LSD

202

I_europharmaco!ogy.
Transactions
of the 2nd Conference_
14ay 25-27_ 1955. Princeton_
N.J. Ed.by H.A.
Abramson.
Josiah i{acy Jr. Foundation_
_,IewYork 1956
R_SEARCH
ON SCHIZOPHRENIA
*
p.183.
bn

_7_
_0
dqi

HUMPHRY

OSMOND
Saskatchewan
Hospital
Weyburn, Saskatchewan,Canada

..'Ji_
S

....

HIZOPHRENICPEOPLE are the bas_s of some extraordinarily fasct{_ing and interesting work.
The psychiatrist, approaching
them
through
_L
,
.
.
ieurology, neurophys,ology,
pharmacology and biochemistry, and
t_r0ugh elegant and frequently astoundingly brilliant techniques, comes
tgl a point where he begins to wish to find out more about this illness or
group of illnesses of these sick people, some of whom we call "schizophrenics. ,, It is here of course, that difficulty arises, because now it
becomes uncertain (a) whether there is such a condition at all, (b)
Whether this condition is so all-embracing that we are all schizophrenics,
{'_) whether this is simply a normal mode of people responding to a
_6rtain type of sociological setting, or (d) whether this is, in fact, an
Hifiess which exists like other illnesses, of which there are more or less
SeVere cases and different cases.
:_So numerous are the references and so varied are the opinions among
_chiatrists
as to what is meant by "schizophrenic," that it is essential
_,_ me to give some idea of what I think it means; otherwise, we may
b:gtalking about something quite different.
. To begin with, I do not accept the view that schizophrenics are to be
iSoked upon as any but the end process of an illness, nor do I take the
view which some hold, that schizophrenic people are necessarily either
antisocial or not useful. On the contrary, there is ample evidence
that some of the most brilliant and gifted and valuable people who have
ever lived have suffered from mental illness. I immediately think of
William Blake (1,2,3) and of Sir lsaac Newton (4). The latter's
strange ailment would certainly have led him to a psychiatrist if he had
lived three hundred years later, and one has the feeling that as his illness
The work discussed here was done under the auspices of the Saskatchewan Committee for
Schizophrenia
Research c/o Psychiatric Services Branch, Dept. of Public Health, Regina,
Saskatchewan.
Funds were provided by the Provincial Government
of Saskatchewan,
the
l_aderal Government
of Canada through the Department
of Health & Welfare,
and the
Rockefeller
Foundation.
.-i_[

t83

1
/

.<

184

N euro pharmac olo gy

continued on and off for about fifteen years, he might have ha_ _
leukotomy. However, Sir Isaac got very well after about 8 months, and
was governing the Mint at the time and, he produced one of his more
famous books many years after he had had his first bout of severe paranoid illness. Simultaneously, he was devoted to his work on numerology
and discovering "The Beast," among other things. One can think of
many contemporary people from the rather less satisfactory Rudolph
Hess (5) to the genius and wonder of Franz Kafka (6,7).
Many would be prepared to say this is complete nonsense on my part,
because schizophrenia has _he unique virtue of being an illness from
which there is no recovery. It has been said that if the patient does re5
cover, he really did not have it. Of course, if this is true, it is extreme_
unfortunate, but, luckily, common observation does not suggest thisi:_fi!
fact, from time to time, one has the extraordinary experience of seeing
someone who has been ill for 10, 15, 20, or even 25 years leaving the
hospital and apparently recovering.
My picture of schizophrenia is that it is an illness which is characterized by disturbances in thinking, in mood, and in perception (and sometimes in posture, which may or may' not be a result). These three great
groups of disturbances may be combined or may not be combined, and
they may be congruous or incongruous. I do not see any reason why they
should necessarily be combined, but, as a matter of common observation,
they quite often are. Clearly, where there is incongruity between thinking, mood, and perception, one would suppose, at any rate, that corn:
plete social disintegration is practically certain, though this is not certain,
as a matter of fact. On the other hand, where there is a little incongruity;
one would believe that social integration is possible.
Unfortunately, the information available as to what makes for social
integration is very small. We have no reason to think that this simple
picture of the degree of congruity, being very important, is, in fact,
what keeps people in our large mental hospitals. But my picture of an
illness is one which I personally see. Dr. Kallmann's work* suggests,
as do field studies, that for every schizophrenic patient treated in mental
hospitals, there are at least two or three out of the hospital. I would
say that even this is an understatement, bu_ I have done very little field
work.
However, I know a few schizophrenic people who are living happily
in a community and who are keenly interested in things around them.
One end of the parameter shows the schizophrenic person lying in
*Prof. Franz J. Kallmann,
Department
of Medical Genetics of the New York State Psychiatric Institute, Columbia University, New York, N. Y.: Personal communication,
1954.

Research on Schizophrenia

185

dismal conditions, in some hospital where this word is almost a courtesy

and where the great tradition of American psychiatry and of BritishQuaker psychiatry and of French psychiatry of the early nineteenth
century has been forgotten, where Kirkbride and Dorothea Dix, Tuke
(8), and Pinel would be scourging those who are responsible for it.
This is one end of the parameter. The other end shows someone rare like
Blake or Franz Kafka, outside an institution and carrying on useful
activity.
This is my picture of the strange, mysterious, and really, very odd
illness. I came to it through seeing many of these illnesses, being
puzzled by them, and finding them incomprehensible some of the time,
but incredibly fascinating. I have always been unable to find any
formula, apart from this very rough one, which, even among the great
classics, such as Bleuler (9) and Kraepelin (10), and the numerous
neoclassicists that followed them, seemed to fit in with what I saw. And
every so often I have seen things which did not seem to fit in anywhere.
This terrible illness, which invariably led one to a mental hospital for
many years, could suddenly turn out to be a highly benign illness that
lasted a short time. Or an illness that was supposed to be highly benign
could suddenly become malignant. On the other hand, a patient suffering from a long-term illness that appeared to be diagnostically extremely
malignant and considered hopeless, might recover in 10 years or so.
Some years ago, when I was in London with John Smythies (11,12,13,
14), a colleague of mine, I found that he had interested himself in
mescaline. Dr. Smythies is a philosopher, and his other interests lie
in the fields of neurophysiology and, to a lesser extent, in psychiatry. He
was deeply interested in the reality of the phenomena of schizophrenia.
It was in connection with this that he became interested in mescaline
and, while experimenting with it, he made the observation which we
now know was a very old one, that mescaline has some resemblance to
epinephrine. Since neither of us knew any biochemistry, we became
tremendously excited about this. It was, of course, a very naive observation on our part, but interestingly enough, although chemists have
known this for a long time, chemically minded psychiatrists have very
rarely pointed out that, for this reason, it would be an extremely interesting thing to correlate the mescaline phenomenon and the schizophrenic phenomenon. If they have done it I have never known it.
Also, if they have done it, they have never made any systematic correlation between the effects of epinephrine and the effects of mescaline.
Nor have they, except for sporadic forays, made any very systematic
investigations of the effects of mescaline and similar compounds, and
then correlated them with the effects of schizophrenia.

