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Arch.Neurol.Psychiatr., Chicago 81, 20-27 (1959)


on Lysergir

Acid Diethvlamidc
the lXl_)-Reactlon Agents


Attempts to Attenuate Ncurohumoral Blocking

in Man by Pretreatntent

HARRIS ISBELLt M.D.; C. R. LOGAN, and |. J. MINER, Lexington,


Interest in possible chemical transmission of impulses in the central nervous system has been increasing. The tmurohumors involved include acetylcholine, 1,2 norepinephfine, 24 and serotonin. 4"6 These. theories of central chemical synaptic transmission have led, in turn, to hypotheses which ascribe the psychosis induced by lysergic acid diethylamide (LSD-25) and other psychotomitactic drugs to derangements in central nervous system function because of cornpetition with one or another of the neurohumors or, on the contrary, to accentuation of the effects of the neurohumors by the psychotomimetic agents. The greatest interest has centered on Imssible interactions of serotonin and LSD. Woolley and Shaw _ and Gaddum e independently evolved a hypothesis which ascribes the LSD psychosis to competition between LSD and serotonin for receptor sites on or in neurons, This hypothesis, which might be tenned the serotonin-deficiency theory, is based in part on the following evidence: Serotonin is found in brain, n,7 and the concentration of serotonin in tissue is reduced s by reserpine, a drug with powerful effects on the central nervous system; in certain concentrations, serotonin and LSD have antagonistic efrects on isolated smooth-muscle preparationsg; reserpine and serotonin prolong sleeping time induced by hexobarbital in mice, and L.%D abolishes this enhancement of hexobarbital sleeping time. 1_) .It is also possible to hypothesize that LSD induces a psychosis by enhancing the Received for publication Dec. 3, 1957. U. S. Deparnnemt of Health, Education and Welfare, National Institute of Meutal Health. Addiction Research Cemer. P. H. S. Hospital. 20

effects of serotonin. 11a2 This possibility is favored by the following evidence: Low concentrations of LSD increase serotonininduced contractions in isolated smoothmuscle preparations rather than reducing them a3; elevation of the serotonin content of brain brought about either by feeding the precursor of serotonin, 5-hydroxytryptophan, 14 or by giving iproniazid, followed by reserpine, 4 produces symptoms in anireals resembling those induced by LSD; injection of serotonin into the lateral ventricles of the brain causes abnormal behavior in animals, x_ and LSD and serotonin both inhibit postsynaptic transmission in a transcallosal synapse, x6,_7 It is also possible to hypothesize that the LSD psychosis is due to disturbances in central adrenergic mechanisms. The following facts suggest such a possibility: A number of drugs with adrenergic effects (cocaine, amphetamine, and methamphetamine) will, if taken in sufficient dose, cause a toxic psychosis; a number of the signs and symptoms seen after administration of LSD in man (pupillary dilatation, elevation of blood pressure, goose flesh, anorexia, insonmia, and anxiety) suggest hyperactivitv of the sympathetic (adrenergic) division of the autonomic ner_'ous system; LSD and a number of adrenergic drugs have the same kind of inhibitor}" effect on transcallosal postsynaptic transmission2,16; Rothlin and co-workers _7,zs state that LSD produces a state of central vegetative (aut(_ nomlc) stinmlation. Chlorpromazine partially ameliorates the LSD reaction _9-_. and since chlorpromazine is a peripheral, 22 and possibly a central, 2s adrenergic blockcn-, one might hypothesize that chlorpromazine

STUDIES attenuates adrenergic



DIETHYLAMIDE by virtue of Pfeiffer since the and Jenney _9 postulated alkaloids and that

psychosis effects.






