ed by (, g
cyclohe/ylamine. "he mi/ture 3as held at steam@bath temperature for 1 h, diluted 3ith (, m! H$9, seeded 3ith a crystal of product, and cooled
overnight at (, deg C. "he bright yello3 crystals 3ere removed by filtration, and air dried to yield (,.2 g of (@'0,+@methylenedio/yphenyl-@$@nitropropene
3ith a mp of %0@%+ deg C. "his 3as raised to %2@%) deg C by recrystalli6ation from acetic acid. "he more conventional efforts of nitrostyrene synthesis
using an e/cess of nitroethane as a solvent and anhydrous ammonium acetate as the base, gives impure product in very poor yields. "he nitrostyrene
has been successfully made from the components in cold ?e9H, 3ith aFueous 5a9H as the base.
A suspension of $, g !AH in $&, m! anhydrous "HB 3as placed under an inert atmosphere and stirred magnetically. "here 3as added, drop3ise, () g
of (@'0,+@methylenedio/yphenyl-@$@nitropropene in solution in "HB and the reaction mi/ture 3as maintained at reflu/ for 01 h. After being brought back
to room temperature, the e/cess hydride 3as destroyed 3ith (& m! IPA, follo3ed by (& m! of (&K 5a9H. An additional &, m! H$9 3as added to
complete the conversion of the aluminum salts to a loose, 3hite, easily filtered solid. "his 3as removed by filtration, and the filter cake 3ashed 3ith
additional "HB. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum, and the residue dissolved in dilute H$S9+. Iashing 3ith
0/2& m! CH$Cl$ removed much of the color, and the aFueous phase 3as made basic and ree/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent
yielded (0., g of a yello3@colored oil that 3as distilled. "he fraction boiling at ),@%, deg C at ,.$ mm 3eighed (,.$ g and 3as 3ater@3hite. It 3as
dissolved in 1, m! of IPA, neutrali6ation 3ith concentrated HCl, and diluted 3ith ($, m! of anhydrous <t$9 3hich produced a lasting turbidity. Crystals
formed spontaneously 3hich 3ere removed by filtration, 3ashed 3ith <t$9, and air dried to provide (,.+ g of 0,+@methylenedio/yamphetamine
hydrochloride '?;A- 3ith a mp of ()2@()) deg C.
'from 0,+@methylenedio/yphenylacetone- "o a solution of 0$.& g anhydrous ammonium acetate in ($, m! ?e9H, there 3as added 2.($ g 0,+@
methylenedio/yphenylacetone 'see under ?;?A for its preparation- follo3ed by $., g sodium cyanoborohydride. "he resulting yello3 solution 3as
vigorously stirred, and concentrated HCl 3as added periodically to keep the pH of the reaction mi/ture bet3een 1 and 2 as determined by e/ternal damp
universal pH paper. After several days, undissolved solids remained in the reaction mi/ture and no more acid 3as reFuired. "he reaction mi/ture 3as
added to 1,, m! of dilute HCl, and this 3as 3ashed 3ith 0/(,, m! CH$Cl$. "he combined 3ashes 3ere back@e/tracted 3ith a small amount of dilute
HCl, the aFueous phases combined, and made basic 3ith $&K 5a9H. "his 3as then e/tracted 3ith 0/(,, m! CH$Cl$, these e/tracts combined, and
the solvent removed under vacuum to provide 0.) g of a red@colored residue. "his 3as distilled at ),@%, deg C at ,.$ mm8Hg to provide $.$ g of an
absolutely 3ater@3hite oil. "here 3as no obvious formation of a carbonate salt 3hen e/posed to air. "his 3as dissolved in (& m! IPA, neutrali6ed 3ith
$& drops of concentrated HCl, and diluted 3ith 0, m! anhydrous <t$9. Slo3ly there 3as the deposition of 3hite crystals of 0,+@
methylenedio/yamphetamine hydrochloride '?;A- 3hich 3eighed $.$ g and had a mp of ()2@()) deg C. "he preparation of the formamide 'a
precursor to ?;?A- and the acetamide 'a precursor to ?;<- are described under those entries.
;9SAC<E ), @ (1, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- "he coming on 3as gradual and pleasant, taking from an hour to an hour and one half to do so. "he trip 3as
euphoric and intense despite my having been naturally depleted from a 3orking day and having started so late. 9ne thing that impressed itself upon me
3as the feeling I got of seeing the play of events, of 3hat I thought to be the significance of certain people coming into my life, and 3hy my Sdance7, like
everyone else7s, is uniFue. I sa3 that every encounter or event is a potential for gro3th, and an opportunity for me to reali6e my completeness at 3here
I am, here and no3, not at some future 3here I must lug the pieces of the past for a final assemblage Sthere.7 I 3as reminded of living the moment to its
fullest and I felt that seeing this 3as indicative that I 3as on the right track.
'3ith ($) mg- Borty@five minutes after the second dosage, 3hen I 3as seated in a room by myself, not smoking, and 3here there 3as no possible source
of smoke rings, an abundance of curling gray smoke rings 3as readily observed in the environment 3henever a rela/ed approach to subGective
observation 3as used. Misually these had complete reality and it seemed Fuite unneccessary to test their properties because it 3as surely kno3n and
fully appreciated that the source of the visual phenomena could not be e/ternal to the body. Ihen I concentrated my attention on the details of the
curling gray forms by trying to note ho3 they 3ould be affected by passing a finger through their apparent field, they melted a3ay. "hen, 3hen I rela/ed
again, the smoke rings 3ere there. I 3as as certain that they 3ere really there as I am no3 sure that my head is on top of my body.
'3ith (+, mg- I vomited Fuite abruptly, and then everything 3as 9. I had been drinking probably e/cessively the last t3o days, and maybe the body
needed to unpoison itself. "he tactile sense is beautiful, but there seems to be some numbness as 3ell, and I feel that nothing erotic 3ould be do@able.
Intimacy, yes, but no performance I7m pretty sure. I sa3 the e/perience start drifting a3ay only four hours into it, and I 3as sad to see it go. It 3as an all
around delightful day.
'3ith $,, mg, $/(,, mg spaced ( h- :"he first portion 3as apparent at one@half hour. "here 3as microscopic nausea shortly after the second portion
3as taken, and in an hour there 3as a complete *** developed. "he rela/ation 3as e/treme. And there seemed to be time distortion, in that time
seemed to pass slo3ly. "here 3as a occasional !S;@like moment of profoundness, but by and large it 3as a simple into/ication 3ith most things
seeming Fuite hilarious. "he into/ication 3as also Fuite e/treme. Some food 3as tried later in the e/periment, and it tasted good, but there 3as
absolutely no appetite. 5one at all.
'3ith 1, mg of the N:N isomer- "here 3as a light and not too gentle development of a some3hat brittle 3ound@up state, a * or even a **. Chills, and I
had to get under an electric blanket to be comfortable. "he effects smoothed out at the fourth hour, 3hen things started to return to baseline. 5ot too
entertaining.
'3ith (,, mg of the N:N isomer- :apid development from the +, minute point to an hour and a Fuarter; largely a pleasant into/ication, but there is
something serious there too. 5o great insights, and not too much interference 3ith the day7s goings@on. Completely clear at the ) hour point.
'3ith ($, mg of the N:N isomer- "his is a stoning into/icant. I 3ould not choose to drive, because of possible Gudgement problems, but my hand3riting
seems to be clear and normal. "he mental e/citement dropped rapidly but I 3as a3are of physical residues for several additional hours.
'3ith ), mg of the NSN isomer- A very thin, light threshold, 3hich is Fuite delightful. I am Fuite 3illing to push this a bit higher.
'3ith ($, mg of the NSN isomer- Perhaps to a one *. Mery light, and very much like ?;?A, but perhaps shorter lived. I am pretty much baseline in three
hours.
'3ith (1, mg of the NSN isomer- "he development is very rapid, and there is both muscular tremor and some nausea. "he physicals are Fuite
bothersome. Iith eyes closed, there are no effects noticeable, but 3ith eyes open, things are Fuite bright and sparkling. "he muscular spasms persist,
and there is considerable teeth clenching. I feel that the mental is not 3orth the physical.
<="<5SI95S A5; C9??<5"A:>E "here are about t3enty different synthetic routes in the literature for the preparation of ?;A. ?any start 3ith
piperonal, and employ it to make methylenedio/yphenylacetone or a methylenedio/ydihydro@cinnamic acid amide instead of the nitrostyrene. "he
phenylacetone can be reduced in several 3ays other than the cyanoborohydride method mentioned here, and the amide can be rearranged directly to
?;A. And there are additional methods for the reduction of the nitrostyrene that use no lithium aluminum hydride. Also there are procedures that have
safrole or isosafrole as starting points. "here is even one in the underground literature that starts 3ith sassafras root bark. In fact, it is because safrole
is one of the ten essential oils that ?;A can humorously be referred to as one of the "en <ssential Amphetamines. See the comments under "?A.
"here is a broad and checkered history concerning the use and abuse of ?;A, and it is not the case that all the use 3as medical and all the abuse 3as
social. 9ne of the compulsive drives of both the military and the intelligence groups, Gust after Iorld Iar II, 3as to discover and develop chemical
agents 3hich might serve as Ntruth serumsN or as incapacitating agents. "hese government agencies considered the area of the psychedelics to be a
fertile field for searching. "he giving of relatively une/plored drugs in a cavalier manner to kno3ing and unkno3ing subGects 3as commonplace. "here
3as one case in (%&0, involving ?;A and a psychiatric patient named Ho3ard .lauer that proved fatal. "he army had contracted 3ith several
physicians at the 5e3 >ork State Psychiatric Institute to e/plore ne3 chemicals from the <dge3ood Arsenal and one of these, 3ith a chemical 3arfare
code number of <A@($%), 3as ?;A. "he last and lethal inGection into .lauer 3as an intravenous dose of &,, milligrams.
"here have been a number of medical e/plorations. 4nder the code SB@& 'and trade name of Amphedo/amine- it 3as e/plored as an anore/ic agent.
It has been found promising in the treatment of psychoneurotic depression. "here are several medical reports, and one book 'Claudio 5aranGo7s "he
Healing Dourney-, that describe its values in psychotherapy.
?;A 3as also one of the maGor drugs that 3as being popularly used in the late (%1,7s 3hen the psychedelic concept e/ploded on the public scene.
?;A 3as called the Nhug@drugN and 3as said to stand for ?ello3 ;rug of America. "here 3as no difficulty in obtaining unending Fuantities of it, as it 3as
available as a research chemical from several scientific supply houses 'as 3ere mescaline and !S;- and 3as sold ine/pensively under its chemical
name.
A fe3 e/perimental trials 3ith the pure optical isomers sho3 a consistency 3ith all the other psychedelic compounds that have been studied in their
separated forms, the higher potency 3ith the N:N isomer. "he less potent NSN isomer seemed to be more peaceful and ?;?A@like at lo3er doses, but
there 3ere 3orrisome to/ic signs at higher levels.
"he structure of ?;A can be vie3ed as an aromatic ring 'the 0,+@methylenedio/yphenyl ring- 3ith a three carbon chain sticking out from it. "he amine
group is on the second of the three carbon atoms. "he isomers, 3ith the amine function moved to the first of these carbons atoms 'a ben6ylamine- and
3ith the amine function moved to the third 'furthest out atom- of these carbon atoms 'a 'n-@propylamine-, are kno3n and both have been assayed.
"he ben6ylamine counterpart 'as if one 3ere to move the amine function from the beta@carbon to the alpha@carbon of the three carbon chain of the
amphetamine molecule- is alpha@ethyl@0,+@methylenedio/yben6ylamine or (@amino@(@'0,+@methylenedio/yphenyl-propane, A!PHA. "he hydrochloride
salt has a mp of (%%@$,( deg C. At lo3 threshold levels '(, milligram area- there 3ere eyes@closed NdreamsN 3ith some body tingling. "he compound
3as not anore/ic at any dose 'up to (+, milligrams- and 3as reported to produce a pleasant, positive feeling. It is very short@lived 'about 0 hours-. "he
5@methyl homologue is alpha@ethyl@5@methyl@0,+@methylenedio/yben6ylamine or (@methylamino@(@'0,+@methylenedio/y@phenyl-propane, ?@A!PHA. It is
similar in action, but is perhaps t3ice as potent 'a plus one or plus t3o dose is 1, milligrams- and of t3ice the duration.
"he 'n-@propylamine counterpart 'as if one 3ere to move the amine function the other direction, from the beta@carbon to the gamma@carbon of the three
carbon chain of the amphetamine molecule- is gamma@0,+@methylenedio/yphenylpropylamine or (@amino@0@'0,+@methylenedio/yphenyl-propane,
CA??A. "he hydrochloride salt has a mp of $,+@$,& deg C. At oral levels of $,, milligrams there 3as some physical ill@at@ease, possible time
distortion, and a feeling of being keenly a3are of one7s surroundings. "he duration of effects 3as + hrs.
"he phenethylamine that corresponds to ?;A 'removing the alpha@methyl group- is 0,+@methylenedio/yphenethylamine, or homopiperonylamine, or
?;P<A, or simply H in the vocabulary of the ?uni@?etro 3orld. "his compound is an entry in its o3n rights. "he adding of another carbon atom to the
alpha@methyl group of ?;A gives compound D, and leads to the rest of the ?uni@?etro series ', ! etc-. All of this is e/plained under ?<"H>!@D. "he
bending of this alpha@methyl group back to the aromatic ring gives an aminoindane, and 3ith D one gets an aminotetralin. .oth compounds react in
animal discrimination studies identically to ?;?A, and they appear to be free of neurochemical to/icity.
"he t3o possible homologues, 3ith either one or t3o methyl groups on the methylene carbon of the methylenedio/y group of ?;A, are also kno3n. "he
ethylidene compound 'the acetaldehyde addition to the catechol group- has been encoded as <;A, and the acetone 'isopropylidine addition to the
catechol group- is called I;A. In animal discrimination studies, and in in vitro neurotransmitter studies, they both seem to be of decreased potency.
<;A is do3n t3o to three@fold from ?;A, and I;A is do3n by a factor of t3o to three@fold again. Human trials of up to (&, milligrams of the
hydrochloride salt of <;A producd at best a threshold light@headedness. I;A remains untested as of the present time. "he homologue of ?;A 'actually
of ?;?A- 3ith the added carbon atom in, rather than on, the methylenedio/y ring, is a separate entry; see ?;?C.
A final isomer to be mentioned is a positional isomer. "he
0,+@methylene@dio/y group could be at the $,0@position of the amphetamine skeleton, giving $,0@methylenedio/yamphetamine, or 9:"H9@?;A. It
appears to be a stimulant rather than another ?;A. At &, milligrams, one person 3as a3ake and alert all night, but reported no ?;A@like effects.

#151 M0A; #-AY-M0A; ',(-METHYE#E0"%+Y-#- AYAM,HETAM"#E
S>5"H<SISE A total of about $, m! allylamine 3as introduced under the surface of $, m! concentrated HCl, and the mi/ture stripped of volatiles under
vacuum "he resulting $+ g of 3et material did not yield any crystals 3ith either acetone or <t$9. "his 3as dissolved in 2& m! ?e9H, treated 3ith +.+& g
0,+@methylenedio/y@phenylacetone 'see under ?;?A for its preparation-, and finally 3ith (.( g sodium cyanoborohydride. Concentrated HCl 3as added
as needed over the course of & days to keep the pH constant at about 1. "he reaction mi/ture 3as then added to a large amount of H$9, acidified 3ith
HCl, and e/tracted 3ith 0/(,, m! CH$Cl$. "he aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. <vaporation
of the solvent from these e/tracts yielded 0.1 g of an amber oil 3hich, on distillation at %,@%& deg C at ,.$ mm8Hg, yielded $.1 g of an off@3hite oil. "his
3as dissolved in (, m! IPA, neutrali6ed 3ith about $& drops of concentrated HCl, and the resulting clear but viscous solution 3as diluted 3ith <t$9 until
crystals formed. "hese 3ere removed by filtration, 3ashed 3ith IPA8<t$9 '(E(-, then 3ith <t$9, and air dried to constant 3eight. "here 3as thus
obtained $.& g of 0,+@methylenedio/y@5@allylamphetamine hydrochloride '?;A!- 3ith a mp of (2+@(21 deg C and a proton 5?: spectrum that sho3ed
that the allyl group 3as intact. Anal. 'C(0H()Cl59$- 5.
;9SAC<E greater than (), mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E Here is another inactive probe, like ?;P:, that could possibly serve as a primer to !S;. "he three carbon chain
on the nitrogen seen 3ith ?;P: is almost identical to the three carbon chain on the nitrogen atom of ?;A!. And yet, 3here an NinactiveN level of (),
milligrams of ?;P: is a rather fantastic enhancer of !S; action, the same 3eight of this compound not only does not enhance, but actually seems to
some3hat antagoni6e the action of !S;. All this difference from Gust a couple of hydrogen atoms. Identical carbon atoms, identical o/ygen atoms, and
an identical nitrogen atom. And all in identical places. Simply C(0H()Cl59$ rather than C(0H$,Cl59$.
So, apparently, almost identical is not good enoughO
#15$ M0./; #-./TY-M0A; ',(-METHYE#E0"%+Y-#-./TYAM,HETAM"#E
S>5"H<SISE A total of 0, m! butylamine 3as introduced under the surface of 00 m! concentrated HCl, and the mi/ture stripped of volatiles under
vacuum. "he resulting glassy solid 3as dissolved in (1, m! ?e9H and treated 3ith 2.$ g 0,+@methylenedio/yphenylacetone 'see under ?;?A for its
preparation-. "o this there 3as added &,K 5a9H drop3ise until the pH 3as at about 1 as determined by the use of e/ternal dampened universal pH
paper. "he solution 3as vigorously stirred and $.) g sodium cyanoborohydride 3as added. Concentrated HCl 3as added as needed, to keep the pH
constant at about 1. "he addition reFuired about t3o days, during 3hich time the reaction mi/ture first became Fuite cottage@cheese like, and then
finally thinned out again. All 3as dumped into ( ! H$9 acidified 3ith HCl, and e/tracted 3ith 0/(,, m! CH$Cl$. "hese e/tracts 3ere combined,
e/tracted 3ith $/(,, m! dilute H$S9+, 3hich 3as combined 3ith the aFueous fraction above. "his latter mi/ture 3as made basic 3ith $&K 5a9H, and
e/tracted 3ith 0/(&, m! CH$Cl$. <vaporation of the solvent yielded +., g of an amber oil 3hich, on distillation at %,@(,, deg C at ,.(& mm8Hg, yielded
0.$ g of a 3hite clear oil. "his 3as dissolved in $, m! IPA, neutrali6ed 3ith 0, drops of concentrated HCl, and the spontaneously formed crystals 3ere
diluted 3ith sufficient anhydrous <t$9 to allo3 easy filtration. After <t$9 3ashing and air drying, there 3as obtained $.) g of 0,+@methylenedio/y@5@
butylamphetamine hydrochloride '?;.4- as 3hite crystals 3ith a mp of $,,@$,,.& deg C. Anal. 'C(+H$$Cl59$- 5.
;9SAC<E greater than +, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E Straight chain homologues on the nitrogen atom of ?;A longer than t3o carbons are probably not active. "his
butyl compound provoked no interest, and although the longer chain counterparts 3ere made by the general sodium cyanoborohydride method 'see
under ?;.A-, they 3ere not tasted. All mouse assays that compared this homologous series sho3ed a consistent decrease in action 'anesthetic
potency and motor activity- as the alkyl chain on the nitrogen atoms 3as lengthened.
"his synthetic procedure, using the hydrochloride salt of the amine and sodium cyanoborohydride in methanol, seems to be Fuite general for ketone
compounds related to 0,+@methylenedio/yphenylacetone. 5ot only 3ere most of the ?;@group of compounds discussed here made in this manner, but
the use of phenylacetone 'phenyl@$@propanone, P@$@P- itself appears to be eFually effective. "he reaction of butylamine hydrochloride in methanol, 3ith
phenyl@$@propanone and sodium cyanoborohydride at pH of 1, after distillation at 2,@2& deg C at ,.0 mm8Hg, produced 5@butylamphetamine
hydrochloride '$0.+ g from (1.0 g P@$@P-. And, in the same manner 3ith ethylamine hydrochloride there 3as produced 5@ethylamphetamine '$$.+ g
from $$.( g P@$@P- and 3ith methylamine hydrochloride there 3as produced 5@methylamphetamine hydrochloride '$+.1 g from $1.) g P@$@P-. "he
reaction 3ith simple ammonia 'as ammonium acetate- gives consistently poor yields in these reactions.

#15' M0.6; #-.E#6Y-M0A; ',(-METHYE#E0"%+Y-#-.E#6YAM,HETAM"#E
S>5"H<SISE "o a suspension of ().1 g ben6ylamine hydrochloride in &, m! 3arm ?e9H there 3as added $.+ g of 0,+@methylenedio/yphenylacetone
'see under ?;?A for its preparation- follo3ed by (., g sodium cyanoborohydride. Concentrated HCl in ?e9H 3as added over several days as reFuired
to maintain the pH at about 1 as determined 3ith e/ternal, dampened universal paper. Ihen the demand for acid ceased, the reaction mi/ture 3as
added to +,, m! H$9 and made strongly acidic 3ith an e/cess of HCl. "his 3as e/tracted 3ith 0/(&, m! CH$Cl$ 'these e/tracts must be saved as
they contain the product- and the residual aFueous phase made basic 3ith $&K 5a9H and again e/tracted 3ith +/(,, m! CH$Cl$. :emoval of the
solvent under vacuum and distillation of the ).2 g pale yello3 residue at slightly reduced pressure provided a colorless oil that 3as pure, recovered
ben6ylamine. It 3as best characteri6ed as its HCl salt '$ g in (, m! IPA neutrali6ed 3ith about $& drops concentrated HCl, and dilution 3ith anhydrous
<t$9 gave beautiful 3hite crystals, mp $12@$1) deg C-. "he saved CH$Cl$ fractions above 3ere e/tracted 3ith 0/(,, m! dillute H$S9+. "hese pooled
e/tracts 3ere back@3ashed once 3ith CH$Cl$, made basic 3ith $&K 5a9H, and e/tracted 3ith 0/&, m! CH$Cl$. "he solvent 3as removed from the
pooled e/tracts under vacuum, leaving a residue of about ,.& g of an amber oil. "his 3as dissolved in (, m! IPA, neutrali6ed 3ith concentrated HCl
'about & drops- and diluted 3ith ), m! anhydrous <t$9. After a fe3 min, 0,+@methylenedio/y@5@ben6ylamphetamine hydrochloride '?;.A- began to
appear as a fine 3hite crystalline product. After removal by filtration, <t$9 3ashing and air drying, this 3eighed ,.&& g, and had a mp of (2,@(2( deg C
3ith prior shrinking at (1& deg C. Anal. 'C(2H$,Cl59$- 5.
;9SAC<E greater than (&, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "he ben6yl group is a good ally in the synthetic 3orld of the organic chemist, in that it can be easily removed by
catalytic hydrogenation. "his is a trick often used to protect 'for a step or series of steps- a position on the molecule, and allo3ing it to become free and
available at a later part in a synthetic scheme. In pharmacology, ho3ever, it is often a disappointment. Iith most centrally active alkaloids, there is a
t3o@carbon separation bet3een the 3eak base that is called the aromatic ring, and the strong base that is called the nitrogen. "his is 3hat makes
phenethylamines 3hat they are. "he phen@ is the aromatic ring 'this is a shortened form of prefi/ phenyl 3hich is a 3ord 3hich came, in turn, from the
simplest aromatic alcohol, phenol-; the ethyl is the t3o carbon chain, and the amine is the basic nitrogen. If one carbon is removed, one has a
ben6ylamine, and it is usually identified 3ith an entirely different pharmacology, or is most often simply not active. A vivid e/ample is the narcotic drug,
Bentanyl. "he replacement of the phenethyl group, attached to the nitrogen atom 3ith a ben6yl group, virtually eliminates its analgesic potency.
Here too, there appears to be little if any activity in the 5@ben6yl analogue of ?;A. A number of other variations had been synthesi6ed, and none of
them ever put into clinical trial. Iith many of them there 3as an ongoing problem in the separation of the starting amine from the product amine.
Sometimes the difference in boiling points could serve, and sometimes their relative polarities could be e/ploited. Sometimes, ion@pair e/traction 3ould
3ork 3onders. .ut occasionally, nothing really 3orked 3ell, and the final product had to be purified by careful crystalli6ation.
Several additional 5@homologues and analogues of ?;A are noted here. "he highest alkyl group on the nitrogen of ?;A to give a compound that had
been assayed, 3as the straight@chain butyl homologue, ?;.4. Si/ other 5@alkyls 3ere made, or attempted. Isobutylamine hydrochloride and 0,+@
methylenedio/yphenylacetone 3ere reduced 3ith sodium cyanoborohydride in methanol to give 0,+@methylenedio/y@5@'i-@butylamphetamine boiling at
%&@(,& deg C at ,.(& mm8Hg and giving a hydrochloride salt '?;I.- 3ith a mp of (2%@(), deg C. Anal. 'C(+H$$Cl59$- 5. "he reduction 3ith sodium
cyanoborohydride of a mi/ture of 't-@butylamine hydrochloride and 0,+@methylenedio/yphenylacetone in methanol produced 0,+@methylenedio/y@5@'t-@
butylamphetamine '?;".- but the yield 3as miniscule. "he amyl analog 3as similarly prepared from 'n-@amylamine hydrochloride and 0,+@
methylenedio/yphenylacetone in methanol to give 0,+@methylenedio/y@5@amylamphetamine 3hich distilled at ((,@($, deg C at ,.$ mm8Hg and formed a
hydrochloride salt '?;A?- 3ith a mp of (1+@(11 deg C. Anal. 'C(&H$+Cl59$- 5. A similar reaction 3ith 'n-@he/ylamine hydrochloride and 0,+@
methylenedio/yphenylacetone in methanol, 3ith sodium cyanoborohydride, produced after acidification 3ith dilute sulfuric acid copious 3hite crystals
that 3ere 3ater and ether insoluble, but soluble in methylene chlorideO "his sulfate salt in methylene chloride 3as e/tracted 3ith aFueous sodium
hydro/ide and the remaining organic solvent removed to give a residue that distilled at ((,@((& deg C at ,.$ mm8Hg to give 0,+@methylenedio/y@5@'n-@
he/ylamphetamine 3hich, as the hydrochloride salt '?;H<- had a mp of ())@()% deg C. Anal. 'C(1H$1Cl59$- 5. An attempt to make the +@amino@
heptane analogue from the primary amine, 0,+@methylenedio/yphenylacetone, and sodiumcyanoborohydride in methanol seemed to progress smoothly,
but none of the desired product 0,+@methylenedio/y@5@'+@heptyl-@amphetamine could be isolated. "his base has been named ?;S<, 3ith a S< for
septyl rather than H< for heptyl, to resolve any ambiguities about the use of H< for he/yl. In retrospect, it had been assumed that the sulfate salt 3ould
have e/tracted into methylene chloride, and the e/traordinary partitioning of the sulfate salt of ?;H< mentioned above makes it likely that the sulfate
salt of ?;S< 3ent do3n the sink 3ith the organic e/tracts of the sulfuric acid acidified crude product. 5e/t time maybe ether as a solvent, or citric acid
as an acid. Iith 'n-@octylamine hydrochloride and 0,+@methylenedio/yphenylacetone in methanol, 3ith sodium cyanoborohydride, there 3as obtained
0,+@methylenedio/y@5@'n-@octylamphetamine as a 3ater@insoluble, ether@insoluble sulfate salt. "his salt 3as, ho3ever, easily soluble in methylene
chloride, and 3ith base 3ashing of this solution, removal of the solvent, and distillation of the residue '(0,@(0& deg C at ,.$ mm8Hg- there 3as
eventually gotten a fine hydrochloride salt '?;9C- as 3hite crystals 3ith a mp of $,1@$,) deg C. Anal. 'C()H0,Cl59$- 5.
As to 5,5@dialkylhomologues of ?;A, the 5,5@dimethyl has been separately entered in the recipe for ?;;?. "3o efforts 3ere made to prepare the
5,5@diethyl homologue of ?;A. "he reasonable approach of reducing a mi/ture of diethylamine hydrochloride and 0,+@methylenedio/yphenylacetone in
methanol 3ith sodium cyanoborohydride 3as hopelessly slo3 and gave little product. "he reversal of the functionality 3as successful. "reatment of
?;A 'as the amine- and an e/cess of acetaldehyde 'as the carbonyl source- 3ith sodium borohydride in a cooled acidic medium gave, after acid@base
3orkup, a fluid oil that distilled at )&@%, deg C at ,.(& mm8Hg and 3as converted in isopropanol 3ith concentrated hydrochloric acid to 0,+@
methylenedio/y@5,5@diethylamphetamine '?;;<- 3ith a mp of (22@(2) deg C. Anal. 'C(+H$$Cl59$- 5.
And t3o 3eird 5@substituted things 3ere made. Aminoacetonitrile sulfate and 0,+@methylenedio/yphenylacetone 3ere reduced in methanol 3ith sodium
cyanoborohydride to form 0,+@methylenedio/y@5@cyanomethylamphetamine 3hich distilled at about (1, deg C at ,.0 mm8Hg and formed a hydrochloride
salt '?;C?- 3ith a mp of (&1@(&) deg C after recrystalli6ation from boiling isopropanol. Anal. 'C($H(&Cl5$9$- 5. ;uring the synthesis of ?;C?,
there appeared to have been generated appreciable ammonia, and the distillation provided a fore@run that contained ?;A. "he desired product had an
acceptable 5?:, 3ith the 5@cyanomethylene protons as a singlet at +.0) ppm. A solution of t@butylhydra6ine hydrochloride and 0,+@
methylenedio/yphenylacetone in methanol 3as reduced 3ith sodium cyanoborohydride and gave, after acid@basing and distillation at %&@(,& deg C at
,.(, mm8Hg, a viscous amber oil 3hich 3as neutrali6ed in isopropanol 3ith concentrated hydrochloric acid to provide 0,+@methylenedio/y@5@'t-@
butylaminoamphetamine hydrochloride '?;.A- 3ith a mp of $$,@$$$ deg C 3ith decomposition. Anal. 'C(+H$0Cl5$9$-; 5E calcd, %.22; found, (,.12,
(,.)+.

#15( M0!,M; !Y!%,*%,YMETHY-M0A;
',(-METHYE#E0"%+Y-#-!Y!%,*%,YMETHYAM,HETAM"#E
S>5"H<SISE A solution of %.+ g cyclopropylmethylamine hydrochloride in 0, m! ?e9H 3as treated 3ith (.) g 0,+@methylenedio/yphenylacetone 'see
under ?;?A for its preparation- follo3ed by ,.& g sodium cyanoborohydride. Concentrated HCl 3as added as needed to keep the pH constant at about
1. After several days stirring, the reaction mi/ture 3as added to H$9, acidified 3ith HCl, and 3ashed 3ith $/(,, m! CH$Cl$. "he aFueous phase 3as
made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(&, m! CH$Cl$. :emoval of the solvent from these e/tracts under vacuum yielded $.) g of a crude
product 3hich, on distillation at %,@(,, deg C at ,.( mm8Hg, yielded ,.+ g of a clear 3hite oil. "his 3as dissolved in a small amount of IPA, neutrali6ed
3ith a fe3 drops of concentrated HCl, and diluted 3ith anhydrous <t$9 to the point of turbidity. "here 3as obtained a small yield of crystalline 0,+@
methylenedio/y@5@cyclopropylmethylamphetamine hydrochloride '?;CP?- 3hich 3as filtered off, <t$9 3ashed and air dried. "he mp 3as $()@$$, deg
C, 3ith e/tensive darkening Gust prior to melting. Anal. 'C(+H$,Cl59$- 5.
;9SAC<E greater than (, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "he record of the tasting assay of this compound is pretty embarrassing. "he highest level tried 3as (,
milligrams, 3hich sho3ed no hint of activity. .ut in light of the rather colorful activities of other cyclopropylmethyl things such as CP? and $C@"@) , this
compound might someday 3arrant reinvestigation. It is a certainty that the yield could only be improved 3ith a careful resynthesis.

#15) M00M; #,#-0"METHY-M0A;
',(-METHYE#E0"%+Y-#,#-0"METHYAM,HETAM"#E
S>5"H<SISE "o a 3ell stirred solution of %.2 g dimethylamine hydrochloride in &, m! ?e9H there 3as added 0.&1 g of 0,+@
methylenedio/yphenylacetone 'see under ?;?A for its preparation- follo3ed by ,.)) g sodium cyanoborohydride. A (E( mi/ture of concentrated HCl
and ?e9H 3as added as reFuired to maintain the pH at about 1 as determined 3ith e/ternal, dampened universal paper. "3enty drops 3ere called for
over the first four h, and a total of 1, drops 3ere added over the course of t3o days at 3hich time the reduction 3as complete. After the evaporation of
most of the ?e9H solvent, the reaction mi/ture 3as added to $&, m! H$9 and made strongly acidic 3ith an e/cess of HCl. After 3ashing 3ith $/(,,
m! CH$Cl$ the aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent under vacuum yielded
a nearly colorless oil that 3as distilled at )&@%, deg C at ,.0 mm8Hg. "here 3as obtained (.& g of a 3ater@3hite oil that 3as dissolved in ) m! IPA,
neutrali6ed 3ith concentrated HCl and then diluted 3ith (, m! anhydrous <t$9. "he slightly turbid solution deposited a light lo3er oily layer 3hich
slo3ly crystalli6ed on scratching. Iith patience, an additional 2& m! of <t$9 3as added, allo3ing the formation of a 3hite crystalline mass. "his 3as
removed by filtration and 3ashed 3ith additional <t$9. After air drying there 3as obtained (.0 g of 0,+@methylenedio/y@5,5@dimethylamphetamine
hydrochloride '?;;?- 3ith a mp of (2$@(20 deg C. "he 5?: spectrum '1, mH- of the hydrochloride salt 'in ;$9 and 3ith e/ternal "?S- 3as
completely compatible 3ith the e/pected structure. "he signals 3ereE (.$&, (.02 'd- CCH0, 0H; ArCH$ under the 5'CH0-$, $.%1, )H; CH 'm- 0.1&;
CH$9$ 's- 1.,0 $H; ArH 1.%0 '0H-. AnalE 'C($H()Cl59$- 5.
;9SAC<E greater than (&, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (&, mg- 5o effects 3hatsoever.
'3ith (&, mg- "he effects, if any, 3ere so@so. Perhaps a threshold. .ut my libido 3as non@e/istent for three days.
'3ith &&, mg- I took &&, milligrams of it Saturday night and I had a pretty bad trip. 9n a scale of positive (, to negative (, it 3as about a negative 1. It
really do3ned me. "3o other friends took $,, milligrams. "hey found it very pleasant after about $, minutes. It 3as a plus 0 Pon the @(, to *(, scaleQ.
"hen it 3ore off a little bit; and then, + hours later, it hit them even stronger and 3as about a plus &.
'3ith (,,, mg- I took up to a gram of it and absolutely nothing.
<="<5SI95S A5; C9??<5"A:>E I cannot attest for the actual drug that had been used in the t3o larger@dose reports above. "hese are from an
anonymous source associated 3ith clandestine syntheses. If this material does eventually prove to be active, it is going to reFuire a pretty hefty dose.
.ut it may 3ell have some activity, as there have been reports in the forensic literature of its preparation, or at least its intended preparation, in illicit
laboratories. It seems unlikely that much effort 3ould be directed to3ards the synthesis of a completely inactive compound.
"he reduced potency of ?;;? has been e/ploited in an une/pected 3ay. .ased on the premise that the dialkylation of the amine group of
amphetamine makes the parent compound intrinsically less active but 3ithout interfering 3ith its ability to enter the brain, a large number of materials
have been e/plored to take advantage of this very property. "here is a need in medical diagnosis for agents that can allo3 various organs of the body to
be visuali6ed. 9ne of the most po3erful modalities for this 3ork is the positron camera, and the use of the unusual properties of the positron that allo3 it
to 3ork. In the art of positron emission tomography 'P<"-, an emitted positron 'from a radioactive and thus unstable atom- 3ill Fuickly interact 3ith a
nearby electron and all mass disappears 3ith the complete conversion to energy. "he detection of the produced pair of annihilation gamma rays 3ill
establish 3ith great e/actness the line along 3hich this interaction occurred. So if one 3ere to put an unstable atom into a compound that 3ent to the
tissue of the brain, and this atom 3ere to decay there, the resulting gamma rays 3ould allo3 a NphotographN to be made of the brain tissue. 9ne could
in this 3ay visuali6e brain tissue, and observe abnormalities.
.ut 3hat is needed is a molecule that carries the unstable atom 'and specifically one that emits positrons- and one 3hich goes to the brain as 3ell. 9ne
of the very best unstable atoms for the formation of positrons is iodine, 3here there is an isotope of mass ($$ 3hich is perfect for these needs. And, of
course, the 3orld of the psychedelic drugs is tailor@made to provide compounds that go to the brain. .ut, the last thing that the physician 3ants, 3ith the
diagnostic use of such tools, 3ould be to have the patient bouncing around in some turned@on altered state of consciousness.
So the completely logical union of these reFuirements is to take a compound such as ;9I 'carrying the needed atom and certainly going to the brain-
and put t3o methyl groups on the nitrogen '3hich should reduce the chances for conspicuous biological activity-. "his compound 3as made, and it does
label the brain, and it has sho3n promise as a flo3 indicator in the brain, and it and several of its close relatives are discussed in their o3n separate
recipe, called I;55A.

#151 M0E; M0EA; E=E; #-ETHY-M0A;
',(-METHYE#E0"%+Y-#-ETHYAM,HETAM"#E
S>5"H<SISE 'from ?;A- "o a solution of 0.1 g of the free base of 0,+@methylenedio/yamphetamine '?;A- in $, g pyridine, there 3as added $.0 g
acetic anhydride, and the mi/ture stirred at room temperature for ,.& h. "his 3as then poured into $&, m! H$9 and acidified 3ith HCl. "his aFueous
phase 3as e/tracted 3ith 0/2& m! CH$Cl$, the e/tracts pooled and 3ashed 3ith dilute HCl, and the solvent removed under vacuum. "he pale amber
residue of 5@acetyl@0,+@methylenedio/yamphetamine 3eighed &.$ g as the crude product, and it 3as reduced 3ithout purification. 9n standing it slo3ly
formed crystals. :ecrystalli6ation from a mi/ture of <t9Ac8he/ane '(E(- gave 3hite crystals 3ith a mp of %$@%0 deg C.
A stirred suspension of +.) g !AH in +,, m! anhydrous "HB 3as brought up to a reflu/, and then treated 3ith a solution of &., g of the impure 5@acetyl@
0,+@methylenedio/yamphetamine in $, m! anhydrous "HB. :eflu/ conditions 3ere maintained for 0 days, and then after cooling in an ice bath, the
e/cess hydride 3as destroyed 3ith the careful addition of H$9. "he +.) m! H$9 'in a little "HB- 3as follo3ed 3ith +.) m! of (&K 5a9H, and finally an
additional (& m! H$9. "he 3hite, granular, basic mass of inorganic salts 3as removed by filtration, the filter cake 3ashed 3ith additional "HB, and the
combined filtrate and 3ashings stripped of solvent under vacuum. "he residue 3as dissolved in $, m! IPA, made acidic 3ith +, drops of concentrated
HCl, and diluted 3ith (&, m! anhydrous <t$9. "he crystalline product 3as removed by filtration, 3ashed 3ith ),K <t$9 'containing IPA- follo3ed by
<t$9 itself, and then air dried to provide 0., g of 0,+@methylenedio/y@5@ethylamphetamine hydrochloride '?;<- as fine 3hite crystals 3ith a mp of (%)@
(%% deg C.
'from 0,+@methylenedio/yphenylacetone 3ith aluminum amalgam- "o +, g of thin aluminum foil cut in ( inch sFuares 'in a $ ! 3ide mouth <rlenmeyer
flask- there 3as added (+,, m! H$9 containing ( g mercuric chloride. Amalgamation 3as allo3ed to proceed until there 3as the evolution of fine
bubbles, the formation of a light grey precipitate, and the appearance of occasional silvery spots on the surface of the aluminum. "his takes bet3een (&
and 0, min depending on the freshness of the surfaces and the temperature of the H$9. "he H$9 3as removed by decantation, and the aluminum 3as
3ashed 3ith $/(+,, m! of fresh H$9. "he residual H$9 3as removed as thoroughly as possible by shaking, and there 3as added, in succession and
3ith s3irling, 2$.& g ethylamine hydrochloride dissolved in 1, m! 3arm H$9, (), m! IPA, (+& m! $&K 5a9H, &0 g 0,+@methylenedio/y@phenylacetone
'see under ?;?A for its preparation-, and finally 0&, m! IPA. "he e/othermic reaction 3as kept belo3 1, deg C 3ith occasional immersion into cold
3ater and, 3hen it 3as thermally stable, it 3as allo3ed to stand until it had returned to room temperature and all the insolubles settled to the bottom as a
grey sludge. "he clear yello3 overhead 3as decanted and the sludge removed by filtration and 3ashed 3ith ?e9H. "he combined decantation, mother
liFuors, and 3ashes, 3ere stripped of solvent under vacuum, the residue suspended in (&,, ml of H$9, and sufficient HCl added to make the phase
distinctly acidic. "his 3as then 3ashed 3ith $/(,, m! CH$Cl$, made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! of CH$Cl$. After removal of
the solvent from the combined e/tracts, there remained &%.& g of an amber oil 3hich 3as distilled at (+&@(&, deg C at ,.& mm8Hg, producing +,.0 g of
an off@3hite oil. "his 3as dissolved in 1,, m! IPA, neutrali6ed 3ith about $, m! of concentrated HCl and then treated 3ith 0,, m! anhydrous <t$9.
After filtering off the 3hite crystals, 3ashing 3ith a IPA8<t$9 '$E(- mi/ture, 3ith <t$9 and air drying, the final 0,+@methylenedio/y@5@ethylamphetamine
hydrochloride '?;<- 3eighed 02.+ g.
'from 0,+@methylenedio/yphenylacetone 3ith 5a.H0C5- "o a 3ell stirred solution of 0(., g ethylamine hydrochloride in ((, m! ?e9H there 3as added
1.1 g of 0,+@methylenedio/yphenylacetone 'see under ?;?A for its preparation- follo3ed by 0., g sodium cyanoborohydride. Concentrated HCl in
?e9H 3as added as reFuired to maintain the pH at about 1 as determined 3ith e/ternal, dampened universal pH paper. About $ days 3ere reFuired for
the reduction to be complete as determined by the final stabili6ation of the pH. "he reaction mi/ture 3as added to ( ! H$9 and made strongly acidic
3ith an e/cess of HCl. After 3ashing 3ith $/(,, m! CH$Cl$ the aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m!
CH$Cl$. :emoval of the solvent under vacuum yielded ).0 g of a pale amber oil that 3as distilled at )&@(,, deg C at ,.$ mm8Hg. "here 3as obtained
1., g of a 3ater@3hite oil that 3as dissolved in 1& m! IPA and neutrali6ed 3ith 2& drops of concentrated HCl 3hich produced crystals spontaneously.
"hese 3ere diluted 3ith some $, m! of anhydrous <t$9 removed by filtration, 3ashed first 3ith IPA8<t$9 '$E(-, and then 3ith <t$9. After air drying
there 3as obtained 1.( g of 0,+@methylenedio/y@5@ethylamphetamine hydrochloride '?;<- 3ith a mp of $,(@$,$ deg C. Anal. 'C($H()Cl59$- 5.
;9SAC<E (,, @ $,, mg.
;4:A"I95E 0 @ & h.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- "here 3as a 3arm light all about me. And a gentle, almost alcohol@like, into/ication. "he drug seems to
change my state of a3areness, but it does nothing else. "he 3orld is as intense or as dull as I choose to make it. At the (.& hour point I 3as clearly
dropping, and an hour later yet, completely 3ithout residue.
'3ith (1, mg- "he first effects 3ere felt in forty minutes and I
seemed to be completely there by the end of that first hour. "here
3as an initial slightly di66y into/ication, and then I felt very nice.
A good into/ication, 3ith maybe a little motor incoordination. "here
3as absolutely no appetite at all. "he ne/t morning there 3as still
some feeling of elation but I 3as still very rela/ed. High marks for
the Fuality of the e/perience.
'3ith (1, mg- 9verall this 3as a 3onderful e/perience. I felt that
the effect 3as stronger and smoother than ?;?A, but perhaps the group
enhancement may be partly responsible. I felt definitely fe3er
physiological side@effects than 3ith ?;?A, particularly the urinating
problem; although there 3as dehydration, there 3as less burning
annoyance.
'3ith (1, mg- I 3as hard hit, to the e/tent that there 3as difficulty
in verbali6ing and follo3ing other people7s thoughts. I entered the
e/perience 3ith some cold symptoms, and my sore throat disappeared. I
felt Fuite into/icated and tranFuili6ed.
'3ith $,, mg- Mery stoned. "here 3as some nausea in the beginning of
the e/perience. As it developed I found it very difficult to
concentrate on 3hat I 3as thinking or saying simply due to the
e/traordinary nature of coming on to this material. "here is
noticeable Ga3@clenching and rice crispies in the ears. "his is a
meditative material not unlike ?;?A e/cept there are more difficulties
in forming 3ords. And there is a problem in focusing the eyes, 3hat I
3ant to call Seye@romp.7 ?y anore/ia 3as e/tremely long@lived L
perhaps a total of 2$ hours. "his may have been too high a dosage.
<="<5SI95S A5; C9??<5"A:>E "his immediate homologue of ?;?A has a very similar chronology but reFuires a slightly larger dose. Another
similarity is the occasional report of teeth clenching, especially follo3ing the use of supplemental dosages intended to e/tend the effects of the drug.
"hese supplements have been e/plored in the &, to 2& milligram range, usually at the t3o hour point. In one unpublished clinical e/periment 3ith
?;?A, an e/tension 3as attempted at the ( hour +& minute point 3ith ?;< rather than 3ith ?;?A, to see if there 3as any change in the Fualitative
character of the e/perience. "he effective time of into/ication 3as e/tended, but the group fell surprisingly Fuiet, 3ith a drop in the usual urge to
converse and interact.
"he effects of ?;< are similar in many 3ays to those of ?;?A, but there are believable differences. "he particular magic, and affective transference,
does not appear to be there. "here is a stoning into/ication, as there is 3ith ?;A, and there is a seemingly unre3arding aspect to the upping of the
dosages, again similar to ?;A, and the properties of unusually easy communication and positive self@vie3ing of ?;?A seem to be absent. ?aybe the
NSN isomer 3ould have these properties, and they are lost in the racemate due to something coming from a more potent Ninto/icatingN N:N isomer. "he
optical isomers have never been evaluated separately in man.
"here are only t3o 3ays in 3hich t3o drugs can interact to produce a result that is not obvious from the summing of their individual actions. 9ne is the
process of synergism, 3here t3o active materials are allo3ed to interact 3ithin a single individual and at one time, and the conseFuence of this
interaction is different than that 3hich 3ould have been e/pected. "he other is the process of potentiation, 3here only one drug is active, but the
presence of the second 'and inactive- drug enhances the observed action of the first. ?;< seems to fall in the first category.
"he Npiggy@backN or N3indo3 e/ploitationN studes 3ere first discovered and e/plored 3ith ?;<, and have subseFuently been e/tended most
successfully 3ith ?;?A. "he earliest procedure used 3as to assay modest Fuantities of active materials at the drop@off period of ?;<, to e/ploit the
open and benign state that 3as present. 4sually, only a fraction of the standard dosage of the follo3ing drug 3as necessary to evoke a full e/perience.
In psychotherapy applications, this seFuence has been freFuently used 3ith ?;?A follo3ed by a second material that has been chosen to modify and
e/pand the opening that the ?;?A produced.
Iith the placement of ?;?A under legal control in (%)&, ?;< occasionally appeared in the illicit street trade. It had been called <M<, 3hich carries
some perverse logic in light of the nickname used occasionally for ?;?A, 3hich 3as A;A?. "he term I5"<!!<C" has been used for it as 3ell, but
there has been no apparent reason advanced for this. And a final note on nomenclature. An old literature use of the code ?;< 3as for the compound
0,+@methylenedio/yethanol@amine. See the discussion on this under the recipe for ;?<.
I have been told of an analogue of ?;< that has been synthesi6ed, and e/plored by the researcher 3ho synthesi6ed it. It contains the 5@trifluoroethyl
group common to several pharmaceuticals such as Lua6epam. "he analogue is 0,+@methylenedio/y@5@'$,$,$@trifluoroethyl-amphetamine hydrochloride
'mp $,2@$,% deg C- 3hich 3as made from $,$,$@trifluoroethylamine and 0,+@methylenedio/yphenylacetone and sodium cyanoborohydride in methanol.
"he best final line for this compound is that it is Npossibly active.N "he most heroic dosage schedule mentioned 3as a total of &,, milligrams, taken in
three appro/imately eFual portions over the course of five or si/ hours, 3ith only a very mild into/ication and little or no sympathomimetic effects. And
3hat little there might have been 3as Fuickly gone. A collection of totally une/plored 5@substituted homologues and analogues of ?;< is gathered at
the end of the recipe for ?;.A.
Another direction that has been used to homologate the ?;?A and ?;< structure is 3ith the length of the aliphatic chain that carries the phenyl ring
and the amine function. :HS sho3s the t3o@carbon chain, NIN sho3s the amphetamine chain length, and ?;< can be called <"H>!@I. "he four@carbon
chain is the :DS group, and this entire ?uni@?etro concept is e/plained under ?<"H>!@D.

#152 M0H%ET; HY0*%+YETHY-M0A;
',(-METHYE#E0"%+Y-#-&$-HY0*%+YETHY-AM,HETAM"#E
S>5"H<SISE "o a 3ell stirred solution of $& g ethanolamine hydrochloride in 2& m! ?e9H there 3as added +.+& g of 0,+@methylenedio/yphenylacetone
'see under ?;?A for its preparation- follo3ed by (.( g sodium cyanoborohydride. Concentrated HCl in ?e9H 3as added as reFuired, over the ne/t
fe3 days, to maintain the pH at about 1 as determined 3ith e/ternal, dampened universal pH paper. "he reaction mi/ture 3as added to 0,, m! H$9
and made strongly acidic 3ith an e/cess of HCl. After 3ashing 3ith 0/(,, m! CH$Cl$ the aFueous phase 3as made basic 3ith $&K 5a9H, and
e/tracted 3ith +/(,, m! CH$Cl$. :emoval of the solvent under vacuum yielded 0.& g of a viscous off@3hite oil that 3as distilled at (1, deg C at (.0
mm8Hg to give $., g of a 3hite viscous oil. "he pot residue remained fluid, but 3as discarded. "his distillate 3as dissolved in )., m! IPA to give,
eventually, a clear solution. "his 3as neutrali6ed 3ith concentrated HCl and diluted 3ith (,, m! anhydrous <t$9. "he loose 3hite crystals of 0,+@
methylenedio/y@5@'$@hydro/y@ethyl-amphetamine hydrochloride '?;H9<"- that formed 3ere removed by filtration, 3ashed 3ith <t$9, and air dried.
"hese 3eighed $.0 g, and had a mp of (+2@(+) deg C. Anal. 'C($H()Cl590- 5.
;9SAC<E greater than &, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E ?ost compounds 3ith bare, e/posed polar groups like hydro/yls are not centrally active, as they simply do not
have any 3ay of getting into the brain. ?;H9<" is certainly not very active, if it is active at all.
"here 3as one report that at very high doses some central effects 3ere indeed observed. Iith Fuantities in the several hundreds of milligrams a picture
emerged of changes in perceived color and depth perception, but 3ithout euphoria. It 3as said to resemble a mild dose of ketamine. "his is an
interesting comment, in that ketamine has found its maGor medical use as an anesthetic, and ?;H9<" is among the most effective of all the 5@
substituted ?;A derivatives assayed in several animal analgesia models.
#153 M0",; #-"S%,*%,Y-M0A;
&',(-METHYE#E0"%+Y-#-"S%,*%,YAM,HETAM"#E-
S>5"H<SISE "o a 3ell stirred and cooled solution of (+.2& g isopropylamine in (,, m! ?e9H there 3as added +.+& g of 0,+@
methylenedio/yphenylacetone 'see under ?;?A for its preparation- follo3ed by a (E( mi/ture of concentrated HC! and ?e9H, sufficient to bring the pH
to about +. "his 3as follo3ed 3ith (.( g sodium cyanoborohydride, and stirring 3as continued overnight. Ihen the pH increased to over 1 there 3as
added an additional ,.& g of the borohydride, and additional methanolic HCl 3as added as needed to maintain the pH there. Ihen the pH became
stable, the reaction mi/ture 3as brought soundly acid 3ith the addition of yet additional HCl, and all solvents 3ere removed under vacuum. "he
residues 3ere added to &,, m! H$9 and 3ashed 3ith 0/(,, m! CH$Cl$. "he aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith
+/(,, m! CH$Cl$. :emoval of the solvent under vacuum yielded $.) g of an amber liFuid that 3as distilled at %&@((, deg C at ,.0 mm8Hg. "here 3as
obtained about $ m! of a 3hite oil that 3as dissolved in (, m! of IPA, neutrali6ed 3ith about $, drops of concentrated HCl producing spontaneous
crystals. "hese 3ere diluted 3ith some +, m! of anhydrous <t$9, removed by filtration, 3ashed 3ith <t$9, and then air dried. "here 3as obtained (.1 g
of 0,+@methylenedio/y@5@isopropylamphetamine hydrochloride '?;IP- 3ith a mp of ()1@()1.& deg C 3ith prior sintering at ()& deg C. Anal.
'C(0H$,Cl59$- 5.
;9SAC<E greater than $&, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $&, mg- At 0& minutes there 3as an
e/tremely slight head disturbance 3hich increased over the ne/t fe3
minutes. I 3ould have missed it if there had been any sensory input
at all. At the one hour point there 3as a slight physical malaise,
but no 7open 3indo37 of any kind, either like ?;?A or like !S;. At
the most, this 3as a threshold, and in another half hour, I 3as
completely baseline.
<="<5SI95S A5; C9??<5"A:>E "he structure of ?;IP can be looked at as
e/actly that of ?;< but 3ith an additional methyl group 'one carbon-
hanging off the ethyl that is on the nitrogen. And 3ith that slight
additional 3eight, the activity has disappeared. 9n those occasions
3here research has sho3n a compound to be inactive, there has been
some study made that could be called a NprimerN e/periment. Ihy not
take advantage of the fact that an NinactiveN compound might 3ell be
sitting in some receptor site in the brain 3ithout doing anythingH
?ight its presence, 3herever it might be, have some effect if only a
person 3ere to e/plore it in the correct 3ayH ?ight it augment or
interfere 3ith the action of another compoundH ?any e/periments of
this kind have been performed, geared to milk additional information
out of a ne3 trial of a ne3 material.
Here is an e/ample of a primer e/periment that involved ?;IP. Some
five hours follo3ing an inactive trial 3ith ($, milligrams of ?;IP
'maybe a slight disturbance at one hour, nothing at t3o hours- a
calibration dose of ), milligrams of ?;?A 3as taken. "he effects of
the ?;?A 3ere noted at the 00 minute point, and an honest plus one 3as
achieved at one hour. At this point a second ), milligrams 3as added
to the inventory that 3as already on board, and the general
into/ication and the eye effects that follo3ed 3ere completely
e/plained by the ?;?A alone. It 3as obvious that the t3o drugs did
not see one@another.
Sometimes an e/periment can involve the assay of an unkno3n material at the supplement time of an active drug. "his has been called Npiggybacking.N
Here is an e/ample. At the five hour point of an e/periment 3ith (+, milligrams of ?;< 'this had been a light e/perience, a plus one 3hich had not
laster more than t3o hours- a dosage of $,, milligrams of ?;IP rekindled a *( e/perience, a pleasant into/ication of the ?;< sort, but one that 3as
Fuite invested 3ith tremor and some feelings of eye@popping. It 3as almost as if the physical to/ic effects out3eighed the mental virtues. Imagine an
iceberg, 3ith the bulk of its mass under3ater. "he ?;< had had its o3n modest effects, and had submerged into invisibility, and the response to a little
bit of an other3ise inactive ?;IP 3as to refloat a bit of the other3ise unseeable ?;<.
#154 M0MA; M0M; A0AM; E!STASY; ',(-METHYE#E0"%+Y-#-METHYAM,HETAM"#E
S>5"H<SISE 'from ?;A- A solution of 1.&& g of 0,+@methylenedio/yamphetamine '?;A- as the free base and $.) m! formic acid in (&, m! ben6ene
3as held at reflu/ under a ;ean Stark trap until no further H$9 3as generated 'about $, h 3as sufficient, and (.+ m! H$9 3as collected-. :emoval of
the solvent gave an ).) g of an amber oil 3hich 3as dissolved in (,, m! CH$Cl$, 3ashed first 3ith dilute HCl, then 3ith dilute 5a9H, and finally once
again 3ith dilute acid. "he solvent 3as removed under vacuum giving 2.2 g of an amber oil that, on standing, formed crystals of 5@formyl@0,+@
methylenedio/yamphetamine. An alternate process for the synthesis of this amide involved holding at reflu/ for (1 h a solution of (, g of ?;A as the
free base in $, m! fresh ethyl formate. :emoval of the volatiles yielded an oil that set up to 3hite crystals, 3eighing 2.) g.
A solution of 2.2 g 5@formyl@0,+@methylenedio/yamphetamine in $& m! anhydrous "HB 3as added drop3ise to a 3ell stirred and reflu/ing solution of 2.+
g !AH in 1,, m! anhydrous "HB under an inert atmosphere. "he reaction mi/ture 3as held at reflu/ for + days. After being brought to room
temperature, the e/cess hydride 3as destroyed 3ith 2.+ m! H$9 in an eFual volume of "HB, follo3ed by 2.+ m! of (&K 5a9H and then another $$ m!
H$9. "he solids 3ere removed by filtration, and the filter cake 3ashed 3ith additional "HB. "he combined filtrate and 3ashes 3ere stripped of solvent
under vacuum, and the residue dissolved in $,, m! CH$Cl$. "his solution 3as e/tracted 3ith 0/(,, m! dilute HCl, and these e/tracts pooled and
made basic 3ith $&K 5a9H. </traction 3ith 0/2& m! CH$Cl$ removed the product, and the pooled e/tracts 3ere stripped of solvent under vacuum.
"here 3as obtained 1.& g of a nearly 3hite residue 3hich 3as distilled at (,,@((, deg C at ,.+ mm8Hg to give &., g of a colorless oil. "his 3as dissolved
in $& m! IPA, neutrali6ed 3ith concentrated HCl, follo3ed by the addition of sufficient anhydrous <t$9 to produce a lasting turbidity. 9n continued
stirring, there 3as the deposition of fine 3hite crystals of 0,+@methylenedio/y@5@methylamphetamine hydrochloride '?;?A- 3hich 3ere removed by
filtration, 3ashed 3ith <t$9, and air dried, giving a final 3eight of +.) g.
'from 0,+@methylenedio/yphenylacetone- "his key intermediate to all of the ?;@series can be made from either isosafrole, or from piperonal via (@'0,+@
methylenedio/yphenyl-@$@nitropropene. "o a 3ell stirred solution of 0+ g of 0,K hydrogen pero/ide in (&, g ),K formic acid there 3as added,
drop3ise, a solution of 0$.+ g isosafrole in ($, m! acetone at a rate that kept the reaction mi/ture from e/ceeding +, deg C. "his reFuired a bit over ( h,
and e/ternal cooling 3as used as necessary. Stirring 3as continued for (1 h, and care 3as taken that the slo3 e/othermic reaction did not cause
e/cess heating. An e/ternal bath 3ith running 3ater 3orked 3ell. ;uring this time the solution progressed from an orange color to a deep red. All
volatile components 3ere removed under vacuum 3hich yielded some 1, g of a very deep red residue. "his 3as dissolved in 1, m! of ?e9H, treated
3ith 01, m! of (&K H$S9+, and heated for 0 h on the steam bath. After cooling, the reaction mi/ture 3as e/tracted 3ith 0/2& m! <t$9, the pooled
e/tracts 3ashed first 3ith H$9 and then 3ith dilute 5a9H, and the solvent removed under vacuum "he residue 3as distilled 'at $., mm8(,)@(($ deg C,
or at about (1, deg C at the 3ater pump- to provide $,.1 g of 0,+@methylenedio/yphenylacetone as a pale yello3 oil. "he o/ime 'from hydro/ylamine-
had a mp of )&@)) deg C. "he semicarba6one had a mp of (1$@(10 deg C.
An alternate synthesis of 0,+@methylenedio/yphenylacetone starts originally from piperonal. A suspension of 0$ g electrolytic iron in (+, m! glacial
acetic acid 3as gradually 3armed on the steam bath. Ihen Fuite hot but not yet 3ith any 3hite salts apparent, there 3as added, a bit at a time, a
solution of (,., g of (@'0,+@methylenedio/yphenyl-@$@nitropropene in 2& m! acetic acid 'see the synthesis of ?;A for the preparation of this nitrostyrene
intermediate from piperonal and nitroethane-. "his addition 3as conducted at a rate that permitted a vigorous reaction free from e/cessive frothing. "he
orange color of the reaction mi/ture became very reddish 3ith the formation of 3hite salts and a dark crust. After the addition 3as complete, the heating
3as continued for an additional (.& h during 3hich time the body of the reaction mi/ture became Fuite 3hite 3ith the product appeared as a black oil
climbing the sides of the beaker. "his mi/ture 3as added to $ ! H$9, e/tracted 3ith 0/(,, m! CH$Cl$, and the pooled e/tracts 3ashed 3ith several
portions of dilute 5a9H. After the removal of the solvent under vacuum, the residue 3as distilled at reduced pressure 'see above- to provide )., g of
0,+@methylenedio/yphenylacetone as a pale yello3 oil.
"o +, g of thin aluminum foil cut in ( inch sFuares 'in a $ ! 3ide mouth <rlenmeyer flask- there 3as added (+,, m! H$9 containing ( g mercuric
chloride. Amalgamation 3as allo3ed to proceed until there 3as the evolution of fine bubbles, the formation of a light grey precipitate, and the
appearance of occasional silvery spots on the surface of the aluminum. "his takes bet3een (& and 0, min depending on the freshness of the surfaces,
the temperature of the H$9, and the thickness of the aluminum foil. 'Aluminum foil thickness varies from country to country.- "he H$9 3as removed by
decantation, and the aluminum 3as 3ashed 3ith $/(+,, m! of fresh H$9. "he residual H$9 from the final 3ashing 3as removed as thoroughly as
possible by shaking, and there 3as added, in succession and 3ith s3irling, 1, g methylamine hydrochloride dissolved in 1, m! 3arm H$9, (), m! IPA,
(+& m! $&K 5a9H, &0 g 0,+@methylenedio/yphenylacetone, and finally 0&, m! IPA. If the available form of methylamine is the aFueous solution of the
free base, the follo3ing seFuence can be substitutedE add, in succession, 21 m! +,K aFueous methylamine, (), m! IPA, a suspension of &, g 5aCl in
(+, m! H$9 that contains $& m! $&K 5a9H, &0 g 0,+@methylenedio/yphenylacetone, and finally 0&, m! IPA. "he e/othermic reaction 3as kept belo3
1, deg C 3ith occasional immersion into cold 3ater and, 3hen it 3as thermally stable, it 3as allo3ed to stand until it had returned to room temperature
3ith all the insolubles settled to the bottom as a grey sludge. "he clear yello3 overhead 3as decanted and the sludge removed by filtration and 3ashed
3ith ?e9H. "he combined decantation, mother liFuors and 3ashes, 3ere stripped of solvent under vacuum, the residue suspended in $+,, ml of H$9,
and sufficient HCl added to make the phase distinctly acidic. "his 3as then 3ashed 3ith 0/2& m! CH$Cl$, made basic 3ith $&K 5a9H, and e/tracted
3ith 0/(,, m! of CH$Cl$. After removal of the solvent from the combined e/tracts, there remained && g of an amber oil 3hich 3as distilled at (,,@((,
deg C at ,.+ mm8Hg producing +( g of an off@3hite liFuid. "his 3as dissolved in $,, m! IPA, neutrali6ed 3ith about (2 m! of concentrated HCl, and
then treated 3ith +,, m! anhydrous <t$9. After filtering off the 3hite crystals, 3ashing 3ith an IPA8<t$9 mi/ture, '$E(-, 3ith <t$9, and final air drying,
there 3as obtained +$., g of 0,+@methylenedio/y@5@methylamphetamine '?;?A- as a fine 3hite crystal. "he actual form that the final salt takes
depends upon the temperature and concentration at the moment of the initial crystalli6ation. It can be anhydrous, or it can be any of several hydrated
forms. 9nly the anhydrous form has a sharp mp; the published reports describe all possible one degree melting point values over the range from (+)@
(&0 deg C. "he variously hydrated polymorphs have distinct infrared spectra, but have broad mps that depend on the rate of heating.
;9SAC<E ), @ (&, mg.
;4:A"I95E + @ 1 h.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- ?;?A intrigued me because everyone I asked, 3ho had used it, ans3ered the Fuestion, 7Ihat7s it likeH7 in
the same 3ayE 7I don7t kno3.7 7Ihat happenedH7 75othing.7 And no3 I understand those ans3ers. I too think nothing happened. .ut something seemed
changed. .efore the 73indo37 opened completely, I had some somatic effects, a tingling sensation in the fingers and temples L a pleasant sensation,
not distracting. Ho3ever, Gust after that there 3as a slight nausea and di66iness similar to a little too much alcohol. All these details disappeared as I
3alked outside. ?y mood 3as light, happy, but 3ith an underlying conviction that something significant 3as about to happen. "here 3as a change in
perspective both in the near visual field and in the distance. ?y usually poor vision 3as sharpened. I sa3 details in the distance that I could not
normally see. After the peak e/perience had passed, my maGor state 3as one of deep rela/ation. I felt that I could talk about deep or personal subGects
3ith special clarity, and I e/perienced some of the feeling one has after the second martini, that one is discoursing brilliantly and 3ith particularly acute
analytical po3ers.
'3ith (,, mg- .eforehand, I 3as a3are of a dull, uncaring tiredness that might have reflected too little sleep, and I took a modest level of ?;?A to see if
it might serve me as a stimulant. I napped for a half hour or so, and 3oke up definitely not improved. "he feeling of insufficient energy and lack of spark
that I7d felt before had become something Fuite strong, and might be characteri6ed as a firm feeling of negativity about everything that had to be done
and everything I had been looking for3ard to. So I set about my several tasks 3ith no pleasure or enGoyment and I hummed a little tune to myself during
these activities 3hich had 3ords that 3entE 7I shouldn7t have done that, oh yes, I shouldn7t have done that, oh no, I shouldn7t have done that; it 3as a
mistake.7 "hen I 3ould start over again from the beginning. I 3as stuck in a gray space for Fuite a 3hile, and there 3as nothing to do but keep doing
3hat I had to do. After about 1 hours, I could see the 3hole mental state disintegrating and my pleasant feelings 3ere coming back. .ut so 3as my
plain, ornery tiredness. ?;?A does not 3ork like ;e/edrine.
'3ith ($, mg- I feel absolutely clean inside, and there is nothing but pure euphoria. I have never felt so great, or believed this to be possible. "he
cleanliness, clarity, and marvelous feeling of solid inner strength continued throughout the rest of the day, and evening, and through the ne/t day. I am
overcome by the profundity of the e/perience, and ho3 much more po3erful it 3as than previous e/periences, for no apparent reason, other than a
continually improving state of being. All the ne/t day I felt like 7a citi6en of the universe7 rather than a citi6en of the planet, completely disconnecting time
and flo3ing easily from one activity to the ne/t.
'3ith ($, mg- As the material came on I felt that I 3as being enveloped, and my attention had to be directed to it. I became Fuite fearful, and my face
felt cold and ashen. I felt that I 3anted to go back, but I kne3 there 3as no turning back. "hen the fear started to leave me, and I could try taking little
baby steps, like taking first steps after being reborn. "he 3oodpile is so beautiful, about all the Goy and beauty that I can stand. I am afraid to turn
around and face the mountains, for fear they 3ill overpo3er me. .ut I did look, and I am astounded. <veryone must get to e/perience a profound state
like this. I feel totally peaceful. I have lived all my life to get here, and I feel I have come home. I am complete.
'3ith (,, mg of the N:N isomer- "here 3ere the slightest of effects noted at about an hour 'a couple of paresthetic t3inges- and then nothing at all.
'3ith (1, mg of the N:N isomer- A disturbance of baseline at about forty minutes and this lasts for about another hour. <verything is clear by the third
hour.
'3ith $,, mg of the N:N isomer- A progression from an alert at thirty minutes to a soft and light into/ication that did not persist. "his 3as a modest *, and
I 3as at baseline in another hour.
'3ith 1, mg of the NSN isomer- "he effects began developing in a smooth, friendly 3ay at about a half@hour. ?y hand3riting is 9 but I am 3riting faster
than usual. At the one hour point, I am Fuite certain that I could not drive, time is slo3ing do3n a bit, but I am mentally very active. ?y pupils are
considerably dilated. "he dropping is evident at t3o hours, and complete by the third hour. All afternoon I am peaceful and rela/ed, but clear and alert,
3ith no trace of physical residue at all. A very successful **.
'3ith (,, mg of the NSN isomer- I feel the onset is slo3er than 3ith the racemate. Physically, I am e/cited, and my pulse and blood pressure are Fuite
elevated. "his does not have the 7fire7 of the racemate, nor the rush of the development in getting to the plateau.
'3ith ($, mg of the NSN isomer- A rapid development, and both 3riting and typing are impossible before the end of the first hour. !ying do3n 3ith eyes
closed eliminates all effects; the visual process is needed for any a3areness of the drug7s effects. Some teeth clenching, but no nystagmus. </cellent
sleep in the evening.
<="<5SI95S A5; C9??<5"A:>E In clinical use, largely in psychotherapeutic sessions of 3hich there 3ere many in the early years of ?;?A study, it
became a common procedure to provide a supplemental dosage of the drug at about the one and a half hour point of the session. "his supplement,
characteristically +, milligrams follo3ing an initial ($, milligrams, 3ould e/tend the e/pected effects for about an additional hour, 3ith only a modest
e/acerbation of the usual physical side@effects, namely, teeth clenching and eye t3itching. A second supplement 'as, for instance, a second +,
milligrams at the t3o and a half hour point- 3as rarely felt to be 3arranted. "here are, more often than not, reports of tiredness and lethargy on the day
follo3ing the use of ?;?A, and this factor should be considered in the planning of clinical sessions.
Iith ?;?A, the usual assignments of activity to optical isomers is reversed from all of the kno3n psychedelic drugs. "he more potent isomer is the NSN
isomer, 3hich is the more potent form of amphetamine and methamphetamine. "his 3as one of the first clear distinctions that 3as apparent bet3een
?;?A and the structurally related psychedelics '3here the N:N isomers are the more active-. "olerance studies also support differences in mechanisms
of action. In one study, ?;?A 3as consumed at %E,, A? each day for almost a 3eek '($, milligrams the first day and (1, milligrams each subseFuent
day- and by the fifth day there 3ere no effects from the drug e/cept for some mydriasis. And even this appeared to be lost on the si/th day. At this point
of total tolerance, there 3as consumed 'on day R2, at %E,, A?- ($, milligrams of ?;A and the response to it 3as substantially normal 3ith proper
chronology, teeth clench, and at most only a slight decrease in mental change. A complete holiday from any drug for another 1 days led to the reversal
of this tolerance, in that ($, milligrams of ?;?A had substantially the full e/pected effects. "he fact that ?;?A and ?;A are not cross@tolerant
strengthens the argument that they act in different 3ays, and at different sites in the brain.
A 3ide populari6ation of the social use of ?;?A occurred in (%)+@(%)& and, 3ith the reported observation of serotonin nerve changes in animal models
resulting from the administration of the structurally similar drug ?;A, an administrative move 3as launched to place it under legal control. "he
placement of ?;?A into the most restrictive category of the Bederal Controlled Substances Act has effectively removed it from the area of clinical
e/perimentation and human research. "he medical potential of this material 3ill probably have to be developed through studies overseas.
A 3ord of caution is in order concerning the intermediate 0,+@methylene@dio/yphenylacetone, 3hich has also been called piperonylacetone. A devilish
ambiguity appeared in the commercial market for this compound, centered about its name. "he controversy focused on the meaning of the prefi/,
piperonyl, 3hich has t3o separate chemical definitions. !et me try to e/plain this fascinating chaos in non@chemical terms. Piperonyl is a term that has
been used for a t3o@ring system 'the methylenedio/yphenyl group- either 3ithout, or 3ith, an e/tra carbon atom sticking off of the side of it. "hus,
piperonylacetone can be piperonyl 'the t3o@ring thing 3ithout the e/tra carbon atom attached- plus acetone 'a three carbon chain thing-; the total
number of carbons sticking out, three. 9r, piperonylacetone can be piperonyl 'the t3o@ring thing but 3ith the e/tra carbon atom attached- plus acetone
'a three carbon chain thing-; the total number of carbons sticking out, four.
;oes this make senseH
"he three carbon sticking out Gob gives rise to ?;A and to ?;?A and to many homologues that are interesting materials discussed at length in these
.ook II comments. "his is the usual item of commerce, available from both domestic and foreign suppliers. .ut the four@carbon sticking out Gob 3ill
produce totally 3eird stuff 3ithout any apparent relationship to psychedelics, psychoactives or psychotropics 3hatsoever. I kno3 of one chemical supply
house 3hich supplied the 3eird compound, and they never did ackno3ledge their unusual use of the term piperonyl. "here is a simple difference of
properties 3hich might be of value. "he three carbon 'correct- ketone is an oil 3ith a sassafras smell that is al3ays yello3 colored. "he four carbon
'incorrect- ketone has a 3eak terpene smell and is 3hite and crystalline. "here should be no difficulties in distinguishing these t3o compounds. .ut
unprincipled charlatans can al3ays add mineral oil and butter yello3 to other3ise 3hite solids to make them into yello3 oils. Caveat emptor.
#115 M0M!; E0MA; ',(-ETHYE#E0"%+Y-#-METHYAM,HETAM"#E
S>5"H<SISE "o a solution of $2.1 g protocatechualdehyde '0,+@dihydro/yben6aldehyde- in $&, m! acetone there 3as added &2 g finely po3dered
anhydrous $C90 and +0 g (,$@dibromoethane. "he mi/ture 3as held at reflu/ for (1 h, and then the acetone removed by evaporation. "he remaining
tar@like goo 3as distributed bet3een eFual volumes of H$9 and CH$Cl$, and the phases separated by centrifugation. "he organic phase 3as 3ashed
3ith $/&, m! &K 5a9H, and the solvent removed under vacuum. "he residue '$$., g 3ith the smell of the starting halide- 3as distilled to give a fraction
that boiled at ((, deg C at ,.$& mm8Hg to yield 0,+@ethylenedio/yben6aldehyde '(,+@ben6odio/ane@1@carbo/aldehyde- as a 3hite oil 3eighing 1.)) g.
"his spontaneously crystalli6ed to give 3hite solids that melted at &,@&( deg C.
A solution of 1.1+ g 0,+@ethylenedio/yben6aldehyde in +, m! nitroethane 3as treated 3ith ,.$1 g anhydrous ammonium acetate and held at reflu/ for 0
days. "!C analysis sho3ed that there 3as much aldehyde remaining unreacted, so an additional ,.2 g ammonium acetate 3as added, and the mi/ture
held at reflu/ for an additional 1 h. "he e/cess nitroethane 3as removed under vacuum. "he residue 3as dissolved in 0, m! hot ?e9H 3hich, 3ith
patience and slo3 cooling, finally deposited a heavy yello3@gold po3der. "his product (@'0,+@ethylenedio/yphenyl-@$@nitro@propene melted at %&@%1 deg
C and 3eighed 1.,0 g 3hen air dried to constant 3eight. :ecrystalli6ation from either ?e9H or <t9Ac gave the product as a yello3 solid, but 3ithout
any improvement in mp.
A solution of +., g of (@'0,+@ethylenedio/yphenyl-@$@nitropropene 3as made in 0, m! 3arm acetic acid. "his 3as added to a suspension of (1 g
elemental electrolytic iron in 2& m! acetic acid. "he mi/ture 3as heated on the steam bath, and an e/othermic reaction set in at about 2, deg C.
Heating 3as continued and the reaction allo3ed to proceed until the mass 3as a thick gray color and a dirty scum had been formed on the surface.
After about $ h, the entire mi/ 3as poured into $ ! H$9 and filtered free of a little residual unreacted iron 3hich 3as 3ashed 3ith CH$Cl$. "he filtrate
and 3ashes 3ere e/tracted 3ith 0/(,, m! CH$Cl$ and the pooled organic e/tracts 3ashed 3ith $/&, m! &K 5a9H. :emoval of the solvent gave 0.0)
g of an amber oil 3hich 3as distilled. "he product (@'0,+@ethylenedio/yphenyl-@$@propanone distilled as a 3hite oil, at (,&@((, deg C at ,.$ mm8Hg. It
3eighed $.2+ g.
"o $., g. of ( inch sFuares of light@3eight aluminum foil there 3as added a solution of &, mg mercuric chloride in 2, m! 3ater. After standing at room
temperature for 0, min, the H$9 3as drained a3ay, and the amalgamated aluminum 3ashed t3ice 3ith H$9, and shaken as dry as possible. "here
3as then added, promptly and in immediate seFuence, a solution of 0 g methylamine hydrochloride in 0 m! H$9, % m! IPA, 2.$& m! $&K 5a9H, $.2, g
of (@'0,+@ethylenedio/yphenyl-@$@propanone, and () m! IPA. "he mi/ture 3as heated on the steam bath until an e/othermic reaction set in, and then it
3as continuously s3irled as the reaction proceeded. Ihen the aluminum 3as consumed, there 3as a colorless gray sludge, and this 3as filtered and
3ashed 3ith $/(, m! ?e9H. "he combined mother liFuors and 3ashes 3ere stripped of solvent under vacuum. "he t3o phase residue 3as
suspended in +,, m! H$9 containing sufficient H$S9+ to make the resulting 3ater solution acidic to pH paper. "his 3as 3ashed 3ith 0/&, m! CH$Cl$,
made basic 3ith $&K 5a9H, and the product e/tracted 3ith 0/&, m! CH$Cl$. "he resulting 0.,( g slightly amber residue oil 3as distilled at ((,@($,
deg C at ,.$& mm8Hg to give $.&0 g of a 3hite oil, 3hich did not appear to absorb carbon dio/ide. "his 3as dissolved in ($ m! IPA, neutrali6ed 3ith (
m! concentrated HCl and diluted 3ith anhydrous <t$9 to the point of initial turbidity. "here separated 3hite crystals of 0,+@ethylenedio/y@5@
methylamphetamine hydrochloride '?;?C- 3hich 3eighed, 3hen air dried to constant 3eight, $.&0 g.
;9SAC<E $,, or more mg.
;4:A"I95E 0 @ & h.
L4A!I"A"IM< C9??<5"SE '3ith (&, mg- A flood of paresthesia at the 0, minute point, and then nothing. "here 3as the development of a plus one@
and@a half effect over the ne/t hour 3ith the tendency to drift into a do6ing state 3ith hypnogogic imagery. "here 3ere colored letters in the periphery of
my visual field. "here 3as no appetite loss nor 3as there any blood pressure rise. And no eye Giggle or teeth clenching. I 3as out of the e/perience in +
to & hours. A repeat of this level a fe3 days later gave a bare possible threshold 3ith no other effects.
'3ith $,, mg- "here 3as something unmistakable at +& minutes, 3ith hints of nystagmus. Possibly ?;?A@like, 3ith no indicators of anything
psychedelic. Subtle return to baseline, and there 3ere no after@effects.
'3ith $&, mg- Alert at +, minutes, and to a clear ** at an hour. Slight something in the eye muscles. ;ropping thirty minutes later, and baseline at three
hours.
'3ith $&, mg- I am at a bare threshold at best.
<="<5SI95S A5; C9??<5"A:>E Ihat a strange and completely unsatisfactory compoundO In the original run@up from lo3 levels to increasing
higher levels, there never 3as a dosage that 3as a minus, that had no effect. At every level, something 3as thought to be there, usually at a level of a
single plus or thereabouts. .ut 3ith different people, different responses. "here is no 3ay of guessing 3hat an active level might be, or ho3 consistent
that level might be bet3een different people, or for that matter 3hat the responses are that might be e/pected at that level.
"his 3as yet one more effort to find an ?;?A@like substitute by the miniscule manipulation of the ?;?A molecule. Perhaps a small molecular change
might leave the particular magic of the ?;?A action alone, but eliminate the serotonin neuron problem in test animals. ?aybe the serotonin neuron
change is essential for ?;?A to have the action it has. Iho can tellH
"he original name that this compound got, during the several e/plorations of ?;?A analogues, 3as based on the nickname for ?;?A 3hich 3as
Adam. HA;7<? 3as mentioned 3ith the hydro/y compound, ?A;A? 3ith the 1@methyl homologue, and B!A;A? 3ith the 1@fluoro analogue. "his
compound got the sobriFuet ?ACA;A? from that horrible black gooey mess generated at the aldehyde stage. "his 3as shortened to :CS and
eventually the :CS 3as added to the ?;?A parent name. "hus, ?;?C. It doesn7t really make sense; <;?A is more reasonable. .ut then there is no
reason 3hy ?;?C should make sense.