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N europharmac olo gy

We then carried out a sort of rough correlation. I think it is, again,

of interest to say that although the pure alkaloid was isolated and its
psychological effects described very clearly by Heffter (15) in 1896, we
have never seen a paper that gave a really clear picture of the effect of
different doses of the alkaloid in the same and in different people.
Neither did we find any comparison of these effects with those of
schizophrenic illness. It must have been done but we have never run
across it. There was no map to guide us so we made our own. From
this it seems that if a wide range of schizophrenia and mescaline intoxication is studied, the great majority of symptoms is found in both. The
more the range is narrowed, the smaller is the overlap.
One of the interesting things about schizophrenia is the fact that at
one end of the parameter there can be a man in whom apparently only
one area of experience has been altered, and at the other end of the
parameter there can be a man who is totally out of touch with everything. There is a curious distinction which we made between the toxic
confusional illnesses, those intoxications in which clouding of consciousness occurs, and the schizophrenic illnesses. In the former there
is unawareness of immediate surroundings, such as not knowing the
date or the time, disorientations. The latter are said not to include this,
but in actual fact, they appear to be a continuum. Many psychiatrists do
not seem to be able to make a distinction between the two.
We could find nothing in the huge continuum of mescaline phenomena which could not also be found in certain schizophrenic illnesses. We
then tried to find out whether many had suggested looking for substances that had the power of epinephrine and its derivatives, and the
psychoactivity of mescaline but not its pressor effects. Again, this was
an extremely naive idea, but it did not do us any harm.
Sherwood: You started by stating that for your definition of schizophrenia, it was necessary to have a disorder in one or more of the following classes: thought, mood, perception, and posture.
Osmond: Posture came in as a fourth because I am not sure that it is
not a derivative. I am inclined to think it is not a derivative.
Sherwood: You say that any of these may affect only one area or
more ?
Osrnond: No.
Sherwood: You didn't say "area," you referred to those classes.
Osmond: I referred to these things as classes, yes. This is a bad definition on my part, but I have deliberately made this wide because, not
being a psychologist and not being a philosopher, I find the definitions
of these things difficult, and I go in the tradition of William James,
(16), who, whenever definitions came, took the greatest care to avoid

Research on Schizophrenia

187

them. When he was reproached at the time, he said that he was not
made that way.
Fremont-Smith: May I support you ? I think that definitions, unless
made for a specific and limited goal, have no value other than to be
restrictive and to interfere with thought and experimentation. I think
that definitions, on the whole, are to be avoided, except a working definition for a specific, limited, and stated goal.
Sherwood: I only wanted to make sure that I knew what you meant
by"area."
Fremont-Smith: And you gave us a chance. I am very much in agreement with you.
Osmond: As to posture, there is a good deal of neural evidence. I
think that there are specific disorders of posture that occur, but, here
again, occasionally you get an interpretation of a catatonic posture in a
person that makes one feel that, in fact, as one would expect, these are
psychological entities. Certainly, to the catatonic person, his posture
may represent holding up the earth or punishment for cutting his father's
throat, or something of that sort. But, again, in this particular instance,
if one makes too narrow a definition or if one narrows oneself, it does
not help, and I feel that the posture entities are very important.
At any rate, we started our investigation from this, not really having
any idea what to do, but making numerous consultations. We obtained
a great deal of help from Dr. J. Harley Mason, University Demonstrator in Organic Chemistry, Cambridge, England, and from Dr. C. M.
Scott, Director hnperial Chemical industries (Pharmaceuticals),
Blackley, Manchester, England. We decided to collect numerous compounds,
starting with mescaline and working slowly and progressively toward
epinephrine.
Leake: Did you by any chance run into Louis Lewin's Phantastica
(17)?
Osmond: Yes, but never in an English translation, unfortunately. It
went out of print in England in about 1935.
Leake: Did you go into Sigmund FrSnkel's Die Arzneimittel-Synthese
(18)?
Osmond: No.
Leake: That, again, is not available in English. So much of this was
rather clearly anticipated in connection with type of activity, many years
ago, but unfortunately, in a narrow, restricted field, in relation to chemical constitution and biological action. It did not come into clinical
attention, so the possible value of it, either from the standpoint of experimentation or even of clinical investigation, was not appreciated.
Another work of similar interest is Lewin's Die Gifte in der Well-

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N e ur op harmac olo g y

geschichte
(19) which has a lot of incidental information
these lines. It is not a popular item, but much more detailed.

all along

Osmond: At any rate, we started on this orderly progression,

or so it
seemed to us. Dr. Scott made methyl mescaline and some other related
compounds for us, and fortunately at about this time, I went to Canada

and started to work with my colleague,Abram Holler

(20,21,22).
We
had not done any simple arithmetic, because, otherwise, I think it would
have struck us that the orderly progression that we had in mind represented something like ten thousand compounds.
There was the further
detriment to this orderly progression
that each compound,
as we soon
discovered, takes a long time to try, and we had no animal methods
worked out in our minds. Only recently, Dr. Mirsky has been working
on some animal methods, but we did not know about these, and it would
have been a very long journey. There is the added fact, of course, that
the number of people who are prepared to engage in taking ten thousand
unknown
compounds
is limited, and, therefore,
on a volunteer
basis
alone, one is soon going to run out of subjects.
I took mescaline in 1951 and I found this a most extraordinary
experience which I will describe later. My experience was recorded and
in order to find other subjects, my colleague, John Smythies, thought that
we would play this recording to others in order to encourage them to
try it (23,24,25).
We at length found a man who we thought would be a very good
subject. He was a young history professor, and we felt that he would
be intelligent, interested, and able to make a clear report. We also
thought that he might produce aspects of experience that would be
interesting for us to study.
As this man listened to the recording, he appeared rather ill. When
asked what was the matter, he said that the recorded reactions were
familiar to him. He said that he was a severe asthmatic and that when
he suffered from asthma badly,
things happened to him.