ing findings in experimental animals support the adrenergie concept. Elder et al. 24 surveyed antagonists to LSD and found that pretreatment with chlorpromazine reduced LSD-induced hyperthermia in tabbits and "feline mania" in cats. In addition, phenoxybenzamine (Dibenzyline), an adrenergic blocker with no known central effects, attenuated "feline mania." Gogerty et al. 25 studied the interactions of LSD and reserpine in rabbits. given to rabbits two hours If LSD was after reserpine,

mazine have persistent acetylcholine-like actions, cholinergic drugs that pass the blood-brain barrier should have effects on behavior which resemble those induced by the tranquilizers. These authors (lemonstrated that 'arecoline, pilocarpine, and physostigmine reduced or abolished a conditioned avoidance response in rats protected from the peripheral effects of the cholinergic drugs by methyl atropine, a cholinergic blocker which not cross the blcxxt-brain presumably does barrier, hi this

hyperthermia was accentuated. At this particular time reserpine-induced release of norepinephrine from brain, =6 as well as of serotonin, should be occurring. If LSD was given 10 hours after reserpine, hyperthernfia after LSD was reduced. At this time the norepinephrine tent of brain is almost A hypothesis relating sis to central interactions and zero. serotonin con-

hypothesis, a "muscarinic" drug is regarded as being an antipsychotic agent, whereas muscarinic blockers are reg_trded as psychotomimetic. Some of the actions of LSD (pupillary dilatation, facial flush, and elcration of temperature) are similar to those of atropine. imply that Pfeiffer and Jenney, the LSD psychosis nmscarinic therefore. I-ossibly blocking

the LSD psychowith acetylcholine

might be due to central actions of LSD.

may be suggested by the following: The cholinergic blocking drugs, atropine and scopolamine, can cause toxic psychoses, Acetylcholine and inhibitors of cholinesterase (physostigmine, isoflurophate U. S. P., etc.) stimulate the brain-stem reticular formation, 27 leading to an "alert" electroencephalographic pattern, whereas the cholinergic blocking drug, activity in the reticular duces a "sleep" pattern atropine, reduces formation and inin the EEG (even In the pattern, 2s;

In view of these alternatives, it seemed of interest to determine whether neurohumoral blocking agents would attenuate or enhance the I.SD reaction in man. The purpose of this communication is to show that pretreatment with an acetylcholine blocker, scopolamine; an adrenergic blocker, phenoxybenzamine (Dibenzyline *), and a serc)tonin antagonist, 5-methoxytryptamine significant effect on induced hy LSI) 3 1-benzyl-2-methyl(BASt). had no the mental reactions

though the animal may be awake). rabbit, LSD causes an "alert" EEG similar to that induced by

in man. Methods


so one could speculate that this LSD-induced activation of the EEG is due to some effect in the suggests nervous of LSD reticular on cholinergic formation. transmission Marrazzi 16

Subjects.--All were adaalt Negro me11who volunteered for the experiments and who were serving sentences for violating Federal narcotic laws. Their ages ranged from 21 to 50 years. All subjects were in excellent physic:d health, and all had been abstinent from opiates for a least se_'eral months before participation in the experiments. There was no evidence of psychosis in any of the patients, * Supplied through the eourlesy of Mr. The_hwe \Vallaee, Smith, Kline & French Laboratories. Philadelphia. -_Supplied through the courtesy of Dr. Frederick K. Heath, Merck Sharp & Dohme, Philadelphia. 21

that a balance exists in the central system between synaptic excitation

by acetylcholine and inhibition by adrenergic neurohumors, so that disturbance of either chemical member of this balanced system tion. may result in abnormal mental func-

Isbell et al.



A. M.

A. ARCtlIlV:.S





and all were ,!ia,enosed as havblg character disorders. The eftt'cts of I.S[) ilt such subjects have lx-en shown to i.. _imilar to tile effects observed in other groups _" .uhjecis from a different environmerit and backgromul, a_ Different groups of patiemts were u_l i, evaluatint_- the various blocking drugs. 3leans of 3t,'a.rurcment and Analysis.--Methods previously described _ were used. The patellar reflex, pupillar 3, size, :uvl restin V systolic blood pressure were measured hours after In hourly for two hours prior of LSD (or to ,and eight L.RD adnfinistration the experiments

LSD were administered was randomized by using a table of. random mmabers and a Latin-.vluare design, Means and standard errors of means were calculated by standard statistical techniques. Significance of differmmes was, however, evaluated by- the t-test for paired observations. *a Results /q,q.5".--lll patients In used, were

given BAg or

13AS placebos.