#111 M0ME%; #-METH%+Y-M0A; ',(-METHYE#E0"%+Y-#-METHY%+YAM,HETAM"#E
S>5"H<SISE "o a solution of $,.% g metho/yamine hydrochloride in 2& m! ?e9H 'a strongly acidic solution- there 3as added +.+& g 0,+@
methylenedio/yphenylacetone 'see under ?;?A for its preparation- follo3ed by (.(, g sodium cyanoborohydride. "here 3as the immediate formation
of a solid phase, and the evolution of 3hat appeared to be hydrogen cyanide. "o this there 3ere added about + m! &K 5a9H 3hich brought the pH to
the vicinity of 0 or +. Another (., g of sodium cyanoborohydride 3as added 'no gas evolution this time- and stirring 3as continued at ambient
temperature for 1 days. All 3as added to &,, m! H$9, acidified 3ith (, m! HCl, and e/traction 3ith 0/(,, m! CH$Cl$ removed almost all the color.
"he aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith +/(,, m! CH$Cl$. <vaporation of the solvent from these e/tracts yielded (.)
g of a pale yello3 oil 3hich, on distillation at %,@%& deg C at ,.& mm8Hg, gave a (.1 g fraction of an absolutely 3hite, viscous, clear oil. "his 3as
dissolved in ) m! IPA and neutrali6ed 3ith concentrated HCl. "he product 3as an e/ceptionally 3eak base, and appropriate end points must be
respected on the e/ternal pH paper 'yello3 to red, rather than purple to orange-. Anhydrous <t$9 3as added to the point of turbidity, and as soon as
crystalli6ation had actually started, more <t$9 3as added 3ith stirring, for a net total of $,, m!. After a couple of h standing, the fine 3hite crystalline
0,+@methylenedio/y@5@metho/yamphetamine hydrochloride '?;?<9- 3as removed by filtration, <t$9 3ashed, and air dried to constant 3eight. "here
3as obtained (.2 g of a product 3ith a mp of (+0@(+1 deg C. "he proton 5?: 3as e/cellent 3ith the 5@metho/yl group a sharp singlet at +.,1 ppm.
Anal. 'C((H(1Cl590- 5.
;9SAC<E greater than (), mgs.
;4:A"I95E unkno3n
<="<5SI95S A5; C9??<5"A:>E Ihy the interest in the 5@metho/y analogue of ?;AH "here are several reasons. 9ne, this is an isostere of ?;<
and it 3ould be interesting to see if it might serve as a primer to the promotion of the effectiveness of other drugs 'see primer discussion under ?;P:-.
In one e/periment, 3herein a 1, microgram dosage of !S; 3as used an hour and a half after a (), milligram load of ?;?<9, there 3as no
augmentation of effects. "hus, it 3ould appear not to be a primer. Another reason for interest 3as that the material, although having an e/tremely
similar overall structure to most of the active ?;@series compounds, is very much a 3eaker base. And ?;9H, 3hich is also a very much 3eaker base
than ?;A, still sho3s the action and potency of ?;A. And, as this compound appears to be inactive, base strength is not a sole predictor of activity.
"he ultimate reason for making ?;?<9 3as, of course, that it could be made. "hat reason is totally sufficient all by itself.
#11$ M0ME%ET; #-METH%+YETHY-M0A;
',(-METHYE#E0"%+Y-#-&$-METH%+YETHY-AM,HETAM"#E
S>5"H<SISE A crude solution of metho/yethylamine hydrochloride 3as prepared from (2.2 g metho/yethylamine and $, m! concentrated HCl 3ith all
volatiles removed under vacuum. "his 3as dissolved in 2& m! ?e9H and there 3as added +.+& g of 0,+@methylenedio/yphenylacetone 'see under
?;?A for its preparation- follo3ed by (.0 g sodium cyanoborohydride. Concentrated HCl in ?e9H 3as added as reFuired to maintain the pH at about 1
as determined 3ith e/ternal, dampened universal pH paper. About +.& m! 3ere added over the course of & days, at 3hich time the pH had stabili6ed.
"he reaction mi/ture 3as added to +,, m! H$9 and made strongly acidic 3ith an e/cess of HCl. After 3ashing 3ith $/(,, m! CH$Cl$ the aFueous
phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith +/2& m! CH$Cl$. :emoval of the solvent under vacuum yielded 1., g of an amber oil that
3as distilled at ((,@($, deg C at ,.$ mm8Hg. "here 3as obtained +.2 g of a crystal@clear 3hite oil that 3as dissolved in 0, m! IPA and neutrali6ed 3ith
+& drops of concentrated HCl producing a heavy mass of spontaneous crystals that had to be further diluted 3ith IPA Gust to be stirred 3ith a glass rod.
"hese 3ere diluted 3ith $,, m! of anhydrous <t$9, removed by filtration, and 3ashed 3ith additional <t$9. After air drying there 3as obtained +.% g of
0,+@methylenedio/y@5@'$@metho/yethyl-amphetamine hydrochloride '?;?<9<"- 3ith a mp of ()$.&@()0 deg C. Anal. 'C(0H$,Cl590- 5.
;9SAC<E greater than (), mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "his is another e/ample of the replacement of a neutral atom out near the end of a chain, 3ith a more basic and a
more polar one. ?;?<9<" 3ould be called an isostere of ?;.4 in that it has the same shape, 3ith a methylene unit 'the CH$- replaced by an o/ygen
atom. 5o activity turned up 3ith either compound, so nothing can be learned from this particular e/ample of change of polarity.

#11' M0M,; a,a,#-T*"METHY-',(-METHYE#E0"%+Y-,HE#ETHYAM"#E;
METHYE#E0"%+YME,HE#TE*M"#E
S>5"H<SISE "o a 3ell stirred solution of (.1+ g of (@'5@'ben6ylo/ycarbonyl-amino-@(,(@dimethyl@$@'0,+@methylenedio/yphenyl-ethane 'see under ?;PH
for its preparation- in (, m! anhydrous "HB there 3as added a suspension of ,.0) g !AH in $& m! "HB. All 3as held at reflu/ for $+ h, the e/cess
hydride 3as destroyed by the addition of (.& m! H$9, and sufficient aFueous 5a9H 3as added to make the reaction mi/ture basic and flocculant
enough to be filterable. "he inorganic solids 3ere removed by filtration and, follo3ing 3ashing 3ith "HB, the combined filtrate and 3ashings 3ere
stripped of organic solvent under vacuum. "he residue 3as dissolved in (,, m! <t$9 and 3ashed 3ith $/&, m! saturated aFueous 5aHC90. After
drying the organic phase 3ith anhydrous ?gS9+, the solvent 3as removed under vacuum to give a yello3 oil. "his 3as dissolved in &, m! absolute
<t9H and neutrali6ed 3ith concentrated HCl. :emoval of the solvent under vacuum yielded an off@3hite solid that 3as recrystalli6ed from an
<t9H8<t9Ac mi/ture to provide ,.)+ g of a,a,5@trimethyl@0,+@methylenedio/yphenethylamine hydrochloride '?;?P- 3ith a mp of $,1@$,) deg C. "he
5?: spectrum sho3ed the a,a@dimethyl pair as a singlet at (.0) ppm. Anal. 'C($H()Cl59$- C,H,5.
;9SAC<E above ((, mg.
;4:A"I95E perhaps 1 hours.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- "here 3as a faint, dull alerting at Gust over a half hour. "he time sense 3as out of order, and an absence of
visuals but a generali6ed attentiveness to my surroundings 3as suggestive of ?;?A. 5othing remained at the si/ hour point.
'3ith ((, mg- "here 3as a light@headedness, and a complete absence of libido. 5othing in any 3ay psychedelic, but there are hints of discomfort 'Ga3
tension- that 3ill bear close 3atching at higher dosages. It might evolve at higher levels into something like ?;?A.
<="<5SI95S A5; C9??<5"A:>E "his is one of several candidates for clinical use as a substitute for ?;?A, but there 3ill have to be a much
broader study of its Fualitative action in man. It is clearly not psychedelic at these modest levels, and in in vitro animal studies it 3as apparently inactive
as a serotonin releaser. "he 3arped logic for looking at phentermine analogs 3as discussed in the comments that concerned ?;PH. "he initials used
here have been chosen 3ith care. ?;? should not be used as it has found some currency as an abbreviation for ?;?A '?ethylene@;io/y@
?ethamphetamine-. ?;?P fits neatly 3ith ?ethylene@;io/y@?e@Phentermine.

#11( M0%H; #-HY0*%+Y-M0A; ',(-METHYE#E0"%+Y-#-HY0*%+YAM,HETAM"#E
S>5"H<SISE "o a 3ell stirred solution of (+.) g hydro/ylamine hydrochloride in ($, m! ?e9H there 3as added 0.1 g of 0,+@
methylenedio/yphenylacetone 'see under ?;?A for its preparation- follo3ed by (., g sodium cyanoborohydride. "he o/ime, prepared from the ketone
and hydro/ylamine in ?e9H 3ith pyridine, may be substituted for these t3o components. Concentrated HCl 3as added over the course of a couple of
days, to keep the pH near neutrality. Ihen the reaction 3as complete, it 3as added to H$9, made strongly acidic 3ith HCl, and 3ashed 3ith 0/(,, m!
CH$Cl$. "he aFueous phase 3as made basic 3ith $&K 5a9H, and ree/tracted 3ith 0/(,, m! of CH$Cl$. "he e/tracts 3ere pooled, and the solvent
removed under vacuum to give (.2 g of an oily residue 3hich, 3ith pumping under a hard vacuum for a fe3 minutes, changed to a 3hite solid. "his can
be ugelrohred if the vacuum is sufficiently good to keep the temperature during the distillation belo3 (,, deg C. "he e/tremely viscous distillate
formed crystals immediately upon 3etting 3ith IPA. It 3as dissolved in $, m! of 3arm IPA and neutrali6ed 3ith concentrated HCl, 3ith the titration end@
point being red rather than orange on universal pH paper. ?odest addition of <t$9 allo3ed the formation of 0,+@methylenedio/y@5@hydro/yamphetamine
hydrochloride '?;9H- as 3hite crystals, 3hich 3eighed (.+ g 3hen air dried. If the temperature of distillation e/ceeded (,, deg C, there 3as e/tensive
decomposition during distillation, 3ith the formation of 0,+@methylenedio/yamphetamine '?;A- and the o/ime of the ketone. 4nder these
circumstances, the only base isolated 3as ?;A. "he surest isolation procedure 3as to obtain ?;9H as the free base, as a crystalline solid 3hich could
be recrystalli6ed from & volumes of boiling IPA. "he free base had a mp of %+@%& deg C 'and should not be confused 3ith the o/ime of 0,+@
methylenedio/yphenylacetone 3hich has a mp of )1@)) deg C since the mi/ed mp is depressed, mp &1@1$ deg C, or 3ith the free base of ?;A 3hich is
an oil-. Anal. 'C(,H(0590- 5. "he hydrochloride salt had a mp of (+%@(&, deg C 'and should not be confused 3ith the hydrochloride of ?;A 3hich
has a mp of ()&@()1 deg C since the mi/ed mp is depressed, mp ($)@(0) deg C-. Anal. 'C(,H(+Cl590- 5. Acetic anhydride can serve as a useful
tool for distinguishing these materials. ?;A gives an 5@acetyl derivative 3ith an mp of %$@%0 deg C. ?;9H gives an 5,9@diacetyl derivative 3ith a mp
of 2$@2+ deg C. ?ethylenedio/yphenylacetone o/ime gives an 9@acetyl derivative that is an oil.
;9SAC<E (,, @ (1, mg.
;4:A"I95E 0 @ 1 h.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- I felt hampered the first hour by some internal barrier, 3hich prevented total enGoyment. Ho3ever, this began
to break through in a 3onderful 3ay Gust before the supplement 3as offered. Since I felt I 3as beginning to move through the barrier, I declined the
supplement, particularly since I 3as an/ious to compare the after@effects 3ith my first e/perience. I had found the first time very remarkable, but felt
unusually tired for several days follo3ing. I feel it is important to kno3 3hether this is a specific drug@induced effect, or the result of psychological
phenomena. "he e/perience continued in a rich, meaningful 3ay. "here 3as a marvelous inner glo3, the 3armth from all the other participants 3as
3onderful to feel, nature 3as most beautiful. "here 3ere no dramatic breakthroughs, or rushes of insight or energy, but Gust a 3onderful contemplative
space 3here things gently unfolded as you put your attention on them.
'3ith (,, mg- "he material came on fairly rapidly. In about 0, minutes, I 3as intensely into/icated, and more deeply than 3ith ?;?A. It 3as a glorious
feeling, and beauty 3as every3here enhanced. Iith eyes closed it felt marvelous, and it 3as appealing to pursue the inner e/perience. I did notice an
internal dryness 3hich 3as characteristic of ?;?A, and I had similar difficulty in urinating, but not as intense as 3ith ?;?A.
'3ith ($, mg- "he colors of the market@place, of all the fresh foods, constituted a beautiful mosaic. 5othing practical, simply a real treasure to be used
3ith individual intention and enGoyment. <verything 3as seen 3ith ne3 eyes, ne3 meanings, faces, figures, the colors of the rainbo3 subconsciously
individually applied. A 7soul@scape7. "he follo3ing day very e/hausted, tired, back@pain.
<="<5SI95S A5; C9??<5"A:>E "he first time that ?;9H 3as synthesi6ed,
it had inadvertently and unkno3ingly been converted to ?;A. And the search for proper dosage and characteri6ation of effects of this product 3as, of
course, the rediscovery of the dosage and the effects of ?;A. It is one of the 3orld7s most remarkable coincidences that after the second synthesis of
?;9H, 3hen ?;9H had really and truly been actually prepared, the brand ne3 search for proper dosage and characteri6ation of effects revealed that
they 3ere almost identical to the earlier observations for 'the inadvertently produced- ?;A.
"his reminds me of my speculations in the discussion of both B!<A and the H9" compound 3here they also sho3ed paired molecular structures 3ith
their prototypes that differ only by a single o/ygen atom. Again, might there be some metabolic interconversion 3ithin the bodyH "he immediate thought
3ould be that the o/ygen atom 'the hydro/y group- might be metabolically removed, and the effects of either drug are due to the action of ?;A. .ut the
opposite direction is in many 3ays more appealing, the in vivo conversion of ?;A to ?;9H. Ihy more appealingH Bor one thing, o/idative changes
are much more common in the body than reductive changes. Bor another, the conversion of amphetamine to 5@hydro/yamphetamine is an intermediate
in the conversion of amphetamine to phenylacetone, a kno3n metabolic process in several animal species. And that intermediate, 5@
hydro/yamphetamine, is a material that gives the famous cytochrome P@+&, comple/ that has fascinated biochemists studying the so@called 5A;PH@
dependent metabolism.
I 3ould put my money on the likelihood of ?;A going to ?;9H if it
should turn out that the t3o drugs interconvert in the body. And in that case, it 3ould be ?;9H, or another metabolite on do3n the line that is common
to both ?;A and ?;9H, that is the factor intrinsic to the into/ication that is produced. Human metabolic studies are needed, and they have not yet
been done.

#11) M0,EA; ',(-METHYE#E0"%+Y,HE#ETHYAM"#E; H%M%,",E*%#YAM"#E
S>5"H<SISE A suspension of +., g !AH in 0,, m! anhydrous <t$9 3as stirred and heated to a gentle reflu/ in an inert atmosphere. "here 3as added
0.% g 0,+@methylenedio/y@beta@nitrostyrene 'see under .9H for its preparation- by allo3ing the condensing <t$9 to leach it out from a So/hlet thimble.
After the addition 3as complete, the reaction mi/ture 3as held at reflu/ for an additional +) h. It 3as then cooled and the e/cess hydride 3as destroyed
by the cautious addition of 0,, m! of (.& 5 H$S9+. Ihen both phases 3ere completely clear, they 3ere separated, and the aFueous phase 3ashed
once 3ith &, m! <t$9. "here 3as then added (,, g potassium sodium tartrate, follo3ed by sufficient base to bring the pH U%. "his 3as e/tracted 3ith
0/2& m! CH$Cl$, and the solvent from these pooled e/tracts 3as removed under vacuum. "he residue 3as dissolved in (&, m! anhydrous <t$9 and
saturated 3ith anhydrous HCl gas. "here 3as a heavy crystalli6ation of 0,+@methylenedio/yphenethylamine hydrochloride '?;P<A- 3hich 3eighed 0.,
g and had a mp of $($@$(0 deg C.
;9SAC<E greater than 0,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $,, mg- It 3as taken t3ice at different
times in a dosage of $,, milligrams each time, 3ithout the slightest
peripheral or central effects.
'3ith 0,, mg- ?y tinnitus had disappeared. Probably nothing.
<="<5SI95S A5; C9??<5"A:>E Ho3 strange. <ven more than ;?P<A, this cyclic analogue ?;P<A is a potential prodrug to dopamine, and
3ould be a prime candidate for central activity. So 3hy is this drug not activeH "he usual reason advanced by the pharmacologists is that the body is
full of potent en6ymes kno3n as monoamine o/idases, and this is a monoamine, and so the body simply che3s a3ay on it in an o/idative manner,
inactivating it before it ever makes it to some target receptor.
"hat is the pitch given in the te/tbooks. Phenethylamines are subGect to easy en6ymatic o/idation, hence they are not active. "he presence of an alpha@
methyl group 'the corresponding amphetamines- blocks the compound from easy access to the en6yme, and since that protects them from o/idative
destruction, they are active. "he oft@Fuoted e/ception is mescaline, and even it is largely destroyed, as evidenced by the large amount needed for
activity 'a fraction of a gram-. Sorry, I can7t buy it. "his entire book is peppered 3ith phenethylamines that are active at the fe3@milligram area. Ihy
aren7t they also destroyed as 3ellH "he te/tbooks simply are not right.
?;P<A 3as one of the seven compounds evaluated as to to/icity and animal behavior at the 4niversity of ?ichigan under contract from the Army
Chemical Center. Its <dge3ood Arsenal code number 3as <A@($%2. "he number for ?;A itself 3as <A@($%).
"he beta@hydro/y analogue of ?;P<A is the ethanolamine ?;<, standing for methylenedio/yethanolamine. "his is an old term, and in the more recent
literature, since (%2& certainly, ?;< has been used to represent methylenedio/yethylamphetamine. "he ethanolamine compound is discussed in the
recipe for ;?<.
"here is a family of compounds, to be discussed else3here, that is called the ?uni@?etro 'see under ?<"H>!@D-. "he simplest member is this
compound, ?;P<A, and under its chemically acceptable synonym, homopiperonylamine, it can be called :HS. Bollo3ing that code, then, the 5@methyl
homologue of ?;P<A is ?<"H>!@H, and it has been looked at, clinically, as an antitussive agent. 5@?<"H>!@?;P<A, or ?<"H>!@H, or 5@methyl@0,+@
methylenedio/yphenethylamine is effective in this role at dosages of about 0, milligrams, but I have read nothing that 3ould suggest that there 3ere any
central effects. I have tried it at this level and have found a little tightness of the facial muscles, but there 3as nothing at all in the mental area.

#111 M0,H; a,a-0"METHY-',(-METHYE#E0"%+Y-
PH<5<"H>!A?I5<; 0,+@?<"H>!<5<;I9=>PH<5"<:?I5<
S>5"H<SISE "o (&, m! of "HB, under an atmosphere of nitrogen, there 3as added ((.$ g diisopropylamine, and the solution 3as cooled 3ith e/ternal
dry ice8IPA. "here 3as then added +) m! of a $.0 ? solution of butyllithium in he/ane, drop3ise, 3ith good stirring. "his 3as 3armed to room
temperature, stirred for a fe3 min, and then all 3as cooled again in the dry ice bath. Bollo3ing the drop3ise addition of +.+ g of isobutyric acid there 3as
added (,.& m! he/amethylphosphoramide. Again, the stirred reaction mi/ture 3as brought to room temperature for about ,.& h. "here 3as then
added, drop@3ise, ).& g 0,+@methylenedio/yben6yl chloride and the mi/ture allo3ed to stir overnight at room temperature. "he reaction mi/ture 3as
poured into (,, m! (,K HCl, and the e/cess "HB 3as removed under vacuum. "he acidic aFueous residue 3as e/tracted 3ith $/(&, m! <t$9. "hese
e/tracts 3ere pooled, 3ashed 3ith (,K HCl, and then e/tracted 3ith 0/2& m! of + 5 5a$C90. "hese e/tracts 3ere pooled, made acidic 3ith HCl, and
again e/tracted 3ith <t$9. After drying the pooled e/tracts 3ith anhydrous ?gS9+, the solvent 3as removed under vacuum to give a residue that
spontaneously crystalli6ed. :ecrystalli6ation from he/ane yielded 1.& g of $,$@dimethyl@0@'0,+@methylenedio/yphenyl-propionic acid as 3hite crystals
3ith a mp of 2(@20 deg C. "he 5?: spectrum in C;Cl0 sho3ed the alpha@dimethyl groups as a sharp singlet at (.() ppm. Anal. 'C($H(+9+- C,H.
"he triethylamine salt of $,$@dimethyl@0@'0,+@methylenedio/yphenyl-propionic acid '&.+ g amine, ((.+ g acid- 3as dissolved in (, m! H$9 and diluted
3ith sufficient acetone to maintain a clear solution at ice@bath temperature. A solution of 1.+ g ethyl chloroformate in +, m! acetone 3as added to the ,
deg C solution over the course of 0, min, follo3ed by the addition of a solution of +.( g sodium a6ide in 0, m! H$9. Stirring 3as continued for +& min
3hile the reaction returned to room temperature. "he aFueous phase 3as e/tracted 3ith (,, m! toluene 3hich 3as 3ashed once 3ith H$9 and then
dried 3ith anhydrous ?gS9+. "his organic solution of the a6ide 3as heated on a steam bath until nitrogen evolution had ceased, 3hich reFuired about
0, min. "he solvent 3as removed under vacuum and the residue 3as dissolved in 0, m! ben6yl alcohol. "his solution 3as heated on the steam bath
overnight. :emoval of the e/cess ben6yl alcohol under vacuum left a residue (0.& g of (@'5@'ben6ylo/ycarbonyl-amino-@(,(@dimethyl@$@'0,+@
methylenedio/yphenyl-ethane as an amber oil. "he dimethyl group sho3ed, in the 5?:, a sharp singlet at (.0, ppm in C;CH0. Anal. 'C(%H$(59+-
C,H. "his carbamate 3as reduced to the primary amine 'belo3- or to the methylamine 'see under ?;?P-.
A solution of 0.$2 g of (@P5@'ben6ylo/ycarbonyl-aminoQ@(,(@dimethyl@$@'0,+@methylenedio/yphenyl-ethane in $&, m! absolute ethanol 3as treated 3ith
,.& g (,K palladium on carbon. "his mi/ture 3as shaken under hydrogen at 0& pounds pressure for $+ h. "he carbon 3as removed by filtration
through Celite, and the filtrate titrated 3ith HCl. "he solvent 3as removed under vacuum, and the residue allo3ed to crystalli6e. "his produce 3as
recrystalli6ed from an <t9H8<t9Ac mi/ture to provide a,a@dimethyl@0,+@methylenedio/yphenethylamine hydrochloride '?;PH-. "he 3hite crystals
3eighed (.10 g and had a mp of (),@()( deg C. Anal. 'C((H(1Cl59$- C,H,5.
;9SAC<E (1, @ $+, mg.
;4:A"I95E 0 @ & h.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- "he alert 3as felt in forty minutes and I 3as pretty much there at an hour and t3enty. Luite like ?;A,
simple, 3ith no lines, no colors, no motion, no fantasy. I am pleasantly stoned. "he anore/ia is real, as is the impotency. "he drop from the +th to the
1th hour 3as softened by a modest amount of 3ine, and this proved to be e/tremely into/icating. ?y speech 3as slurred, and there 3as later amnesia
for the rather aggressive and uninhibited behavior that occurred. I felt that there 3as more drug than alcohol contributing to this episode. ?y dream
patterns 3ere disturbingly unreal.
'3ith (1, mg- A very Fuiet development. "here 3as no body load 3hatsoever. And no visual, and I sa3 it fading a3ay all too soon. "his might be a good
promoter, like ?;P:. I felt refreshed and rela/ed on the follo3ing morning.
'3ith $,, mg- "his has an inordinately foul taste. I felt slightly Fueasy. "here 3ere short daydreams 3hich 3ere Fuickly forgotten. I see no values that
are 3orth the hints of physical problems, a little eye mismanagement and some clenching of teeth, and a tendency to s3eat. I 3as able to sleep at only
five hours into it, but there 3ere a couple of darts. "his is not as re3arding 'stoning- as ?;A, and has none of the magic of ?;?A. It 3as a short@lived
plus t3o.
<="<5SI95S A5; C9??<5"A:>E Ihat is the train of thought that leads from the structure of a kno3n compound '3hich is active- to the structure of
an unkno3n one '3hich may or may not be active-H Certainly the e/trapolations involve many 3hat@if7s and maybe7s. "he path can be humorous, it
certainly can be tortuous, and it often calls for special things such as faith, insight, and intuition. .ut can one say that it is logicalH
!ogic is a tricky thing to evaluate. 9ne of the earliest approaches 3as laid do3n by Aristotle, in the form of the syllogism. In it there are three
lines consisting of t3o premises and a conclusion, a form that is called a Nmood.N All are statements of relationships and, if the premises are true, there
are only certain conclusions that may logically follo3. Bor e/ampleE
<very man is a lover.
<very chemist is a man.
"herefore, every chemist is a lover.
!etting lover be the maGor term NaN and letting chemist be the minor term NbN and letting man be the middle term NmN, this reduces toE
<very m is a,
<very b is m.
"herefore, every b is a
and it is a valid mood called .arbara.
9f the $&1 possible combinations of all7s and some7s and none7s and are7s and are@not7s, only $+ moods are valid. "he reasoning here 3ith ?;PH goesE
Some stimulants 3hen given a methylenedio/y ring are ?;?A@like.
Some ring@unsubstituted (,(@dimethylphenylethylamines are stimulants.
"herefore, some ring@unsubstituted (,(@dimethylphenylethylamines 3hen given a methylenedio/y
ring are ?;?A@like.
In symbolic form this isE
Some m is a, and
Some b is m, then
Some b is a
and this is not one of the $+ valid moods. Civen the first premise as some m is a, there is only one valid syllogism form that can follo3, and this is kno3n
as ;isamis, orE
Some m is a, and
<very m is b, then
Some b is a
3hich translates asE
Some stimulants 3hen given a methylenedio/y group are ?;?A@like.
<very stimulant is a ring@unsubstituted (,(@dimethylphenylethylamine.
"herefore, some ring@unsubstituted (,(@dimethylphenylethylamines 3hen given a methylenedio/y group are ?;?A@like.
"he conclusion is the same. .ut the second premise is false so the entire reasoning is illogical. Ihat is the false second premiseH It is not a fact that
every stimulant is a phentermine. "here are lots of stimulants that are not phentermines.
So much for applying syllogistics to pharmacology.

#112 M0,; #-,*%,A*8Y-M0A; #-,*%,Y#Y-M0A;
',(-METHYE#E0"%+Y-#-,*%,A*8YAM,HETAM"#E-
S>5"H<SISE A solution of (,.& g propargylamine hydrochloride in +, m! ?e9H 3as treated 3ith $., g 0,+@methylenedio/yphenylacetone 'see under
?;?A for its preparation- follo3ed by ,.&& g sodium cyanoborohydride. Concentrated HCl 3as added as needed, to keep the pH constant at about 1.
"he reaction seemed to progress very slo3ly. After about five days, the reaction mi/ture 3as added to +,, of H$9, acidified 3ith HCl, and e/tracted
3ith 0/(,, m! CH$Cl$. "he aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. <vaporation of the solvent from
these e/tracts yielded (.1 g of a clear amber, strong smelling oil 3hich, on distillation at (,&@((, deg C at ,.$ mm8Hg, yielded (., g of an almost
colorless oil. "his 3as dissolved in $, m! IPA, neutrali6ed 3ith about (, drops of concentrated HCl, and the spontaneously formed crystals 3ere diluted
3ith &, m! anhydrous <t$9. After filtration, <t$9 3ashing and air drying, there 3as obtained (.( g 3hite crystals of 0,+@methylenedio/y@5@
propargylamphetamine hydrochloride '?;P!- 3ith a mp of ()%@(%, deg C. Anal. 'C(0H(1Cl59$- 5.
;9SAC<E greater than (&, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "here is a continuing uncertainty about the name for the three@carbon radical that contains a triple bond. "he
hydrocarbon is propyne, although it has been referred to as methylacetylene in the older literature. "he adGective, going from the triple bond out to the
point of attachment, is called propargyl, as in propargyl chloride. Ihen the adGective must be built on the parent hydrocarbon, the double bond is on the
outside and one reads a3ay from it, as in $@propynyl something. Ho3ever, 3hen the hydrocarbon is essentially the entire structure, then things get
named going to3ards the triple bond, as in 0@chloro@(@propyne. Iait. I7m not done yetO Ihen the actual hydrocarbon name becomes distorted into the
derivative, then the triple bond is again at the high end of the numbering scheme. Propynol is $@propyn@(@ol, 3hich is, of course, the same as 0@
hydro/ypropyne, or propargyl alcohol. "he code ?;P! takes the first and last letter of the t3o of them, both propargyl and propynyl.

#113 M0,*; #-,*%,Y-M0A; ',(-METHYE#E0"%+Y-#-,*%,YAM,HETAM"#E
S>5"H<SISE A total of $, m! concentrated HCl 3as added beneath the surface of $, m! propylamine, and 3hen the addition 3as complete, the mi/ture
3as stripped of volatiles under vacuum. "he slightly yello3 residual oil 3eighed $,.2 g and set up to crystals on cooling. It 3as dissolved in 2& m!
?e9H, and there 3as added +.+& g of 0,+@methylenedio/yphenylacetone 'see under ?;?A for its preparation- follo3ed by (.( g sodium
cyanoborohydride. Concentrated HCl in ?e9H 3as added as reFuired to maintain the pH at about 1 as determined 3ith e/ternal, dampened universal
pH paper. Ihen the generation of base had stopped, the ?e9H 3as allo3ed to evaporate and the residue 3as suspended in ( ! 3ater. "his 3as made
strongly acidic 3ith an e/cess of HCl. After 3ashing 3ith CH$Cl$, the aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m!
CH$Cl$. :emoval of the solvent from the pooled e/tracts under vacuum yielded 0.0 g of a pale amber oil that 3as distilled at )&@%, deg C at ,.$
mm8Hg. "his fraction 3as 3ater@3hite and 3eighed $.0 g. It 3as dissolved in (, m! IPA and neutrali6ed 3ith $& drops concentrated HCl 3hich
produced crystals spontaneously. "hese 3ere diluted 3ith anhydrous <t$9, removed by filtration, 3ashed 3ith additional <t$9, and air dried. In this 3ay
there 3as obtained $.0 g of 0,+@methylenedio/y@5@propylamphetamine hydrochloride '?;P:- 3ith a mp of (%,@(%$ deg C. :ecrystalli6ation from IPA
gave a mp of (%+@(%& deg C. "he 5?: spectrum 3as completely consistent 3ith the assigned chemical structure. Anal. 'C(0H$,Cl59$- 5.
;9SAC<E greater than $,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $,, mg- "here are the slightest hints of physical response, maybe a smidgin of a lightheadedness at the one hour
point. Perhaps a slight teeth clench. Certainly there is no central mental effect.
<="<5SI95S A5; C9??<5"A:>E "his particular drug, considering that it 3as 3ithout activity, has proven one of the richest veins of pharmacological
ra3 material. "3o clues suggested its potential value. A number of reports in the (&, to $,, milligram area suggested that something 3as taking place
in the periphery even 3ithout any clear central effects. "he term Nbody 3indo3N 3as used occasionally by e/perimenters, an outgro3th of the term
N3indo3N that 3as used 'at that time, the mid@(%2,7s- to describe the mental effects of ?;?A. It 3as as if the body 3as opened up and made receptive,
instead of the mind. "he second clue came from many anecdotal reports that methedrine 'a potent central nervous system stimulant- 3ould augment
the effects of an !S; dosage 3hich follo3ed it. "he putting of a drug on top of an inactive drug is the NprimerN concept. It turned out that ?;P: 3as an
e/traordinary primer to some follo3ing psychedelic, especially !S;, even at modest doses. "he putting of a drug on top of an active drug, usually during
the latter part of its effectiveness is, as previously stated, called Npiggy@backing.N A third drug@drug interaction has also been studied; the simultaneous
administration of t3o active drugs, to study synergism. "here may be an enhancement, or an inhibition, of one 3ith the other. !et7s no3 re@enter the
subsection NLualitative CommentsN again, 3ith this primer concept in mind.
L4A!I"A"IM< C9??<5"SE '3ith (1, mg follo3ed at $ h by 1, &gs !S;- :"he visual phenomena 3ere e/traordinary. Ie 3ere at the beach Gust south
of ?endocino. In anything that had ever been living, there 3as an endlessly deep microcosm of detail. <ndless, and forever more microscopic in
intricacy. A sea urchin shell, a bit of drift3ood, a scrap of dried sea3eed, each 3as a treasure of Ge3els. I have never had such 3ealth of visual
eroticism and bliss before. !ater, 3e visited the pygmy forest, but these living fossils 3ere not as magical.
'3ith (1, mg follo3ed at $ h by 1, &gs !S;- :Ie both felt the first effects at about 0, minutes, and an hour later 3e found ourselves in a startling folie@
a@deu/, involved in reliving the origins of man7s arrival on earth. Ie 3ere deep in a tropic environment, defending ourselves against the nasties of
nature 'insects, threatening things, blistering heat- and determining that man could indeed live here and perhaps survive. A shared eyes@closed fantasy
that seemed to be the same script for both of us.
'3ith (1, mg follo3ed at $ h by(,, &gs !S;- :"his proved to be almost too into/icating, and a problem arose that had to have a solution. "he entire
research group 3as here, and all 3ere follo3ing this same regimen. "3o hours into the second half of the e/periment a telephone call came that
reminded me of a promise I had made to perform in a social afternoon 3ith the viola in a string Fuartet. Ihy did I ans3er the phoneH ?y entire
e/perience 3as, over the course of about $, minutes, pushed do3n to a fragile threshold, and I drove about (, minutes to attend a s3ank afternoon
event and played an early .eethoven and a middle ?o6art 3ith an untouched glass of e/pensive ?erlot in front of me. I could al3ays blame the boo6e.
I declined the magnificent food spread, split, and returned to my o3n party. Safely home, and given $, more minutes, I 3as back into a rolling *** and I
no3 kno3 that the mind has a remarkable ability to control the particular place the psyche is in.
'3ith $,, mg follo3ed at $ h by 1, &gs !S;- :"here 3as a steady climb from the half@hour point to about $ hours. "here 3as not the slightest trace of
anything sinister. "here 3as simply a super tactile person@to@person 3indo3. I had an overpo3ering urge to go out and interact 3ith other people. "o
see, to talk, to be 3ith others. "here are unending fantasies of things erotic. Perhaps being 3ith others should be circumspect. .y evening the effects
had largely 3orn off, but this 3as an incredible day, beautiful and une/pectedly rela/ing.
<="<5SI95S A5; C9??<5"A:>E "here is need for more commentary. It must be noted that all of the above comments used rather modest dosages
of !S;. "he notes of this period, some t3o years of e/ploring interactions of the ?; series of compounds as preludes to true psychedelics, are difficult
to distill into a simple pattern. ?ost of these studies used !S; in the 1,@(,, microgram range 3hich is fundamentally a modest level. ?any trials 3ere
made 3here the challenge of acid plopped right on top of an active residue of another drug 3as more in keeping 3ith the NpiggybackN argument. An
illustration of this is a trial in 3hich the primer 3as ?;?A follo3ed at & hours 'this is at a time of almost no effect- 3ith a larger dose of !S; '$&,
micrograms-. "he !S; over3helmed the residual numbing of the ?;?A, and the generated state 3as over3helmingly erotic and out of body. "here
can be no 3ay of analytically organi6ing such a gemisch of drug@drug interactions 3ith any logic that 3ould allo3 a definitive interpretation. And !S; is
not the only agent that can be used to challenge the Nbody 3indo3N such as that produced by ?;P:. $C@., $C@"@$ and $C@"@2 have all been used 3ith
fine success as 3ell.
In general, the use of an ?; compound 'looking at it as a stimulant and primer- follo3ed by a psychedelic, brings about an e/aggeration and
enhancement of the latter compound. ?uch 3ork must be done in this area to make sense of it all.
#114 ME; METAES!A"#E; ',(-0"METH%+Y-)-ETH%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a vigorously stirred suspension of ().1 g of &@bromobourbonal in (,, m! CH$Cl$ there 3as added (+.$ g methyl iodide, (., g
decyltriethylammonium iodide, and ($, m! &K 5a9H. "he color 3as a deep amber, and 3ithin ( min the top phase set up to a solid. "his 3as largely
dispersed 3ith the addition of another &, m! of 3ater. "he reaction 3as allo3ed to stir for $ days. "he lo3er phase 3as 3ashed 3ith H$9, and saved.
"he upper phase 3as treated 3ith another (,, m! CH$Cl$, &, m! of $&K 5a9H, another g of decyltriethylammonium iodide, and an additional &, m!
of methyl iodide. "he formed solids dispersed by themselves in a fe3 h to produce t3o relatively clear layers. Stirring 3as continued for an additional 0
days. "he lo3er phase 3as separated, 3ashed 3ith H$9, and combined 3ith the earlier e/tract. "he solvent 3as removed under vacuum to give $,.0
g of an amber oil that 3as distilled at ($,@(00 deg C at ,.+ mm8Hg to yield (&.1 g of 0@bromo@+@metho/y@&@etho/yben6aldehyde as a 3hite crystalline
solid 3ith a mp of &$@&0 deg C.
A mi/ture of (&.1 g 0@bromo@+@metho/y@&@etho/yben6aldehyde and (, m! cyclohe/ylamine 3as heated 3ith an open flame until it appeared free of
H$9. "he residue 3as put under a vacuum ',.& mm8Hg- and distilled at (+)@(&& deg C yielding (%.$ g 0@bromo@5@cyclohe/yl@+@metho/y@&@
etho/yben6ylidenimine as an off@3hite crystalline solid 3ith a melting point 11@1).& deg C. :ecrystalli6ation from (,, m! boiling ?e9H gave a mp of 12@
1).& deg C. "he CT5 stretch in the infra@red 3as at (1+, cm@(. Anal. 'C(1H$$.r59$- C,H.
A solution of (2 g 0@bromo@5@cyclohe/yl@+@metho/y@&@etho/yben6yl@idenimine in $,, m! anhydrous <t$9 3as placed in an atmosphere of He, stirred
magnetically, and cooled 3ith an e/ternal dry@ice acetone bath. "hen 0) m! of a (.&& ? solution of butyllithium in he/ane 3as added over $ min,
producing a clear yello3 solution. "here 3as then added $& m! of butyl borate at one time, and the stirred solution allo3ed to return to room
temperature. "his 3as follo3ed 3ith (,, m! of saturated aFueous ammonium sulfate. "he <t$9 layer 3as separated, 3ashed 3ith additional saturated
ammonium sulfate solution, and evaporated under vacuum "he residue 3as dissolved in $,, m! of &,K ?e9H and treated 3ith ($ m! of 0,K
hydrogen pero/ide. "his reaction 3as mildly e/othermic, and 3as allo3ed to stir for (& min, then added to an aFueous solution of &, g ammonium
sulfate. "his 3as e/tracted 3ith $/(,, m! CH$Cl$, the pooled e/tracts 3ashed once 3ith H$9, and the solvent removed under vacuum. "he residue
3as suspended in dilute HCl, and heated on the steam bath for ,.& h. Stirring 3as continued until the reaction 3as again at room temperature and then
it 3as e/tracted 3ith $/(,, m! CH$Cl$. "hese e/tracts 3ere pooled and in turn e/tracted 3ith $/(,, m! dilute 5a9H. "he aFueous e/tracts 3ere
reacidified 3ith HCl, and ree/tracted 3ith $/(,, m! CH$Cl$. After pooling, the solvent 3as removed under vacuum to yield an oily residue. "his 3as
distilled at (()@(0, deg C at ,.$ mm8Hg to yield 2.& g of 0@etho/y@&@hydro/y@+@metho/yben6aldehyde as a distillate that set to 3hite crystals.
:ecrystalli6ation from cyclohe/ane gives a product 3ith a mp of 22@2) deg C. Anal. 'C(,H($9+- C,H.
A solution of 2.0 g of 0@etho/y@&@hydro/y@+@metho/yben6aldehyde in (,, m! acetone 3as treated 3ith & m! methyl iodide and )., g finely po3dered
anhydrous $C90, and held at reflu/ on a steam bath for 1 h. "he solvent 3as removed under vacuum, and the residue 3as suspended in H$9. After
making this strongly basic, it 3as e/tracted 3ith 0/&, m! CH$Cl$, the e/tracts 3ere pooled, and the solvent removed under vacuum. "he residual
amber oil 3as distilled at ((,@($, deg C at ,.+ mm8Hg to yield 2.0 g of a 3hite oil. "his spontaneously set to 3hite crystals of 0,+@dimetho/y@&@
etho/yben6aldehyde 3hich had a mp of +%@+%.& deg C. Anal. 'C((H(+9+- C,H. "his same aldehyde can be obtained, but in a less satisfactory yield, by
the ethylation of 0,+@dimetho/y@&@hydro/yben6aldehyde described under the preparation of metaproscaline '?P-.
A solution of 2.$ g 0,+@dimetho/y@&@etho/yben6aldehyde in (,, m! nitromethane containing ,.( g anhydrous ammonium acetate 3as held at reflu/ for
&, min. "he e/cess nitromethane 3as removed under vacuum producing 1.) g of a red oil 3hich 3as decanted from some insoluble material. Addition
of (, m! hot ?e9H to the decantings, gave a homogeneous solution that spontaneously crystalli6ed on cooling. "he yello3 crystals 3ere removed by
filtration, 3ashed sparingly 3ith ?e9H and air dried yielding 0.& g yello3 crystals of 0,+@dimetho/y@&@etho/y@beta@nitrostyrene, 3ith a mp of )%.&@%, deg
C after recrystalli6ation from ?e9H. Anal. 'C($H(&59&- C,H.
A solution of $., g !AH in (,, m! anhydrous "HB under He 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, (.0 m! of (,,K
H$S9+, follo3ed by the drop3ise addition of a solution of 0.( g 0,+@dimetho/y@&@etho/y@beta@nitrostyrene in &, m! anhydrous "HB, over the course of (,
min. "he mi/ture 3as stirred at , deg C for a 3hile, and then brought to a reflu/ on the steam bath for 0, min. After cooling again, the e/cess hydride
3as destroyed 3ith IPA in "HB, follo3ed by the addition of $, m! (,K 5a9H 3hich 3as sufficient to convert the solids to a 3hite and granular form.
"hese 3ere removed by filtration, the filter cake 3ashed 3ith IPA, the mother liFuor and filtrates combined, and the solvents removed under vacuum.
"he residue 3as added to (&, m! dilute H$S9+, and the cloudy suspension 3ashed 3ith $/2& m! CH$Cl$ 3hich removed much of the color. "he
aFueous phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/&, m! CH$Cl$. "he solvent 3as removed from these pooled e/tracts and the
residue distilled at (,0@((1 deg C at ,.$& mm8Hg to provide $.0 g of a colorless viscous liFuid. "his 3as dissolved in (, m! IPA, neutrali6ed 3ith about
$& drops of concentrated HCl, 3hich produced an insoluble 3hite solid. "his 3as diluted 3ith +, m! anhydrous <t$9 added slo3ly 3ith continuous
stirring. "he 3hite crystalline 0,+@dimetho/y@&@etho/yphenethylamine hydrochloride '?<- 3as isolated by filtration, 3ashed 3ith <t$9, and air dried, and
3eighed $.+ g. It had a mp of $,$@$,0 deg C 3hich increased by one degree upon recrystalli6ation from boiling IPA. Anal. 'C($H$,Cl590- C,H.
;9SAC<E $,, @ 0&, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith $,, mg- It tasted pretty strong. Ho3ever, the taste 3as soon gone, and an energetic feeling began to take over me. It
continued to gro3. "he feeling 3as one of great camaraderie, and it 3as very easy to talk to people. <veryone 3as talking to everyone else. I found it
most pleasant, energetic and at the same time rela/ing, 3ith my defenses do3n. "his material did not seem to lead to introspection; ho3ever, it might if
one took it 3ithout other people around. Heightened visual a3areness 3as mild, but the audio a3areness 3as Fuite heightened. "he feeling of being
3ith everyone 3as intense.
'3ith $&, mg- Initially I took $,, milligrams of metaescaline, and the e/perience developed for me very gradually at first, and very pleasantly. After about
one half hour I became a3are of a 3all that seemed to shut me in, not unpleasantly. "he 3all slo3ly dissolved, but I 3as afraid I might get into a
negative e/perience. I felt immediate relief 'from this isolation- upon taking the additional &, mg 'at $E$0 into the e/periment- as though glad of the
decision. I lay do3n outside on a blanket. "here 3as a marvelous feeling inside, although no imagery. I felt the 3all dissolve completely, and I desired
to Goin the group. Brom this point on the e/perience 3as most enGoyable, euphoric. Although not dramatic like some psychedelics, it 3as most
re3arding for me personally. I felt a marvelous bond 3ith everyone present, 3ith clear@headed, e/cellent thinking, and e/cellent communication. All in
all, a most re3arding and enGoyable e/perience. After3ards I felt much strengthened, 3ith good energy and good insight. I have a strong feeling that the
group tailored the nature of the e/perience, and that I and others 3ere most desirous of group interaction. I feel that one could do a lot of other things
3ith it if one turned one7s attention to it.
'3ith $2& mg- 9nset of both physical and mental change 3as slo3 relative to other psychochemicals. Mery gradual internal stirrings 3ere felt at about
the hour@and@a@half point. "hese 3ere mostly feelingful rather than cognitive, and 3ere Fuite pleasurable. At about the t3o@and@a@half hour point I gre3
Fuite thirsty, and drank a pint of beer. Almost immediately, and Fuite une/pectedly, I tomsoed to a much higher level and remained there for another
three hours until the 3hole e/perience 3aned. P"he verb, to tomso, means a sudden rekindling of the drug@induced altered state 3ith a small amount of
alcohol. It is e/plained in the recipe for "9?S9.Q ;uring the e/perience heights, and in fact before it reached its height, talking 3as easy and
unimpeded. "he transference feelings so characteristic of ?;?A 3ere basically not there. .ut for purposes of psychotherapy, there 3ere some
advantagesE fluent associations, undefended positions, and general bonaise.
'3ith +,, mg- Ingested 0,, milligrams at about (E0, in the afternoon. Mery Fuiet climb. 9ccasional ya3ns. ?atter@of@fact vie3 of the 3orld. 5o rosy
glo3. At the end of the second hour, I seem to be stuck at a **. "ake another (,, milligrams at 0E+& P?. Still tastes a3ful. Beel a small head@rush
fifteen minutes after taking the supplement, and 3ithin a half hour I am completely *0. Bor a 3hile this 3as a sterner mescaline. Sa3 the eternal,
continual making of choices, all opposites continually in motion 3ith each other. >in and yang every3here, giving life to every molecule. "he universe
itself keeps alive by the action@reaction, the yes@no, the black@3hite, male@female, plus@minus. All life is a continual making of choices on all levels.
"hen I closed my eyes, and I found myself floating up to the very top of a temple, 3here there 3as radiant light and a sense of homecoming. ?aking
love is a clear stream over and through rocks and canyons L the earth and sky make love, and the rocks make love to other rocks, and the 3ater is the
teasing, fondling, living and moving actions of loving. "o reali6e that, on some level, all e/istence makes love to all other e/istence. "he Dapanese
CardenE a structured 3ay of laying out a small glimpse into cosmic love@making, so that it can be read by other human souls. All loving, 3hen direct and
free and undemanding, is a touching of the Source. "he hardest lesson, of course, is ho3 to love yourself that same 3ay. And it remains both the first
lesson of indergarten and the Ph.;. final. I 3as able to drift into sleep at about +E,, A?.
<="<5SI95S A5; C9??<5"A:>E "he reorientation of the single ethyl group of escaline '<- to the meta@position produces metaescaline '?<-. In
cats, in studies of over &, years ago, the t3o compounds produced similar effects at similar dosages. In man, ?< also appears to be similar to
mescaline in potency. Ho3ever, a subtle difference is apparent bet3een ?< and Peyote, the natural source of mescaline. Iith Peyote itself, the initial
taste of the crude cactus is more than Gust foul; it might better be described as unbelievably foul. .ut in the middle of a Peyote e/perience, the taste of
the cactus is truly friendly. Ihen ?< 3as retasted in the middle of an e/perience, the taste 3as still foul.
"here are other distinctions from mescaline. 4nlike mescaline or Peyote, there is rarely any body discomfort during the early phase of into/ication, no
nausea and only an occasional comment suggesting hyperrefle/ia. And, also unlike mescaline, most subGective reports on ?< claim that music
produces little imagery, and the e/aggeration of color perception is more reserved. Appetite is normal, the tastes and te/tures of food are unusually
re3arding. 5o subGect has ever e/pressed a reluctance to repeat the e/perience. Sleep is easy, refreshing, and the follo3ing day seems free from
residue.

#1$5 ME0A; '-METH%+Y-(,)-ETHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE "o a solution of &, g 0,+@dihydro/y@&@metho/yben6aldehyde in (,, m! distilled acetone there 3as added 2, g ethylene bromide and &) g
finely po3dered anhydrous $C90. "he mi/ture 3as held at reflu/ for & days. "his 3as then poured into (.& ! H$9 and e/tracted 3ith +/(,, m!
CH$Cl$. :emoval of the solvent from the pooled e/tracts gave a residue 3hich 3as distilled at (% mm8Hg. Several of the fractions taken in the $,0@$(,
deg C range spontaneously crystalli6ed, and they 3ere pooled to give ().0 g of 0@metho/y@+,&@ethylenedio/yben6aldehyde as 3hite solids 3ith a mp of
),@)( deg C. A small sample 3ith an eFual 3eight of malononitrile in <t9H treated 3ith a fe3 drops of triethylamine gave 0@metho/y@+,&@
ethylenedio/yben6almalononitrile as pale yello3 crystals from <t9H 3ith a mp of (&0@(&+ deg C.
A solution of (.&, g 0@metho/y@+,&@ethylenedio/yben6aldehyde in 1 m! acetic acid 3as treated 3ith ( m! nitroethane and ,.&, g anhydrous ammonium
acetate, and held on the steam bath for (.& h. "o the cooled mi/ture H$9 3as cautiously added until the first permanent turbidity 3as observed, and
once crystal@li6ation had set in, more H$9 3as added at a rate that 3ould allo3 the generation of additional crystals. Ihen there 3as a residual turbidity
from additional H$9, the addition 3as stopped, and the beaker held at ice temperature for several h. "he product 3as removed by filtration and 3ashed
3ith a little &,K acetic acid, providing ,.%0 g (@'0@metho/y@+,&@ethylenedio/yphenyl-@$@nitropropene as dull yello3 crystals 3ith a mp of ((1@((% deg C.
:ecrystalli6ation of an analytical sample from ?e9H gave a mp of ((%@($( deg C.
A stirred suspension of 1.) g !AH in &,, m! anhydrous <t$9 under an inert atmosphere 3as brought up to a gentle reflu/. A total of %.+ g (@'0@metho/y@
+,&@ethylenedio/yphenyl-@$@nitropropene in 3arm <t$9 3as added over the course of ,.& h. :eflu/ing 3as maintained for 1 h, and then the reaction
mi/ture 3as cooled and the e/cess hydride destroyed by the cautious addition of +,, m! (.& 5 H$S9+. "he t3o clear phases 3ere separated, and the
aFueous phase 3as brought to pH of 1 by the addition of a saturated 5a$C90 solution. "his 3as filtered free of a small amount of insolubles, and the
clear filtrate 3as heated to ), deg C. "o this there 3as added a solution of %.$ g picric acid '%,K material- in (,, m! boiling <t9H, and the clear mi/ture
allo3ed to cool in an ice bath. Scratching generated yello3 crystals of the picrate salt. "his salt 3as filtered free of the aFueous environment, treated
3ith &, m! of &K 5a9H, and stirred until the picric acid 3as totally in the form of the soluble sodium salt. "his 3as then e/tracted 3ith 0/(,, m!
CH$Cl$, the e/tracts pooled, and the solvent removed under vacuum. "he residue 3eighed 1., g, and 3as dissolved in (,, m! anhydrous <t$9, and
saturated 3ith dry HCl gas. "he 3hite solids that formed 3ere filtered free of the <t$9, and ground up under &, m! of slightly moist acetone, providing
+.%$ g of 0@metho/y@+,&@ethylenedio/yamphetamine hydrochloride monohydrate '?<;A- as 3hite crystals.
;9SAC<E greater than $,, mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "here are times 3hen the Cods smile in une/pectedly nice 3ays. Having found the activity of ??;A, the
NscientificN thing to do 3ould be to compare it against the other NpsychotomimeticN amphetamine that 3as kno3n at that time 'this 3as (%1$-, namely
"?A. Comparing their structures, the only difference of any kind 3as that t3o of the adGacent metho/yl groups of "?A 3ere replaced 3ith a &@
membered ring, called the methylenedio/y ring.
Ihere does one go ne/tH Some perverse inspiration suggested increasing the si6e of this ring to a 1@membered ring, the ethylenedio/y 'or dio/ene-
homologue. Iell, if you thought that getting myristicinaldehyde 3as a difficulty, it 3as nothing compared to getting this 1@membered counterpart. .ut I
huffed and I puffed, and I did make enough to taste and to evaluate. And it 3as here that I got the divine messageO 5o activityOO So, rather than being
condemned forever a la Sisyphus to push ever larger rings up my psyche, I gave myself permission to pursue another path. "he message 3asE N;on7t
change the groups. !eave them as they are, but relocate them instead.N And that led directly to "?A@$ and its story.
A couple of diversions may be mentioned here. .efore the blessed inactivity of ?<;A 3as established, the 2@membered ring counterpart, 0@metho/y@
+,&@trimethylenedio/yamphetamine '?"?A- 3as prepared by essentially the same procedure. "he above 0@metho/y@+,&@dihydro/yben6aldehyde 3ith
trimethylene bromide gave 0@metho/y@+,&@trimethylenedio/yben6aldehyde, 3hite solids, 3ith a malononitrile derivative 3ith a mp of (0+@(0& deg C; the
aldehyde 3ith nitroethane gave the nitropropene 3ith a mp of )1@)2 deg C; and this 3ith !AH gave ?";A as the hydrochloride 'mp (1,@(1( deg C-
again isolated first as the picrate. It had been tasted at up to an ) milligram dosage 'no activity, but none e/pected- before being abandoned. And, an
initial effort 3as made to synthesi6e a five@member ring 'methylenedio/y- 3ith a methyl sticking out from it. "his ethylidine homologue got as far as the
aldehyde stage. "he reaction bet3een 0,+@dihydro/y@&@metho/yben6aldehyde and (,(@dibromoethane in acetone containing anhydrous potassium
carbonate gave a minuscule amount of a product that 3as a t3o@component mi/ture. "his 3as resolved by do6ens of separate inGections into a
preparatory gas chromatography system, allo3ing the isolation of the second of the t3o components in a Fuantity sufficient to demonstrate 'by 5?:
spectroscopy- that it 3as the desired 0@metho/y@+,&@ethylidinedio/yben6aldehyde. Starting 3ith the pre@prepared dipotassium salt or the lead salt of the
catecholaldehyde gave nothing. Iith no activity being found 3ith ?<;A, all 3as abandoned.
"here are some comments made under ?;A for successful chemistry 'using a different approach- aloRng these lines 3hen there is no metho/yl group
present. "hese are the compounds <;A and I;A. .ut the pharmacology 3as still not that e/citing.
#1$1 MEE; (,)-0"ETH%+Y-$-METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of (11 g bourbonal in ( ! ?e9H there 3as added a solution of 11 g 9H pellets in 0,, m! H$9. "here 3as then added ($,
g ethyl bromide, and the mi/ture 3as held at reflu/ on the steam bath for 0 h. "he reaction 3as Fuenched 3ith three volumes of H$9, and made
strongly basic by the addition of $&K 5a9H. "his 3as e/tracted 3ith 0/0,, m! CH$Cl$, and the pooled e/tracts stripped of solvent under vacuum.
"here remained (&& g of 0,+@dietho/yben6aldehyde as a fluid oil that had an infra@red spectrum identical 'e/cept for being slightly 3et- to that of a
commercial sample from the <astman odak Company.
A solution of (%+ g 0,+@dietho/yben6aldehyde in 1,, g glacial acetic acid 3as arranged in a flask that could be magnetically stirred, yet cooled as
needed 3ith an e/ternal ice bath. A total of $(, g of +,K peracetic acid in acetic acid 3as added at a rate such that, 3ith ice cooling, the e/othermic
reaction never raised the internal temperature above $1 deg C. "he reaction developed a deep red color during the $ h needed for the addition. At the
end of the reaction the mi/ture 3as Fuenched by the addition of three volumes of H$9, and the remaining acidity 3as neutrali6ed by the addition of solid
5a$C90 '2,, g 3as reFuired-. "his aFueous phase 3as e/tracted several times 3ith CH$Cl$, and the solvent 3as removed from the pooled e/tracts
under vacuum. "he residue 3as a mi/ture of the intermediate formate ester and the end product phenol. "his 3as suspended in ),, m! (,K 5a9H,
and held on the steam bath for (.& h. After cooling, this 3as 3ashed once 3ith CH$Cl$ 'discarded- and then acidified 3ith HCl. "here 3as the
formation of an intensely hydrated comple/ of the product phenol, reminiscent of the problem encountered 3ith 0@etho/y@+@metho/yphenol. "his 3as
3orked up in three parts. "he entire acidified aFueous phase 3as e/tracted 3ith <t$9 '0/$,, m!- 3hich on evaporation gave ), g of an oil. "he
hydrated glob 3as separately ground up under boiling CH$Cl$ 3hich, on evaporation, gave an additional 0, g of oil, and the aFueous mother liFuor from
the glob 3as e/tracted 3ith $/$,, m! CH$Cl$ 3hich provided, after removal of the solvent, an additional (, g. "hese crude phenol fractions 3ere
combined and distilled at (.& mm8Hg. Bollo3ing a si6eable forerun, a fraction boiling at (&)@(1, deg C 3as the anhydrous product, 0,+@dietho/yphenol.
It 3as a clear, amber oil, and 3eighed 2,., g. "he slightest e/posure to H$9, even moist air, give a solid hydrate, 3ith mp of 10@1+ deg C. "his phenol
can be used for the synthesis of ?<< 'this recipe- or for the preparation of <<< 'see the separate recipe-. A solution of $., g of this phenol in & m!
CH$Cl$ 3as diluted 3ith (& m! he/ane. "his 3as treated 3ith $ g methyl isocyanate follo3ed by a fe3 drops of triethylamine. After about & min, 3hite
crystals formed of 0,+@dietho/yphenyl@5@methyl carbamate, 3ith a mp of %,@%( deg C.
A solution of $1.1 g 0,+@dietho/yphenol in &, m! ?e9H 3as mi/ed 3ith another containing %.1 g 9H pellets dissolved in $,, m! hot ?e9H. "here 3as
then added $(.+ g methyl iodide, and the mi/ture 3as held at reflu/ for $ h on the steam bath. "his 3as then Fuenched in 0 volumes of 3ater, made
strongly basic 3ith $&K 5a9H, and e/tracted 3ith 0/(&, m! CH$Cl$. <vaporation of the solvent from the pooled e/tracts gave (%.0 g of (,$@dietho/y@
+@metho/yben6ene '0,+@dietho/yanisole- as a clear, pale amber oil that solidified 3hen cooled. "he mp 3as $,@$( deg C.
A mi/ture of 0$., g 5@methyl formanilide and 01.$ g P9Cl0 3as allo3ed to stand until it 3as a deep red color 'about ,.& h-. "o this there 3as added
().0 g (,$@dietho/y@+@metho/yben6ene and the e/othermic reaction 3as heated on the steam bath for $.& h. "his 3as then poured over 1,, m!
chipped ice, and the dark oily material slo3ly began lightening in color and te/ture. A light oil 3as formed 3hich, on continued stirring, became
crystalline. After the conversion 3as complete, the solids 3ere removed by filtration producing, after removal of as much H$9 as possible by suction,
$1.% g of crude aldehyde. A small sample pressed on a porous plate had a mp of )2.&@)).& deg C. :ecrystalli6ation of the entire damp crop from &, m!
boiling ?e9H gave, after cooling, filtering, and air drying, (2.2 g of +,&@dietho/y@$@metho/yben6aldehyde as fluffy, off@3hite crystals 3ith a mp of ))@)).&
deg C. A solution of (., g of this aldehyde and ,.& g of malononitrile dissolved in 3arm absolute <t9H 3as treated 3ith 0 drops triethylamine. "here
3as the immediate formation of crystals 3hich 3ere filtered and air dried to constant 3eight. "he product, +,&@dietho/y@$@metho/yben6almalononitrile,
3as a bright yello3 crystalline material, 3hich 3eighed (., g and had a mp of (&1@(&2 deg C.
"o a solution of (+.2 g +,&@dietho/y@$@metho/yben6aldehyde in +1 g glacial acetic acid, there 3as added )., g nitroethane and &., g anhydrous
ammonium acetate. "he mi/ture 3as heated on the steam bath for $ h, becoming progressively deeper red in color. "he addition of a small amount of
H$9 to the hot, clear solution produced a slight turbidity, and all 3as allo3ed to stand overnight at room temperature. "here 3as deposited a crop of
orange crystals that 3as removed by filtration and air dried. "here 3as obtained 2., g (@'+,&@dietho/y@$@metho/yphenyl-@$@nitropropene as brilliant
orange crystals that had a mp of )%@%,.& deg C. "his 3as tightened up, but not improved, by trial recrystalli6ation from acetic acid, mp )%@%, deg C, and
from he/ane, mp %,@%,.& deg C. Anal. 'C(+H(%59&- C,H.
"o a gently reflu/ing suspension of &., g !AH in +,, m! anhydrous <t$9 under a He atmosphere, there 3as added 1.& g (@'+,&@dietho/y@$@
metho/yphenyl-@$@nitropropene by allo3ing the condensing <t$9 to drip into a shunted So/hlet thimble containing the nitrostyrene. "his effectively
added a 3arm saturated solution of the nitrostyrene drop3ise. :eflu/ing 3as maintained for & h, and the reaction mi/ture 3as cooled 3ith an e/ternal
ice bath. "he e/cess hydride 3as destroyed by the cautious addition of +,, m! of (.& 5 H$S9+. Ihen the aFueous and <t$9 layers 3ere finally clear,
they 3ere separated, and (,, g of potassium sodium tartrate 3as dissolved in the aFueous fraction. AFueous 5a9H 3as then added until the pH 3as
U%, and this 3as e/tracted 3ith 0/$,, m! CH$Cl$. :emoval of the solvent under vacuum produced an off@3hite oil that 3as dissolved in anhydrous
<t$9 and saturated 3ith anhydrous HCl gas. "he crystals of +,&@dietho/y@$@metho/yamphetamine hydrochloride '?<<- that formed 3ere very fine and
slo3 to filter, but finally 3ere isolated as a 3hite po3der 3eighing &.+ g and melting at (2).&@(), deg C. Anal. 'C(+H$+Cl590- C,H,5.
;9SAC<E greater than +.1 mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E "here 3ere early trials made 3ith ?<<, before it became kno3n 3hat direction the etho/y substitution results
3ould take. A number of progressive trials, up to a dosage of +.1 milligrams, 3ere 3ithout any central effects at all.
"here is an instinct in structure@activity studies to think of a change as a success or a failure, depending on 3hether there is an increase or a decrease in
the desired activity. .ut if one 3ere to look at the effects of putting an etho/y group onto "?A@$ in place of a metho/y group as a 3ay of decreasing the
effectiveness, then the +@position becomes the 3orst position '?<? is eFuipotent to "?A@$-, and the &@position is perhaps a little less bad '??< is
almost as potent- and the $@position is the best by far '<?? is out of it, potency@3ise-. In other 3ords, in the comparison of the $@ and the &@positions,
the lengthening of the &@position gives modest loss of activity, and the lengthening of the 3hatever in the $@position is the most disruptive. Iith this as a
basis for prediction, then ?<< '3hich differs from ?<? only by a lengthening of the &@position substituent- might be only a little less active than ?<?
and, as ?<? is about the same as "?A@$, it is distinctly possible that ?<< may sho3 activity in the area at dosages that are not much above the $& to
&, milligram area. 9f all the dietho/y homologues, it 3ould be the most promising one to e/plore.
Ihich brings to mind a Fuotation of a hero of mine, ?ark "3ain. :I like science because it gives one such a 3holesome return of conGecture from such
a trifling investment of fact.

#1$$ MEM; $,)-0"METH%+Y-(-ETH%+YAM,HETAM"#E
S>5"H<SISE A solution of )0 g bourbonal 'also called ethyl vanillin, or vanillal, or simply 0@etho/y@+@hydro/yben6aldehyde- in &,, m! ?e9H 3as
treated 3ith a solution of 0(.& g 9H pellets ')&K material- dissolved in $&, m! H$9. "here 3as then added 2( g methyl iodide, and the mi/ture 3as
held under reflu/ conditions for 0 h. All 3as added to 0 volumes of H$9, and this 3as made basic 3ith the addition of $&K 5a9H. "he aFueous phase
3as e/tracted 3ith &/$,, m! CH$Cl$. "he pooling of these e/tracts and removal of the solvent under vacuum gave a residue of )&.& g of the product 0@
etho/y@+@metho/yben6aldehyde, 3ith a mp of &$@&0 deg C. Ihen this product 3as recrystalli6ed from he/ane, its mp 3as +%@&, deg C. Ihen the
reaction 3as run 3ith the same reactants in a reasonably anhydrous environment, 3ith methanolic 9H, the maGor product 3as the acetal, 0@etho/y@
a,a,+@trimetho/ytoluene. "his 3as a 3hite glistening product 3hich crystalli6ed readily from he/ane, and had a mp of ++@+& deg C. Acid hydrolysis
converted it to the correct aldehyde above. "he addition of sufficient H$9 in the methylation completely circumvents this by@product. A solution of (., g
of this aldehyde and ,.2 g malononitrile in $, m! 3arm absolute <t9H, 3hen treated 3ith a fe3 drops of triethylamine, gave immediate yello3 color
follo3ed, in a fe3 min by the formation of crystals. Biltration, and 3ashing 3ith <t9H, gave bright yello3 crystals of 0@etho/y@+@
metho/yben6almalononitrile 3ith a mp of (+(@(+$ deg C.
A 3ell stirred solution of ($&.+ g 0@etho/y@+@metho/yben6aldehyde in ++& m! acetic acid 3as treated 3ith (&) g +,K peracetic acid 'in acetic acid- at a
rate at 3hich, 3ith ice cooling, the internal temperature did not e/ceed $2 deg C. "he addition reFuired about +& min. "he reaction mi/ture 3as then
Fuenched in some 0 ! H$9. "here 3as the generation of some crystals 3hich 3ere removed by filtration. "he mother liFuor 3as saved. "he solid
material 3eighed, 3hile still 3et, 2, g and 3as crude formate ester. A small Fuantity 3as recrystalli6ed from cyclohe/ane t3ice, to provide a reference
sample of 0@etho/y@+@metho/yphenyl formate 3ith a mp of 10@1+ deg C. "he bulk of this crude formate ester 3as dissolved in $,, m! concentrated HCl
3hich gave a deep purple solution. "his 3as Fuenched 3ith 3ater 3hich precipitated a fluffy tan solid, 3hich 3as hydrated phenolic product that
3eighed about 0& g, and melted in the ),@%, deg C. range. "he mother liFuors of the above filtration 3ere neutrali6ed 3ith 5a$C90, then e/tracted 3ith
0/(,, ml <t$9. :emoval of the solvent gave a residue of about ), g that 3as impure formate 'containing some uno/idi6ed aldehyde-. "o this there
3as added &,, m! (,K 5a9H, and the dark mi/ture heated on the steam bath for several h. After cooling, the strongly basic solution 3as 3ashed 3ith
CH$Cl$, and then treated 3ith $,, m! <t$9, 3hich knocked out a heavy semi@solid mass that 3as substantially insoluble in either phase. "his 3as,
again, the crude hydrated phenol. "he <t$9 phase, on evaporation, gave a third crop of solids. "hese could actually be recrystalli6ed from ?e9H8H$9,
but the mp al3ays remained broad. Ihen subGected to distillation conditions, the H$9 3as finally driven out of the hydrate, and the product 0@etho/y@+@
metho/yphenol distilled as a clear oil at (),@(%, deg C at ,.) mm8Hg. "his product, +&.( g, gave a fine 5?: spectrum, and in dilute CCl+ sho3ed a
single 9H band at 01$, cm@(, supporting the freedom of the 9H group on the aromatic ring from adGacent o/ygen. <fforts to obtain an 5?: spectrum in
;$9 immediately formed an insoluble hydrate. "his phenol can serve as the starting material for either ?<? 'see belo3- or <<? 'see separate recipe-.
"o a solution of ($.0 g 0@etho/y@+@metho/yphenol in $, m! ?e9H, there 3as added a solution of +.) g flaked 9H in (,, m! heated ?e9H. "o this
clear solution there 3as then added (,.2 g methyl iodide, and the mi/ture held at reflu/ on the steam bath for $ h. "his 3as then Fuenched in 0 volumes
H$9, made strongly basic 3ith (,K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent from the pooled e/tracts under vacuum gave
%.+ g of an amber oil 3hich spontaneously crystalli6ed. "he mp of (,+@dimetho/y@$@etho/yben6ene 3as +$@+0.& deg C, and 3as used, 3ith no further
purification, in the follo3ing step.
A mi/ture of (2.0 g 5@methylformanilide and (%.1 g P9Cl0 3as allo3ed to stand for ,.& h, producing a deep claret color. "o this there 3as added %.$ g
(,+@dimetho/y@$@etho/yben6ene, and the mi/ture 3as held on the steam bath for $ h. It 3as then poured into chipped ice and, 3ith mechanical stirring,
the dark oily phase slo3ly became increasingly crystalline. "his 3as finally removed by filtration, providing a bro3n solid mat 3hich sho3ed a mp of
(,0.&@(,1.& deg C. All 3as dissolved in 2& m! boiling ?e9H 3hich, on cooling, deposited fine crystals of $,&@dimetho/y@+@etho/yben6aldehyde that
3ere colored a light tan and 3hich, after air drying to constant 3eight, 3eighed ).& g and had a mp of (,)@(,%.& deg C. Search 3as made by gas
chromatography for evidence of the other t3o theoretically possible positional isomers, but none could be found. "he 5?: spectrum sho3ed the t3o
para@protons as clean singlets, 3ith no noise suggesting other isomers. "here 3as a single peak by CC 'for the recrystalli6ed product- but the mother
liFuors sho3ed a contamination that proved to be 5@methylformanilide. A ,.0 g sample, along 3ith ,.0 g malononitrile, 3as dissolved in (, m! 3arm
absolute <t9H, and treated 3ith a drop of triethylamine. "here 3as the immediate formation of a yello3 color follo3ed, in ( min, by the deposition of fine
yello3 needles. Biltering and air drying gave ,.$& g of $,&@dimetho/y@+@etho/yben6almalononitrile, 3ith a mp of (2(@(2$ deg C.
A solution of 2.0 g $,&@dimetho/y@+@etho/yben6aldehyde in $& g glacial acetic acid 3as treated 3ith 0.1 g nitroethane and $.$& g anhydrous ammonium
acetate, and heated on the steam bath. After t3o h, the clear solution 3as diluted 3ith an eFual volume of H$9, and cooled in an ice bucket. "here 3as
the formation of a heavy crop of orange crystals 3hich 3ere removed by filtration. "he dry 3eight of (@'$,&@dimetho/y@+@etho/yphenyl-@$@nitropropene
3as +.) g and the mp 3as ($,@($+ deg C. :ecrystalli6ation of an analytical sample from ?e9H gave a mp of ($)@($% deg C. Anal. 'C(0H(259&- C,H.
"o a gently reflu/ing suspension of 0.0 g !AH in +,, m! anhydrous <t$9 under a He atmosphere, there 3as added +.0 g (@'$,&@dimetho/y@+@etho/y-@$@
nitropropene by allo3ing the condensing <t$9 to drip into a shunted So/hlet thimble apparatus containing the nitrostyrene, thus effectively adding a
3arm saturated ether solution of it to the hydride mi/ture. "he addition took $ h. :eflu/ing 3as maintained for & h, and then the reaction mi/ture 3as
cooled to , deg C 3ith an e/ternal ice bath. "he e/cess hydride 3as destroyed by the cautious addition of 0,, m! of (.& 5 H$S9+. Ihen the aFueous
and <t$9 layers 3ere finally clear, they 3ere separated, and (,, g of potassium sodium tartrate 3as dissolved in the aFueous fraction. AFueous 5a9H
3as then added until the pH 3as U%, and this 3as then e/tracted 3ith 0/(,, m! CH$Cl$. <vaporation of the solvent from the pooled e/tracts produced
an almost 3hite oil that 3as dissolved in (,, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas. "here 3as deposited a 3hite crystalline solid
of $,&@dimetho/y@+@etho/yamphetamine hydrochloride '?<?- 3hich 3eighed 0.( g and had a mp of (2(@(2$.& deg C. Anal. 'C(0H$$Cl590- C,H,5.
;9SAC<E $, @ &, mg.
;4:A"I95E (, @ (+ h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- I e/perienced some physical discomfort, but doesn7t that tell us about the 3ork to be done, rather than the
property of the materialH "he breakthrough I had 3as the follo3ing day 'and this seems to be the 3ay ?<? operates, i.e., first the energy and
e/pansion, ne/t day insight- 3as of the highest value and importance for me. I 3as given a methodology for dealing 3ith my shado3 parts. 5o small
gift. And I did it all alone and the results 3ere immediate. I am so grateful.
'3ith $, mg, at (.& h follo3ing ($, mg ?;?A- :"he transition 3as very smooth, 3ith no obvious loss of the ?;?A e/perience. I felt less of a need to
talk, but the intimate closeness 3ith the others 3as maintained. "he e/perience continues to gro3 more profound and euphoric and I prayed, in the
latter part of the afternoon, that it 3ouldn7t stop. It continued until midnight 3ith marvelous feelings, good energy, and much hilarity. And it abated very
little over the ne/t several days leaving me 3ith the feeling of lasting change 3ith important insights still coming to mind one 3eek later.
'3ith $& mg, at $ h follo3ing ($, mg ?;?A- :I found that sounds in general 3ere distracting. 5o, they 3ere out@and@out annoying. I may have been in
an introspective mood, but I really 3anted to be alone. 5o body problems at all. Belt good. I developed some color changes and some pattern
movement. 5ot much, but then I didn7t e/plore it much. "he 3ine party after3ards 3as certainly most pleasant. "he soup 3as a great pleasure. And
that hard bread 3as good. "he material 3as clearly not anore/ic, or at least I overcame 3hatever anore/ia there might have been.
'3ith 0, mg- I 3as a3are of this in thirty minutes and it slo3ly developed from there to an almost *** in the follo3ing hour. "here 3ere visual
phenomena, 3ith some color enhancement and especially a considerable enhancement of brights and darks. "he first signs of decline 3ere at about si/
hours, but there 3as something still 3orking there after another si/ hours had passed. A slo3 decline, certainly.
'3ith &, mg- I came into the e/perience kno3ing that yesterday had been a very fatiguing and tense day. I felt this material 3ithin the first ten minutes
3hich is the fastest that I have ever felt anything. "he ascent 3as rapid and for the first hour I tended to an in3ard fantasying 3ith a distinct sensual
tinge. "here 3as a persistent Fueasiness that never left me, and it contrasted oddly 3ith a good feeling of out3ard articulation and lucidity 3hich
succeeded in coming to the fore after the introverted first hour. Sleep 3as difficult, but the ne/t day 3as calm and clear.
'3ith &, mg- !ots of energy, best directed into activity. Clear imaging, thinking. Intense yet serene. Cood feeling of pleasantness and some euphoria. I
felt the need to keep moving. Hard to stay still.
'3ith 2, mg, in t3o parts- :"he effects of the +, milligrams 3ere muted by another drug e/periment yesterday morning, and I never got much over a
plus (. "here is an erotic nature, tactile sensitivity perhaps not as delicate as 3ith $C@., but it is there. At the $ hour point, an additional 0, milligrams
increased the body impact 'a distinct tremor and sensitivity- but someho3 not a lot more mental. I have been compromised by yesterday.
<="<5SI95S A5; C9??<5"A:>E ?<? 3as both a valuable and dramatic compound, as 3ell as a drug that played a 3atershed role. "he
completion of all the possible trimetho/yamphetamines 'the "?A7s- sho3ed that only t3o of them combined the values of dependability of positive
psychedelic effects 3ith a reasonably high potency. .oth "?A@$ and "?A@1 are treasures, both active in similar dosages, and both offer metho/yl
groups that are begging to be replaced by other things. "he first focus 3as on "?A@$, partly because the needed synthetic chemistry 3as better kno3n,
and partly because I had discovered its activity earlier. .ut there 3ere three entirely different and distinct metho/yl groups to 3ork on, in "?A@$. "here
is one at the $@position, one at the +@position, and one at the &@position. "he most obvious thing to do, it seemed, 3as to make each of them one carbon
longer. :eplace a metho/y 3ith an etho/y. And a logical naming pattern could follo3 the use of ? for metho/y, and < for etho/y, in seFuence right
around the ring from the $@ to the +@ to the &@positions. "he first group to be compared, then, 3ould be <??, ?<?, and ??<. And of these three, it
3as only ?<? that 3as right up there in drama and in potency. .ut, by the time that became apparent, I had already completed the dietho/y
possibilities '<<?, <?<, and ?<<- as 3ell as the trietho/y homologue, <<<. Iith the discovery that the +@position 3as the magic leverage point, and
that the homologues at positions $@ and &@ 3ere clearly less interesting, all emphasis 3as directed at this target, and this has led to the many +@
substituted families that are no3 kno3n to be highly potent and felt by many to be personally valuable.
Ihy put such emphasis on potency, I am freFuently askedH Ihy should it matter ho3 much of a compound you take, as long as the effective level is
much lo3er than its to/ic levelH Iell, in a sense, that is the very reason. "here are no guides as to 3hat the to/ic levels of any of these many
compounds might really be in man. "here is simply no 3ay of determining this. 9nly a fe3 have been e/plored in animals in the pursuit of an !;@&,
level. ?ost of them are similar to one@another, in that they are, in mice, of relatively lo3 to/icity and, in rat, of relatively high to/icity. .ut this to/icity
appears not to be related to potency in man. So, if one might e/trapolate that they are of more or less the same risk to man 'from the to/ic point of vie3-
then the lo3er the dosage, the greater the safety. ?aybe. In the absence of anything factual, it makes a reasonable operating hypothesis.
?any of the reports of ?<? effects have been 3ith e/periments in 3hich an effective dose of ?;?A had been taken shortly earlier. "here has
developed a concept, embraced by a number of researchers, that the ease and Fuietness usually seen 3ith the development of the ?;?A e/perience
can mitigate some of the physically disturbing symptoms sometimes seen 3ith other psychedelics. "his may be partly due to a familiar entry into a
altered place, and partly due to a lessening of dosage usually reFuired for full effects. ?<? seems to have had more trials using this combination than
many of the other psychedelic drugs.