if he took epinephrine,

some of these

We interpreted
that, rightly or wrongly, I am not certain, to mean
that if there are people in whom the pressor effects of epinephrine do not
take place, then either epinephrine itself or some of its metabolites could
produce this type of disturbance, and this began to shift our attention
a little bit.
We found that this was not very uncommon
know, there is a curious relationship
between
a small group of people. We found that quite
have these very curious disturbances,
often in

with asthmatics.
As you
asthma and psychosis in
a few asthmatics, in fact,
affect and sometimes in

Research on Schizophrenia

189

perception. One very interesting reaction was described to us by a

medical student. He said that he used to use an epinephrine nose spray
for asthma and, as he never had much money, he used to keep his nose
spray a long time and it would get yellowish and off-color. He found,
at the time of using this off-color epinephrine, that he got a curious
feeling of indifference toward people which really only worried him in
retrospect; it did not worry him at the time. For example, when he was
driving, if he saw a child in the road, he would suddenly find that it was
an intellectual process, and not an affective process, as to whether or not
he would slow up. He did not worry, as you or I would if we saw a
child in front of the car; he merely wondered if he would get into
trouble if he did run it down.
As you can see, this tiny change is, in fact, an enormous change,
psychologically, and this gave us a clue. Finally, Dr. E. Asquith* who
is an anesthetist at Regina General Hospital, told us that while in England during the war and his co-workers had some epinephrine that had
"gone off," and was a sort of pinkish color. The anesthetists used it and
found that it had very inadequate pressor effects. They gave a considerable amount of it and, of course, they were giving it to people who had
been given atropine which fact I think may be important. They found
that many of these patients would go quite crazy. This effect lasted for
only a day or two, but it upset the anesthetists. When the patients came
out of the anesthetic, they would be visually hallucinating. We asked
Dr. Asquith why he didn't inquire into this, and he gave what seemed
to him a very satisfactory reply--they just gave up using this epinephrine.
We therefore began to think that it might be of value to look more
closely into epinephrine. Another idea that came to us was, why should
we not find out all the substances that produce psychological effects
similar to mescaline, with minimal biological effects ? We felt that if,
as we had hypothecated, the body itself might produce something which
produced obvious and gross changes in the sympathetic and parasympathetic systems, they would have been found out a long time ago, and
therefore there would not be any argument. In fact, the literature is full
of arguments as to whether the sympathetic or the parasympathetic system predominates, and what, in fact, is happening. We felt that it was
an essential part of the thing we were looking for, that it should have
very little obvious effects, and that effects had not yet been classified;
therefore, we started to look at the known substances that produce
these conditioning disturbances.
The substances that I know of up to the moment are mescaline,
*Private

communication,

1952.

190

N europharmacolo gy

lycergic acid, harmine, norepinephrine, indole (found in ibogaine),

epinephrine, adrenochrome, and adrenolutin.
The first and most striking thing, of course, is the extraordinarily
small number of these substances; however, they are widespread
throughout the world, and some of them have enormous antiquity and
tremendous social importance.
Marrazzi: Would you clarify what you were saying about looking for
substances which I thought you said did not have obvious autonomic
effects ?
Osmond: What we were looking for was substances that were known
to have more or less obvious psychological effects and less obvious
autonomic effects, such as would not be easy to classify. This is why
we ruled out atropine. There is no doubt that an individual can be made
quite psychotic when given atropine if he is given enough, but, at the
same time, it is quite obvious that he has had atropine. And so this
could hardly be a substance of the sort that would produce this extremely
fugitive and strange illness:
The earliest one that we have on record is soma. No one knows what
soma is, because, apparently, it was introduced into India from the
north, between two and three thousand years ago. The high caste Indians
also called it homa, suma, funa, and a great many other names. The
only person who appears to know much about it is Dr. Andreyi Puharich,
of the Round Table Foundation, Glen Cove, Maine, who is making a
study of it and has started with Herodotus and early Egyptian sources.
Soma has an enormous and very ancient history. Its story, according to
India, is this: It used to be imported, and the high caste Indians took it
as part of religious ceremonies. They went on taking it for many generations, and apparently it was dangerous. It was said to be a creeping
plant, supposedly coming from somewhere in Central Asia. Eventually
it was no longer possible to obtain so the devotees took up yoga as a
way of trying to produce the same sort of experience. Since then, they
have been carrying on with yoga. I do not know whether or not this is
completely accurate, but I understand that Philippe de Felice (26) claims
that is what happened. At any rate, we were certainly not able to obtain
soma and so, of course, we do not know what it was.
I believe the next one in antiquity of which we are certain is Indian
hemp, hashish, which, again, is very old, and to which we did not pay too
much attention, because, the battle about the active principle still seems
to be in progress. We felt that it would be quite useless to enter into
that. It may have been solved by now, but we came to the conclusion
from the literature available that there was almost no end to this.

Research on Schizophrenia

191

Furthermore, the hemp is extremely variable; even samples from the

same crop differ greatly. But it has a long and noble history.
Then came peyotl. Peyotl, again, has a great history, and we, naturally, started off with the papers of Havelock Ellis (27) and S. W.
Mitchell (28). As you know, peyotl has been, from the psychiatric
point of view, one of the more curious incidents in psychiatry, because
there is tremendous ambivalence among psychiatrists toward it. At one
moment, they are tremendously interested, and they are being urged on
by the scientists and the poets to do something about it, every so often.
Heinrich Kl_ver (29), for instance, has spent years urging psychiatrists
to interest themselves in mescaline.
Leake: May I interrupt for a moment to say that it is wise to remember the slow development of appreciation of the euphoric and dreamproducing effects of opium ? This drug was well known to the early
Romans, and has a long history of gradual understanding of its hallucinating properties. One should also remember the long popular mythology associated with the mandrake or mandragora (30). In this
connection there was also the ancient recognition of hallucinations from
atropine-containing plants.
Probably older than peyotl is the use of tobacco as an intoxicant
among the Amerinds. In the South Seas, the natives used kava, and in
the Andes, the Incas chewed coca leaves. On the other hand, in India,
rauwolfia, was recognized by the Hindus as an antiphrenetic. Dioscorides, the Greek medical writer, described this as "serpentina," also
noting its antiphrenetic action. Many other similar native agents are
described in Lewin's Phanlastica (17).
Osmond: We ruled out opium because of its extremely narcotic
effects.
Leake: I know; but it produces many of the symptoms.
Osmond: Yes; it does.
Leake: It produces many of the symptoms that are involved in some
degree of loss of touch with reality.
Osmond: But the ones we had to rule out were those that did not
pertain to the clinical picture with which we were faced. But, on the
other hand, I entirely agree with you that these others are clearly of
extreme importance in the total psychological picture. However, we
felt, from the clinical picture, it was less likely that those opium-like
substances-Leake: But even of greater antiquity, and with wider distribution than
any of these, are the fermented drinks, such as beer and wine. Beer was
well known to the old Egyptians, and wine from the utmost antiquity.
Their intoxicating properties were well recognized by the ancients.