1S were


the as


given with were

the drug given



amounts experience l'atients


phenoxvber|zamine, additional measureme.t_ts of res(Rug pulse rate and of lml._c rate after standing for one minute vcrc made. "l'he :,.ventge of tile two pre-LSD and the measured measmemmlts was used :_s a ba_ line,

increased cumulaled,



are, under the,m curve was with ;t planimeter, a_ or was caleulate*t

(loses. and tinalt.v three doses, at intervals of six hours. The patients did not report
any subjective effects until two doses of

by the effects of of \Vimer assessed l:lataker, s= The meth(xi I.SI) were and menial by administering am_tificalionof the qlmstionnitireof '\hrmnson et al. '_" hourly, twice before and eight times after LS1) or I.SD ptacelx_. The number of l_itive

100 rag. of BA.q had been

sensations after the did not first dose appear of BAS were

until g (2 hours

hottrs after

the second
12-16 sisted


responses after LSD or LSD placebo wa_ counted, ellminatinR" an5" positive answers that were also scored l*_silively prior to administration of the drug. The itltensilv of the reaction was graded ,,n a scale of 0 t_* 4, using criteria pre_iously described." The grade was based on a short either hourly psychior at

h,mr_ after the for 48-72 hours

most pronotmeed first dose, and perafter the last dose.

The outstanding subjective effects included fatig-ue, drowsiness, atgtominal discomfort,

blurring ,_f vision, and dizziness. Nasal sylnp-

atric exarninauon carrie, t out the height ol the reaction. /)rugs.-All _c q_olamine the taste of cherry syrup.

stuffiness was seldom retmrted. These

toms who to 200 those There rate, were present received two

,h-ugs were given orally. LSD mid were given in a _lution in which lhe SCOl.,lzunine was ma_ked wilh a I'AS was givml was in tablet in fiwm, and capsules.

in all of the 11 patients or three doses of 150

nag. of ]3AS. Symptoms resmnbling induced by LSI) were not reported. were no significant changes in pulse



Appropriale identicalTheplaceb_*s were used to of adcontrol all experiments. doses and times ministration of each of the drugs are describe_t bek,w ma(ler the strparate experimmlts. Preliminary experiments, in which BAS or pllenoxyt_.nzamine was given alone, were carried out prior to lwgi_ming the critical exlx'riments in order to establish effective dosage schedules for these blocking drugs. Experiments were conducted at weekly iniervals in ,,rd(.r I.SI_ 15.vperh_wntcd Design.--.-\ "cross-over" design. il_ which e;a_h person serxx_l as his oven control, was used. The bl_ccking expermt_mts always in,olved four sel,a,-;tte drug c_nnbitutti,ms in tile same gro:ll_ placcl._;

blood pressure,

temperature, No



or tendon reported after


symptoms were this group of

"l'ml I3AS which

of the
al,_nc were combinations

used of

who had
in the



io prevent

the develol_nmn

of tolerance


24, I..";D from The 16.



BAS anti I.SD were cxt)eriment, patients reBA.q l,lacebo) to LSD or 2 hours prior

ceived 150 rag. of BAS (or :rod

1,1aceb_. The
0.5 to 1.3v.g/k_. rt'>tlll>

(lose of





subjects: I.SD pins

LSI) bku'kcr placet_ xxcle

plltcelx_ placebo; plus


blocker plus paof


bhwke,'._i_lld ,,bservers :rod I.S]_ ll_c, nledws,*_tm_ ,Xl,:llt:,,q:i (".h.ul,h.


blocker. Of the &_ring


are presented in Table 1. Although /L'_S prevented the characteristic rise ill sx>htlic I,h_d presstlre after LSD,
the other a-l,ecls the: nit'Ilia] of the LSD reaction, inc]ud}ng

a, immi,wred !,lind"

a particular The order ;rod


effects, were unchanged

"/'he 1,,1 drowsiness, 81, .hln.. 1959

m w',m';, llu. _:_:,,_t_ (_,ml,in:di<m_ 22

_t" bh,tker_

_lI inlensilv

,r duratic,n.

T .................................