#1$' ME,EA; '-METH%+Y-(-ETH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of (,., g 0@metho/y@+@etho/yben6aldehyde in (&, m! nitromethane 3as treated 3ith (.2 g anhydrous ammonium acetate, and
heated on the steam bath for ( h. "he e/cess nitromethane 3as removed under vacuum, yielding a loose, yello3 crystalline mass that 3as filtered and
modestly 3ashed 3ith cold ?e9H. "he )., g of damp yello3 crystals thus obtained 3ere dissolved in &, m! of vigorously boiling CH0C5, decanted
from a small amount of insolubles 'probably ammonium acetate residues- and cooled in an ice bath. "he crystals so obtained 3ere removed by
filtration, 3ashed 3ith $/& m! cold CH0C5, and air dried to constant 3eight. "he yield of +@etho/y@0@metho/y@beta@nitrostyrene 3as 1.0 g of beautiful
yello3 crystals.
A solution of $.0 g !AH in 2, m! anhydrous "HB 3as cooled, under He to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added $.0 m!
(,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of 1.$ g 0@etho/y@+@metho/y@beta@nitrostyrene in anhydrous "HB. After
a fe3 min further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath, and then all 3as cooled again to , deg C. "he e/cess
hydride 3as destroyed by the cautious addition of IPA follo3ed by sufficent (,K 5a9H to give a 3hite granular character to the o/ides, and to assure
that the reaction mi/ture 3as basic. "he reaction mi/ture 3as filtered and the filter cake 3ell 3ashed 3ith "HB. "he filtrate and 3ashes 3ere combined
and stripped of solvent under vacuum. "he residue 3as dissolved in dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$, 3hich removed the
residual yello3 color. "he remaining aFueous phase 3as made basic 3ith 5a9H, and e/tracted 3ith 0/2& m! CH$Cl$. "hese e/tracts 3ere combined
and the solvent removed under vacuum. "he residue 3as distilled at (,)@((& deg C at ,.+ mm8Hg to give +.$ g of a mobile, colorless liFuid. "his 3as
dissolved in ($ m! IPA, neutrali6ed 3ith 1, drops concentrated HCl, and diluted 3ith (,, m! anhydrous <t$9. "here 3as deposited a fine 3hite
crystalline product 3hich, after removal by filtration, ether 3ashing, and air drying, yielded 0.) g of 0@metho/y@+@etho/yphenethylamine hydrochloride
'?<P<A-.
;9SAC<E 0,, mg or greater.
;4:A"I95E short.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- I am at perhaps a *(, a very slight effect of lightness, 3ithout any body a3areness at all. And then in
another hour, I 3as completely baseline again.
'3ith 0,, mg- Ihatever changes took place 3ere complete at the end of an hour. "he effects 3ere very Fuiet, very pleasant, and very light. "here 3as
nothing psychedelic here, but rather a gentle lifting of spirits. 5o sensory enhancement or other e/pected changes.
<="<5SI95S A5; C9??<5"A:>E "his is one of the very fe3 phenethylamines 3ith only t3o substituents that sho3s even a hint of central activity.
And there is an interesting story attached. I got a call out of absolutely no3here, from a Stanislov Iistupkin, that he had discovered a number of ne3
psychedelic drugs 3hich he 3ould like to share 3ith me. "3o of them 3ere simple phenethylamines, one 3ith an etho/y group at the +@position, and
one 3ith an allylo/y group there. .oth, he said, 3ere mood elevators active bet3een (,, and 0,, milligrams. 9ne of them 3as this material, here
called ?<P<A, and the other one 3as 0@metho/y@+@allylo/yphenethylamine, or ?AP<A. Ihen I did meet him in person, he gave me a most remarkable
publication 3hich had been authored some ten years earlier, by a person named !eminger, no3 dead. It 3as all in C6ech, but Fuite unmistakably, right
there on the third page, 3ere the structures of ?<P<A and ?AP<A, and the statement that they 3ere active at bet3een (,, and 0,, milligrams. I have
not yet made the allylo/y compound, but I feel that it too might be a gentle mood elevator similar to the etho/y.
A most appealing e/tension of these materials 3ould be the amphetamine derivatives, things 3ith a 0@metho/y group, and something small and terse on
the +@position. "he immediate analogies of ?<P<A and ?AP<A 3ould be 0@metho/y@+@etho/y@ 'and 0@metho/y@+@allylo/y-@amphetamine. And eFually
interesting 3ould be the +@hydro/y analogue. "his 3ould be an easily made compound from vanillin, one of our most enGoyable spices in the kitchen
cabinet, and it 3ould be directly related to the essential oils, eugenol and isoeugenol. "his amphetamine compound has already been synthesi6ed, but it
is still une/plored in man.
Some years ago a report appeared in the forensic literature of Italy, of the sei6ure of a small semitransparent capsule containing (+( milligrams of a
3hite po3der that 3as stated to be a ne3 hallucinogenic drug. "his 3as sho3n to contain an analogue of ;9?, 0@metho/y@+@methylamphetamine, or
??A. "he Italian authorities made no mention of the net 3eight contained in each dosage unit, but it has been found that the active level of ??A in
man is in the area of +,@1, milligrams. "he compound can apparently be Fuite dysphoric, and long lived.
In the C6echoslovakian publication that presented ?<P<A and ?AP<A. there 3ere descriptions of escaline '<-, proscaline 'P-, and the allylo/y
analogue 'A!-. "hese are all active in man, and have been entered else3here. "his is the only published material dealing 3ith psychedelic drugs I have
ever been able to find, from the laboratory of 9takar !eminger. Ihat sort of man 3as this chemistH He 3orked for years in industry, and only at the
time of his retirement did he publish this little gem. He lived at 4sti, directly north of Praha, on the !abe river '3hich is called by the better kno3n name,
the <lbe, as soon as it enters Cermany-. ?ight there be other treasures that he had discovered, and never publishedH Ias young Iistupkin a student
of hisH Are there unrecogni6ed notes of 9takar !eminger sitting in some farm house attic in 5orthern C6echoslovakiaH I e/tend my heartfelt salute to
an almost unkno3n e/plorer in the psychedelic drug area.

#1$( META-0%.; )-.*%M%-$,(-0"METH%+YAM,HETAM"#E
S>5"H<SISE "he reaction of $,+@dimetho/yamphetamine '$,+@;?A- 3ith elemental bromine proceeded directly to the formation of &@bromo@$,+@
dimetho/yamphetamine 3hich 3as isolated as the hydrobromide salt 3ith a melting point of $,+.&@$,&.& deg C and in a 12K yield. A mp of (),@()(
deg C has also been published.
;9SAC<E &, @ (,, mg.
;4:A"I95E & @ 1 h.
<="<5SI95S A5; C9??<5"A:>E "here is very little synthetic information available, and some of it is contradictory. "he initial human report in the
medical literature says only that a dosage of about (,, milligrams produced effects that 3ere similar to those produced by ?;A. .oth the Fuality of the
e/perience and the potency of the compound have been modified in more recent publications by the originators of this compound. A +, milligram dose,
after an induction period of an hour, produced a vague uneasiness that 3as interpreted originally as a threshold psychedelic effect. At doses in the 1, to
%, milligram range, there 3ere produced feelings of an/iety and paranoid fantasies, and distinct to/ic signs such as flushing, palpitations, and occasional
nausea, vomiting and diarrhea. Any psychedelic effects seem to have been blurred by the more obvious to/ic actions of the drug. I have been told that
their final conclusion 3as that the drug appears to/ic in the &, to 1, milligram range. I have not personally e/plored this positional isomer of ;9..
"he positional isomer of ;9. 3ith the bromine in the ortho@position is +,&@dimetho/y@$@bromoamphetamine and is called, not surprisingly, 9:"H9@;9..
It has been made by the condensation of $@bromo@+,&@dimetho/yben6aldehyde 3ith nitroethane to give (@'$@bromo@+,&@dimetho/yphenyl-@$@nitropropene
3ith a mp of (,&@(,1 deg C. :eduction to the amphetamine had to be conducted at a lo3 temperature and using only an eFuimolar amount of lithium
aluminum hydride, to minimi6e reductive removal of the bromo group. "he hydrochloride salt of $@bromo@+,&@dimetho/yamphetamine '9:"H9@;9.-
had a mp of $(+@$(&.& deg C, and the hydrobromide salt a melting point of (%1@(%2 deg C or of $(, deg C. .oth have been reported. "he yield from
the direct bromination of 0,+@;?A 3as apparently very bad. I do not think that the compound has ever gone into man.
"here are three other dimetho/yamphetamine isomers kno3n, and each has been e/plored chemically as to its reactivity 3ith elemental bromine. Iith
$,0@;?A, a mi/ture of the &@.r@$,0@;?A and 1@.r@$,0@;?A 3as formed; 3ith $,1@;?A, 0@.r@$,1@;?A 3as formed; and 3ith 0,&@;?A, a mi/ture of $@.r@
0,&@;?A and the $,1@dibromo product 3as produced. "he bromination of $,&@;?A is, of course, the preferred procedure for the synthesis of +@.r@$,&@
;?A, or ;9., F.v. 5one of these positional isomers has evear been put into man, but 0@.r@$,1@;?A and the iodo@counterpart have been e/plored as
potential radio@fluorine carriers into the brain. "his is all discussed in the 0,+@;?A recipe.

#1$) META-0%T; $,(-0"METH%+Y-)-METHYTH"%AM,HETAM"#E
S>5"H<SISE "o $2 g (,0@dimetho/yben6ene that 3as being 3ell stirred, there 3as added, drop3ise, $% g concentrated H$S9+ over a period of (& min.
Stirring 3as continued for ( hour, and then the mi/ture 3as poured slo3ly into $&, m! of saturated aFueous $C90. "he precipitate that formed 3as
removed by filtration, and dried at ($& deg C to give &%.1 g crude potassium $,+@dimetho/yben6enesulfonate. "his 3as finely ground, and 0, g of it 3as
treated 3ith 0& g of P9Cl0 and the mi/ture heated on the steam bath for $ h. "his 3as cooled to room temperature, and then poured over 0,, m!
crushed ice. Ihen all had tha3ed, this 3as e/tracted 3ith $/(&, m! <t$9. "he e/tracts 3ere pooled, 3ashed 3ith saturated brine, and the solvent
removed under vacuum to give a residue 3hich solidified. "here 3as thus obtained (+.$ g $,+@dimetho/yben6enesulfonyl chloride as 3hite solids 3ith a
mp of 1%@2$ deg C. Heating of a small portion 3ith concentrated ammonium hydro/ide gave the corresponding sulfonamide 3hich, on recrystalli6ation
from <t9H, produced 3hite needles 3ith a mp of (1&.&@(11.& deg C.
"o a stirred and gently reflu/ing suspension of (( g !AH in 2&, m! anhydrous <t$9, there 3as added (0.$ g $,+@dimetho/yben6enesulfonyl chloride in
an <t$9 solution. "he reflu/ing 3as maintained for +) h then, after cooling e/ternally 3ith ice 3ater, the e/cess hydride 3as destroyed by the slo3
addition of 1,, m! of (,K H$S9+. "he phases 3ere separated, and the aFueous phase e/tracted 3ith $/$,, <t$9. "he organics 3ere pooled,
3ashed once 3ith $,, m! H$9, and the solvent removed under vacuum. "he residue 3as dried a6eotropically through the addition and subseFuent
removal of CH$Cl$. ;istillation of the residue provided )., g $,+@dimetho/ythiophenol as a colorless oil, boiling at )%@%$ deg C at ,.& mm8Hg.
"o a solution of 2.) g $,+@dimetho/ythiophenol in +, m! absolute <t9H there 3as added a solution of + g )&K 9H in 1& m! <t9H. "his 3as follo3ed
by the addition of & m! methyl iodide, and the mi/ture 3as held at reflu/ for 0, min. "his 3as poured into $,, m! H$9, and e/tracted 3ith 0/&, m!
<t$9. "he pooled e/tracts 3ere 3ashed once 3ith aFueous sodium hydrosulfite, then the organic solvent 3as removed under vacuum. "he residue
3as distilled to give )., g of $,+@dimetho/ythioanisole as a colorless oil 3ith a bp of (,,@(,0 deg C at ,.1 mm8Hg.
"o a mi/ture of (& g P9Cl0 and (+ g 5@methylformanilide that had been 3armed briefly on the steam bath there 3as added 2.) g of $,+@
dimetho/ythioanisole. "he reaction 3as heated on the steam bath for an additional $, min and then poured into $,, m! H$9. Stirring 3as continued
until the insolubles had become completely loose and granular. "hese 3ere removed by filtration, 3ashed 3ith H$9, sucked as dry as possible, and
then recrystalli6ed from boiling ?e9H. "he product, $,+@dimetho/y@&@'methylthio-ben6aldehyde, 3as an off@3hite solid 3eighing ).1 g. It could be
obtained in either of t3o polymorphic forms, depending on the concentration of aldehyde in ?e9H at the time of crystal appearance. 9ne melted at
(,%@((, deg C and had a fingerprint I: spectrum including peaks at 1%(, 20+, )(% and %%+ cm@(. "he other melted at ($+.&@($&.& deg C and had maGor
fingerprint peaks at 1%+, 20(, )0% and )%2 cm@(. Anal. 'C(,H($90S- C,H.
A solution of ).$ g $,+@dimetho/y@&@'methylthio-ben6aldehyde in 0, m! nitroethane 3as treated 3ith (.) g anhydrous ammonium acetate and heated on
the steam bath for + h. :emoval of the e/cess nitroethane under vacuum gave a colored residue 3hich crystalli6ed 3hen diluted 3ith ?e9H.
:ecrystalli6ation of the crude product from boiling <t9H gave, after filtration, 3ashing and air drying to constant 3eight, ).0 g (@'$,+@dimetho/y@&@
methylthiophenyl-@$@nitropropene 3ith a mp of (($@((0 deg C. Anal. 'C($H(&59+S- C,H,5.
A suspension of 1.& g !AH in $&, m! anhydrous "HB 3as placed under a 5$ atmosphere and stirred magnetically and brought to reflu/. "here 3as
added, drop3ise, )., g of (@'$,+@dimetho/y@&@methylthiophenyl-@$@nitropropene in &, m! "HB. "he reaction mi/ture 3as maintained at reflu/ for () h.
After being brought to room temperature, the e/cess hydride 3as destroyed by the addition of 1.& m! H$9 in 0, m! "HB. "here 3as then added 1.& m!
of 05 5a9H, follo3ed by an additional $, m! H$9. "he loose, 3hite, inorganic salts 3ere removed by filtration, and the filter cake 3ashed 3ith an
additional &, m! "HB. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum yielding a residue that 3as distilled. "he free base
boiled at ($&@($) deg C at ,.( mm8Hg and 3as a 3hite oil 3hich solidified on standing. It 3eighed &.( g and had a mp of +2@+).& deg C. "his 3as
dissolved in &, m! IPA, neutrali6ed 3ith concentrated HCl 'until dampened universal pH paper sho3ed a deep red color- and diluted 3ith anhydrous
<t$9 to the point of turbidity. "here 3as a spontaneous crystalli6ation providing, after filtering, 3ashing 3ith <t$9, and air drying, $,+@dimetho/y@&@
methylthioamphetamine hydrochloride '?<"A@;9"- 3ith a mp of (+,.&@(+$ deg C. Anal. 'C($H$,Cl59$S- C,H,5.
;9SAC<E greater than 0& mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith 0& mg- "here 3as a vague a3areness of something all afternoon, something that might be called a thinness. Possibly
some brief cardiovascular stimulation, but nothing completely believable. "his is a threshold level at the very most.
<="<5SI95S A5; C9??<5"A:>E Again, as 3ith the studies 3ith 9:"H9@;9", it is apparent that the activity of ?<"A@;9" is going to be 3ay do3n
from the most interesting of these isomers, PA:A@;9" 'A!<PH@(, or Gust A!<PH-. In the rectal hyperthermia assay '3hich calculates the psychedelic
potential of compounds by seeing ho3 they influence the body temperature of e/perimental animals in comparison to kno3n psychedelics- the three
;9"7s 3ere compared 3ith ;9?. And the results fell into line in keeping 3ith the activities 'or loss of activities- found in man. PA:A@;9" 3as about
half as active as ;9?, but both 9:"H9@;9" and the compound described here, ?<"A@;9", 3ere do3n by factors of &,/ and 0,/ respectively. "hese
animal studies certainly seem to give results that are reasonable 3ith a vie3 to other kno3n psychedelic drugs, in that mescaline 3as do3n from ;9?
by a factor of more than (,,,/, and !S; 3as some 00/ more potent than ;9?.
I have a some3hat Gaundiced vie3 of this rabbit rectal hyperthermia business. 9ne is presumably able to tell 3hether a compound is a stimulant or a
psychedelic drug by the profile of the temperature rise, and ho3 potent it 3ill be by the e/tent of the temperature rise. .ut the concept of pushing
thermocouples into the rear ends of restrained rabbits someho3 does not appeal to me. I 3ould rather determine both of these parameters from human
studies.
#1$1 METHY-0MA; 0MMA; $,)-0"METH%+Y-#-METHYAM,HETAM"#E
S>5"H<SISE "o a stirred solution of $).1 g methylamine hydrochloride in ($, m! ?e9H there 3as added 2.) g $,&@dimetho/yphenylacetone follo3ed
by $.1 g sodium cyanoborohydride. HC! 3as added as needed to maintain the pH at about 1. "he reaction 3as complete in $+ h, but 3as allo3ed to
stir for another 0 days. "he reaction mi/ture 3as poured into 1,, m! H$9, acidified 3ith HCl 'HC5 evolution, caution- and 3ashed 3ith 0/(,, m!
CH$Cl$. AFueous 5a9H 3as added, making the solution strongly alkaline, and this 3as then e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent
from the pooled e/tracts under vacuum gave ).0 g of a clear, off@3hite oil that distilled at %&@(,& deg C. at ,.$& mm8Hg. "he 1.& g of colorless distillate
3as dissolved in $& m! IPA, neutrali6ed 3ith concentrated HCl, and then diluted 3ith anhydrous <t$9 to the point of cloudiness. As crystals formed,
additional <t$9 3as added in small increments, allo3ing clearing crystalli6ation bet3een each addition. In all, $,, m! <t$9 3as used. After
filtering,<t$9 3ashing, and air drying, there 3as obtained 1.$ g of $,&@dimetho/y@5@methylamphetamine hydrochloride '?<"H>!@;?A- as fine 3hite
crystals 3ith a mp of ((2@(() deg C. "he mi/ed mp 3ith $,&@;?A '((+@((1 deg C- 3as depressed to %1@(,& deg C. An alternate synthesis gave the
same overall yield of an identical product, but started 3ith $,&@;?A. It reFuired t3o synthetic steps. "he free base amine 3as converted to the
crystalline formamide 3ith formic acid in ben6ene using a ;ean Stark trap, and this intermediate 3as reduced to ?<"H>!@?;A 3ith !AH.
;9SAC<E above $&, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $&, mg- "here is a slight paresthesia at about +& minutes, an a3areness on the surface of the skin as if I had been
touched by a cold draft of air. .ut nothing more. At three hours, I am completely out, if I 3as ever in. In the evening I assayed ($, milligrams of ?;?A,
and it barely produced a threshold effect, so the t3o materials might be seeing one another.
<="<5SI95S A5; C9??<5"A:>E "his is a difficult compound to pin do3n in the anthology of drugs. Bor some reason it has intrigued several
independent, Fuiet researchers, and I have accumulated a number of interesting reports over the years. 9ne person told me that he had felt nothing at
up to 1, milligrams. Another had found a threshold at &, milligrams, and had complete and thorough e/periences at both (&, and $,, milligrams. >et
another person described t3o incidents involving separate individuals, 3ith intravenous administrations of ,.$ mg8g, 3hich 3ould be maybe (& or $,
milligrams. .oth claimed a real a3areness in a matter of minutes, one 3ith a tingling in the genitalia and the other 3ith a strange presence in the spine.
.oth subGects reported increases in body temperature and in blood pressure. Apparently the effects 3ere felt to persist for many hours.
"here is an interesting, and potentially informative, convergence of the metabolite of one drug 3ith the structure of another. 4nder +@?A, mention 3as
made of a bronchodilator that has been 3idely used in the treatment of asthma and other allergenic conditions. "his compound, $@metho/y@5@
methylamphetamine is kno3n by the generic name of metho/yphenamine, and a variety of trade names 3ith 9rtho/ine '4pGohn- being the best kno3n.
"he typical dosage of metho/yphenamine is perhaps (,, milligrams, and it may be used several times a day. It apparently produces no changes in
blood pressure and only a slight cardiac stimulation. And one of the maGor metabolites of it in man is the analogue 3ith a hydro/yl group at the &@
position of the molecule. "his phenolic amine, &@hydro/y@$@metho/y@5@methylamphetamine is Gust a methyl group a3ay from ?<"H>!@;?A; it could
either be methylated to complete the synthesis, or ?<"H>!@;?A could be demethylated to form this phenol. "here is plentiful precedent for both of
these reactions occuring in the body. It is al3ays intriguing 3hen drugs 3hich sho3 distinctly different actions can, in principle, intersect metabolically at
a single structure. 9ne 3onders Gust 3hat the pharmacology of that common intermediate might be.
"hree additional 5@methylated homologues of kno3n psychedelics 3arrant mention, but do not really deserve separate recipes. "his is because they
have had only the most cursory assaying, 3hich I have learned about by personal correspondence. All three 3ere synthesi6ed by the reduction of the
formamide of the parent primary amine 3ith !AH. ?<"H>!@"?A 'or 5@methyl@0,+,&@trimetho/yamphetamine- had been run up in several trials to a
ma/imum of $+, milligrams, 3ith some mental disturbances mentioned only at this highest level. ?<"H>!@"?A@$ 'or 5@methyl@$,+,&@
trimetho/yamphetamine- had been tried at up to ($, milligrams 3ithout any effects. ?<"H>!@"?A@1 'or 5@methyl@$,+,1@ trimetho/yamphetamine- had
been tried at up to 0, milligrams and it, too, 3as apparently 3ithout effects. "hese are reports that I have heard from others, but I have had no personal
e/perience 3ith them. "hose that I can describe from personal e/perience are entered separately as recipes of their o3n. And there are many, many
other 5@methyl homologues 3hich have been prepared and characteri6ed in the literature, and have yet to be tasted. So far, ho3ever, the only
consistent thing seen is that, 3ith 5@methylation, the potency of the psychedelics is decreased, but the potency of the stimulants appears to be pretty
much maintained.

#1$2 METHY-0%.; (-.*%M%-$,)-0"METH%+Y-#-METHYAM,HETAM"#E
S>5"H<SISE "o a solution of 1., g of the free base of $,&@dimetho/y@5@methyl@amphetamine 'see recipe under ?<"H>!@;?A- in 0, m! glacial acetic
acid there 3as added, drop3ise and 3ith good stirring, a solution of &.& g bromine in (& m! acetic acid. "he reaction became Fuite 3arm, and turned
very dark. After stirring an additional +& min, the mi/ture 3as poured into $,, m! H$9 and treated 3ith a little sodium hydrosulfite 3hich lightened the
color of the reaction. "here 3as added $, m! concentrated HCl, and the reaction mi/ture 3as 3ashed 3ith $/(,, m! CH$Cl$ 3hich removed most of
the color. "he aFueous. phase 3as made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. "he removal of the solvent from the pooled
e/tracts under vacuum gave (.) g of an oil 3hich 3as dissolved in (, m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith (,, m! anhydrous
<t$9. 5o crystals 3ere obtained, but rather an oily and some3hat granular insoluble lo3er phase. "he <t$9 3as decanted, and the residue 3ashed by
grinding up under 0/(,, m! <t$9. "he original decanted material 3as combined 3ith the three 3ashes, and allo3ed to stand for several h. "he
product +@bromo@$,&@dimetho/y@5@methylamphetamine hydrochloride '?<"H>!@;9.- separated as fine 3hite crystals 3hich 3eighed, after filtering and
air drying, ,.0 g and had a mp of (+%@(&, deg C. "he <t$9@insoluble residue finally set up to a pale pink mass 3hich 3as finely ground under a fe3 m!
acetone. Biltration and air drying gave a second crop of product as ,.% g of pale lavender solids, 3ith a mp of (+0@(+& deg C.
;9SAC<E greater than ) mg.

;4:A"I95E probably rather long.
L4A!I"A"IM< C9??<5"SE '3ith )., mg- At an hour and t3enty minutes, I 3as suddenly Fuite light headed. An hour later I must say that the effects
are real, and generally good. I am spacey L nothing tangible. And a couple of hours yet later I am still a3are. ?y teeth are some3hat rubby, and as
things have been pretty steady for the last three hours, this 3ill prove to be long lasting. "here are a lot of physical effects that may be kidding me into
providing myself some of the mental. At the si/th hour, I find that this is almost entirely physical. ?y teeth are tight, there is a general physical
tenseness, my refle/es seem e/aggerated, and my eyes are Fuite dilated. All of these signs are lessened by the eighth hour, and do not interfere 3ith
sleep at the t3elfth hour. "here is no desire to proceed any further, at least at the present time. ?ental '*- physical '**-. 5e/t day, slight impression of
persistence of to/icity.
'3ith (, mg- 5othing psychedelic, but a3fully hard on the bod. "he ne/t day '$+ hours later- I had a severe response to & milligrams of psilocybin.
<="<5SI95S A5; C9??<5"A:>E "he mention above, of the (, milligrams of ?<"H>!@;9. follo3ed by & milligrams of psilocybin, leads to some
interesting speculation. "he usual pattern that is seen 3hen t3o psychedelic drugs are taken too closely together is that the second e/perience is less
effective than 3ould have been e/pected. "his is the property that is called tolerance, and it is freFuently seen in pharmacology. "he t3o e/posures
may be to a single drug, or they may be to t3o different drugs 3hich usually have some properties in common. It is as if the spirit of the receptor site
had become a little tired and needed a 3hile to rest up and recuperate. Ihen there is a demand for a repeat of full effectiveness, the user 3ill
customarily increase the dosage of the drug that is used. It is one of the built@in protections, in the area of psychedelics that, after one e/perience, you
must 3ait for a period of time to lose the refractoriness that has set in.
"he measure of the degree of tolerance that can be shared bet3een different drugs, called cross@tolerance, can be used as an estimate of the
similarities of their mechanisms of action. In other 3ords, if A and . are someho3 seen by the body as being similar, then a normally effective dose of A
3ill make a ne/t@day7s normally effective dose of . 3eaker than e/pected. 9r not active at all. And . 3ill do the same Gob on A. If t3o drugs are
different in their 3ays of doing things in the body, there is most often no cross@tolerance seen. "his 3as described for ?;?A and ?;A, and is the basis
of the argument that they act by distinctly separate mechanisms. A person 3ho used 3hat 3ould be held as an active dose of ?;?A for several days
lost all response to the drug. He 3as tolerant to its effects. .ut an e/posure to an effective dose of ?;A at the time that tolerance to ?;?A 3as
complete, provided a normal response to the ?;A. "he drugs are not cross@tolerant and the body recogni6es them as distinct individuals.
.ut for one drug to promote, or to e/aggerate, the effect of another is called potentiation, and can be a clue to the dynamics going on in the brain or
body. Here, admittedly in only a single report, ?<"H>!@;9. had someho3 sensiti6ed the subGect to a rather light dosage of psilocybin. .ut there have
been other reports like this that I have heard of, from here and there. I have been told of an e/periment 3ith the de/tro@isomer of ;9? 'this is the
inactive optical isomer- at a level that 3as, not surprisingly, 3ithout any effects. "he researcher had a severe reaction the follo3ing day 3ith 3hat 3as
referred to as NpoorN hashish. A similar form of potentiation has been commented upon under the recipe for "9?S9, 3here an inactive drug, and a most
modest amount of alcohol, add together to create an une/pectedly intense into/ication. .ut note that in each of these cases, it is a phenethylamine
interacting 3ith a non@phenethylamine 'psilocybin is an indole, hashish is a non@alkaloid terpene thing, and alcohol is, 3ell, alcohol-.
"he bottom line 3ith ?<"H>!@;9. is, as 3ith the other 5@methylated psychedelics, that it is 3ay do3n in potency, and probably not 3orth pursuing.
#1$3 METHY-;; M.0.; E0E#;
$-METHYAM"#%-1-&',(-METHYE#E0"%+Y,HE#Y-./TA#E;
#-METHY-1-&1,'-.E#6%0"%+%-)-Y--$-./TA#AM"#E
S>5"H<SISE A solution of ,.($ g mercuric chloride in (), m! H$9 3as added to & g aluminum foil that had been cut into ( inch sFuares, and
amalgamation allo3ed to proceed for ,.& h. "he gray cloudy aFueous phase 3as decanted, and the resulting aluminum 3ashed 3ith $/$,, m! H$9.
After shaking as dry as possible, there 3as added, in seFuence, a solution of 2.1 g methylamine hydrochloride in an eFual 3eight H$9, $0 m! IPA, ().0
m! $&K 5a9H, 1.2$ g (@'0,+@methylenedio/yphenyl-@$@butanone 'see under the recipe of D for its preparation-, and finally ++ m! additional IPA. "he
mi/ture 3as occasional s3irled, and cooled e/ternally as needed to keep the temperature belo3 &, deg C. After the reduction 3as completed 'no
metallic aluminum remaining, only gray sludge-, it 3as filtered and the residues 3ashed 3ith ?e9H. "he combined filtrate and 3ashes 3ere stripped of
organic volatiles under vacuum, the residue treated 3ith (,, m! <t$9, and this 3as e/tracted 3ith $/&, m! 0 5 HCl. After 3ashing the pooled aFueous
e/tracts 3ith 0/(,, m! CH$Cl$, they 3ere made basic 3ith an e/cess of $&K 5a9H and e/tracted 3ith &/&, m! CH$Cl$. ;rying of these e/tracts 3ith
anhydrous ?gS9+ and removal of the solvent gave a residue that 3as distilled at )) deg C at ,.,) mm8Hg to give a colorless oil that 3as dissolved in
IPA and neutrali6ed 3ith concentrated HCl. "he solids that separated 3ere removed by filtration, <t$9 3ashed, and air dried to provide 1.,2 g $@
methylamino@(@'0,+@methylenedio/yphenyl-butane hydrochloride '?<"H>!@D or ?.;.- as 3hite crystals 3ith a mp of (&1 deg C. Anal.
'C($H()Cl59$- C,H,5. :eductive amination of the butanone 3ith methylamine hydrochloride in ?e9H, employing sodium cyano@borohydride, gave an
identical product but in a smaller yield.
;9SAC<E (), @ $(, mg.
;4:A"I95E + @ 1 h.
L4A!I"A"IM< C9??<5"SE '3ith $(, mg- Cenerally very, very friendly, very Fuiet effect. I can read easily, but looking at pictures in most books is
relatively meaningless. ;istinct de@stressing effect, to the point 3here it7s too much trouble to set out to do anything at all, really. "here is Gust no drive,
and it isn7t even bothersome to be missing it. ;o I like itH >es, very much. Beel that I7ve Gust begun to e/plore it, though. Iould I consider this material
in therapyH Iell, sure, it7s 3orth trying. ;estressing 3ould be e/cellent, and better than ?;?A in some 3ays, but the empathy and intuition levels have
yet to be e/plored in a therapy setting. I feel that they may be someho3 lo3er.
'3ith $(, mg- 9nset rapid. Alert $, minutes, and to a *$.& at 0, to 0& minutes. 5o physical symptoms, i.e., teeth clench, no stomach problems. Cood
visual enhancement; eyes open L bright colors L no visuals 3ith eyes closed. 5o 7cone of silence7 that I get 3ith ?;?A 'and enGoy-, other3ise I7m not
sure I could tell 3hich 3as 3hich if I took them blind.
'3ith $(, mg and a &, mg supplement- :"asted perfectly rotten. Suspect I 3as getting some type of alert in & minutes 'I often get one Fuickly 3ith
?;?A- and at 0, minutes, a full blo3n high developed rather abruptly. It 3ould be difficult to describe the high. I suspect it is the lack of language for
the phenomenon. I 3ould describe it some3hat like an alcohol high 3ithout the disabling side effects of confusion, slurring, staggering and etc. "he
high never got any more intense than at that 0, minute point and 3ith a noticeable drop in another hour, I took a &, mg supplement. I enGoyed the high.
I rela/ed 3ith the material. Ho3ever, it did not seem to have the same Fualities as ?;?A, in that it 3as not as stimulating, and it had very little visual
activity. I talked 3ith others, but found it easy to lie do3n and rela/. "here 3as some Ga3@clenching to3ards the end, and I had considerable nystagmus
at the peak 3hich I could control. After the e/perience, I did not 3ant to drink alcohol very much 'sell it as a substitute for <t9HO-.
'3ith $(, mg and a 2, mg supplement- :I begin to feel the rush at $, minutes, increasing rapidly. Mery much like ?;?A, only more intense into/ication.
9ther3ise same symptomsE intense euphoria that I call a feeling of grace, soft skin, voices, youthful appearance, animated discussions, feelings of great
closeness to others. I start to drop noticeably at less than an hour and a half into it, but I delayed a supplement until the hour and fifty minute point. It
does not get me back to the original into/ication. Ho3ever, it is very nice, very much like ?;?A. 9nly difference is that there seems to be more
Fuietness, less inclination to talk than 3ith an ?;?A supplement. ?y conclusionE Seems an e/cellent substitute for ?;?A, 5e/t time may try
some3hat lo3er amount, supplement sooner.
<="<5SI95S A5; C9??<5"A:>E An observer 3ho 3as familiar 3ith the out3ardly apparent effects 3ith groups e/perimenting 3ith ?;?A felt that,
although most subGects commented favorably in their comparisons of ?<"H>!@D 3ith ?;?A, there 3as lacking some of the spontaneity, the 3armth,
and the clear intimacy of the latter drug. "he dosage range e/plored is remarkably tight, attesting to a consistency of response. "he typical supplement
used, if any, 3as 2, milligrams or less, Gust before the t3o hour point. "his indicates a chronology similar to that of ?;?A, and about t3o thirds the
potency.
"he arguments that 3eigh the use of the code name of ?.;. against the use of ?<"H>!@D are present in the recipe for .;. 'or D-. .ut 3hat is the
source of this H, I, D, naming thing that I have called the ?uni ?etroH
Birst, a little bit of local color. In San Brancisco, there is a public transportation called the S.B. ?unicipal ?etropolitan System comple/ that has
integrated an underground street@car system that emerges above ground and connects 3ith a bus net3ork. A number of the street@car lines fan across
the city to the outer reaches 3hich are called the Avenues. "hese lines are named by seFuential letters. "here is the D Church Street line, the
Ingelside line, the ! "araval line, the ? 9cean line, and the 5 Dudah. And in the pharmacological comple/ that involved the lengthening of the aliphatic
chain, there 3ere t3o coincidental benchmarks in the names that 3ere proposed. "hose 3ithout an alpha@substituent 'no carbon atoms at the position
alpha to the amine group, the phenethylamines- 3ere originally called the H compounds. H stood for Nhomopiperonylamine.N And the first of those 3ith
the alpha@ethyl group there 't3o carbon atoms at the position alpha to the amine group- 3as familiarly called NDacobamineN in recognition of a famous
chemist 3ho had set the synthetic 3heels in motion.
It is Fuite obvious, that 3ith one carbon atom lying on that alpha@position, you are precisely half@3ay bet3een no carbons and t3o carbons. And there
3as one letter of the alphabet that lies precisely half@3ay bet3een an H and a D. So, an natural naming pattern developed. "he I compounds 3ere
already pretty 3ell kno3n by names such as ?;A and ?;?A and ?;<, so I, and ?<"H>!@I, and <"H>!@I, didn7t have any appeal. .ut for the ne3, the
alpha@ethyl compounds, 3hy not call them the D@compoundsH If it has a methyl on the nitrogen it 3ill be ?<"H>!@D and if it has an ethyl group it 3ill be
<"H>!@D. And in the ne/t longer group, the 0@carbon propyl group on the alpha@position becomes the family, and the +@carbon butyl group located
there, the ! family. <ach 3ith its ?<"H>! and <"H>! prefi/es, if the nitrogen atoms are substituted 3ith a methyl or and ethyl group. M7la, comme on
dit en BranVccedil;ais. !e systiVegrave;me ?uni ?etro. Plus simple.

#1$4 METHY-<; $-METHYAM"#%-1-&',(-METHYE#E0"%+Y,HE#Y-,E#TA#E;
#-METHY-1-&1,'-.E#6%0"%+%-)-Y--$-,E#TYAM"#E
S>5"H<SISE "he Crignard reagent of butyl bromide 3as prepared in anhydrous <t$9 by the drop3ise addition of 1) g n@butyl bromide to a 3ell@stirred
suspension of (+ g magnesium turnings in &,, m! anhydrous <t$9. Ihen the e/othermic reaction had stopped, there 3as added a solution of 1, g
piperonal in about (,, m! <t$9, over the course of ( h. After the e/othermic addition 3as complete, the reaction mi/ture 3as held at reflu/ for several
h, then cooled and decomposed by the addition of dilute HCl. "he phases 3ere separated, and the aFueous phase e/tracted 3ith $/2& m! CH$Cl$.
"he organics 3ere combined and gave, after the removal of the solvents under vacuum, )+ g of (@hydro/y@(@'0,+@methylenedio/yphenyl-pentane as a
yello3 liFuid. "his 3as used in the follo3ing dehydration step 3ithout further purification.
A mi/ture of &$ g of the crude (@hydro/y@(@'0,+@methylenedio/yphenyl-pentane and $ g po3dered HS9+ 3as heated 3ith a flame until there 3as no
more apparent generation of H$9. "he resulting dark, fluid oil 3as distilled at (,,@((, deg C at ,.0 mm8Hg to give $%.& g of (@'0,+@
methylenedio/yphenyl-@(@pentene as a light yello3 liFuid. "his 3as employed in the follo3ing o/idation step 3ithout further purification.
"o ($, m! of %,K formic acid there 3as added, 3ith good stirring, (& m! H$9, follo3ed by $0 m! of 0&K H$9$ "o this mi/ture, cooled 3ith an e/ternal
ice bath, there 3as added a solution of $+ g crude (@'0,+@methylenedio/yphenyl-@(@pentene in ($, m! acetone at a rate slo3 enough to keep the
internal temperature from e/ceeding 0& deg C. At the end of the addition, the temperature 3as brought up to +& deg C by heating briefly on the steam
bath, and then the reaction mi/ture 3as allo3ed to stand and stir at ambient temperature for several h. All volatiles 3ere removed under vacuum, 3ith a
bath temperature maintained at +& deg C. "he residue 3as dissolved in 0, m! ?e9H, then there 3as added $,, m! (&K H$S9+ and the mi/ture held
on the steam bath for (.& h. "here 3as then added an additional 0,, m! H$9, and this 3as e/tracted 3ith $/$&, m! of a petroleum ether8<t9Ac '&E(-
mi/ture. "he e/tracts 3ere pooled, and the solvents removed under vacuum to give a residue that 3as distilled at ((&@($, deg C at ,.0 mm8Hg. "his
light yello3 liFuid 3eighed (0.& g and 3as substantially pure (@'0,+@methylenedio/yphenyl-@$@pentanone by "!C.
"o &., g of aluminum foil cut into ( inch sFuares, there 3as added a solution of (&, mg HgCl$ in $,, m! H$9. "he mi/ture 3as heated briefly until
there 3ere clear signs of active amalgamation, such as fine bubbling for the aluminum surfaces and the beginning of the formation of a gray, amorphous
solid phase. "he HgCl$ solution 3as decanted off and the aluminum 3as 3ashed 3ith $/$,, m! additional H$9. After shaking as dry as possible, there
3as added, in seFuence and 3ith good s3irling agitation bet3een each addition, (, g methylamine hydrochloride in (, m! H$9, $2 m! IPA, $$ m! of
$&K 5a9H, &., g (@'0,+@methylenedio/yphenyl-@$@pentanone, and finally an additional &, m! IPA. "he mi/ture 3as heated on the steam bath
periodically to maintain the reaction rate at a vigorous boil. Ihen all of the aluminum had been consumed, the cooled mi/ture 3as filtered and the solids
3ashed 3ith ?e9H. "he combined filtrate and 3ashings 3ere stripped of solvent under vacuum. "he residue 3as dissolved in dilute H$S9+ and
3ashed 3ith $/2& m! CH$Cl$. After making basic again 3ith $&K 5a9H, this 3as e/tracted 3ith $/(,, m! CH$Cl$, and the pooled e/tracts 3ere
stripped of solvent under vacuum. "he residue 3as distilled at (,&@((, deg C at ,.0 mm8Hg to give $.2 g of a colorless liFuid. "his 3as dissolved in (&
m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith 2& m! anhydrous <t$9 3hich allo3ed a delayed appearance of a fine 3hite crystal. "his
3as removed by filtration, <t$9 3ashed, and air dried to give $.+& g $@aminomethyl@(@'0,+@methylenedio/yphenyl-pentane hydrochloride '?<"H>!@-
as a 3hite product 3ith a mp of (&&@(&1 deg C. Anal. 'C(0H$,Cl59$- C,H.
;9SAC<E greater than (,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- "here 3ere no effects. I 3as busy and totally 3ound up and didn7t sleep until 0 A?, but this 3as probably
unrelated to the ?e@.
<="<5SI95S A5; C9??<5"A:>E "he 3ell appears to be running dry, 3ith a pentane chain as a basic skeleton. ?<"H>!@D, at this level, 3as
already sho3ing a number of hints and clues, largely physical such as coldness in the feet and a slight mastoidal pressure, that activity 3as right around
the corner. .ut ?<"H>!@ gave no such hints. "he unmethylated homologue, $@amino@(@'0,+@methylenedio/yphenyl-pentane '-, 3as also made, by
the reductive amination of (@'0,+@methylene@dio/yphenyl-@$@pentanone 3ith ammonium acetate and sodium cyanoborohydride in methanol. It 3as a
3hite crystalline solid, mp $,$@$,0 deg C, but is given here in the comments only, as its human assaying had never even been initiated. Anal.
'C($H()Cl59$- C,H. "he 5@ethyl homologue, $@ethylamino@(@'0,+@methylene@dio/yphenyl-pentane '<"H>!@-, is entered 3ith its o3n recipe, on the
other hand, since testing had been started 3ith it.
And the longest chain that has been e/plored in this ?uni ?etro series is the si/@carbon he/yl chain 3hich is, Fuite logically, the !@series, sort of the end
of the "araval line 'see under ?<"H>!@D for an e/planation-. "he central compound for all the !@compounds 3as the ketone (@'0,+@
methylenedio/yphenyl-@$@he/anone, 3hich 3as prepared by the Crignard reagent of 'n-@amyl bromide 3ith piperonal to give (@hydro/y@(@'0,+@
methylenedio/yphenyl-he/ane, dehydration of this 3ith potassium bisulfate to the olefin, and o/idation of this 3ith hydrogen pero/ide and formic acid to
the !@ketone 3hich 3as an orange@colored liFuid 3ith a bp of ($&@(0& deg C at ,.0 mm8Hg. "his ketone 3as reductively aminated 3ith ammonium
acetate and sodium cyanoborohydride in methanol to produce $@amino@(@'0,+@methylenedio/yphenyl-he/ane hydrochloride '!- as a 3hite crystalline
product 3ith a mp of (&2@(&) deg C. Anal. 'C(0H$,Cl59$- C,H. And this ketone 3as reductively aminated 3ith methylamine hydrochloride and
amalgamated aluminum in isopropanol to produce $@methylamino@(@'0,+@methylenedio/yphenyl-he/ane hydrochloride '?<"H>!@!- as a 3hite crystalline
product 3ith a mp of (0%@(+( deg C. Anal. 'C(+H$$Cl59$- C,H. "he reduction of this ketone in a similar manner 3ith ethylamine hydrochloride
produced $@ethylamino@(@'0,+@methylenedio/yphenyl-he/ane '<"H>!@!-. 5one of this series has yet been e/plored either as psychedelic or
entactogenic materials.

#1'5 METHY-MA; ,MMA; 0%%#E; (-MMA; (-METH%+Y-#-METHYAM,HETAM"#E
S>5"H<SISE A solution of $, g methylamine hydrochloride in (&, m! hot ?e9H 3as treated 3ith (,., g +@metho/yphenylacetone and stirred
magnetically. After returning to room temperature, there 3as added &., g sodium cyanoborohydride, follo3ed by cautious addition of HCl as reFuired to
maintain the pH at about 1. "he reaction 3as complete after a fe3 days, and the mi/ture 3as poured into ),, m! H$9. "his 3as acidified 3ith HCl
'HC5 evolutionO- and 3ashed 3ith 0/2& m! CH$Cl$, 3hich removed most of the yello3 color. "here 3as $&K 5a9H added to make the reaction
mi/ture strongly basic, and this 3as e/tracted 3ith 0/2& m! CH$Cl$. "he solvent 3as removed from the pooled e/tracts under vacuum, and the (,.0 g
of residue distilled at ,.0 mm8Hg. "he %.2 g of colorless oil that distilled at 2&@%, deg C 3as dissolved in &, m! IPA, neutrali6ed 3ith +.& m!
concentrated HCl, and then diluted 3ith (,, m! anhydrous <t$9. "here 3ere generated glistening crystals of +@metho/y@5@methylamphetamine
hydrochloride '?<"H>!@?A or ;995<- that 3eighed, after 3ashing 3ith <t$9 and air drying to constant 3eight, ((., g and 3hich had a mp of (22@(2)
deg C. "he same base can be made by the action of ethyl chloroformate on +@?A in the presence of triethylamine to make the carbamate, or the action
of formic acid to make the formamide. "hese can then be reduced 3ith !AH to this same end product.
;9SAC<E greater than (,, mg.
;4:A"I95E short.
L4A!I"A"IM< C9??<5"SE '3ith ((, mg- 9ne hour into it, my pulse 3as up over (,,, and I 3as compulsively ya3ning. "here 3as some eye muscle
disturbance, a little like the physical side of ?;?A, but there 3as none of its central effects. .ut all the hints of the cardiovascular are there. .y the
fourth hour, I am pretty much back to baseline, but the ya3ning is still very much part of it. I might repeat this, at the same level, but 3ith continuous
close monitoring of the body.
<="<5SI95S A5; C9??<5"A:>E Ihy 3ould there be interest in this particular compoundH "he track record from the comparison of active
compounds that are primary amines, and their 5@methyl homologues, has sho3n that, in general, the stimulant component might be maintained, but the
NpsychedelicN contribution is generally much reduced. ?;?A is, of course, an e/ception, but then, that particular compound is a one@of@a@kind thing
3hich simply defies all the rules any3ay, and I drop it from this kind of reasoning. And as +@?A is a pretty pushy stimulant 3ith little if any sensory
sparkle, 3hy bother 3ith the 5@methyl compound at allH
Bor a completely silly and romantic reason. Ihen the ?;?A story became front@page ne3s back in mid@(%)&, the cartoonist@author of ;oonesbury,
Cary "rudeau, did a t3o@3eek feature on it, playing it humorous, and almost 'but not Fuite- straight, in a hilarious seFuence of t3elve strips. 9n August
(%, (%)& he had ;uke, president of .aby ;oc College, introduce the drug design team from 4SC in the form of t3o brilliant t3ins, ;rs. Albie and .unny
Corp. "hey vividly demonstrated to the enthusiastic conference that their ne3 drug NIntensityN 3as simply ?;?A 3ith one of the t3o o/ygens removed.
NMoila,N said one of them, 3ith a molecular model in his hands, N!egal as sea salt.N And 3hat is ?;?A 3ith one o/ygen atom removedH It is +@metho/y@
5@methylamphetamine or ?<"H>!@?A 3hich, according to the t3ins, should give the illusion of substance to one7s alter ego. So, I called it
;oonesamine, or simply :;995<S for short. ?aybe that 3as also a homonym for Brank Herbert7s science fiction book, N;une,N 3herein the magical
drug NspiceN provided a most remarkable alteration of the user7s state of consciousness.
"his comic strip presentation 3as the first nationally distributed allusion to the term Ndesigner drugs,N and perhaps it lent une/pected support for the
passage, Gust a year later, of the Controlled Substances Analogue <nforcement Act of (%)1. "his intentionally vague piece of legislation makes the
giving of, or the taking of, or even the possession 3ith the intent to take, any drug that in any 3ay alters your state of consciousness, a felony. A
shameful and desperate effort by the governmental authorities to maintain the image of control in a lost situation.
<nough editorial. .ack to historic technicalities. In truth, ?<"H>!@?A is a 3ell studied drug, at least in animals. In both mice and rats, it is an
e/ceptionally potent agent in creating the state of catatonia. Animal studies, prompted by the clandestine synthesis of ?<"H>!@?A, have sho3n that
there is indeed locomotor stimulation and some central effects, but these effects are someho3 different than those of a simple amphetamine@like agent.
"he e/perimenter7s conclusions, based on its structural resemblance to +@?A and its proclivity to produce catatonia in some animal species and the
ever@present possibility that there might be unsuspected neurochemical changes to be seen 3ith its use, are that human e/perimentation should be
discouraged. I have come to the same conclusion, but in my case this is based on a much more succinct observationE I tried it and I didn7t like it.
A brief comment on t3o of the 5,5@dimethylhomologues of metho/yamphetamine. 9ne 3as +@metho/y@5,5@dimethylamphetamine, +@?55A. "his
material, made by the reductive amination of +@metho/yphenylacetone 3ith dimethylamine, 3as a colorless oil, 3hich distilled at 2,@)& deg C at ,.0
mm8Hg. "he corresponding $@metho/y@5,5@dimethylamphetamine 3as similarly made. $@?55A 3as also a colorless oil and had the same bp. .oth of
them 3ere fluorinated 3ith ()B labelled acetyl hypofluorite '0K and 1K yields respectively- but neither of them 3as pursued any further in the search for
a brain blood flo3 indicator.

#1'1 METHY-MM0A-$; $-METH%+Y-#-METHY-(,)-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE A suspension of (2.+ g electrolytic elemental iron in (,, g glacial acetic acid 3as heated on the steam@bath until there 3ere the first signs
of bubbling and reaction, about 1, deg C. "here 3as then added, in small portions, a suspension of %.$ g (@'$@metho/y@+,&@methylenedio/yphenyl-@$@
nitropropene 'see under ??;A@$ for its preparation- in +, g 3arm glacial acetic acid. "he reaction 3as e/tremely e/othermic. After the color had
lightened as much as possible, there 3as added an additional Fuantity of iron sufficient to completely discharge the residual yello3 color. ?echanical
stirring 3as maintained as the reaction mi/ture 3as allo3ed to return to room temperature. All 3as poured into ),, m! H$9, and the insolubles 3ere
removed by filtration. "hese 3ere 3ashed alternately 3ith H$9 and 3ith CH$Cl$, the combined filtrate and 3ashes 3ere separated, and the aFueous
phase e/tracted 3ith 0/(,, m! CH$Cl$. All organics 3ere combined, 3ashed 3ith $/2& m! &K 5a9H '3hich removed most of the color- and the
solvent removed under vacuum. "he ).2 g residue 3as distilled at %,@(,& deg C at ,.$ mm8Hg to give 1.2 g of $@metho/y@+,&@
methylenedio/yphenylacetone as a pale yello3 oil.
"o a magnetically stirred solution of 0, g methylamine hydrochloride in (&, m! 3arm ?e9H, there 3as added 1.& g $@metho/y@+,&@
methylenedio/yphenylacetone follo3ed by 0., g sodium cyano@borohydride. Concentrated HCl 3as added as 3as reFuired to keep the mi/ture at a pH
of about 1. Ihen the reaction 3as complete, it 3as added to ( ! H$9 and made strongly basic 3ith $&K 5a9H. "his 3as e/tracted 3ith 0/(,, m!
CH$Cl$, and the pooled e/tracts 3ere, in turn, e/tracted 3ith $/(,, m! dilute H$S9+. "his aFueous phase 3as 3ashed 3ith CH$Cl$, made basic 3ith
5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent from these pooled e/tracts under vacuum gave ).2 g of an amber oil. "his 3as
distilled at ((,@($& deg C at ,.$& mm8Hg to give &.( g of a colorless oil. "his 3as dissolved in 0, m! IPA, neutrali6ed 3ith about 0 m! concentrated HCl,
and diluted 3ith 1, m! anhydrous <t$9. "he clear solution slo3ly deposited 3hite crystals 3hich 3ere removed by filtration and air dried to give +.$ g $@
metho/y@5@methyl@+,&@methylenedio/yamphetamine hydrochloride '?<"H>!@??;A@$- 3ith a mp of (1)@(1% deg C. Anal. 'C($H()Cl590- C,H.
;9SAC<E greater than 2, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith 2, mg- ?aybe a threshold L pleasant but not possible to characteri6e it.
<="<5SI95S A5; C9??<5"A:>E Iith the effective dosage of the unmethylated homologue being the range of $& to &, milligrams, this 5@methyl
compound is, as 3ith the other 5@methylated materials discussed here, again of reduced activity. "he highest dose yet reported 3as 2, milligrams, and
there is no 3ay of estimating 3hat miight be an active level nor, once there, 3hat the Fuality of the effects might be.
"his is the only ??;A analogue that has been e/plored as an 5@methyl derivative. A more highly substituted analogue has also been made, the 5@
methyl derivative of ;??;A. Isoapiole 'see its preparation under ;??;A- 3as o/idi6ed 3ith formic acid and hydrogen pero/ide to the ketone '$,&@
dimetho/y@0,+@methylenedio/yphenylacetone, a solid 3ith a mp of 2&@21 deg C from methanol- 3hich 3as reductively aminated 3ith methylamine and
amalgamated aluminum to give $,&@dimetho/y@5@methyl@0,+@methylenedio/yamphetamine hydrobromide monohydrate '?<"H>!@;??;A, or
;??;?A- as a 3hite crystalline solid 3ith a mp of %(@%$ deg C. "he hydrochloride salt 3as a hygroscopic solid. Anal. 'C(0H$$.r59&- C,H. "he
above ketone has also been used in the synthesis of another methylated ;??;A, on the beta@carbon. "his is described under ;??;A itself.
;??;?A has not yet been launched into an evaluation program, and I 3ouldn7t be surprised if the needed dosage might be up there some3here over
(,, milligrams. I feel Fuite sure that the ans3ers may be kno3n in the near future. "here is a surprisingly large number of inconspicuous chemical
e/plorers out there all over the 3orld, doing their synthetic thing in their private laboratories. "hey are truly the astronauts of inner space.

#1'$ MM0A; '-METH%+Y-(,)-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE 'from protocatechualdehyde- A solution of () g commercial protocatechualdehyde '0,+@dihydro/yben6aldehyde- in $,, m! 3arm acetic
acid 3as filtered free of any insolubles, to provide a very dark but clear solution. Iith good stirring there 3as then added $, g elemental bromine. "he
reaction spontaneously heated to about 0, deg C and solids appeared in about & min. Stirring 3as continued for ( h, and then the light gray solids that
had formed 3ere removed by filtration and lightly 3ashed 3ith acetic acid. "hese 3ere air dried on the steam bath until free of acetic acid smell. "he
product, 0@bromo@+,&@dihydro/yben6aldehde, 3eighed ((.2 g and had a mp of $$$ deg C.
"o a solution of ((.2 g 0@bromo@+,&@dihydro/yben6aldehyde in 01 m! ;?S9 there 3as added $% g methylene iodide follo3ed by $,.) g anhydrous
$C90. "his 3as heated on the steam bath for 0 h, added to ( ! H$9, made strongly basic 3ith 5a9H, then e/tracted 3ith 0/(,, m! CH$Cl$. "hese
e/tracts 3ere pooled, 3ashed 3ith H$9, and the solvent removed under vacuum. "he dark bro3n semi@solid residue 3as distilled 3ith the maGor
fraction '1., g- coming over at ($,@(0, deg C at ,.0 mm8Hg. "his, upon recrystalli6ation from 0& g boiling ?e9H, gave (.0 g of 0@bromo@+,&@
methylenedio/yben6aldehyde as an off 3hite crystalline solid 3ith a mp of ($0@($+ deg C.
A mi/ture of $.$ g 0@bromo@+,&@methylenedio/yben6aldehyde and 0.1 m! cyclohe/ylamine in a distillation flask 3as heated to (,, deg C to effect
solution, and then 3ith an open flame until the signs of H$9 evolution 3ere evident. "his 3as then placed under a hard vacuum to remove the
generated 3ater and e/cess cyclohe/ylamine, and the product distilled at ($,@($& deg C at ,.$ mm8Hg. "here 3as obtained $.+ g of the Schiff base of
the aldehyde and the amine, melting at )1@%1 deg C. :ecrystalli6ation of an analytical sample from & volumes of ?e9H gave 0@bromo@+,&@
methylenedio/yben6ylidine@5@cyclohe/ylamine as a 3hite solid 3ith a mp of %2.&@%).& deg C. Anal. 'C(+H(1.r59$- H; CE calcd, &+.$,; found, &0.2).
A solution of $.$ g 0@bromo@+,&@methylenedio/yben6ylidine@5@cyclohe/ylamine 'the above Schiff base- in &, m! anhydrous <t$9 3as placed in a He
atmosphere, stirred magnetically, and cooled 3ith a dry ice8acetone bath. A 3hite fine crystalline phase appeared. "here 3as then added &.$ m! (.&&
? butyllithium in he/ane 'the fine solids dissolved- follo3ed by +., m! of tributyl borate. After returning to room temperature, the reaction 3as Fuenched
3ith $, m! of saturated aFueous ammonium sulfate. "he <t$98he/ane layer 3as separated, 3ashed 3ith additional ammonium sulfate solution, and
then stripped of volatiles under vacuum. "he residue 3as dissolved in (,, m! &,K ?e9H, treated 3ith $ m! of 0,K hydrogen pero/ide and, after (&
min s3irling, Fuenched 3ith a solution of (, g ammonium sulfate in &, m! H$9. "his aFueous phase 'pH about )- 3as e/tracted 3ith $/&, m! CH$Cl$,
the e/tract pooled and stripped of solvent under vacuum, and the residue dissolved in 3arm, dilute HCl. After all the residue had dissolved 'a fe3 min
heating 3as sufficient-, the solution 3as cooled to room temperature and e/tracted 3ith $/&, m! CH$Cl$. "hese organics 3ere pooled and e/tracted in
turn 3ith $/&, m! &K 5a9H. Acidification of the pooled aFueous fractions 3ith HCl, follo3ed by e/traction 3ith $/&, m! CH$Cl$ gave, after
evaporation of the solvent, a residue that 3as distilled at (+,@(&, deg C at ,.$& mm8Hg to give 0@hydro/y@+,&@methylenedio/yben6aldehyde. "his 3as
recrystalli6ed from toluene '+, m!8g- to give ,.+1 g of an off@3hite product 3ith a mp of (0+@(0+.& deg C. Anal. 'C)H19+- C,H.
A solution of ,.++ g 0@hydro/y@+,&@methylenedio/yben6aldehyde in (, m! dry acetone 3as treated 3ith ,.& g methyl iodide and ,.& g po3dered
anhydrous $C90, and 3as held at reflu/ for 1 h. All volatiles 3ere stripped under vacuum, the residue dissolved in 3ater, made strongly basic 3ith
5a9H, and e/tracted 3ith 0/&, m! CH$Cl$. :emoval of the solvent gave myristicinaldehyde 'mp (00@(0+ deg C- 3hich, on recrystalli6ation from
he/ane, gave a final yield of ,.+$ g 3ith a mp of (0+@(0& deg C. Care must be taken 3ith t3o seFuential products that have identical mps. A mi/ed mp
3ith the unmethylated phenol above is strong depressed, 3hereas that 3ith an authentic sample is not.
A solution of %.) g myristicinaldehyde in 0& m! glacial acetic acid 3as treated 3ith &.0 m! nitroethane and 0.$ g anhydrous ammonium acetate, and
heated on the steam bath for (.& h. It 3as removed, treated 3ith H$9 3ith good stirring to Gust short of turbidity, seeded 3ith product nitrostyrene, and
allo3ed to come slo3ly to room temperature. "he bright yello3 solids that formed 3ere removed by filtration, 3ashed 3ith a small amount of aFueous
acetic acid, and sucked as free of solvent as possible. "his material, pressed on a porous plate, had a mp of (,2@((, deg C. :ecrystalli6ation from 1,
m! boiling <t9H gave, after filtering and air drying, &.( g of (@'0@metho/y@+,&@methylenedio/yphenyl-@$@nitropropene as light yello3 solids 3ith a mp of
(,%@((, deg C.
A suspension of 2.& g !AH in &,, m! anhydrous <t$9 3as magnetically stirred, and heated in an inert atmosphere to a gentle reflu/. "he condensing
<t$9 leached out a total of %.) g (@'0@metho/y@+,&@methylenedio/yphenyl-@$@nitropropene from a So/hlet thimble in a shunted reflu/ condenser. "his, in
effect, added the nitrostyrene to the reaction medium as a 3arm saturated <t$9 solution. Ihen the addition 3as completed, the reflu/ing 3as
maintained for an additional & h, then the reaction mi/ture 3as cooled and the e/cess hydride destroyed by the addition of +,, m! (.& 5 H$S9+ 'the
first $, m! a drop at a time and 3ith very good stirring-. "he phases 3ere separated, and sufficient saturated aFueous 5a$C90 3as added to the
aFueous phase to bring the pH up to about 1.,. "his 3as heated to ), deg C and filtered through a coarse sintered glass funnel to remove some
insoluble fines. "he clear filtrate 3as brought up almost to a boil, and treated 3ith a solution of (,.$ g of %,K picric acid in ((, m! boiling <t9H.
Crystals of the picrate formed immediately at the edges, and as the reaction flask 3as cooled in an ice tub, the entire reaction set to a yello3 mass of
crystals. "hese 3ere removed by filtration, 3ashed sparingly 3ith ),K <t9H, and air dried to give (+., g of the picrate salt of ??;A, 3ith a mp of ()$@
()+ deg C. :ecrystalli6ation of a small sample from <t9H dropped this to (2%@()( deg C. "his salt 3as treated 3ith 0, m! &K 5a9H, and the red
solution decanted from some insolubles. Additional H$9 and 5a9H effectively dissolved everything, and the resulting basic aFueous phase 3as
e/tracted 3ith 0/&, m! CH$Cl$. "he pooled e/tracts 3ere stripped of solvent under vacuum, and the residue dissolved in $,, m! anhydrous <t$9 and
saturated 3ith anhydrous HCl gas. "here 3as a heavy precipitation of 3hite crystals, 3hich 3ere removed by filtration, <t$9 3ashed, and air dried to
give 1.02 g 0@metho/y@+,&@methylenedio/yamphetamine hydrochloride '??;A- 3ith a mp of (%,@(%( deg C. Anal. 'C((H(1Cl590- Cl.
'from 9il of 5utmeg- "he careful distillation of 9il of 5utmeg 'or the 9il of ?ace- allo3ed the isolation of a number of compounds in varying degrees of
purity. "he fraction that boiled in the ((,@((& deg C range at about (., mm8Hg 3as myristicin '0@metho/y@+,&@methylenedio/yallylben6ene-. It
constituted some 2K of the original oil of commerce and, in its original isolated form, 3as obtained 3ith a purity of )2K. "he maGor contaminant 3as
elemicin '0,+,&@trimetho/yallylben6ene-. A solution of (,, g myristicin in (,, g absolute <t9H 3as treated 3ith $,, g solid 9H and heated on a steam
bath overnight. :emoval of the volatiles under vacuum, flooding the residue 3ith H$9, and e/traction 3ith 0/(,, m! CH$Cl$ gave, after removal of the
solvent from the combined e/tracts, a residue of crude isomyristicin 'a mi/ture of the cis@ and trans@isomers-. "his product 3as distilled, and the fraction
boiling at ($&@(0, deg C at ( mm8Hg gave 10 g of isomyristicin as a pale yello3 oil that spontaneously crystalli6ed. "he mp 3as +(.&@+$.& deg C. Part
of the losses associated 3ith the purification of these solids 3as due to formation of the cis@isomer of isomyristicin, 3hich 3as an oil.
A solution of &, g isomyristicin in 0,, m! dry acetone containing $+ g pyridine 3as vigorously stirred and cooled to , deg C 3ith an ice bath. "o this
there 3as added &+ g tetranitromethane 3hich had been pre@cooled to , deg C. Stirring 3as continued for e/actly $ min, and then the reaction 3as
Fuenched by the addition of a cold solution of (1.) g 9H in 0,, m! H$9. Stirring 3as continued until the temperature had again been lo3ered to near
, deg C. "he product 3as removed by filtration. </traction of the filtrate 3ith CH$Cl$ and removal of the solvent provided additional nitrostryrene, for a
combined yield of &,.2 g 3ith a mp of (,0 deg C due to the presence of a small amount of free myristicinaldehyde. A recrystalli6ation from ?e9H
produced (@'0@metho/y@+,&@methylenedio/yphenyl-@$@nitropropene 3ith a mp of (,%@((, deg C. "his material 3as completely adeFuate for the above@
described reduction to ??;A. "he conversion of this nitropropene to myristicinaldehyde is an alternative to the lengthy synthesis given above-, and can
be used in the preparation of !9PH9PHI5<.
A mi/ture of &, g (@'0@metho/y@+,&@methylenedio/yphenyl-@$@nitropropene and $1 g racemic a@methylben6ylamine 3as heated on the steam bath. "he
mi/ture gradually formed a clear solution 3ith the steady evolution of nitroethane. Ihen the reaction became Fuiet, there 3as added a mi/ture of $, m!
concentrated HCl in (,, m! H$9. "he reaction mi/ture dissolved completely, and as the temperature continued to rise there 3as the abrupt
solidification as the formed myristicinaldehyde crystalli6ed out. "his product 3as removed by filtration and, 3hen combined 3ith a second crop obtained
by the he/ane e/traction of the filtrate, gave 01.% g of myristicinaldehyde. "he mp of ($)@($% deg C 3as raised to (00@(0+ deg C by recrystalli6ation
from he/ane.
;9SAC<E (,, @ $&, mg.
;4:A"I95E moderate.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- I felt completely rela/ed at one hour. Almost as if I 3as floating. "here 3ere no obvious effects on taste, and
the rela/ation and composed feeling is much like a small dose, maybe $, mikes, of !S;. "here 3as some dilation, and in the evening I 3as a little
restless and slightly tired. I slept 3ell, and a3oke refreshed and happy.
'3ith (,, mg- It seemed to take +& minutes to 3ork and then it came on very suddenly, as if my eyeballs 3ere being pulled out and my 3hole head
e/panding. Soon a cold feeling set in 3ith shivering L this 3as not unpleasant. ?y state in about t3o hours seemed to be one of empathy and
passivity, compassion of an impersonal sort. "he music sounded artificial and canned and tinny, in contrast to the voices, 3hich sounded rich and full
and finely articulated and melodious.
'3ith (&, mg- Ie are on the beach at the river mouth drying sea3eed, on split red3ood. "here is a slight nausea, slight cramps, and then my visual
field starts to light up. Still vertigo but only 3ith my eyes open, and heaviness and time stretches out; numbness in the chest as 3hen an opiate is taken.
"here are geometric patterns, but the e/cess light on my closed eyelids interferes 3ith this. A dance of the glittering diamond studded sea 3aves,
increasing motion and beauty. ?ore landscapes appear inside. "his is a good introductory drug to the drugs of this class, to become familiar 3ith the
drug state in as gentle a fashion as possible. "his substance seems to have a much gentler action than others of this class; perhaps more like cannabis
or psilocybin. "here is very little paranoia. I note hallucinations of t3o typesE those 3hich are strictly retinal and more minute and small and influenced
by light and focused on the light ahead on the retina or lids; and the other, those deep in the visual tract and occiput 3hich are larger and more global
and dream@like and, 3hen solid, are Fuite dramatic and unforgettable as in meditation.
'3ith $(, mg- ??;A tastes a3ful. "he bitter alkaloid taste is follo3ed by a distinctively chemical laboratory flavor as if from old rubber tubing. 5othing
seems to happen for about +& minutes 3hen rather suddenly an anvil seems to lo3er itself over your head; you feel disoriented, and tend to 3ithdra3
from social contact a little. "he drug gives less feeling of being ill than mescaline. "he effect definitely reaches a clima/ 3ith a pleasant afterglo3
follo3ing. Apparently there are no profound motor coordination problems. ??;A yields that 7Sunday afternoon7 feeling of desiring to lie do3n and enGoy
life; a lu/urious feeling of 7layback.7 5o enhancement of colors in visual scene 'e/cept for some greenish tinges in faces- but upon closing eyes
hallucinations appear to be Fuite real in 0@;, like 3atching a movie. Birst these dreams appear in black and 3hite, but later colors start appearing.
Chartreuse and magenta first appear, then blue and finally red. Birst I had visions of large numbers on gaming tables, then people. ??;A appears to
bring dreams to the conscious level; is a link bet3een the subconscious and the conscious.
'3ith $$& mg- I had a strange a3areness of my hands in about $, minutes L not a feeling in them as Gust that I 3as attracted to them someho3. "hen I
began to get fearful, an acute e/perience of aloneness. I lay face do3n 'a depressed position for me-. 5e/t I 3as talking to the kids at school 'an
image- or to other teachers. "his 3as very vivid. "he scenes at school 3ere more vivid that the real scenes around me here. "hose people 3ere much
more real. I am actually very sleepy right no3 during the e/periment. 9f any e/perience I have had, this 3as most like a series of dreams easily
remembered. Ihen it 3as over, I felt as if I had had a long period of sleeping L I had gone to bed and had a series of dream@like states very vivid and
colorful and real.
<="<5SI95S A5; C9??<5"A:>E "he phrase that had been used by several of the subGects in the early trials 3ith ??;A, again and again, 3as
Nbrain movies.N Apparently the richest of the effects 3ere to be had 3ith the eyes closed. "his is the compound that I had first completed in (%1$, and
had named it ??;A, and had begun the e/ploring of it 3hen I heard that ;r. Cordon A. Alles, a professor of pharmacology at 4. C. !. A. 3ho had his
o3n private laboratory in !os Angeles, had also synthesi6ed it in (%1$, had also named it ??;A, and had also begun e/ploring it. Ie made a date to
meet and share ideas, and then he died, at the age of 1$, in (%10.
"his is a material that might be a contributing factor to the pharmacology of nutmeg. "he maGor essential oil from that spice is myristicin, and it is the
easiest source of ??;A. It has been reported that the passage of this oil through the liver of a rabbit 3ill generate ??;A in that animal. "he only
difference bet3een the t3o molecules, structurally, are the elements of ammonia. ?yristicin plus ammonia gives ??;A. Another natural source of
myristicin is 9il of Parsley, 3hich is also an e/cellent source of apiole, mentioned under ;??;A. A rumor that had currency in the (%1,7s, that parsley
could get you high, probably had its origins in the reports of myristicin being present, coupled 3ith myristicin being the principal source of ??;A. "he
relationship to myristicin 'an essential oil- led to the classifying of ??;A as a <ssential Amphetamine. "hese relationships are e/panded upon, under
"?A.
At the time that the B;A issued its proclamation of dangerous drugs 'in the mid@(%1,7s-, ??;A 3as being talked about, and in fact it had Gust become
available commercially in <ngland through the och !ight Industries. .ut to my kno3ledge it had never appeared on the street, so its having being
s3ept into the listings of evil drugs 3as simply a coincidence of bad timing. "he close resemblance of initials bet3een ??;A, and the currently
notorious ?;?A, has led to no small amount of confusion in the popular press. "hey remain totally separate and completely different drugs.

#1'' MM0A-$; $-METH%+Y-(,)-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE A solution of ((.& g pellet 9H ')&K- in 2& m! <t9H 3as treated 3ith $& g sesamol follo3ed by $2 g methyl iodide. "his 3as brought to
reflu/ on the steam bath. Salt formation 3as apparent in $, min, and reflu/ing 3as main@tained for a total of + h. "he solvent 3as removed under
vacuum, and residue poured into +,, m! H$9. "his 3as acidified 3ith HCl and e/tracted 3ith 0/(&, m! CH$Cl$. "he pooled e/tracts 3ere 3ashed
3ith 0/(,, m! &K 5a9H, 3hich removed most of the color. "he solvent 3as removed under vacuum to provide $+., g of 0,+@methylenedio/yanisole as
a pale amber oil.
A mi/ture of &1.+ g P9Cl0 and +%.( g 5@methylformanilide 3as allo3ed to stand for +, min and then it 3as poured into a beaker containing 1+ g 0,+@
methylenedio/yanisole. "here 3as an immediate e/othermic reaction 3ith darkening and the generation of bubbles. "his 3as heated on the steam
bath for ( h, then poured into ( ! H$9 3ith e/tremely vigorous stirring. "he dark bro3n phase 3as Fuite opaFue, and then there 3as a sudden
lightening of color 3ith the generation of a fine pale yello3 solid. Stirring 3as continued for $ h, then these crystals 3ere removed by filtration. "his
crude product 3as recrystalli6ed from +,, m! boiling ?e9H yielding, after filtering, 3ashing, and air drying to constant 3eight, ++.( g $@metho/y@+,&@
methylenedio/yben6aldehyde 3ith a mp of ((,@((( deg C. 9nly one positional isomer 3as visible in the final product by CC, but e/traction of the original
mother liFuors 3ith CH$Cl$ produced, after evaporation of the solvent under vacuum, $ g of a red oil that sho3ed t3o earlier peaks on 9M@(2. "hese
3ere consistent 3ith about (K of each of the t3o alternate positional isomers that could result from the Milsmeier formylation reaction.
A solution of +0 g $@metho/y@+,&@methylenedio/yben6aldehyde in ()& g nitroethane 3as treated 3ith %.0 g anhydrous ammonium acetate and heated on
the steam bath for +.& h. "he e/cess nitroethane 3as removed under vacuum to give a residue that spontaneously crystalli6ed. "hese solids 3ere
3ashed out mechanically 3ith the aid of $,, m! cold ?e9H, and the brilliant orange crystals recovered by filtering and air drying to constant 3eight.
"here 3as obtained 0&.2 g (@'$@metho/y@+,&@methylenedio/yphenyl-@$@nitropropene 3ith a mp of (11@(12 deg C. "his 3as not improved by
recrystalli6ation from IPA. <vaporation of solvent from the methanolic 3ashes gave yello3 solids '+.1 g melting at ()+@()1 deg C- 3hich, on
recrystalli6ation from "HB8he/ane, melted at ())@(%, deg C. "his sho3ed a molecular 3eight of +(1 by chemical ioni6ation mass spectroscopy
'isobutane at ,.& torr- and is the C$,H$,5$9) adduct of one molecule each of nitrostyrene, aldehyde, and ammonia that freFuently appears as a very
insoluble impurity in aldehyde@nitroethane condensations that are cataly6ed by ammonium acetate.
"o a reflu/ing suspension of 01 g !AH in ( ! anhydrous "HB under an inert atmosphere, there 3as added ++.0 g (@'$@metho/y@+,&@
methylenedio/yphenyl-@$@nitropropene in hot "HB. "he solubility 3as very lo3, so that it 3as necessary to use a heat lamp on the dropping funnel to
maintain a clear solution for addition. "he addition reFuired $ h and the reflu/ 3as maintained for 01 h. "he reaction mi/ture 3as then cooled in an ice
bath and there 3as added, in seFuence and commensurate 3ith heat evolution, 01 m! H$9, 01 m! (&K 5a9H, and finally (,) m! H$9. "he granular
solids 3ere removed by filtration and 3ashed 3ith "HB. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum yielding &).) g of a
pale amber oil. "his 3as dissolved in (,, m! IPA, neutrali6ed 3ith con@centrated HCl '$, m! 3as needed- and diluted 3ith &,, m! anhydrous <t$9.
?ore IPA 3as reFuired to keep an oil phase from appearing. After the crystalline product 3as completely formed, it 3as removed by filtration, 3ashed
3ith IPA8<t$9, and finally 3ith <t$9. Air drying gave 0(.( g of $@metho/y@+,&@methylenedio/yamphetamine hydrochloride '??;A@$- 3ith a mp of ()1@
()2 deg C.
;9SAC<E $& @ &, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith $& mg- Had some not@too@pleasant Gangly effects L this is not the smoothest of drugs. ;urationE onset at ( (8$ hours
'dose after lunch-, acute 0 to + hours, seconal at (( hours to stop residual effects so I could sleep. 9ccasionally from & to (, hours acute abdominal
distress, resembling gas pains but unable to defecate. Abdominal muscles tight and hard. "his occurred for about (& minutes every hour or so. :ather
unpleasant.
'3ith 0, mg- "here 3as the first subtle note at +& minutes, and the slo3 development makes the changes easy to assimilate, but difficult to Fuantitate.
?y a3areness is truly enhanced. 5othing is distorted, so there can be no misrepresentation as a result. "his 3ould be a good material to introduce
someone to the slo3@on slo3@off type of e/perience. It 3ould be impossible for any person, at this level, on this drug, to have a bad e/perience. "his is
very much like a slo3 ?;A, perhaps ), milligrams of it, and fully as controllable. "he 5@methyl of this is a must.
'3ith +, mg- "he chemical is primarily a visual enhancer 3ith only an e/tremely modest amount of visual distortion. "he retinal activity 3as of a minor
and non@threatening nature. "he chemical seemed to facilitate empathic communication and the emotions felt strong and clean. Conversation flo3ed
easily, 3ithout inhibitions or defensiveness. Anore/ia accompanied e/perience. "here 3as no impotence. "here 3as some restless movement 3hich
dissipated 3ith e/ercise '3alking and playing frisbee-. 5e/t day 3oke feeling energetic, no muscular stiffness, alert. I 3ould repeat this e/perience.
'3ith &, mg- I 3as coming on 3ithin +,@1, minutes, easy and slo3, but the body 3as *0 before the mind. "he mental 3as strange for the first $@0 hours
L I called it 7High Sierras7 L realistic, dispassionate, not kind. Some dark areas are persistent. Iatched last half of Circus of ;r. !ao and the 3hole
feeling changed from pornographic to erotic. ;elightful. Some fantasy. 9n coming do3n, sleep 3as difficult. "he body feels une/pectedly depleted.
:ubber legs and hand3riting Gerky.
<="<5SI95S A5; C9??<5"A:>E A comparison of this material to ?;A 3as often made by subGects 3ho 3ere familiar 3ith both. .ut it is hard to
separate that 3hich is intellectuali6ed from that 3hich is felt. An a3areness of the chemical structure immediately sho3s, of course, the close
resemblance. "here is the complete ?;A molecule, 3ith the addition of a metho/y group. And for the non@chemist, the name itself '??;A@$-
represents the second possible metho/y@?;A. Certainly one property that is shared 3ith ?;A is the broad variety of opinions as to the Fuality of its
action. Some like it much, and some like it not at all. "he 5@methyl homologue 3as indeed made, for direct evaluation in comparison to 5@methyl ?;A
'3hich is ?;?A-.
"he phenethylamine analog of ??;A@$ has been prepared by the condensation of the above ben6aldehyde 3ith nitromethane 'in acetic acid 3ith
ammonium acetate catalyst, giving an eFual 3eight of the nitrostyrene as deep orange crystals 3ith a mp of (11@(12 deg C from ethyl acetate- follo3ed
by lithium aluminum hydride reduction 'in ether-. "he product, $@metho/y@+,&@methylenedio/yphenethylamine hydrochloride '$C@$- melted at $()@$(%
deg C. "here 3ere no effects observed at up to $.1 milligrams, but no higher trials 3ere made. "he +@carbon homologue 3as made similarly 'from the
aldehyde and nitropropane but using tert@butylammonium acetate as a reagent in (,,K e/cess and isopropanol as solvent, giving orange crystals
melting at %)@%% deg C from methanol- follo3ed by reduction '3ith lithium aluminum hydride in ether- to give (@'$@metho/y@+,&@methylenedio/yphenyl-@$@
aminobutane hydrochloride '+C@$- 3ith a mp of (2$@(2+ deg C. "his material has never even been tasted.
"he "3eetio homologue of ??;A@$ has been tasted, ho3ever. "his is $@etho/y@+,&@methylenedio/yamphetamine, or <?;A@$. "he allyl ether of
sesamol '0,+@methylenedio/y@allylo/yben6ene- 3as rearranged to the $@allyl phenol 3hich 3as, in turn, converted to the ethyl ether. :eaction 3ith
tetranitromethane gave the nitrostyrene intermediate 3hich had a mp of ($,@($( deg C. "he final hydrochloride salt of <?;A@$ had a mp of ())@()).&
deg C. At (0& milligrams, there have been reported eyes@closed visual phenomena, 3ith intense colors. "he overall duration is similar to ??;A@$
'some (, hours- and there are reported sleep disturbances. At ()& milligrams, the feelings 3ere intensified, there 3ere Nmarvelous eyes@closed visuals
'the colors 3ere incredible-, good concentration, but distinct body@tingles and rushes.N "he time span 3as about ($ hours from start to finish, but it
proved to be impossible to sleep after3ards. "his homologue is thus about a third the potency of ??;A@$.