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N europharmacolo gy

Many phases of their intoxicating action resemble various types of

mental disturbance, at least from the standpoint of unusual behavior,
including disturbances of thought, mood, and perception.
Abramson: How about wormwood ?
Leake: No; wormwood was always used, as far as I know, for expelling worms.
Abramson: What about pernod ?
Leake: Absinthe is derived from wormwood, but its effect, as far as I
know, did not become known generally until the distillation process
developed during the Middle Ages. Then, this peculiar use of absinthe
developed somewhere in the seventeenth or eighteenth century.
Abramson: But that would disturb thought, mood, perception, and
posture.
Leake: Yes; but it certainly did not come out of antiquity.
Cerletti: I would say that it is a certain danger to think that all possibilities of mental disturbances by drugs have to do with your problem.
I think we should try to limit the problem to more specific drugs and
make a distinction between, let us say, intoxication by alcohol, as an
example on the one side, and what Dr. Gerard calls psychosomimetic
drug effects on the other. Otherwise, we must cover the whole field of
pharmacology. There are several other examples. Perhaps you remember, that during the war between Italy and Abyssinia the story became
known that the Abyssinians drank a special tea t)efore going into battle.
This tea was made of Catha edulJs, the active principle of which is
known to be closely related to ephedrine and amphetamine. This might
be a more typical example for your field, but I still doubt if it is possible
to take into consideration all kinds of drug intoxication.
Leake: I know the problems. Nevertheless, let me defend my position.
In considering the relation of chemical constitution to action on the
central nervous system, let us remember the enormous scope of the type
of chemicals that are active. It is important to select those that produce
the most striking effects, and to investigate them most thoroughly. But I
certainly think that we would be unwise, in a general discussion of
neuropharmacology with particular reference to mental disorder, if we
neglected addiction drugs, or if we neglected the whole scope implied
by the consideration.
Cerletti: I am also thinking, for example, of Schmiedeberg's old
description (31) of urethan as a drug producing something like a
psychotic state in animals. When urethan was used for the treatment
of leukemia, some cases of mental disturbances in patients were
described.

Research on Schizophrenia

193

Leake: If we are interested in obtaining any clue regarding possible

chemical disturbances occurring in mental illness, we cannot really forget or neglect any drug that may produce some abnormality in that
regard. It may give us an important clue.
Osmond: I limited our work, as far as I could to those drugs that did
not produce disorientation and confusion, not because any of these
things occurred even with the large doses with which we worked, but
we sought essentially disturbances in perception, thinking, and mood.
If the person who doesn't get DT's takes a sufficient quantity of alcohol,
he becomes unconscious. Again, if he takes opium, he is on the fringe
of the curious narcotic state that De Quincey (32) described. He is not
this way if he takes peyotl or mescaline. That, therefore, was our rough
way of division, and that is why it brought us down to this small group.
Whether, in the long run, this will prove to be of any use or not, we do
not know, of course.
After peyotl came mescaline. Of others that followed, one of the
most respectable and one of the oldest is, of course, cohoba, which is
derived from the seeds of Piptadenia peregrina (33). It appears that it
was merely an accident that tobacco and not cohoba was introduced to
the West. It is interesting to speculate on the psycho-social consequences
had cohoba been substituted. Ramon Pane, who sailed with Columbus,
seems to have been the first to notice it. In Cuba, the natives used two
types of snuff, one of which was tobacco snuff and the other cohoba. One
suspects that when they came across the predatory white men, they came
to the conclusion that they would give them the less potent of the two.
This decision was a fortunate one for them, because in South America
and Central America, where the Indians interested the white man in
their own invention--peyotl--the
white man's immediate response was
to forbid it. This is characteristic of the white man: Those activities
in other cultures of which he does not approve he bans as vices, but his
own vices he spreads determinedly. So we see the disappearance of the
home-grown methods of altering psychic experience, and the imposition
of the white man's own method--alcohol,
although there is not the
slightest evidence that his own is either better, safer, or more desirable
than the native's method; rather to the contrary. The evidence before
the Commission on Indian hemp held by the British in the 1890's in
India (34) seemed to show that, on the whole, the hemp is less objectionable than alcohol, except, of course, where it is occasionally used in
combination with datura, when it turns out to be very powerful. This
will be discussed in more detail later.
Rh_kel: Dr. Osmond, the natives use a special machine for the snuff
which they make out of cohoba, and one of the original pieces of appara-

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N euro pharmacology

tus is at the museum in Philadelphia and another one is in Heidelberg.

As far as I know, those are the only original ones which exist.
Osmond: Dr. Schultes (35) sent me a very good paper of his dealing
with another substance which is taken as a snuff. This is called yopo or
yarge and it is made by heating the resin exuded from a certain nutmeglike tree, once it has been barked. This snuff is very powerful and
we would like to obtain some, but it would mean taking an expedition a considerable distance up the Amazon. The Indians who live near
white men pretend to be ignorant of it. I do not know of anyone who is'
working on it and only heard about it recently. Now, I don't know of
any work on bufotenin, but I am told there is some being done. We did
not know this at the time of our work.
Rinkel: Bufotenin, as far as I know, does not produce any particular
mental symptoms. Is that correct, Dr. Cerletti ?
Cerletti: That is just what I wanted to ask. Has it been shown that
bufotenin can produce the symptoms of cohoba ?
Osmond: It is alleged that it can.
Cerletti." It has been isolated from cohoba, but it has not yet been
found that it produces the symptoms of cohoba, as far as I know.
Osmond: It is so claimed, in monkeys.
Cerletti.. I know that in monkeys effects similar to those produced with
LSD have been described, but with very large doses bufotenin produced
some unspecific toxic symptoms, just like the ones I described in the dog.
Osmond: I have had no experience with it. We have been trying to
obtain some. Dr. Marrazzi, have you had an), ?
Marrazzz: No.
Cantoni: I think, with bufotenin, the experiments were mostly done
in a scientific manner, and this is most unfortunate in that this drug was
not used by the Indians in a scientific manner. The real way to test the
drug would be to apply it with a snuffer, that is, one of these pieces of
apparatus Dr. Rinkel has described. I think that this experiment has
been planned, or is being planned, in Bethesda, and until such time as
it is actually carried out, all one can tell is that bufotenin, when injected
intravenously, does not produce psychic effects. This is not particularly
significant. If the same negative results should be observed when
bufotonin is applied in the more usual way, that would be quite significant.
Osmond: This business of the snuffer is a fascinating sort of anomaly,
isn't it, Dr. Cantoni, because there are connections between the nerve
endings that go right into the nasal area, do they not ?
Fremont-Smith." They are very short, only a few millimeters, right tip
into the olfactory bulb.