MCII) I)IF. Ttt)'LAMILYE TABI.F. 1.--Effect of BAS on th; L3"D Reaction

Drugs BAS Placebo BAS Placebo plus LSD +2.024-0.43 +4.54=1;:0.28 +2.484-0.46 424-13 1.34-0.1 BAS plus LSD LSD B._S plus Plaeebo

Measure Patellar Pupillary Systolic Number Clinical reflex size * ................... * ...................

plus LSD Placebo +0.1340.14 --0.114-0.22 +0.594-0.18 0.7+0.9 04-0

+2.044-0.29 +3.794-0.35 +0.76+0.36 434-12 l.l:i_0.1

+1.174-0.17 +1.37-4-0.5.', A-0.124-0.3l 5=t=0 ;4 0.34-0,3

blood pressure * .......... of positive answers f ...... grade ;....................

Expressed a8 the mean 4- the standard a'negative figure, a decrease, as compared ? Me_,ns 4 standard errors. For number

error of the area under with predrug controls. of subjects, doses, and

curves methods,



A positive




an incre;tse;

see text.

fatigue, liminary

etc., reported tests were

after ]3AS in the prealso prominent in this of miosis

pressure and the increase in pulse rate after epinephrine were enhanced both three and five hours benzamine. after the last In addition, dose of phenoxya marked dcv, rcL"

experiment. was observed

No significant degree with BAS alone,

Phenoxybcnzaminc.--Two preliminary experiments were conducted with phenoxybenzamine. In one of these experiments, four patients received a placebo and 0.4 to 0.6 rag. of epinephrine before and two to three hours after oral administration of 1.0 mg/kg, of phenoxybenzamine hvdrochloride. The pulse rate and systolic and diastolic blood pressures were determined twice before and at intervals of 5, 10, 15, 20, 30, 40, and 60 minutes after epinephrine or epinephrine placebo. The rise in systolic pressure after epinephrine was less after phenoxybenzamine, but the difference was not sufficiently great to bc significant statistically. The decrease in diastolic pressure after epinephrine was enhanced by phenoxybenzamine. In another experiment, eight patients were "challenged" with a placebo and with 0.6 mg. of epinephrine subcutaneously before and at three and five hours after administration of the last of three doses of phenoxybenzamine (0.5, 1.0, and 1.0 mg/kg, of phenoxybenzamine hydrochloride at 8 a.m. and 6 p. m. on the day prior to epinephrine injections and at 6 a. m. on the day of "challenge"). nephrine-induced pressure hours mine, was after the whereas In this experiment the epiincrease in systolic blood reduced five

of postural hypotension and tachycardia was present. No symptoms suggestive of central effects of phenoxybenzaminc were reported bv the patients. Four patients received 0.5/_g/kg. of L._D, and six patients received 1.0_g/kg. of LSI) two hours after a single dose of 1 mg/kg. of phenoxybcnzamine hydrochloride. Since the results of these experiments were almost identical with the findings of the experiment described below, even though the degree of adrenergic blockage was not as great, they will not be reported in detail. Ten patients received 0.5, 1.0. and l.O mg/kg, of phenoxybenzamine hydr_'hloride 24, ll, and 2 hours prior to ,ldministration of 1.0_g/kg. of LSD. The results are shown in Table 2. Miosis, marked 1,o> turaI tachycardia, and postural hy[s>tc,sion with fainting on standing of 5 of the 10 patients after phenoxybenzamine alone ill dicated that a considerable degree of ad renergic dilatation blockage was present. I'upillary after LSD was partially blocked

by phenoxybenzamine, but no other aspect of the LSD reaction was altered significantly. LSD reduced the postural tachycardia and phenoxybenzamine. Scopolamine.--Eleven 0.42, mine 0.64, and hydrobromide 0.85 hypotension patients rag. of simultaneously caused by


received scot_lawith 23

last dose of phenoxybenzathe decrease in diastolic

Isbell et al.