#1'( MM0A-'a; $-METH%+Y-',(-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE "o a solution of (,, g of $,0@dihydro/yanisole in ( ! dry acetone there 3as added ((, g of po3dered anhydrous $C90 follo3ed by $(, g
of methylene iodide. "his 3as brought up to a reflu/ on the steam bath. "here 3as a sudden appearance of a solid phase, and then a gentle reflu/ 3as
maintained for three days, during 3hich time much of the heavy solid that initially formed had redissolved. "he reaction mi/ture 3as filtered to remove
the insoluble salts, and these 3ere 3ashed 3ith hot acetone. "he combined mother liFuor and 3ashes 3ere stripped of solvent under vacuum, leaving
a solid residue. "his 3as leached 3ith several portions of boiling he/ane. "hese 3ere pooled, and removal of the solvent under vacuum provided &0.1
g of $,0@methylenedio/yanisole as 3hite crystals 3ith a sharp spicy smell.
A mi/ture of ($, g 5@methylformanilide and (02 g P9Cl0 3as allo3ed to incubate at ambient temperature for ,.& h, then there 3as added &0 g of crude
$,0@methylenedio/yanisole. "he dark reaction mi/ture 3as heated on the steam bath for $ h and then poured into a beaker filled 3ith shaved ice. "his
3as stirred until hydrolysis 3as complete, and the black, almost crystalline gunk that separated 3as removed by filtration. "he &0.1 g of crude product
3as analy6ed by CC using an ethylene glycol succinate column at (%, deg C. "hree peaks 3ere apparent and had baseline separation. "he maGor
peak at 2.) min constituted )$K of the product and 3as $@metho/y@0,+@methylenedio/yben6aldehyde. A minor peak at ($., min represented (1K of the
product and 3as the positional isomer +@metho/y@$,0@methylenedio/yben6aldehyde. A trace component '$K- lay intermediate 'at %.& min- and 3as
myristicinaldehyde. "he mps of the t3o maGor ben6aldehydes 3ere sufficiently different that they could serve as means of identification. "he maGor
product 3as obtained directly from the black gunk by repeated e/traction 3ith boiling cyclohe/ane 3hich, upon removal of the solvent, gave 00.( g of a
yello3@colored product. "his, upon one additional recrystalli6ation from boiling cyclohe/ane, gave $+.+ g of $@metho/y@0,+@methylenedio/yben6aldehyde
as pale yello3 crystals 3ith a mp of (,0@(,& deg C. "he mother liFuors 3ere pooled and, after removal of all volatiles under vacuum, yielded an amber@
colored solid that upon recrystalli6ation provided a yello3ish crystals. "hese, after yet another crystalli6ation from cyclohe/ane, gave +.( g of +@metho/y@
$,0@methylenedio/yben6aldehyde 3ith a mp of )&@)1 deg C. "his latter isomer 3as used in the synthesis of ??;A@0b.
"o a solution of 0.& g $@metho/y@0,+@methylenedio/yben6aldehyde in (+ g acetic acid there 3as added (.+ g anhydrous ammonium acetate and $.0 m!
of nitroethane. "he mi/ture 3as brought to reflu/ and held there for 0& min. It 3as then Fuenched by the addition of +, m! H$9, knocking out an
orange, gummy solid. "his 3as removed by filtration, and recrystalli6ed from &, m! boiling ?e9H. After cooling for a fe3 h in an ice bath, the bright
yello3 crystals 3ere removed by filtration, 3ashed 3ith ?e9H and air dried to constant 3eight, yielding $.(& g (@'$@metho/y@0,+@methylenedio/yphenyl-@
$@nitropropene. "he mp 3as (,1@(,2 deg C. :ecrystalli6ation from <t9H raised this mp to (,%.&@((,.& deg C.
A suspension of $.$ g !AH in 0,, m! anhydrous <t$9 under an inert atmosphere 3as brought to a gentle reflu/. "he reflu/ condensate 3as passed
through a modified So/hlet thimble containing (.%& g (@'$@metho/y@0,+@methylenedio/yphenyl-@$@nitropropene effectively adding it, over the course of
,.& h, to the reaction mi/ture as a saturated <t$9 solution. "he mi/ture 3as maintained at reflu/ for (1 h. After cooling to , deg C 3ith an ice bath, the
e/cess hydride 3as destroyed by the addition of (.& 5 H$S9+. "he phases 3ere separated, and the aFueous phase 3ashed 3ith $/(,, m! <t$9. "o
the aFueous phase there 3as added &, g potassium sodium tartrate follo3ed by sufficient $&K 5a9H to raise the pH U%. "his 3as then e/tracted 3ith
0/(,, m! CH$Cl$, and the solvent from the pooled e/tracts removed under vavuum. "he residual 3hite oil 3as dissolved in $&, m! anhydrous <t$9,
and saturated 3ith anhydrous HCl gas. "here 3as produced a crop of 3hite microcrystals of $@metho/y@0,+@methylenedio/yamphetamine hydrochloride
'??;A@0a- 3hich 3as removed by filtration, 3ashed 3ith <t$9, and air dried to a constant 3eight of (.$ g. "he mp 3as (&+@(&& deg C.
;9SAC<E $, @ ), mg.
;4:A"I95E (, @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- I became a3are at about an hour, and an hour later I found myself suddenly caught up in the marvelous 3orld
of insects. :ight alongside a pile of bricks I sa3 a measuring 3orm, and 3ith great tenderness and patience I picked him up, observed his fore and aft
7feet7 and finally replaced him and 3atched him acclimate himself. "here 3as also a spider on the bricks, and I 3as compelled to 3atch him in action. I
3as grateful that I 3as not being observed. "ime 3as moving slo3ly, and I felt I should intentionally move slo3ly, so as not to e/haust myself.
'3ith +, mg- "his developed bet3een one and t3o hours into it, and there 3ere considerable body tremors. "alking directed the energy out3ards, and I
became a3are of a visually sparkling 3orld about me. I started dropping 3ay too soon; it 3ould have been interesting to have gone higher. .y early
evening I 3as left only 3ith an a3areness of some residual physical hypersensitivity, and there 3as light diarrhea. I am not at all sure Gust 3hat to
compare this drug to. It is gentle.
'3ith 1, mg- "here 3ere visuals of a soft sort L things moved 3ith eyes open, and 3ith eyes closed the music 3as great. "here seemed to be some
lasting stimulation, but it didn7t get in the 3ay of sleeping. "he ne/t morning, ho3ever, I 3as still on. A good compound.
<="<5SI95S A5; C9??<5"A:>E "he term ??;A@0a has the feel of being complicated, but there is a reason for the code. As had been mentioned,
??;A 3as the initials for metho/y 'the ?- methylenedio/y 'the ?;- amphetamine 'the A-. And 3ith a molecule of amphetamine there are si/ 3ays of
sticking these t3o groupings on the aromatic ring. "he numbers (@1 had already been assigned to the si/ 3ays of sticking three metho/yl groups onto
an amphetamine molecule '3ith the trimetho/yamphetamines, the "?A7s- and I decided to he3 to the same convention 3ith the methylenedio/y
counterparts. Ho3ever, there are t3o R07s 'the metho/y and the methylenedio/y can go onto the three o/ygen atoms in a ro3 in t3o different 3ays,
3hereas the three metho/ys can go on in Gust one 3ay- and there can be no R1 'since a methylenedio/y must, perforce, have t3o o/ygens that are
adGacent, and there are none to be so found in the $,+,1@orientation of "?A@1-. So, 3ith t3o possible ??;A@07s it becomes reasonable, in fact
essential, to name one of them NaN and the other NbN. "he NaN orientation occurs in nature as the essential oil cro3eacin, or (@allyl@$@metho/y@0,+@
methylenedio/yben6ene. It thus can allo3 ??;A@0a to be classified as an <ssential Amphetamine, since it can arise, in principle, by amination in the
liver in vivo. .ut in the laboratory, cro3eacin is certainly not a practical starting material in this synthesis.
I have been told of a number of clinical trials that have e/plored ??;A@0a at considerably higher levels, but I have no e/plicit Fuotations to give, and the
details are Fuite sketchy. "hree trials at ), milligrams, and one at (,, milligrams, all made comparisons, in both Fuantity and Fuality of the e/perience,
to (,, micrograms of !S;. Ho3ever, t3o events occurred that may or may not be related to these trials; one subGect had a spontaneous peak
e/perience five days after the e/periment, and another made a symbolic suicide attempt.
And, as 3ith ??;A@$, both the $@carbon NphenethylamineN analogue and the +@carbon :A:IA;5<S analogue of ??;A@0a have been made. "he
phenethylamine analog 3as prepared by the condensation of 2.1 g of the above ben6aldehyde 3ith nitromethane 'in acetic acid 3ith ammonium acetate
catalyst, giving &.+ g of the nitrostyrene 3ith a mp of ((&.&@((1.& deg C from methanol- follo3ed by lithium aluminum hydride reduction 'in ether-. "he
product, $@metho/y@0,+@methylenedio/yphenethylamine hydrochloride '$C@0a- melted at (+0@(+& deg C. A series of subGective evaluations 3ere made,
and there are reports of marginal effects in the +, to ($, milligram range. At +, milligrams, perhaps the hint of a psychic energi6er; at 1& milligrams,
there 3as a pleasant mood elevation; at ), milligrams, there 3as a brief paresthetic t3inge noted at about the hour and a half point, and at ($,
milligrams, about the same at one hour, and then nothing. "he fact that there can be such a modest change of effect over a three@fold range of dosage
suggests that this compound might have some merit as an anti@depressant. It 3ould be interesting to kno3 if it blocks serotonin reuptakeO
"he +@carbon analog 3as made similarly 'from the aldehyde and nitropropane but using tert@butylammonium acetate as a reagent in (,,K e/cess and
isopropanol as solvent, giving bright yello3 crystals melting at (,&.&@(,1.& deg C from $& volumes of boiling methanol- follo3ed by reduction '3ith
lithium aluminum hydride in ether- to give (@'$@metho/y@0,+@methylenedio/yphenyl-@$@aminobutane hydrochloride '+C@0a- 3ith a mp of ()0@()& deg C
3ith prior sintering at (20 deg C. "his material has been tasted at up to 0.& milligrams 3ith nothing noted. "here have been no trials at any higher dose.

#1') MM0A-'b; (-METH%+Y-$,'-METHYE#E0"%+YAM,HETAM"#E
S>5"H<SISE A solution of 2., g of %)K pure 'by CC- +@metho/y@$,0@methylenedio/yben6aldehyde 'see under ??;A@0a for its preparation- in 0, m!
glacial acetic acid 3as treated 3ith & m! nitroethane and 0 g anhydrous ammonium acetate, and heated on the steam bath for 0.& h. H$93as added to
the hot solution to the point of turbidity, then it 3as allo3ed to cool to room temperature 3ith occasional stirring. A modest crop of yello3 crystals formed
3hich 3ere removed by filtration, 3ashed 3ith aFueous acetic acid and air dried to constant 3eight. "here 3as obtauned +.1 g of (@'+@metho/y@$,0@
methylenedio/phenyl-@$@nitropropene, 3ith a mp of %&@(,$ deg C. :ecrystalli6ation from <t9H tightened this to %2@(,(.& deg C. "he infra@red spectrum
is completely different from that of its positional isomer (@'$@metho/y@0,+@methylenedio/yphenyl-@$@nitropropene.
A suspension of 2., g !AH in ( ! anhydrous <t$9 under an inert
atmosphere 3as brought to a gentle reflu/. "he reflu/ condensate 3as passed through a So/hlet thimble containing 1.(& g (@'+@metho/y@$,0@
methylenedio/yphenyl-@$@nitropropene 3hich 3as effectively adding the nitropropene as a saturated solution. "he mi/ture 3as maintained at reflu/ for
(1 h. After cooling to , deg C 3ith an ice bath, the e/cess hydride 3as destroyed by the addition of ),, m! of (.& 5 H$S9+. "he phases 3ere
separated, and the aFueous phase 3ashed 3ith $/(,, m! <t$9. "o this phase there 3as added (2& g potassium sodium tartrate follo3ed by sufficient
$&K 5a9H to raise the pH U%. "his 3as then e/tracted 3ith 0/(,, m! CH$Cl$, and the solvent from the pooled e/tracts removed under vacuum. "he
residual off@3hite oil 3eighed &.+ g and 3as dissolved in $&, m! anhydrous <t$9 and saturated 3ith anhydrous HCl gas. "here 3as produced a crop of
slightly sticky 3hite solids that finally became granular and loose. "hese 3ere removed by filtration, 3ashed 3ith <t$9, and air dried to give &.&1 g of +@
metho/y@$,0@methylenedio/yamphetamine hydrochloride '??;A@0b- 3ith a mp of (%1@(%% deg C. A small sample from propanol had a mp of (%%@$,,
deg C, and a sample from nitromethane8?e9H '&E(- had a mp of $,(@$,$ deg C.
;9SAC<E greater than ), mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- ;efinitely active. Lualitatively like ?;A; Fuantitatively perhaps less.
'3ith ), mg- 5o more effective than 1, mg.
<="<5SI95S A5; C9??<5"A:>E And that7s all there is kno3n as to the activity of ??;A@0b in man. Mery, very little. 5othing has ever been tried in
e/cess of ), milligrams that I kno3 of, and the above trials 3ere made over $, years ago. "here can be little argument that the 0b is less effective than
the 0a, but no one can say by ho3 much. "he literature statement is that it is threefold less, but that 3as based on the relative responses at Gust@above@
threshold levels. "he effects here are hand@3avingly similar to those reported for ??;A@0a at $, milligrams, but these are difficult to compare
accurately as they 3ere reported by different people. "here have been absolutely no animal studies reported 3ith ??;A@0b in the scientific literature.
And neither the $@carbon nor the +@carbon analogues of ??;A@0b has even been prepared.
"he remaining ??;A@analogue that has been prepared, is the $,0,1@isomer. "he flo3 diagram started 3ith sesamol '0,+@methylenedio/yphenol- 3hich
3as methylated 3ith methyl iodide, converted to the aldehyde using butyllithium and 5@methylformanilide 'putting the ne3 group directly bet3een the
t3o o/ygen atoms, giving $,0@methylenedio/y@1@metho/yben6aldehyde-, reaction 3ith nitroethane to the nitrostyrene, and its reduction 3ith lithium
aluminum hydride in ether. "he product, 1@metho/y@$,0@methylenedio/yamphetamine hydrochloride '??;A@&- is practically une/plored in man. I have
heard one report that 0, milligrams 3as modestly active, but not a particularly pleasant e/perience. Another person told me that he had tried (&
milligrams, but he neglected to mention if there had been any effects. I have not tried it myself. .ut, I have succumbed to the pressure of the
e/perimental pharmacologists to give a number for the N>@a/isN of their animal behavior studies. So I said to myself, if this is active at 0, milligrams, and
mescaline is active at 0,, milligrams, 3hy not say that it is (,/ the activity of mescalineH So I did. .ut I have absolutely no confidence in that number.
And if the information on ??;A@& is sparse, look at the positional isomer, ??;A@+, 3hich I have discussed under its analogue "?A@+. Here nothing is
kno3n at all, since the compound itself is unkno3n. 5o one has yet found a 3ay of making it.

#1'1 MME; $,(-0"METH%+Y-)-ETH%+YAM,HETAM"#E
S>5"H<SISE A solution 3as made of (11 g ethylvanillin '+@etho/y@0@metho/yben6aldehyde- in 1,, m! glacial acetic acid and arranged so that it can be
stirred continuously, magnetically, and cooled as needed 3ith an e/ternal ice bath. "here 3as then added a total of $() g of +,K peracetic acid in acetic
acid, at a rate that permitted the temperature to stay at $& deg C 3ith the continuous application of the ice bath. "he temperature should not drop belo3
$0 deg C 'the reaction stops- but it absolutely cannot be allo3ed to e/ceed $% deg C 'the reaction can no longer be controlled-. "he addition takes
about (.& h. At the end of the reaction, there 3as added 0 volumes of H$9, and all acids 3ere neutrali6ed 3ith solid $C90. "he 0 or so ! of black,
gooey mess 3as e/tracted 3ith $/+,, m! boiling <t$9 3hich, on pooling and evaporation, provided 1, g of a black oil 3hich 3as a mi/ture containing
mainly the intermediate formate and the product phenol. "his 3as treated 3ith 0,, m! (,K 5a9H, and heated on the steam bath for ( h. After cooling,
this 3as 3ashed 3ith $/(&, m! CH$Cl$ 'discarded-, acidified 3ith HCl, and e/tracted 3ith 0/$,, m! <t$9. "he pooled e/tracts 3ere 3ashed 3ith
$/$,, m! saturated 5aHC90, and then the <t$9 3as removed under vacuum. "he residual black oil, +(.0 g, 3as distilled at (., mm8Hg to give a
fraction boiling at (+,@(+& deg C as a pale amber oil that set up as crystals. "he 3eight of the isolated +@etho/y@0@metho/yphenol 3as $%.( g. An
analytical sample had a mp of +&.&@+1 deg C. "his product can be used either for the synthesis of ??< 'see belo3- or for the synthesis of <?< 'see
separate recipe-. A solution of ,.& g of this phenol, and ,.& g methyl isocyanate in (, m! he/ane containing ( m! CH$Cl$ 3as treated 3ith three drops
of triethylamine. In about ( h, there 3as the spontaneous formation of 3hite crystals of +@etho/y@0@metho/yphenyl 5@methyl carbamate, 3ith a mp of
(,+@(,& deg C.
A solution of (+ g of the distilled, solid +@etho/y@0@metho/yphenol in $, m! ?e9H 3as treated 3ith a solution of &.0 g 9H in (,, m! hot ?e9H. "here
3as then added ((.% g methyl iodide, and the mi/ture 3as held at reflu/ temperature for $ h. "he reaction 3as Fuenched 3ith 0 volumes H$9, made
strongly basic by the addition of ( volume of &K 5a9H, and e/tracted 3ith $/(&, m! <t$9. Pooling the e/tracts and removal of the solvent under
vacuum gave %.2 g of $,+@dimetho/y@(@etho/yben6ene as a clear, off@3hite oil that sho3ed a single peak by CC. An acceptable alternate synthesis of
this ether is the ethylation of $,+@dimetho/yphenol, 3hich is described in the recipe for "?A@+. "he inde/ of refraction 3as n;$& T (.&$(,.
A mi/ture of (2.0 g 5@methylformanilide and (%.1 g P9Cl0 3as allo3ed to stand at room temperature until a strong red color had been generated 'about
,.& h-. "here 3as then added %.$ g $,+@dimetho/y@(@etho/yben6ene and the mi/ture 3as heated on the steam bath for $ h. "he black, viscous product
3as poured onto ),, m! cracked ice, and mechanically stirred. "he deep color gradually faded to a yello3 solution, and then yello3 crystals began to
form. After standing overnight, these 3ere removed by filtration and sucked as dry as possible, yielding (1 g of a 3et, crude product. "his 3as
dissolved in (,, m! boiling ?e9H 3hich, on cooling, deposited fluffy, 3hite crystals of $,+@dimetho/y@&@etho/yben6aldehyde. "he dry 3eight 3as ).) g
and the mp 3as (,2@(,) deg C. "he mother liFuor sho3ed no isomeric aldehydes by CC, but there 3ere small suggestions of isomers seen in the
CH$Cl$ e/tracts of the original 3ater filtration. A sample of ,.2 g of the aldehyde obtained as a second crop from the methanolic mother liFuors 3as
dissolved, along 3ith ,.& g malononitrile, in $, m! hot <t9H. "he addition of 0 drops of triethylamine generated the almost immediate formation of
brilliant yello3 crystals, (.+ g after filtration and <t9H 3ashing, 3ith a mp of (0+@(0&.& deg C. :ecrystalli6ation from toluene gave an analytical sample
of $,+@dimetho/y@&@etho/yben6almalononintrile 3ith a mp of (0&@(01 deg C.
A solution of 1.2 g $,+@dimetho/y@&@etho/yben6aldehyde in $0 g glacial acetic acid 3as treated 3ith 0.0 g nitroethane and $.,& g anhydrous ammonium
acetate. "he mi/ture 3as heated on the steam bath for $.& h. "he addition of a little 3ater to the cooled solution produced a gel 3hich 3as a mi/ture of
starting aldehyde and product nitrostyrene. "he solvent 3as decanted from it, and it 3as triturated under ?e9H, to provide a yello3 solid 3ith a mp of
21@)+ deg C. :ecrystalli6ation from 0, m! boiling ?e9H gave, after filtering and air drying, +.0 g of a yello3 solid 3ith a mp of %,@%$ deg C. "here 3as
still appreciable aldehyde present, and this 3as finally removed by yet another recrystalli6ation from toluene. "he product, (@'$,+@dimetho/y@&@
etho/yphenyl-@$@nitropropene, 3as obtained as bright yello3 crystals 3ith a mp of %1@%2 deg C. "he analytical sample 3as dried in vacuum for $+ h to
completely dispel the tenacious residual traces of toluene. Anal. 'C(0H(259&- C,H.
"o a gently reflu/ing suspension of (.1 g !AH in ($, m! anhydrous <t$9 under a He atmosphere, there 3as added $.( g (@'$,+@dimetho/y@&@
etho/yphenyl-@$@nitropropene by allo3ing the condensing ether to drip into a shunted So/hlet thimble containing the nitrostyrene. "his effectively added,
drop3ise, a 3arm saturated solution of the nitrostyrene to the reaction mi/ture. :eflu/ing 3as continued for 1 h, and after cooling the reaction flask to ,
deg C the e/cess hydride 3as destroyed by the cautious addition of (.& 5 H$S9+. Ihen the aFueous and <t$9 layers 3ere finally clear, they 3ere
separated, and +, g of potassium sodium tartrate 3as dissolved in the aFueous fraction. AFueous 5a9H 3as then added until the pH 3as U%, and this
3as then e/tracted 3ith 0/$,, m! CH$Cl$. <vaporation of the solvent under vacuum produced (.1 g of an amber oil that 3as dissolved in 0,, m!
anhydrous <t$9 and saturated 3ith anhydrous HCl gas. "here 3as an immediate 3hite blush, then there 3as the generation of an oily solid that upon
further administration of HCl became a fine, loose 3hite po3der. "his 3as removed by filtration, <t$9 3ashed, and air dried to give (.1 g $,+@dimetho/y@
&@etho/yamphetamine hydrochloride '??<- 3ith a mp of (2(@(2$ deg C. Anal. 'C(0H$$Cl590- C,H,5.
;9SAC<E +, mg and above.
;4:A"I95 E probably 1 @ (, h.
L4A!I"A"IM< C9??<5"SE '3ith +, mg- At the one hour point there 3as a real threshold, and at the second hour, 3hile I 3as 3alking do3n $+th
Street, there 3as an honest (*. .y the third hour it 3as at, or Gust under a **, 3ith the earmarks of a possibly interesting collection of effects, 3ere it Gust
a bit more intense. I had une/pected diarrhea at hour R&, and by R1 I 3as mending, and by R) I 3as largely do3n. "he day 3as very encouraging, and
this must be re@tried at &, or 1, milligrams.
<="<5SI95S A5; C9??<5"A:>E "his is one of the very fe3 compounds 3ith 3hich I actually risked 'and took- the lives of e/perimental animals. I
3as still impressed by the scientific myth that pharmacological research 3asn7t really acceptable 3ithout animal support data. And I had access to an
e/perimental mouse colony at the 4niversity. I inGected one mouse 3ith a dose of 0,, mg8g., i.p. "hat sounds pretty scientific. .ut 3hat it really
means is that I picked up a mouse by the scruff of the back 3ith my left hand, then turned my hand over so that the mouse 3as belly@up. I put the ring
finger over a hind leg to keep things relatively immobile. 4sually at this point there is a little urine evident 3here there had been none before. And I took
a syringe eFuipped 3ith a very fine needle and containing about ) milligrams of ??< in a fraction of a m! of a 3ater solution and pushed that needle
into the mouse at about 3here the navel 3ould be if one could see the mouse7s navel, and then I pulled the needle back Gust a little so that there should
be nothing at the business end but the loose folds of the peritoneum. "hen I pushed the syringe plunger home, effectively sFuirting the 3ater solution
into the area that surrounds the intestines. I dropped the mouse back into his cage, and 3atched. In this case, the mouse 3ent into a t3itching series of
convulsions 'kno3n as clonic in the trade- and in five minutes he 3as dead.
Bired 3ith the lust for killing, I grabbed another mouse, and nailed him 3ith (2& mg8g. ;ead in 1 minutes. Another one at (,2 mg8g. ;ead in &
minutes. Another at 2& mg8g. Iell, he looked pretty sick there for a 3hile, and had some shakes, and then he seemed to be pretty much 9. 9ne
final orgy of murder. I inGected & mice at (,, mg8g i.p., and 3atched four of them die 3ithin $, minutes. I took in my hands the sole survivor, and I
3ent outside the laboratory and let him loose on the hillside. He scampered a3ay and I never sa3 him again.
And 3hat did I learn, at the cost of seven precious lives 3hich I can never replaceH 5ot a damned thing. ?aybe there is an !;@&, some3here around
1, or ), mg8g. "his is for mice, not for men. I 3as intending to take an initial trial dose of 0,, micrograms of this completely untested compound, and
it 3ould have made no difference to me if the !;@&, had been 1,, mg8g or 1 mg8g. I still took my trial dose, and had absolutely no effects, and I
never killed another mouse again. 5o, that is simply out@and@out dishonest. I had an invasion of field mice last 3inter coming up through a hole in the
floor behind the garbage holder under the kitchen sink, and I blocked the hole, but I also set some mouse traps. And I caught a couple. .ut never again
for the simple and stupid reasons of being able to say that N"his compound has an !;@&, in the mouse of 2, mg8g.N Iho caresH Ihy killH
.ut there are t3o very valuable things that have come out of this simple study 3ith ??<. 9ne is, of course, that it is an active compound and as such
3arrants additional attention. And the other, and even more important, is that as one of the three possible etho/y homologues of "?A@$, it is less active
than ?<?. "he third possible etho/y compound is <?? and, as 3ill be found else3here in this book, it is even less active. "hus it is ?<?, only, that
maintains the potency of "?A@$, and this 3as the initial observation that really focused my attention on the importance of the +@position.
#1'2 M,; META,*%S!A"#E; ',(-0"METH%+Y-)-&n--,*%,%+Y,HE#ETHYAM"#E
S>5"H<SISE "here 3as mi/ed %1 g of &@bromovanillin and %, m! $&K 5a9H. "he solution 3as almost complete, 3hen there 3as a sudden deposition
of a heavy precipitate. "his 3as diluted 3ith $,, m! 3ater. "here 3as then added 0,, m! methylene chloride, )& g methyl iodide, and 0 g
decyltriethylammonium chloride. "he heterogenous mi/ture 3as vigorously stirred for $ days. "he organic phase 3as separated, and the aFueous
phase e/tracted once 3ith (,, m! CH$Cl$. "he organic phase and e/tract 3ere pooled, 3ashed 3ith 3ater and the solvent removed under vacuum
"he residue 3eighed +1.0 g and spontaneously crystalli6ed. It 3as recrystalli6ed from +, m! of ?e9H to yield 0+ g of 0@bromo@+,&@
dimetho/yben6aldehyde as 3hite crystals 3ith a mp of 1,.&@1( deg C. An additional + g product 3as obtained from the mother liFuor. Acidification of
the aFueous phase above produced, after recrystali6ation from IPA8acetone, (0.$ g of recovered &@bromo@vanillin, 3ith a mp of (11@(1% deg C.
A mi/ture of 0).2 g 0@bromo@+,&@dimetho/yben6aldehyde and (2.$ g cyclohe/ylamine 3as heated 3ith an open flame at about ($, deg C until it
appeared to be free of H$9. "he residue 3as put under a vacuum ',.$ mm8Hg- and distilled at (+1@(1, deg C yielding ++.1 g 0@bromo@5@cyclohe/yl@
+,&@dimetho/yben6ylidenimine as a clear oil 3hich did not crystalli6e. "he imine stretch in the infra@red 3as at (1+, cm@(. Anal. 'C(&H$,.r59$- C,H.
A solution of 0(.1 g 0@bromo@5@cyclohe/yl@+,&@dimetho/yben6ylidenimine in 0,, m! anhydrous <t$9 3as placed in an atmosphere of He, stirred
magnetically, and cooled 3ith an dry ice8acetone bath. "hen 2( m! of a (.&& ? solution of butyllithium in he/ane 3as added over a $ min period. "he
reaction mi/ture turned cloudy and a light precipitate formed 3hich seemed heaviest at the half@3ay point. Stirring remained easy and 3as continued for
(, min. "here 3as then added 0& m! of butyl borate at one time. "he precipitate dissolved, and the stirred solution allo3ed to return to room
temperature. "here 3as then added $,, m! of an aFueous solution containing $, g ammonium sulfate. "he <t$9 layer 3as separated, 3ashed 3ith
saturated ammonium sulfate solution, and the organic solvents removed under vacuum. "he residue 3as dissolved in $&, m! of 2,K ?e9H and (+ m!
of 0,K hydrogen pero/ide added in small portions. "his reaction 3as very e/othermic, and stirring 3as continued for ( h. "he reaction mi/ture 3as
then added to &,, m! H$9, 3hich knocked out 3hite solids. A small sample of this intermediate, 5@cyclohe/yl@0,+@dimetho/y@&@hydro/yben6ylidineimine
3as recrystalli6ed from ?e9H to a 3hite crystal 3ith a mp of (+)@(+% deg C and 3hich sho3ed the CT5 bond as a doublet at (10& and (1+& cm@( in
the infra@red. "hese 3et solids 3ere suspended in $,, m! &K HCl and heated on the steam bath for ( h. Stirring 3as continued until the reaction 3as
again at room temperature and then it 3as e/tracted 3ith $/(,, m! CH$Cl$. "hese e/tracts 3ere pooled and in turn e/tracted 3ith $/2& m! dilute
5a9H. "he aFueous e/tracts 3ere reacidified 3ith HCl, and ree/tracted 3ith $/(,, m! CH$Cl$. "hese e/tracts 3ere pooled, and the solvent removed
under vacuum to yield a bro3n viscous oil as a residue. "his 3as distilled at (,&@($, deg C at ,.$ mm8Hg to yield ).) g of 0,+@dimetho/y@&@
hydro/yben6aldehyde as a distillate that set to 3hite crystals. :ecrystalli6ation from toluene8he/ane gave a sample 3ith the mp 1+@1& deg C. "he
literature mps are several, ranging from at about 1, deg C to about 2, deg C.
A solution of +.2 g of 0,+@dimetho/y@&@hydro/yben6aldehyde in 2& m! acetone 3as treated 3ith 1., g po3dered I, (1 m! '$( g- propyl bromide, and 2.,
g finely po3dered anhydrous $C90, and this mi/ture 3as held at reflu/ on a steam bath for (& h. "he reaction mi/ture 3as added to ( ! H$9, made
strongly basic, and e/tracted 3ith 0/(,, m! CH$Cl$. "he e/tracts 3ere pooled, 3ashed 3ith &K 5a9H, and the solvent removed under vacuum
yielding ).) g of a yello3 oil, undoubtedly containing propyl iodide. "his residue 3as distilled at (00@(+& deg C at ,.(& mm8Hg to yield +.& g of 0,+@
dimetho/y@&@'n-@propo/yben6aldehyde as a 3hite oil 3hich did not crystalli6e. "here 3as an appreciable pot residue. "his product 3as clearly impure,
having a minor, slo3er moving component not the starting phenol, as seen by "!C 'on silica gel, 3ith CH$Cl$ as a developing solvent-. Busion of a
small amount of impure aldehyde 3ith p@anisidine produced a crystalline anil 3hich, on hydrolysis 3ith dilute acid, produced an aldehyde sample free of
this impurity. .ut as this sample also remained as an oil, the above crude product 3as used in the follo3ing preparation.
"o a solution of 0.) g 0,+@dimetho/y@&@'n-@propo/yben6aldehyde in &, m! nitromethane, there 3as added ,.& g anhydrous ammonium acetate. "his 3as
held at reflu/ for &, min. "he e/cess nitromethane 3as removed under vacuum and $ volumes of boiling ?e9H 3ere added to the residue. "he hot
solution 3as decanted from some residual insolubles, and on cooling spontaneously crystalli6ed. "hese solids 3ere removed by filtration, 3ashed
sparingly 3ith ?e9H and air dried yielding 0.0 g yello3 crystals of 0,+@dimetho/y@beta@nitro@&@'n-@propo/ynitrostyrene as yello3 crystals melting at 2%@)(
deg C. :ecrystalli6ation from ?e9H or cyclohe/ane neither improved the mp nor freed the product from a residual opalescenceseen in the melt. Anal.
'C(0H(259&- C,H.
A solution of (.& g !AH in 0, m! anhydrous "HB under He 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, (., m! of (,,K
H$S9+, follo3ed by the drop3ise addition of a solution of $.0 g 0,+@dimetho/y@beta@nitro@&@'n-@propo/ynitrostyrene in (, m! anhydrous "HB, over the
course of & min. "he mi/ture 3as stirred at , deg C for a 3hile, and then brought to a reflu/ on the steam bath. After cooling again, the e/cess hydride
3as destroyed 3ith IPA added drop3ise, follo3ed by the addition of about (, m! of (,K 5a9H 3hich 3as sufficient to covert the solids to a 3hite,
granular form. "hese 3ere removed by filtration, the filter cake 3ashed 3ith IPA, the mother liFuor and filtrates 3ere combined, and the solvents 3ere
removed under vacuum to yield an amber oil. "his residue 3as added to 2& m! dilute H$S9+ 3hich produced a gummy insoluble phase 3hich 3as
physically removed 3ith a spatula. "he aFueous phase 3as 3ashed 3ith 0/&, m! CH$Cl$. It 3as then made basic 3ith $&K 5a9H, and e/tracted 3ith
$/2& m! CH$Cl$. "he solvent 3as removed from these pooled e/tracts and the residue distilled at (,1@((1 deg C at ,.$ mm8Hg to provide (.0 g of the
product as a colorless liFuid. "his 3as dissolved in + m! IPA, neutrali6ed 3ith about $, drops of concentrated HCl, and diluted 3ith + volumes of
anhydrous <t$9 added slo3ly 3ith continuous stirring. A 3hite crystalline salt crystalli6ed out spontaneously and 3as isolated by filtration, 3ashed first
3ith IPA, then 3ith <t$9, and air dried giving (.0 g 0,+@dimetho/y@&@'n-@propo/yphenethylamine hydrochloride '?P- 3ith a mp of (2,@(2( deg C. Anal.
'C(0H$$Cl590- C,H.
;9SAC<E greater than $+, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (1, mg- "here might have been some disturbance at the three to four hour point, but it 3as e/tremely light if at all.
'3ith $+, mg- 5o effects 3hatsoever.
<="<5SI95S A5; <=":AP9!A"I95SE "he loss of activity on lengthening the carbon chain on the meta@o/ygen from t3o to three 'from metaescaline
to metaproscaline- discouraged any further e/ploration at this specific point of the molecule. "he isopropyl analog '0,+@dimetho/y@&@'i-@
propo/yphenethylamine, metaisoproscaline, ?IP- 3as started and carried along as far as the aldehyde, and abandoned 3ith the discovery that
metaproscaline 3as 3ithout activity. "here 3ere other fish to fry.

#1'3 M,M; $,)-0"METH%+Y-(-&n--,*%,%+YAM,HETAM"#E
S>5"H<SISE "o a solution of 1) g $,&@dimetho/yben6aldehyde in $&, m! glacial acetic acid that had been 3armed to $& deg C and 3ell stirred, there
3as added, drop3ise, )1 g of a +,K peracetic acid solution 'in acetic acid-. "he reaction 3as e/othermic, and the rate of addition 3as dictated by the
need to maintain the internal temperature 3ithin a fe3 degrees of $) deg C. </ternal cooling 3as used as needed. "he addition took ( h, and 3hen the
reaction had clearly been completed 'there 3as no further temperature rise- the entire reaction mi/ture 3as added to 0 volumes of H$9. "he e/cess
acid 3as neutrali6ed 3ith solid $C90. "he dark solution 3as e/tracted 3ith 0/(,, m! <t$9, the e/tracts pooled, and stripped of solvent under vacuum
to give &% g of crude $,+@dimetho/yphenyl formate. "his 3as suspended in $,, m! (,K 5a9H, and the mi/ture heated on the steam bath for ( h. 9n
cooling, the reaction mi/ture 3as 3ashed 3ith $/$,, m! methylene chloride, acidified 3ith HCl, and e/tracted 3ith 0/$,, m! CH$Cl$. "he e/tracts
3ere pooled and the solvent removed under vacuum. "here remained as residue, +2.+ g $,&@dimetho/yphenol 3hich 3as deep amber in color, but clear
and fluid. It 3as homogenous by CC and completely correct by 5?:. It 3as used 3ithout further purification.
"o a solution of 0.,) g $,&@dimetho/yphenol in $, g ?e9H, there 3as added a solution of (.$1 g flaked 9H in $, g hot ?e9H. "here 3as then added
$.+1 g n@propyl bromide, and the mi/ture held at reflu/ for $ h on the steam bath. "his 3as Fuenched in & volumes H$9, made strongly basic 3ith (,K
5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent from the pooled e/tracts left $., g of (,+@dimetho/y@$@'n-@propo/yben6ene as a
clear, amber oil. "he I: spectrum 3as appropriate, no phenol 3as present, and this residue 3as used in the follo3ing reaction 3ithout further
purification or characteri6ation.
A mi/ture of 0.& g 5@methylformanilide and +., g P9Cl0 3as held at room temperature for ,.& h producing a deep red color. "o this there 3as added $.,
g (,+@dimetho/y@$@'n-@propo/yben6ene, and the mi/ture 3as held on the steam bath for (.2& h. It 3as then poured over +,, m! shaved ice, and
vigorous stirring 3as maintained until the dark comple/ had completely broken up. "his aFueous mi/ture 3as allo3ed to stand overnight, and the crude
aldehyde solids that had formed 3ere removed by filtration, 3ater 3ashed, and sucked as dry as possible. "his $., g damp material 3as crystalli6ed
from $, m! boiling ?e9H giving, after filtering and drying to constant 3eight, (.+ g $,&@dimetho/y@+@'n-@propo/yben6aldehyde as reddish@tan solids, 3ith
a mp of %2@%) deg C. "o the methanolic mother liFuors of this crystalli6ation there 3as added a gram of malononitrile and a fe3 drops of triethylamine.
"he eventual addition of a little H$9 encouraged the separation of crystals 3hich 3ere removed, and had a mp of (&,@(&$ deg C. :ecrystalli6ation from
toluene gave gold@colored crystals of the ben6almalononitrile 3ith a mp of (&0.&@(&& deg C, but the melt remained slightly cloudy.
"o a solution of (.+ g $,&@dimetho/y@+@'n-@propo/yben6aldehyde and ,.1& g nitroethane in +.+ g glacial acetic acid there 3as added ,.+ g anhydrous
ammonium acetate, and the mi/ture 3as heated on the steam bath for & h. "he addition of a modest amount of H$9 and scratching 3ith a glass rod
produced crystal seed. "he reaction 3as diluted 3ith about & m! H$9, seeded, and allo3ed to stand at room temperature overnight. "here 3as
generated a crystalline product 3hich 3as removed by filtration and air dried. "here 3as thus obtained ,.1 g (@'$,&@dimetho/y@+@'n-@propo/yphenyl-@$@
nitropropene as yello3@orange crystals, 3ith a mp of )0@)+ deg C. "he addition of H$9 to the mother liFuors provided an additional ,.0 g of an orange
solid 3hich proved to be largely unreacted starting aldehyde.
"o a stirred, 3arm suspension of ,.& g !AH in $, m! anhydrous <t$9 under a He atmosphere, there 3as added ,.1 g (@'$,&@dimetho/y@+@'n-@
propo/yphenyl-@$@nitropropene dissolved in a little anhydrous <t$9. "he mi/ture 3as heated and stirred for a fe3 h, and the e/cess hydride
decomposed 3ith 0, m! (.& 5 H$S9+. "he t3o layers 3ere separated, and (& g potassium sodium tartrate 3as dissolved in the aFueous fraction.
AFueous 5a9H 3as then added until the pH 3as U%, and this 3as then e/tracted 3ith 0/&, m! CH$Cl$. :emoval of the solvent under vacuum gave ,.2
g of an amber oil that 3as dissolved in anhydrous <t$9 and saturated 3ith anhydrous HCl gas. 5o crystals formed, and so the ether 3as removed under
vacuum, leaving a residue that set up to crystals that 3ere then no longer soluble in ether. "hey 3ere, ho3ever, very soluble in chloroform. "hese 3ere
ground under dry <t$9, removed by filtration, and air dried giving ,.0& g $,&@dimetho/y@+@'n-@propo/yamphetamine hydrochloride '?P?- 3ith a mp of
($0 @ ($& deg C.
;9SAC<E 0, mg or more.
;4:A"I95E probably short.
L4A!I"A"IM< C9??<5"SE '3ith (& mg- "his is Gust barely threshold. A marginal into/ication at best. "his level is producing less response that the ((
mg. trial of ?<?, so the propo/y is off in potency. At four and a half hours I am out of 3hatever little there 3as.
'3ith 0, mg- .y the mid@second hour, I am at a valid plus one. I cannot identify the nature L 3ith eyes closed it 3ould be lost, as it 3ould also be if I
3ere 3atching a play or movie. It 3ould have been interesting to see 3here it could have gone. Seventh hour, completely clear.
<="<5SI95S A5; C9??<5"A:>E "he +@propo/y homologue of "?A@$ and ?<? is clearly less active, and this has discouraged me from putting too
much more effort in this direction. "hree additional materials of this pattern 3ere prepared and either sho3n to be even less active, or simply 3ere not
assayed at all. "hese are the +@isopropo/y isomer '?IP?-, the 'n-@buto/y homologue '?.?-, and the 'n-@amyl homologue '?A?-. "hey scarcely
3arrant separate recipes as they 3ere all made in a manner similar to this one describing ?P?.
Bor the preparation of ?IP?, the above phenol, $,&@dimetho/yphenol 3as isopropylated 3ith isopropyl bromide in methanolic 9H giving $,&@dimetho/y@
(@'i-@propo/yben6ene as an oil. "his formed the ben6aldehyde 3ith the standard Milsmeier conditions, 3hich melted at 22@2) deg C from he/ane and
3hich gave a yello3 malononitrile derivative melting at (2(.&@(20 deg C. "he nitrostyrene, from nitroethane in acetic acid 3as orange colored and
melted at (,,@(,( deg C from either methanol or he/ane. "his 3as reduced 3ith lithium aluminum hydride in ether to give $,&@dimetho/y@+@'i-@
propo/yamphetamine hydrochloride '?IP?-. "he properties of the isolated salt 3ere strange 'soluble in acetone but not in 3ater- and the microanalysis
3as lo3 in the carbon value. "he molecular structure had a pleasant appeal to it, 3ith a complete reflection symmetry sho3n by the atoms of the
amphetamine side chain and the isopropo/y side chain. .ut the nature of the actual product in hand had no appeal at all, and no assay 3as ever
started.
Bor the preparation of ?.?, the starting phenol 3as alkylated to $@'n-@buto/y@(,+@dimetho/yben6ene in methanolic 9H 3ith n@butyl bromide. "he
ben6aldehyde melted at 2%.&@)( deg C from methanol, and formed a malononitrile derivative that had a melting point of (0+.&@(0& C. "he nitrostyrene
from the aldehyde and nitroethane in acetic acid crystalli6ed from methanol 3ith a mp of 2(@2$ deg C. !ithium aluminum hydride reduction in ether gave
the ether@insoluble chloroform@soluble product +@'n-@buto/y@$,&@dimetho/yamphetamine hydrochloride '?.?- 3ith a melting point of ($)@(0, deg C.
"his product met all tests for structural integrity, and assays 3ere started. At levels of up to ($., milligrams, there 3ere no effects noted.
As to the preparation of ?A?, the e/act same seFuence 3as used, e/cept for the employment of n@amyl bromide. "he ben6aldehyde crystalli6ed from
methanol 3ith a mp of 2%@), deg C, and formed a malononitrile derivative 3hich 3as bright yello3 and melted at (,0@(,+ deg C. "he nitrostyrene, 3hen
pure, melted at &2@&).& deg C but proved very difficult to separate from the aldehyde. "he final product, +@'n-@amyl@$,&@dimetho/yamphetamine
hydrochloride '?A?- 3as obtained by lithium aluminum hydride reduction in ether and melted at ($&@($2 deg C. It 3as assayed at up to (1 milligrams,
at 3hich level there 3as noted a heaviness in the chest and head at the $@hour point, but no cardiovascular disturbance and no mydriasis. "his 3as
called an inactive level, and no higher one has yet been tried.
#1'4 %*TH%-0%T; (,)-0"METH%+Y-$-METHYTH"%AM,HETAM"#E
S>5"H<SISE "o $1.+ g veratrol that 3as being magnetically stirred 3ithout any solvent, there 3as added &, g chlorosulfonic acid a bit at a time over the
course of $, min. "he reaction 3as e/othermic, and evolved considerable HCl. "he deeply colored mi/ture that resulted 3as poured over +,, m!
crushed ice and 3hen all had tha3ed, it 3as e/tracted 3ith $/(&, m! CH$Cl$. :emoval of the solvent under vacuum gave a residue that set up as a
crystalline mass. "he 3eight of the crude 0,+@dimetho/yben6enesulfonyl chloride 3as 02.( g and it had a mp of 10@11 deg C. :ecrystalli6ation raised
this to 2$@20 deg C. :eaction 3ith ammonium hydro/ide gave the sulfonamide as colorless needles from <t9H, 3ith a mp of (0$@(00 deg C.
"he finely pulveri6ed 0,+@dimetho/yben6enesulfonyl chloride '00 g- 3as added to %,, m! of crushed ice in a $ ! round@bottomed flask eFuipped 3ith a
heating mantle and reflu/ condenser. "here 3as then added && m! concentrated H$S9+ and, 3ith vigorous mechanical stirring, there 3as added &, g
of 6inc dust in small portions. "his mi/ture 3as heated until a vigorous reaction ensued and reflu/ing 3as continued for (.& h. After cooling to room
temperature and decantation from unreacted metallic 6inc, the aFueous phase 3as e/tracted 3ith 0/(&, m! <t$9. "he pooled e/tracts 3ere 3ashed
once 3ith saturated brine and the solvent 3as removed under vacuum. "he residue 3as distilled to give $,.) g of 0,+@dimetho/ythiophenol boiling at )1@
)) deg C at ,.+ mm8Hg.
A solution of (, g 0,+@dimetho/ythiophenol in &, m! absolute <t9H 3as protected from the air by an atmosphere of 5$. "here 3as added a solution of
& g )&K 9H in ), m! <t9H. "his 3as follo3ed by the addition of 1 m! methyl iodide, and the mi/ture 3as held at reflu/ for 0, min. "his 3as poured
into $,, m! H$9 and e/tracted 3ith 0/&, m! <t$9. "he pooled e/tracts 3ere 3ashed once 3ith aFueous sodium hydrosulfite, then the organic solvent
3as removed under vacuum. "he residue 3as distilled to give (,.0 g of 0,+@dimetho/ythioanisole 3ith a bp of %+@%& deg C at ,.+ mm8Hg. "he product
3as a colorless oil that crystalli6ed on standing. Its mp 3as 0(@0$ deg C.
"o a mi/ture of (& g P9Cl0 and (+ g 5@methylformanilide that had been 3armed briefly on the steam bath there 3as added ).$ g of 0,+@
dimetho/ythioanisole, the e/othermic reaction 3as heated on the steam bath for an additional $, min, and then poured into $,, m! H$9. Stirring 3as
continued until the insolubles had become completely loose and granular. "hese 3ere removed by filtration, 3ashed 3ith H$9, sucked as dry as
possible, and then recrystalli6ed from (,, m! boiling <t9H. "he product, +,&@dimetho/y@$@'methylthio-ben6aldehyde, 3as an off@3hite solid, 3eighing
).,& g and having a mp of (($@((0 deg C. Anal. 'C(,H($90S- C,H.
A solution of $., g +,&@dimetho/y@$@'methylthio-ben6aldehyde in ) m! nitroethane 3as treated 3ith ,.+& g anhydrous ammonium acetate and heated on
the steam bath for +.& h. :emoval of the e/cess solvent under vacuum gave a red residue 3hich 3as dissolved in & m! boiling ?e9H. "here 3as the
spontaneous formation of a crystalline product 3hich 3as recrystalli6ed from $& m! boiling ?e9H to give, after cooling, filtering and air drying, (.)& g of
(@'+,&@dimetho/y@$@methylthiophenyl-@$@nitropropene as bright orange crystals 3ith a mp of (,+@(,& deg C. Anal. 'C($H(&59+S- C,H,5.
A suspension of (.0 g !AH in &, m! anhydrous "HB 3as placed under an inert atmosphere and stirred magnetically. Ihen this had been brought to
reflu/ conditions, there 3as added, drop3ise, (.1& g of (@'+,&@dimetho/y@$@methylthiophenyl-@$@nitropropene in $, m! "HB. "he reaction mi/ture 3as
maintained at reflu/ for () h. After being brought back to room temperature, the e/cess hydride 3as destroyed by the addition of (.0 m! H$9 in (, m!
"HB. "here 3as then added (.0 m! of 05 5a9H follo3ed by an additional 0.% m! H$9. "he loose, inorganic salts 3ere removed by filtration, and the
filter cake 3ashed 3ith additional $, m! "HB. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum yielding a light yello3 oil as a
residue. "his 3as dissolved in $, m! IPA, neutrali6ed 3ith ,.% m! concentrated HCl, and diluted 3ith $,, m! anhydrous <t$9. "here 3as thus formed
(.$, g of +,&@dimetho/y@$@methylthioamphetamine hydrochloride '9:"H9@;9"- as a pale yello3 crystalline product. "his melted at $()@$(%.& deg C,
and recrystalli6ation from <t9H yielded a 3hite product and increased the mp to $$$@$$0 deg C 3ith decomposition Anal. 'C($H$,Cl59$S- C,H,5.
;9SAC<E greater than $& mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $& mg- Mague a3areness, 3ith the feeling of an impending something. !ight food sat uncomfortably. .y the late
afternoon there 3as absolutely nothing. "hreshold at best.
<="<5SI95S A5; C9??<5"A:>E "his material, 9:"H9@;9", can be looked at as the sulfur homologue of "?A@$ 3ith the sulfur atom located in
place of the o/ygen at the $@position of the molecule. At 3hat level this compound might sho3 activity is completely unkno3n, but 3herever that might
be, it is at a dosage greater than that for the PA:A@;9" isomer, A!<PH@( 'or A!<PH-, 3hich 3as fully active at (, milligrams 'A!<PH can be looked at
as "?A@$ 3ith the sulfur atom located in place of the o/ygen at the +@position of the molecule-. A lot of variations are easily makable based on this
structure, but 3hy botherH A!<PH is the much more appealing candidate for structural manipulation.

#1(5 ,; ,*%S!A"#E; ',)-0"METH%+Y-(-&n--,*%,%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of &.) g of homosyringonitrile 'see under < for its synthesis-, (,, mg decyltriethylammonium iodide, and (, g n@propyl bromide
in &, m! anhydrous acetone 3as treated 3ith 1.% g finely po3dered anhydrous $C90 and held at reflu/ for (, h. An additional & g of n@propyl bromide
3as added to the mi/ture, and the reflu/ing continued for another +) h. "he mi/ture 3as filtered, the solids 3ashed 3ith acetone, and the combined
filtrate and 3ashes stripped of solvent under vacuum. "he residue 3as suspended in acidified H$9, and e/tracted 0/(2& m! CH$Cl$. "he pooled
e/tracts 3ere 3ashed 3ith $/&, m! &K 5a9H, once 3ith dilute HCl '3hich lightened the color of the e/tract- and then stripped of solvent under vacuum
giving %., g of a deep yello3 oil. "his 3as distilled at (0$@(+$ deg C at ,.0 mm8Hg to yield +.) g of 0,&@dimetho/y@+@'n-@propo/yphenylacetonitrile as a
clear yello3 oil. Anal. 'C(0H(2590- C H 5.
A solution of +.2 g 0,&@dimetho/y@+@'n-@propo/yphenylacetonitrile in $, m! "HB 3as treated 3ith $.+ g po3dered sodium borohydride. "o this 3ell@stirred
suspension there 3as added, drop3ise, (.& m! trifluoroacetic acid. "here 3as a vigorous gas evolution from the e/othermic reaction. Stirring 3as
continued for ( h, then all 3as poured into 0,, m! H$9. "his 3as acidified cautiously 3ith dilute H$S9+, and 3ashed 3ith $/2& m! CH$Cl$. "he
aFueous phase 3as made basic 3ith dilute 5a9H, e/tracted 3ith $/2& m! CH$Cl$, the e/tracts pooled, and the solvent removed under vacuum. "he
residue 3as distilled at ((&@($& deg C at ,.0 mm8Hg to give (.& m! of a colorless oil 3hich upon dissolving in & m! IPA, neutrali6ing 3ith $2 drops
concentrated HCl, and dilution 3ith $& m! anhydrous <t$9 yielded (.& g 0,&@dimetho/y@+@'n-@propo/yphenethylamine hydrochloride 'P- as spectacular
3hite crystals. "he catalytic hydrogenation process for reducing the nitrile 'see under <- also succeeded 3ith this material. "he mp 3as (2,@(2$ deg C.
Anal. 'C(0H$$Cl590- C,H,5.
;9SAC<E 0, @ 1, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith 0, mg- Proscaline dulled my sense of pain and made the other senses really sharp. <verything felt really soft, and
clean and clear. I could feel every hair my hand 3as touching. I felt so rela/ed and at ease. I kno3 that under the appropriate circumstances, this
material 3ould lead to uninhibited eroticism.
'3ith 0& mg- "he 3hole e/periment 3as very Fuiet. "here 3as no nystagmus, no anore/ia, and insignificant visuals 3ith the eyes closed. I 3as restless
3ith a bit of tremor for the first couple of hours, and then became dro3sy. Iould I do this againH Probably not. It doesn7t seem to offer anything e/cept
speculation about the nature of the high. "he high 3as pleasant, but Fuite uneventful.
'3ith +, mg- Bor me there 3as a deep feeling of peace and contentment. "he euphoria gro3s in intensity for several hours and remains for the rest of
the day making this one of the most enGoyable e/periences I have ever had. It 3as marvel@ous talking and Goking 3ith the others. Ho3ever, I 3as a little
disappointed that there 3as no enhanced clarity and no deep reali6ations. "here 3as not a problem to be found. "here 3ere no motivations to discuss
anything serious. If I had any obGection, it 3ould be 3ith the name, not the pharmacology.
'3ith 1, mg- "he development of the into/ication 3as complete in a couple of hours. I feel that there is more physical effect than mental, in that there is
considerable irritability. "his should probably be the ma/imum dose. ;espite feeling Fuite drunk, my thinking seems straight. "he effects 3ere already
3aning by the fifth hour, but sleep 3as not possible until after the t3elth hour. "here 3as no hangover the ne/t day.
<="<5SI95S A5; C9??<5"A:>E "here is a very early report describing the human use of proscaline tucked a3ay in the C6echoslovakian literature
that describes e/periments at up to ), milligrams. At these dosages, there 3ere reported some difficulty 3ith dreams, and the residual effects 3ere still
apparent even after ($ hours.
"he amphetamine homologue of proscaline, 0,&@dimetho/y@+@'n-@propo/y@amphetamine is an une/plored compound. Its synthesis could not be achieved
in parallel to the description given for P. :ather, the propylation of syringaldehyde to give 0,&@dimetho/y@+@'n-@propo/yben6aldehyde, follo3ed by
coupling 3ith nitroethane and the reduction of the formed nitrostyrene 3ith lithium aluminum hydride 3ould be the logical process. Bollo3ing the
reasoning given under <, the initials for this base 3ould be 0C@P, and I 3ould guess it 3ould be active, and a psychedelic, in the $, to +, milligram
range.

#1(1 ,E; ,HE#ES!A"#E; ',)-0"METH%+Y-(-,HE#ETHY%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of &.) g homosyringonitrile 'see under < for its preparation- in &, m! of acetone containing (,, mg decyltriethylammonium
iodide, there 3as added (+.) g beta@phenethylbromide and 1.% g of finely po3dered anhydrous $C90. "he greenish mi/ture 3as reflu/ed for 0 days,
3ith t3o additional + g batches of anhydrous $C90 being added at $+ h intervals. After addition to aFueous base, the product 3as e/tracted 3ith
CH$Cl$, the pooled e/tracts 3ere 3ashed 3ith dilute base 'the organic phase remained a deep purple color- and then finally 3ith dilute HCl 'the organic
phase became a pale yello3-. "he solvent 3as removed giving (&.1 g crude 0,&@dimetho/y@+@phenethylo/yphenylacetonitrile 3hich distilled at (1&@()&
deg C at ,.0 mm8Hg to yield 0,&@dimetho/y@+@phenethylo/yphenylacetonitrile as a reddish viscous oil 3eighing ).( g. Anal. 'C()H(%590- C,H.
A solution of 2.% g of distilled 0,&@dimetho/y@+@phenethylo/yphenylacetonitrile in (& m! dry "HB 3as added to a , deg C solution of AH prepared from a
vigorously stirred solution of +.1 g !AH in (1, ml "HB 3hich had been treated, at , deg C 3ith 0.1 m! (,,K H$S9+ under an atmosphere of He. "he
gelatinaceous reaction mi/ture 3as brought to a brief reflu/ on the steam bath, then cooled again. It 3as treated 3ith & m! IPA 3hich destroyed the
unreacted hydride, follo3ed by sufficient (&K 5a9H to give loose, 3hite filterable solids. "hese 3ere removed by filtration and 3ashed 3ith "HB. "he
filtrate and the 3ashes 3ere combined and, after removal of the solvent under vacuum, there remained 2.) g of the product as a crude base 3hich
crystalli6ed spontaneously. ;istillation of this product at (2,@(), deg C at ,.0& mm8Hg gave &.( g 3hite solids, 3ith a mp of )&@)1 deg C from he/ane.
"his base 3as dissolved in $, m! 3arm IPA and treated 3ith (.1 m! concentrated HCl. "o the resulting clear solution, there 3as added 2& m!
anhydrous <t$9 3hich gave, after a fe3 moments of stirring, a spontaneous crystalli6ation of 0,&@di@metho/y@+@phenethylo/yphenethylamine
hydrochloride 'P<- as beautiful 3hite crystals. "he 3eight 3as &.+ g after air drying, and the mp 3as (&(@(&$ deg C. Anal. 'C()H$+Cl590- C,H.
;9SAC<E greater than (&, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (&, mg- At most, there 3as a bare threshold over the course of the afternoon. A vague unreal feeling, as if I had not
had Fuite enough sleep last night. .y late afternoon, even this had disappeared and I 3as left 3ith an uncertainty that anything at all had occurred.
<="<5SI95S A5; C9??<5"A:>E "here is not much there, so there is not much to make commentary on. "his response is called a NthreshholdN
effect, and cannot be used to predict 3ith any confidence Gust 3hat level 'if any- 3ould produce psychological effects.
A similar chain on the +@position, but 3ith one less carbon atom, deserves special comment. :ather than a phenethylo/y group, this 3ould be ben6ylo/y
group '3hich in this day and age of Chemical Abstracts purity should probably be called a phenylmetho/y group-. If one 3ere to follo3 the naming
philosophy of :proscaline eFuals P and buscaline eFuals .S convention, one 3ould call it +@ben6escaline, and give it the code name .A. "he
nomenclature purist 3ould probably call the compound P? 'for phenylmescaline or, more likely phenylmetho/ydimetho/yphenethylamine-, since the
term .A is a3k3ard and misleading. It is a code name that has been given to a potent C5S agent kno3n as Fuinuclidin@0@yl ben6ilate, 3hich is a
chemical and biological 3arfare 'C.I- incapacitating agent currently being stored by the military to the e/tent of $,,,,, pounds. And, .A has also
recently become the Gargon name given to ben6odia6epine receptors. "hey have been called the .A@receptors.
Ho3ever, let7s be a3k3ard and misleading, and call this ben6ylo/y@base .A. Bor one thing, the three@carbon analogue 0C@.A has already been
described in its o3n recipe using this code. And the +@fluoroanalogue of it, 0C@B.A, is also mentioned there. And .A has already been described
synthetically, having been made in e/actly the procedure given for escaline, e/cept that the reduction of the nitrile 3as not done by catalytic
hydrogenation but rather by sodium borohydride in the presence of cobalt chloride. It has been sho3n to be a effective serotonin agonist, and may
3arrant human e/perimentation. "he serotonin activity suggests that it might be active at the same levels found for proscaline.
All of this says very little about P<. .ut then, there is very little to say about P< e/cept that it may be active at very high levels, and I am not sure Gust
ho3 to get there safely.

#1($ ,EA; ,HE#ETHYAM"#E
S>5"H<SISE "his compound has been made industrially by a number of routes, the motant being the reduction of ben6yl cyanide and the
decarbo/ylation of phenylanaline. It is offered in the catalogs of all the maGor chemical supply houses for a fe3 pennies per gram. It is a very strong
base 3ith a fishy smell, and rapidly forms a solid carbonate salt upon e/posure to the air. It is a natural biochemical in both plants and animals.
;9SAC<E greater than (1,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $,,, +,,, ),, and (1,, mg- 5o effects.
'3ith &,, mg- 5o effects.
'3ith ),, and (1,, mg- 5o effects.
'3ith $& and &, mg i.v.- :5o effects.
<="<5SI95S A5; C9??<5"A:>E Here is the chemical that is central to this entire book. "his is the structural point of departure for every compound
that is discussed here. It is the :PS in PIHA!. It is 3ithout activity in manO Certainly not for the lack of trying, as some of the dosage trials that are
tucked a3ay in the literature 'as abstracted in the NLualitative CommentsN given above- are pretty heavy duty. Actually, I truly doubt that all of the
e/perimenters used e/actly that phrase, N5o effects,N but it is patently obvious that no effects 3ere found. It happened to be the phrase I had used in my
o3n notes.
"his, the simplest of all phenethylamines, has al3ays been the darling of the psychopharmacologists in that it is structurally clean, it is naturally present
in various human fluids and tissues, and because of its close chemical relationship to amphetamine and to the neurotransmitters. "hese facts
continuously encourage theories that involve P<A in mental illness. Its levels in urine may be decreased in people diagnosed as being depressed. Its
levels may be increased in people diagnosed as being paranoid schi6ophrenics. ?aybe it is also increased in people under e/treme stress. "he human
trials 3ere initially an attempt to provoke some psychological change, and indeed some clinicians have reported intense headaches generated in
depressives follo3ing P<A administration. .ut then, others have seen nothing. "he studies evolved into searches for metabolic difference that might be
of some diagnostic value. And even here, the Gury is still out.
Phenethylamine is found throughout nature, in both plants and animals. It is the end product of phenylalanine in the putrefaction of tissue. 9ne of its
most populari6ed occurrences has been as a maGor component of chocolate, and it has hit the Sunday Supplements as the love@sickness chemical.
"hose falling out of love are compulsive chocolate eaters, trying to replenish and repair the body7s loss of this compound L or so the myth goes. .ut this
amine is voraciously metaboli6ed to the apparently inactive compound phenylacetic acid, and to some tyramine as 3ell. .oth of these products are also
normal components in the body. And, as a 3ry side@comment, phenylacetic acid is a maGor precursor in the illicit synthesis of amphetamine and
methamphetamine.
Phenethylamine is intrinsically a stimulant, although it doesn7t last long enough to e/press this property. In other 3ords, it is rapidly and completely
destroyed in the human body. It is only 3hen a number of substituent groups are placed here or there on the molecule that this metabolic fate is avoided
and pharmacological activity becomes apparent.
"o a large measure, this book has emphasi6ed the NphenylN end of the phenethylamine molecule, and the N3hat,N the N3here,N and the Nho3
manyN of the substituent groups involved. "here is a broad variety of chemical groups that can be attached to the ben6ene ring, at one or more of the
five available positions, and in an unending number of combinations. And, in any given molecule, the greater the number of substituents on the ben6ene
ring, the greater the likelihood that there 3ill be psychedelic action rather that stimulant action.
.ut 3hat can be said about the NethylamineN end of the phenethylamine moleculeH "his is the veritable backbone that holds everything
together, and simple changes here can produce ne3 prototypes that can serve as starting points for the substituent game on the ben6ene ring. "hus,
Gust as there is a NfamilyN of compounds based on the foundation of phenethylamine itself, there is an eFually varied and rich NfamiliesN of other
compounds that might be based on some phenethylamine 3ith a small modification to its backbone.
So, for the moment, leave the aromatic ring alone, and let us e/plore simple changes in the ethylamine chain itself. And the simplest structural
unit of change is a single carbon atom, called the methyl group. Ihere can it be placedH
"he adding of a methyl group adGacent to the amine produces phenylisopropylamine, or amphetamine. "his has been e/ploited already as one of the
richest families of psychedelic drugs; and over half of the recipes in .ook II are specifically for amphetamine analogues 3ith various substituents on the
aromatic ring. "he further methylation of amphetamine 3ith yet another methyl group, this time on the nitrogen atom, yields methamphetamine. Here
the track record 3ith various substituents on the aromatic ring is not nearly as good. ?any have been e/plored and, 3ith one e/ception, the Fuality and
potency of human activity is do3n. .ut the one e/ception, the 5@methyl analogue of ?;A, proved to be the most remarkable ?;?A.
"he placement of the methyl group bet3een the t3o carbons 'so to speak- produces a cyclopropyl system. "he simplest e/ample is $@
phenylcyclopropylamine, a drug 3ith the generic name of tranylcypromine and the trade name Parnate. It is a mono@amine o/idase inhibitor and has
been marketed as an antidepressant, but the compound is also a mild stimulant causing insomnia, restlessness and photophobia. Substitutions on the
ben6ene ring of this system have not been too promising. "he ;9? analogue, $,&@dimetho/y@+@methyltranylcypromine is active in man, and is
discussed in its o3n recipe under ;?CPA. "he inactive mescaline analogue "?" is also mentioned there.
"he dropping of one carbon from the phenethylamine chain gives a ben6yl amine, basically an inactive nucleus. "3o families deserve mention,
ho3ever. "he phencylidine area, phenylcyclohe/ylpiperidine or PCP, is represented by a number of ben6yl amines. etamine is also a ben6yl amine.
"hese are all analgesics and anesthetics 3ith central properties far removed from the stimulant area, and are not really part of this book. "here is a
ben6yl amine that is a pure stimulant, 3hich has been closely compared to amphetamine in its action "his is ben6ylpipera6ine, a base that is active in
the $, to (,, milligram range, but 3hich has an acceptability similar to amphetamine. If this is a valid stimulant, I think that much magic might be found
in and around compounds such as '(- the ?;?A analogue, 5@'0,+@methylenedio/yben6yl-pipera6ine 'or its 5@methyl@counterpart 5@'0,+@
methylenedio/yben6yl-@57@methylpipera6ine- or '$- the ;9? analogue, $,&@dimetho/y@+@methylben6ylpipera6ine. "he ben6yl amine that results by the
relocation of the amine group of ?;A from the beta@carbon atom to the alpha@carbon atom is kno3n, and is active. It, and its 5@methyl homologue, are
described and discussed in the commentary under ?;A. ;ropping another carbon atom gives a yet shorter chain 'no carbons at allO- and this is to be
found in the phenylpipera6ine analogue 0@trifluoromethylphenylpipera6ine. I have been told that this base is an active hallucinogen as the
dihydrobromide salt at &, milligrams sublingually, or at (& milligrams intravenously in man. "he corresponding 0@chloro analogue at $, to +, milligrams
orally in man or at ) milligrams intravenously, led to panic attacks in some (,K of the e/perimental subGects, but not to any observed psychedelic or
stimulant responses.
Ihat happens if you e/tend the chain to a third carbonH "he parent system is called the phenyl@'n-@propylamine, and the parent chain structure, either
as the primary amine or as its alpha@methyl counterpart, represents compounds that are inactive as stimulants. "he ;9?@analogues have been made
and are, at least in the rabbit rectal hyperthermia assay, uninteresting. A commercially available fine chemical kno3n as piperonylacetone has been
offered as either of t3o materials. 9ne, correctly called 0,+@methylenedio/yphenylacetone or 0,+@methylenedio/yben6yl methyl ketone, gives rise upon
reductive amination to ?;A 'using ammonia- or ?;?A 'using methylamine-. "his is an aromatic compound 3ith a three@carbon side@chain and the
amine@nitrogen on the beta@carbon. "he other so@called piperonylacetone is really 0,+@methylenedio/yben6ylacetone, an aromatic compound 3ith a
four@carbon side@chain. It produces, on reductive amination 3ith ammonia or methylamine, the corresponding alpha@methyl@'n-@propylamines, 3ith a
four@carbon side@chain and the amine@nitrogen on the gamma@carbon. "hey are completely une/plored in man and so it is not kno3n 3hether they are
or are not psychedelic. As possible mis@synthesi6ed products, they may appear Fuite unintentionally and must be evaluated as totally ne3 materials.
"he gamma@amine analogue of ?;A, a methylenedio/y substituted three carbon side@chain 3ith the amine@nitrogen on the gamma carbon, has indeed
been made and evaluated, and is discussed under ?;A. "he e/tension of the chain of mescaline to three atoms, by the inclusion of an o/ygen atom,
has produced t3o compounds that have also been assayed. "hey are mentioned in the recipe for mescaline.
"he chain that reaches out to the amine group can be tied back in again to the ring, 3ith a second chain. "here are $@aminoben6oindanes 3hich are
phenethylamines 3ith a one@carbon link tying the alpha@position of the chain back to the aromatic ring. And there are $@aminotetralines 3hich are
phenethylamines 3hich have a t3o@carbon link tying the alpha@position of the chain back to the aromatic ring. .oth unsubstituted ring systems are
kno3n and both are fair stimulants. .oth systems have been modified 3ith the ;9? substituent patterns 'called ;9?@AI and ;9?@A" respectively-, but
neither of these has been tried in man. And the analogues 3ith the ?;A substitution pattern are discussed else3here in this book.
And there is one more obvious remaining methylation pattern. Ihat about phenethylamine or amphetamine compounds 3ith t3o methyl groups on the
nitrogenH "he parent amphetamine e/ample, 5,5@dimethylamphetamine, has received much notoriety lately in that it has become a scheduled drug in
the 4nited States. <phedrine is a maGor precursor in the illicit synthesis of methamphetamine, and 3ith the increased la3@enforcement attention being
paid to this process, there has been increasing promotion of the unrestricted homologue, 5@methylephedrine, to the methamphetamine chemist. "his
starting material gives rise to 5,5@dimethylamphetamine 3hich is a material of dubious stimulant properties. A number of 5,5@dimethylamphetamine
derivatives, 3ith NpsychedelicN ring substituents, have been e/plored as iodinated brain@flo3 indicators, and they are e/plicitly named 3ithin the
appropriate recipes. .ut none of them have sho3n any psychedelic action.
"his is as good a place as any to discuss t3o or three simple compounds, phenethylamines, 3ith only one substituent on the ben6ene ring. "he $@
carbon analog of +@?A, is +@metho/yphenethylamine, or ?P<A. "his is a kissing cousin to ;?P<A, of such fame in the search for a urine factor that
could be related to schi6ophrenia. And the end results of the search for this compound in the urine of mentally ill patients are as controversial as they
3ere for ;?P<A. "here has been no confirmed relationship to the diagnosis. And efforts to see if it is centrally active 3ere failures L at dosages of up
to +,, milligrams in man, there 3as no activity. "he +@chloro@analogue is +@chlorophenethylamine '+@Cl@P<A- and it has actually been pushed up to
even higher levels 'to &,, milligrams dosage, orally- and it is also 3ithout activity. A passing bit of charming trivia. A positional isomer of ?P<A is 0@
metho/yphenethylamine '0@?P<A- and, although there are no reported human trials 3ith this, it has been graced 3ith an <dge3ood Arsenal code
number, vis., <A@(0,$.

#1(' ,*%,Y#Y; ',)-0"METH%+Y-(-&$-,*%,Y#Y%+Y-,HE#ETHYAM"#E
S>5"H<SISE "o a solution of &.) g homosyringonitrile 'see under < for its preparation- in &, m! acetone containing (,, mg decyltriethylammonium
iodide, there 3as added ($ g of an ),K solution of propargyl bromide in toluene and 1.% g of finely po3dered anhydrous $C90. "his mi/ture 3as held
at reflu/ on the steam bath for ($ h, after 3hich the solvent 3as removed under vacuum. "he residues 3ere added to ,.& ! H$9, acidified, and
e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere pooled, 3ashed 3ith &K 5a9H, and then 3ith dilute HCl 3hich discharged the deep color. :emoval
of the organic solvent under vacuum yielded 1.1 g of crude product. "his 3as distilled at (0)@(+) deg C at ,.$& mm8Hg, yielding +.0 g 0,&@dimetho/y@+@
'$@propynylo/y-phenylacetonitrile 3hich spontaneously crystalli6ed. A small sample from ?e9H had a mp of %+@%& deg C. Anal. 'C(0H(0590- C,H.
A suspension of $.) g !AH in 2, m! anhydrous "HB 3as cooled to , deg C 3ith good stirring under He, and treated 3ith $., g (,,K H$S9+. "o this, a
solution of +.$ g 0,&@dimetho/y@+@'$@propynylo/y-phenylacetonitrile in 0, m! anhydrous "HB 3as added very slo3ly. After the addition had been
completed, the reaction mi/ture 3as held at reflu/ on the steam bath for ,.& h, cooled to room temperature, treated 3ith IPA to decompose the e/cess
hydride, and finally 3ith (&K 5a9H to convert the solids to a 3hite filterable mass. "he solids 3ere separated by filtration, the filter cake 3as 3ashed
3ith "HB, and the filtrate and 3ashes 3ere pooled. After removal of the solvent, the residue 3as added to (,, m! dilute H$S9+, and 3ashed 3ith 0/2&
m! CH$Cl$. "he aFueous phase 3as made basic 3ith dilute 5a9H, and the product e/tracted 3ith $/2& m! CH$Cl$. After removal of the solvent under
vacuum, the residue 3as distilled at ($&@(&& deg C at ,.0 mm8Hg to provide $.+ g of a light amber viscous liFuid. "his 3as dissolved in (, m! IPA,
acidified 3ith concentrated HCl until a droplet produced a red color on dampened, e/ternal universal pH paper, and then diluted 3ith +, m! anhydrous
<t$9 3ith good stirring. After a short delay, 0,&@dimetho/y@+@'$@propynylo/y-phenethylamine hydrochloride 'P:9P>5>!- spontaneously crystalli6ed.
"he product 3as removed by filtration, 3ashed first 3ith an IPA8<t$9 mi/ture, and finally 3ith <t$9. "he yield 3as 0., g of 3hite needles.
;9SAC<E ), mg or more.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith && mg- I have cold feet L literally L I don7t mean that in the spiritual or adventurous sense. .ut also I am some3hat
physically fu66y. I feel that if I 3ere in public my behavior 3ould be such that someone 3ould notice me. <verything 3as 9 3ithout any Fuestion at the
ninth hour. I could 3alk abroad again.
'3ith ), mg- "here is a body load. "he flo3 of people around me all day has demanded my attention, and 3hen I had purposefully retreated to be by
myself, there 3as no particular re3ard as to visuals or anything 3ith eyes closed, either. Sleep 3as easy at midnight 'the t3elth hour of the e/periment-
but the morning 3as sluggish, and on recalling the day, I am not sure of the events that had taken place. Higher might be all right, but 3atch the status of
the body. "here certainly 3asn7t that much mental stuff.
<="<5SI95S A5; C9??<5"A:>E 5o e/periments have been performed that describe the action of this drug at full level. "his compound does not
seem to have the magic that 3ould encourage e/ploration at higher levels.