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Magoun: My guess would be that this was brought into the mucosal
vessels and thus into the circulation.
Kety: May I summarize the situation on cohoba to avoid confusion
about what is known of this substance? Horning's laboratory at the
National Heart Institute in Bethesda isolated bufotenin (33), which is
dimethyl serotonin, from cohoba. Evarts at the National Institute of
Mental Health (36) found that bufotenin given intravenously, in large
doses, to monkeys produces the same symptoms as do large doses of
LSD; these symptoms seem to be blindness and certain disturbances in
motor behavior, but there was no evidence of subtle mental aberrations
with small doses. Bufotenin cannot be given to man intravenously in
large doses because of its profound circulatory effects, which resemble
those of serotonin. Dr. Homing tells me that there are other substances
in cohoba besides bufotenin which may very well be the active principle.
Harris Isbell, at the United States Public Health Service Addiction
Research Center in Lexington, is administering bufotenin by the intranasal route, in order to test the possibility that this may be the mode of
administration necessary. He is going to prepare it the way the Indians
used it, and to administer it that way. He is having great difficulty
because his subjects sneeze violently when given the crude drug, while
pure bufotenin by aerosol has not yet shown any mental effects (37).
To the best of my knowledge, that seems to be the situation at the
present time.
Abramso_e: I might add that the sneezing might be connected with
the particle size of the aerosol which it produces in the snuff.
Kety: That is an interesting point.
Fre,mnt-S,zith: _rould a tiny speck of anesthetic of some sort prevent
the sneezing ?
Kety: That is another good point.
Marrazzh How large were the doses of LSD and how did you detect
the blindness ?
Ketj: These were appreciable doses, something of the order of milligrams.
Cerletti: I have seen 1 mg./kg, in a report.
Kety." And the blindness was obvious from the behavior of the
monkey. The monkey would run into things, and did not seem to react
to visual stimuli.
Cer/etti: Should not the possibility also be considered that, if something is applied by snuffing, the stimulation of olfactory endings could
influence the psychic functions? Such studies have been made with
special products of the perfume industry. Perhaps there is an effect only
in certain people with abnormal or psychopathic tendencies.

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Kety: Of course, to a number of us, it seemed that there might be a

blood-brain barrier problem here, and that the introduction by the intranasal route might get the substance immediately into the cerebrospinal
system without having to pass the blood-brain barrier.
Marrazzi: You say the intranasal route would get in directly ? How ?
Kety: Aren't there fairly direct communications between the olfactory
nerve endings at the top of the nose and the rest of the brain ?
Sherwood: It is a well known fact that particles of India ink will
migrate from the nose through the cribriform plate and into the area
of the olfactory bulb.
Marrazzi: I don't know that drugs would necessarily.
Kety: We didn't know, either, but it was a possibility.
Cantoni: That is what they want to find out. I might add that one of
the substances which Homing has identified in cohoba seeds is the
quaternary derivative of serotonin, the trimethyl serotonin, which is a
positively charged compound, and this might have some properties
which might aid penetration and be, perhaps, advantageous in that
respect. One doesn't know.
Osmond: It hasn't been experimented with yet, really.
Kety: Obviously, the reason for the great interest in cohoba is the
fact that (1) the active ingredients, or should I say an important ingredient, is so closely related to serotonin (2) because Page (38) has
isolated from normal human urine substances which appear to be
methylated derivatives of serotonin.
Cerlettk Why did you not include bulbocapnine in this comparative
chemical list ?
Osmond: Because we had all done such an enormous amount of work
on it and also because we had very little information about its psychological effect. However, its effect was shown in cats. We felt though,
that the dosage involved seemed to be a very large one.
Sherwood: Yes; it is something of the order of 20 rag. Ingrain and
Ranson (39) used that amount to obtain their experimental catatonia
in cats. But this, incidentally, is the only drug that Feldberg and I (40)
have found to do much the same thing whether it is given through the
ventricles or subcutaneously. The only difference is the dosage; good
effects are obtained with a dose of 500 /_g. to 1 rag. in the ventricle.
Some experimental work along these lines has been described by de Jong
Osn_ond," And, of course, all the time, we were looking for something
that we thought might turn up in the body, which limits one's field. We
could find substances at that time--and we didn't find cohoba then. Since
then, we have found one o1: two more that we would have liked to

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investigate, and one that we did investigate; that was ololiuqui (an
Aztec name) which comes from the seeds of Rivea corymbosa. I will
come back to ololiuqui later in the discussion. I found it very interesting as it was the primary narcotic of the Aztecs, and peyotl was,
in fact, their secondary narcotic. They esteemed ololiuqui highly and
kept it secret from the Spaniards while they allowed the invaders to
learn about peyotl. It is odd that although they had this extraordinary
substance, peyotl, to work with, they preferred to work with ololiuqui,
but there is little doubt that they did. For many years the inquisitors
used to ask whether the Indians had taken the "devil's root," and also
ololiuqui, the "devil's seed," but all they managed to get was peyotl.
Rinkel: Dr. Osmond, since you have talked about ololiuqui, will you
please elaborate on it a little more? I know from your work that there
are some quite intriguing facets to it. I thought we might have some
details.
Osmond: I thought it would be more logical to return to ololiuqui
later, and for the present, to discuss harmine, about which there is a
good deal in the literature. I have never found any satisfactory psychological experiments with it, however. It was not easy to obtain. I have
some seeds of the harmala and have eaten some of them. They are very
unpleasant, and they do not seem to produce any effects, but I think
that may be because we have not eaten enough.
Ibogaine is the next one. I wrote to Dr. Albert Schweitzer to try to
get information about ibogaine. I believe Lewin (17) has information
about it, also, doesn't he ?
Leake: Yes. Janot and Goutarel (d2) have isolated voacangine from
Voaca_2ga africaIza, which is related to ibogaine. Voacangine is a
methoxy indole.
Osmond: We have tried to obtain a supply of that from the S. B.
Penick Company of New York, but it is apparently quite difficult to
collect the right bean, and the Penick Company was concerned that we
might get a supply of the wrong bean, and, of course, so were we. For
that reason, we have never taken ibogaine. Albert Schweitzer's (43)
account of it certainly suggests that it should be tried and experimented
with.
We got a group of these substances together, and then it seemed to
us that there was a possible pattern here. It was conceivable that if
mescaline joined into some sort of indole-like compound, possibly, there
might be some sort of unit),.
Armed with this idea and with the pink epinephrine idea, we went
to our colleagues in the University of Saskatchewan, Prof. Charles
McArthur and Prof. Vernon _roodford of the Department of Bio-