A. M. A. ARCHII_tiS "I'ABLF 2.--F.ffect of 1)ll,'noxyhenzamine




on the L'D Reaction


I'henoxybenzamme Measure Pulse Pulse rate, rate, recumbent stamling .......... .................... re'umbent ..... Placebo plus LSD l'lacebo -}-2.08-4-0.52 +3.634-1._5 +0.684-0.64 +0.794-0.33 --1.254-0.43 0.24-0.08 04-0

Phenoxybenzamine Placebo plus LSD q-5.64-1.t_7 -}-1.24-2.32 +1.7_54-0.23 +3.550.38 + t.66_0.3 334-12 1.65==0.37

Phenoxybenzamlne plus LSD -{-7.744-1.3 +1.604-3.98 -[-1.884-0.27 +2.384-0.18 +2.094-0.4 474-15 1.854-0.37

Phenoxybenzamine LSD plus Placebo

q-4.84-1.01 +15.74-4.5 q-0.964-0.32 --0.354-0.89 +0.234-0.28 0.1 4-0.9 04-0

Systolic Pupillary Patellar Number Clinical

blood pressure, size ..............

reflex ................... of positive answers grade ...............


* Expressed a negative f Means

as the mean a decrease,

4- the For

standard number

error with

of the predrug

area under controls. do_s,




A positive




an increase;


as compared

4- standard


of subjects,

and methods,

see text.

1.Ol,.g/kg. of I.SD. Since the results with these doses of scopolamine were not essentially different from the results obtained with 1.3 mg. of scopolamine hydrobromide combined with LSD, they will not be described in detail. Side-effects attributable to scopolamine (d W mouth, blurred vision, difficulty in swallmving, and pnpillary dilatatir*n) occurred with the smallest dose (0.42 rag.) used and became more pronounced as the dose was increased. Mental confusion, depersonalization, hallucinations, and dehlsions did not occur with any of the closes. _f scopolamine, Twelve patients received 1.2 rag. (1/50 grain) of scopolamine hydrobromide cornbined with 1.0/_g/kg. of LSD. The results are -show1_ in Table 3. Although dryness of the mouth, bluired vision, and sleepiness were pronounced, the patients did not reporl_ the marked changes in visual perception after SCOl_)lamine alone that are so
Tam.l-: 3.--l_ff,'ct ,,] %'opolamine

characteristic of the LSD psychosis, and they did not report any hallucinations or delusions. I'upillary dilatation after the combination of scopolamine and LSD was greater than after LSD alone. The characteristic LSD-induced rise in blood pressure was blocked by scopolamine. Assessment of the mental effects of the combination of scopol;mfine and LSD was somewhat complicated. The mean number of positive answers increased from 65 after LSI) alone to 116 after the combination of LSD and scopolamine. The mean number of answers after scopolamine alone, however, was 42. Counts of the number of times specific symptoms were reported showed that dryness of the mouth, dryness of skin, blurring of vision, and sleepiness accounted for almost all (95%) of the positive responses after scopolamine alone. Increases in frequency Of these particular symptoms also accounted fox- most of the increase in the
,m the L.S'D R,'aclion

] )rugs Seopolamin,, Measure Patellar Papillary Systolic Number Clinical reflex blood grade ........... pressure ................ _ answers.. _ . Pla('(.bo phls LSD l'laeel)o 4-0.834-0.42 4-0.M4-0.24 4-0.784-0.62 104 0:t:0 Scopolamine Plaeci)o plus LSD 4-3.080.36 4-3.450.32 4-2.004-0.37 654-16 1.14-0.34 Scopolamine plus LSD +3.264-0.46 4-4.654-0.27 4-0.430.52 1164-42 1.54-0.4 Scopolamine plus LSD Placebo +1.444-0.38 4-2.(R}0.31 --0.514-0.6 424-20 0.360.37

size ................ of positive

* Expressed a negative Means

as lhe


4- the standard "_s t'ompared For nulnbor


of the

area under controls. do_s, and

curves methods,



A positive






figure, a decrease, 4- standard e-rots.

with pretlrug oi subjects,

see text.


Vol. Sl, Jam.. 1959


T .........................................................................