#1(( S.; SYM.ES!A"#E; ',)-0"ETH%+Y-(-METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of (& g (,0@dietho/yben6ene and (& m! of 5,5,57,57@tetramethylethylenediamine in $,, m! anhydrous <t$9 3as placed in a He
atmosphere, magnetically stirred, and cooled to , deg C 3ith an ice bath. 9ver the course of (, min there 3as added 10 m! of a (.1 ? solution of
butyllithium in he/ane, 3hich produced a fine 3hite precipitate. After an additional (& min stirring, $, m! of tributyl borate 3as added 3hich dissolved
the precipitate. "he stirring 3as continued for an additional (& min. "he reaction 3as Fuenched by the addition of &, m! of a concentrated aFueous
solution of ammonium sulfate. "he resulting Ncottage cheeseN mass 3as transferred to a beaker, treated 3ith an additional 0,, m! of the ammonium
sulfate solution, and allo3ed to stir until the solids had dispersed to a fine te/ture. "he organic phase 3as separated and the aFueous phase e/tracted
3ith $/(,, m! <t$9. "he organic phases 3ere combined, evaporated under vacuum, and the off@3hite residue dissolved in (,, m! ?e9H. "his cloudy
solution 3as cooled 'ice bath- and, 3ith stirring, $, m! of 0&K hydrogen pero/ide 3as added portion3ise, . "he reaction 3as allo3ed to continue
stirring for (& min, and then 3ith the addition of 1,, m! H$9, crystalline solids 3ere formed. "hese 3ere removed, 3ashed 3ith H$9, and upon drying
yielded (&.+ g of $,1@dietho/yphenol 3ith a mp of 2%.&@)(.& deg C. <fforts to diethylate pyrogallol produced mi/tures of $,1@dietho/yphenol and the
isomer, $,0@dietho/yphenol, and these proved difficult to separate. "he pure $,0@isomer 3as synthesi6ed from ortho@dietho/yben6ene by the process
used above, and the product 3as an oil. .oth phenols yielded crystalline 0,&@dinitroben6oates. "his derivative of $,1@dietho/yphenol, upon
recrystalli6ation from CH0C5 had a mp of (1(@(1$ deg C. "he derivative from $,0@dietho/yphenol, also upon recrystalli6ation from CH0C5, melted at
(12@(1) deg C. "he mi/ed mp 3as appropriately depressed 'mp (02@(+, deg C.-.
A solution of 2.1 g $,1@dietho/yphenol in +, m! ?e9H 3as treated 3ith +.% g of a +,K aFueous solution of dimethylamine follo3ed by 0.1 g of a +,K
aFueous solution of formaldehyde. "he mi/ture 3as heated ( h on the steam bath, and all volatiles 3ere removed under vacuum. "he residual dark oil
3as dissolved in 01 m! IPA and (,.0 g of methyl iodide 3as added. "here 3as spontaneous heating, and the deposition of fine 3hite solids. After
standing for (, min, these 3ere removed by filtration, and the filter cake 3ashed 3ith more IPA. "he crude product 3as freed from solvent 'air dried
3eight, (.2 g- and dissolved in 2 m! hot H$9. "o this hot solution there 3as added (.2 g sodium cyanide 3hich slo3ly discharged the color and again
deposited flocculant 3hite solids. After cooling, these 3ere removed by filtration, 3ashed 3ith H$9, and after thorough drying the isolated 0,&@dietho/y@
+@hydro/yphenylacetonitrile 3eighed ,.& g and had a mp of (,2.&@(,).& deg C. Anal. 'C($H(&590- C,H.
"o a solution of $.( g 0,&@dietho/y@+@hydro/yphenylacetonitrile in $, m! anhydrous acetone, there 3as added 0, mg triethyldecylammonium iodide, +.1
g methyl iodide, and finally $.0 g po3dered anhydrous $C90. "his mi/ture 3as held at reflu/ for & h. "he reaction mi/ture 3as Fuenched 3ith $,, m!
acidified H$9 and e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere pooled, 3ashed 3ith $/2& m! &K 5a9H, and finally once 3ith dilute HCl. "he
solvent 3as removed under vacuum, and the residue distilled at ((,@((& deg C at ,.0 mm8Hg to provide 0,&@dietho/y@+@metho/yphenylacetonitrile as a
solid. "his 3eighed (.0 g and had a mp of &)@&% deg C. Anal. 'C(0H(2590- C,H.
"o 0, m! of a ( ? solution !AH in "HB that had been cooled to , deg C 3ith vigorous stirring, under a He atmosphere, there 3as added drop3ise ,.2)
m! of (,,K H$S9+. Ihen the addition 3as complete, there 3as added drop3ise a solution of (.0 g of 0,&@dietho/y@+@metho/yphenylacetonitrile in (,
m! anhydrous "HB. "he reaction mi/ture 3as brought to room temperature and stirred an additional (, min, then reflu/ed on a steam bath for (.& h.
After cooling to room temperature the e/cess hydride 3as destroyed by the addition of about $ m! IPA, follo3ed by sufficient (&K 5a9H to make the
reaction basic to e/ternal pH paper and to render the aluminum o/ides 3hite and filterable. "hese 3ere removed by filtration, the filter cake 3as 3ashed
3ith IPA, then the filtrate and 3ashes 3ere combined. "he solvents 3ere removed under vacuum and the residue dissolved in dilute H$S9+. "his 3as
3ashed 3ith $/2& m! CH$Cl$, the aFueous phase made basic 3ith &K 5a9H, and e/tracted 3ith 0/2& m! CH$Cl$. "he e/tracts 3ere pooled, the
solvent removed under vacuum, and the residue distilled at ($,@(+, deg C at ,.0 mm8Hg to yield ,.% g of a 3hite oil. "his 3as dissolved in + m! of IPA
and neutrali6ed 3ith concentrated HCl to an end@point determined by damp e/ternal pH paper. "here 3as the immediate formation of solids 3hich 3ere
removed by filtration and 3ashed first 3ith IPA and then 3ith <t$9. "his provided (., g of 0,&@dietho/y@+@metho/yphenethylamine hydrochloride 'S.- as
3hite crystals, 3ith a mp of ()1@()2 deg C. Anal. 'C(0H$$Cl590- C,H.
;9SAC<E above $+, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- "here 3ere no effects. Sleep that evening 3as strange, ho3ever, and I 3as fully a3ake at +E,, A?, alert,
and mentally restless. And there 3as a strange outburst of anger in the mid@morning. ?ight these be related to the material the previous dayH
'3ith $+, mg- "here 3as a slight chill that reminded me that I had taken symbescaline a half hour earlier. "here 3as 3hat might be called a vague
threshold for about three hours, then nothing more. "his material had a Cod@a3ful taste that lingers in the mouth far too long. If ever again, it 3ill be in a
gelatin capsule.
<="<5SI95S A5; C9??<5"A:>E It must be concluded that S. is NprobablyN not active. "here 3as no convincing evidence for much effect at levels
that 3ould clearly be active for mescaline. "his is the kind of result that puts some potentially ambiguous numbers in the literature. 9ne cannot say that
it is inactive, for there might 3ell be something at +,, or ),, or ($,, milligrams. .ut since it has been tried only up to $+, milligrams, I have used the
phrase that the activity is greater than $+, milligrams. "his 3ill be interpreted by some people as saying that it is active, but only at dosages higher than
$+, milligrams. Ihat is meant, is that there 3as no activity observed at the highest level tried, and so if it is active, the active dose 3ill be greater than
$+, milligrams, and so the potency 3ill be less than that of mescaline. Ho3ever you phrase it, someone 3ill misinterpret it.

#1() TA; $,',(,)-TET*AMETH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of &, g $,0,+@trimetho/yben6aldehyde in (&2 m! glacial acetic acid 3hich 3as 3ell stirred and preheated to $& deg C there
3as added &&.1 g +,K peracetic acid in acetic acid. "he rate of addition 3as adGusted to allo3 the evolved heat of the e/othermic reaction to be
removed by an e/ternal ice bath at a rate that kept the internal temperature 3ithin a degree of $& deg C. Ihen the addition 3as complete and there
3as no more heat being evolved, the reaction mi/ture 3as diluted 3ith 0 volumes of H$9, and neutrali6ed 3ith solid $C90. All 3as e/tracted 3ith
0/$&, m! <t$9, and the removal of the solvent from the pooled e/tracts under vacuum gave +$ g of residue that appeared to be mainly phenol, 3ith a
little formate and aldehyde. "his 3as dissolved in $,, m! of (,K 5a9H, allo3ed to stand for $ h at ambient temperature, 3ashed 3ith $/2& m! CH$Cl$,
acidified 3ith HCl, and e/tracted 3ith 0/(,, m! <t$9. "he pooled e/tracts 3ere 3ashed 3ith saturated 5aHC90, and the solvent removed to give 0+.2
g of $,0,+@trimetho/yphenol as an amber oil 3hich 3as used 3ithout further purification. "he infra@red spectrum sho3ed no carbonyl group, of either the
formate or the starting aldehyde.
A solution of ((.+ g flaked 9H in (,, g <t9H 3as treated 3ith 00.0 g $,0,+@trimetho/yphenol and $(.% g allyl bromide. "he mi/ture 3as held at reflu/
for (.& h, then poured into & volumes of H$9, made basic 3ith the addition of $&K 5a9H, and e/tracted 3ith 0/$,, m! CH$Cl$. :emoval of the solvent
from the pooled e/tracts gave about +, g of a crude $,0,+@trimetho/y@(@allylo/yben6ene that clearly had unreacted allyl bromide as a contaminant.
A 0% g sample of crude $,0,+@trimetho/y@(@allylo/yben6ene in a round@bottomed flask 3ith an immersion thermometer 3as heated 3ith a soft flame. At
$$& deg C there 3as a light effervescence and at $+, deg C an e/othermic reaction set in that raised the temperature immediately to $1& deg C. It 3as
held there for & min, and then the reaction 3as allo3ed to cool to room temperature. CC and I: analysis sho3ed the starting ether to be gone, and that
the product 3as largely $,0,+@trimetho/y@1@allylphenol. It 3eighed 0+.+ g.
"o a solution of %.+ g 9H in (,, m! ?e9H, there 3as added 00.0 g of $,0,+@trimetho/y@1@allylphenol and $(.$ g methyl iodide and the mi/ture 3as
held on the steam bath for $ h. "his 3as poured into aFueous base, and e/tracted 3ith 0/(,, m! CH$Cl$. :emoval of the solvent from the pooled
e/tracts gave 0, g of an amber oil residue that 3as distilled at (,,@($& deg C at ,.& mm8Hg to provide $0.0 g of nearly colorless $,0,+,&@
tetrametho/yallylben6ene.
"he total distillation fraction, $0.0 g $,0,+,&@tetrametho/yallylben6ene, 3as dissolved in a solution of $& g flaked 9H in $& m! <t9H and heated at (,,
deg C for $+ h. "he reaction mi/ture 3as poured into &,, m! H$9, and e/tracted 3ith $/(,, m! CH$Cl$. "he aFueous phase 3as saved. "he pooled
organic e/tracts 3ere stripped of solvent under vacuum to give (0.) g of a fluid oil that 3as surprising pure $,0,+,&@tetrametho/ypropenylben6ene by
both CC and 5?: analysis. "he basic aFueous phase 3as acidified, e/tracted 3ith $/(,, m! CH$Cl$, and the solvent stripped to give 2.& g of an oil
that 3as phenolic, totally propenyl 'as opposed to allyl-, and by infra@red the phenolic hydro/yl group 3as adGacent to the olefin chain. "his crude $@
hydro/y@0,+,&@trimetho/ypropenylben6ene 3as methylated 3ith methyl iodide in alcoholic 9H to give an additional &.1 g of the target $,0,+,&@
tetrametho/ypropenylben6ene. "his 3as identical to the original isolate above. "he distilled material had an inde/ of refraction, n;$+ T (.&+,%.
A 3ell stirred solution of (2.% g $,0,+,&@tetrametho/ypropenylben6ene in ), m! distilled acetone 3as treated 3ith 1.% g pyridine, and cooled to , deg C
3ith an e/ternal ice bath. "here 3as then added (+ g tetranitromethane over the course of a ,.& min, and the reaction 3as Fuenched by the addition of
a solution of +.1 g 9H in ), m! H$9. As the reaction mi/ture stood, there 3as a slo3 deposition of yello3 crystals, but be3are, this is not the product.
"his solid 3eighed +., g and 3as the potassium salt of trinitromethane. "his isolate 3as dried and sealed in a small vial. After a fe3 days standing, it
detonated spontaneously. "he filtrate 3as e/tracted 3ith 0/2& m! CH$Cl$, and the removal of the solvent from these e/tracts gave a residue of $,.) g
of crude $@nitro@(@'$,0,+,&@tetrametho/yphenyl-propene 3hich did not crystalli6e.
A solution 3as made of $,.0 g of the crude $@nitro@(@'$,0,+,&@tetrametho/yphenyl-propene in $,, m! anhydrous <t$9, and this 3as filtered to remove
some $.2 g of insoluble material 3hich appeared to be the potassium salt of trinitromethane by infra@red analysis. A suspension of (+ g !AH in ( !
anhydrous <t$9 3as stirred, placed under an inert atmosphere, and brought up to a gentle reflu/. "he above clarified ether solution of the propene 3as
added over the course of ( h, and the mi/ture 3as held at reflu/ for $+ h. After cooling, the e/cess hydride 3as destroyed by the cautious addition of ( !
(.& 5 H$S9+ 'initially a drop or t3o at a time- and 3hen the t3o phases 3ere complete clear, they 3ere separated. "he aFueous phase 3as treated
3ith 0&, g potassium sodium tartrate, and brought to a pH U% 3ith base. "his 3as e/tracted 3ith 0/(&, m! CH$Cl$, and the removal of the solvent
from the pooled e/tracts gave a residue that 3as dissolved in $,, m! anhydrous <t$9, and saturated 3ith anhydrous HCl gas. An <t$9@insoluble oil
3as deposited and, after repeated scratching 3ith fresh <t$9, finally gave a granular 3hite solid. "his product 3as recrystalli6ed from acetic anhydride,
giving 3hite crystals that 3ere removed by filtration, <t$9 3ashed, and air dried. "he yield of $,0,+,&@tetrametho/yamphetamine hydrochloride '"A- 3as
(.% g and had a mp of (0&.&@(01.& deg C.
;9SAC<E probably above &, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith 0, mg- ;efinite threshold. "here 3as eye dilation, and some unusual humor L a completely 3ild day 3ith chi@sFuare
calculations on the P;P@2 that 3ere on the edge of bad taste. .ut I 3as definitely baseline in the afternoon during the ?otor Mehicle ;epartment
interactions.
'3ith 0& mg- I had some gastric upset, but nonetheless there 3as a distinct into/ication. "he ne/t morning I had a foul headache.
<="<5SI95S A5; C9??<5"A:>E "his is pretty thin stuff from 3hich to go out into a 3orld that is populated by pharmacological sharks and stake out
claims as to psychedelic potency. "he structure of this molecule has everything going for it. It is an overlay of "?A 'active- and "?A@$ 'even more
active- so it is completely reasonable that it should be doing something at a rational dosage. .ut that dosage might 3ell be in the many tens of
milligrams.
"ens of milligrams. 5o3 there is a truly 3ishy@3ashy phrase. "here is an art to the assignment of an e/act number or, as is sometimes desperately
needed, a fu66y number, to a collection of things. In my youth 'some3here 3ay back yonder in the early part of the century- I had been taught rules of
grammer that 3ere unFuestionably e/pected of any 3ell@educated person. If you used a !atin stem, you used a !atin prefi/. And if you used a Creek
stem, you used a Creek prefi/. Consider a collection of things 3ith simple geometric sides 'a side is a latus in !atin-. 9ne 3ould speak of a one@sided
obGect as being unilateral, and a bilateral obGect has t3o sides. A trilateral, and Fuadrilateral, and 3ay up there to multilateral obGects, are referred to as
having three or four or a lot of sides, respectively. Dust the opposite occurs 3ith geometric obGects 3ith faces. A face is a hedra in Creek, so one really
should use the Creek structure. If one has Gust one face, one has a monohedron, a dihedron has t3o faces, and there are trihedron, tetrahedron, and
polyhedron for things that have three, four, or a lot of faces. Actually, the prefi/ NpolyN s3ings both 3ays. It 3as initially a Creek term, but as 3as the
fate of many Creek 3ords, it 3andered its 3ay from <ast to Iest, and ended up as a !atin term as 3ell.
.ut back to the problem of ho3 to refer to something that is more than one or t3o, but not as much as a lotH If you kno3 e/actly ho3 many, you should
use the proper prefi/. .ut 3hat if you don7t kno3 ho3 manyH "here are terms such as Nsome.N And there is Nseveral.N "here is a Nfe3N and a Nnumber
ofN and NnumerousN and Na hand full.N 9ne desperately looks for a term that is a collective, but 3hich carries the meaning of an undefined number. "here
are <nglish gems such as a pride of lions and a host of daffodils. .ut 3ithout a specific animal or plant of reference, one must have a target collective
that is appropriate, to let the term NmanyN or Nfe3N imply the proper si6e. "here 3ere many hundreds of persons 'a fe3 thousands of persons- at the rally.
Several do6en hunters 'a fe3 score hunters- 3ere gathered at the lake. A 3onderful prefi/ is NoligoN 3hich means a fe3, not a lot, and it means that I am
not sure Gust ho3 many are meant. Say, for e/ample, that you have synthesi6ed something in a biochemical mi/ture that contains three or four peptides.
;i@and tri@ and tetrapeptides are e/act terms, but they do not describe 3hat you have done. Polypeptide is 3ay too big. Ho3ever, an oligopeptide
means that there are a fe3 peptide units, I7m not sure ho3 many. "his may 3ell be the most accurate description of Gust 3hat you have.
I love the .ritish modesty that is sho3n by hiding a person7s physical 3eight by referring to it 3ith the dimension kno3n as the stone. "his is, as I
remember, something like (+ pounds. So, if stones 3ere the 3eight eFuivalent of (, milligrams, the activity of "A 3ould be several stone. And since the
synthetic intermediate (@allyl@$,0,+,&@tetrametho/yben6ene is one of the ten essential oils, the amination step from our hypothetical reaction in the
human liver 3ould make "A one of the so@called "en <ssential Amphetamines.

#1(1 '-TAS.; '-TH"%ASYM.ES!A"#E;
(-ETH%+Y-'-ETHYTH"%-)-METH%+Y,HE#ETHYAM"#E
S>5"H<SISE Iithout any solvent, there 3as combined $(.2 g of solid &@bromovanillin and ((.+ m! cyclohe/ylamine. "here 3as the immediate
generation of a yello3 color and the evolution of heat. "he largely solid mass 3as ground up under &, m! of boiling IPA to an apparently homogeneous
yello3 solid 3hich 3as removed by filtration and 3ashed 3ith IPA. "here 3as thus obtained about $2 g of 0@bromo@5@cyclohe/yl@+@hydro/y@&@
metho/yben6ylidenimine 3ith a mp of $$%@$0( deg C and 3hich proved to be insoluble in most solvents '<t9H, CH$Cl$, acetone-. A solution in dilute
5a9H 3as unstable 3ith the immediate deposition of opalescent 3hite solids of the phenol sodium salt. A small scale recrystalli6ation from boiling
cyclohe/anone yielded a fine yello3 solid 3ith a lo3ered mp '$(,@$(& deg C-. Anal. 'C(+H().r59$- C,H. A solution of 0$.& g 0@bromo@5@cyclohe/yl@+@
hydro/y@&@metho/yben6ylidenimine in 1, m! of hot ;?B 3as cooled to near room temperature, treated 3ith $+.& g ethyl iodide and follo3ed by (+., g of
flake 9H. "his mi/ture 3as held at reflu/ for ( h, cooled, and added to ( ! H$9. Additional base 3as added and the product 3as e/tracted 3ith 0/(&,
m! CH$Cl$. "hese pooled e/tracts 3ere 3ashed 3ith dilute 5a9H, then 3ith H$9, and finally the solvent 3as removed under vacuum. "he crude
amber@colored residue 3as distilled. "he fraction coming over at (()@(0& deg C at ,.+ mm8Hg 3eighed ).2 g, spontaneously crystalli6ed, and proved to
be 0@bromo@+@etho/y@&@metho/yben6aldehyde, melting at &%@1, deg C after recrystalli6ation from ?e9H. Anal. 'C(,H((.r90- C,H. "he fraction that
came over at (0&@(&& deg C at ,.$ mm8Hg 3eighed (,.& g and also solidified in the receiver. "his product 3as 0@bromo@5@cyclohe/yl@+@etho/y@&@
metho/yben6ylidenimine 3hich, upon recrystalli6ation from t3o volumes ?e9H, 3as a 3hite crystalline material 3ith a mp of 1,@1( deg C. Anal.
'C(1H$$.r59$- C,H. "he t3o materials have identical mps, but can be easily distinguished by their infra@red spectra. "he aldehyde has a carbonyl
stretch at (1%$ cm@(, and the Schiff base a CT5 stretch at (1+( cm@(.
A solution of $,.& g 0@bromo@5@cyclohe/yl@+@etho/y@&@metho/yben6ylidenimine in about 0,, m! anhydrous <t$9 3as placed in a He atmosphere, 3ell
stirred, and cooled in an e/ternal dry ice acetone bath to @), deg C. "here 3as then added &, m! of (.1 5 butyllithium in he/ane. "he mi/ture became
yello3 and very viscous 3ith the generation of solids. "hese loosened up 3ith continuing stirring. "his 3as follo3ed by the addition of (,.2 g
diethyldisulfide. "he reaction became e/tremely viscous again, and stirring 3as continued 3hile the reaction 3as allo3ed to 3arm to room temperature.
After an additional ,.& h stirring, the reaction mi/ture 3as added to ),, m! of dilute HCl. "he <t$9 phase 3as separated and the solvent removed
under vacuum. "he residue 3as returned to the original aFueous phase, and the entire mi/ture heated on the steam bath for $ h. "he bright yello3
color faded and there 3as the formation of a yello3ish phase on the surface of the H$9. "he aFueous solution 3as cooled to room temperature,
e/tracted 3ith 0/(,, m! CH$Cl$, the e/tracts pooled, 3ashed first 3ith dilute HCl, then 3ith saturated brine, and the solvent removed under vacuum.
"he residue 3as an amber oil 3eighing $,.+ g, and 3as distilled at (0,@(+, deg C at ,.0 mm8Hg to yield ($.% g of +@etho/y@0@ethylthio@&@
metho/yben6aldehyde as a stra3 colored oil that did not crystalli6e. Anal. 'C($H(190S- C,H.
A solution of (., g +@etho/y@0@ethylthio@&@metho/yben6aldehyde in $, g nitromethane 3as treated 3ith about ,.$ g of anhydrous ammonium acetate and
heated on the steam bath. "!C analysis sho3ed that the aldehyde 3as substantially gone 3ithin $, min and that, in addition to the e/pected
nitrostyrene, there 3ere four scrudge products 'see the discussion of scrudge in the e/tensions and commentary section under 0@"S.-. :emoval of the
e/cess nitromethane under vacuum gave an orange oil 3hich 3as diluted 3ith & m! cold ?e9H but 3hich could not be induced to crystalli6e. A seed
3as obtained by using a preparative "!C plate '$,/$, cm- and removing the fastest moving spot 'development 3as 3ith CH$Cl$-. Placing this in the
above ?e9H solution of the crude nitrostyrene allo3ed crystalli6ation to occur. After filtering and 3ashing 3ith ?e9H, ,.$, g of fine yello3 crystals 3ere
obtained 3hich melted at 2&@22 deg C. :ecrystalli6ation from ?e9H gave a bad recovery of yello3 crystals of +@etho/y@0@ethylthio@&@metho/y@beta@
nitrostyrene that no3 melted at 2).&@2% deg C. Anal. 'C(0H(259+S- C,H. "his route 3as discarded in favor of the Iittig reaction described belo3.
A mi/ture of $2 g methyltriphenylphosphonium bromide in (&, m! anhydrous "HB 3as placed under a He atmosphere, 3ell stirred, and cooled to , deg
C 3ith an e/ternal ice 3ater bath. "here 3as then slo3ly added &, m! of (.1 5 butyllithium in he/ane 3hich resulted in the initial generation of solids
that largely redissolved by the completion of the addition of the butyllithium and after allo3ing the mi/ture to return to room temperature. "here 3as then
added ((.2 g of +@etho/y@0@ethylthio@&@metho/yben6aldehyde 3ithout any solvent. "here 3as the immediate formation of an unstirrable solid, 3hich
partially broke up into a gum that still 3ouldn7t stir. "his 3as moved about, as 3ell as possible, 3ith a glass rod, and then all 3as added to +,, m! H$9.
"he t3o phases 3ere separated and the lo3er, aFueous, phase e/tracted 3ith $/2& m! of petroleum ether. "he organic fractions 3ere combined and
the solvents removed under vacuum to give the crude +@etho/y@0@ethylthio@&@metho/ystyrene as a pale yello3 fluid liFuid.
A solution of (, m! of borane@methyl sulfide comple/ '(, ? .H0 in methyl sulfide- in 2& m! "HB 3as placed in a He atmosphere, cooled to , deg C,
treated 3ith $( m! of $@methylbutene, and stirred for ( h 3hile returning to room temperature. "his 3as added directly to the crude +@etho/y@0@ethylthio@
&@metho/ystyrene. "he slightly e/othermic reaction 3as allo3ed to stir for ( h, and then the e/cess borane 3as destroyed 3ith a fe3 m! of ?e9H 'in
the absence of air to avoid the formation of the dialkylboric acid-. "here 3as then added (% g of elemental iodine follo3ed, over the course of about (,
min, by a solution of + g 5a9H in &, m! hot ?e9H. "he color did not fade. Addition of another + m! $&K 5a9H lightened the color a bit, but it
remained pretty ugly. "his 3as added to &,, m! H$9 containing & g sodium thiosulfate and e/tracted 3ith 0/(,, m! petroleum ether. "he e/tracts
3ere pooled, and the solvent removed under vacuum to provide crude (@'+@etho/y@0@ethylthio@&@metho/yphenyl-@$@iodoethane as a residue.
"o this crude (@'+@etho/y@0@ethylthio@&@metho/yphenyl-@$@iodoethane there 3as added a solution of $, g potassium phthalimide in (&, m! anhydrous
;?B, and all 3as held at reflu/ overnight. After adding to &,, m! of dilute 5a9H, some (.+ g of a 3hite solid 3as generated and removed by filtration.
"he aFueous filtrate 3as e/tracted 3ith $/2& m! <t$9. "hese e/tracts 3ere combined, 3ashed 3ith dilute HCl, and the solvent removed under vacuum
providing $0.1 g of a terpene@smelling amber oil. "his 3as stripped of all volatiles by heating to (2, deg C at ,.+ mm8Hg providing &.+ g of a sticky
bro3n residue. "his consisted largely of the desired phthalimide. "he solids proved to be a purer form of (@'+@etho/y@0@ethylthio@&@metho/y-@$@
phthalimidoethane and 3as recrystalli6ed from a very small amount of ?e9H to give fine 3hite crystals 3ith a mp of (,2.&@(,).& deg C. Anal.
'C$(H$059+S- C,H. "he 3hite solids and the bro3n impure phthalimide 3ere separately converted to the final product, 0@"AS..
A solution of (.$ g of the crystalline (@'+@etho/y@0@ethylthio@&@metho/yphenyl-@$@phthalimidoethane in +, m! of 3arm n@butanol 3as treated 3ith 0 m! of
11K hydra6ine, and the mi/ture 3as heated on the steam bath for +, min. "he reaction mi/ture 3as added to ),, m! dilute H$S9+. "he solids 3ere
removed by filtration, and the filtrate 3as 3ashed 3ith $/2& m! CH$Cl$. "he aFueous phase 3as made basic 3ith $&K 5a9H, e/tracted 3ith 0/2& m!
CH$Cl$, and the solvent from these pooled e/tracts removed under vacuum yielding 1.$ g of a residue that 3as obviously rich in butanol. "his residue
3as distilled at (0)@(++ C. at ,.0 mm8Hg to give ,.1 g of a colorless oil. "his 3as dissolved in $.+ m! IPA, neutrali6ed 3ith concentrated HCl, and
diluted 3ith $& m! anhydrous <t$9. "he solution remained clear for about (, seconds, and then deposited 3hite crystals. "hese 3ere removed by
filtration, 3ashed 3ith additional <t$9, and air dried to give ,.+ g +@etho/y@0@ethylthio@&@metho/yphenethylamine hydrochloride '0@"AS.- 3ith a mp of
(+,@(+( deg C. Anal. 'C(0H$$Cl59$S- C,H. "he amber@colored impure phthalimide, follo3ing the same procedure, provided another ,.% g of the
hydrochloride salt 3ith a mp of (0)@(0% deg C.
;9SAC<E about (1, mg.
;4:A"I95E (, @ () h.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- "his is no more than a plus one, and it didn7t really get there until about the third hour. .y a couple of hours
later, I feel that the mental effects are pretty much dissipated, but there is some real physical residue. 4p 3ith some caution.
'3ith (1, mg- "he taste is completely foul. ;uring the first couple of hours, there 3as a conscious effort to avoid nausea. "hen I noticed that people7s
faces looked like marvelous parodies of themselves and that there 3as considerable time slo3ing. "here 3as no desire to eat at all. .et3een the
eighth and t3elth hour, the mental things drifted a3ay, but the body 3as still 3ound up. Sleep 3as impossible until about 0E,, A? 'the ()th hour of the
e/periment- and even the ne/t day I 3as e/tremely active, anore/ic, alert, e/cited, and plagued 3ith occasional diarrhea. "his is certainly a potent
stimulant. "he ne/t night I felt the tensions drop, and finally got an honest and easy sleep. "here is a lot of adrenergic push to this material.
<="<5SI95S A5; C9??<5"A:>E 5o pharmacological agent has an action that is pure this or pure that. Some pain@killing narcotics can produce
reverie and some sedatives can produce paranoia. And Gust as surely, some psychedelics can produce stimulation. Iith 0@"AS. 3e may be seeing the
shift from sensory effects over to out@and@out stimulation. It 3ould be an interesting challenge to take these polyethylated phenethylamines and assay
them strictly for their amphetamine@like action. Sadly, the potencies are by and large so lo3, that the human animal can7t be used, and any sub@human
e/perimental animal 3ould not enable the psychedelic part of the eFuation to be ackno3ledged. If an order of magnitude of increased potency could be
bought by some minor structural change, this Fuestion could be addressed. ?aybe as the three@carbon amphetamine homologs, or as the $,+,&@ or
$,+,1@ substitution patterns, rather than the 0,+,&@pattern used in this set.

#1(2 (-TAS.; (-TH"%ASYM.ES!A"#E;
'-ETH%+Y-(-ETHYTH"%-)-METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of $,.& g 5,5,57,57@tetramethylethylenediamine and $$.0 g of 0@etho/yanisole 3as made in (,, m! he/ane under a He
atmosphere 3ith good stirring. "here 3as added ($& m! (.1 ? butyllithium in he/ane, 3hich formed a 3hite granular precipitate. "his 3as cooled in an
ice bath, and there 3as added $+.+ g of diethyldisulfide 3hich produced an e/othermic reaction and changed the precipitate to a creamy phase. After
being held for a fe3 min at reflu/ temperature, the reaction mi/ture 3as added to &,, m! dilute H$S9+ 3hich produced t3o clear phases. "he he/ane
phase 3as separated, and the aFueous phase e/tracted 3ith $/2& m! methylcyclopentane. "he organics 3ere combined, and the solvents removed
under vacuum. "here 3as obtained a residue 3hich 3as distilled under a vacuum. At ,.0 mm8Hg the fraction boiling at %&@(,& deg C 3as a yello3
liFuid 3eighing $).& g 3hich 3as largely 0@etho/y@$@'ethylthio-anisole 3hich seemed to be reasonably pure chromatographically. It 3as used as such in
the bromination step belo3.
"o a stirred solution of (&., g of 0@etho/y@$@'ethylthio-anisole in (,, m! CH$Cl$ there 3as added ($ g elemental bromine dissolved in $& m! CH$Cl$.
"here 3as the copious evolution of H.r. After stirring at ambient temperature for 0 h, the dark solution 3as added to 0,, m! H$9 containing sodium
dithionite. Shaking immediately discharged the residual bromine color, and the organic phase 3as separated, "he aFueous phase 3as e/tracted once
3ith (,, m! CH$Cl$, the pooled e/tracts 3ashed 3ith dilute base, and then the solvent 3as removed under vacuum to give a light bro3n oil. "his 3et
product 3as distilled at (($@($$ deg C at ,.0 mm8Hg to yield +@bromo 'and8or 1@bromo-@0@etho/y@$@'ethylthio-anisole as a light orange oil. "his 3as
used in the follo3ing ben6yne step 3ithout separation into its components.
"o a solution of 01 m! diisopropylamine in (&, m! anhydrous "HB under a He atmosphere, and 3hich had been cooled to @(, deg C 3ith an e/ternal
ice8?e9H bath, there 3as added (,& m! of a (.1 ? solution of butylithium in he/ane. "here 3as then added &.( m! of dry CH0C5 follo3ed by the
drop3ise addition of (&., g +@bromo@'and8or 1@bromo-@0@etho/y@$@'ethylthio-anisole diluted 3ith a little anhydrous "HB. "here 3as an immediate
development of a dark red@bro3n color. "he reaction 3as 3armed to room temperature and stirred for ,.& h. "his 3as then poured into 1,, m! of dilute
H$S9+. "he organic phase 3as separated, and the aFueous fraction e/tracted 3ith $/&, m! CH$Cl$. "hese e/tracts 3ere pooled and the solvent
removed under vacuum. "he residue 3as a dark oil and Fuite comple/ as seen by thin layer chromatography. "his material 3as distilled at ,.0 mm8Hg
yielding t3o fractions "he first boiled at (($@($& deg C and 3eighed 0.% g. It 3as largely starting bromo compound 3ith a little nitrile, and 3as
discarded. "he second fraction distilled at (0,@(2& deg C and also 3eighed 0.% g. "his fraction 3as rich in the product 0@etho/y@+@ethylthio@&@
metho/yphenylacetonitrile, but it also contained several additional components as seen by thin layer chromatographic analysis. 9n standing for t3o
months, a small amount of solid 3as laid do3n 3hich 3eighed ,.& g after cleanup 3ith he/ane. .ut even it consisted of three components by "!C, none
of them the desired nitrile. "he crude fraction 3as used for the final step 3ithout further purification or microanalysis.
A solution of !AH in anhydrous "HB under 5$ '(& m! of a (., ? solution- 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise,
,.+, m! (,,K H$S9+, follo3ed by about 0 g of the crude 0@etho/y@+@ethylthio@&@metho/yphenylacetonitrile diluted 3ith a little anhydrous "HB. "he
reaction mi/ture 3as stirred until it came to room temperature, and then held at reflu/ on the steam bath for $ h. After cooling to room temperature,
there 3as added IPA to destroy the e/cess hydride 'there 3as Fuite a bit of it- and then (&K 5a9H to bring the reaction to a basic pH and convert the
aluminum o/ide to a loose, 3hite, filterable consistency. "his 3as removed by filtration, and 3ashed first 3ith "HB follo3ed by IPA. "he filtrate and
3ashes 3ere stripped of solvent under vacuum, the residue added to (,, m! dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$, made basic 3ith
$&K 5a9H, and e/tracted 3ith $/&, m! CH$Cl$. After combining, the solvent 3as removed under vacuum providing a residue that 3as distilled. A
fraction boiling at ($$@(+, deg C at ,.0 mm8Hg 3eighed (., g and 3as a colorless oil. "his 3as dissolved in (, m! of IPA, and neutrali6ed 3ith $, drops
of concentrated HCl and diluted, 3ith stirring, 3ith +, m! anhydrous <t$9. "here 3as the slo3 formation of a fine 3hite crystalline salt, 3hich 3as
removed by filtration, 3ashed 3ith <t$9, and air dried. "he product 0@etho/y@+@ethylthio@&@metho/yphenethylamine hydrochloride '+@"AS.-, 3eighed
,.& g, and had a mp (0%@(+, deg C. Cas chromatographic analysis by capillary column chromatography of the free base 'in butyl acetate solution on
silica S<@&+- sho3ed a single peak at a reasonable retention time, verifying isomeric purity of the product. Anal. 'C(0H$$Cl59$S- C,H.
;9SAC<E 1, @ (,, mg.
;4:A"I95E (, @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- "he compound has a petroleum@refinery type taste. "here 3as a looseness of the bo3els as I got into it.
Here 3e have another of these 7Ihat is it7 or 7Ihat isn7t it7 compounds. Someho3 I seemed to have to push the erotic, the visual, the 3hole psychedelic
shmeer, to document that this 3as indeed effective. I am not impressed.
'3ith (,, mg- "here 3ere some trivial physical problems during the early stages of this e/periment. .ut there 3as fantasy stuff to music, and some
Gumpy stuff to music. Is there a neurological hyperrefle/iaH I 3as able to sleep at the ($ hour point but I felt Fuite irritable. I am agitated. I am t3itchy.
"his has been very intense, and I am not completely comfortable yet. !et7s 3ait for a 3hile.
'3ith (,, mg- ?usic 3as lovely during the e/periment, but pictures 3ere not particularly e/citing. I had feelings that my nerve@endings 3ere ra3 and
active. "here 3as 3ater retention. "here 3as heartbeat 3rongness, and respiration 3rongness. ;uring my attempts to sleep, my eyes@closed fantasies
became e/tremely negative. I could actually feel the continuous electrical impulses travelling bet3een my nerve endings. ;isturbing. "here 3as
continuous erotic arousability, and this seemed to be part of the same over@sensitivity of the nervous system; orgasm didn7t soothe or smooth out the
feeling of vulnerability. "his is a very threatening material. ;9 59" :<P<A".
<="<5SI95S A5; C9??<5"A:>E Again, another drug 3ith more physical problems than psychic virtue, but 3ith no obvious structural feature to hang
it all onto. Some day this 3ill all make senseO
#1(3 )-TAS.; )-TH"%ASYM.ES!A"#E;
',(-0"ETH%+Y-)-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of ((.& g 0@bromo@5@cyclohe/yl@+,&@dietho/yben6ylidinimine 'see under AS. for its preparation- in (&, m! anhydrous <t$9 3as
placed in a He atmosphere, 3ell stirred, and cooled in an e/ternal dry ice8acetone bath to @), deg C. "here 3as light formation of fine crystals. "here
3as then added $& m! of (.1 5 butyllithium in he/ane and the mi/ture stirred for (& min. "his 3as follo3ed by the addition of +.0 m! dimethyldisulfide
over the course of $, min, during 3hich time the solution became increasingly cloudy and then thinned out again. "he mi/ture 3as allo3ed to come to
room temperature over the course of an additional h, and then added to +,, m! of dilute HCl. "here 3as the generation of a lot of yello3 solids, and the
<t$9 phase 3as almost colorless. "his 3as separated, the solvent removed under vacuum, and the residue combined 3ith the original aFueous phase.
"his phase 3as then heated on the steam bath for $ h. "he aFueous solution 3as cooled to room temperature, e/tracted 3ith 0/(,, m! CH$Cl$, the
e/tracts pooled, 3ashed 3ith H$9, and the solvent removed under vacuum to yield %.+ g of an amber oil 3hich spontaneously crystalli6ed. "his 3as
distilled at ($&@(0$ deg C at ,.$ mm8Hg to yield 2.( g of 0,+@dietho/y@&@'methylthio-ben6aldehyde as a 3hite oil that spontaneously crystalli6ed. "he
crude product had a mp of 20@2+ deg C that actually decreased to 2$@20 deg C after recrystalli6ation from ?e9H. Anal. 'C($H(190S- C,H.
A solution of (1.$ g methyltriphenylphosphonium bromide in $,, m! anhydrous "HB 3as placed under a He atmosphere, 3ell stirred, and cooled to ,
deg C 3ith an e/ternal ice 3ater bath. "here 3as then added 0, m! of (.1 5 butyllithium in he/ane 3hich resulted in the generation of a clear yello3
solution. "he reaction mi/ture 3as brought up to room temperature, and 2., g 0,+@dietho/y@&@'methylthio-ben6aldehyde in &, m! "HB 3as added
drop3ise, dispelling the color, and the mi/ture 3as held at reflu/ on the steam bath for ( h. "he reaction 3as Fuenched in ),, m! H$9, the top he/ane
layer separated, and the aFueous phase e/tracted 3ith $/2& m! of petroleum ether. "he organic fractions 3ere combined and the solvents removed
under vacuum to give ($., g of the crude 0,+@dietho/y@&@methylthiostyrene as a pale amber@colored oil.
A solution of 1., m! of borane@methyl sulfide comple/ '(, ? .H0 in methyl sulfide- in +& m! "HB 3as placed in a He atmosphere, cooled to , deg C,
treated 3ith ($.1 g of $@methylbutene, and stirred for ( h 3hile returning to room temperature. "o this there 3as added a solution of the impure 0,+@
dietho/y@&@methylthiostyrene in $& m! "HB. "his 3as stirred for ( h during 3hich time the color deepened to a dark yello3. "he e/cess borane 3as
destroyed 3ith about $ m! ?e9H 'all this still in the absence of air-. "here 3as then added ((.+ g elemental iodine follo3ed by a solution of $.+ g 5a9H
in 0, m! of boiling ?e9H, added over the course of (, min. "his 3as follo3ed by sufficient $&K 5a9H to discharge the residual iodine color 'about +
m! 3as reFuired-. "he reaction mi/ture 3as added to &,, m! 3ater, and sodium hydrosulfite 3as added to discharge the remaining iodine color 'about +
g-. "his 3as e/tracted 3ith 0/(,, m! petroleum ether, the e/tracts pooled, and the solvent removed under vacuum to provide $&.% g of crude (@'0,+@
dietho/y@&@methylthiophenyl-@$@iodoethane as a pale yello3 fluid oil. "hin layer chromatographic analysis of this material on silica gel plates 'using a
%,E(, mi/ture of CH$Cl$8methylcyclopentane as solvent- sho3ed largely the iodo@product ':f ,.%- 3ith no visible starting aldehyde ':f ,.2-.
"o this crude (@'0,+@dietho/y@&@methylthiophenyl-@$@iodoethane there 3as added a solution of ($ g potassium phthalimide in %, m! anhydrous ;?B, and
all 3as held at reflu/ in a heating mantle. "he reaction progress 3as follo3ed by "!C, and at (.& h it 3as substantially complete. After adding to &,, m!
&K 5a9H, the organic phase 3as separated, and the aFueous phase 3as e/tracted 3ith $/2& m! <t$9. "he organic fractions 3ere combined, and the
solvent removed under vacuum providing (%.0 g of an amber oil. "he residual volatiles 3ere removed by distillation up to (2, deg C at ,.$ mm8Hg. "he
distillate 3eighed 2., g and contained little if any phthalimide by "!C. "he pot residue 3as a viscous amber oil, and also 3eighed 2., g. About half of
this 3as employed in the follo3ing hydrolysis step, and the rest 3as rubbed under an eFual volume of ?e9H providing (@'0,+@dietho/y@&@
methylthiophenyl-@$@phthalimidoethane as a 3hite solid. A small sample 3as recrystalli6ed from an eFual volume of ?e9H to give 3hite crystals 3ith a
mp of 2%.&@)( deg C. :e@recrystalli6ation from ?e9H produced an analytical sample 3ith a mp of )0@)+ deg C. Anal. 'C$(H$059+S- C,H.
A solution of 0.$ g of the impure (@'0,+@dietho/y@&@methylthiophenyl-@$@phthalimidoethane in (&, m! of n@butanol there 3as added $, m! of 11K
hydra6ine, and the mi/ture 3as heated on the steam bath for $ h. "his 3as added to 1,, m! of dilute H$S9+, and the t3o layers 3ere separated. "he
butanol layer 3as e/tracted 3ith $/(,, m! dilute H$S9+. "hese e/tracts 3ere added to the original aFueous phase, and this 3as 3ashed 3ith 0/2& m!
CH$Cl$. "his 3as then made basic 3ith &K 5a9H, e/tracted 3ith 0/2& m! CH$Cl$, and the solvent from these pooled e/tracts removed under vacuum.
"he residue '3hich 3eighed %.2 g and contained much butanol- 3as distilled at (+,@(+& deg C at ,.0 mm8Hg to give ,.2 g of a colorless oil. "his 3as
dissolved in 0., m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith ($ m! anhydrous <t$9 to give a solution that immediately crystalli6ed to
provide 3hite crystals of 0,+@dietho/y@&@methylthiophenethylamine hydrochloride '&@"AS.-. "hese 3eighed ,.2 g after 3ashing 3ith <t$9 and drying to
constant 3eight. "he mp 3as ()$@()0 deg C, and an analytical sample 3as dried at (,, deg C for $+ h. Anal. 'C(0H$$Cl59$S- C,H.
;9SAC<E about (1, mg.
;4:A"I95E about ) h.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- ?aybe there is something at about hour &. ?y talking 3ith innocent people had hints of strangeness. And
there 3as the slightest suggestion of some physical effect. Call it an overall '*-.
'3ith (1, mg- I am immediately 3arm at the e/tremities. An a3areness gro3s upon me for a couple of hours. I am a little light@headed, and I feel that
there is more physical than there is mental, and it is not all entirely nice. I am slightly hyperrefle/ive, and there is a touch of diarrhea. I am happy that I
held this at (1, milligrams. I am mentally flat at the eighth hour, although there are some physical residues. "he effects are real, but I don7t 3ant to go
higher. Some trace physical memory seems to stay 3ith me as a constant companion.
<="<5SI95S A5; C9??<5"A:>E "here is a ponderousness about adding a couple of ethyl groups and a sulfur that seems to say, :no fun. &@"AS.
has something going for it 'but not much- and 0@"AS. is Fuite a bit more peppy and, actually, +@"AS. has Fuite a bit of life. .ut there is a sense of N3hy
botherHN "here 3ere a couple of bouts of light@headedness, but there 3as no une/pected e/citement discovered in this methodical study. 5o surprises.
eep the chain lengths do3n.

#1(4 T.; (-TH"%./S!A"#E; ',)-0"METH%+Y-(-&n--./TYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution 3as made of ($.( g 5,5,57,57@tetramethylethylenediamine and (0.) g of (,0@dimetho/yben6ene in $,, m! 0,@1, deg C
petroleum ether. "his 3as stirred vigorously under a He atmosphere and cooled to , deg C 3ith an e/ternal ice bath. "here 3as added 11 m! of (.1 ?
butyl lithium in he/ane 3hich produced a 3hite granular precipitate. "he reaction mi/ture 3as brought up to room temperature for a fe3 minutes, and
then cooled again to , deg C. "here 3as then added ().2 g of di@'n-@butyl disulfide 'this reagent 3as Fuite yello3, but 3as used 3ithout any purification-
3hich changed the granular precipitate to a strange salmon color. Stirring 3as continued 3hile the reaction mi/ture 3as brought up to room temperature
and finally up to reflu/. "he reaction mi/ture 3as then added to 1,, m! of dilute H$S9+. "he t3o phases 3ere separated, and the aFueous phase
e/tracted 3ith $/2& m! <t$9. "he organic phases 3ere combined and the solvent removed under vacuum. "he residue 3eighed 00., g and 3as a dark
yello3 oil. <fforts to remove this color by reductive e/traction of a CH$Cl$ solution 3ith aFueous sodium hydrosulfite 3ere futile. "he residue 3as
distilled at ,.0 mm8Hg to give t3o fractions. "he first boiled at %&@((& deg C, 3eighed +.( g and 3as largely recovered dibutyl disulfide. "he product $@
'n-@butylthio@(,0@dimetho/yben6ene boiled at ((&@(0& deg C and 3eighed (%.& g. It 3as a pale amber oil that could not be induced to crystalli6e. Anal.
'C($H()9$S- C,H.
"o a stirred solution of (%.& g of $@'n-@butylthio@(,0@dimetho/yben6ene in 2& m! CH$Cl$ there 3as added (+.& g elemental bromine dissolved in 2& m!
CH$Cl$. "he evolution of H.r 3as evident, but the reaction 3as not e/othermic. "he reaction 3as allo3ed to stir for ( h and then heated briefly to a
reflu/ on the steam bath. It 3as then 3ashed 3ith H$9 containing sodium hydrosulfite 3hich discharged the residual color. After 3ashing 3ith saturated
brine, the solvent 3as removed under vacuum leaving $1., g of a pale amber oil. "his 3as distilled at ($,@(+, deg C at ,.+ mm8Hg yielding +@bromo@$@
'n-@butylthio@(,0@dimetho/yben6ene as a yello3@orange oil. It could not be crystalli6ed. Anal. 'C($H(2.r9$S- C,H.
"o a solution of ((.& m! diisopropylamine in &, m! he/ane that 3as stirred under 5$ there 3as added &, m! of (.1 ? butyllithium. After (& min stirring,
the reaction mi/ture became very viscous, and it 3as diluted 3ith (&, m! anhydrous "HB. After cooling in an ice bath there 3as added $., m! CH0C5
follo3ed in ( min 3ith 1., g of +@bromo@$@'n-@butylthio@(,0@dimetho/yanisole a bit at a time over the course of ( min. "here 3as the immediate formation
of a deep red color. After stirring for ,.& h, the mi/ture 3as poured into dilute H$S9+. "he organic layer 3as separated, and the aFueous layer
e/tracted 3ith 0/2& m! CH$Cl$. "hese e/tracts 3ere pooled, dried 3ith anhydrous $C90, and the solvent 3as removed under vacuum. "he residue
3as distilled at ,.$& mm8Hg and yielded t3o fractions. "he first fraction boiled at ($&@(+& deg C, 3eighed ,.) g and 3as discarded. "he second fraction
came over at (+&@(2& deg C as a light yello3 oil and 3eighed $.$ g. "his product, +@'n-@butylthio@0,&@dimetho/yphenylacetonitrile, 3as reduced as such
3ithout further purification or analysis.
A solution of !AH under 5$ '$, m! of a ( ? solution in anhydrous "HB- 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, ,.&0
m! (,,K H$S9+, follo3ed by $., g +@'n-@butylthio@0,&@dimetho/yphenylacetonitrile in (, m! anhydrous "HB. "he reaction mi/ture 3as stirred at , deg
C for a fe3 min, then brought to room temperature for ( h, and finally to a reflu/ for ( h on the steam bath. After cooling back to room temperature, there
3as added IPA 'to destroy the e/cess hydride- follo3ed by (,K 5a9H 3hich brought the reaction to a basic pH and converted the aluminum o/ides to a
loose, 3hite, filterable consistency. "hese 3ere removed by filtration, and 3ashed 3ith "HB and IPA. "he filtrate and 3ashes 3ere stripped of solvent
under vacuum, the residue 3as suspended in (&, m! of dilute 5a9H and e/tracted 3ith 0/(,, CH$Cl$. "hese e/tracts 3ere pooled and e/tracted 3ith
$/2& m! diluteH$S9+. <mulsions reFuired that a considerable additional Fuantity of H$9 be added. "he aFueous phase 3as made basic, and
e/tracted 3ith $/(,, m! CH$Cl$. After combining these e/tracts, the solvent 3as removed under vacuum providing a residue that 3as distilled. "he
product distilled at (0)@(1) deg C at ,.+ mm8Hg as a 3hite oil 3eighing ,.2 g. "his 3as dissolved in a small amount of IPA, neutrali6ed 3ith
concentrated HCl and, 3ith continuous stirring, diluted 3ith several volumes of anhydrous <t$9. After filtering, <t$9 3ashing, and air drying, +@'n-@
butylthio@0,&@dimetho/yphenethylamine hydrochloride '".- 3as obtained, 3eighed ,.1 g, and had a mp of (&+@(&& deg C. Anal. 'C(+H$+Cl59$S- C,H.
;9SAC<E 1, @ ($, mg.
;4:A"I95E about ) h.
L4A!I"A"IM< C9??<5"SE '3ith 0& mg- I 3as a3are of something at about an hour, and it developed into a benign and beautiful e/perience 3hich
never Fuite popped into anything psychedelic. At the fifth hour there 3as a distinct drop, and I made 3hat might be thought of as a foolish effort to
rekindle the state 3ith an additional $, milligrams but it 3as too little and too late. "here 3as no regeneration of anything additional.
'3ith 1, mg- A very subtle threshold, probably, and si/ hours into it there seems to have been little if any effect. ?y memory of it is not that certain and
no3 I am not sure that there had been anything at all.
'3ith ), mg- I am vaguely a3are of something. "he body discomfort may reflect the use of sardines in tomato sauce for lunch, but still things are not
Fuite right. Bive hours into it I am still in a 3onderful place spiritually, but there seem to be some dark edges. I might be neurologically sensitive to this.
'3ith ($, mg- "he course of the action of this is e/tremely clear. "he development 3as from & P? to 2 P? Pthe e/periment started at + P?Q and by (,
P? I 3as dropping and by midnight I 3ent to bed and slept 3ell. Bood 3as not too interesting, and a glass of 3ine before sleeping produced no
noticeable effect. "his 3as an uneventful e/perience that never really made it off the ground. It 3as pleasant, but certainly not psychedelic.
<="<5SI95S A5; C9??<5"A:>E "here is a term Ndose@dependentN in pharmacology. Ihen there is a comple/ action produced by a drug, then
each of the components of this mi/ture of effects should be e/pected to become more intense follo3ing a bigger dose of the drug. "his is certainly true
3ith most of the actions of psychoactive drugs.
As to the psychedelic aspects of some drugs, there can be visual effects, eyes@open 'edge@ripples or colors or retinal games- or eyes@closed 'images of
the elaborately decorated doors of the mosFue, or of an orchestra floating suspended by its music- or fantasy 'you are moving beyond the confines of
your body and invading someone else7s space-. "he same applies to tactile enhancement, to the anaesthetic component, to the depth of insight reali6ed
from a drug. "he more the drug, as a rule, the more the effect, up to the point that ne3 and disruptive effects are reali6ed. "his latter is called to/icity.
As to the stimulant component, the same is true. "he person gets 3ired up, and there is no sleep because there is no hiding from a cascade of images
and meanings, and the body lies there un3illing to yield guard since both the pounding heart and the interpretive psyche are demanding attention.
"hese aspects also intensify 3ith increasingly higher doses.
.ut an e/ception to this is the euphoria@producing aspect of a drug. 9ne sees 3ith increasing doses a continuing NthresholdN that makes you a3are, that
fluffs the senses, but 3hich seems not, at any level, to take over or to command the ship. It is truly a catalytic on or off. >ou are or you are not. In the
N"omsoN effect, this action is produced by alcohol. "here is disinhibition 3ith alcohol 3hich allo3s a central into/ication from the drug "9?S9 regardless
of the amount of drug used 'see under "9?S9-. 9ne sees again, here 3ith "., the case of a perpetual series of Nthresholds.N 5ever the psychedelic or
the stimulant action that increases 3ith increased dose. Al3ays the simple and ephemeral catalyst of euphoria 3ithout substance and 3ithout body. It is
a compound that can never be pinned and labeled in the butterfly collection since it defies an accepted classification.
"his action 3as seen first 3ith the compound called A:IA;5< and 3hen it 3as called an anti@depressant, it proved to be commercially interesting. It is
fully possible that ". 3ould be of value to certain depressed people in e/actly the same 3ay.
#1)5 '-TE; '-TH"%ES!A"#E;
(-ETH%+Y-)-METH%+Y-'-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of (,.+ g of 0@bromo@5@cyclohe/yl@+@etho/y@&@metho/yben6ylidenimine 'see under 0@"AS. for its preparation- in ($& m!
anhydrous <t$9, in a He atmosphere, 3as cooled 3ith an e/ternal dry ice acetone bath to @), deg C 3ith good stirring. "o this clear pale yello3 solution
there 3as added $& m! (.1 ? butyllithium in he/ane 'about a $&K e/cess- 3hich produced a fine 3hite precipitate over the follo3ing (& min. "here 3as
then added +.$ g dimethyl disulfide. At the half@addition point, the generated solids became so heavy that stirring became difficult, but to3ards the end
of the addition the reaction thinned out again and became Fuite loose. "he dry ice bath 3as removed and the reaction allo3ed to come to room
temperature, 3hich again allo3ed the formation of a heavy solid phase 3hile 3arming and, again, a loose and easily stirred mi/ture 3hen finally at room
temperature. All 3as added to +,, m! H$9 3hich had been strongly acidified 3ith HCl. "he t3o phases 3ere separated, and the aFueous phase
'3hich contained a small amount of yello3 oily matter insoluble in either phase- 3as heated on the steam bath for ,.2& h. 9n cooling, the oily
component set to a yello3 solid, 3hich 3as removed by filtration and 3ashed 3ith H$9. "his crude product, &.% g of yello3 solid, 3as distilled ((&@($&
deg C at ,.0 mm8Hg to give +.% g of +@etho/y@0@metho/y@&@'methylthio-ben6aldehyde as a pale yello3 solid that had a mp of +0@+& deg C.
:ecrystalli6ation from ?e9H gave a mp of +2@+) deg C. Anal. 'C((H(+90S- C,H. "his product can also be prepared from the anion of 0@
thiosyringaldehyde 'mp (+(@(+0 deg C as crystals from ?e9H- by reaction 3ith ethyl iodide in the presence of phase@transfer catalyst, but the yield is
Fuite poor.
"o a solution of +.+ g +@etho/y@&@metho/y@0@'methylthio-ben6aldehyde in 2& m! nitromethane, there 3as added ,.& g anhydrous ammonium acetate and
the mi/ture 3as heated on the steam bath for ), min. Care must be taken in the length of time, and there must be freFuent "!C montoring, as there is a
rapid scrudge buildup 'see under 0@"S. for a discussion of scrudge-. "he reaction mi/ture 3as stripped of nitromethane under vacuum, and the
residual deep@yello3 oil 3as dissolved in $, m! of boiling ?e9H. "his 3as decanted from a small amount of insoluble matter and, upon cooling,
deposited bright yello3 crystals of +@etho/y@&@metho/y@0@methylthio@beta@nitrostyrene. "his 3as removed by filtration and, after 3ashing 3ith cold
?e9H and air drying, 3eighed $.+ g. "he mp 3as ambiguous. "he above crude material melted at %$@%0 deg C, 3hich is probably too highO <arlier
samples 3hich melted in the lo3 ),7s appeared to have a mp, after repeated recrystalli6ation from ?e9H, of )2@)) deg C. "his latter 3as the property
of the analytical sample. Anal. 'C($H(&59+S- C,H. "he mp of the "!C lo3@moving component is al3ays Fuite high, and might have been a factor in
the assignment of this physical property.
AH 3as prepared in the usual manner from a suspension of $., g !AH in 2& m! anhydrous "HB, cooled to , deg C, 3ell stirred in an inert atmosphere of
He, and treated 3ith (.00 m! of (,,K H$S9+ added drop3ise. "here 3as added, drop3ise and over the course of (, min, a solution of $.+ g +@etho/y@
&@metho/y@0@methylthio@beta@nitrostyrene in (& m! anhydrous "HB. "he reaction 3as e/othermic, and 3as heated on the steam bath at reflu/ for an
additional (, min. After cooling again, there 3as added enough IPA to decompose the e/cess hydride and sufficient (,K 5a9H to convert the
aluminum o/ide solids to a 3hite, easily filterable mass. "his 3as filtered, the filter cake 3ashed 3ith additional IPA, the filtrate and 3ashes combined,
and the solvent removed under vacuum. "his 3as dissolved in (,, m! of dilute H$S9+ 3hich 3as 3ashed 3ith $/&, m! CH$Cl$. "he aFueous phase
3as made basic 3ith 5a9H, e/tracted 3ith $/&, m! CH$Cl$, and the e/tracts pooled and the solvent removed under vacuum to yield a residue of a
colorless oil. "his distilled at (()@($$ deg C at ,.+ mm8Hg producing (.% g of a colorless oil. "his 3as dissolved in (, m! IPA, neutrali6ed 3ith 0, drops
of concentrated HCl and, 3ith good stirring, diluted 3ith $, m! anhydrous <t$9. "he product +@etho/y@&@metho/y@0@methylthiophenethylamine
hydrochloride '0@"<- 3as removed by filtration, 3ashed 3ith <t$9, and air dried to provide a 3hite solid that 3eighed (., g and melted at about (), deg
C. Anal. 'C($H$,Cl59$S- C,H.
;9SAC<E 1, @ ), mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- "here may 3ell be time slo3ing. I noticed that the voices on the radio seemed to be of a deeper pitch. And
3ith music there is a most easy flight of fantasy. I tried to keep a logical conversation going on the telephone, but I am pretty sure there 3ere problems.
I found myself do3n sooner than I 3ould have liked.
'3ith 2, mg- I found myself in a good, rich place, and thoroughly enGoyed my introspection. I didn7t 3ant to talk and interact, and that seemed Gust fine
3ith everyone else. Several of the others seemed restless, but I lay back and let them do their thing. ?y appetite 3as fine to3ards the end, and I might
have actually overeaten. I 3as able to drive home that evening, but there seemed to be some slight residual something after 3aking in the morning. I
3ould certainly repeat 3ithout hesitation.
'3ith ), mg- Art interpretation and imagery 3ith music are remarkable. "his material touches on the psychedelic L rather than Gust being stoned. "he
body is higher than the mind, but 3here the mind is makes it all 9. It7s 3orth the cost. ?y getting to sleep 3as easy that evening, but sleep 3as not
too restful and there 3as something strange about it.
<="<5SI95S A5; C9??<5"A:>E "here is a good lesson to be learned in the attempts to predict the potency of 0@"< before it 3as actually e/plored.
All pharmacological prediction follo3s pretty much a single mechanism. Bind things that are close in some 3ay, and arrange them in a manner that
allo3s comparison. A relates to . in this 3ay, and A relates to C in that 3ay, and since ; incorporates both this and that of each, it 3ill probably be such@
and@such. "he :oman sFuare.
Here is the sFuare 3ith the hori6ontal arro3 adding a sulfur in the 0@position and the vertical arro3 adding an ethyl group in place of a methyl group at
the +@positionE
?escaline / 0.& 0@"?
$,,@+,, mg 1,@(,, mg
/ 1
<scaline 0@"< :/$,S
+,@1, mg T (,@$, mg
and one 3ould predict a potency of some $,/ that of mescaline, or something in the range of (& mg.
Here is an eFually likely sFuare, based on the hori6ontal arro3 relocating a sulfur from the +@position to the 0@position, and the vertical arro3 again
adding an ethyl group in place of a methyl group in the +@positionE
"hiomescaline / ,.0 0@"hiomescaline
$,@0, mg 1,@(,, mg
/ (
"hioescaline 0@"< :/,.0S
$,@0, mg T 1,@(,, mg
and one 3ould predict a potency of some one third of that of thiomescaline, or something in the range of ), milligrams.
"his latter sFuare gave a prediction that 3as very close to the observed potency, but it 3ould be careless, and probably 3rong, to assume that the latter
relationships had any more significance than the former ones. As one accumulates the potencies of many compounds it is tempting to dra3 comple/
relationships such as these, and to be seduced into believing that they must e/plain things. And, especially, be3are the multivariable po3er of the
computer 3hich can e/plore monstrous numbers of variables at breakneck speeds, and spe3 forth fantastic correlations 3ith marvelous ease.
.ut nothing can ever substitute for the simple art of tasting something ne3.

#1)1 TE; (-TE; (-TH"%ES!A"#E; ',)-0"METH%+Y-(-ETHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution 3as made of +&.$ g 5,5,57,57@tetramethylethylenediamine and +(.+ g of (,0@dimetho/yben6ene in 0,, m! he/ane. "his 3as
stirred vigorously under a He atmosphere and cooled to , deg C 3ith an e/ternal ice bath. "here 3as added $$& m! of (.1 ? butyllithium in he/ane
3hich produced a 3hite granular precipitate. "he reaction mi/ture 3as stirred for (& min. "here 3as then added 0) m! of diethyl disulfide 3hich
changed the granular precipitate to a creamy character. Stirring 3as continued for an additional & min, then the reaction mi/ture 3as poured into ( ! of
dilute H$S9+. "he t3o phases 3ere separated, and the aFueous phase e/tracted 3ith $/(&, m! <t$9. "he organic phases 3ere combined, and the
solvent removed under vacuum to provide 1, g of $@ethylthio@(,0@dimetho/yben6ene as an off@3hite oil that spontaneously crystalli6ed. It 3as distilled
nonetheless, boiling at )&@%1 deg C at ,.+ mm8Hg. "his distillate can be recrystalli6ed from he/ane to form long needles 3ith a mp of +&@+1 deg C.
Anal. 'C(,H(+9$S- C,H.
"o a stirred solution of 1, g of $@ethylthio@(,0@dimetho/yben6ene in 0,, m! CH$Cl$ there 3as added +% g elemental bromine dissolved in (,, m!
CH$Cl$. "he reaction 3as not e/othermic, and it 3as allo3ed to stir for $ h. "he reaction mi/ture 3as 3ashed 3ith H$9, then 3ith aFueous 5a9H, and
finally 3ith H$9 that contained sodium hydrosulfite. "he solvent 3as removed under vacuum leaving )+ g of an amber oil as residue. "his 3as distilled
at (,&@((& deg C at ,.(& mm8Hg yielding 20.0 g of +@bromo@$@ethylthio@(,0@dimetho/yben6ene as a light yello3 oil. Anal. 'C((H(&.r9$S- C,H.
"o a solution of $2 m! diisopropylamine in (&, m! anhydrous "HB that 3as stirred under a 5$ atmosphere and cooled to @(, deg C 3ith an e/ternal
ice8?e9H bath, there 3as added in seFuence )0 m! of (.1 ? butyllithium in he/ane, +.+ m! of dry CH0C5 over the course of & min, and finally ($.( g of
+@bromo@$@ethylthio@(,0@dimetho/yben6ene 3hich had been dissolved in $, m! "HB 'also added over the course of & min-. "he color progressed from
yello3 to orange to deep red@bro3n. Stirring 3as continued for (, min, and then the reaction mi/ture 3as poured into 0,, m! dilute H$S9+. "he
organic layer 3as separated, and 3as 3ashed 3ith more dilute H$S9+. "he aFueous phases 3ere combined, and e/tracted 3ith $/(,, m! CH$Cl$.
"hese e/tracts 3ere pooled 3ith the original organic phase, and the solvents removed under vacuum. "he residue 3as distilled into t3o fractions at ,.0
mm8Hg. "he first fraction boiled at %&@((& deg C and 3eighed +.% g. It 3as made up of several components, but it contained little nitrile material and
3as discarded. "he second fraction came over at (+&@U$,, deg C and 3eighed $.% g. .y thin layer chromatography this fraction 3as largely 0,&@
dimetho/y@+@ethylthiophenylacetonitrile, and 3as used as such in the follo3ing reduction.
A suspension of (.$& g !AH in &, m! anhydrous "HB under 5$ 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, ,.) m! (,,K
H$S9+, follo3ed by $.2 g 0,&@dimetho/y@+@ethylthiophenylacetonitrile, neat, over the course of & min. "he reaction mi/ture 3as stirred at , deg C for a
fe3 min, then brought to a reflu/ for (& min on the steam bath. After cooling back to room temperature, there 3as added (& m! IPA to destroy the
e/cess hydride and (,K 5a9H to bring the reaction to a basic pH and convert the aluminum o/ide to a loose, 3hite, filterable consistency. "his 3as
removed by filtration, and 3ashed 3ith &, m! portions of IPA. "he filtrate and 3ashes 3ere stripped of solvent under vacuum, and the residue
suspended bet3een &, m! CH$Cl$ and &, m! dil. H$S9+. "he organic phase 3as separated, and e/tracted 3ith $/&, m! dilute H$S9+. "he original
aFueous phase and these t3o e/tracts 3ere combined, made basic 3ith aFueous 5a9H, and e/tracted 3ith 0/&, m! CH$Cl$. "hese e/tracts 3ere
stripped of solvent under vacuum. "he residue 3as distilled at (($@(0& deg C at ,.$ mm8Hg to give (.( g of a slightly yello3 viscous liFuid. "his 3as
dissolved in + m! IPA, neutrali6ed 3ith (+ drops of concentrated HCl and, 3ith continuous stirring, diluted 3ith (, m! anhydrous <t$9. "he product 3as
removed by filtration, 3ashed 3ith <t$9, and air dried to give (., g of 0,&@dimetho/y@+@ethylthiophenethylamine hydrochloride '"<- as 3hite crystals 3ith
some solvent of crystalli6ation. "he crude mp of (,(@(,1 deg C 3as only slightly improved by recrystalli6ation from CH0C5 'mp (,1@(,% deg C-. .ut
upon fusion and resolidification, the melting point 3as (12@(1) deg C and this sample 3as further dried by heating at (,, deg C for $+ h before analysis.
Anal. 'C($H$,Cl59$S- C,H.
;9SAC<E $, @ 0, mg.
;4:A"I95E % @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- I feel it in my ovaries. It is very sensuous. "his is total energy, and I am a3are of my every membrane. "his
has been a marvelous e/perience, very beautiful, Goyous, and sensuous. .ut maybe the dose is a little too high as there is too much body tingling. I am
Gangly.
'3ith $, mg- "he predominant characteristic 3as the feeling of clean burning, pure energy, a long@lasting clear@headedness and clarity of thought, and
an ease of talking and sharing. I did not have a strong feeling of Presence, but more a 3onderful feeling of converting energy into action. I found that
my initial look in3ards 3as al3ays a look of fear, and I 3ondered if this might not be the same feeling that others e/press as e/citement. "hey 3ere
certainly of the same nature, they arose at the same point on the fringe of the unkno3n, and they point to a basic difference in attitude. "he e/citement
is for the ne3, and is based on trust. "he fear is a return to the past, and is defensive, 3ith reluctance to ree/perience past pain. "he aftermath of this
e/perience 3as the most profound of any that I have had in a long time. Bor the follo3ing 3eek, I found myself on a ne3 level of functioning, very
energetic and very much in the flo3 of life and free of mental distractions. I have become a great deal more a3are of the traps of meditation, and ho3
you can build 3alls around yourself and around certain concepts, if you are not careful.
'3ith $$ mg- "otally developed at $ hours, to a ***. 5o clearing of the sinuses, so it is not a decongestant. "here is a lot of visual activity. In the group
there is good communication, and a lot of laughter.
'3ith $& mg- "here is a disconnection, there is comple/ depth 3ithout definition. Iithout music, this is almost negative, as I can find no definition. .ut
talking gives me some structure. And I got into some pretty e/traordinary conversations. About President Hoover, 9mni maga6ine, the colors of spices,
and a couple of personal relatives. "his is e/tra@good for ideas and talking. It is indeed a clean e/perience, and superb for communication.
'3ith 0, mg- I 3as at a plus three for certainly three hours. "here 3ere some visuals, some eyes@closed fantasy, but little imagery. Someho3 I could at
no time interlock 3ith music. It seemed al3ays to get in the 3ay. Se/ual activity is an e/cellent 3ay to relieve the muscular tension and the body7s
heaviness. "here 3as little hunger and I ate lightly, and I felt someho3 depleted. Sleep 9 at the t3elth hour. "he A? 3as fine, but on retrospect the
e/perience 3as overall strangely cloudy, not negative, but there 3as not enough mental to balance the physical.
'3ith 0, mg- ?y alert 3as in +, minutes, and I 3as completely developed by $ hours. "here 3as a large measure of erotic fantasy, but the body load
3as also Fuite heavy. I had a slight cloak effect, 3here I 3as over@energi6ed but someho3 under a blanket of Fuietness. I 3ould certainly repeat this,
but at maybe $& milligrams.
<="<5SI95S A5; C9??<5"A:>E Although the ethyl group 'of the ethylthio on the +@position- is Gust one carbon atom longer than the methyl group
'of "?- that small change already produces hints and indicators of some physical to/icity. "he propyl compound 'see "P- is still of similar potency, but
appears to be yet more difficult, physically. "he butyl homolog never made it off the ground at all as a psychedelic, but the physical difficulties seem less
as 3ell. All that 3as left to come through 3as the euphoria. If this +@position sulfur analogue series of mescaline is ever to be more carefully e/plored, it
must almost certainly be 3ith the shortest possible chain '"?, as a psychedelic- or 3ith long, long chains 'the four@carbon chain of the butyl group in
".-, as a feel@good compound.

#1)$ $-T"M; $-TH"%"S%MES!A"#E; ',(-0"METH%+Y-$-
METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A short fore3ord to the synthetic portion is needed. Birst, although the reFuired thioanisole, $,0@dimetho/ythioanisole, is no3 commercially
available, it is of the utmost importance that it be free of the impurity, veratrole. I kno3 that the material presently available from Aldrich Chemical
Company is satisfactory, as I have had a hand in making it. .ut, if veratrole is present, there are very difficult separations encountered during these
preparations. And secondly, the synthesis of $@"I? and +@"I? reFuires a separation of isomers. "he first intermediates are common to both. "hey 3ill
be presented here, under this recipe for $@"I?.
A solution of (&, m! of (.1 ? butyllithium in he/ane under 5$ 3as vigorously stirred and diluted 3ith (&, m! petroleum ether '0,@1, deg C- and then
cooled 3ith an e/ternal ice bath to , deg C. "he addition of $1.2 g of veratrole produced a flocculant 3hite precipitate. 5e/t, there 3as added a solution
of $0.$ g of 5,5,57,57@tetramethylethylenediamine in (,, m! anhydrous <t$9 and the stirred reaction mi/ture 3as allo3ed to come to room temperature.
"he subseFuent addition of $,.2 g of dimethyl disulfide over the course of several min produced an e/othermic response, and this 3as allo3ed to stir for
an additional 0, min. "here 3as then added (, m! <t9H follo3ed by $&, m! of &K 5a9H. "he organic phase 3as 3ashed first 3ith (&, m! &K
5a9H, follo3ed by $/(,, m! portions of &K dilute HCl. "he removal of solvent and bulb@to@bulb distillation of the residue provided $,0@
dimetho/ythioanisole boiling at 2$@), deg C at ,.+ mm8Hg as a 3hite oil. "his product contained some $,K unreacted veratrole as a contaminant and
the isolation of subseFuent products from this impure material 3as e/traordinarily difficult. "he effort needed for careful purification at this point 3as
completely Gustified. "he product could be obtained in a pure state by distillation at ,.( mm8Hg through a 1 cm Migreau/ column 3ith collection of several
fractions. "hose that distilled at )+@)2 deg C 3ere pure $,0@dimetho/ythioanisole. An analytical sample can be obtained by cooling a concentrated
?e9H solution in dry ice, filtering the generated crystals, and 3ashing 3ith cold ?e9H. "his product melts at 01.&@02 deg C. Anal. 'C%H($9$S- C,H,S.
"he picrate can be formed by treatment 3ith a saturated <t9H solution of picric acid. It formed orange crystals 3ith a mp of 20@2) deg C. Anal.
'C(&H(&509%S- 5.
"o () m! of P9Cl0 there 3as added $& m! 5@methylformanilide and the solution allo3ed to stand at room temperature for ,.& h, until the color had
developed to a rich claret. "here 3as then added $&., g of $,0@dimetho/ythioanisole and the mi/ture heated on the steam bath for $.& h. "his 3as
added to &,, m! H$9 and stirred at ambient temperature for $ h. "he product 3as e/tracted 3ith +/(&, m! CH$Cl$, the e/tracts combined, and the
solvent removed under vacuum. "he residue 3as distilled through a Migreau/ column under vacuum ',.( mm8Hg- 3ith the fraction boiling at ($&@(0&
deg C being richest in aldehydes, as determined by CC analysis. If the starting $,0@dimetho/ythioanisole contains appreciable veratrole as a
contaminant, then this aldehyde fraction contains three components. "here is present both $,0@dimetho/y@+@'methylthio-ben6aldehyde and 0,+@
dimetho/y@$@'methylthio-ben6aldehyde 'the t3o desired precursors to +@"I? and $@"I?, respectively-, but also present is 0,+@dimetho/yben6aldehyde
from the veratrole contamination. "he 3eight of this fraction 3as ((.% g and 3as a 3hite oil free of starting thioether.
Although efforts to separate this mi/ture 3ere not effective, one of the aldehydes could be isolated in small yield by derivative formation. "his 3as too
3asteful to be of preparative value, but it did allo3 the generation of seed that 3as of great value in the later separation of the mi/ed nitrostyrenes that
3ere prepared. If a ( g portion of this mi/ture 3as fused 3ith ,.1 g p@anisidiine over an open flame and then cooled, the melt set up as a solid.
"riturating under ?e9H gave a yello3 solid ',.+& g, mp 22@), deg C- 3hich on recrystalli6ation from he/ane appeared to be a single one of the three
possible Schiff7s bases that could theoretically be prepared. It had a mp of ),@)( deg C. Anal. 'C(2H(%590S- C,H. Hydrolysis 3ith hot 0 5 HCl freed
the ben6aldehyde 3hich 3as isolated by Fuenching in H$9 and e/traction 3ith CH$Cl$. "he e/tracts 3ere stripped of solvent under vacuum and the
residue distilled bulb@to@bulb under vacuum to give 3hite crystals of 0,+@dimetho/y@$@'methylthio-ben6aldehyde 'the $@"I? aldehyde- 3ith a mp of $0@$+
deg C. A micro@scale conversion of this to the corresponding nitrostyrene provided the seed that 3as effectively used in the large scale preparation
described belo3.
A solution of %., g of a mi/ture of 0,+@dimetho/y@$@'methylthio-ben6aldehyde and $,0@dimetho/y@+@'methylthio-ben6aldehyde in &, m! of nitromethane
3as treated 3ith (.& g anhydrous ammonium acetate and held at reflu/ for & h. "he e/cess nitromethane 3as removed under vacuum to yield (,.+ g of
a dark orange oil 3hich, upon dissolving in +, m! hot ?e9H and being allo3ed to cool and slo3ly evaporate at ambient temperatures, provided dark
colored crystals. Biltration 'save the mother liFuorsO- and recrystalli6ation from +, m! ?e9H provided 1.0 g of a yello3 crystalline solid. A second
recrystalli6ation from &, m! ?e9H gave &., g of lemon yello3 plates 0,+@dimetho/y@$@methylthio@beta@nitrostyrene 3ith a mp of (,$@(,0.& deg C. An
analytical sample, from IPA, had a mp of (,0@(,+ deg C and a single spot on "!C 3ith CHCl0, 3ith an :f of ,.&+. Anal. 'C((H(059+S- C,H. Ihen
there had been veratrole left as a contaminant in the original $,0@dimetho/ythioanisole, the nitrostyrene that 3as isolated by this method had, after
recrystalli6ation, a mp of %0@%& deg C. "his substance acted as a single compound through a number of recrystalli6ation trials, but on "!C analysis
al3ays gave t3o components 'silica gel, chloroform- 3ith :f7s of ,.&+ and ,.+2. It proved to be a mi/ture of 0,+@dimetho/y@$@methylthio@beta@
nitrostyrene and 0,+@dimetho/y@beta@nitro@styrene in an e/act molecular ratio of $E(. "his latter nitrostyrene is the precursor to ;?P<A, F.v. Anal.
'C0$H02509($S$- C,H. "he mother liFuor above is the source of the +@"I? nitrostyrene, and its isolation is described in the recipe for +@"I?.
A solution of +.$ g !AH in 2, m! anhydrous "HB 3as cooled to , deg C under He and 3ith stirring. "here 3as added, drop3ise, $.) m! of (,,K
H$S9+, follo3ed by +.+ g of 0,+@dimetho/y@$@'methylthio-@beta@nitrostyrene dissolved in $& m! "HB. Stirring 3as continued for a fe3 min as the reaction
returned to room temperature, and then it 3as heated to a reflu/ for (, min on the steam bath. "he reaction 3as cooled again, and $&K 5a9H 3as
added drop3ise until a 3hite granular precipitate 3as obtained. "his 3as removed by filtration, and the filter cake 3as 3ashed 3ith $/&, m! <t$9. "he
filtrate 3as e/tracted into (,, m! dilute H$S9+ 3hich 3as, in turn, made basic again and e/tracted 3ith $/(,, m! CH$Cl$. "he e/tracts 3ere pooled,
and the solvent removed under vacuum to give a residue of crude product. "his 3as distilled from (,,@((& deg C at ,.0 mm8Hg yielding 0.$ g of a clear
3hite oil. "his 3as dissolved in $& m! IPA, neutrali6ed 3ith $0 drops of concentrated HCl, and diluted 3ith 2& m! anhydrous <t$9. "here 3as a
deposition of beautiful 3hite platelets of 0,+@dimetho/y@$@methylthiophenethylamine hydrochloride '$@"I?- 3hich 3ere removed by filtration, 3ashed 3ith
ether, and air dried. "his hydrochloride salt contained a Fuarter mole of H$9 of crystalli6ation. "he mp 3as ()0@()+ deg C. Anal. 'C((H()Cl59$Sa(8+
H$9- C,H,5.
;9SAC<E greater than $+, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (1, mg- "here 3as perhaps some a3areness in an hour or so, but in another hour there 3as absolutely nothing. A
small amount of 3ine in the evening 3as Fuite into/icating.
'3ith $+, mg- 5o effects of any kind.
<="<5SI95S A5; C9??<5"A:>E "he problems that might be associated 3ith the making of the three amphetamines that correspond to $@"I?, 0@
"I? and +@"I? might very 3ell prove Fuite e/citing. "hese 3ould be the three thio analogues of "?A@0; vis, 0,+@dimetho/y@$@methylthioamphetamine,
$,+@dimetho/y@0@methylthioamphetamine, and $,0@dimetho/y@+@thioamphetamine. "he first challenge 3ould be to name them. 4sing the $C@0C
convention, they 3ould be the 0C analogs of trivially named $@carbon compounds, namely 0C@$@"I?, 0C@0@"I? and 0C@+@"I?. 4sing the thio
convention 'the number before the " is the position of the sulfur atom-, they 3ould be $@"@"?A@0, 0@"@"?A@0 and +@"@"?A@0. "he second challenge
3ould be their actual synthesis. "he information gained from the separation of the $@carbon nitrostyrenes and that most remarkable mi/ed@nitrostyrene
thing that acted as a single pure material, 3ould not be usable. .ut it is intriguing to speculate if there might be some parallel problems in the 0@carbon
3orld. It seems almost certain that none of the compounds 3ould be pharmacologically active, so the incentive 3ould be the challenge of the chemistry.
Some day, maybe.
#1)' '-T"M; '-TH"%MES!A"#E; $,(-0"METH%+Y-'-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A mi/ture of 0.( g P9Cl0 $.) g 5@methylformanilide 3as heated on a steam bath until it 3as a deep claret color 'about & min-. "o this there
3as then added 0., g of $,1@dimetho/ythioanisole 'see under +@"? for its preparation-, and heating 3as continued for 0, min. "he reaction mi/ture 3as
then added to 2& m! H$9 and stirred overnight. "he dark oily mi/ture 3as e/tracted 3ith 0/2& m! CH$Cl$, the e/tracts pooled, and the solvent
removed under vacuum. "he residue 3as e/tracted 3ith 0/$, m! boiling he/ane, each e/tract being poured off from the insoluble residue. Pooling and
cooling these e/tracts yielded (.& g of $,+@dimetho/y@0@'methylthio-ben6aldehyde as an off@3hite crystalline solid 3ith a mp of 12@1% deg C.
:ecrystalli6ation from either ?e9H or cyclohe/ane tightened the mp, but lo3ered it to 12@1) deg C and 11@12 deg C, resp. Anal. 'C(,H($90S- C,H.
"o a solution of (.0 g $,+@dimetho/y@0@'methylthio-ben6aldehyde in 1, m! nitromethane there 3as added ,.0 g anhydrous ammonium acetate and the
mi/ture 3as heated at reflu/ for 0 h. "he hot solution 3as decanted from a little insoluble material, and the e/cess nitromethane 3as removed under
vacuum. "he residue dissolved in (, m! hot ?e9H. 9n cooling, yello3 crystals of $,+@dimetho/y@0@methylthio@beta@nitrostyrene 3ere obtained 3hich
3ere removed by filtration and air@dried, and 3eighed ,.% g. "he mp 3as (0,@(00 deg C and could be improved to (01@(02 deg C follo3ing
recrystalli6ation from ?e9H '(, g8g-. Anal. 'C((H(059+S- C,H.
A 3ell@stirred solution of ,.1 g !AH in (, m! anhydrous "HB 3as cooled to , deg C under He. "here 3as added, drop3ise, ,.+ m! of (,,K H$S9+,
follo3ed by ,.1 g of $,+@dimetho/y@0@methylthio@beta@nitrostyrene dissolved in a little "HB. Stirring 3as continued for a fe3 min as the reaction returned
to room temperature, and then it 3as heated to a reflu/ for & min on the steam bath. "he reaction 3as cooled again, and $&K 5a9H 3as added
drop3ise until a 3hite granular precipitate 3as obtained. "his 3as removed by filtration, and the filter cake 3as 3ashed 3ith $/$& m! <t$9. "he filtrate
3as e/tracted into $& m! dilute H$S9+ 3hich 3as, in turn, made basic again and e/tracted 3ith $/$& m! CH$Cl$. "he e/tracts 3ere pooled, and the
solvent removed under vacuum to give a residue of crude product. "his 3as distilled from ($,@(+, deg C at ,.0 mm8Hg yielding ,.$& g of a clear 3hite
oil. "his 3as dissolved in & m! IPA, neutrali6ed 3ith about 0 drops of concentrated HCl, and diluted 3ith (& m! anhydrous <t$9. Scratching 3ith a glass
rod instigated crystalli6ation of bright 3hite solids 3hich 3ere filtered, 3ashed 3ith <t$9, and air dried. "he 3eight of $,+@dimetho/y@0@
methylthiophenethylamine hydrochloride '0@"I?- 3as ,.$ g and the mp 3as $,+@$,1 deg C 3ith decomposition. "his hydrochloride appeared to be a
hemihydrate. Anal. 'C((H()Cl59$Sa(8$ H$9- C,H,5.
;9SAC<E greater than $+, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $+, mg- .riefly I thought that there might have been an alert at the $ to 0 hour point, but I no3 think it 3as nothing.
;uring the follo3ing day I had a mild stomach upset off and on, but I can7t believe that it 3as connected 3ith 0@"I?.
<="<5SI95S A5; C9??<5"A:>E Isomescaline itself is not active, but there is no 3ay of kno3ing Gust ho3 Nnon@activeN it really is. If it 3ere to be
active Gust beyond the levels assayed, then the introduction of a sulfur into the molecule in place of an o/ygen could have increased the potency to
3here it might have some effect. "he absence of any activity from this "I?, and the other t3o "I?s, might 3ell suggest that isomescaline is really very
Nnon@active,N if that makes senseO

#1)( (-T"M; (-TH"%"S%MES!A"#E;
$,'-0"METH%+Y-(-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE "he mother liFuors from the initial crystalli6ation of the $@"I? nitrostyrene 'see under $@"I?- 3as the source and ra3 material for all +@"I?
chemistry. 9nce the bulk of the $@"I? nitrostyrene has been removed, these mother liFuors could be processed to give the +@"I? nitrostyrene. "he
easier procedure 3as to evaporate these mother liFuors to a residue under vacuum, and hope for a spontaneous crystalli6ation. If this failed, flash
chromatography could be used. Bor reference purposes, the three nitrostyrenes involved in the $@"I?8+@"I? problem movedon silica gel "!C 3ith CHCl0
solvent in the follo3ing mannerE $,0@dimetho/y@+@methylthio@beta@nitrostyrene 'leading to +@"I?-, :f T ,.1(; 0,+@dimetho/y@$@methylthio@beta@nitrostyrene
'leading to $@"I?-, :f T ,.&+; and 0,+@dimetho/y@beta@nitrostyrene 'leading to ;?P<A-, :f T ,.+2. Bor flash chromatography, a small portion of the
residue from the mother liFuor 3as dissolved in CHCl0, and placed on a silica gel column. CHCl0 3as used as the eluding solvent. "he first material
breaking through from the column 3as the +@"I? nitrostyrene and on evaporation of this fraction, seed 3as obtained as gold@colored crystals that had a
mp of 2(@20 deg C. "his, 3hen added to the residues from the described $@"I? synthesis nitrostyrenes, started the crystalli6ation process. "he gummy
solid that 3as produced 3as triturated under ?e9H, and the crystals so revealed 3ere removed by filtration. :ecrystalli6ation from (, m! ?e9H gave
(.% g of solids. A second recrystalli6ation from & m! ?e9H provided ,.2 g of pumpkin@colored crystals of $,0@dimetho/y@+@methylthio@beta@nitrostyrene
3ith a mp of 2,@2( deg C.
A solution of (.$ g !AH in $, m! anhydrous "HB 3as cooled to , deg C under He and stirred. "here 3as added, drop3ise, ,.) m! of (,,K H$S9+,
follo3ed by ,.% g of $,0@dimetho/y@+@methylthio@beta@nitrostyrene dissolved in $, m! "HB. Stirring 3as continued for a fe3 min as the reaction returned
to room temperature, and then it 3as heated to a reflu/ for & min on the steam bath. "he reaction 3as cooled again, <t9Ac 3as added to destroy the
e/cess hydride, follo3ed by $&K 5a9H added drop3ise until a 3hite granular precipitate 3as obtained. "his 3as removed by filtration, and the filter
cake 3as 3ashed 3ith $/0& m! <t$9. "he filtrate 3as e/tracted into &, m! dilute H$S9+ 3hich 3as 3ashed 3ith <t$9 and, in turn, made basic again
and e/tracted 3ith $/&, m! CH$Cl$. "he e/tracts 3ere pooled, and the solvent removed under vacuum to give a residue of crude product. "his
distilled cleanly from (,,@((& deg C at ,.0 mm8Hg yielding ,.+& g of a clear 3hite oil. "his 3as dissolved in 1 m! IPA, neutrali6ed 3ith & drops of
concentrated HCl, and diluted 3ith $& m! anhydrous <t$9. "here 3as a deposition of 3hite solids 3hich 3ere removed by filtration, 3ashed 3ith <t$9,
and air dried. "he $,0@dimetho/y@+@methylthiophenethylamine hydrochloride so obtained '+@"I?- 3eighed ,.0 g and contained a molecule of H$9 of
crystalli6ation. "he mp 3as $($@$(0 deg C. Anal. 'C((H()Cl59$SaH$9- C,H,5.
;9SAC<E greater than (1, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (1, mg- <verything seemed normal. Pulse 3as under ),, there 3as nothing 3ith eyes@closed, my appetite 3as
normal. "he compound 3as completely inactive.
<="<5SI95S A5; C9??<5"A:>E "here has been much noise made about the effectiveness of an unusual substitution group at the +@position of the
phenethylamine molecule. Here is a methylthio group at this position, and it is an inactive compound. I 3as Gust a little bit surprised.