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chemistry, and Prof. Duncan Hutcheon of the Department of Pharmacology, and asked their advice. We were thinking of a breakdown
product of epinephrine that would be active but without its pressor
qualities. We had not, however, reached a firm decision as to what this
might be, so we asked them. Dr. Hutcheon, who is now with Chas.
Pfizer & Co., suggested adrenochrome, which he and his pupil, Mr. Eade,
made.
They tested it on mice, and we began to go into the literature on it
and found that there is an extensive literature in many directions except
on its psychologic effects. Apparently, it has always been known to be
rather unstable and difficult to deal with. Dr. Leake tells me that it is
always resonating and becoming something else, so that it is clearly an
interesting substance. Also, Chevremont (44) has done some work on
it in relation to the mitosis of cells.
If we were right in our supposition that there is a toxic substance in
human beings, those already loaded with it, i.e., abnormal humans,
psychotic patients, would obviously be entirely unsatisfactory subjects
for study, so for that reason we have always felt that it was essential to
study the effect of the drug on normal human beings. In the same way,
if you give someone a large dose of LSD and then another there appears
to be very little effect. I think L. Cholden* has shown that if LSD is
given at short intervals, eventually it becomes quite ineffective, something, presumably, having happened.
Abramson: Tolerance to LSD-25 was first observed by Dr. Harris
Isbell and his group (45) at Lexington, Kentucky. I think that is important for the record.
Osmond: Yes. The difficulty was that, although in actual fact, it is
rather nontoxic with mice (46), we did not know what it would do
when administered to human beings, and we did not know how to administer it. We gave it initially by subcutaneous injection, which is very
painful, and we started at what we thought were extremely low doses,
about 0.5 mg. I have some reason to suppose that the dosage which we
used was larger than we intended as we had a new electrical balance
which I do not think we were using properly. I suspect that our initial
doses were at least ten times what we supposed they were, and that we
started off first with 1 mg. and then with about 5 mg. Certainly our
later experiments suggest that about 10 mg. is about the lowest effective
dose.
Then, of course, we began to run into some of the difficulties with
methodology because, ideally, one should really have all these things
*Unpublished

data.

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set up with double-dummy experiments and things of that sort. I gave

the first dose of this to Abram Hoffer, and the only reaction he had was
a long pain.
Marrazzi: Where ?
Osmond: In his arm.
Fremont-Smith: This injection was subcutaneous ?
Osmond: Yes, subcutaneous. Then, Dr. Hoffer gave me an alleged
0.5 rag. dose also in the arm, and I got a lot of pain. I should say, and
I think the blood pressure records suggested this, that I had no dryness
of the mouth, so I do not think there was any epinephrine in the dose.
Secondly, I do not think I was unduly expecting anything, because I was
quite convinced that it would not work, for two reasons: I believed the
dose to be 0.5 rag., and it seemed extremely unlikely that anything so
small would produce any effect. The other thing was that I was somewhat preoccupied by the pain.
Fremont-Smith: It kept on hurting, did it ?
Osmond: Yes; it continued to hurt all through the night but, as time
passed, I did not seem to worry about it.
Leake: Was this subcutaneous ?
Osmond: Yes; it was.
Fremont-Smith: How large a volume ?
Osmond: We originally made up about 2 ml.
Leake: In distilled water ?
Osmond: Yes, in distilled water.
Abramson: That produces the pain ?
Osmond: Yes ; I found out something here.
Fremont-Smith: But not persistent pain from distilled water.
Osmond: I think that the substance itself produced some pain, too.
Anyway, of course, in any sort of experiment of this kind it is necessary
to ask whether or not the subject frequently has experiences of this sort,
if so, the value of the experiment is reduced, of course. You should
know, then, that I developed a mild delirium when I had a fever of 104
F. and was being heavily treated with sulphonamides; however, I do not
normally develop a delirium under 104 F., and I do not appear to have
any specific sensitivity to any of the various drugs. I am not particularly
sensitive to barbiturates, for instance. I am somewhat sensitive to
benzedrine, but not in the direction of my becoming grossly overexcited
or psychotic with it; I merely become very depressed. I think that these
things are important because I suspect that people have a wide range
of psychological differences in their reactions to all these substances
and we have very little information with which to work at the moment.
At any rate, I felt nothing much, and I was convinced that nothing

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much would happen; in fact, we were discussing what dose we really