,S'7"UDIIiS ON L i'.qF.RGIc number of answers after

ACID tile

1)1t: TH )'LAMII9 combinalion

f: time m irate, az but, unlike I..<IL is n,,t

of LSD and sc_vpolamine. The frequency of tile more specific symptoms of the L.':,D reaction (vistutl-perceplual distortions, de personalization, and oi,tical tmllucinau,,n_ was as great after the combination of l.SI) and soq)olamine as after LSD ahmc. bul no greater. The clinical grade of rcacti<,n after l.Sl) and scopolamine was somewhat higher than after 1.SI) alone, but the increase was not signiticant statisticalh-. ()ccasional reports of anxiety and ncrvousn<'ss in 4 of the 11 patients account for the positive clinical grade with scopolamine ahme. The data, therefore, did not suggest any si_'cilic accentuation of the mental effects of [.SD by sc_,l,olamine. They seem more conipatible with <haaplc addilion of different symt)toms caused by two di(fcrcnt drugs. Comment "]'here was no definite evidence of any attenuation or accentuation of the mental aspects of the I.SI) reaction after 1,retreatment with any of the neurohumoral agents, The data. therefore, do not favor any of the hypotheses which attribute the I.SD psychosis to derangements in neurohumoral mechanisms within the central nervous svstern. These experiments do not, of c(mrse, disprove these hypotheses, since unknown factors, such as varying penetratioll, of lhe blood-brain barrier, relative affinity for receptor sites, etc., might account for the negative results, The results with the serotonin anlagonist, BAS. are of especial interest. Although BAS did induce sympton> suggestive of effects on the central nervous system (w(lation), it did n(_t cause any mental reaction resembling that seen after LSD. \Vilkins a._ has also reported sedation after P,AS. Sireilar results have been reported with a congener of LSD, 2-bromo-d-lysergicacid diethylamide (BOL-148). This compound is as tx_tent as I.SD in antagonizing serotonin-evoked contractions in isolated smooth-muscle preparations a6 or in reversing enhancement of hexobarbital sleeping lsbell el al.

a potent l,sychc,t,mdn_etic drug. :'_ It :-. thcref_we, apparent that anta_sm 1,, ,,.q,mmin is nol c,,rvela.*ed with the ability _,f a ,lru/ to 1,r_.luc_- a l_-),hosis. Sin,,P,OI.-14R shouM 1,enclrate the bloom _rau! barrier readily, tim hypothesis that a deficiencv of serotonin is rc_p<,u>ible for ;he 1.SgD psych_sis n,, longer seem_ plausit.,Ic. Recenliv (;inzel and Maver-Gr_,ss hax, rep_wled that l,retvcmncnt of patients (,,r lwo _lays with l{(-)l.-14g attcnu.tted lhe l..ql) rezwlhm, as This finding could posibly be iuterl,iclc,l :e; favoring lhe hSpoth csis that an excess of semtonin-likc effect is reslumsible for the 1.SD reaction. Such au iuterpretati_m i/ltlst bt. regarded with cauti_,n, <ince (iinzcl and Mayer-(;rc,ss found th;tt one day's prctrcam_ent wilh I{O1.-148 does not completely block the effect, _,f l..qD and, also. that l;OL-14g will not reverse the I.SI) rc;tctiou _mce i1 has been dcvelol_ed. These results are more suggestive of cross toh'rance lx'tween LSD and P,( )1.-168 than of bhwkade of the effect of I.Sl) by B()L. Failure tion of becau>e of scrotoniu in man reacti_,n antagonism the amelior;lc,b>crved in

to confirm the I2":.1)

animals e4 after lwetreatment with phcnoxybenz:tmine might be due to the relatively enormous doses of l.Sl) necessary in ant real exl,erimentation , to diff, cuhv in equating behavioral chan.ges iu animals wilh 1,sychose_ in man. or to a c,)mlfinati_m of the_e fact, ws. Summary Pretre, mnent with the netm_humoral blockil_/ drugs l,hcnoxybenzamine (l)ibcnzylim'), SCOlUtlaminc. and l-benzyl-2-methyl5_methoxytryl,tamine (BAS) did not attenuate ()r acccntuale the iy.-ergic acid diethylmnide (1..':,[)-25)psychosis in man. X. 1. M. H. Addicli,m t'. 11. S. Hospital. Research ('enu.r, I'..%

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