#1)) '-TM; '-TH"%MES!A"#E; ',(-0"METH%+Y-)-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE "o an ice cold and 3ell stirred solution of (& g vanillin and $, g sodium thiocyanate in (&, m! acetic acid there 3as added, drop3ise over
the course of (& min, a solution of (1 g elemental bromine in +, m! acetic acid. "his 3as follo3ed by the addition of 0, m! of &K HCl and 0,, m!
<t9H, and stirring 3as continued for an additional 0, min. "he mi/ture 3as heated to its boiling point, and filtered 3hile hot. "he mother liFuor 3as
diluted 3ith an eFual volume of H$9, 3hich initiated the crystalli6ation of crude &@formyl@2@metho/y@$@o/o@(,0@ben6o/athiole as a flocculant yello3 solid.
9n filtration and air@drying, this 3eighed ($.& g. After recrystalli6ation from <t9H, the product 3as 3hite and had a mp of (1+ deg C sharp.
A suspension of ($.& g of crude &@formyl@2@metho/y@$@o/o@(,0@ben6o/athiole in (,, m! ?e9H containing $).+ g methyl iodide 3as treated 3ith a
solution of ($ g 5a9H in (,, m! 3arm ?e9H. "he mi/ture 3as held at reflu/ for ( h and then the solvents 3ere removed under vacuum. A solution of
(+.$ g methyl iodide in (,, m! ;?S9 3as added and the mi/ture stirred for ( h. An additional $.+ g of 5a9H and (1 g methyl iodide 3ere added, and
the stirring 3as continued for another $ h. "he reaction mi/ture 3as poured into ),, m! H$9, acidified 3ith HCl, and e/tracted 3ith 0/2& m! CH$Cl$.
"he pooled e/tracts 3ere 3ashed 3ith &K 5a9H, then 3ater, and the solvent removed under vacuum. ;istillation at ((,@(0, deg C at ,.+ mm8Hg gave
,.% g 0,+@dimetho/y@&@'methylthio-ben6aldehyde 3hich had a mp of &2@&) deg C after crystalli6ation from <t9H. Anal. 'C(,H($90S- C,H.
A solution of ,.% g 0,+@dimetho/y@&@'methylthio-ben6aldehyde in (,, m! nitromethane containing ,.& g anhydrous ammonium acetate 3as held at reflu/
for + h. "he e/cess nitromethane 3as removed under vacuum, and the deep bro3n residue 3as dissolved in + m! hot ?e9H. 9n cooling, the yello3
crystals 3ere removed by filtration, 3ashed 3ith cold ?e9H and air dried yielding ,.+ g yello3 crystals of 0,+@dimetho/y@&@metho/y@beta@nitrostyrene,
3ith a mp of ((%.&@($,.& deg C after recrystalli6ation from <t9H. Anal. 'C((H(059+S- C,H.
"o a solution of (., g !AH in $& m! anhydrous "HB under He, cooled to , deg C and vigorously stirred, there 3as added, drop3ise, ,.2 m! of (,,K
H$S9+, follo3ed by a solution of ,.2 g 0,+@dimetho/y@&@methylthio@beta@nitrostyrene in (, m! anhydrous "HB. "he mi/ture 3as brought briefly to a
reflu/, cooled again, and the e/cess hydride destroyed 3ith H$9 in "HB, follo3ed by the drop3ise addition of (&K 5a9H until the solids became 3hite
and granular. "he solids 3ere removed by filtration, the filter cake 3ashed 3ith "HB, the mother liFuor and filtrates combined, diluted 3ith an eFual
volume of <t$9, and e/tracted 3ith $/+, m! dilute H$S9+. "he aFueous e/tracts 3ere combined, 3ashed 3ith <t$9, made basic 3ith aFueous 5a9H,
and e/tracted 3ith $/&, m! CH$Cl$. "he solvent 3as removed from these e/tracts and the residue distilled to provide ,.+ g of a 3hite oil boiling at ($+@
(0, deg C at ,.$ mm8Hg. "his oil 3as dissolved in ) m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith 0, m! anhydrous <t$9. "he 3hite
crystalline product 3as the monohydrate of 0,+@dimetho/y@&@methylthiophenethylamine hydrochloride '0@"?- 3hich melted at (12@(1) deg C and
3eighed ,.$% g. Anal. 'C((H()Cl59$SaH$9- C,H,5.
;9SAC<E 1, @ (,, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith ), mg- I 3ent into the e/perience 3ith the Fuestion of 3hether it '0@"?- might be a 3riting aid. I found a considerable
color enhancement 'this 3as at the one hour point- and there seems to be no problem in 3riting physical 3ords. .ut there is no urge to, as there are no
ne3 things. "his is progressing into something more comple/ and there is an interesting shielding effect. I still have the desire to 3rite and I sense that
many things are going on underneath, but my conscious control suppresses their availability. It is no3 the third hour. ?usic. I 3ould like to try this
material at (,, milligrams. 5o3 a3areness seems much more pointed. I have need to build a 3riting table. "his material is physically rela/ing,
insisting repose, but 3ith conflicting energy. Seated in a chair, but I seem unable to find a comfortable position in order to 3rite.
NPine trees seem a good place
"o start. 5ot3ithstanding this table
9f pine, unfinished, unruled,
"he pulp upon 3hich 3e reveal
"he unnerved thoughts.
Ho3 casual 3e are at discarding
9ur feelings, a rubble 3e
!eave behind for the living.
Iho among us can absorb
"he spiritual load 3e see as
Ihat others carry.N
"his material is not poetic, I should say, does not enhance poetry, prose is much more comfortable. I think I should let the e/perience develop further. It
is no3 the fifth hour. "here is something of a violence 'emotional- suppressed in all of us, a socially repressed vision of oneself in a direct conflict 3ith
oneself. "he music has a lot to do 3ith this material. And it changes 3ith time. In the first part there is sublimity, peacefulness, mild into/ication. And a
lot more tension in the part that follo3ed the four hour point. "here the territories seem much better defined, 3ith the benign shielding of the first half
largely dissipated. I have developed a slightly irritated vie3 of myself, probably 3anting once again to regain the serenity.
'3ith ), mg- ;elightful day. 5ot insight depth but persistent feeling of pleasant good humor. It is good@natured and very verbal. <veryone talked and the
instinct 3as to e/press and comment on everything. "here 3ere no visuals during the first three to four hours L 3ith the eyes open one could barely
detect the into/ication. <yes closed L Fuiet lovely 3indo3, no images. About *$. And then someone brought in a radio 3ith music on, into the room.
"here 3as a tremendous eruption of closed@eyes visual images and fantasy. .right colors, funny, rich and elaborate. ?arvelous. I 3as suddenly at *0.
5e/t day, no hangover. Pleasant feeling persisted.
'3ith (,, mg- I found the day had t3o halves. "he first fe3 hours 3ere characteri6ed by occasional defensiveness 'paranoia- and irritability. In
interpersonal interactions there 3as a guardedness, due to a feeling of vulnerability. I 3ent off by myself, and 3ith eyes closed, there 3as rich imagery
and color synthesis to musical imput. And then things smoothed out, and I could e/press an easy flo3 of ideas and concepts 3ithout al3ays 3atching
my step. And then all too soon, the intensity of the e/perience began fading a3ay.
<="<5SI95S A5; C9??<5"A:>E "he amphetamine 3hich 3ould correspond 3ith this base 3ould be 0,+@dimetho/y@&@methylthioamphetamine '0@"@
"?A- and should be an active compound. Its synthesis should be straightfor3ard from the ben6aldehyde described above, employing nitroethane rather
than nitromethane. It is apparently an unkno3n compound.

#1)1 TM; (-TM; (-TH"%MES!A"#E;
',)-0"METH%+Y-(-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of $+.$ g 5,5,57,57@tetramethylethylenediamine and $2.1 g of (,0@dimetho/yben6ene 3as dissolved in +,, m! anhydrous
he/ane. "his 3as stirred vigorously under a 5$ atmosphere and cooled to , deg C 3ith an e/ternal ice bath. "here 3as added ($& m! of $., ?
butyllithium in he/ane. "he stirred reaction mi/ture became yello3 and sludgy, and 3as briefly 3armed back to room temperature to allo3 easy stirring.
After cooling again to , deg C, there 3as added ().) g of dimethyl disulfide 3hich converted the viscous yello3 phase to a loose 3hite solid. Stirring
3as continued 3hile the reaction mi/ture 3as brought up to room temperature, and then all 3as added to $ ! of dilute H$S9+. "here 3as the immediate
formation of a 3hite cystalline solid 3hich 3as removed by filtration, sucked relatively free of 3ater, and recrystalli6ed from &, m! of boiling ?e9H.
"here 3as thus obtained ().% g of $,1@dimetho/ythioanisole as 3hite crystals 3ith a mp of )(@)$ deg C. </traction of the aFueous filtrate 3ith $/&, m!
CH$Cl$ and removal of the solvent under vacuum gave a residue 3hich, 3hen combined 3ith the mother liFuors from the ?e9H crystalli6ation, afforded
an additional 0.0 g product 3ith a mp 22@2% deg C.
"o a stirred solution of ().% g of $,1@dimetho/ythioanisole in $,, m! CH$Cl$ there 3as added (1 g elemental bromine dissolved in 2& m! CH$Cl$. "he
initial dark red color gradually faded to a pale yello3 color and there 3as a copious evolution of H.r. "he solvent 3as removed under vacuum leaving
$2.& g of a pale yello3 residual oil. "his 3as distilled at (()@($( deg C at ,.$& mm8Hg to yield 0@bromo@$,1@dimetho/ythioanisole as a 3hite oil 3eighing
$&.0 g. Crystalli6ation from he/ane provided 3hite crystals 3ith a mp of 0,@0,.& deg C. Anal. 'C%H((.r9$S- C,H.
"o a solution of (%.0 g diisopropylamine in (&, m! anhydrous "HB that 3as stirred under a 5$ atmosphere and cooled to @(, deg C 3ith an e/ternal
ice8?e9H bath, there 3as added in seFuence )0 m! of (.1 ? butyllithium in he/ane, +.+ m! of dry CH0C5, and ((.1 g of 0@bromo@$,1@
dimetho/ythioanisole '3hich had been dissolved in a little anhydrous "HB-. "he turbid reaction mi/ture gradually developed color, initially yello3 and
progressively becoming orange and finally a deep red bro3n. Stirring 3as maintained for a total of $, min, and then the reaction mi/ture 3as poured
into ( ! H$9 that containing (, m! concentrated H$S9+. "his 3as e/tracted 3ith 0/2& m! CH$Cl$, these e/tracts pooled, 3ashed 3ith dilute H$S9+
follo3ed by saturated brine, and the solvent 3as removed under vacuum yielding ).2 g of a viscous oil as a residue. "his 3as distilled at ,.(( mm8Hg
yielded t3o fractions. "he first boiled at ((&@($& deg C and 3eighed 0.) g. "his material set to an oily crystalline mass 3hich 3as filtered, 3ashed 3ith
cold ?e9H and then recrystalli6ed from ?e9H. "he 3hite solids had a mp of 1,@10 deg C and 3ere not the desired product. "his material has not yet
been identified. "he second fraction came over at (&,@(), deg C, 3eighed (.) g and spontaneously crystalli6ed. It 3as triturated under cold ?e9H and
filtered yielding, after air drying, (.( g 0,&@dimetho/y@+@ methylthiophenylacetonitrile, 3hich had a mp of %&@%1.& deg C. Anal. 'C((H(059$S- C,H.
A suspension of (., g !AH in +, m! anhydrous "HB under 5$ 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, ,.2 m! (,,K
H$S9+, follo3ed by (.$ g 0,&@dimetho/y@+@methylthiophenylacetonitrile in (, m! anhydrous "HB. "he reaction mi/ture 3as stirred at , deg C for a fe3
min, then brought to room temperature for ( h, and finally to a reflu/ for 0, min on the steam bath. After cooling to room temperature, there 3as added (
m! H$9 in & m! "HB to destroy the e/cess hydride, follo3ed by 0 m! of (&K 5a9H to bring the reaction to a basic pH, and finally $ m! H$9 3hich
converted the aluminum o/ide to a loose, 3hite, filterable consistency. "his 3as removed by filtration, and 3ashed 3ith "HB. "he filtrate and 3ashes
3ere stripped of solvent under vacuum, the residue 3as dissolved in $,, m! CH$Cl$, and this 3as e/tracted 3ith 0/(,, m! diute H$S9+. "hese
e/tracts 3ere pooled, 3ashed 3ith CH$Cl$, made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$. After combining, the solvent 3as
removed under vacuum providing (.$ g of a colorless oil as a residue. "his 3as distilled at ($$@(0$ deg C at ,.,& mm8Hg to give a colorless oil. "his
3as dissolved in ) m! of IPA, neutrali6ed 3ith concentrated HCl and, 3ith continuous stirring, diluted 3ith (,, m! anhydrous <t$9. "he product 3as
removed by filtration, 3ashed 3ith <t$9, and air dried to give ,.%& g. 0,&@dimetho/y@+@methylthiophenethylamine hydrochloride '+@"?- as spectacular
3hite crystals 3ith a mp of (%0@(%+ deg C. Anal. 'C((H()Cl59$S- C,H.
;9SAC<E $, @ +, mg.
;4:A"I95E (, @ (& h.
L4A5"I"A"IM< C9??<5"SE '3ith $& mg- I 3as first a3are of any effects as I 3as sitting in back of the house on a big fluffy pillo3. "he sun 3as 3arm
and the grass tall and green, but I felt strange inside. "here 3as distinct uterine cramping, and I could not find a comfortable position for sitting. "he
others had gone out to the garden leaving me here. It seemed that 3alking might relieve the physical discomfort, so I 3ent to find them. Ialking 3as
easy, but I 3as a little light@headed and I had to 3atch my steps 3ith care. "hey 3ere not there '3e had passed on opposite sides of the house- and I
returned in some haste to my 3arm nest behind the house to find my pillo3 gone. A strange detail, but it perhaps gave me the flavor for my day. "he
pillo3 3as for me. It 3as gone. ?y place 3as gone. "herefore I am gone. I am dead and yet I can see and think. "he small touch of panic at finding
myself dead dispelled any internal concerns and I ran inside to find the others; they had brought my pillo3 in. I 3as alive again, but the entire day
balanced bet3een the alive unreality and the illusion that I 3as something removed and merely 3atching the surrounding alive unreality. <verything that
happened 3as completely unlikely.
!ike the soup scene. Ie decided that some hot soup 3ould be 3elcome, and so :. brought out three cans of Campbell soup for the three of us. .ut
one 3as cream mushroom, one asparagus, and one tomato. "he discussion as to ho3 to use t3o cans only, 3hich t3o, 3ithout mi/ing, and even ho3
to decide to decide 3as totally beyond any of us. "he situation 3as hopelessly unresolvable, hilariously funny, and distinctly schi6ophrenic.
9r like the kite scene. Ie 3ere returning from a short 3alk to the back of the property, and I spotted a red thing in the parking area. It had not been
there before. 5one of us could identify it from this distance, and 3e speculated 3ildly as to 3hat it 3as, as 3e came closer. And at the last approach,
3e found that there 3as loose string every3here about the drive3ay, all part of a do3ned kite. "he red obGect had apparently fallen from the sky, right
here in front of the garage. "here had been no sounds of voices of kite@flyers, and there 3as no one to be seen in any direction. And then one of us
spotted a sheet of paper, torn to the center 3here there 3as a small hole, and it 3as flattened up against the kite. "here 3as a message. Apparently
3hoever had been flying it had put a message on the string, and let the 3ind take it up to the kite itself. I reached for the sheet of paper, and removed it.
5othing on either side. "he message 3as that there 3as no message. </actly out of ?arshall ?c!uhan. Completely appropriate for this particular day.
"hat evening 3e 3ere to be picked up by my friends for dinner. Choosing 3hat to 3ear, ho3 to dress myself, ho3 to adGust my persona to fit other
people, all this 3as chaotic. Someho3 the dinner succeeded, but I 3as able to flip in and out of the immediate company easily, but not completely
voluntarily. Sleep 3as com@fortable that night, and I feel that the entire day had been very intense, not too much fun, but someho3 Fuite re3arding.
'3ith 0, mg- At the one and a half hour point, I 3as reminded more than anything of !S;, 3ith a distinct feeling of standing Gust a fe3 feet to the right of
ordinary reality. "here has been a mild tremor ever since the first effects 3ere evident, but it doesn7t bother me e/cept to make my hand3riting
uncertain. I 3ould not 3ant to double this level. Suddenly the concept of my &E0,7s s3ept over me. I had a penetrating vie3 of myself as a person 3ho
had become invested in a pattern of behavior that I had succumbed to, to come home and complete my day 3ith a transition from the 3ork@3orld to the
home@3orld, by changing the inside clock at &E0,. ?y 3ife had been my &E0, for nearly 0, years and this had been my tacit agreement 3ith her. 5ever
Fuestioned, never challenged, and certainly never violated. And 3ith her death, I have found myself imposing this same &E0,@ness on myself, as some
form of an emasculating pattern that is comfortable and stable. 5o, it is not comfortable, it is simply the course of the least thought and the least
disruption. If I 3ere to meet someone else, 3ould I have such a negative image of myself that I 3ould e/pect her to become my &E0, so as not to have
to disrupt these tired and comfortable patternsH "hat 3ould be completely unfair to this other person. And I can see 3here it is completely destructive to
me. 5o ne3 person should ever have to play my 3ife7s old role. I need never again play my old role. And I 3on7t.
'3ith 0, mg- At $E$, P? I ingested 0, mg of "?. It had a mildly alkaloid taste. Since the afternoon 3as 3arm, I took a t3o mile 3alk 3ith the dog, and
3ith my t3o companions .". and "."., both also 3ith 0, mg. Ie talked 3ithout any difficulty even after the onset of the first signs of effect. "he maGor
emotional and physical effects came on very gradually and Fuite pleasantly as 3e sat in the patio. .ut soon 3e all gre3 chilled, and put on more
clothing. 5othing really helped the in3ard chill, and 3e 3ere to discover that it stayed 3ith us throughout the e/@perience. At 0E0, 3e 3ent inside 3here
the room temperature 3as set at 2, degrees, and 3e all lay do3n. I launched into an engrossing, some3hat chaotic and erotic reverie, that follo3ed no
linear progression, but 3hich lasted perhaps an hour. "he ease of talking surprised me; the content 3as cogent and I felt myself to be articulate. It
da3ned on me after about t3o hours had gone by, that the height of the e/periment had already passed 3ithout any real e/hilaration on my part. .ut my
companions suggested that my e/pectations from the past had been misleading me and, as time 3ent on, they proved to be correct. "he clarity and the
continued ability to talk, especially 3ith .". on a personally difficult topic, 3ere for me the particular genius of this material. Ihen I 3ent in3ard, 3hich I
could do 3ithout effort, the sensations 3ere neutral in affect but restful in some 3ay. .ut coming out 3as entirely lucid and pleasant. I soon found that I
preferred this. I enGoyed a light supper at )E0, and found the dropoff gentle, and the conversation most amiable until 3e separated at (E,, A?. Sleep
did not come until 0E,, A? and then only after (, mg !ibrium to Fuell the active mental processes. "he ne/t day I a3oke around )E0, A? feeling
languid but cheerful.
'3ith +, mg- Bor Fuite a 3hile there 3as some physical concern. 5ot actual nausea but a generali6ed uneasiness, 3ith a distinct body tremor. "here
3as little urine produced '&,, m! in () hours-, and I felt the need to search out fluids. "here 3as mild intestinal cramping. I found that my thoughts
3ere able to go in several directions at once, but since they stayed no3here long enough to structure anything, this 3as more annoying than
constructive. I sa3 this as a reality shell about me like a ?Vouml;bius strip, continuous, yet 3ith no consistent side being presented. I 3as reminded of
a similar place 3ith ;9., some fe3 years ago. Ihile lying do3n 3ith eyes closed, I found the imagery to be very impressive, but my thought processes
3ere Fuite convoluted and disGointed. Some 3ere most interesting, and some 3ere ugly. I cannot see this as a party drug.
<="<5SI95S A5; C9??<5"A:>E "he dosage range has been broadened to include the $, milligram level, in that several subGects found that even
3ith that small amount there 3as difficulty in 3alking and in keeping one7s eFuilibrium. Ialking 3as described as a floating procedure, and one could tilt
to one side or the other if care 3as not taken. Anore/ia 3as occasionally noted, and most people commented on some degree of anesthesia to touch.
All in all, this drug evoked a mi/ed bag of responses. "he most startling and une/pected property 3as the dramatic increase in potency over the parent
prototype, mescaline. "he substitution of a sulfur atom for an o/ygen atom increased the po3er of the drug some ten@fold, 3ithout any apparent
decrease in comple/ity of action. As there 3ere many materials that 3ere outgro3ths of mescaline 3ith the studies of ethyl this and diethyl that, each
and all of these 3ould be interesting candidates for synthesis 3ith this or that o/ygen atom replaced 3ith sulfur. ?ost of these have been made, and
many of them have proven to be interesting.
Ihat is meaning of the phrase, Nsulfur@for@o/ygen replacementHN !et me try to e/plain it for non@chemists.
9ne of the most e/citing bits of architecture in science is the Periodic "able. "he principles of electrons and orbitals and different counts of protons in a
nucleus gets to be a comple/ story to try to e/plain the grid@like structure of the arrangements of atoms. It is easier to simply give the music. And this
melody goesE As you look across a ro3, elements are simple in their binding arrangements on the left, become more comple/ to3ards the center 3here
they kind of change polarity, and then get progressively simple again but 3ith the opposite charge as you approach the right@hand side.
And 3hen you look at a column from top to bottom, the bonding comple/ity stays pretty much the same but the atom gets more and more massive as
you go do3n the column.
"he combinations of atoms from the Periodic "able, by and large, is the province of the inorganic chemist. "ake one of this, and t3o of that, and the
combination is called a salt, or a comple/, or an adduct, and probably has interesting colors, and may even be found in nature as part of a rock
some3here, or coming out of the vent of a volcano.
.ut if one 3ere to look at Gust four elements, three in the middle right of the first ro3, namely carbon, nitrogen and o/ygen, and the one up there at the
top and the lightest of all, hydrogen, you 3ould find Fuite a different story. "hese can be combined in an infinity of 3ays since there can be do6ens of
atoms hooked to one@another; this is the territory of the organic chemist, and this is the chemistry of life. Iith a fe3 e/ceptions, every molecule 3ithin
the body, and the food that maintains the body, and the drugs that affect the body, are made up of a bunch of carbons, and an occasional o/ygen or t3o,
usually a nitrogen some3here, and all the remaining loose ends satisfied 3ith hydrogen atoms.
Almost every drug that is to be found in this book is nothing more than a different arrangement of atoms of these four elements.
"his compound, thiomescaline, is a by3ay that takes advantage of one of those vertical columns. ;irectly belo3 the element o/ygen, there is found
sulfur, 3hich has much the same binding comple/ity, but is t3ice as massive. "he prototype of all the phenethylamine drugs being discussed in this
book is mescaline, a very simple compound containing these basic four elements of life and pharmacology; it contains eleven carbon atoms, three
o/ygen atoms, one nitrogen atom, and there are a total of seventeen hydrogen atoms reFuired to balance the books. 9ne of the o/ygen atoms holds a
central position, and the other t3o are reflections of one another and cannot be distinguished chemically. "he structure of thiomescaline is generated by
plucking out that central o/ygen atom of mescaline, and putting a sulfur atom back in its place. "he definition of the term NthioN is Fuite simple L it
means a sulfur@in@place@of@an@o/ygen, 3ith everything else left alone. It is a little a3e@inspiring to think that every o/y anything can have a thio something
as a spatially similar analogue. And there are a lot of o/y things in the body and in the medicine cabinet. A number of them are discussed in this book.

#1)2 TMA; ',(,)-T*"METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of 0%.$ g 0,+,&@trimetho/yben6aldehyde in 0, m! 3arm <t9H there 3as added (&.2 g nitroethane follo3ed by (.& m! n@
butylamine. "he reaction mi/ture 3as allo3ed to stand at +, deg C for 2 days. Iith cooling and scratching, fine yello3 needles 3ere obtained 3hich,
after removal by filtration and air drying, 3eighed +) g. :ecrystalli6ation from <t9H gave $@nitro@(@'0,+,&@trimetho/yphenyl-propene as yello3 crystals
3ith a mp of %+@%& deg C. Anal. 'C($H(&59&- C,H,5. Alternatively, a solution of $, g of the aldehyde in 2& m! nitroethane 3as treated 3ith + g
anhydrous ammonium acetate and heated on the steam bath until a deep red color had been generated. :emoval of the e/cess solvent8reagent under
vacuum gave a red oil 3hich 3as dissolved in an eFual volume of boiling ?e9H. 9n cooling, yello3 crystals of the nitropropene separated.
:ecrystalli6ation from ?e9H gave, after air drying to constant 3eight, (0., g 3ith the same mp.
4nder an inert atmosphere, 0) g !AH 3as 3etted 3ith (,, m! anhydrous <t$9, and then suspended in ( ! dry "HB. "his 3as brought up to a gentle
reflu/, and there 3as added, slo3ly, a solution of +0.2 g $@nitro@(@'0,+,&@trimetho/yphenyl-propene in (1, m! "HB. :eflu/ing 3as continued for 01 h,
and then the reaction mi/ture 3as cooled 3ith an e/ternal ice bath. "he e/cess hydride 3as destroyed by the cautious addition of 0) m! H$9, and this
3as follo3ed by 0) m! (&K 5a9H, and finally another ((+ m! H$9. "he inorganic salts 3hich should have ended up as a loose, granular, easily
filterable mass, looked rather like library paste, but they 3ere filtered nonetheless. Iashing 3ith "HB 3as attempted, but it 3as not efficient. "he
combined filtrate and 3ashes 3ere stripped of solvent under vacuum giving 0(.& g of the crude base as an amber oil. "his 3as dissolved in (+, m! IPA,
neutrali6ed 3ith concentrated HCl '(& m! 3as reFuired-, and diluted 3ith 1&, m! anhydrous <t$9. "here 3as an initial oily phase 3hich on continued
stirring changed to pale pink solids. "hese 3ere finely ground under CH0C5 to give (&.$ g of 0,+,&@trimetho/yamphetamine hydrochloride '"?A- as
3hite crystals that melted at (%&@$(( deg C. All aluminum salts from every3here 3ere dissolved in dilute HCl, and ( g of potassium sodium tartrate
3as added. "here as added $&K 5a9H allo3ed the pH to bring the pH to U% 3ithout the precipitation of basic alumina. </traction of this phase 3ith
CH$Cl$ 3as follo3ed by removal of the solvent and salt formation as described above, allo3ed the isolation of an additional 1.+ g "?A. "he product
prepared in this manner contains some (,@(&K 0,&@dimetho/y@+@hydro/yamphetamine as an impurity. A solution of $, g of the "?A made in this
manner in $,, m! &K 5a9H 3as e/tracted 3ith $/$,, m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith +/(,, m! &K 5a9H, and the aFueous
3ashes 3ere pooled 3ith the original base phase. "he organic phase 3as stripped of its CH$Cl$ under vacuum to give an oil that 3as dissolved in +,
m! IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith +,, m! anhydrous <t$9. "here 3as the immediate formation of spectacular 3hite crystals
of pure 0,+,&@trimetho/yamphetamine hydrochloride, 3eighing (&.+ g and having a mp of $$,@$$( deg C. "he aFueous phase 3as brought to neutrality,
treated 3ith (, g potassium di@hydrogen phosphate, brought to pH %., 3ith the careful addition of 5a9H, and e/tracted 3ith &/(,, m! CH$Cl$.
<vaporation of the solvent under vacuum gave an oil that spontaneously crystalli6ed. "his product, 0,&@dimetho/y@+@hydro/yamphetamine could be
further purified by sublimation at (0, deg C at ,.$ mm8Hg. It 3as a 3hite crystalline solid that slo3ly discolored in the air. "he literature describes a
picrate salt 3ith a mp of $$& deg C from <t9H.
;9SAC<E (,, @ $&, mg.
;4:A"I95E 1 @ ) h.
L4A!I"A"IM< C9??<5"SE '3ith (0& mg- I had no nausea, although I al3ays vomit 3ith mescaline. Someho3 my personality 3as divided and
e/posed, and this allo3ed me to understand my psychic structure more clearly. .ut maybe others could look in there, too. "he psychiatric use of this
drug 3ould be interesting to pursue. It is not completely pleasant, maybe because of this personal intimacy.
'3ith (+, mg- "here 3ere not the color changes of mescaline there, but certainly a good humor and an over@appreciation of Gokes. "he images behind
the eyes 3ere remarkable and tied in 3ith the music, and I became annoyed at other people7s conversations that got in the 3ay. I 3as out of it in eight
hours. I 3ould eFuate this to 0,, or 0&, milligrams of mescaline and I rather think that I 3ould prefer the latter.
'3ith $$& mg- "here 3as Fuite a bit of nausea in the first hour. "hen I found myself becoming emotionally Fuite volatile, sometimes gentle and peaceful,
sometimes irritable and pugnacious. It 3as a day to be connected in one 3ay or another 3ith music. I 3as reading .ernstein7s 7Doy of ?usic7 and every
phrase 3as audible to me. 9n the radio, :achmaninoff7s $nd piano concerto on the radio put me in an eyes@closed foetal position and I 3as totally
involved 3ith the structure of the music. I 3as suspended, inverted, held by fine filigreed strands of the music 3hich had been 3oven from the arpeggios
and knotted 3ith the chords. "he commercials that follo3ed 3ere irritating, and the ne/t piece, Slaughter on Bifth Avenue, made me Fuite violent. I 3as
told that I had a, 7;on7t cross me if you kno3 3hat is good for you,7 look to me. I easily crushed a rose, although it had been a thing of beauty.
<="<5SI95S A5; C9??<5"A:>E "?A 3as the very first totally synthetic psychedelic phenethylamine that 3as found to be active in man, for 3hich
there had been any attempt to describe such drug effects in any detail. "his 3as the report of research done in Canada, and it appeared in (%&&, si/
years before my o3n report on the material. "here 3as an earlier report on "?P<A 3hich is mentioned in the appropriate recipe, but there 3ere fe3
details given. Also there had been interest in reports that adrenalin that had become old and discolored seemed to elicit central effects in man. "he
o/idation products 3ere identified as the deeply colored indolic compound adrenochrome and the colorless analogue adrenolutin. "he controversy that
these reports created Gust sort of died a3ay, and the adrenochrome family has never been accepted as being psychedelic. 5o one in the scientific
community today is looking in and about the area, and at present this is considered as an interesting historical footnote. .ut, in any case, they are not
phenethylamines and so not part of this book.
"he Canadian studies 3ith "?A involved the use of a stroboscope as a tool for the induction of visual phenomena. "hese e/periments used levels in
the &,@(&, milligram range, and generally employed pre@treatment 3ith ;ramamine for the successful prevention of nausea. "here 3as reported
giddiness and light@headedness, and some remarkable flash@induced visuali6ations. Iith higher levels, the visual syntheses are present 3ithout
e/ternal stimulation. .ut there is a thread of negativity that seems to pervade the e/perience at these higher levels, and the appearance of a publication
that emphasi6ed the possible antisocial nature to "?A seemed to discourage further medical e/ploration. ?ilitary interest 3as maintained ho3ever,
apparently, as "?A became a part of the chemical 3arfare studies 3here it 3as referred to 3ith the code name <A@(0(%. It had been used in human
trials 3ith psychiatric patients, but no details of these e/periments have been published.
"he presence of a potentially active impurity in "?A deserves some comment. In the Canadian 3ork, the material used 3as described as melting at
$(%@$$, deg C, 3hich is the property given for the impurity@free material above. If this 3as the actual material used in those studies, this impurity '0,&@
dimetho/y@+@hydro/yamphetamine- 3as probably not present. "he Army studies use a material of unreported melting point. In my o3n studies, the
lo3er melting product 3as used. "here is an intriguing and unans3ered FuestionE 3hat contribution did this phenolic component make to the nature of
the observed effects of "?AH Assays on the isolated contaminant could ans3er that, but they have not yet been made.
"here is an old saying that has gotten many people into troubleE NIf one is good, then t3o is better.N And if a statement of the measure of 3orth of a
compound can be made from its potency, then "?A is a step in the right direction. And this 3as a chemically simple direction to follo3 further. !ooking
at mescaline as a compound 3ith no carbons on its side@chain, and "?A as a mescaline molecule 3ith one carbon on its side chain, then 3hat about a
compound 3ith t3o carbons there, or three, or nine carbonsH
4sing this pattern of naming, "?A can be seen as alpha@methylmescaline, or A??. And the t3o carbon homologue 3ould be alpha@ethyl mescaline, or
A<?. Its proper name is $@amino@(@'0,+,&@trimetho/yphenyl-butane. It and its several higher homologues are discussed in a separate recipe entry
called A<? 'R(-.
A final comment. .ut maybe a long oneO <lse3here, I have made comparisons bet3een myristicin and ??;A, and bet3een safrole and ?;A. And
here there is a similar parallel bet3een elemicin and "?A. Ihat are these relationships bet3een the essential oils and the amphetaminesH In a 3ord,
there are some ten essential oils that have a three carbon chain, and each lacks only a molecule of ammonia to become an amphetamine. So, maybe
these essential oils, or NalmostN amphetamines, can serve as an inde/ for the corresponding real amphetamine counterparts. I had originally called this
family the NnaturalN amphetamines, but my son suggested calling them the NessentialN amphetamines, and I like that. At the time that I had synthesi6ed
"?A, back there in the 7&,s, I had the impulse to e/plore this body of <ssential Amphetamines. As the old folk@3isdom saysE N5ature is trying to tell us
something.N
9ne of the banes of the archivist is having to choose one pattern of organi6ation over another. "he book store o3ned by a language scholar 3ill have
the Cerman poets and play3rights and novelists here, and the Brench ones over there. 5e/t door, the book store is run by a letters scholar, and the
poetry of the 3orld is here, and the plays of the 3orld are there, regardless of the language of origin. "he same obtains 3ith spices, and essential oils,
and amphetamines. "he spice cabinet is a rich source of chemical treasures, each source plant containing a host of com@pounds, some of 3hich are
true essential oils. And the ne/t spice from the ne/t plant has some of the same components and some ne3 ones. ;oes one organi6e by plant 'spice
or herb- or by essential oil 'amphetamine-H !et7s do it by the ring substitution pattern of the amphetamine, and gather the spices and oils as a
secondary collection.
'(- "he +@metho/y pattern. "he pivotal essential oil is +@allylanisole, or methyl chavicol, or estragole 'called esdragol in the old literature-. "his allyl
compound is found in turpentine, anise, fennel, bay, tarragon, and basil. Its smell is light, and reminiscent of fennel. "he propenyl analogue is called
anethole, or anise camphor, and it is found in both anise and camphor. It is a 3a/y solid, and has a very intense smell of anise or fennel. At lo3
concentrations, it is s3eet, as in magnolia blossoms, 3here it is also found. "he drinks that turn cloudy 3ith 3ater dilution 'Pernod@like liFueurs, and
ou6o and roki-, are heavy 3ith it, since it 3as the natural flavoring in the original absinthe. "hat drink 3as very popular in the last century, as an
into/icant 3hich produced an altered state of consciousness beyond that 3hich could be ascribed to alcohol alone. It contained 3orm3ood, 3hich
proved to be neurologically damaging. "he flavorings, such as anethole, are still big things in synthetic liFueurs such as vermouth. 9ld anethole, 3hen
e/posed to air and light, gets thick and sticky and yello3ish, and becomes Fuite disagreeable to taste. ?aybe it is polymeri6ing, or maybe o/idi6ing to
stuff that dimeri6es. Ihatever. "hese changes are 3hy old spices in the cabinet are best discarded. And adding ammonia to any of these natural
product oils produces, in principle, +@metho/yamphetamine, +@?A.
'$- "he 0,+@dimetho/y pattern. "he main actor here is methyleugenol, or +@allyl@(,$@dimetho/yben6ene. "his is located in almost every item in the spice
cabinet. It is in citronella, bay '3hich is laurel, 3hich is myrtle-, pimiento, allspice, pepper, tree@tea oil, and on and on. It has a faint smell of cloves, and
3hen dilute is immediately mistaken for carnations. "he propenyl analogue is, not unreasonably, methylisoeugenol, a bit more scarce, and seems to
al3ays be that little minor peak in any essential oil analysis. "he compounds missing that methyl group on the +@o/ygen are famous. "he allyl material
is eugenol, +@allylguaiacol, and it is in cinnamon, nutmeg, cloves, sassafras and myrrh. >ou taste it and it burns. >ou smell it and think immediately of
cloves. And its property as an anesthetic, in the form of a clove, is 3ell kno3n in the folk@treatment of toothaches. Actually, flo3ers of clove 'the
gillyflo3er, like the carnation- are the small, pointy things that decorate baked hams and, 3hen stuck into apples, make pomander balls. "his anesthetic
property has recently led to a drug abuse fad, called clove cigarettes. Mery strong, very flavorful, and very corrosive things from Southeast Asia. "he
eugenol that is present numbs the throat, and allo3s many strong cigarettes to be smoked 3ithout pain. "he propenyl analogue is isoeugenol, 3ith a
smell that is subtle but very long lasting, used more in soaps and perfumes than in foods. "he amine addition to the methyleugenol 3orld produces 0,+@
dimetho/yamphetamine, or 0,+@;?A. "he isomer 3ith the other methyl group missing is chavibetol '0@hydro/y@+@metho/yallylben6ene- and is found in
the pepper leaf that is used 3ith betel nut. A couple of positional rearrangement isomers of methyleugenol are kno3n in the plant 3orld. "he $,+@isomer
is called osmorrhi6ole, and the conGugated form is isoosmorrhi6ole or nothosmyrnol; both are found in carrot@like vegetables. "hey, 3ith ammonia, 3ould
give $,+@;?A. And the 0,&@dimetho/yallylben6ene isomer from artemisia 'a pungent herb commonly called mug3ort- and from sage, 3ould give rise to
0,&@;?A. "his is an une/plored isomer 3hich 3ould be both an antidote for opium as 3ell as a stimulant, if the classical reputation of mug3ort is
transferred to the amphetamine.
'0- "he 0,+@methylenedio/y pattern. 9ne of the most famous essential oils is safrole, or +@allyl@(,$@methylenedio/yben6ene. "his is the mainstay of
sassafras oil, and it and its conGugated isomer isosafrole have a smell that is immediately familiarE root beerO "hese are among the most 3idely
distributed essential oils, being present in most of the spices, including the heavies such as cinnamon and nutmeg. I am not a3are of the $,0@isomer
ever having been found in nature. Adding ammonia to either 3ould give ?;A. '+- "he 0@metho/y@+,&@methylenedio/y pattern. "he parent compound is
myristicin, &@allyl@(@metho/y@$,0@methylenedio/yben6ene, and the source of this is nutmeg 'or the botanically parallel material, mace-. "he nutmeg is the
seed of the tree ?yristica fragrans and mace is the fibrous covering of the seed. "he t3o spices are virtually identical as to their chemical composition.
?yristicin and the conGugated isomer isomyristicin are also found in parsley oil, and in dill. "his 3as the oil that 3as actually sho3n to be converted to
??;A by the addition of ammonia by passage through an in vitro liver preparation. So here is the maGor Gustification for the eFuation bet3een the
essential oils and the <ssential Amphetamines. Care must be taken to make an e/act distinction bet3een myristicin 'this essential oil- and myristin 'the
fat- 3hich is really trimyristin or glyceryl trimyristate from nutmeg and coconut. "his is the fat from myristic acid, the C@(+ fatty acid, and these t3o
similar names are often interchanged even in the scientific literature.
'&- "he $@metho/y@0,+@methylenedio/y pattern. "his is the second of the three natural metho/y methylenedio/y orientations. Cro3eacin is $@metho/y@
0,+@methylenedio/yallylben6ene, and it takes its name from the binomial for the plant <riostemon cro3ei from the 3orlds of rue and the citrus plants. It
corresponds to the essential amphetamine ??;A@0a. "his oil is found in plants of the Bamily :utaceae. ?y memories of this area of botany are of
:uta graveolens, the common rue, 3hose small leaves smelled to me, for all the 3orld, like cat urine. "his plant has al3ays fascinated me because of a
most remarkable recipe that I 3as given by a very, very conservative fello3@club member, one evening, after rehearsal. He told me of a formula that had
provided him 3ith the most complete relief from arthritic pain he had ever kno3n. It 3as a native decoction he had learned of many years eariler, 3hen
he 3as traveling in ?e/ico. 9ne took eFual Fuantities of three plants, :uta graveolens 'or our common rue-, :osmarinus officinalis 'better kno3n as
rosemary-, and Cannabis sativa '3hich is recogni6ed in many households simply as mariGuana-. "hree plants all kno3n in folklore, rue as a symbol for
repentance, rosemary as a symbol of remembrance, and pot, 3ell, I guess it is a symbol of a lot of things to a lot of people. Any3ay, eFual Fuantities of
these three plants are allo3ed to soak in a large Fuantity of rubbing alcohol for a fe3 3eeks. "hen the alcoholic e/tracts are clarified, and allo3ed to
evaporate in the open air to a thick sludge. "his then 3as rubbed on the skin, 3here the arthritis 3as troublesome, and al3ays rubbed in the direction of
the e/tremity. It 3as not into, but onto the body that it 3as applied. All this from a very conservative :epublican friendO
"he metho/y@methylenedio/y pattern is also found in nature 3ith the $,+,&@orientation pattern. "he allyl@$,+,&@isomer is called asaricin. It, and its
propenyl@isomer, carpacin, are from the Carpano tree 3hich gro3s in the Solomon Islands. All these plants are used in folk medicine. "hese t3o
systems, the $,0,+@ and the $,+,&@orientations, potentially give rise, 3ith ammonia, to ??;A@0a and ??;A@$.
'1- "he 0,+,&@trimetho/y pattern. <lemicin is the 3ell studied essential oil, &@allyl@(,$,0@trimetho/yben6ene, primarily from the oil of elemi. It is, like
myristicin, a component of the 9il of 5utmeg, but it is also found in several of the 9ils of Camphor, and in the resin of the Pili in the Philippines. "his tree
is the source of the 9il of <lemi. I had found a trace component in nutmeg many years ago that proved to be &@metho/yeugenol, or elemicin 3ithout the
+@methyl group; it is also present in the magnolia plant. "he aldehyde that corresponds to this is syringaldehyde, and its prefi/ has been spun into many
natural products. Any natural product 3ith a syring some3here in it has a hydro/y bet3een t3o metho/ys. "he amphetamine base from elemicin or
isoelemicin 3ould be "?A, the topic of this very recipe.
'2- "he $,+,&@trimetho/y pattern. "here is an essential oil called asarone that is $,+,&@trimetho/y@(@propenylben6ene. It is the trans@ or alpha@isomer,
and the cis@isomer is kno3n as beta@asarone. It is the isomeri6ation analogue of the much more rare (@allyl@$,+,&@trimetho/yben6ene, gamma@asarone,
or euasarone, or sekishone. Asarone is the maGor component of 9il of Calamus obtained from the rhi6omes of Acorus calamus, the common S3eet Blag
that gro3s 3ild on the edges of s3amps throughout 5orth America, <urope, and Asia. It has been used as a flavoring of liFueurs and, as almost every
other plant kno3n to man, has been used as a medicine. In fact, in ?anitoba this plant 3as called :at@root by the Cree Indians in the !ake Iinnipeg
area kno3n as 5e3 Iceland, and Indian@root by the Icelandic pioneers. It 3as used e/ternally for the treatment of 3ounds, and internally for most
illnesses. "here apparently is no report of central effects. "he corresponding propanone, acoramone 'or $,+,&@trimetho/yphenylacetone-, is also
present in 9il of Calamus. "he styrene that corresponds to asarone is found in a number of plants, and is surprisingly to/ic to brine shrimp. "he older
literature describes an allyl@trimetho/y ben6ene called calamol, but it has never been pinned do3n as to structure. "he isolation of gamma@asarone or
euasarone from 9il of =i/in 'from 3ild ginger- has given rise to a potential problem of nomenclature. 9ne of the Cenus names associated 3ith 3ild
ginger is Asiasarum 3hich looks very much like the name asarone, 3hich comes from the Cenus Acorus. And a second Cenus of medical plants also
called 3ild ginger is simply called Asarum. "here is an Asarum forbesi from central China, and it is kno3n to give a pleasant smell to the body. And
there is Asarum seiboldi 3hich is largely from orea and ?anchuria. It has many medical uses, including the treatment of deafness, epilepsy, and
rheumatism. "he amphetamine that 3ould arise from this natural treasure chest is "?A@$.
')- "he $,&@dimetho/y@0,+@methylenedio/y pattern. "he parent allyl ben6ene is apiole '3ith a final NeN- or parsley camphor, and it is the maGor
component of parsley seed oil. Its conGugated isomer is called isoapiole, and they are valuable as the chemical precurors to the amination product,
;??;A. Ihereas both of these essential oils are 3hite solids, there is a green oily liFuid that had been broadly used years ago in medicine, called
green, or liFuid apiol '3ithout the final NeN-. It comes from the seeds of parsley by ether e/traction, and 3hen the chlorophyll has been removed, it is
kno3n as yello3 apiol. Iith the fats removed by saponification and distillation, the old term for the medicine 3as apiolin. I 3ould assume that any of
these 3ould give rise to 3hite, crystalline apiole on careful distillation, but I have never tried to do it. "he commercial 9il of Parsley is so readily
available.
'%- "he $,0@dimetho/y@+,&@methylenedio/y pattern. "he second of the three tetrao/ygenated essential oils is (@allyl@$,0@dimetho/y@+,&@
methylenedio/yben6ene, commonly called dillapiole and it comes, not surprisingly, from the oils of any of the several dill plants around the 3orld. It is a
thick, almost colorless liFuid, but its isomeri6ation product, isodillapiole, is a 3hite crystalline product 3hich melts sharply. "his, by the theoretical
addition of ammonia, gives ;??;A@$.
'(,- "he tetrametho/y pattern. "he third and last of the tetra@o/ygenated essential oils, is (@allyl@$,0,+,&@tetrametho/yben6ene. "his is present as a
minor component in the oil of parsley, but it is much more easily obtained by synthesis. It, and its iso@compound, and the amination product, are
discussed under the last of the"en <ssential Amphetamines, "A.
9ne must remember that the term NessentialN has nothing to do 3ith the meaning of needed, or reFuired. "he 3ord7s origin is essence, something 3ith
an odor or smell. "hus, the essential oils are those oils that have a fragrance, and the <ssential Amphetamines are those compounds that can, in
principle, be made from them by the addition of ammonia in the body.
"here 3ere a fe3 interesting e/perimental trials that 3ere based on these natural oils. ?etho/yeugenol 3as assayed up to a (, milligram level, and
asarone at up to a 2, milligram level, and neither had any effects at all. And, in an attempt to challenge the Noil@to@amphetamineN concept, I made up a
mi/ture of ( part ?;A, $ parts "?A and & parts ??;A. A total of (,, milligrams of this combination '3hich I had named the NPseunut CocktailN for
pseudo@nutmeg- should be eFuivalent to the safrole, elemicin and myristicin that 3ould be in & grams of nutmeg. And (,, milligrams indeed produced
Fuite a sparkle and considerable eye@dilation. .ut then, I have never taken & grams of nutmeg, so I cannot make any comparisons.

#1)3 TMA-$; $,(,)-T*"METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of &, g $,+,&@trimetho/yben6aldehyde in (2& m! nitroethane there 3as added (, g anhydrous ammonium acetate and the
mi/ture 3as heated on the steam bath for $ h. "he e/cess nitroethane 3as removed under vacuum, and the deep orange oily residue 3as drained out
into a beaker, and the flask 3ashed 3ith 0/1, m! boiling ?e9H. 9n stirring the combined decantation and 3ashings, there 3as a spontaneous
formation of crystals. After cooling, these 3ere removed by filtration, 3ashed sparing 3ith ?e9H, and air dried to constant 3eight to yield 0&.( g of $@
nitro@(@'$,+,&@trimetho/yphenyl-propene as yello3 crystals 3ith a mp of %)@%% deg C. :ecrystalli6ation from ?e9H increased the mp to (,(@(,$ deg C.
A suspension of 0(.1 g po3dered !AH in ( ! anhydrous "HB containing a little anhydrous <t$9 3as brought to a gentle reflu/, and then there 3as
added a solution of +,., g of $@nitro@(@'$,+,&@trimetho/yphenyl-propene in $,, m! anhydrous "HB over the course of + h. "he mi/ture 3as held at reflu/
temperature for $+ h, cooled to , deg C 3ith e/ternal ice, and the e/cess hydride destroyed by the addition, in seFuence, of 0$ m! H$9 '3hich had
been diluted 3ith a little "HB-, 0$ m! (&K 5a9H, and finally 3ith %1 m! H$9. "he 3hite inorganic solids 3ere removed by filtration, and the filter cake
3as 3ashed 3ith "HB. "he combined filtrate and 3ashings 3ere stripped of solvent under vacuum to give +) g of an impure amber oil. "his 3as
dissolved in (), m! IPA, neutrali6ed 3ith 0, m! concentrated HCl, and the mi/ture diluted 3ith (&,, m! anhydrous <t$9. After a short induction period,
an oily precipitate separated, 3hich on stirring changed into a loose crystalline phase. "his 3as removed by filtration, 3ashed 3ith <t$9, and air dried to
yield $%., g of $,+,&@trimetho/yamphetamine hydrochloride '"?A@$- as fine 3hite crystals 3ith a mp of ()).&@()%.& deg C. Anal. 'C($H$,Cl590-
C,H,5. A +., g sample of the free base 3as dissolved in (& m! pyridine, treated 3ith $.& m! acetic anhydride, heated on the steam bath for $, min,
added to +,, m! H$9, acidified 3ith HCl, and e/tracted 3ith 0/2& m! CH$Cl$. After 3ashing 3ith H$9 the pooled e/tracts 3ere stripped of solvent
under vacuum to give +.& g of flakey, off@3hite solids 3hich, on recrystalli6ation from ?e9H, 3ere 3hite, 3eighed $.0 g, and had a mp of (0$@(00 deg C.
:ecrystalli6ation from this acetamide from ?< did not improve its Fuality. Anal. 'C(+H$(59+- C,H,5.
;9SAC<E $, @ +, mg.
;4:A"I95E ) @ ($ h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- I took it in t3o (, milligram doses, spaced by t3o hours. "here 3as a slight movement of surface te/tures,
my hearing 3as deepened and spatially defined. "he body 3as rela/ed and stretching seemed necessary. "he further I got into it the more I reali6ed
that I 3as totally la6y. Mery lethargic, to the point of laughter. At the si/th hour, I 3as seeing more life in the 3ood3ork, and the 3ooden angel hanging
on the ceiling 3as flesh and feathers 3hen I stared at it. Creat vision. .ut by no means over3helming. Sleep 3as fine.
'3ith $, mg- "he first t3o hours seemed like an eternity, 3ith time passing slo3ly. "hen it settled into a very calm and enGoyable event 'not that it 3asn7t
already-. "he material seemed some3hat hypnotic. I suspect that I 3ould believe suggestions, or at least not challenge them too much. I had a little
confusion but it 3as not troublesome. 9n reflection, the material 3as Fuite good. It 3as benign in the sense that there appeared to be no dark spots. I
3ould try it again, perhaps at 0, milligrams. Almost base@line after ($ hours, but not Fuite.
'3ith $+ mg- I took the dosage in t3o halves, an hour apart. Initially, I 3as a little nauseous, 3ith light tremors and modest eye dilation. .ut after another
hour, there 3as the entire package of mescaline, missing only the intense color enhancement. "he 3orld is filled 3ith distorted. moving things. "hen my
little fingers on both hands got periodically numb. And there 3as an occasional light@headedness that hinted at fainting. "he t3o phenomena alternated,
and never got in each other7s 3ays. .oth passed, once I reali6ed that I 3ould recover from this e/perience. "hen the humor and Goy of the 3orld
returned. "he drop@off 3as Fuite rapid from the fifth to eighth hour, and no effects remained at all by the t3elfth hour.
'3ith +, mg- Mery slo3 coming on. ;idn7t feel it for an hour, but then at a full *** in another hour. .eautiful e/perience. <rotic e/cellent. <yes@closed
imagery and fantasy to music. 5o dark corners. .enign and peaceful and lovely. "here 3ere brief intestinal cramps early, and a little diarrhea, but no
other problems. I 3as able to sleep after eight hours, but had guarded dreams.
'3ith +, mg- .eautiful plus 0. Some visuals, but not intrusive. ?oderate, good@mannered kaleidoscopic imagery against dark. ?usic superb. Clear
thinking. Calmly cosmic. "his is a seminal, or archetypal psychoactive material. A very good e/perience and good for repeats. About (,@($ hrs. Sleep
difficult but 9.
<="<5SI95S A5; C9??<5"A:>E "here 3as absolutely no reason to suspect that the simple rearrangement of the metho/y groups of "?A from the
classic 0,+,&@positions to this ne3, $,+,&@orientation, 3ould dramatically increase potency like this. ?escaline, 0,+,&@trimetho/yphenethylamine, is an
e/traordinary compound, but it is not particularly potent, reFuiring hundreds of milligrams for a trip. And going from its 0,+,&@pattern to the $,+,&@pattern
of "?P<A makes the compound even less potent. "here 3as essentially nothing reported in the scientific literature about central activity of $,+,&@
substituted stuff, so there could not have been any logical preparation for the activity of "?A@$. ?y very first trials 3ere 3ith a rather liberal +,,
micrograms, and the levels being e/plored leaped up in fairly large steps, mostly on separate days. 9n 5ovember $1, (%1$, at 1E,, A?, 3hen ($
milligrams proved to be inactive, another ($ milligrams 3ent in and do3n an hour later. "his 3as the $+ milligram discovery e/periment, a fragment of
3hich is given above. "he an/iety of being thrust into the unkno3n certainly played a role in 3hat can no3 be seen as obvious psychosomatic
difficulties.
"he une/pected ten@fold increase of effectiveness uncovered by the simple relocation of a single metho/y group of "?A gave the further Guggling of
metho/y groups a very high priority. "here are a total of si/ arrangements possible for the three groups, namely, 0,+,&@ 'the original "?A-, $,+,&@ 'the
present "?A@$-, and then and in systematic seFuence, $,0,+@, $,0,&@, $,0,1@, and $,+,1. "hese compounds 3ere totally unkno3n at that time, and they
could and 3ould be assigned the seFuential names "?A@0, "?A@+, "?A@& and "?A@1, respectively. I made them all, and they are all included in this
book.
Having found the treasure of $,+,&@ness, it is instructive to look back at nature, to see 3hat its plant eFuivalents might be. "here are indeed a fe3
essential oils that have their metho/y groups in this arrangement. "?A@$ is thus one of the <ssential Amphetamines, and most of the botanical
connections are discussed under "?A. "he natural skeleton is found in asarone, 3ith alpha@asarone being trans@propenyl, beta@asarone the cis@
propenyl and gamma@asarone 'also called euasarone- being the allyl@isomer. I had mentioned, in the spice cabinet discussion under "?A, the tasting of
asarone at up to 2, milligrams 3ithout any effects.
A couple of additional e/periments involving "?A@$ had been set up and started, but someho3 never had enough fire to get completed. Studies on the
optical isomers had gotten up to assays of 1 milligrams on each of the separate isomers, but had never been taken higher. "he N:N isomer is much the
more potent in rabbit assays, but the human comparisons remain unkno3n at present. Also, a study of the (+C labeled racemate '& microcuries in +,
milligrams- 3as conducted 3ith a vie3 to metabolite analysis, but again, the proGect 3as abandoned before any results 3ere obtained. In the rat, the +@
metho/yl carbon appeared as e/pired carbon dio/ide to the e/tent of about $,K. And this is some four times the amount seen from either of the other
t3o metho/yl carbon atoms.
9ne final memory in the "?A@$ area. About t3enty years ago I co@authored a rather thorough revie3 article in the .ritish Gournal 5ature, that described
the structure@activity relationships bet3een the simpler one@ringed psychotomimetics. It also Fuietly served as a vehicle for mentioning a number of
ne3ly@discovered compounds and their human activities. .ut as a magnificent attestment to youth and brashness, 3e proposed a comple/ compound
that embraced each and every clue and hint that might tie it to the neurological process. "his hybrid monster 3as $,beta@dihydro/y@+,&@
dimetho/yphenethylamine. It had everything. "he 1@hydro/ydopamine hydro/y group and the rest of the dopamine molecule intact as represented by
the t3o metho/yl groups. And the beta@hydro/y group gave it the final NnorepinephrineN touch. And, 3ith due modesty, 3e proposed that it might be Nan
endogenous psychotogen.N Ihy not Nthe endogenous psychotogenHN And then, to compound the picture, 3hat should arrive in the mail a month or t3o
later, and from a most respected scientist, but a sample of Gust this stuff, synthesi6ed for our investigations. I must have bought a little of my o3n
promotion, as I noted that even after my first four graded dosages 3ith the compound, I 3as still only up to a $&, microgram dose. And then, as the
sample became increasingly bro3n and 3as clearly decomposing, the proGect 3as finally abandoned.
A sad note on ho3 things have changed since that time. I recently Fueried the editors of 5ature, about their thoughts concerning a t3enty year
retrospective of this area, 3ritten by the three authors of the original revie3. Ie had each follo3ed Fuite divergent paths, but each of us 3as still keenly
the researcher. It 3ould have been a marvelous paper to put together, and it 3ould have delighted the reading audience of 5ature, had it been the
audience of t3enty years ago. .ut not today. "he Gournal is no3 dedicated to neutron stars and /@ray sources. "he respected old <nglish Gournal of
interdisciplinary interests is not the grand and curious lady she used to be. "he <ditor7s reply 3as polite, but negative. NSuch an article 3ould be
unsuitable for publication in 5ature at present,N they said. And, I am sad to say, they7re right.
And I am afraid that the American counterpart Gournal, Science, has suffered a similar deterioration. It, too, has abandoned multidisciplinary interest, but
in a different direction. "hey are no3 dedicated to chromosomes, and nucleotide identification, and are totally captivated by the attention paid to, and
the apparent importance of, the human genome proGect. "here is 3here you automatically go to publish, no3, if you have unraveled some ;5A
seFuence from the !atvian cockroach.

#1)4 TMA-'; $,',(-T*"METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of ($.+ g $,0,+@trimetho/yben6aldehyde in +& m! glacial acetic acid, there 3as added 2 m! nitroethane and +.( g anhydrous
ammonium acetate, and all 3as held at reflu/ temperature for (.& h. "o the cooled and 3ell stirred reaction mi/ture, H$9 3as added slo3ly, dropping
out an oily crystalline solid mass. "his 3as separated by filtration, and ground under a Fuantity of &,K aFueous acetic acid, and re@filtered. "he 1.& g of
crude product 3as recrystalli6ed from boiling ?e9H to give, after air drying to constant 3eight, &., g of $@nitro@(@'$,0,+@trimetho/yphenyl-propene, 3ith a
mp of &1@&2 deg C. Anal. 'C($H(&59&- C,H.
"o a gently reflu/ing suspension of 0., g !AH in 0,, m! anhydrous <t$9 under a He atmosphere, there 3as added 0.1& g $@nitro@(@'$,0,+@
trimetho/yphenyl-propene by allo3ing the condensing <t$9 drip into a shunted So/hlet thimble containing the nitrostyrene and effectively adding a
3arm saturated solu@tion of it drop3ise. :eflu/ing 3as maintained for & h follo3ing the completion of the addition of the nitrostyrene. "he milky reaction
mi/ture 3as cooled and the e/cess hydride destroyed by the addition of $,, m! (,K H$S9+. Ihen the aFueous and <t$9 layers 3ere finally clear,
they 3ere separated, and 2& g of potassium sodium tartrate 3as dissolved in the aFueous fraction. 5a9H '$&K- 3as then added until the pH 3as U%,
and this 3as then e/tracted 3ith 0/2& m! CH$Cl$. <vaporation of the solvent under vacuum produced $.& g of a nearly colorless clear oil that 3as
dissolved in 0,, m! anhydrous <t$9 3hich 3as saturated 3ith anhydrous HCl gas. "he product, $,0,+@trimetho/yamphetamine hydrochloride '"?A@0-
separated as a fine 3hite solid. "his 3as removed by filtration, <t$9 3ashed, and air dried to constant 3eight. "he yield 3as (.1& g of a product 3hich,
after recrystalli6ation from IPA, had a mp of (+)@(+% deg C. Anal. 'C($H$,Cl590- C,H.
;9SAC<E greater than (,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- "here 3ere no effects at all. 5o eye dilation, no believable diversion from complete normalcy. Appetite 3as
normal, as 3ell.
<="<5SI95S A5; C9??<5"A:>E "here is a small lesson to be learned from this completely inactive compound. "here is no 3ay of saying that it is
or is not in@active. All that can be said is that trials 3ere made 'in this case using three separate individuals- at an oral level of (,, milligrams. And, at
this level, nothing happened. And since a bottom threshold for mescaline 3ould be perhaps $,, milligrams, it can be honestly said that the activity of
this compound, if e/pressed relative to mescaline 'using mescaline units- is less than $ ?.4. Had $,, milligrams been inactive, it 3ould have been less
than (., ?.4. If $ grams had been inactive, it 3ould have been less than ,.( ?.4. .ut the actual printed form, activity W $., ?.4. 3as accepted by many
readers as indicating that "?A@0 3as active, but at dosages greater than (,, milligrams. All that can be said is, if there is activity, then it 3ill be at oral
levels greater than (,, milligrams At the moment, as far as I kno3, this compound is not active in man, but then I kno3 of no trials in e/cess of (,,
milligrams.
"his admonition applies to all the published ?.4. values that are preceded by the Nless thanN sign, the NW.N

#115 TMA-(; $,',)-T*"METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of 1) g $,+@dimetho/yben6aldehyde in $&, m! glacial acetic acid that had been 3armed to $& deg C and 3ell stirred, there
3as added, drop3ise, )1 g of a +,K peracetic acid solution 'in acetic acid-. "he reaction 3as e/othermic, and the rate of addition 3as dictated by the
need to maintain the internal temperature 3ithin a fe3 degrees of $) deg C. </ternal cooling 3as used as needed. "he addition took ( h, and 3hen the
reaction had clearly been completed 'no further temperature rise- the entire reaction mi/ture 3as added to 0 volumes of H$9. "he e/cess acid 3as
neutrali6ed 3ith solid $C90 '$)0 g 3ere reFuired-. "his 3as e/tracted 3ith 0/(,, m! <t$9, the e/tracts pooled, and stripped of solvent under vacuum
to give 11 g of crude $,+@dimetho/yphenyl formate. "his 3as suspended in ($& m! (,K 5a9H, and the mi/ture heated on the steam bath for (.& h. 9n
cooling, the reaction mi/ture set to a heavy black solid. "his 3as removed by filtration, 3ashed 3ith H$9, and dissolved in $&, m! CH$Cl$. "he
organic phase 3as 3ashed 3ith dilute HCl, and then 3ith aFueous 5aHC90, 3hich removed much of the color. :emoval of the solvent under vacuum
gave a deep red goo that 3as dissolved in $,, m! anhydrous <t$9 and filtered through paper. "he resulting clear solution 3as stripped of solvent,
yielding 0+.+ g of $,+@dimetho/yphenol as a red oil that crystalli6ed on cooling. A (., g sample in + m! pyridine 3as treated 3ith ,.% g ben6oyl chloride
and heated on the steam bath for a fe3 min. "he addition of H$9 gave a pasty solid that 3as isolated by pressing on a porous plate. "he yield of crude
$,+@dimetho/yphenyl ben6oate 3as (.( g. :ecrystalli6ation from cyclohe/ane gave a 3hite product 3ith a mp of )1@)2 deg C. A second recrystalli6ation
from cyclohe/ane raised this to )%@%, deg C, 3hich is in agreement 3ith the literature value.
"o a solution of 0(., g crude $,+@dimetho/yphenol in 1, m! absolute <t9H there 3as added a solution of ((.$& g 9H in %, m! boiling <t9H. "o this,
there 3as then added $) g allyl bromide 3hich produced an immediate 3hite precipitate of .r. "he mi/ture 3as held at reflu/ for $ h and then
Fuenched in 0 volumes of H$9. Sufficient (,K 5a9H 3as added to make the reaction strongly basic, and this 3as e/tracted 3ith 0/(,, m! <t$9.
:emoval of the solvent under vacuum gave 00.$ g of (@allylo/y@$,+@dimetho/yben6ene, sho3n to be free of phenol starting material by CC analysis.
Analyses must be carried out at lo3 column temperatures 'belo3 (), deg C- on an ethylene glycol succinate substrate. If a silicone column is used,
even at these lo3 temperatures, there is considerable Claisen rearrangement taking place on the column. !o3 temperature distillation can be used for
further purification '(,2@((, deg C at (., mm8Hg-.
A 0(., g sample of (@allylo/y@$,+@dimetho/yben6ene 3as gently heated 3ith a soft flame until the internal temperature reached $(& deg C. An
e/othermic reaction took place, 3ith the temperature rising to $2, deg C. "he residue left in the flask 3as largely $@allyl@+,1@dimetho/yphenol, that
contained perhaps (,K of $,+@dimetho/yphenol 3hich resulted from the pyrolytic loss of the allyl group. "his mi/ture 3as methylated 3ithout further
purification.
"o a solution of 0, g impure $@allyl@+,1@dimetho/yphenol in a little absolute <t9H there 3as added a boiling solution of ).2 g 9H in 2& m! absolute
<t9H follo3ed, immediately, by $$.+ g methyl iodide in a little <t9H. "he mi/ture 3as held at reflu/ for 0 h, then added to + volumes of H$9. Sufficient
(,K 5a9H 3as added to make the mi/ture strongly basic, and this 3as e/tracted 3ith +/(,, m! <t$9. :emoval of the solvent gave $) g of (@allyl@
$,0,&@trimetho/yben6ene. CC analysis sho3ed some (,K of the e/pected impurity, (,$,+@trimetho/yben6ene.
"o a solution of $1 g crude (@allyl@$,0,&@trimetho/yben6ene in an eFual 3eight of absolute <t9H there 3as added &$ g of flaked 9H. "he mi/ture 3as
heated on the steam bath overnight, and then Fuenched 3ith much H$9. "his 3as e/tracted 3ith 0/(,, m! <t$9 3hich, on removal under vacuum
gave $+.1 g of product. "his contained, by CC analysis, largely cis@ and trans@(@propenyl@$,0,&@trimetho/yben6ene and the e/pected (,$,+@
trimetho/yben6ene. "his mi/ture 3as dissolved in an eFual volume of pentane, and cooled in dry ice. Luick filtration gave %.$ g of an amber solid
3hich had a melting point of 0%@+(.& deg C. :ecrystalli6ation from he/ane provided pure trans@(@propenyl@$,0,&@trimetho/yben6ene 3ith a mp of ++@+&
deg C. <vaporation of the original pentane mother liFuor provided an impure sample of mi/ed cis@ and trans@ isomers.
A solution of 2.$ g trans@(@propenyl@$,0,&@trimetho/yben6ene in +( g dry acetone 3as treated 3ith 0.0 g dry pyridine and, 3ith good stirring, cooled to ,
deg C. "here 3as then added 1.% g of tetranitromethane over the course of ( min, and the reaction mi/ture 3as allo3ed to stir for an additional $ min.
"he reaction mi/ture 3as then Fuenched 3ith a solution of $.$ g 9H in +, m! H$9. After the addition of more H$9, the product 3as e/tracted 3ith
0/&, m! CH$Cl$. :emoval of the solvent under vacuum yielded 2., g of an impure product 3hich 3ould not crystalli6e. "his 3as distilled under vacuum
to give four fractions, all of 3hich crys@talli6ed spontaneously. Cuts R( and R$ 'bp (,,@($, deg C and ($,@(0, deg C at $ mm8Hg- 3ere combined,
3eighed ,.) g, and after crystalli6ation from he/ane yielded 3hite crystals 3ith a mp of 1$@10 deg C. "he 5?: spectrum 'in C;Cl0- 3as in agreement
3ith $,0,&@trimetho/yben6aldehyde, and the literature mp has been reported as being 1$@10 deg C. Cuts R0 and R+ 'bp (0,@(2, deg C and (2,@(2&
deg C at $ mm8Hg 3ith the bulk coming over in the latter fraction- 3ere combined to give 0., g of yello3 crystals. "hese 3ere triturated under a little
cold ?e9H, and then recrystalli6ed from ?e9H to give (.(& g of yello3 crystals of $@nitro@(@'$,0,&@trimetho/yphenyl-propene, 3ith a mp of )2@)) deg C.
"he forerun of the distillation contained considerable unreacted trans@(@propenyl@$,0,&@trimetho/yben6ene and some (,$,+@trimetho/yben6ene, by CC
analysis.
"o a reflu/ing and stirred suspension of (.( g !AH in (&, m! anhydrous <t$9 and under an inert atmosphere, there 3as added a solution of (.( g $@
nitro@(@'$,0,&@trimetho/yphenyl-propene in &, m! anhydrous <t$9. "he creamy mi/ture 3as held at reflu/ for + h, cooled, and then the e/cess hydride
cautiously destroyed by the addition of (.& 5 H$S9+. "here 3as then added $, g potassium sodium tartrate follo3ed by sufficient aFueous 5a9H to
raise the pH to U%. "he <t$9 phase 3as separated, and the remaining aFueous phase e/tracted 3ith 0/2& m! CH$Cl$. "he organic phase and
e/tracts 3ere combined, and the solvent removed under vacuum yielding ,.% g of a colorless oil. "his 3as dissolved in $,, m! anhydrous <t$9 3hich
3as saturated 3ith anhydrous HCl gas. "here 3as generated a thick oil that did not crystalli6e. "he <t$9 3as decanted from this, and allo3ed to stand
for several days in a sealed container at room temperature. "here 3as the deposition of fine 3hite needles of $,0,&@trimetho/yamphetamine
hydrochloride '"?A@+- 3eighing, after <t$9 3ashing and air drying, ,.0( g. "he mp 3as (()@((% deg C. Anal. 'C($H$,Cl590- C,H. "he residual oil
3as dissolved in H$9, made basic 3ith 5a9H, and e/tracted 3ith CH$Cl$. <vaporation of the solvent gave ,.+, of a 3hite oil 3hich 3as dissolved in a
little ?e9H containing ,.$$ g o/alic acid. "here 3as the immediate deposition of crystals of the o/alate salt of $,0,&@trimetho/yamphetamine, 3ith a mp
of about ((, deg C.
;9SAC<E greater than ), mg.
;4:A"I95E perhaps 1 h.
L4A!I"A"IM< C9??<5"SE '3ith ), mg- I 3as concerned about life issues, 3ith much introspection, for about 1 hours. "here 3ere no subGective
physical symptoms. It 3as comparable to about &, micrograms of !S;, or to ($, milligrams "?A, for me.
<="<5SI95S A5; C9??<5"A:>E "hat is the sum total of the kno3ledge of subGective effects that e/ist. "here 3as such a precious small amount of
the final hydrochloride salt that, by the time the needed build@up of dosage had been completed, there 3as Gust enough left for this single trial, 3hich 3as
conducted in South America. .ased upon the volunteered comparisons to !S; and "?A, a potency for this compound has been published that states
that it is +/ the potency of mescaline, or + ?.4. "he material must be re@synthesi6ed, and re@evaluated 3ith the no3@accepted protocol.
In the future re@synthesis, there 3ill be a considerable improvement made 3ith the several steps that are described above. "he products from the
preparations of the phenol, the allyl ether, the Claisen rearrangement, the methylation of the ne3 phenol, and the isomeri6ation to the mi/ture of cis@ and
trans@propenylben6enes 3ere all conducted 3ithout the benefit of a ugel@:ohr apparatus. "he products became progressively thick and blacker, and it
3as only by the grace of getting a solid at the trans@propenyl stage that some degree of purity could finally be obtained. All of the intermediates are
certainly 3hite oils, and 3hen this preparation is repeated, they 3ill be distilled at each and every stage.
"his $,0,&@orientation of the metho/y groups on the aromatic ring is far and a3ay the most difficult tri@substitution pattern kno3n to chemists. "here Gust
isn7t any simple 3ay to put it together. "he $@carbon phenethylamine '$,0,&@trimetho/yphenethylamine- had been synthesi6ed Fuite a 3hile ago. Its role
as a substrate for liver amine o/idase in in vitro studies has been e/plored, but it has never been tried in man. <ven more bi6arre is the amphetamine
3ith this o/ygenation pattern, in 3hich a methylenedio/y ring has replaced the t3o adGacent metho/yl groups. "his is the material $,0@methylenedio/y@&@
metho/yamphetamine, or ??;A@+. ;espite its theoretical appeal 'being one of the si/ possible ??;A derivatives- and it7s synthetic challenge 'as 3ith
the $,0,&@trimetho/y things above, everything is simply in the 3rong position- the compound is of unkno3n pharmacology. "his follo3s, Fuite logically,
from the fact that it has never been synthesi6ed. 5o one has yet put together a 3orkable procedure that 3ould make it. In the course of making all
possible positional isomers of ??;A e/plicitly Schedule I drugs, the ;<A has named this compound, and since it 3as specifically named, it 3as entered
into the Chemical Abstracts. So it is listed in the literature, at least it is in the Chem. Abstracts. .ut it is in reality completely unkno3n. Some day, some
one some3here 3ill have a light bulb go on over his head, and find a synthetic process that 3ill make it. 9f course, the moment it is made, an illegal act
3ill have occurred, at least in the 4nited States as long as the present la3s remain unchanged, as it is currently a Schedule I drug.
5eedless to say, the $@carbon analog of ??;A@+, $,0@methylenedio/y@&@metho/yphenethylamine '3ould $C@??;A@+ be a reasonable nameH- is also
unkno3n.