could next use with safety when I began to feel that the lighting in the
room had changed.
I can normally improve on my hypnagogic phenomena by taking a
few drinks in the evening after having had a hard day. Under these circumstances, with my eyes closed, I can see patterns of blues and blacks
but nothing very vivid; if I am very tired, I can sometimes see more vivid
coloring. I have to have the lights off to do this, incidentally. What
happened on this occasion, however, was something different. In our
particular laboratory, the light is quite bright, and the place seemed to
be painted a very bright blue color. I closed my eyes, and had the very
odd feeling of being at the bottom of an aquarium and of seeing curious
things like sea anemones and bright flashing colors; I was becoming
preoccupied with this.
Of course, I felt at the time that this must clearly be some sort of odd
imagination, but the fact that I went on looking was an indication of
how odd it was, because normally I would have quickly opened my eyes
and stopped this. Meanwhile my colleagues were urging me to let them
know what was happening but I found myself getting less and less
interested in them.
She,'wood." Did you have any disturbances in other sensory rnodalities,
or only in the visual?
Osmond: No. Just visual. I opened my eyes again, and I felt the lighting had changed in the room. Of course, I was not an unsophisticated
subject for this; I had taken mescaline, for instance. But I began to think
that it was odd. I noticed that a van Gogh picture on the wall had a
peculiar plasticity and depth about it which I had not noticed before. I
think this is quite important because I am not normally very sensitive to
pictures. This particular picture had never struck me very much, except,
as is true of some of the pictures van Gogh painted when he was in the
asylum ; they can be very unpleasant. However, the picture now began to
become highly plastic and highly unpleasant. I began to feel uneasy,
and I wanted to get out of the place. I found it depressing.
My colleagues kept urging me to begin a Rorschach test which they
had. I was not anxious to but finally did. This is interesting because
I have always deliberately refrained from doing the Rorschach test but
on this occasion I did not feel any particular reason for not doing it.
Moreover, when I looked at the test I found it much more interesting
than ever before, and also I saw things in it which I have never seen
before nor have I seen since. There were parts of it that were really
quite fascinating, particularly card 10 in which I saw a shrimp salesman.
In the laboratory I was fairly happy although I didn't like the ques-

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tioning, I didn't much like the colors, and I didn't like the van Gogh,
but then we went outside and there was a curious sensation of the place
having changed.
We were driving along a familiar road but it didn't seem familiar. I
would look into a house and see a lamp there, and this would seem
significant; then I would begin to think and brood about it. The other
thing I noticed was that I was extremely disinterested in my colleagues.
They kept saying how interesting this was and I felt that I ought to feel
that it was fascinating, but I didn't.
Marrazzi: This was different from the feeling of being at the bottom
of an aquarium ?
Osmond: Yes. This was while I was out in the outer world. I didn't
return very much to the aquarium sensation. I should say, again, that
this was an unscientific experiment because we did not have any particular intention of doing the experiment that night. We finally arrived
home and some people came in. I sat there for the best part of 3 hours,
quite disinterested in them. I didn't want to talk. I found that I could
be interested in and preoccupied with things and really felt happy with
them, but people were a great strain. They seemed to make very silly
remarks which they always wanted to press on me. It was almost as
though they were intruding upon me. The only other time I have had
an experience in any way similar was after I had taken mescaline. I
normally do not feel this extreme reluctance to relate to people.
Sherwood: Would you care to say whether what you experienced then
was caused primarily by an impairment of memory of a relatively recent
kind or was it the cognitive power that was impaired ?
Osmond: The memory was excellent. I could name the street quite
easily, but it did not look just the way it normally did. It wasn't a case
of being disoriented and not knowing where I was.
Sherwood: So the significance of things was your difficulty ?
Osmond: Yes; that is it; the significance.
Fremont-Smith: It doesn't seem to me that this quite describes it,
either, because the significance would mean from one point of view. You
recognized the street was leading you to the place where you expected to
go, b{atthen it also seemed strange. It seems to me that what you are
describing is the quality of a strangeness combined with the fact that it
was still the street it was supposed to be.
Leake: Were you in any way disoriented in time ?
Osmond: No; I knew where I was. I knew, if pressed, I could verv
well say what time I took this drug and that we were making an experiment, but this appeared to be very unimportant.

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Sherwood: Did you have any difficulty in understanding what ,people

were saying to you ?
Osmond: No; I understood very well what they were saying, but I
had great difficulty in being interested in it.
Leake: But you did not feel hostile to them ?
Osmond: I felt hostile when they kept on talking because I didn't
want to talk to them. It was a feeling of being intruded upon. At any
rate, on the first occasion when I took this drug, the effect wore off
by the next day; however, the following morning and all that day I
felt extremely lively and active and interested, in fact, rather hyperactive.
About a week later I took a second dose and I assumed that the effect
would all be gone by the next day, as before, but a curious thing happened. I was supposed to go to a meeting and at this meeting I was to
undertake certain discussions about mental health propaganda. I also
wanted to drive to the meeting. I had taken the dose the night before at
eight, and this was the second dose. That morning, at seven, I got up
but I was extremely slow in dressin_ and getting out. There seemed to
be a great deal of time and it did not seem to matter if I was late.
When I got my car out I decided that I couldn't drive so persuaded
someone else to drive for me as far as there was heavy traffic. Then I
thanked him and drove on, not giving him a tip for this service, although,
normally, I would have done so.
When I got to the meeting, I felt all right, but I suddenly began to
realize that I couldn't relate to these people, that I couldn't talk to them,
and I had a queer feeling that somehow there was a sort of glass between
them and me. I made one or two remarks--as I felt I had to do something, but it was a great effort. I was beginning to get preoccupied
about driving the car as it was a 70-mile journey back across the prairies.
Fortunately, I was able to arrange for a friend to drive me home. As
we drove along, I realized that the reason why I couldn't possibly have
driven the car before was that I didn't know where other cars were. 1
would see a car on the horizon and I would think it was going to run
into us. Then I would think again that this was nonsense; it was a half
mile away. Then there would be a queer panic, a sort of shuffling between not knowing whether it was close and intellectually knowing it
was far away but not feeling that it was far. It really proved to be a
very unpleasant journey back.
About halfway home we stopped at a restaurant and another curious
and rather unpleasant thing happened. There were two cars nearby
which had obviously been in an accident and were badly damaged. I
went inside for coffee but found that I did not like the place. In particular, there seemed to be a lot of unpleasant-looking
individuals present,

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so I went out. Then I found that I just couldn't get myself away from
the two wrecked cars. There was a feeling that I was involved with
them, that the accident they had been in had something to do with me.
I wondered what had happened to them and then I came to think that I
knew, which, of course, was not true.
This effect, I am glad to say, wore off completely after about 24 hours.
We then carried out two more experiments with Dr. Hoffer, one of
which he assured me at the time had produced no results. He told me
that some of his things had been stolen by people in the building and
that there were many fiendish people about. Of course, this was not
true. In fact, the things were there and I was able to find them. Later
on that day he made arrangements to buy an expensive picture when he
didn't have the money to pay for it. He did not need the picture, and,
in fact, he had to go back the next day and tell the rather disappointed
artist that he did not want it.
We came to the conclusion that this substance produced peculiar
changes in affect and perception of the subject and which, when you
knew him were easy to spot and very obviously were there. One of the
effects really worried us. Dr. Holler gave his wife 10 rag. of adrenochrome, and 2 days later I found her in what was quite clearly a clinical
depression. She had lost insight in us. She said that she was sure it had
nothing to do with the injection, but that everything seemed so hopeless
and she didn't have any energy. We both were certainly alarmed; however the depression went away after 3 days.
Another curious thing was the fact that about eight or nine years ago
Mrs. Hoffer had had a quite severe jaundice. Evidence has been accumulating with LSD and with mescaline that in some people, there are
prolonged reactions after jaundice.* Again, this is not a thing on which
anyone has done much systematic experimenting. It may not be jaundice;
infectious hepatitis seems to be the relevant one, but, again, we do not
know.
Fremont-Smith: It would be a good point, though for anyone working with LSD or these other compounds, to make a historical note for
each subject, as to whether or not there was a history of jaundice.
Osvmnd: We are very careful about it.
Fremont-Smith:
of us.