#111 TMA-); $,',1-T*"METH%+YAM,HETAM"#E
S>5"H<SISE A solution of (,, g (,$,+@trimetho/yben6ene in ( ! he/ane 3as cooled to (& deg C and treated 3ith +,, m! of a (&K solution of n@
butyllithium in he/ane. A 3hite precipitate formed immediately, and stirring 3as continued for an additional $ h 3hile the reaction returned to room
temperature. "here 3as then added a solution of +, g freshly distilled propionaldehyde in (,, m! he/ane. "he reaction 3as e/othermic and, as the
stirring 3as continued, the precipitate gradually dissolved. Stirring 3as continued overnight at room temperature. "here 3as then added ( ! H$9, and
the reaction 3as acidified 3ith HCl. "he he/ane phase 3as separated, and the remaining aFueous phase 3as e/tracted 3ith he/ane, then 3ith <t$9.
"he pooled organic e/tracts 3ere stripped of solvent under vacuum, and the residue distilled to give 1, g ethyl $,0,1@trimetho/yphenyl carbinol, 3ith an
inde/ of refraction n;$, T (.&(%$. Anal. 'C($H()9+- C,H. Brom the <t$9 e/tracts above, additional carbinol 3as obtained, containing a small amount
of the starting (,$,+@trimetho/yben6ene. "he t3o materials 3ere readily separated by vacuum distillation, providing an additional $( g of carbinol.
"he above alcohol, 1, g of ethyl $,0,1@trimetho/yphenyl carbinol, 3as stirred 3ithout solvent and cooled to , deg C 3ith an e/ternal ice bath. "here 3as
then added ), g P.r0 at a rate that maintained the temperature belo3 1, deg C. At the end of the addition, there 3ere added Fuantities of chipped ice,
follo3ed by H$9. "he reaction mi/ture 3as e/tracted 3ith 0/(,, m! <t$9, and removal of the solvent provided 1, g of (@bromo@(@'$,0,1@
trimetho/yphenyl-propane 3hich 3as used in the follo3ing dehydrobromination step 3ithout further purification.
A solution of the above 1, g of (@bromo@(@'$,0,1@trimetho/yphenyl-propane in an eFual 3eight of <t9H 3as treated 3ith ($, g of flaked 9H. "he
e/othermic reaction 3as allo3ed to run its course 3ith stirring continued overnight. "he mi/ture 3as then Fuenched in H$9 and e/tracted 3ith 0/$,,
m! CH$Cl$. :emoval of the solvent from the pooled e/tracts gave a crude product 3hich contained no starting bromo material, but 3hich 3as
contaminated 3ith an appreciable Fuantity of the etho/y analogue, (@etho/y@(@'$,0,1@trimetho/yphenyl-propane. "his impure product 3as heated briefly
to ), deg C 3ith &,K H$S9+. Cooling, dilution 3ith 3ater, and re@e/traction 3ith 0/(,, m! CH$Cl$ gave, after removal of the volatiles under vacuum,
(@'$,0,1@trimetho/yphenyl-propene. "his 3as distilled to provide 2., g of a clear oil that 3as a ($E( ratio of the trans@ and cis@isomers.
A 3ell@stirred solution of 1.) g of the mi/ed isomers of (@'$,0,1@trimetho/yphenyl-propene in +, g of dry acetone 3as treated 3ith 0.$ g pyridine and
cooled to , deg C 3ith an e/ternal ice bath. "here 3as then added 1.& g tetranitromethane over the course of ( min, the stirring 3as continued for an
additional $ min, and then the reaction mi/ture 3as Fuenched by the addition of $.$ g 9H in +, m! H$9. "here 3as additional H$9 added, and the
organics 3ere e/tracted 3ith 0/2& m! CH$Cl$. "he solvent from the pooled e/tracts 3as removed under vacuum, and the &.0 g residue distilled at ,.$
mm8Hg. A fraction boiling at (&,@(2, deg C proved to be largely $,0,1@trimetho/yben6aldehyde. A second fraction '(2,@$,, deg C at ,.$ mm8Hg- also
spontaneously crystalli6ed to a yello3 solid. "his 3as recrystalli6ed from ?e9H to provide, after drying to constant 3eight, $.) g of $@nitro@(@'$,0,1@
trimetho/yphenyl-propene 3ith a mp of 20@2+ deg C. Anal. 'C($H(&59&- C,H.
"o a reflu/ing and stirred suspension of $.+ g !AH in 0,, m! anhydrous <t$9 and under an inert atmosphere, there 3as added a solution of $.+ g $@
nitro@(@'$,0,1@trimetho/yphenyl-propene in (,, m! anhydrous <t$9. "he mi/ture 3as held at reflu/ for + h, cooled, and then the e/cess hydride
cautiously destroyed by the addition of (.& 5 H$S9+. "here 3as then added +, g potassium sodium tartrate follo3ed by sufficient aFueous 5a9H to
raise the pH to U%. "he <t$9 phase 3as separated, and the remaining aFueous phase e/tracted 3ith 0/(,, m! CH$Cl$. "he organic phase and
e/tracts 3ere combined, and the solvent removed under vacuum yielding (.) g of a colorless oil. "his 3as dissolved in $,, m! anhydrous <t$9 3hich
3as saturated 3ith anhydrous HCl gas. "here 3as generated a thick oil that slo3ly crystalli6ed. "he resulting 3hite crystalline solid 3as removed by
filtration, providing $.$ g $,0,1@trimetho/yamphetamine hydrochloride '"?A@&-. "he mp 3as ($+@($& deg C. Anal. 'C($H$,Cl590- C,H.
;9SAC<E 0, mg or more.
;4:A"I95E ) @ (, h.
L4A!I"A"IM< C9??<5"SE '3ith $, mg- "here appeared to be a slight stimulation. ?odest eye dilation, but normal pulse. If this is the marginal edge
of into/ication, then it is not a psychotomimetic, but a stimulant. Co up 3ith care.
'3ith 0, mg- Intense introspection. Comparable to about 2& micrograms of !S;, or more.
<="<5SI95S A5; C9??<5"A:>E "?A@&, as 3as the case 3ith "?A@+, has only been superficially e/plored. "he above t3o Fuotations are from t3o
different people, and together no more than hint at the possibility that it might be active in the several tens of milligrams.
Pharmacologists have developed Fuite an art in the design and evaluation of animal behavior models for the study of psychedelic drugs. "hey have
al3ays faced t3o formidable tasks, ho3ever. "here is the Fualitative FuestionE is the drug a psychedelicH And there is the Fuantitative FuestionE ho3
potent is itH
"he first Fuestion is addressed by taking a number of kno3n psychedelic drugs, and searching for some animal responses that are common to all.
Since there is little logic in the argument that animals can e/perience, let alone reveal, altered states of consciousness or fantasy fugues or colored
imagery, the investigator must look for obGective signs such as conditioned responses to stimuli, or unusual behavior. If one e/plores ten drugs that are
kno3n psychedelics, and all ten produce, say, bi6arre nest@building behavior in mice, and an eleventh drug of unkno3n pharmacology does e/actly the
same thing, then the eleventh drug can be suspected of being a psychedelic drug.
And the second Fuestion, ho3 potent, is ans3ered by seeing ho3 much of the drug is reFuired to evoke this standardi6ed behavior. "his is called the
dose@response curve, in 3hich the more drug you give, the more response you get. "his curve gives confidence that the drug is indeed responsible for
the activity that is seen, as 3ell as giving a Fuantitative measure of that activity.
.ut this entire discipline depends on the acceptance of the fact that the first ten drugs are indeed psychedelic materials. And these inputs can only
come from human trials. Ihat is the validity of these assumptions 3ith "?A@&H 5ot very good. "he statement that it is psychedelic has actually been
published in revie3s solely on the basis of the above t3o studies; the potency has been put at some ten times that of mescaline. ?escaline is certainly
an effective psychedelic drug in the 0,,@&,, milligram range, and this factor of ten implies that "?A@& is also a psychedelic drug and is active in the 0,@
&, milligram range. And indeed, both statements may be true, but confidence in these conclusions must a3ait more e/tensive trials.
"he t3o@carbon analogue of "?A@& is $,0,1@trimetho/yphenethylamine 'or $C@"?A@& or $,0,1@"?P<A-. "his is a kno3n material, although there has
been some controversy as to its physical properties. It has been studied in monoamine o/idase systems, and appears to be either a competitive
substrate or an inhibitor of that en6yme. .ut as far as I kno3, no one has nibbled it, so its human activity is unkno3n.

#11$ TMA-1; $,(,1-T*"METH%+YAM,HETAM"#E
S>5"H<SISE "o a solution of (,, g phloroglucinol dihydrate in 0$, m! ?e9H there 3as added && m! of concentrated H$S9+, and the clear solution
held under reflu/ conditions overnight. After cooling, there 3as added &,, m! H$9, and the bulk of the ?e9H 3as removed under vacuum. "he
residual oil 3as e/tracted 3ith <t$9, and the removal of this left 1, g of a red oil as residue. "his 3as dissolved in 0,, g methyl sulfate 'caution, this is
e/tremely to/ic through skin contact, and any e/posure must be flushed thoroughly 3ith dilute ammonium hydro/ide-. Iith good stirring, this 3as
cautiously treated 3ith &,, g of +,K aFueous 9H, and the e/othermic reaction allo3ed to run its course. </traction 3ith 0/(,, m! <t$9 gave, after
evaporation of the solvent from the pooled e/tracts, an oil that became largely crystalline. "his 3as suspended in (,, m! he/ane, and filtered through a
coarse fritted funnel. Iith evaporation there 3as obtained &2 g of (,0,&@trimetho/yben6ene as a pale amber solid that melted at ++@&, deg C. A sample
purified by recrystalli6ation from <t9H had the proper mp of &+@&& deg C.
A mi/ture of 1$.% g 5@methylformanilide and 2(.0 g of P9Cl0 3as allo3ed to stand for ,.& h producing a light claret color. "here 3as then added 0,.% g
of (,0,&@ trimetho/yben6ene and the mi/ture heated on the steam bath for $ h. "he reaction mi/ture then 3as poured into chipped ice, and allo3ed to
stir for several h. "he dark gummy mess 3as e/tracted 3ith $/(,, m! <t$9 'this 3as discarded- and then 3ith +/$,, m! CH$Cl$. "he latter e/tracts
3ere pooled, and stripped of solvent under vacuum yielding (+ g of an amber solid. "his 3as recrystalli6ed from ), m! boiling ?e9H '3ith decolori6ing
charcoal employed and filtration of the boiling solution through paper- to give (,., g of $,+,1@trimetho/yben6aldehyde as a 3hite crystalline solid 3ith a
mp of ((&@((1 deg C. "he literature values are generally one@degree ranges, and they are reported as high as ($( deg C. "he malononitrile adduct
3as prepared from a solution of ,.& g aldehyde and ,.& g malononitrile in (, m! 3arm ?e9H treated 3ith a drop of triethylamine. "here 3as an
immediate formation of a yello3 crystalline mass 3hich 3as removed by filtration, 3ashed 3ith <t9H, and air dried. "he yield of $,+,1@
trimetho/yben6almalononitrile 3as ,.& g and the mp 3as (2+@(2& deg C. Anal. 'C(0H($5$90- 5.
A solution of & g $,+,1@trimetho/yben6aldehyde in $, g nitroethane 3as treated 3ith (., g of anhydrous ammonium acetate and held on the steam bath
for $+ h. "he e/cess solvent8reagent 3as stripped from the deep@red colored solution under vacuum yielding a residue that spontaneously set to a
crystalline mass. "his 3as 3ell triturated under & m! ?e9H, filtered, and 3ashed 3ith 0 m! additional ?e9H to give &.+ g of $@nitro@(@'$,+,1@
trimetho/yphenyl-propene as yello3 crystals. "he mp of the crude material 3as (0&@(+$ deg C 3hich could be raised to (+2@(+) deg C by
recrystalli6ation from <t9H. "he use of an alternate procedure for the synthesis of this nitrostyrene, using acetic acid as solvent and a stoichiometric
amount of nitroethane 'and ammonium acetate as catalyst-, gave very poor yields. "he use of butylamine as catalyst gave considerably better results.
A suspension of &, g !AH in ( ! anhydrous "HB 3as placed under an inert atmosphere, stirred magnetically, and brought to a gentle reflu/. "here 3as
added a total of &1.% g $@nitro@(@'$,+,1@trimetho/yphenyl-propene as a saturated solution in "HB. "his 3as achieved by letting the condensed "HB drip
through a So/hlet thimble containing the nitrostyrene 3ith direct addition to the reaction mi/ture. "he solubility 3as e/tremely lo3. "he stirred mi/ture
3as maintained at reflu/ for 01 h, generating a smooth creamy gray color. After being brought to room temperature, the e/cess hydride 3as destroyed
by the patient addition of &, m! H$9, follo3ed 3ith &, m! (&K 5a9H 'still some heat evolved- and then (&, m! additional H$9. Stirring 3as continued
until the insoluble salts 3ere 3hite and loose. "hese solids 3ere removed by filtration, and the filter cake 3ashed 3ith additional "HB. "he combined
filtrate and 3ashes 3ere stripped of solvent under vacuum, and the 20 g of pale amber residue dissolved in $,, m! IPA, neutrali6ed 3ith appro/imately
&, m! concentrated HC!, and diluted 3ith $ ! anhydrous <t$9. A lo3er, oily phase separated slo3ly set up as a crystalline mass. "his 3as removed by
filtration, <t$9 3ashed, and allo3ed to air dry to constant 3eight. "he 3eight of $,+,1@trimetho/yamphetamine hydrochloride 3as +(.0 g and the color
3as an off@3hite. "here 3as a tendency to discolor upon air e/posure. "he mp 3as $,+@$,& deg C 3hich 3as increased to $,2@$,) deg C upon
recrystalli6ation from IPA. "he literature gives a mp of $(+@$(& deg C for this salt after isolation and purification as the picrate salt '3ith a mp $($@$(0
deg C from <t9H-.
;9SAC<E $& @ &, mg.
;4:A"I95E ($ @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith $& mg- I 3as outside at the California@Iashington State football game, 3hich 3as completely nutty. As 3as I. Iith
the cro3d activity, it 3as impossible to separate the drug7s action from the environment. !ater I simply sat in the car, and tried to define 3hat the effects
really 3ere. "hings 3ere completely benign, there 3as ease 3ith concepts, and 3riting 3as good and smooth. At t3elve hours, comfortably do3n.
?aybe a plus t3o.
'3ith 0& mg- ?y body 3as tingling all over, and there 3ere times 3hen 3alking 3as unsteady. "hinking 3as a little difficult, as I 3as Fuite into/icated
most of the day 'all of the day, no3 that I think that over-. "o accomplish anything, such as toasting the toast in the toaster, 3as difficult. And things
3ere so funny most of the time. Setting the table for supper, si/ hours later, proved to be hilarious. I like to think of the day as a mi/ture of the mad
hatter7s tea party, and a trip to the moon. Ie 3ere all still into/icated at bedtime, 3hatever time that 3as. Had difficult time sleeping. If I 3ere to repeat,
3ould go lighter in dosage, I feel.
'3ith +, mg- "his e/periment 3as begun at noon of a cool rainy day. Almost all of the day had to be spent indoors, 3ithout benefit of sunshine, "his is
3orth mentioning because there 3as, for the first eight hours of the e/periment, a decided feeling of inner chill 3hich might not have occurred so strongly
had it been a 3arm day. ?ost, if not all, of the other eight subGects also reported the same chill. "here 3as some visual sparkle 3hich persisted
throughout. At the t3o hour point a minor but persistent stomach Fueasiness came on, preceded by a diarrhea@like bo3el movement. "here 3as no
impairment of speech, but there 3as some halting Fuality to all thought processes. It 3as easy to talk about personal matters, but there did not seem to
be a significant insight increase. Appetite for food 3as lessened. Sleep 3as decidedly difficult after the effects of the material seemed other3ise gone.
'3ith +, mg- As the e/perience gro3s in intensity for the first four hours, I feel a strange mi/ture of plateaus, e/uberance, and strong negative feelings,
all replacing each other. I found myself inside a stout, hemispherical shell, curled up in the solid part, thoroughly 3alled off but absolute master 3ithin
the shell, calling all shots, making all decisions, in complete control. ?oving beyond the half@shell meant becoming vulnerable, 3hich I refused to do.
ConseFuently my difficulty in hearing 3hat other people say, becoming involved in their perceptions and lives. I keep relationships shallo3, pull a3ay
inside my shell rather than become involved. I like to be by myself. "his 3as a great revelation; I had never seen it before. "his material had an
enormous drive. I feel e/tremely grateful for e/posing a very deep personal problem.
'3ith &, mg- ?y previous try at this level produced a record that said, 7alteration of consciousness, but no visual, no anything,7 and oh my, surpriseO It
3as very, very active, visual, colorful, etc., etc. Cood talking, clear and steady control of body, despite intense energy flo3. </tremely funny L great
humor, 3onderful laughter.
<="<5SI95S A5; C9??<5"A:>E Here is a simple and easily made compound that might 3ell bid fair to be one of the most re3arding and
pleasurable of the metho/ylated amphetamines. It is fully as potent as its counterpart, "?A@$. "his latter compound, 3ith its $,+,&@trisubstitution
pattern, has served as a template from 3hich an immense family of very active and fascinating drugs have arisen. "he $,&@dimetho/y aspect has been
kept intact, and modifications in the +@position have given rise to treasures such as ;9?, ;9., ;9<", ;9I, and the Aleph compounds. And, of course,
the entire 3orld of the $C@=7s has e/ploited this same orientation.
Here, there is the blatant, parallel call from "?A@1. It can serve, as the $,+,1@counterpart, as a similar template compound. And the first indicators are
that, in keeping the $,1@dimetho/y aspect intact, a completely analogous series could be made, again 3ith modifications of the +@position. "hese have
been named the psu@series, or psi@series, as an abbreviation for the prefi/, pseudo, and can be differentiated from the $,+,&@things 3ith the use of the
Creek letter NgammaN. "hus there is the gamma@;9? 'called A@2 in this book, and certainly an active compound-, and gamma@;9., gamma@;9<",
gamma@;9I, and the gamma@A!<PH compounds. And, of course, the gamma@$C@= counterparts. I 3ould e/pect all of them to be active and, certainly,
some of them interesting. "hey 3ill be considerably more difficult to synthesi6e. Ho3ever, some of them, specifically things such as gamma@$C@"@+,
have already been prepared, and are being evaluated.
9ne of the guiding premises of this .ook II 3as to make all recipes employ commercially available materials as starting materials. And in the case of
"?A@1, the reFuired ben6aldehyde '$,+,1@trimetho/yben6aldehyde- is an easily obtained trade item from any of several supply houses. Ihy not start
the recipe thereH Ihy tell ho3 to make it from (,0,&@trimetho/yben6ene 'also presently available from commercial sources- and ho3 to make the ether
in turn, from phloroglucinolH "his simply reflects a valid paranoia of our times. "oday the aldehyde is available 'at #$8g- and can be easily purchased.
.ut tomorro3H Ihat about in the year $,,0H Iho can tell 3hat 3ill, or 3ill not, be easily available thenH "here might be a 3orld@3ide
ackno3ledgment that the N3ar on drugsN is more destructive than any drug itself could ever be, and every la3 that had been 3ritten in the attempt to
dictate human behavior 3ill have been transformed into a force that truly educates and allo3s choice. "his might really happen. .ut maybe, on the
other hand, no fine chemicals may be permitted to be held in any hands, at any price, e/cept for those of licensed chemists and in authori6ed
laboratories. "he black market price for the aldehyde might be #(,,,8g 3ith another #(,,, for protection. .ut, it 3ill be impossible to remove
phloroglucinol from availability.
It is available as a natural component in the free form, in sources as diverse as the cones of the SeFuoia sempervirens 'the coast red3ood tree- and
species of Camillia 'that provides the leaves of our morning tea-. And combined 3ith a molecule of glucose in the form of its glucoside, it is called
phlorin, and it is present in the discarded rinds of almost all citrus fruits as 3ell as the resins from many of the <ucalyptus species. And one step yet
further back into nature, there is a dihydrochalcone glucoside called phlorid6in 3hich practically drips out of all parts of the apple and pear trees e/cept
for the apple or pear itself. It, on base hydrolysis, gives phlorin, 3hich on acid hydrolysis gives phloroglucinol, 3hich 3hen dissolved in methanol and
sulfuric acid gives L. 5ature is indeed most bountiful.
"he phenethylamine homologue of "?A@1 is 3ell kno3n, but is virtually une/plored pharmacologically. "he above ben6aldehyde 3ith nitromethane in
glacial acetic acid containing ammonium acetate gave the appropriate beta@nitrostyrene as yello3 crystals 3ith a mp (22@(22.& deg C. "his, 3ith !AH in
ether, gave $,+,1@trimetho/yphenethylamine '$,+,1@"?P<A, or $C@"?A@1- as the picrate salt 'mp $,+@$,& deg C- or the hydrochloride salt 'mp $0+@$0&
deg C-. It has been sho3n not to be a substrate to the soluble amine o/idase from rabbit liver, a property it shares 3ith mescaline, but 3hether it is or is
not active in man is at present unkno3n.

#11' '-TME; '-TH"%METAES!A"#E;
(,)-0"METH%+Y-'-ETHYTH"%,HE#ETHYAM"#E-
S>5"H<SISE A solution of (0., g of 0@bromo@5@cyclohe/yl@+,&@dimetho/yben6ylidenimine 'see under ?P for its preparation- in ($& m! anhydrous <t$9
in a He atmosphere 3as cooled 3ith an e/ternal dry ice acetone bath to @), deg C 3ith good stirring. "o this clear pale yello3 solution there 3as added
0$ m! (.&& ? butyllithium in he/ane 'about a $&K e/cess- 3hich 3as stirred for (, min producing a fine 3hite precipitate. "here 3as then added 2., g
diethyl disulfide. "he dry ice bath 3as removed and the reaction stirred as it came to room temperature. "his 3as then added to 0,, m! dilute HCl and
the aFueous phase separated and heated on the steam bath for +& min. A yello3 oil 3as formed 3ith a nearly colorless aFueous overhead. "his 3as
removed by decantation, and the remaining oil 3as diluted 3ith a little ?e9H and additional concentrated HCl. After further heating on the steam bath,
this 3as added to the separated phase, all 3as cooled and e/tracted 3ith $/&, m! CH$Cl$. :emoval of the solvent from these pooled e/tracts gave
((.) g of a residue that 3as distilled. "he product, 0@ethylthio@+,&@dimetho/yben6aldehyde boiling at (,1@($& deg C at ,.+ mm8Hg and 3as an almost
colorless oil 3eighing ).0 g. Anal. 'C((H(+90S- C,H.
"o a solution of ).$ g 0@ethylthio@+,&@dimetho/yben6aldehyde in ($& m! nitromethane, there 3as added (., g of anhydrous ammonium acetate and the
mi/ture 3as heated on the steam bath for (.& h. "he reaction mi/ture 3as stripped of nitromethane under vacuum, and the residual red oil 3as
dissolved in $, m! of boiling ?e9H. "his 3as decanted from a small amount of insolubles, and allo3ed to cool to room temperature. After considerable
manipulation of a small sample 3ith dry ice cooling, a seed of crystal 3as obtained, 3hich successfully promoted crystalli6ation of the entire ?e9H
solution. After standing for ( h, the product 0@ethylthio@+,&@dimetho/y@beta@nitrostyrene 3as removed by filtration and, after air drying, 3eighed 0.$ g 3ith
a mp of %1@%) deg C. 4pon recrystalli6ation from ?e9H, the mp 3as tightened to %)@%% deg C. Anal. 'C($H(&59+S- C,H.
AH 3as prepared in the usual manner from a suspension of $., g !AH in 2& m! anhydrous "HB, cooled to , deg C and 3ell stirred in an inert
atmosphere of He, and treated 3ith (.00 m! of (,,K H$S9+ added drop3ise. "here 3as added, drop3ise and over the course of (, min, a solution of
0.( g 0@ethylthio@+,&@dimetho/y@beta@nitrostyrene in (& m! anhydrous "HB. At the end of the addition, the reaction mi/ture 3as returned to room
temperature, and finally heated on the steam bath for (, min. After cooling again, there 3as added enough IPA to decompose the e/cess hydride and
sufficient (,K 5a9H to convert the aluminum o/ide to a 3hite, easily filterable mass. "his 3as removed by filtration, the filter cake 3ashed 3ith
additional IPA, and the filtrate and 3ashes combined and the solvent removed under vacuum. "his 3as dissolved in (,, m! of dilute H$S9+, 3hich 3as
3ashed 3ith $/&, m! CH$Cl$. "he aFueous phase 3as made basic 3ith 5a9H, e/tracted 3ith $/&, m! CH$Cl$, and the e/tracts pooled and the
solvent removed under vacuum to yield a residue of a colorless oil. "his 3as distilled at (1,@(2, deg C at (., mm8Hg yielding $.1 g of a colorless liFuid.
"his 3as dissolved in ($ m! IPA, neutrali6ed 3ith $+ drops of concentrated HCl and diluted 3ith $& m! anhydrous <t$9. "he clear solution 3as
decanted from a little solid material, and the decantings diluted 3ith a further &, m! anhydrous ether. "he still clear solution became cloudy after a fe3
min, and then there 3as the slo3 formation of 0@ethylthio@+,&@dimetho/yphenethylamine hydrochloride '0@"?<- as a fine 3hite crystalline product.
:emoval by filtration, 3ashing 3ith <t$9, and air drying yielded $.) g of 3hite gran@ular solids that melted at (2(@(2$ deg C. Anal. 'C($H$,Cl59$S-
C,H.
;9SAC<E 1, @ (,, mg.
;4:A"I95E (, @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- As important as the e/perience 3as, itself, I feel that it 3as in the t3o or three days that follo3ed that it had
the most profound impact on me. It 3as at the time of the death of my 3ife7s mother, and I found that I could look directly to3ards death and its
ramifications. Including my o3n death. I felt very close to the Higher Po3ers that seemed to make their presence felt all around. And there 3as still the
deep internal strength that 3as the direct product of the 0@"?< e/perience. I feel it very strongly, still, but I have no desire to repeat the e/perience right
a3ay. It is almost as if the effects are still in evidence, and one should take one7s time in letting it manifest all its ramifications. .ut it is certainly an
e/perience one should have once a year, if not oftener.
'3ith (,, mg- I 3as a3are of the development Fuite early, and by the end of an hour and a half, I 3as in Fuite a remarkable state. I 3as e/tremely
disinhibited, 3ith easy verbal play and easily self@revealing, but not at too deep a level. "here 3as great fun 3ith a set of 3ater colors but, 3hen a used
leene/ became my canvas, the others failed to share my humor. I drove home at midnight 3ith considerable care and 3as unable to sleep for another
t3o hours. I 3ould be very 3illing to repeat this e/periment, at this level, to see if the good humor of it all 3as a consistent property.
'3ith (,, mg- I had a sudden revelation L 3hat I called the 3et@paint theory of Christ. Ho3 does one find and identify the ?essiahH It is most simple.
All of life is nothing more than a freshly painted fence separating us from the rest of the 3orld. And the fence has many, many signs on it that sayE
.e3are. ;on7t "ouch. Iet Paint. And if you touch too soon, indeed you get a dirty finger because the paint really is still 3et. .ut the very first man to
touch it and find it dryH "here is your natural leader, your Son of Cod, and all those 3ho touch later than He are the follo3ers of the leader 3ho first
touched and found the paint dry.
<="<5SI95S A5; C9??<5"A:>E A short unraveling of the codes used here for the various materials is very much needed. "here are 07s and +7s
and ?7s and I7s and incipient confusion. ?escaline is mescaline. "hat much is simple. All homologs are the first letter of the homolog. <scaline is <,
Proscaline is P, etc. If the group is at the three@position, then the term NmetaN is used and an ? preceeds the name of the homolog, i.e., ?< is
?etaescaline. "he number '0@ or +@ or &@- gives the position of the sulfur, 3hich is represented by the prefi/ N"hioN so this compound, 0@"?<, has the
sulfur at the 0@position, and by chance, the ethyl group there as 3ell.
Here is a brief presentation of the needed :osetta StoneE
5umber of all three
are 9ne o/ygen is re@
ethyl groups o/ygen atoms placed
3ith sulfur
none ? 0@"?
+@"?
one < 0@"<
+@"<
?< 0@"?<
+@"?<
&@"?<
t3o S. 0@"S.
+@"S.
AS. 0@"AS.
+@"AS.
&@"AS.
three ":IS 0@"@":IS
+@"@":IS


#11( (-TME; (-TH"%METAES!A"#E;
'-ETH%+Y-)-METH%+Y-(-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of &.( g 5,5,57,57@tetramethylethylenediamine and 1.) g of 0@etho/yanisole 3as dissolved in ), m! he/ane. "his 3as stirred
vigorously under a He atmosphere and cooled to , deg C 3ith an e/ternal ice bath. "here 3as added $2.& m! of (.1 ? solution of butyllithium in
he/ane. "he stirred reaction mi/ture deposited a fine 3hite precipitate. It 3as 3armed to room temperature and stirred for (& min. After cooling again
to , deg C, there 3as added +.1 m! of dimethyl disulfide 3hich converted the precipitate to a creamy 3hite material. Stirring 3as continued 3hile the
reaction mi/ture 3as brought up to room temperature, and continued for an additional h. All 3as then added to $,, m! dilute H$S9+. "he solids
dissolved and there 3as the formation of t3o phases. "hese 3ere separated, the aFueous phase e/tracted 3ith 3ith $/2& m! <t$9, the organic phases
combined and evaporated under vacuum. "he residue 3eighed ((.( g and set up to a 3a/y solid. "his 3as ground under ( m! of he/ane, filtered,
3ashed sparingly 3ith he/ane, and air dried yielding 2.1 g of 0@etho/y@$@'methylthio-anisole as 3hite crystals. "he mp 3as 0&@01 deg C 3hich 3as not
improved follo3ing recrystalli6ation from he/ane. Anal. 'C(,H(+9$S- C,H.
"o a stirred solution of 2.1 g of 0@etho/y@$@'methylthio-anisole in (,, m! CH$Cl$ there 3as added 1.$ g elemental bromine dissolved in &, m! CH$Cl$.
"he initial dark red color gradually faded to a pale yello3 and there 3as a steady evolution of H.r. An added crystal of iodine did not appear to increase
the rate of reaction. After + min the color 3as a pale orange. "he reaction mi/ture 3as e/tracted 3ith H$9 containing sufficient dithionite to remove
most of the residual color. "he solvent 3as removed under vacuum leaving ($.$ g of a pale yello3 fluid oil. "his 3as distilled at (,,@((, deg C at ,.0
mm8Hg to yield a mi/ture of +@bromo@0@etho/y@$@'methylthio-anisole and 1@bromo@0@etho/y@$@'methylthio-anisole as a pale yello3, highly refractory oil
that 3as used as such in the follo3ing reaction. Anal. 'C(,H(0.r9$S- C,H.
"o a solution of ($ m! diisopropylamine in 2& m! anhydrous "HB that 3as stirred under an 5$ atmosphere and cooled to @(, deg C 3ith an e/ternal
ice8?e9H bath, there 3as added in seFuence 0& m! of (.1 ? butyllithium in he/ane, (.) m! of dry acetonitrile, and &., g of +@bromo@ 'and 1@bromo-@0@
etho/y@$@'methylthio-anisole. "he reaction mi/ture changed color from yello3 to red to reddish bro3n. Stirring 3as maintained for an additional ,.& h,
and then the reaction mi/ture 3as poured into ), m! of dilute H$S9+. "he phases 3ere separated, and the aFueous phase 3as e/tracted 3ith (,, m!
CH$Cl$. "he organic phases 3ere combined, and the solvent 3as removed under vacuum. "he oily residue 3as distilled at ,.$ mm8Hg yielded t3o
fractions. "he first fraction boiled at %,@((& deg C and 3eighed (.2 g. "his material proved to be largely the unreacted bromo starting materials. "he
second fraction came over at (+,@ (2, deg C, 3eighed (.2 g, and it crystalli6ed 3hen seeded 3ith a small crystal obtained e/ternally 3ith dry ice. "his
fraction 3as recrystalli6ed from (, m! ?e9H, filtered, and 3ashed sparingly 3ith cold ?e9H. After air drying, there 3as obtained ,.& g 0@etho/y@&@
metho/y@+@methylthiophenylacetonitrile 3hich had a mp of 1&@11 deg C. Anal. 'C($H(&59$S- C,H.
A suspension of ,.& g !AH in &, m! anhydrous "HB under 5$ 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, ,.0& m! (,,K
H$S9+, follo3ed by ,.+& g 0@etho/y@&@metho/y@+@methylthiophenylacetonitrile in (, m! anhydrous "HB. "he reaction mi/ture 3as stirred at , deg C for
a fe3 min, then brought to a reflu/ for a fe3 min on the steam bath. After allo3ing the mi/ture to return to room temperature, there 3as added IPA
sufficient to destroy the e/cess hydride follo3ed by (,K 5a9H to bring the reaction to a basic pH and to convert the aluminum o/ide to a loose, 3hite,
filterable consistency. "his 3as removed by filtration, and 3ashed 3ith &, m! IPA. "he filtrate and 3ashes 3ere stripped of solvent in vacuo, and the
residue suspended in dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$, made basic 3ith aFueous 5a9H, and the product e/tracted 3ith $/2& m!
CH$Cl$. After combining these e/tracts, the solvent 3as removed under vacuum providing (.$ g of a residue 3hich 3as distilled at (0$@(+, deg C at
,.+ mm8Hg to give ,.0& g of a colorless oil. "his 3as dissolved in 2 m! of IPA, neutrali6ed 3ith 2 drops of concentrated HCl and diluted 3ith 0 volumes
of anhydrous <t$9. "he product 3as removed by filtration, 3ashed 3ith <t$9, and air dried to give ,.0, g 0@etho/y@&@metho/y@+@
methylthiophenethylamine hydrochloride '+@"?<- as 3hite crystals 3ith a mp of (1+@(1& deg C. Anal. 'C($H$,Cl59$S- C,H.
;9SAC<E 1, @ (,, mg.
;4:A"I95E (, @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- "here 3as a strange off@baseness for several hours in the middle of the day, 3hich 3as replaced by a mild
gastric upset in the evening. "he mild mental disturbance is neither visual nor particularly interesting.
'3ith (,, mg- A benign and gentle altered state became progressively sad and morbid. 5othing 3ent together 3ell L I could not empathi6e 3ith anyone,
and trying to 3rite at the type3riter 3as useless. So 3ere efforts to sleep at midnight, but this 3as totally relieved 3ith $,, milligrams of ?ilto3n. In the
morning I seemed still to be off baseline, and I 3as e/tremely sleepy, 3ith much lethargy. <ven several days later there 3ere problems trying to
integrate my emotions and feelings. I am not yet completely at peace.
<="<5SI95S A5; C9??<5"A:>E Sometimes things 3ork 3ell in their mysterious 3ays. "he reports 3ith +@"?< 3ere more to the to/ic than to the
Goyous side, and this by chance 3ith a compound that could only be obtained in an atrociously small yield.

#11) )-TME; )-TH"%METAES!A"#E;
'-ETH%+Y-(-METH%+Y-)-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of (,.+ g of 0@bromo@5@cyclohe/yl@+@metho/y@&@etho/yben6ylidenimine 'see under ?< for its preparation- in (&, m! anhydrous
<t$9 in a He atmosphere 3as cooled 3ith an e/ternal dry ice acetone bath to @), deg C 3ith good stirring. "he addition of &$ m! (.1 ? butyllithium in
he/ane produced a thick precipitate 3hich 3as stirred for & min. "here 3as then added ).& m! of dimethyl disulfide and the reaction mi/ture gradually
became thinner and lighter. "he dry ice bath 3as removed and the reaction allo3ed to come to room temperature over the course of (& min. "his 3as
then added to +,, m! of dilute HCl. "he t3o phases 3ere separated, and the aFueous phase 3as heated on the steam bath for ( h 3hich generated a
separate yello3 oily phase. 9n cooling, this set to a yello3 solid, 3hich 3as removed by filtration, 3ashed 3ith H$9, and sucked relatively free of H$9.
"hese yello3 solids 3eighed (+.+ g and 3ere ground under $, m! of cold cyclohe/ane 3hich removed almost all the color and, after filtering and air
drying, there remained ($.% g of an off@3hite crystalline solid that melted at )0@)+ deg C. :ecrystalli6ation from cyclohe/ane produced 0@etho/y@+@
metho/y@&@'methylthio-ben6aldehyde as a 3hite fluffy crystalline material 3ith a melting point of )+@)& deg C. Anal. 'C((H(+90S- C,H.
"o a solution of )., g 0@etho/y@+@metho/y@&@'methylthio-ben6aldehyde in (,, m! nitromethane, there 3as added ,.& g anhydrous ammonium acetate
and the mi/ture 3as heated on the steam bath for (.& h, at 3hich time most of the aldehyde had disappeared and there 3as a si6eable Fuantity of
nitrostyrene as 3ell as a cascade of 3rong things do3n to the origin, as seen by "!C on silica gel, 3ith CH$Cl$. "he e/cess nitromethane 3as removed
under vacuum, and the residual red oil 3as dissolved in $& m! of hot ?e9H and decanted from a small amount of insoluble material. Iith cooling in an
ice bath for $, min, bright yello3 crystals 3ere formed 3hich 3ere removed by filtration, 3ashed 3ith ?e9H and air dried, producing +.( g 0@etho/y@+@
metho/y@&@methylthio@beta@nitrostyrene 3hich melted at ),@)$ deg C. "his sample, on resolidification and remelting, melted at (,%@((, deg C. "his
higher@melting polymorphic form 3as also produced by recrystalli6ation of the product from cyclohe/ane. "he t3o polymorphs 3ere chromatographically
and analytically identical. Anal. 'C($H(&59+S- C,H.
AH 3as prepared in the usual manner from a suspension of 0., g !AH in (,, m! anhydrous "HB, cooled to , deg C, 3ell stirred in an inert atmosphere
of He, and treated 3ith $., m! of (,,K H$S9+ added drop3ise. "here 3as then added a solution of $.+ g 0@etho/y@+@metho/y@&@methylthio@beta@
nitrostyrene in $, m! anhydrous "HB. "he reaction 3as e/othermic, and had come nearly to a boil at the half@addition point. "he reaction 3as cooled
again to , deg C and the remaining nitro@styrene then added. "his 3as brought to a reflu/ briefly on the steam bath, then cooled again and stirred for an
additional ( h. IPA 3as carefully added to decompose the e/cess hydride follo3ed by sufficient (,K 5a9H to convert the aluminum o/ide to a 3hite,
easily filterable mass. "his 3as filtered, the filter cake 3ashed 3ith additional IPA, and the filtrate and 3ashes combined and the solvent removed under
vacuum. "his 3as dissolved in (,, m! of dilute H$S9+, 3hich 3as 3ashed 3ith $/&, m! CH$Cl$. "he aFueous phase 3as made basic 3ith sodium
hydro/ide, e/tracted 3ith $/&, m! CH$Cl$, and the e/tracts pooled, dried over anhydrous $C90, and stripped of solvent under vacuum to yield a
nearly colorless residue. "his 3as distilled at ($&@(0& deg C at ,.0 mm8Hg producing $., g of a 3ater@3hite oil. "his 3as dissolved in ) m! IPA,
neutrali6ed 3ith $0 drops of con@centrated HCl and, 3ith good stirring, diluted 3ith $, m! anhydrous <t$9. "he product 0@etho/y@+@metho/y@&@
methylthiophenethylamine hydrochloride '&@"?<- 3as removed by filtration, 3ashed 3ith <t$9, and air dried to provide a 3hite solid that 3eighed $., g
and melted at (1)@(1% deg C. Anal. 'C($H$,Cl59$S- C,H.
;9SAC<E greater than $,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $,, mg- "here 3as a noticeable tinnitus, but then that comes and goes at odd times 3ithout any reason needed.
"here 3as perhaps a brush of light@headedness at the third hour point, but other than that, nothing. 5o effect that can be ascribed to today7s drug trial.
<="<5SI95S A5; C9??<5"A:>E 5othing comes to mind. "his, along 3ith most of the di@ and triethylated thiomescaline analogues, represents a lot
of synthetic effort 3ithout useful Fualitative data. If there is any activity, it 3ould only be seen 3ith monster dosages, and 3hy put the body through such
potential impactH

#111 $T-MM0A-'a; ',(-METHYE#E0"%+Y-$-METHYTH"%AM,HETAM"#E
S>5"H<SISE A solution of 0, g piperonal in $& m! cyclohe/ylamine 3as brought to a boil on a hot plate, until there 3as no more 3ater apparently being
evolved. "he resulting melt 3as distilled giving +& g of 5@cyclohe/yl@0,+@methylenedio/yben6ylideneimine boiling at ((+@(0& deg C at ,.$ mm8Hg as a
light yello3 oil.
In +,, m! anhydrous <t$9 there 3as dissolved +,.0 g 5@cyclohe/yl@0,+@methylenedio/yben6ylidenimine and 0, m! 5,5,57,57@
tetramethylethylenediamine '"?<;A-. "his solution 3as put under an inert atmosphere, and 3ith good stirring brought to @2) deg C 3ith an e/ternal dry
ice8acetone bath, 3hich produced a light 3hite crystalline precipitate. "here 3as then added ($, m! of (.&& ? butyllithium, 3hich produced an
immediate darkening and a dissolving of the fine precipitate. After (, min stirring, there 3as added $, m! of dimethyl disulfide. "he color immediately
vanished and there 3as the formation of a 3hite precipitate. "he temperature 3as allo3ed to return to ice bath temperature, and then all volatiles 3ere
removed under vacuum. "he residue 3as poured into &,, m! H$9 and acidified 3ith HCl. After heating for ( h on the steam bath, the reaction mi/ture
3as cooled, producing a gummy solid that 3as sho3n to be a comple/ mi/ture by "!C. .ut there 3as a single fluorescent spot that 3as the product
aldehyde and it 3as pursued. </traction 3ith 0/2& m! CH$Cl$ gave, after pooling and stripping of the solvent, a residue 3hich 3as e/tracted 3ith four
separate passes, each 3ith 2& m! boiling he/ane. "he deposited crystals from each 3ere separated, and all recrystalli6ed from boiling ?e9H to give
0.0 g of 0,+@methylenedio/y@$@'methylthio-ben6aldehyde, 3ith a mp of 22@), deg C.
"o a solution of 0., g 0,+@methylenedio/y@$@'methylthio-ben6aldehyde in $& m! IPA there 3as added $ m! nitroethane, ,.(( m! ethylenediamine and ,.(
m! acetic acid. "his 3as held at reflu/ temperature for () h, and the solvents removed under vacuum. "he residue sho3ed a total of eight spots on
"!C analysis, e/tending from the origin to the spot of the product nitrostyrene itself. "rituration of this residue under $& m! ?e9H gave a crude
nitrostyrene 3hich 3as, after separation, recrystalli6ed from $, m! of boiling ?e9H. "he final isolation of (@'0,+@methylenedio/y@$@methylthiophenyl-@$@
nitropropene gave ,.& g of a product that had a mp of %+@%& deg C. "he mi/ed mp 3ith the nitrostyrene from piperonal 'mp %2@%) deg C- 3as soundly
depressed 'mp 12@2% deg C-.
A solution of AH 3as prepared by the treatment of a solution of ,.& g !AH in (, m! "HB, at , deg C and under He, 3ith ,.0$ m! (,,K H$S9+. A
solution of ,.+& g (@'0,+@methylenedio/y@$@methylthiophenyl-@$@nitropropene in (, m! "HB 3as added drop3ise, and the stirring 3as continued for ( h.
After a brief period at reflu/, the reaction mi/ture 3as returned to room temperature, and the e/cess hydride destroyed by the addition of IPA. "he salts
3ere converted to a filterable mass by the addition of &K 5a9H, and after filtering and 3ashing 3ith IPA, the combined filtrate and 3ashings 3ere
stripped of solvent under vacuum. "he residue 3as dissolved in dilute H$S9+ 3hich 3as 3ashed 3ith 0/2& m! CH$Cl$. After alkalinification 3ith $&K
aFueous 5a9H, the product 3as e/tracted 3ith $/2& m! CH$Cl$. "he e/tracts 3ere pooled, and the solvent removed under vacuum. ;istillation of the
residue gave a fraction that boiled at (02@(&, deg C at ,.0 mm8Hg and 3eighed ,.0 g. "his 3as dissolved in (.1 m! IPA, neutrali6ed 3ith 1 drops of
concentrated HCl, 3armed to effect complete solution, and diluted 3ith + m! of anhydrous <t$9. "he formed crystals 3ere collected by filtration, and
after <t$9 3ashing and air drying to constant 3eight, gave ,.0 g 0,+@methylenedio/y@$@methylthioamphetamine hydrochloride '$"@??;A@0a-.
;9SAC<E greater than ($ mg.
;4:A"I95E unkno3n.
<="<5SI95S A5; C9??<5"A:>E And visions of sugar@plums danced through their heads. "here are many trisubstituted amphetamine analogues
that have been documented 3ith varying degrees of activity. "here are si/ "?A7s and if one 3ere to systematically make every possible thio@analogue
of each of these, there 3ould be a total of si/teen thio@analogues of the "?A. !et7s go for it, said I to myself. !et7s get the (1 thio analogues in hand.
"hat is 3here the action7s at. .ut hold on a minute. <ach and every ??;A isomer has, by definition, three possible thio analogues, so there are
eighteen more possible thio compounds Gust 3ith them. Sure, let7s make them allO It 3ill be an unprecedented coup for students of structure@activity
relationships. !et7s 3hip out some 0+ compounds, and test them all, and maybe 3e 3ill begin to understand Gust 3hy those 3hich are active are, indeed,
active. And maybe not.
Any3ay, this 3as the most manic of all manic programs ever, involving thio@analogues. And it 3as totally compelling. Another synthetic clue stemmed
from the fact that vanillin also formed the cyclic carbonate 3ith sodium thiocyanate and it could, in principle, be brought around in time to 0@metho/y@&,+@
methylenethioo/yamphetamine, or &"@??;A. "hat made t3o of the magic analogues, and only some 0$ to go. Ihat a marvelous task for a graduate
student. 'Ihat a horribly dull task for a graduate student.- .ut in any case there 3as no graduate student, and this appeared to be the end of the line.
Some day, let7s make all these possibilities. A magnificent tour@de@force, but at the present time, not 3orth the effort. 9ther directions are more e/citing
and more appealing.
A last note of simple humor. 9ne of the compounds used in this preparation 3as 5,5,57,57@tetramethylethylenediamine, 3hich has been abbreviated
"?<;A. "here is a pattern, 3ithin any active inner cliFue of research chemists intently pursuing a goal, to begin condensing comple/ comcepts into
deceptively simple terms. Ie N?9?@ed the hydro/y group of the "@.9C@ed amine.N I have recently heard the above tetramethyl monster referred to in
the chemist7s Gargon as a pronounced, rather than a spelled out, 3ord. It sounds very much like NtomatoN spoken by a native of the .ron/.

#112 (T-MM0A-$; 1-&$-AM"#%,*%,Y--)-METH%+Y-1,'-.E#6%+ATH"%;
$-METH%+Y-(,)-METHYE#ETH"%%+YAM,HETAM"#E
S>5"H<SISE "o a 3ell@stirred solution of ($, g thiourea in ),, m! $5 HC!, there 3as added a solution of (,, g ben6oFuinone in &,, m! acetic acid
over the course of (& min. Stirring 3as continued for an additional ,.& h at room temperature, and then the reaction mi/ture 3as heated on the steam
bath for ( h. Iith cooling in ice 3ater, a heavy crop of crystals separated. "hese 3ere removed by filtration and air dried to provide %,.( g of &@hydro/y@
(,0@ben6o/athiol@$@one '$@mercaptohydroFuinone cyclic carbonate ester- 3ith a melting point of (2,.&@(2$.& deg C.
"o a suspension of (,, g finely po3dered anhydrous $C90 in +,, m! acetone containing &, g methyl iodide there 3as added +( g &@hydro/y@(,0@
ben6o/athiol@$@one, and the mi/ture stirred overnight at room temperature. "he solids 3ere removed by filtration, and the solvent removed under
vacuum. "he residue 3as distilled to give a fraction subliming over as a solid at an oven temperature of ((, deg C at ,.( mm8Hg. "his 3as a yello3ish
solid, 3eighing $2.+ g and having a mp of 11@2$ deg C. :ecrystalli6ation from ?e9H gave &@metho/y@(,0@ben6o/athiol@$@one as a 3hite solid 3ith a mp
of 2&.&@21.& deg C.
"o a solution of 0, g )&K 9H in 2& m! 3arm H$9, there 3as added an eFual volume of 3arm ?e9H follo3ed by (1 g &@metho/y@(,0@ben6o/athiol@$@
one, and the mi/ture 3as held under reflu/ conditions for $ h. After cooling to room temperature, the mi/ 3as acidified 3ith HCl and e/tracted 3ith
$/(,, m! CH$Cl$. :emoval of the solvent from the pooled e/tracts gave a yello3 oil that crystalli6ed on standing. "he product, $@mercapto@+@
metho/yphenol, 3eighed (+ g and had a mp of &1@&2 deg C.
A solution of (, g $@mercapto@+@metho/yphenol in (,, m! ?< 3as added over the course of ( h to a vigorously stirred suspension of $& g finely
po3dered anhydrous $C90 in $,, m! ?< that contained (+ g methylene bromide. "he reflu/ 3as maintained for +) h. After cooling, the mi/ture
3as freed of solids by filtration and the filter cake 3ashed 3ith &, m! additional ?<. "he combined 3ashes and filtrate 3ere stripped of solvent under
vacuum, and the product distilled to give 0.0 g of &@metho/y@(,0@ben6o/athiol as a yello3ing oil that had a bp of ((,@($, deg C at (.2 mm8Hg. "here
3as considerable residue in the pot, 3hich 3as discarded. "he 5?: spectrum 3as e/cellent, 3ith the methylene protons a t3o@hydrogen singlet at &.1
ppm.
"o a mi/ture of 0.$ g P9Cl0 and $.) g 5@methylformanilide that had been heated briefly on the steam bath 'to the formation of a deep claret color- there
3as added $.0 g &@metho/y@(,0@ben6o/athiol, and steam bath heating 3as continued for an additional & min. "he reaction mi/ture 3as poured into (,,
m! H$9, and after a fe3 minutes stirring, the insolubles changed to a loose solid. "his 3as collected by filtration, H$9 3ashed and, after sucking as dry
as possible, recrystalli6ed from 0, m! boiling ?e9H. "his provided (.% g of 1@formyl@&@metho/y@(,0@ben6o/athiol as bro3nish needles that melted at
((%@($, deg C.
A solution of (.& g 1@formyl@&@metho/y@(,0@ben6o/athiol in &, m! nitroethane 3as treated 3ith ,.0 g anhydrous ammonium acetate and heated on the
steam bath for & h. :emoval of the solvent under vacuum gave a residue that crystalli6ed. "his 3as recrystalli6ed from ((, m! boiling <t9H providing,
after fil@tering and air drying, (.0 g &@metho/y@1@'$@nitro@(@propenyl-@(,0@ben6o/athiol as San Brancisco Ciants@orange@colored crystals.
A solution of AH 3as prepared by the treatment of a solution of (.0 g !AH in (, m! "HB, at , deg C and under He, 3ith ,.) m! (,,K H$S9+. A solution
of (.( g of &@metho/y@1@'$@nitro@(@propenyl-@(,0@ben6o/athiol in $& m! "HB 3as added drop3ise, and the stirring 3as continued for ( h. After a brief
period at reflu/, the reaction mi/ture 3as returned to room temperature, and the e/cess hydride destroyed by the addition of IPA. "he salts 3ere
converted to a filterable mass by the addition of &K 5a9H and, after filtering and 3ashing 3ith IPA, the combined filtrate and 3ashings 3ere stripped of
solvent under vacuum. "he residue 3as dissolved in dilute H$S9+ 3hich 3as 3ashed 3ith 0/2& m! CH$Cl$ and then, after being made basic 3ith $&K
5a9H, the product 3as e/tracted 3ith $/2& m! CH$Cl$. "he e/tracts 3ere pooled, and the solvent removed under vacuum. ;istillation of the residue
gave a fraction that boiled at (+,@(&& deg C at ,.0 mm8Hg 3hich 3eighed ,.2 g. "his 3as dissolved in + m! IPA, neutrali6ed 3ith (+ drops of
concentrated HCl, heated to effect complete solution, then diluted 3ith (, m! of anhydrous <t$9. "he 3hite crystals that formed 3ere removed, <t$9
3ashed, and air dried to give ,.1 g 1@'$@aminopropyl-@&@metho/y@(,0@ben6o/athiol hydrochloride '+"@??;A@$-.
;9SAC<E greater than $& mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $& mg- At three hours after having taken the material, I felt that there might have been a little e/hilaration. And maybe
a hint of tremor and of teeth clench. Perhaps this is a threshold dose.
<="<5SI95S A5; C9??<5"A:>E "here is no logical 3ay to try to guess 3here the active level of this might be. In a comparison of +@o/y 3ith +@thio@
and 3ith +@alkyl 'as, for e/ample, "?A@$, PA:A@;9" and ;9?- the analogue 3ith the sulfur atom lies intermediate in potency bet3een the o/ygen
atom and the carbon atom. "hen, perhaps, +"@??;A@$ should be some3hat more potent than ??;A@$. Ihich is 3here the trials have gone to, and
the absence of effects therefore declares that line of reasoning invalid. Ihat else could be used for cluesH "he 3hole ben6ofuran proGect, 3hich had
the same cyclic nature, 3as 3ithout activity. "hey had a carbon 3here the sulfur 3as of +"@??;A@ $, so, by that reckoning, this compound should be
even less active. ?aybe that is the formula to follo3. "he bottom line is inescapable. 5one of these e/trapolations can hold a candle to the only
e/periment that can give believable findings, the actual trial of a ne3 compound in man.
"he positional isomer of the heterocyclic carbonate used here is also kno3n. Instead of using ben6oFuinone as a starting material 3ith thiourea as the
sulfur source 'giving the (,+@ o/ygen orientation-, one can start 3ith resorcinol in reaction 3ith ammonium thiocyanate as the sulfur source 'in the
presence of copper sulfate- and get the positional isomer 3ith a (,0@ o/ygen orientation. "his material 'also kno3n as thio/olone, or tio/olone, or 1@
hydro/y@(,0@ben6o/athiol@$@one, and 3hich is commercially available- should follo3 the same chemistry sho3n here for the &@hydro/y analogue, and
give &"@??;A@$ '&@'$@aminopropyl-@1@metho/y@(,0@ben6o/athiole or $@metho/y@&,+@methylenethioo/yamphetamine- as a final product. I 3ould guess,
based on the findings that compare &@"9? 3ith ;9?, that this 3ould be a relatively lo3@potency compound. At least it should be an easy one to makeO

#113 TM,EA; $,(,)-T*"METH%+Y,HE#ETHYAM"#E
S>5"H<SISE "o a solution of 0%.$ g $,+,&@trimetho/yben6aldehyde in (1, m! nitromethane there 3as added 2., g anhydrous ammonium acetate, and
the mi/ture 3as heated on the steam bath for $ h. "he e/cesssolvent8reagent 3as removed under vacuum, leaving a deeply colored residue that
spontaneously crystalli6ed. "his 3as mechanically removed and triturated under 1, m! cold ?e9H. Biltration, 3ashing 3ith cold ?e9H and air drying,
gave +%.0 g of bright orange crystals. "rial recrystalli6ations from <t9Ac gave a mp of (0$@(00 deg C; from CH0C5, (0,.&@(0(.& deg C. "he entire
product 3as recrystalli6ed from (.( ! boiling IPA to provide, after filtration, IPA 3ashing, and air drying, 0+.& g of beta@nitro@$,+,&@trimetho/ystyrene as
yum@yum orange crystals 3ith a mp of (0$@(00 deg C. !iterature values are usual one@degree ranges, any3here in the area of ($2@(0, deg C.
"o a suspension of 0, g po3dered !AH in ),, m! of 3ell stirred and reflu/ing anhydrous "HB there 3as added a solution of 0+.% g beta@nitro@$,+,&@
trimetho/ystyrene in $,, m! anhydrous "HB. "he mi/ture 3as maintained at reflu/ for an additional 01 h, cooled, and the e/cess hydride activity
destroyed by the addition of 0, m! H$9 follo3ed by 0, m! (&K 5a9H, and finally 3ith another %, m! H$9. "he solids 3ere removed by filtration,
3ashed 3ith "HB, and the pooled mother liFuor and 3ashings stripped of solvent under vacuum. "he residue 3as dissolved in CH$Cl$, 3ashed 3ith
both &K 5a9H and then H$9, removing much of the color. It 3as then e/tracted 3ith 0/2& m! 5 HCl. "he pooled red@colored acid e/tracts 3ere
3ashed 3ith CH$Cl$, made basic 3ith $&K 5a9H, and e/tracted 3ith 0/2& m! CH$Cl$. :emoval of the solvent gave some $& g of residue 3hich 3as
dissolved in (,, m! IPA and neutrali6ed 3ith concentrated HCl. "he crystalline mass that formed 3as diluted 3ith an eFual volume of <t$9, and the
solids removed by filtration. Iashing 3ith cold IPA, follo3ed by <t$9 and air drying, gave (2.2 g of $,+,&@trimetho/yphenethylamine hydrochloride
'"?P<A- as a 3hite product. "he reported melting point 3as ()2@()) deg C.
;9SAC<E greater than 0,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith less than 0,, mg- Since it 3as not easy, ho3ever, to Gudge the e/tent of a 7:ausch7@action from e/periments on
animals, some inGections of beta@$,+,&@trimetho/yphenethylamine 3ere administered to the author, and finally a control test 3as carried out 3ith an eFual
Fuantity of mescaline. "he action of both these substances in these e/periments agreed only to a limited e/tent 3ith the effects described for mescaline
by, for e/ample, .eringer. It must be remembered, ho3ever, in this connection, that the Fuantities used by .eringer 3ere larger than the doses
administered in these e/periments. 5evertheless, it may be concluded that the pharmacological action of beta@$,+,&@trimetho/yphenethylamine agrees
to a large e/tent 3ith that of mescaline. Ho3ever, the ne3 compound had more unpleasant secondary effects 'nausea- and did not bring about the
euphoristic state caused by mescaline.
'3ith 0,, mg- 4nder double blind conditions, I 3as unable to distinguish this from a placebo. .oth 3ere 3ithout any of the changes described after the
ingestion of psychotomimetic drugs.
'3ith $,, mg, follo3ed after +& minutes, 3ith (,, mg mescaline- :"he
normally modest effects kno3n to be due to mescaline alone at this level, 3ere strongly potentiated 3ith the earlier taking of $,+,&@"?P<A. "he effects
3ere stronger as 3ell as longer lived.
<="<5SI95S A5; C9??<5"A:>E "he code letters used for this drug are not as ambiguous as they might seem at first glance. A large number of the
$@carbon homologues are given names based on the code for the 0@carbon compound. 9n that basis, this should be $C@"?A@$, since it is the $@carbon
counterpart of "?A@$. .ut since the first of the trimetho/yphenethylamines already had a trivial name, mescaline, the code "?P<A 3as unassigned.
So, here is the logical place to use it.
"here have been Gust t3o reports published of self@e/perimentation 3ith "?P<A, and these comments are taken from them.
"he first is presented here, 3ord for 3ord, as it 3as originally published 'this 3as in (%0(-. It leaves much to be desired. "he administration 3as by
inGection 'intramuscular inGectionH-. "he dose 3as not given, but it 3as less than those reported by .eringer in his studies 3ith mescaline, and this latter
e/perimenter7s published levels 3ere all bet3een 0,, and &,, milligrams. Ihat can one conclude from all thisH 9nly that "?P<A apparently did not
measure up to mescaline in his comparisons.
"he second, reported some +, years later, is not really contradictory. Here the "?P<A 3as administered orally, and the subGect surrounded himself 3ith
a battery of psychological tests. "his might allo3 statistics to provide an aura of validity to the observations. .ut the comments are pretty self@
e/planatory. "he drug 3as not active in its o3n right, but 3hen employed preliminary to mescaline, greatly enhanced the effects of the latter.
"his is an area of research that deserves more attention. "he simple compound that results from the stripping of all three of the 9@methyl groups from
"?P<A is the e/tremely potent neuroto/in, 1@hydro/ydopamine. Ihen it is ad@ministered to an other3ise intact e/perimental animal, it produces
sympathectomy, effectively destroying the sympathetic nervous system. And some of the methyl groups of "?P<A are kno3n to be stripped off through
the normal metabolic processes that occur in the liver. "here are many fascinating psychedelics that have a signature of metho/yl groups para to one@
another. It is kno3n that they, too, can lose a methyl group or t3o. It 3ould be intriguing to see if there 3as some biochemical overlap bet3een the
metabolism of some of these centrally active drugs and the metabolic fate of 1@hydro/ydopamine. .ut in a test animal, of course, rather than in man.

#114 $-T%ET; (-ETHY-)-METH%+Y-$-METHYTH"%AM,HETAM"#E
S>5"H<SISE A mi/ture of $+.+ g ortho@ethylphenol and ().% m! methyl iodide 3as added to a solution of (&.1 g )&K 9H in (,, m! hot ?e9H. "he
mi/ture 3as kept at reflu/ temperature overnight, stripped as much as possible of the ?e9H, and poured into ( ! H$9. An e/cess of &K 5a9H 3as
added and this 3as e/tracted 3ith 0/2& m! CH$Cl$. "he pooled e/tracts 3ere 3ashed 3ith (K 5a9H, and the solvent removed under vacuum to give
0$.) g of a pale amber oil. "his 3as distilled at &&@1& deg C at ,.+ mm8Hg to yield $$., g of $@ethylanisole as a colorless oil.
"o a $(.2 g sample of $@ethylanisole, 3ell stirred but 3ithout solvent, there 3as added, ( m! at a time, $( m! of chlorosulfonic acid. "he color
progressed from 3hite to yello3, and finally to deep purple, 3ith the evolution of much HCl. "he e/othermic reaction mi/ture 3as allo3ed to stir until it
had returned to room temperature 'about ,.& h-. It 3as then poured over +,, m! cracked ice 3ith good mechanical stirring, 3hich produced a mass of
pale pink solids. "hese 3ere removed by filtration, 3ashed 3ell 3ith H$9, and air dried to give about $2 g of 0@ethyl@+@metho/yben6enesulfonyl chloride
as an off@3hite solid that retained some H$9. A sample recrystalli6ed from cyclohe/ane had a mp of ++@+1 deg C. A sample treated 3ith ammonium
hydro/ide provided 3hite crystals of 0@ethyl@+@metho/yben6enesulfonamide 3hich could be recrystalli6ed from H$9 to give tufts of crystals 3ith a mp of
%2@%) deg C. Anal. 'C%H(0590S- C,H.
In a $ ! round bottomed flask eFuipped 3ith a mechanical stirrer there 3as added $,, m! cracked ice, +& m! of concentrated H$S9+, $1.2 g of still
moist 0@ethyl@+@metho/yben6enesulfonyl chloride, and +& g elemental 6inc dust. Iith e/ternal heating, an e/othermic reaction set in and the
temperature 3as maintained at reflu/ conditions for + h. After cooling to room temperature, the reaction mi/ture 3as filtered and the insolubles 3ashed
alternately 3ith H$9 and 3ith CH$Cl$. "he mother liFuors and 3ashings 3ere diluted 3ith sufficient H$9 to allo3 CH$Cl$ to become the lo3er phase.
"hese phases 3ere separated, and the aFueous phase e/tracted 3ith 0/(,, m! CH$Cl$. "he original organic phase and the e/tracts 3ere pooled,
3ashed 3ith H$9, and the solvent removed to give (&.2 g of a smelly amber oil. "his 3as distilled at 2$@)+ deg C at ,.0 mm8Hg to give ($.( g of 0@
ethyl@+@metho/ythiophenol as a 3ater@3hite oil. "he infra@red 3as perfect '3ith the SH stretch at $&1$, 9CH0 at $)02 and (,1(, and 3ith fingerprint
peaks at ),1, )),, (,&$, '(,1(-, ((+$ and ((2% cm@(-. Anal. 'C%H($9S- C,H.
"o a solution of ((.2 g of 0@ethyl@+@metho/ythiophenol and 1.& m! methyl iodide in (,, m! ?e9H there 3as added, 3ith good stirring and a bit at a time,
a solution of &.& g )&K 9H in $& m! hot ?e9H. "he mi/ture 3as held at reflu/ on the steam bath for (.& h, and then stripped of volatiles under
vacuum. "he residues 3ere added to +,, m! H$9, made strongly basic 3ith &K 5a9H, and e/tracted 3ith 0/2& m! CH$Cl$. "he pooled e/tracts 3ere
back@3ashed 3ith (K 5a9H, and the solvent removed under vacuum. "he (0.$ g residue 3as distilled giving $@ethyl@+@'methylthio-anisole as a fraction
boiling at 2)@)& deg C at ,.$ mm8Hg. "he 3eight 3as ((.1 g for an isolated yield of over %,K of theory. "he mp 3as at about , deg C. "he infra@red
sho3ed no SH or other functionality, but an 9CH0 at $)0$ and (,0(, and a fingerprint spectrum 3ith peaks at ),), %2,, '(,0(-, (,&(, ((++ and ((2%
cm@(. Anal. 'C(,H(+9S- C,H.
A solution of ((.$ g $@ethyl@+@'methylthio-anisole and % g dichloro@methyl methyl ether in $,, m! dry CH$Cl$ 3as treated 3ith (0 g anhydrous aluminum
chloride, added a bit at a time. "he color progressed from pink to claret to deep claret, 3ith a modest evolution of HCl. Stirring 3as continued for ( h,
then the reaction 3as Fuenched by the cautious addition of $&, m! H$9. "he t3o phase mi/ture 3as stirred an additional hour and then separated.
"he aFueous phase 3as e/tracted 3ith $/(,, m! CH$Cl$. "he organics 3ere pooled, 3ashed 3ith &K 5a9H, then 3ith saturated brine, and the
solvent removed under vacuum. "he residue 3as an amber oil 3eighing (0.2 g. "his 3as distilled at ,.$ mm8Hg. A first fraction 3as a yello3 oil boiling
at %,@(,, deg C, and 3eighing $.% g. It 3as a mi/ture of starting anisole and the desired ben6aldehyde. A second fraction, boiling at (,,@(0, deg C
3as a viscous yello3 oil 3eighing +.) g. .y "!C it 3as free of starting anisole, and contained a si6eable Fuantity of a second ben6aldehyde. Brom this
fraction, seed crystal 3as obtained, and 3hen the oil 3as dissolved in an eFual volume of ?e9H, the seed took, producing a yello3 solid. "his 3as
filtered and air dried, to give $.$ g of +@ethyl@&@metho/y@$@'methylthio-ben6aldehyde 3ith a mp of 1$@10 deg C. A small sample from ?e9H 3as almost
3hite, and melted at 1(@1$ deg C. "he mi/ed mp 3ith +@ethyl@$@metho/y@&@'methylthio-ben6aldehyde '&2@&) deg C- 3as severely depressed '02@++ deg
C-. A cooled solution of the first fraction of the distillation, in ?e9H, provided an additional (.1 g product, 3ith a mp &%@1( deg C. "he combined mother
liFuors gave additional product for an overall 3eight of &.0 g. Anal. 'C((H(+9$S- C,H.
A solution of (.% g +@ethyl@&@metho/y@$@'methylthio-ben6aldehyde in 2& m! nitroethane 3as treated 3ith ,.0 g anhydrous ammonium acetate, and held
on the steam bath for $.& h. "he e/cess solvent8reagent 3as removed under vacuum, and the deep orange oil residue 3as dissolved in (, m! boiling
?e9H. As this cooled, there 3as the spontaneous generation of crystals. After cooling in an ice bath for a fe3 h, these 3ere removed by filtration,
3ashed 3ith ?e9H, and air dried to constant 3eight. A total of (.+ g of (@'+@ethyl@&@metho/y@$@methylthiophenyl-@$@nitropropene 3as obtained as
canary@yello3 crystals melting at )0@)+ deg C 3hich 3as not improved by recrystalli6ation from ?e9H. Anal. 'C(0H(2590S- C,H.
"o a solution of (.& g !AH in 0, m! anhydrous "HB that 3as cooled to , deg C and stirred under a He atmosphere, there 3as added, slo3ly, (.,& m!
freshly prepared (,,K H$S9+ 'prepared by adding ,.% g $,K fuming H$S9+ to (., g %1K concentrated H$S9+-. "his 3as follo3ed by the addition of
a solution of (.+ g (@'+@ethyl@&@metho/y@$@methylthiophenyl-@$@nitropropene in $, m! "HB, over the course of (, min. "he color of the nitrostyrene
solution 3as discharged immediately upon addition. Iith continued stirring, this 3as allo3ed to come to room temperature, and then to a gentle reflu/
for $ h. After cooling again to room temperature, the e/cess hydride 3as destroyed by the addition of IPA. Sufficient &K 5a9H 3as added to generate
the inorganic salts as a loose filterable mass, and these 3ere removed by filtration. "he filter cake 3as 3ell 3ashed 3ith additional IPA, and the
combined mother liFuors and 3ashes 3ere stripped of solvent under vacuum. "he residue 3as dissolved in (,, m! dilute H$S9+, 3ashed 3ith
CH$Cl$, made basic 3ith &K 5a9H, and e/tracted 3ith $/2& m! CH$Cl$. :emoval of the solvent gave a residue that 3as distilled at (,$@((2 deg C at
,.(& mm8Hg. "he colorless liFuid that distilled ',.2 g- 3as dissolved in 1 m! IPA and neutrali6ed 3ith (( drops of concentrated HCl. "he solids that
formed 3ere dissolved by heating the mi/ture briefly to a boil, and this clear solution 3as diluted 3ith $, m! anhydrous <t$9. "he 3hite crystals of +@
ethyl@&@metho/y@$@methylthioamphetamine hydrochloride '$@"9<"- 3eighed ,.1 g and had a mp of (1+@(12 deg C. Anal. 'C(0H$$Cl59S- C,H.
;9SAC<E greater than 1& mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith &, mg- After about an hour and a half, I found myself a little light@headed. And maybe a feeling of being physically a
bit fragile. I ate something, but there 3as not much Goy in eating. And the ne/t day there 3as some residual fragility, 3hatever that means. Ahead 3ith
caution.
'3ith 1& mg- ;uring the day this 3as barely noticeable, but pleasant.
<="<5SI95S A5; C9??<5"A:>E It seems as if the sulfur in the $@position makes things less interesting, and less potent, than 3hen it is in the &@
position. $@"9? reFuired t3ice the dosage of &@"9?, and here it appears that it could 3ell take a dosage of t3ice that reFuired for &@"9<", to get $@
"9<" off the ground. "here is an understandable reluctance to push on up3ards in dosage 3ith a ne3 and unkno3n compound, 3hen there are
feelings of physical discomfort that out3eigh the mental effects. "here is nothing tangible here. In the complete report of the &, milligram trial, there is a
mention of an inability to effect erection, and this 3ith the light@headedness and disinterest in food, all suggest some involvement 3ith the sympathetic
nervous system. And 3ith these subtle effects persisting into the ne/t day, 3hy push higherH Instinct said to leave it alone. So I left it alone.
"he $@carbon analogue, $C@$@"9<", 3as made from the same aldehyde intermediate. "he appropriate nitrostyrene came smoothly from the aldehyde
and nitromethane, and gave glistening pumpkin@orange crystals from methanol, that melted at %0@%+ deg C. Anal. 'C($H(&590S- C,H. "he final
phenethylamine hydrochloride salt 3as prepared from its reduction 3ith aluminum hydride in "HB, and 3as isolated in the usual manner. It 3as a 3hite
crystalline mass that melted at $$1@$$2 deg C. It, as 3ith the other $@carbon analogues of the "9?s and "9<"s, remains untasted as of the moment.

#125 )-T%ET; (-ETHY-$-METH%+Y-)-METHYTH"%AM,HETAM"#E
S>5"H<SISE A solution of $& g 0@ethylphenol in (,, m! <t$9 3as eFuipped 3ith a magnetic stirrer, and cooled to , deg C 3ith an e/ternal ice bath.
"here 3as added (1 m! ;?S9. "hen, a total of (& m! chlorosulfonic acid 3as added drop3ise, over the course of 0, min. "he reaction 3as allo3ed to
return to room temperature and stirred overnight. "he overhead <t$9 phase 3as removed by decantation, and the light@colored residue 3as dissolved
in (,, m! IPA. "he clear solution spontaneously generated 3hite crystals 3hich 3ere allo3ed to stand for ( h, removed by filtration, and lightly 3ashed
3ith IPA. After air@drying, this crop of dimethyl@'$@ethyl@+@hydro/yphenyl-@sulfonium chloride 3eighed $,., g and had a mp of (1)@(2, deg C 3ithout
obvious effervescence. A solution of (%.) g of this sulfonium salt in $,, m! H$9 3as diluted 3ith &,, m! ?e9H, and there 3as added 0, g 5a9H. "his
3as heated to reflu/ on the steam bath. "here 3as an initial deposition of some 3hite solids, but after 01 h the solution 3as almost clear. "he e/cess
?e9H 3as removed under vacuum, and the non@volatiles 3ere poured into ( ! H$9. "his 3as acidified 3ith HCl, and e/tracted 3ith 0/(,, m! CH$Cl$.
"he e/tracts 3ere pooled, and the solvent removed under vacuum. "he residue, ($.1 g of an amber oil, 3as distilled at %&@($, deg C at ,.0 mm8Hg to
give (,., g of 0@ethyl@+@'methylthio-phenol as an off@3hite oil. "his spontaneously crystalli6ed to a solid that had a mp of +2@+% deg C. :ecrystalli6ation
of an analytical sample from cyclohe/ane gave a mp of +2@+) deg C.
"o a solution of %.2 g 0@ethyl@+@'methylthio-phenol in &, m! ?e9H there 3as added a solution of +.1 g )&K 9H in &, m! hot ?e9H. "here 3as then
added &.+ m! methyl iodide and the mi/ture 3as held at reflu/ on the steam bath for () h. :emoval of the solvent under vacuum gave a residue that
3as poured into ( ! H$9 and made strongly basic by the addition of &K 5a9H. "his 3as e/tracted 3ith 0/2& m! CH$Cl$, and the e/tracts 3ere pooled
and the solvent removed under vacuum. "here remained ((., g of an almost 3hite oil 3ith a startling apple smell. "his oil 3as distilled at 2)@)) deg C at
,.0 mm8Hg to give 2.% g 0@ethyl@+@'methylthio-anisole as a 3hite oil. Anal. 'C(,H(+9S- C,H.
A mi/ture of 2.) g P9Cl0 and 1.% g 5@methylformanilide 3as heated on the steam bath for a fe3 min, until there 3as the development of a deep claret
color. "his 3as added to 2.2 g 0@ethyl@+@'methylthio-anisole and the mi/ture 3as heated on the steam bath for $ h. "his 3as poured into +,, m! H$9
and stirred overnight, 3hich produced an oily phase 3ith no signs of crystals. "he entire reaction mi/ture 3as e/tracted 3ith 0/2& m! CH$Cl$, and the
pooled e/tracts 3ashed 3ith H$9. :emoval of the solvent under vacuum gave %.$ g of a residue. "his 3as suspended in $& m! he/ane, and after ( h
standing, the overhead clear solution 3as decanted from the settled sludge. "his he/ane solution 3as stripped of solvent under vacuum, giving 2.2 g of
an oil that by "!C 3as a mi/ture of starting ether and desired aldehyde. "his 3as distilled at ,.$& mm8Hg to give three fractions, the first boiling at 2&@
(,, deg C '$.2 g- and the second at (,,@((& deg C '$.1 g-. "hese 3ere largely starting ether and aldehyde, and 3ere chemically processed belo3. A
third fraction, boiling at ($,@(+, deg C, solidified in the receiver, 3eighed (.1 g, and 3as largely the desired aldehyde. Cuts R( and R$ '&.0 g of 3hat
3as mostly recovered aldehyde- 3ere resubmitted to the Milsmeier reaction. A mi/ture of &.+ g P9Cl0 and +.2 g 5@methylformanilide 3as heated on the
steam bath until it became claret@colored. "he recovered aldehyde 3as added, and the mi/ture 3as heated overnight on the steam bath. "his 3as
poured into &,, m! H$9. "he heavy tar that 3as knocked out 3as e/tracted 3ith 0/2& m! CH$Cl$, and the solvent 3as removed from the pooled
e/tracts under vacuum. Some &.) g of residue 3as obtained, and this 3as heated to ($, deg C at ,.$ mm8Hg to remove all materials lo3er boiling than
the desired aldehyde. "he very dark pot 3as e/tracted 3ith 0/&, m! boiling he/ane, and removal of the solvent from these pooled e/tracts under
vacuum gave ,.% g of a yello3 oil. "his 3as distilled at ,.$ mm8Hg to give a fraction boiling at (0,@(+, deg C 3hich spontaneously crystalli6ed. "his
pressed on a porous plate gave almost 3hite crystals 3ith a mp of &&@&2 deg C. :ecrystalli6ation from ,.0 m! cyclohe/ane provided ,.0 g of +@ethyl@$@
metho/y@&@'methylthio-ben6aldehyde 3ith a mp of &2@&) deg C. "he total yield 3as (.% g. Anal. 'C((H(+9$S- C,H.
"o a solution of (.$ g +@ethyl@$@metho/y@&@'methylthio-ben6aldehyde in $& m! nitroethane there 3as added ,.$& g anhydrous ammonium acetate and
the mi/ture 3as heated on the steam bath. "he initial color 3as green, but this Fuickly changed to the more usual yello3 3hich darkened as the reaction
mi/ture 3as heated. After (.& h heating, the e/cess solvent8reagent 3as removed in vacuo. "he yello3 residue 3as dissolved in (, m! hot ?e9H and
allo3ed to stand in the refrigerator overnight. "here 3as an orange oil layer formed underneath the ?e9H. A small sample of this 3as scratched
e/ternally 3ith dry ice, and seed 3as obtained. "he orange oil layer slo3ly set to crystals 3hich, after a fe3 h, 3ere removed by filtration to give (.0 g of
a slightly sticky orange solid 3ith a mp of +0@+& deg C. "his 3as recrystalli6ed from ) m! boiling ?e9H to give, after cooling, filtering, and air drying to
constant 3eight, (.( g of (@'+@ethyl@$@metho/y@&@methylthiophenyl-@$@nitropropene as electrostatic yello3 crystals melting at &%@1, deg C. Anal.
'C(0H(2590S- C,H.
A solution of (., g !AH in $& m! tetrahydrofuran 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added ,.1 m!
(,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of (.( g of (@'+@ethyl@$@metho/y@&@methylthio-@$@nitropropene in a small
amount of "HB. After (, min further stirring, it 3as brought up to room temperature and allo3ed to stand for several days. "he e/cess hydride 3as
destroyed by the cautious addition of IPA follo3ed by sufficient (&K 5a9H to give a 3hite granular character to the aluminum o/ide, and to assure that
the reaction mi/ture 3as basic. "his 3as filtered, and the filter cake 3ashed first 3ith "HB and then 3ith IPA. "he filtrate and 3ashings 3ere pooled and
stripped of solvent under vacuum providing a pale amber residue. "his 3as dissolved in &, m! of dilute H$S9+ and 3ashed 3ith $/&, m! CH$Cl$. "he
aFueous phase 3as made basic 3ith &K 5a9H, and e/tracted 3it $/&, m! CH$Cl$. "hese e/tracts 3ere pooled, stripped under vacuum, and distilled
at ,.(& mm8Hg. "he fraction 3ith a bp of (,$@($) deg C 3eighed ,.+ g and 3as a colorless liFuid. "his 3as dissolved in a small amount of IPA,
neutrali6ed 3ith concentrated HCl and diluted 3ith anhydrous <t$9 to provide the +@ethyl@$@metho/y@&@methylthioamphetamine hydrochloride '&@"9<"-
3hich 3eighed ,.1 g and melted at (+1@(+2 deg C. Anal. 'C(0H$$Cl59S- C,H.
;9SAC<E ($ @ $& mg.
;4:A"I95E ) @ $+ h.
L4A!I"A"IM< C9??<5"SE '3ith ) mg- After my totally freaky e/perience on the very closely related compound in this series, &@"9?, I intended to
approach this 3ith some caution. "hree milligrams 3as 3ithout effects, so I tried eight milligrams. I 3as a little light@headed, and sa3 sort of a
brightness around trees against the blue sky. 5oticed movement on couch in living room, and there 3as some activity in the curtains, almost $C@. like.
In the evening 3riting 3as still difficult, and there 3as eye dilation but minimal nystagmus. ?y sleep 3as fitful, but certainly there 3as no hint of the &@
"9? storm. '3ith () mg- "his 3as too much. "here 3as an e/hausting visual hallucinatory tinsel, continuous movement, and there 3as no escape. It
popped into an !S;@like thing, strong, restless, constantly changing, 3ith too much input. I had to take a ?ilto3n to calm do3n enough for an attempt at
sleep. In the morning, a day later, I 3as still (.& * and tired of it. It 3as the ne/t day after that before I 3as completely clear.
'3ith $, mg- "his has the makings of a superb, e/traordinary material. I didn7t get to a full plus t3o, maybe something around a plus one and three
Fuarters. "he eyes@closed fantasy 3as e/ceptional, 3ith ne3 dimensions. "he nature of the fantasy, the feeling that one had about the fantasy figures
and landscapes, 3as the essence of Goy, beauty, lovingness, serenity. A glimpse of 3hat true heaven is supposed to feel like. 9r maybe a button in the
brain 3as pushed 3hich has not been pushed by previous chemicals. InsightH ;on7t kno3 yet. I 3as able to function 3ithout difficulty 3ith eyes closed
or open. <rotic absolutely e/Fuisite. In fact, the entire e/perience 3as e/Fuisite. 5e/t day, same sense of serene, Fuiet Goy8beauty persisted for most
of the day. A true healing potential. 9n3ards and up3ards. "his one could be e/traordinary.
'3ith 0, mg- "ried to focus on cosmic Fuestions, and succeeded. Mery little fantasy images for the first $@0 hours. After that, lovely interacting, music
okay but not vital. 9n this compound the .rahms Concerto R( gave vivid 7memory7 impressions of house and vegetable garden, like a primitive painting.
"remendous nostalgia for a place I7ve never seen.
<="<5SI95S A5; C9??<5"A:>E Iith the e/traordinary e/perience that had been observed 3ith one person 3ith &@"9?, this ethyl homologue 3as
not only run up 3ith special caution, but that individual ran his o3n personal titration. And he proved to be perhaps t3ice as sensitive to &@"9<" than
any of the other subGects. An approach to 3hat might Gust be some unusual metabolic idiosyncrasy on the part of his liver, is discussed in the recipe for
"9?S9.
"he initials of "9<" progressed Fuite logically from "9?, in an e/act parallel 3ith the relationship bet3een the corresponding sulfur@free analogues,
3here the ethyl compound is ;9<" and the methyl counterpart is ;9?. N"N for NthioN 3hich is the chemical nomenclature term for the replacement of
an o/ygen atom 3ith a sulfur atom. And, as has been discussed in the te/t of this volume, the peculiarities of pronunciation in this series are interesting,
to say the least. "9? is no problem. .ut "9<" could have any of several pronunciations such as N"3o@itN, or N"o3@itN, or N"oo@3etN, but someho3 the
one syllable term N"3atN became regularly used, and the family 3as generally referred to as the N"oms and "3ats.N "he almost@obscene meaning of the
latter 3as progressively forgotten 3ith usage, and has led to some raised eyebro3s at occasional seminars 3hen these compounds are discussed. And
not only at seminars. 9nce at the bet3een@acts intermission at the .erkeley :epertory "heater, the topic came up and the phrase 3as used. "here 3as
a stunned silence about us 3ithin the circle of hearing, and 3e seemed to have been given a little e/tra room immediately thereafter.
As 3ith the other members of the "9?7s and "9<"7s, the phenethylamine homologue of &@"9<" 3as synthesi6ed, but had never been started in human
evaluation. "he aldehyde from above, +@ethyl@$@metho/y@&@'methylthio-ben6aldehyde, 3as condensed 3ith nitroethane 'as reagent and as solvent- and
3ith ammonium acetate as catalyst to give the nitrostyrene as spectacular canary@yello3 electrostatic crystals 3ith a mp of %(@%$ deg C. Anal.
'C($H(&590S- C,H. "his 3as reduced 3ith aluminum hydride 'from cold "HB@dissolved lithium aluminum hydride and (,,K sulfuric acid- to the
phenethylamine +@ethyl@$@metho/y@&@methylthiophenethylamine '$C@&@"9<"- 3hich, 3hen totally freed from 3ater of hydration by drying at (,, deg C
under a hard vacuum, had a mp of $(1@$(2 deg C. Anal. 'C($H$,Cl59S- C,H.

#121 $-T%M; )-METH%+Y-(-METHY-$-METHYTH"%AM,HETAM"#E
S>5"H<SISE "o a solution of 1+.) g of o@cresol and &1 g dimethyl sulfo/ide in 0,, m! <t$9, cooled 3ith an e/ternal ice bath 3ith vigorous stirring, there
3as added +, m! chlorosulfonic acid drop3ise over the course of 0, min. "he cooling bath 3as removed, and the t3o phase mi/ture 3as mechanically
stirred at room temperature for ($ h. "he <t$9 phase 3as then discarded, and the deep red residue that remained 3as thoroughly triturated under 0,,
m! IPA, producing a suspension of pale pink solids. "hese 3ere removed by filtration, 3ashed 3ith an additional (&, m! IPA, and allo3ed to air dry.
"he yield of dimethyl '+@hydro/y@0@methylphenyl-sulfonium chloride 3as 0(.1 g and, upon recrystalli6ation from aFueous acetone, had a mp of (&&@(&1
deg C, 3ith effervescence. Anal. 'C%H(0Cl9S- C,H,S. "his analysis established the anion of this salt as the chloride, 3hereas the literature had
claimed, 3ithout evidence, that it 3as the bisulfate. "he thermal pyrolysis of 0(., g of dimethyl '+@hydro/y@0@methylphenyl-sulfonium chloride resulted
first in the formation of a melt, follo3ed by the vigorous evolution of methyl chloride. "he open flame 3as maintained on the flask until there 3as no
more gas evolution. "his 3as then cooled, dissolved in $,, m! CH$Cl$, and e/tracted 3ith 0/(,, m! of &K 5a9H. "he aFueous e/tracts 3ere pooled,
acidified 3ith concentrated HCl, and e/tracted 3ith 0/2& m! CH$Cl$. "he solvent 3as removed under vacuum, and the residue distilled at (,,@((, deg
C at ,.& mm8Hg yielding $$., g of $@methyl@+@'methylthio-phenol as a 3hite crystalline solid 3ith a mp 01@02 deg C.
"o a solution of $&.& g $@methyl@+@'methylthio-phenol in (,, m! ?e9H there 3as added a solution of ($ g )&K 9H in 1, m! hot ?e9H, follo3ed by
the addition of ($.+ m! methyl iodide. "he mi/ture 3as held at reflu/ for (1 h. "he solvent 3as removed under vacuum, and the residue added to +,,
m! H$9. "his 3as made basic 3ith $&K 5a9H and e/tracted 3ith 0/(,, m! CH$Cl$. "he e/tracts 3ere pooled, the solvent removed under vacuum
giving $).0 g of a light, amber oil as residue. "his 3as distilled at 2$@), deg C at ,.& mm8Hg to provide $@methyl@+@'methylthio-anisole as a pale yello3
oil. Anal. 'C%H($9S- C,H. "he same product can be made 3ith the sulfonyl chloride and the thiol as intermediates. "o 01.1 g $@methylanisole there
3as added, 3ith continuous stirring, a total of 0) m! chlorosulfonic acid at a modest rate. "he e/othermic reaction 3ent through a complete spectrum of
colors ending up, 3hen the evolution of HCl had finally ceased, as deep amber. Ihen it had returned again to room temperature, the reaction mi/ture
3as poured over a liter of cracked ice 3hich, on mechanical stirring, produced a mass of 3hite crystals. "hese 3ere removed by filtration, 3ashed 3ith
H$9, and sucked as dry as possible. "he 3et 3eight yield 3as over +, g and the mp 3as about +% deg C. :ecrystalli6ation of an analytical sample of +@
metho/y@0@methylben6enesulfonyl chloride from cyclohe/ane gave 3hite crystals 3ith a mp of &(@&$ deg C. A small sample of this acid chloride brought
into reaction 3ith ammonium hydro/ide produced the sulfonamide 3hich, after recrystalli6ation from <t9Ac, melted at (0&@(01 deg C. "o a slurry of 0,,
m! cracked ice and 2& m! concentrated H$S9+ in a round@bottomed flask eFuipped 3ith a reflu/ condenser, there 3as added +0 g of the slightly 3et +@
metho/y@0@methylben6enesulfonyl chloride follo3ed by 2& g elemental 6inc dust. "he temperature 3as raised to a reflu/ 3hich 3as maintained for $ h.
"he reaction mi/ture 3as cooled and filtered, 3ith the finely ground filter cake being 3ashed alternately 3ith H$9 and 3ith CH$Cl$. "he combined
mother liFuor and 3ashings 3ere diluted 3ith ( ! H$9, the phases separated, and the aFueous phase e/tracted 3ith (,, m! CH$Cl$ 3hich 3as added
to the organic phase. "his 3as 3ashed 3ith (,, m! H$9, and the solvent removed under vacuum. "he residue 3as a pale amber oil 3eighing $2.0 g
and it slo3ly set up to a crystalline mass that smelled of banana oil. A portion of this, pressed on a porous plate, gave a 3a/y solid 3ith a mp of 0%@+0
deg C 3hich, on recrystalli6ation from ?e9H, gave +@metho/y@0@'methyl-thiophenol 3ith a mp of +&@+1 deg C. Anal. 'C)H(,9S- C,H. A solution of $+ g
of the crude thiol in (,, m! ?e9H 3as treated 3ith a solution of (2 g 9H )&K pellets in (,, m! hot ?e9H, and to this there 3as added (1 m! of
methyl iodide. "his 3as held at reflu/ on the steam bath for (.& h, then stripped of solvent under vacuum, added to ( ! H$9, and made strongly basic
3ith $&K 5a9H. </traction 3ith 0/(,, m! CH$Cl$, pooling of the e/tracts, and removal of the solvent, gave an amber oil 3eighing $$.1 g. "his 3as
distilled at 2,@), deg C at ,.2 mm8Hg to give (1.0 g of $@methyl@+@'methylthio-anisole as a 3hite oil, identical in all respects to the product that came
from the sulfonium salt pyrolysis above.
A solution of $$.( g $@methyl@+@'methylthio-anisole and (2.& g dichloromethyl methyl ether in 1,, m! CH$Cl$ 3as vigorously stirred, and treated 3ith
$+.& g anhydrous aluminum chloride added portion@3ise over the course of ( min. Stirring 3as continued for $, min 3hile the color developed to a dark
red. "here 3as added &,, m! H$9 3ith caution, and stirring 3as continued until the initial yello3 solids redissolved and there 3ere t3o distinct phases
formed. "hese 3ere separated, and the aFueous phase 3as e/tracted 3ith 0/(,, m! CH$Cl$. "he original organic phase and the pooled e/tracts 3ere
combined and 3ashed 3ith &K 5a9H. "he organic solvent 3as removed under vacuum. "he residue 3as distilled, giving t3o maGor fractions. A forerun
')&@%& deg C at ,.& mm8Hg- proved to be largely starting ether. "he maGor fraction ').+ g, boiling at %&@($, deg C- consisted of t3o materials, both
ben6aldehydes. Crystalli6ation of this fraction from 0, m! cyclohe/ane provided, after filtering, 3ashing and air drying, $.% g of &@metho/y@+@methyl@$@
'methylthio-ben6aldehyde as a pale yello3 crystalline solid 3ith a mp of 1%@2, deg C. Anal. 'C(,H($9$S- C,H. "he mother liFuor from this
crystalli6ation contained a slo3er@moving component, $@metho/y@0@methyl@&@'methylthio-ben6aldehyde, 3hich 3as best separated by preparative gas
chromatography. "he proof of the structure of the maGor aldehyde above 3as obtained by its reductive conversion to $,&@dimethyl@+@'methylthio-anisole
3ith amalgamated 6inc and HCl. "he details are given in the recipe for &@"9?.
"o + m! glacial acetic acid there 3as added (., g &@metho/y@+@methyl@$@'methylthio-ben6aldehyde, ,.0& g anhydrous ammonium acetate, and ,.) g
nitroethane, and the mi/ture 3as heated on the steam bath for + h. Another ,.& g of nitroethane 3as added, and the heating continued for an additional
+ h. Standing at room temperature overnight allo3ed the deposition of spectacular orange crystals 3hich 3ere removed by filtration, 3ashed lightly 3ith
acetic acid, and air dried. "his product melted at )$@)0 deg C. :ecrystalli6ation from (, m! boiling ?e9H gave ,.2 g of (@'&@metho/y@+@methyl@$@
methylthiophenyl-@$@nitropropene 3ith a mp of )0@)+ deg C. Anal. 'C($H(&590S- C,H. "he alternate method for the formation of nitrostyrenes, the
reaction of the ben6aldehyde in nitroethane as both reagent and solvent, 3ith ammonium acetate as a catalyst, gave a gummy product that could be
purified only 3ith severe losses. "he overall yield 3ith this latter method 3as $+K of theory.
A solution of (.& g !AH in 2& m! "HB 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (., m! (,,K
H$S9+ drop@3ise, to minimi6e charring. "his 3as follo3ed by the addition of 0., g (@'&@metho/y@+@methyl@$@methylthiophenyl-@$@nitropropene in $, m!
anhydrous "HB. After a fe3 min further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath, and then all 3as cooled again to ,
deg C. "he e/cess hydride 3as destroyed by the cautious addition of IPA follo3ed by sufficient &K 5a9H to give a 3hite granular character to the
o/ides, and to assure that the reaction mi/ture 3as basic. "he reaction mi/ture 3as filtered, and the filter cake 3ashed first 3ith "HB and then 3ith IPA.
"he filtrate 3as stripped of solvent under vacuum providing a light yello3 oil. "his 3as dissolved in (,, m! dilute H$S9+ and then 3ashed 3ith $/&, m!
CH$Cl$. "he aFueous phase 3as made basic 3ith &K 5a9H and e/tracted 3ith $/&, m! CH$Cl$. "hese 3ere pooled, the solvent removed under
vacuum, and the residue distilled at (,&@(0, deg C at ,.$& mm8Hg to give (.1 g of a 3hite oil. "his 3as dissolved in ) m! IPA, neutrali6ed 3ith $+ drops
of concentrated HCl 3hich formed crystals spontaneously. Another $, m! of hot IPA 3as added to effect complete solution, and then this 3as diluted
3ith anhydrous <t$9. 9n cooling fine 3hite crystals of &@metho/y@+@methyl@$@methylthioamphetamine hydrochloride '$@"9?- separated. "hese
3eighed (.&& g and had a mp of (%&@(%1 deg C. Anal. 'C($H$,Cl59S- C,H.
;9SAC<E 1, @ (,, mg.
;4:A"I95E ) @ (, h.
L4A!I"A"IM< C9??<5"SE '3ith 1, mg- "here is a superb body feeling, and food tasted e/cellent but then it Gust might have been e/cellent food. .y
the tenth hour, there 3ere absolutely no residues, and I had the feeling that there 3as no price to pay. Menture up a bit 3ith confidence.
'3ith ), mg- Bor me this 3as e/cellent, in a do3n@to@earth, humorous, matter@of@fact universe@perspective sense. Mery pleasant feeling, although there
3as a strong body a3areness belo3 the 3aist 'not the erotic thing, but rather a slight heaviness, and the ne/t day I came do3n 3ith a C.I. cold-. Mery
good feeling, and I sense that the depth of the e/perience is 3ay out there 3here the big Fuestions lie. I found it easy to go out of body 'in the good
sense- into a 3arm, loving darkness. Sliding do3n by 1, 2th hour, and had no trouble sleeping. Bully scripted dreams, vivid. Mery, very good. Iant to
try (,, mg.
'3ith ), mg- Completely foul taste. "he effects 3ere Fuite subtle, and I found this to be a strange but friendly **. "here 3as much eyes@closed
fantasi6ing to music, even to .ruchner, 3hom I found une/pectedly pleasant. "here 3as a feeling of tenseness at the t3ilight of the e/perience.
<="<5SI95S A5; C9??<5"A:>E "here is a most e/traordinary loss of potency 3ith the simple substitution of a sulfur atom for an o/ygen atom.
;9? is fully active at the & or so milligram area, 3hereas $@"9? is active at maybe the ), milligram area, a loss of potency by a factor of /(& or so.
And the duration is Fuite a bit shorter. It might take a fair amount of learning to become completely at peace 3ith it, but it might be 3orth the effort. And
there are none of the disturbing hints of neurological and physical roughness of &@"9?.
Again, as 3ith the other "9?7s and "9<"7s, the t3o@carbon homologue of this has been synthesi6ed but not yet evaluated. "he common intermediate
ben6aldehyde, &@metho/y@+@methyl@$@'methylthio-ben6aldehyde 3as condensed 3ith nitromethane and ammonium acetate to give the nitrostyrene
3hich, upon re@crystalli6ation from ethanol, had a melting point of (()@(().& deg C. Anal. 'C((H(0590S- C,H. :eduction 3ith aluminum hydride in "HB
gave the crystalline free base 3hich, as the hydrochloride salt, melted at $00@$0+ deg C. Anal. 'C((H()Cl59S- C,H. Luite logically, it has been called
$C@$@"9?.

#12$ )-T%M; $-METH%+Y-(-METHY-)-METHYTH"%AM,HETAM"#E
S>5"H<SISE "o a solution of 1.1 g 9H pellets in (,, m! hot <t9H there 3as added a solution of (&.+ g methylthio@m@cresol '0@methyl@+@
'methylthio-phenol, Cro3n@Aellerbach Corporation- in $& m! <t9H. "his 3as follo3ed by the addition of (2 g methyl iodide, and the mi/ture 3as held at
reflu/ on the steam bath for (1 h. "he reaction mi/ture 3as poured into +,, m! H$9, acidified 3ith HCl, and e/tracted 3ith +/&, m! CH$Cl$. "hese
3ere pooled, 3ashed 3ith 0/&, m! &K 5a9H, once 3ith dilute HCl, and then the solvent 3as removed under vacuum. "he residue 3as 0@methyl@+@
'methylthio-anisole, a clear pale yello3 oil, 3eighing ($.2 g. ;istillation at (&,@(1, deg C at (.2 mm8Hg, or at ),@%, deg C at ,.$& mm8Hg, did not
remove the color, and gave a product 3ith no improvement in purity.
"o a mi/ture of )$ g P9Cl0 and 2$ g 5@methylformanilide that had been heated on the steam bath for (, min, there 3as added 00.1 g 0@methyl@+@
'methylthio-phenol, and heating 3as continued for an additional $ h. "his 3as poured into (.$ ! H$9, producing a bro3n gummy crystalline mass that
slo3ly loosened on continued stirring. "his 3as filtered off, 3ashed 3ith additional H$9, and sucked as dry as possible. "his 3as finely ground under 1,
m! of cold ?e9H, refiltered, and air dried to give (2.) g of a nearly 3hite crystalline solid 3ith a mp of %+@%1 deg C. :ecrystalli6ation from &, m! boiling
?e9H gave a product of higher purity, but at some cost in yield. Iith this step there 3as obtained (0.+ g of $@metho/y@+@methyl@&@
'methylthio-ben6aldehyde 3ith a mp of %)@%% deg C.
An additional recrystalli6ation from IPA increased this mp by another degree. Brom this final recrystalli6ation, a small amount of material 3as left as an
insoluble residue. It 3as also insoluble in acetone, but dissolved readily in CH$Cl$. It melted broadly at about $,, deg C and 3as not identified. Proof
of the structure of $@metho/y@+@methyl@&@'methylthio-ben6aldehyde 3as obtained by its successful reduction '3ith amalgamated An in HCl- to $,&@
dimethyl@+@'methylthio-anisole. "his reference convergence compound 3as prepared separately from $,&@dimethylanisole 3hich reacted 3ith
chlorosulfonic acid to give the +@sulfonyl chloride derivative, 3hich 3as in turn reduced to the +@mercapto derivative '3hite crystals from ?e9H, 3ith a
mp of 0) deg C sharp-. "his, upon methylation 3ith methyl iodide and 9H in ?e9H, gave $,&@dimetho/y@+@'methylthio-anisole '3hite crystals from
?e9H, 3ith a mp of 12@1) deg C-. "he t3o samples 'one from the aldehyde reduction, and the other from this independent synthesis-, 3ere identical in
all respects.
A solution of (.% g $@metho/y@+@methyl@&@'methylthio-ben6aldehyde in +, m! nitroethane 3as treated 3ith ,.& g anhydrous ammonium acetate and
heated under reflu/, 3ith stirring, 3ith a heating mantle for 0.& h, at 3hich time "!C analysis sho3ed no unreacted aldehyde and only a trace of slo3
moving materials. :emoval of the e/cess nitroethane under vacuum gave a yello3 plastic film 'the 3rapping of the magnetic stirrer had dissolved off-
3hich 3as e/tracted first 3ith 0& m! boiling ?e9H, then 3ith $/0& m! boiling IPA. Separately, the ?e9H e/tract and the combined IPA e/tracts, on
cooling, deposited ,.1 g each of fluffy needles. "he mother liFuors 3ere combined and allo3ed to evaporate to about (& m! final volume, providing
another ,.+ g crude product. All three samples melted at (,(@(,$ deg C. "hese 3ere combined, and recrystalli6ed from &, m! boiling ?e9H to
provide, after filtering and air drying, (.+ g of (@'$@metho/y@+@methyl@&@methyl@thiophenyl-@$@nitropropene as bright yello3 crystals 3ith a mp of (,$@(,$.&
deg C. Anal. 'C($H(&590S- C,H.
A solution of $., g !AH in (,, m! anhydrous "HB 3as cooled, under He, to , deg C 3ith an e/ternal ice bath. Iith good stirring there 3as added (.$)
m! (,,K H$S9+ drop3ise, to minimi6e charring. "his 3as follo3ed by the addition of (.0& g (@'$@metho/y@+@methyl@&@methylthiophenyl-@$@nitropropene
in &, m! anhydrous "HB over the course of & min. After a fe3 min further stirring, the temperature 3as brought up to a gentle reflu/ on the steam bath,
and then all 3as cooled again to , deg C. "he e/cess hydride 3as destroyed by the cautious addition of & m! IPA follo3ed by sufficient &K 5a9H to
give a 3hite granular character to the o/ides, and to assure that the reaction mi/ture 3as basic 'about & m! 3as used-. "he reaction mi/ture 3as
filtered, and the filter cake 3ashed first 3ith "HB and then 3ith IPA. "he combined filtrate and 3ashings 3ere stripped of solvent under vacuum and the
residue dissolved in (&, m! dilute H$S9+. "his 3as 3ashed 3ith 0/&, m! CH$Cl$ 'the color stayed in the organic layer-, made basic 3ith aFueous
5a9H, and e/tracted 3ith $/&, m! CH$Cl$. After the solvent 3as removed under vacuum, the residue 3as distilled at ((,@($& deg C at ,.+ mm8Hg to
give ,.% g of a colorless oil. "his 3as dissolved in + m! IPA, neutrali6ed 3ith about (( drops of concentrated HCl, and then diluted 3ith $, m!
anhydrous <t$9. After about a ten second delay, 3hite crystals formed. "hese 3ere removed by filtration and air dried, to give ,.1 g of $@metho/y@+@
methyl@&@methylthioamphetamine hydrochloride '&@"9?- as 3hite crystals 3ith a mp of (&1@(&2 deg C. A second crop obtained from the mother liFuors
on standing 3eighed ,.0 g and melted at (&,@(&1 deg C. Anal. 'C($H$,Cl59S- C,H.
;9SAC<E 0, @ &, mg.
;4:A"I95E 1 @ (, h.
L4A!I"A"IM< C9??<5"SE '3ith 0& mg- "here 3as an a3ful lot of visual activity, and in general I found the day Fuite good, once I got past the early
discomfort.
'3ith +, mg- I kne3 that I 3as sinking into a deep reverie after an hour into it. I 3as not totally unconscious since I seemed to respond to e/ternal stimuli
'at least most of the time-. .ut I certainly 3asn7t all that much there. "he e/per@ience dominated completely. At one point 'perhaps the peakH- I
remember seeing a very Fuiet sea 3ith a hori6ontal shoreline and a clear sky. "his image seemed to come back rather freFuently. At other times I
3ould see a set of disGointed hori6ontal lines on this beach. "hese lines reminded me of spectral lines. Bor a short period of time I thought they 3ere
some kind of e/pression of my energy levels that I didn7t understand. In retrospect, I suspect the hori6ontal lines 3ere only e/pressions of ho3 my mind
3as reacting to the material. I don7t remember talking to anyone until I had started to come do3n from the e/perience. I eventually could see real
images, but they 3ere greatly distorted. It 3as as if I 3as looking at Cubism paintings by Picasso, having intense and strange colorations. As I came
back into the real 3orld, I reali6ed that I had had an e/traordinary trip. I had not been afraid at any time. "he e/perience seemed uniFue, but Fuite
benign. "he e/perience for my fello3 travelers 3as probably much more an/ious. I 3asn7t particularly interested in food 3hen I came do3n. I slept
3ell. I 3as Fuite lethargic the ne/t day. It really took me another day to integrate back into normal life. Iould I repeat itH Possibly, but at a 3ay smaller
dose.
'3ith &, mg- "he body 3as complete 3hacked, and the mental simply didn7t keep up 3ith it. "here 3as some early nausea going into it, and my sinuses
never cleared, and I someho3 became irritable and angry. In fact, the impatience and grimness lasted for a couple of days. "here 3ere some visual
events that might have been interesting to e/plore, but too much other stuff got in the 3ay.
'3ith &, mg- "here 3as much eyes@closed fantasy, and Fuite a bit of it 3ith erotic undertones. In efforts to direct my actions, I found it difficult to find the
point of initiation of a task. :eading and 3riting both impossible. I am someho3 de@focused. .ut art 3ork became Fuite re3arding. "he e/perience
3as heavy going in, but rich coming out. Cood dosage.
<="<5SI95S A5; C9??<5"A:>E "he bottom line is that &@"9? is a pretty heavy@duty e/perience, 3ith more negative reports than positive ones. I
have received no mentions of a completely ecstatic time, and not even very many neutral e/periences. "he consensus is that it 3asn7t 3orth the
struggle. Some cramping, some nausea, and a generali6ed discomfort. And that one case of a catatonic response. An approach to possible individual
variation in the metabolic handling of the sulfur atom is the rationale for the preparation of the compound "9?S9, and it is discussed there.
"he t3o@carbon homologue of &@"9? has been prepared. It uses, of course, the same aldehyde, but the condensation 3as 3ith nitromethane 3hich
yielded the nitrostyrene as an orange po3der 3ith a melting point of (()@((% deg C from methanol. "his 3as reduced 3ith !AH in ether containing
anhydrous AlCl0, giving $@metho/y@+@methyl@&@methylthiophenethylamine hydrochloride as 3hite crystals 3ith a melting point of $&2@$&) deg C. It has
been named $C@&@"9?, but it has not yet been entered into the screening program so it is pharmacologically still a mystery.

#12' T%MS%; $-METH%+Y-(-METHY-)-METHYS/7"#YAM,HETAM"#E
S>5"H<SISE A suspension of ($.2 g (@'$@metho/y@+@methyl@&@methylthiophenyl-@$@nitropropene 'see under &@"9? for its preparation- in &, m! 3arm
acetic acid 3as added to a suspension of $$.& g electrolytic grade elemental iron in (,, m! 3arm acetic acid. "he temperature 3as raised cautiously
until an e/othermic reaction set in, and the mi/ture 3as maintained under reflu/ conditions as the color progressed from yello3 to deep bro3n to
eventually colorless. After coming back to room temperature, the some3hat gummy mi/ture 3as poured into ( ! H$9, and all insolubles 3ere removed
by filtration. "hese 3ere 3ashed 3ith CH$Cl$, and the aFueous filtrate 3as e/tracted 3ith 0/(,, m! CH$Cl$. "he 3ashes and e/tracts 3ere
combined, 3ashed 3ith &K 5a9H until the bulk of the color 3as removed and the 3ashes remained basic, and the solvent 3as then removed under
vacuum. "he residue, ((.1 g of a pale amber oil that crystalli6ed, 3as distilled at ((,@($, deg C at ,.+ mm8Hg to give %.% g $@metho/y@+@methyl@&@
methylthiophenylacetone 3ith a mp of +(@+$ deg C. "his 3as not im@proved by recrystalli6ation from he/ane. Anal. 'C($H(19$S- C,H.
"o a solution of 2.0 g $@metho/y@+@methyl@&@methylthiophenylacetone in 0& m! methanol there 3as added 2.0 m! 0&K hydrogen pero/ide, and the
mi/ture held under reflu/ conditions for +, min. All volatiles 3ere removed under vacuum, and the residue suspended in $&, m! H$9. "his 3as
e/tracted 3ith 0/&, m! CH$Cl$, the e/tracts pooled, and the solvent removed under vacuum. "he residue, ).1 g of an oily solid, 3as recrystalli6ed from
(, m! boiling toluene to provide, after filtering and air drying, &.+ g of $@metho/y@+@methyl@&@methylsulfinylphenylacetone as a 3hite solid 3ith a mp of
)%@)%.& deg C. Anal. 'C($H(190S- C,H.
"o a vigorously stirred solution of &.$ g of $@metho/y@+@methyl@&@methylsulfinylphenylacetone in 2, m! ?e9H there 3as added (2 g anhydrous
ammonium acetate follo3ed by (., g sodium cyanoborohydride. HCl 3as added as needed to maintain the pH at about 1 as determined 3ith damp
universal pH paper. 5o further base 3as generated after 0 days, and the reaction mi/ture 3as poured into &,, m! H$9. After acidification 3ith HCl
'caution, highly poisonous HC5 is evolved-, this 3as 3ashed 3ith $/(,, m! CH$Cl$, made strongly basic 3ith 5a9H, and then e/tracted 3ith 0/(,,
m! CH$Cl$. "he pooled e/tracts 3ere stripped of solvent under vacuum, and the residue 3eighed 2.( g and 3as a pale amber oil. "his 3as distilled at
(&,@(1, deg C at ,.0 mm8Hg to give a colorless oil 3eighing +.+ g. A solution of this in (0 m! IPA 3as neutrali6ed 3ith 0, drops of concentrated HCl
and the resulting solution 3armed and diluted 3ith $, m! of 3arm anhydrous <t$9. Ihite crystals separated immediately and, after filtering, ether
3ashing and air drying, provided +.+ g of $@metho/y@+@methyl@&@methylsulfinylamphetamine hydrochloride '"9?S9- that melted at $$2@$$% deg C after
vacuum drying for $+ hrs. Anal. 'C($H$,Cl59$S- C,H. "he presence of t3o chiral centers 'the alpha@carbon of the amphetamine side chain and the
sulfo/ide group at the &@position of the ring- dictates that this product 3as a mi/ture of diastereoisomeric racemic compounds. 5o effort 3as made to
separate them.
;9SAC<E greater than (&, mg 'alone- or (,, @ (&, mg '3ith alcohol-.
;4:A"I95E (, @ (1 h.
L4A!I"A"IM< C9??<5"SE '3ith (,, mg- "here 3ere no effects at all, and it 3as at the so@called surprise pot@luck birthday lunch for the department
chairman that I ate a little and had t3o glasses of Ainfandel. I shot up to an immediate ** and this lasted all afternoon. I 3ent to San Brancisco by
.A:", and 3alked up ?arket Street and sa3 all the completely bi6arre faces. I 3as absolutely unable to estimate the age of anybody 3ho 3as female,
at least by looking at her face. All aspects, both child@like and old, seemed to be amalgamated into each face, all at the same time. "here 3as
remarkable time@slo3ing; overall the e/perience 3as favorable. "hat certainly 3as not the effect of the alcohol in the 3ine. Bood poisoningH 5o. It
must have been the "9?S9 that had been kindled and promoted to something.
'3ith (&, mg- At best there is a threshold and it is going no3here. At the third hour I drank, over the course of an hour, a tall drink containing 0 o6. of
vodka. Soon I 3as clearly some3here, and three hours later I 3as a rolling plus three. "his lasted until 3ell after midnight, and 3as not an alcohol
response.
<="<5SI95S A5; C9??<5"A:>E "his entire venture into the study of "9?S9 3as an outgro3th of the e/traordinary response that had been sho3n
by one person to &@"9?. "here 3ere t3o obvious approaches that might thro3 some light on the reason for this dramatic sensitivity. 9ne 3ould be to
see if he 3as unusually capable of metaboli6ing sulfur@containing molecules, and the second 3ould be to assume he 3as, and to try to guess Gust 3hat
product he had manu@factured 3ith his liver.
"he individual sensitivity Fuestion 3as addressed in a tidy and direct manner. Ihy not study a simple sulfur@containing model compound that 3ould
probably be metaboli6ed only at the sulfur and that 3ould itself probably be pharmacologically inactive in its o3n rightsH Sounded 9 to me, so I made
up a goodly supply of +@tert@butyl thioanisole, 3hich proved to be a gorgeous 3hite crystalline solid. It seemed Fuite logical that this 3ould be
metaboli6ed at the sulfur atom to produce either or both the sulfo/ide and the sulfone. So I treated a methanol solution of this 3ith a little hydrogen
pero/ide and distilled the neutral e/tracts at (,,@((& deg C at ,.$ mm8Hg to give the sulfo/ide as a solid that melted at 21@22 deg C from he/aneE Anal.
'C((H(19S- C,H. 9n the other hand, if a solution of the thioanisole in acetic acid containing hydrogen pero/ide 3as heated on the steam bath for a fe3
hours and then 3orked up, a ne3 solid 3as isolated that proved to be the sulfone 'a negative Bries@Mogt test-. "his 3as obtained as 3hite crystals 3ith
a mp of %+@%& deg C from aFueous methanol. Anal. 'C((H(1S9$- C,H. And I found that these three compounds separated 3ell from one another by
CC, and that they could be e/tracted from urine. <verything 3as falling into place. ?y thought 3as to determine a safe 'inactive- level of the parent
thioanisole, and determine the distri@bution of metabolites in my urine, and then in the urine of several other people, and then finally in the urine of the
person 3ho 3as the intense reactor to &@"9?. I found that there 3ere no effects, either physical or psychological, at an oral dose of 1, milligrams of +@
tert@butyl@thioanisole. .ut then everything fell apart. "here 3as not a detectable trace of anything, neither parent compound nor either of the potential
metabolites, to be found in my urine. "he material 3as obviously being completely converted to one or more metabolites, but the sulfo/ide and sulfone
3ere not among them. It 3ould be fun, someday, to methodically trace the fate of this compound.
So, on to the second approach. Ihat might the active metabolite of &@"9? actually beH "he sulfo/ide seemed completely reasonable, and that
encouraged the synthesis of "9?S9. "his name 3as given, as it is the sulfo/ide analogue 'S9- of &@"9?. And since only one of these analogues has
been made, the :&S distinction is not needed. .ut it is apparent that this approach to the finding of an e/planation for the idiosyncratic sensitivity to &@
"9? also failed, in that "9?S9 itself appeared to be 3ithout activity.
.ut the fallout of this study 3as the uncovering of an unusual property that alcohol can occasionally have 3hen it follo3s the ingestion of certain inactive
drugs. 9r if it is used at the tail end of an e/perience 3ith an active drug. 4sually some alcohol has been employed as a softener of the residual effects
of the day7s e/periment, or as a social habit to accompany the post@mortem discussions of a day7s e/periences, and perhaps as a help to sleeping. .ut if
there is a rekindling of the effect, rather than the sedation e/pected, then the verb Nto tomsoN can be used in the notes. It represents the promotion of an
inactive situation into an active one, 3ith the catalysis of alcohol. .ut the effect is not that of alcohol. ?ight the e/treme sensitivity of some alcoholics to
even a small amount of alcohol be due to some endogenous NinactiveN factor that is promoted in this 3ay into some centrally florid to/icityH I remember
seeing proposals of some tetrahydroisoFuinolines as potential mis@metabolites in efforts to e/plain the to/icity of alcohol. ?aybe they are nothing more
than psychedelics that are thought to be inactive, but 3hich might be ignited 3ith a glass of 3ine. And the person is tomsoing 3ith his small amount of
alcohol.

#12( T,; TH"%,*%S!A"#E; ',)-0"METH%+Y-(-&n--,*%,YTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution 3as made of ($.( g 5,5,57,57@tetramethylethylenediamine and (0.) g of (,0@dimetho/yben6ene in $,, m! 0,@1, deg C
petroleum ether. "his 3as stirred vigorously under a He atmosphere and cooled to , deg C 3ith an e/ternal ice bath. "here 3as added 11 m! of (.1 ?
butyllithium in he/ane 3hich produced a 3hite granular precipitate. "he reaction mi/ture 3as brought up to room temperature for a fe3 minutes, and
then cooled again to , deg C. "here 3as then added (&.) g of di@'n-@propyl disulfide 3hich changed the granular precipitate to a creamy appearance.
Stirring 3as continued 3hile the reaction mi/ture 3as brought up to room temperature and finally up to reflu/. "he reaction mi/ture 3as then added to
1,, m! of dilute H$S9+. "he t3o phases 3ere separated, and the aFueous phase e/tracted 3ith $/2& m! <t$9. "he organic phases 3ere combined,
and the solvent removed under vacuum. "he residue 3as $+.$ g of a pale amber liFuid 3hich 3as distilled at ,.0& mm8Hg to give t3o fractions. "he first
boiled at )&@%, deg C, 3eighed ,.& g and appeared to be recovered dipropyl disulfide. "he product $@'n-@propylthio@(,0@dimetho/yben6ene boiled at at
(,&@($& deg C, and 3eighed $,.) g. A small sample recrystalli6ed from he/ane had a mp of $2@$) deg C. Anal. 'C((H(19$S- C,H.
"o a stirred solution of (%.) g of $@'n-@propylthio@(,0@dimetho/yben6ene in $,, m! CH$Cl$ there 3as added (&.+ g elemental bromine dissolved in (,,
m! CH$Cl$. "he reaction 3as not e/othermic, and it 3as allo3ed to stir for ( h. "he reaction mi/ture 3as 3ashed 3ith H$9 containing sodium
hydrosulfite '3hich rendered it nearly colorless- and finally 3ashed 3ith saturated brine. "he solvent 3as removed under vacuum leaving 00.& g of a
pale yello3 liFuid. "his 3as distilled at (($@($, deg C at ,.0 mm8Hg to yield +@bromo@$@'n-@propylthio@(,0@dimetho/yben6ene as a pale yello3 oil. Anal.
'C((H(&.r9$S- C,H.
"o a solution of (1.) g diisopropylamine in (,, m! anhydrous "HB that 3as stirred under a 5$ atmosphere and cooled to @(, deg C 3ith an e/ternal
ice8?e9H bath, there 3as added in seFuence 2& m! of (.1 ? butyllithium in he/ane, 0., m! of dry CH0C5, and ).2 g of +@bromo@$@'n-@propylthio@(,0@
dimetho/yben6ene 3hich had been dissolved in $, m! "HB. "he bromo compound 3as added drop3ise over the course of & min. "he color became
deep red@bro3n. Stirring 3as maintained for a total of 0, min 3hile the reaction came to room temperature. It 3as then poured into 2&, m! dilute
H$S9+, the organic layer separated, and the aFueous phase e/tracted 3ith $/(,, m! CH$Cl$. "hese e/tracts 3ere pooled, 3ashed 3ith dilute H$S9+,
and the solvent 3as removed under vacuum yielding a residue that 3as distilled. "3o distillation cuts 3ere taken at ,.0 mm8Hg. "he first fraction boiled
at ((,@(0) deg C and 3eighed ,.2 g and 3as discarded. "he second fraction came over at (+)@(2) deg C and 3eighed 0., g. .y thin layer
chromatography this fraction 3as about ),K pure, and 3as used as such in the follo3ing reduction. A small sample 3as ground under methyl
cyclopentane yielding 3hite crystals of 0,&@dimetho/y@+@'n-@propylthiophenylacetonitrile 3ith a mp of 0&.&@02.& deg C.
A solution of !AH in "HB '(& m! of a ( ? solution- under 5$ 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise, ,.+ m! (,,K
H$S9+, follo3ed by $.2 g 0,&@dimetho/y@+@'n-@propylthiophenylacetonitrile dissolved in (, m! anhydrous "HB. "he reaction mi/ture 3as stirred at , deg
C for a fe3 min, then brought to a reflu/ for 0, min on the steam bath. After cooling back to room temperature, there 3as added IPA to destroy the
e/cess hydride and (,K 5a9H to bring the reaction to a basic pH and converted the aluminum o/ide to a loose, 3hite, filterable consistency. "his 3as
removed by filtration and 3ashed 3ith both "HB and IPA. "he filtrate and 3ashes 3ere stripped of solvent under vacuum, the residue added to ( !
dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$, made basic 3ith aFueous 5a9H, e/tracted 3ith 0/2& m! CH$Cl$, the e/tracts pooled, and the
solvent removed under vacuum. "he residue 3as distilled at (02@(&2 deg C at ,.0 mm8Hg to give (.0 g of a colorless oil. "his 3as dissolved in (, m! of
IPA, neutrali6ed 3ith $, drops of concentrated HCl and, 3ith continuous stirring, diluted 3ith &, m! anhydrous <t$9. "he product 3as removed by
filtration, 3ashed 3ith <t$9, and air dried to give (.+ g of 0,&@dimetho/y@+@'n-@propylthiophenethylamine hydrochloride '"P- as bright 3hite crystals 3ith
a mp of (1+@(1& deg C. Anal. 'C(0H$$Cl59$S- C,H.
;9SAC<E $, @ $& mg.
;4:A"I95E (, @ (& h.
L4A!I"A"IM< C9??<5"SE '3ith () mg- "here 3as very little effect until more than t3o hours, 3hen I came inside out of the cold and Gumped to an
immediate *(. It is hard to define, and I am Fuite 3illing to have it develop more, and if not, Fuite 3illing to go higher ne/t time. I got into several Fuite
technical conversations, but through it all I 3as a3are of a continuous alteration. "here 3as a drop at the seventh hour, and nothing at all 3as left at
t3elve hours.
'3ith $2 mg- ?y body feels heavy. "his is not a negative thing, but it is there. I feel a heavy pressure at the back of the neck, 3hich is probably
unresolved energy. "he nervous system seems to be someho3 vunerable. "o3ards the end of the e/perience I considered a ?ilto3n, but settled on an
aspirin, and I still couldn7t sleep for about $+ hours. "he imagery is e/tremely rich and there is Fuite a bit of eyes@open visual, but mostly eyes closed. I
think the re3ards are not 3orth the body price. Sometime again, maybe lo3erH
<="<5SI95S A5; C9??<5"A:>E "here is a high potency here, but clearly there are signs of increased to/icity as 3ell even over the ethyl
homologue, "<. "he butyl compound 'see ".- 3as the last of this series of phenethylamines and as is noted there, the physical problems lessen, but so
do the psychedelic properties. "he three@carbon amphetamine homologues are completely une/plored. "he most reasonable starting material for these
3ould be +@thiosyringaldehyde, 3ith S@alkylation and then the conventional nitroethane coupling follo3ed 3ith !AH reduction. "he most appealing target
as a potential psychedelic 3ould be the methylthio homologue '0,&@dimetho/y@+@methylthioamphetamine, 0C@"?- or, as a potential euphoriant, the
butylthio homologue '0,&@dimetho/y@+@'n-@butylthioamphetamine, 0C@".-. I am not sure that these alkylthio analogues 3ould Gustify the labor needed to
make them.

#12) T*"S; T*ES!A"#E; T*"SES!A"#E; ',(,)-T*"ETH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of (1.% g of ethyl 0,+,&@trietho/yben6oate in $& m! "HB 3as added to a 3ell stirred suspension of ) g !AH in (&, m! "HB. "he
mi/ture 3as heated at reflu/ for $+ h and and, after cooling, treated 3ith IPA to destroy the e/cess hydride. "here 3as then added sufficient $&K 5a9H
to produce a granular, 3hite form of the aluminum o/ide. "his 3as removed by filtration, the filter cake 3ashed 3ith IPA, and the filtrate and 3ashes
3ere combined and stripped of solvent under vacuum. "he residue 3eighed ($.$ g and 3as distilled at ($,@(+, deg C at ,.+ mm8Hg to yield ).1 g of
0,+,&@trietho/yben6yl alcohol that spontaneously crystalli6ed. It had a mp of $%@0, deg C and 3as free of the parent ester carbonyl absorp@tion at (2,%
cm@( in the infra@red.
"his product 0,+,&@trietho/yben6yl alcohol 3as suspended in 0, m! con@centrated HCl, heated briefly on the steam bath, cooled to room temperature,
and suspended in a mi/ture of 2& m! CH$Cl$ and 2& m! H$9. "he phases 3ere separated, and the aFueous phase e/tracted 3ith another 2& m!
CH$Cl$. "he organic fractions 3ere combined, 3ashed first 3ith H$9 and then 3ith saturated brine. :emoval of the solvent under vacuum yielded an
off@3hite oil that 3as distilled at (($@($& deg C at ,.+ mm8Hg to provide 2.& g of 0,+,&@trietho/yben6yl chloride that spontaneously crystalli6ed. "he
crude product had a mp of 0+@02 deg C 3hich 3as increased to 02.&@0).& deg C upon recrystalli6ation from he/ane. Anal. 'C(0H(%Cl90- C,H.
A solution of +.& g 0,+,&@trietho/yben6yl chloride in (, m! ;?B 3as treated 3ith &., g sodium cyanide and heated for ( h on the steam bath. "he
mi/ture 3as then poured into (,, m! H$9 and the oily phase that resulted immediately crystalli6ed. "his 3as filtered off, 3ashed 3ell 3ith H$9, air
dried, and distilled at ($)@(+, deg C at ,.$& mm8Hg to yield 0.2 g of 0,+,&@trietho/yphenylacetonitrile 3hich melted at &+@&1.& deg C. "here 3as a sharp
nitrile band at $$+% cm@(. Anal. 'C(+H(%590- C,H.
"o ().) m! of a ( ? solution of !AH in "HB under 5$ , vigorously stirred and cooled to , deg C, there 3as added, drop3ise, ,.&, m! (,,K H$S9+.
"his 3as follo3ed by 0.1 g 0,+,&@trietho/yphenylacetonitrile in (, m! anhydrous "HB over the course of & min. "he reaction mi/ture 3as brought to
room temperature and stirred for a fe3 min, and finally held at reflu/ on the steam bath for ( h. After cooling back to room temperature, there 3as added
about $ m! IPA 'to destroy the e/cess hydride- follo3ed by sufficient (&K 5a9H to make the aluminum o/ide granular and 3hite, and the organic
solution basic. "he solids 3ere removed by filtration, and 3ashed 3ith IPA. "he filtrate and 3ashes 3ere stripped of solvent under vacuum, the residue
added to +,, m! dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$, the aFueous phase made basic 3ith aFueous. 5a9H, and the product
e/tracted 3ith $/2& m! CH$Cl$. "hese e/tracts 3ere pooled, the solvent removed under vacuum, and the residue distilled at ((&@(0& deg C at ,.+
mm8Hg to give a 3hite oil. "his 3as dissolved in a fe3 m! of IPA, neutrali6ed 3ith concentrated HCl, and diluted 3ith anhydrous <t$9 to the point of
turbidity. Ihen the crystal formation 3as complete, the product 3as removed by filtration, 3ashed 3ith <t$9, and air dried to give $.) g 0,+,&@
trietho/yphenethylamine hydrochloride '":IS- as 3hite crystals 3ith a mp of (22@(2) deg C.
;9SAC<E greater than $+, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $+, mg- 5o effects 3ere noted at any time follo3ing $+, milligrams of trisescaline. "his 3ould have been a
thoroughly active level of the trimetho/y counterpart, mescaline.
<="<5SI95S A5; C9??<5"A:>E Iith the progressive diminution of human potency 3ith increased ethylation of the mescaline molecule, there is no
suprise in finding that this base is devoid of activity. Studies done years ago in the cat at a dosage of $& mg8g 'i.m.- gave none of the e/pected, and
looked for, signs of behavioral changes 'pilomotor activity, pupillary dilation, gro3ling, hissing, aggressive behavior, 3ithdra3al, or salivation- that are
often seen 3ith the less bulky substituents. It 3as 3ithout action.
?ore lengthy substituents in the 0,+,&@positions '3ith combinations of ethyls and propyls, for e/ample- are presently unkno3n compounds, and there is
small incentive to make them.

#121 '-TS.; '-TH"%SYM.ES!A"#E;
'-ETH%+Y-)-ETHYTH"%-(-METH%+Y,HE#ETHYAM"#E
S>5"H<SISE A solution of (0.+ g 0@bromo@5@cyclohe/yl@+@metho/y@&@etho/yben6ylidenimine 'see under ?< for its preparation- in (&, m! anhydrous
<t$9 3as placed in a He atmosphere, 3ell stirred, and cooled in an e/ternal dry ice8acetone bath to @), deg C. "here 3as the formation of a granular
precipitate. "here 3as then added $) m! of (.1 5 butyllithium in he/ane over the course of & min, and the mi/ture '3hich had turned Fuite creamy- 3as
stirred for (& min. "his 3as follo3ed by the addition of &.& g diethyl disulfide over the course of ( min. "he mi/ture 3as allo3ed to come to room
temperature over the course of ( h, and then added to (,, m! of dilute HCl. "he <t$9 phase 3as separated and the solvent removed under vacuum.
"he residue 3as dissolved in &, m! ?e9H, combined 3ith the original aFueous phase, and the entire mi/ture heated on the steam bath for ,.& h. "he
aFueous solution 3as cooled to room temperature, e/tracted 3ith 0/(,, m! CH$Cl$, the e/tracts pooled, and the solvent removed under vacuum. "he
residue 3as distilled at (0$@(+, deg C at ,.0 mm8Hg to yield %.( g of 0@etho/y@&@ethylthio@+@metho/yben6aldehyde as a 3hite oil that, on standing for
several months, spontaneously crystalli6ed. A small bit of the crystalline solid 3as 3astefully recrystalli6ed from ?e9H to provide 3hite crystals 3ith a
mp of 0(.&@0$.& deg C. Anal. 'C($H(190S- C,H. "he crude distillate 3as used in the follo3ing reactions.
Several attempts 3ere made to prepare the nitrostyrene from this aldehyde and nitromethane. "he most successful, but still inadeFuate, procedure is
described here. A solution of (., g 0@etho/y@&@ethylthio@+@metho/yben6aldehyde in (, m! nitromethane 3as treated 3ith about (&, mg of anhydrous
ammonium acetate and heated on the steam bath. "he course of the reaction 3as follo3ed by "!C. "he bulk of the aldehyde had disappeared in +&
min, and there 3ere several 4M@absorbing spots visible. :emoval of the e/cess nitromethane under vacuum gave an orange oil 3hich, 3hen rubbed
under cold ?e9H, gave $,, mg of yello3 solids. "his 3as 'by "!C- a mi/ture of nitrostyrene, starting aldehyde, and several slo3@moving scrudge
impurities. :ecrystalli6ation from ?e9H gave a poor recovery of a yello3 solid 3ith a mp of (,$.&@(,+ deg C but this 3as still contaminated 3ith the
same impurities. Several repetitions of this synthetic procedure gave little if any of the desired 0@etho/y@&@ethylthio@+@metho/y@beta@nitrostyrene.
A suspension of &.+ g methyltriphenylphosphonium bromide in 0, m! anhydrous "HB 3as placed under a He atmosphere, 3ell stirred, and cooled 3ith
an e/ternal 3ater bath. "here 3as then added (, m! of (.1 5 butyllithium in he/ane 3hich resulted in the generation of a bright pumpkin color. "he
initial heavy solids changed into a granular precipitate. "here 3as then added $.+ g of 0@etho/y@&@ethylthio@+@metho/yben6aldehyde in a little "HB. An
initial gummy phase became granular 3ith patient s3irling and stirring. After 0, min, the reaction 3as Fuenched in &,, m! H$9, the top he/ane layer
separated, and the aFueous phase e/tracted 3ith $/2& m! of petroleum ether. "he organic fractions 3ere combined, 3ashed 3ith H$9, dried over
anhydrous $C90, and the solvents removed under vacuum to give the crude 0@etho/y@&@ethylthio@+@metho/ystyrene as a yello3 mobile liFuid.
A solution of $ m! of borane@methyl sulfide comple/ '(, ? .H0 in methyl sulfide- in $, m! "HB 3as placed in a He atmosphere, cooled to , deg C,
treated 3ith +.$ m! of $@methylbutene, and stirred for ( h 3hile returning to room temperature. "o this there 3as added a solution of the impure 0@
etho/y@&@ethylthio@+@metho/ystyrene in a little anhydrous "HB. "his 3as stirred for ( h. "he e/cess borane 3as destroyed 3ith ( m! ?e9H, follo3ed by
the addition of 0.) g elemental iodine, follo3ed in turn by a solution of ,.) g 5a9H in hot ?e9H added over the course of & min. "he color gradually
faded, and became a pale lime green. "his 3as added to 0,, m! dilute aFueous sodium thiosulfate 3hich 3as e/tracted 3ith $/(,, m! petroleum
ether. "he e/tracts 3ere pooled, and the solvent evaporated under vacuum to provide crude (@'0@etho/y@&@ethylthio@+@metho/yphenyl-@$@iodoethane as
a residue.
"o this crude (@'0@etho/y@&@ethylthio@+@metho/yphenyl-@$@iodoethane there 3as added a solution of 0.2 g potassium phthalimide in &, m! anhydrous
;?B, and all 3as heated on the steam bath. "he reaction seemed to be complete after (& min 'as seen by "!C- and the addition of a second batch of
potassium phthalimide in ;?B produced no further change. After adding to &,, m! of dilute 5a9H, the aFueous phase 3as e/tracted 3ith $/2& m!
<t$9. "hese e/tracts 3ere combined, 3ashed first 3ith dilute 5a9H and then 3ith dilute H$S9+, dried over anhydrous $C90, and the solvent
removed under vacuum 3hich provided an amber oil as residue. "his 3as triturated under cold ?e9H giving 3hite solids 3hich 3ere recrystalli6ed from
$, m! ?e9H. "hus there 3as obtained ,.% g of (@'0@etho/y@&@ethylthio@+@metho/yphenyl-@$@phthalimidoethane as 3hite crystals that melted at 2%@),.&
deg C. A small sample 3as recrystalli6ed from <t9H to give large flat needles 3ith a mp of )(@)$ deg C. Anal. 'C$(H$059+S- C,H.
A suspension of ,.) g of the crystalli6ed (@'0@etho/y@&@ethylthio@+@metho/yphenyl-@$@phthalimidoethane in $& m! of n@butanol 3as treated 3ith $ m! of
11K hydra6ine, and the mi/ture 3as heated on the steam bath for ,.& h. Initially all 3ent into solution, and then there 3as the separation of solids that
resembled cottage cheese. "he reaction mi/ture 3as added to (&, m! dilute H$S9+. "he solids 3ere removed by filtration, and the filtrate 3as 3ashed
3ith 0/&, m! CH$Cl$. "hese 3ashes 3ere discarded. "he H$9 phase 3as then made basic 3ith aFueous 5a9H, e/tracted 3ith $/2& m! CH$Cl$,
and the solvent from these pooled e/tracts removed under vacuum. "he residue 3as distilled at (0&@(&& deg C at ,.0 mm8Hg to give ,.+& g of a
colorless oil. "his 3as dissolved in $.& m! IPA, neutrali6ed 3ith & drops of concentrated HCl, and diluted 3ith (, m! anhydrous <t$9. "he solution
became cloudy, and then deposited lustrous 3hite plates. "hese 3ere removed by filtration, 3ashed 3ith additional <t$9, and air dried to give ,.+ g of
0@etho/y@&@ethylthio@+@metho/yphenethylamine hydrochloride '0@"S.- 3ith a mp of (&0.&@(&+.& deg C. Anal. 'C(0H$$Cl59$S- C,H.
;9SAC<E greater than $,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith $,, mg- 5o effects 3hatsoever, neither mental nor physical.
<="<5SI95S A5; C9??<5"A:>E "he elephant labored and brought forth a mouse. A lot of 3ork for a material 3ithout activity.
I have used the term NscrudgeN in this and other recipes, 3ithout defining it. Iith this aldehyde, as 3ith most aldehydes in this nitrostyrene synthesis
reaction 3here there is no ortho@substituent on the ben6aldehyde, the reaction progress should be carefully follo3ed by thin@layer chromatography. As
the aldehyde disappears from the reaction mi/ture, the nitrostyrene appears, but there is usually the development of one or more slo3er moving
components as seen by "!C. Such a 3rong@product is called scrudge. "he reaction should be continuously titrated, and stopped 3hen there is a
favorable balance bet3een the aldehyde being mostly gone, the nitrostyrene being mostly made, and the slo3er@moving scrudge components being not
yet too plentiful. ?ethylene chloride is an e/cellent solvent to try first, 3ith silica gel plates and 4M detection. "he nitrostyrene is al3ays the fastest
moving component of the reaction mi/ture and often fluoresces a dull purple. "he starting aldehyde is the second spot and usually fluoresces 3hite or
pale yello3. "he scrudge spots then occur in a cascade from the aldehyde to the origin. A maddening property is that they are yello3 or bro3n colored,
and in the probe mass spectrograph they can crack to give rise to 3hat appears to be the right nitrostyrene. 4sually, they are high melting.
In this preparation, there 3as not one but several scrudges, and little if any nitrostyrene. "he same 3as true for the other of the diethyl compounds such
as 0@"AS., &@"AS. and 0@"@":IS. "hus, it is preferable to circumvent this usual synthetic step by using the Iittig reaction instead, as described here.

#122 (-TS.; (-TH"%SYM.ES!A"#E;
',)-0"ETH%+Y-(-METHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of ($.( g 5,5,57,57@tetramethylethylenediamine and (1.1 g of (,0@dietho/yben6ene 3as made in $,, m! 0,@1, deg C petroleum
ether. "his 3as stirred vigorously under a 5$ atmosphere and cooled to , deg C 3ith an e/ternal ice bath. "here 3as added 11 m! of (.1 ? butyllithium
in he/ane. "he stirred reaction mi/ture became a little cloudy and then gradually formed a 3hite granular precipitate. "his 3as brought to room
temperature, stirred for ,.& h, and returned again to , deg C. "here 3as added %.+& g of dimethyl disulfide 3hich converted the loose precipitate to a
creamy te/ture. "he reaction 3as e/othermic. After being held ,.& h at reflu/ temperature, the reaction mi/ture 3as added to 1,, m! dilute H$S9+.
"here 3as the immediate formation of 3hite solids 3hich 3ere insoluble in either phase. "he petroleum ether phase 3as separated, and the aFueous
phase e/tracted 3ith 0/(,, m! <t$9. "he organics 3ere combined, and the solvents removed under vacuum. "here 3as obtained as residue $+.) g of
a slightly oily crystalline solid that, after trituration under 0, m! cold he/ane, filtering, and air drying, 3eighed (1.% g. "his product, $,1@
dietho/ythioanisole, had a mp of 2(@2$ deg C 3hich 3as not im@proved by recrystalli6ation from methylcyclopentane. Anal. 'C((H(19$S- C,H.
"o a stirred solution of (1.2 g of $,1@dietho/ythioanisole in (2& m! CH$Cl$ there 3as added (0 g elemental bromine dissolved in (,, m! CH$Cl$. After
stirring at ambient temperature ( h, the dark solution 3as added to (&, m! H$9 containing ( g of sodium dithionite. Shaking immediately discharged
the residual bromine color, and the organic phase 3as separated. "he aFueous phase 3as e/tracted once 3ith (,, m! CH$Cl$, the pooled e/tracts
3ashed first 3ith H$9, and then 3ith saturated brine. :emoval of the solvent under vacuum provided $).1 g of a pale yello3 oil 3ith several globs of
H$9 present. "his 3et product 3as distilled at (()@($& deg C at ,.$& mm8Hg to yield 0@bromo@$,1@dietho/ythioanisole as a 3hite oil 3eighing $(.& g. It
could not be crystalli6ed. Anal. 'C((H(&.r9$S- C,H.
"o a solution of (%.0 g diisopropylamine in 2& m! he/ane under a He atmosphere there 3as added (,, m! of (.1 ? butyllithium. "he viscous mi/ture
3as loosened by the addition of $,, m! anhydrous "HB, and this stirred mi/ture 3as cooled 3ith an e/ternal ice bath. "here 3as then added +., m! of
dry CH0C5, and ((.1 g of 0@bromo@$,1@dietho/ythioanisole '3hich had been diluted 3ith a little anhydrous "HB-. "he deep red bro3n reaction mi/ture
3as stirred for ,.& h, and then poured into ( ! dilute H$S9+. "his 3as e/tracted 3ith 0/2& m! CH$Cl$, the e/tracts pooled, 3ashed 3ith H$9, dried 3ith
anhydrous $C90, and the solvent 3as removed under vacuum. "he residue 3as distilled at ,.0 mm8Hg yielding t3o fractions. "he first fraction boiled
at ($,@(+, deg C and 3eighed (.$ g. "his fraction partially crystalli6ed, but 3as not investigated further. "he second fraction 3as 0,&@dietho/y@+@
methylthiophenylacetonitrile, 3hich came over at (0&@(1, deg C, 3as a yello3 liFuid, 3eighed 0.$ g, but did not crystalli6e.
A solution of !AH in anhydrous "HB '0, m! of a (., ? solution- under 5$ 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise,
,.2) m! (,,K H$S9+, follo3ed by 0., g 0,&@dietho/y@+@methylthiophenylacetonitrile diluted 3ith a little anhydrous "HB. "he reaction mi/ture 3as
stirred at , deg C for a fe3 min, then brought to reflu/ on the steam bath for (.& h. After cooling back to room temperature, there 3as added IPA to
destroy the e/cess hydride and (,K 5a9H to bring the reaction to a basic pH 3ith the conversion of aluminum o/ide to a loose, 3hite, filterable
consistency. "his 3as removed by filtration, and 3ashed first 3ith "HB follo3ed by IPA. "he filtrate and 3ashes 3ere stripped of solvent under vacuum,
the residue added to ( ! dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$, made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$.
After combining, the solvent 3as removed under vacuum providing an orange oil. "his 3as distilled at (0&@(1, deg C at ,.+ mm8Hg to give a light yello3
oil. "his 3as dissolved in $, m! of IPA, and neutrali6ed 3ith 0$ drops of concentrated HCl producing 3hite crystals spontaneously. "hese 3ere
dissolved by bringing the IPA suspension to a boil on the steam bath and, 3ith stirring, diluted 3ith ), m! of 3arm anhydrous <t$9. "here 3as the
immediate formation of crystals 3hich 3ere removed by filtration, 3ashed 3ith an IPA8<t$9 mi/ture, and then 3ith <t$9. After air drying there 3as
obtained (.& g of 0,&@dietho/y@+@methylthiophenethylamine hydrochloride '+@"S.- as 3hite crystals. "he mp 3as (%+.&@(%1 deg C. Anal.
'C(0H$$Cl59$S- C,H.
;9SAC<E greater than $+, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith ), mg- "here 3as a real effect about three hours into this e/periment L a little bit spacey 3hile I 3as talking to ?r. =.
.ut the talk 3ent 3ell, and 3e 3ere all really friendly. "here 3as no hint that he suspected anything. A couple of hours later, nothing.
'3ith (1, mg- "3inges at a couple of hours, but the rest of the day disappointing as to any effect from the drug.
'3ith $+, mg- 5o effects at all.
<="<5SI95S A5; C9??<5"A:>E Here is an e/cellent presentation of a report that sho3s false positives or maybe false negatives. Something at
lo3 levels. 5othing at higher levels. Al3ays tend to trust the absence of an effect in preference to the presence of an effect, if one of the t3o
observations is presumed to be in error.

#123 '-T-T*"S; '-TH"%T*ES!A"#E; '-TH"%T*"SES!A"#E;
',(-0"ETH%+Y-)-ETHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of ((.& g 0@bromo@5@cyclohe/yl@+,&@dietho/yben6ylidenimine 'see under AS. for its preparation- in (&, m! anhydrous <t$9 3as
placed in a He atmosphere, 3ell stirred, and cooled in an e/ternal dry ice acetone bath to @), deg C. "here 3as light formation of fine crystals. "here
3as then added $& m! of (.1 5 butyllithium in he/ane and the mi/ture stirred for (& min. "his 3as follo3ed by the addition of &.) g diethyl disulfide over
the course of $, min during 3hich time the solution became increasingly cloudy 3ith the eventual deposition of an insoluble gummy phase. "he mi/ture
3as allo3ed to come to room temperature over the course of ( h, and then added to +,, m! of dilute HCl. "he organic phase 3as separated and
stripped of solvent under vacuum. "his residue 3as combined 3ith the original aFueous phase, and the mi/ture 3as heated on the steam bath for $ h.
"he aFueous mi/ture 3as cooled to room temperature, e/tracted 3ith 0/(,, m! CH$Cl$, the e/tracts pooled, 3ashed 3ith H$9, and the solvent
removed under vacuum to yield ((., g of an amber oil. "his 3as distilled at (0,@(&, deg C at ,.$ mm8Hg to yield 2.$ g of 0,+@dietho/y@&@
'ethylthio-ben6aldehyde as a 3hite oil that spontaneously crystalli6ed. "he crude product had a mp of &$@&2 deg C that increased to &2@&) deg C upon
recrystalli6ation from <t9H. Anal. 'C(0H()90S- C,H.
A solution of (+.% g methyltriphenylphosphonium bromide in $,, m! anhydrous "HB 3as placed under a He atmosphere, 3ell stirred, and cooled to ,
deg C 3ith an e/ternal ice 3ater bath. "here 3as then added $2.1 m! of (.1 5 butyllithium in he/ane 3hich resulted in the generation of a yello3 color
3hich 3as at first transient, and then stable. "he reaction mi/ture 3as brought up to room temperature, and 1.) g 0,+@dietho/y@&@
'ethylthio-ben6aldehyde in &, m! "HB 3as added drop3ise dispelling the color, and the mi/ture 3as held at reflu/ on the steam bath for ( h. "he
reaction 3as Fuenched in ),, m! H$9, the top layer separated, and the aFueous phase e/tracted 3ith $/2& m! of petroleum ether. "he organic
fractions 3ere combined and the solvents removed under vacuum to give ($., g of the crude 0,+@dietho/y@&@ethylthiostyrene as a deep yello3 oil.
A solution of &.1 g of borane@methyl sulfide comple/ '(, ? .H0 in methyl sulfide- in +& m! "HB 3as placed in a He atmosphere, cooled to , deg C,
treated 3ith ((.1 g of $@methylbutene, and stirred for ( h 3hile returning to room temperature. "o this there 3as added the crude 0,+@dietho/y@&@
ethylthiostyrene in $& m! "HB and the stirring 3as continued for ( h. "he e/cess borane 3as destroyed 3ith about $ m! ?e9H. "here 3as then added
((.+ g elemental iodine follo3ed by a solution of $.$ g 5a9H in +, m! hot ?e9H. "his 3as follo3ed by sufficient $&K 5a9H to minimi6e the residual
iodine color 'about + m! 3as reFuired-. "he reaction mi/ture 3as added to &,, m! H$9 containing + g sodium hydrosulfite. "his 3as e/tracted 3ith
0/2& m! petroleum ether, and the pooled e/tracts stripped of solvent under vacuum to yield $+.& g of crude (@'0,+@dietho/y@&@ethylthiophenyl-@$@
iodoethane as a viscous yello3 oil.
"his crude (@'0,+@dietho/y@&@ethylthiophenyl-@$@iodoethane 3as added to a solution of ((.( g potassium phthalimide in ), m! ;?B, and all 3as heated
on the steam bath for (.& h. It 3as then flooded 3ith 1,, m! H$9, made basic 3ith 5a9H, and e/tracted 3ith 0/(,, m! <t$9. :emoval of the solvent
under vacuum provided ().& g of a residue that 3as dried to a constant 3eight by heating under vacuum ',.$ mm8Hg-. "he solid residue 3as ground
under ?e9H, and then recrystalli6ed from ?e9H providing (@'0,+@dietho/y@&@ethylthiophenyl-@$@phthalimidoethane as 3hite granular crystals, 3ith a mp
of )1.&@)2.& deg C. Anal. 'C$$H$&59+S- C,H.
"he recrystalli6ed (@'0,+@dietho/y@&@ethylthiophenyl-@$@phthalimidoethane 3as dissolved in n@butanol, treated 3ith 11K hydra6ine, and the mi/ture
heated on the steam bath for (.& h. "his 3as then added to dilute H$S9+, the butanol separated, the aFueous phase 3ashed 3ith $/2& m! <t$9. After
being made basic 3ith aFueous 5a9H, the aFueous phase 3as e/tracted 3ith 0/2& m! CH$Cl$ and the solvent removed under vacuum to provide a
pale amber oil. "his 3as distilled at (+,@(&& deg C at ,.$& mm8Hg to give about ( g of a 3hite oil. "he distillate 3as dissolved in & m! IPA, neutrali6ed
3ith concentrated HCl, and treated 3ith (, m! anhydrous <t$9 to give a solution from 3hich a 3hite crystalline product slo3ly separated. "hese
crystals, 0,+@dietho/y@&@ethylthiophenethylamine hydrochloride '0@"@":IS- 3eighed (.( g and had a mp of (1(@(1$ deg C. Anal. 'C(+H$+Cl59$S- C,H.
;9SAC<E greater than (1, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith (1, mg- "here 3ere no effects. At the %th or (,th hour after having taken the material I 3as a3are of some
neurological irritability. I 3ill not try this at any higher dosage, and let me stretch things a bit by a fe3 percent in good conscience and say that this is
less active than mescaline. "his 3ould allo3 it to be reported as W ( ?.4.
<="<5SI95S A5; C9??<5"A:>E "he term N?.4.N pops up here and there in a lot of the earlier literature on these phenethylamines. It stands for
Nmescaline unitsN and 3as used to give a Fuantitative measure for the relative potency of a compound. Since it became obvious Fuite early in these
studies that mescaline, although the prototypic compound, 3as probably going to remain the least potent, it seemed reasonable to use it as a bench
mark of unity. .y dividing the dose needed of mescaline 'to produce central effects- by the dose needed of another drug, one 3ould generate a number
that represented Gust ho3 many times more potent this ne3 drug 3as than mescaline. I used this term in a very early revie3 of the one@ring
psychotomimetics, and it served satisfactorily for Fuite a 3hile.
Its intrinsic 3orth proved, ho3ever, to be its very limitation. It 3as Fuickly apparent that the principal value, to behavioral researchers, of the reports of
ne3 hallucinogenic drugs, 3as not in the nature of their action but in the amount of stuff needed to produce that action. "his 3as an essential a/is
against 3hich the animal pharmacologist could plot his findings. A number 3as 3anted, and the mescaline unit 3as Gust that number. Sadly, the maGor
Fuestion that is asked by most academic researchers in their evaluation of the psychedelic materials is, NHo3 much does it take,N rather than NIhat
does it do.N "he marvelous nuances of action, the subtle variations of effect, are dismissed as being hopelessly subGective and thus 3ithout scientific
3orth. .ut they are, I believe, of great 3orth. "hat is e/actly 3hat this book is all about.

#124 (-T-T*"S; (-TH"%T*ES!A"#E; (-TH"%T*"SES!A"#E;
',)-0"ETH%+Y-(-ETHYTH"%,HE#ETHYAM"#E
S>5"H<SISE A solution of ($.( g 5,5,57,57@tetramethylethylenediamine and (1.1 g of (,0@dietho/yben6ene 3as made in $,, m! 0,@1, deg C petroleum
ether. "his 3as stirred vigorously under a He atmosphere and cooled to , deg C 3ith an e/ternal ice bath. "here 3as added 11 m! of (.1 ? butyllithium
in he/ane. "he stirred reaction mi/ture became a little cloudy and then gradually formed a 3hite granular precipitate. "his 3as brought to room
temperature, stirred for ,.& h, and returned again to , deg C. "here 3as added ($.) g of diethyl disulfide 3hich seemed to produce an e/othermic
reaction. After being held for a fe3 min at reflu/ temperature, the reaction mi/ture 3as added to 1,, m! dilute H$S9+ 3hich produced t3o clear
phases. "he petroleum ether phase 3as separated, and the aFueous phase e/tracted 3ith $/2& m! <t$9. "he organics 3ere combined, and the
solvents removed under vacuum. "here 3as obtained as residue $+ g of a viscous oil. "his 3as distilled at %0@((, deg C at ,.0 mm8Hg yielding $(.& g
(,0@dietho/y@$@ethylthioben6ene 3hich spontaneously crystalli6ed. Crinding under a small amount of he/ane, filtering, and he/ane 3ashing provided
().& g of 3hite crystals 3ith a mp of $1@$2 deg C. Anal. 'C($H()9$S- C,H.
"o a stirred solution of (2.0 g of (,0@dietho/y@$@ethylthioben6ene in (2& m! CH$Cl$ there 3as added ((.) g elemental bromine dissolved in (,, m!
CH$Cl$. "here 3as an immediate loss of color, and the obvious evolution of H.r gas. After stirring at ambient temperature for ( h, the dark solution
3as added to (&, m! H$9 containing ( g of sodium dithionite. Shaking immediately discharged the residual bromine color, and the organic phase 3as
separated, "he aFueous phase 3as e/tracted once 3ith 2& m! CH$Cl$, the pooled e/tracts 3ashed first 3ith H$9, and then 3ith saturated brine.
:emoval of the solvent under vacuum provided 0+.$ g of a pale yello3 oil 3ith several globs of H$9 that 3ere mechanically removed. "his 3et product
3as distilled at (,&@($& deg C at ,.0& mm8Hg to yield +@bromo@(,0@dietho/y@$@ethylthioben6ene as an off@3hite oil 3eighing $(.1 g. It could not be
crystalli6ed. Anal. 'C($H(2.r9$S- C,H.
"o a solution of $,.$ g diisopropylamine in $,, m! anhydrous "HB that had been cooled to @(, deg C under a He atmosphere 3ith an e/ternal
ice8?e9H bath, there 3as added ($& m! of a (.1 ? solution of butyllithium in he/ane. "here 3as then added, in seFuence, &.( m! of dry CH0C5
follo3ed by the drop3ise addition of (&.0 g +@bromo@(,0@dietho/y@$@ethylthioben6ene diluted 3ith a little anhydrous "HB. "here 3as only a modest color
development. Analysis by thin@layer chromatography sho3ed that the reaction components 3ere largely starting bromide and only a little product nitrile.
An additional $.& m! dry CH0C5 3as added, follo3ed immediately by a solution of lithium diisopropylamide prepared separately from (+ m!
isopropylamine in &, m! he/ane treated 3ith 1, m! butyllithium solution. "here 3as an immediate darkening of color. After (& min stirring, the bromo
starting material 3as gone, by "!C analysis. "he reaction mi/ture 3as then poured into ( ! dilute H$S9+. "he organic phase 3as separated and the
aFueous fraction e/tracted 3ith $/(,, m! CH$Cl$. "hese e/tracts 3ere pooled, 3ashed 3ith H$9, dried 3ith anhydrous $C90, and the solvent 3as
removed under vacuum. "he residue 3as distilled at ,.0 mm8Hg yielding t3o fractions. "he first fraction boiled at ($+@(+& deg C and gave an amber
liFuid 3eighing $.+ g. It 3as largely starting bromo compound 3ith a little nitrile, and 3as not processed further. "he second fraction distilled at (+,@(%,
deg C and 3eighed 1.$ g. Although this 3as largely product nitrile, it 3as Fuite comple/ by chromatographic analysis. It 3as redistil@led at ,.0 mm8Hg
and several fractions taken. "he material collected at (+&@(1& deg C 3eighed 0.$ g and 3as appro/imately ),K 0,&@dietho/y@+@
ethylthiophenylacetonitrile by "!C assay. "his 3as used in the subseFuent reduction. "he earlier fraction in this second distillation '(0,@(+& deg C-
3eighed $.( g but contained only &,K product nitrile by "!C analysis, and 3as discarded.
A solution of !AH in anhydrous "HB under 5$ '$, m! of a (., ? solution- 3as cooled to , deg C and vigorously stirred. "here 3as added, drop3ise,
,.&0 m! (,,K H$S9+, follo3ed by 0., g 0,&@dietho/y@+@ethylthiophenylacetonitrile diluted 3ith a little anhydrous "HB. "he reaction mi/ture 3as stirred
at room temperature for ( h, and then at reflu/ on the steam bath for an additional ,.& h. After cooling back to room temperature, there 3as added IPA to
destroy the e/cess hydride and (,K 5a9H to bring the reaction to a basic pH and convert the aluminum o/ide to a loose, 3hite, filterable consistency.
"his 3as removed by filtration, and 3ashed first 3ith "HB follo3ed by IPA. "he combined filtrate and 3ashes 3ere stripped of solvent under vacuum,
the residue added to ( ! dilute H$S9+. "his 3as 3ashed 3ith $/2& m! CH$Cl$, made basic 3ith $&K 5a9H, and e/tracted 3ith 0/(,, m! CH$Cl$.
After combining, the solvent 3as removed under vacuum providing a residue that 3as distilled. A fraction boiling at (0&@(&, deg C at ,.0 mm8Hg
3eighed (.$ g and 3as a light yello3 oil. "his 3as dissolved in $, m! of IPA, and neutrali6ed 3ith (2 drops of concentrated HCl 3hich produces 3hite
crystals spontaneously. "hese 3ere dissolved by bringing the IPA suspension to a boil on the steam bath and, 3ith stirring, there 3as added +, m! of
hot anhydrous <t$9. "here 3as the immediate formation of crystals 3hich 3ere removed by filtration, 3ashed 3ith an IPA8<t$9 mi/ture, follo3ed by
<t$9. After air drying there 3as obtained (., g of 0,&@dietho/y@+@ethylthiophenethylamine hydrochloride '+@"@":IS- as sparkling 3hite crystals. "he mp
3as (22@(2) deg C. Anal. 'C(+H$+Cl59$S- C,H.
;9SAC<E greater than $,, mg.
;4:A"I95E unkno3n.
L4A!I"A"IM< C9??<5"SE '3ith ($, mg- ?aybe there is some physical effectH "here is a slight tingling or numbing of my hands and fingers, and a
certain amount of gas. It is certainly negative on the mental side, but go up slo3ly due to the physical.
'3ith $,, mg- "here 3as a passing a3areness at the third hour. 9ther3ise, no effects, either mental or physical.
<="<5SI95S A5; C9??<5"A:>E As 3ith the sulfur@free counterpart, the phenethylamine 3ith three ethyl groups hanging out from it is not active in
man. It doesn7t matter 3here the sulfur is, since the 0@"@":IS isomer is also 3ithout action. "he labor of making the amphetamine analogues of these
triethylated things seems hardly 3orth the effort.