This really, I think, might go on the record for all

Pfeiffer: Dr. Osmond made a comment about an apparent change in

*Dr. Roland Fischer (Research Biochemist in the Schizophrenia
Research Unit of the Dept.
of Psychiatry at the l.Jniversity of Saskatchewan)
reported in a persnnal _ommunication
a
prohmged
reaction to mescaline lasting 3 days in a subject who had severe jaundice some
years previously.

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N europharrnac olo gy

the lighting with the use of this compound. We, too, have noticed that
one of the first effects of LSD is an apparent change in the lighting. If
you look at the subject's pupils, however, they are going up and down,
and, of course, their interpretation of "the powerhouse failing" can very
well be this change in pupil size, which occurs very rapidly. Another
thing which occurs is that there may be dilation of one pupil before the
other, in which case they may have a Pulfrich effect (47) in which things
appear to be traveling in arcs instead of straight lines. If these patients
are tested with a pendulum, it will seem to them that it is going in a
circle instead of in its single plane. This is explained by the fact that
the light from one retina gets to the visual cortex ahead of the other.
The ophthalmologist puts a patch over one eye in order to get rid of this
disturbing phenomenon, which can be interpreted, of course, as a central
nervous system effect but it is actually a phenomenon originating in the
eye.
Fremont-Smith: I don't quite understand why a change in the pupil
would make light or the impulse get to the visual cortex faster.
P]eiffer: It is presumably a greater intensity of light on one retina
than on the other.
Osmond: Clearly, there are several other important directions in which
this work might lead us: The first thing we wished to do was obtain more
information about adrenochrome, and, to do this, we carried out a rather
small number of experiments because, unfortunately, we ran out of our
supply and it has been most difficult to obtain. Also it can deteriorate.
Quaste]: What do you mean ?
Osm(md: It ended up as melanin.
Quaslel." You mean, it has gone a stage further ?
Osmond: Yes.
Quastel: Why should it do that ? Was it present in solution ?
Osmond: No; this substance was under nitrogen and made by competent people.
Ouastel: It was supl_osed to be a purified product ?
O.rmond: It was supposed to be a purified product, yes. This has
happened on several occasions when it came from a reliable place.
Rinket: I have been told that it is extremely unstable.
Quaslel: Was the substance kept under nitrogen ?
Rheke]: It has to be handled with the greatest of care. The laboratory
(Eli Lilly Research Laboratories) which produced it for Dr. Hoch and
me sent it to us in packed ice just the day before the experiment. We
used it quite fresh.
Kety: Dr. Osmond, in the light of this, do you feel that the results

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205

which you gave us and which I have no doubt are valid resulted from
adrenochrome or from some yet unknown, unidentified substance ?
Osmond: I only know that this was a red substance, like adrenochrome, and when it went a bit further, it was quite different. It became
a black compound; as long as we were using that red compound we felt
fairly confident. Dr. Duncan Hutcheon who made our adrenochrome
for us was an expert at working with members of the epinephrine
family. His co-worker, Eade (46), has published a description of his
method and Dr. Hutcheon himself will be publishing in the near future.
As I said he is now with Chas. Pfizer & Co. and they are generously
supplying us. I know, however, that even with Dr. Hutcheon some
batches quickly became melanin.
Kety: Have you been able to obtain similar results with your adrenochrome since ?
Osmond: With the next lot, we obtained similar results again, but it
is only recently that we have been able to get our adrenochrome from
the same source.
Leake: Had Dr. Hutcheon any idea of the impurities in the first batch ?
Osmond: I don't know. There were certainly no pressor impurities,
but he does not say what impurities there were.
Cantoni: Do I understand you to say that it was only with adrenochrome made by this particular man in this particular laboratory that
you obtained these effects ?
Osmo,zd: That is correct. We did not obtain any effects with the
other substance because it was wrong; it was black by that time. We
never use it if we can see any black in it at all, and we have had at least
two or three lots like that. Now, we have a third lot, but made in a
different laboratory by Dr. Hutcheon. That is the position, at present.
Marrazzi: Dr. Osmond, this adrenochrome has been chemically characterized as pure ?
Osmond: I gather that Dr. Hutcheon has done it. He says that he is
certain, and his paper will come out and say exactly how it was prepared.
I would not like to give you my views on it.
Marrazzi: My question is a little bit different. It is not only this preparation, but the final characterization after it has been prepared, as a
pure substance ?
Osmond: I think so, but I would not like to say definitely, because,
again, he is writing this now and soon you will be able to read his whole
account of exactly what it is.
Reynolds: At any rate, there was nothing intentionally added to it as
a stabilizer ?

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Neuro pharmacology

Osmond: No! We deliberately avoided that.

Abramson: I would like to tell of an experiment which I tried with
Siamese fighting fish. I added 0.5 gm. of epinephrine base which, as
you know, is insoluble, to an aquarium of 2-gallon capacity. The aquarium contained about 20 fish, and they tried to eat the little particles of
epinephrine. However, after engulfing them, they spit them out. Then,
within an hour or two, the aquarium turned red, probably because of the
presence of adrenochrome and possibly other pigmented compounds, I
assume, which are formed from epinephrine. The fish lived very happily
in this red liquid and with the other products I don't know about, for
2 months, the water becoming redder by the day. I regret that I was
unable to observe any new phenomenon at all; they ate and fought as
usual.
Kety: I would like to ask Dr. Rinkd to indicate what his results were
and whether they were with adrenochrome. I remember reading in the
literature that he was not able to confirm Dr. Osmond's results with
adrenochrome, although I do not know what the nature of his material
was.

Rinkel: I was greatly impressed by Dr. Osmond's results with adrenochrome. We also had come to a similar concept of psychosis, although
from a different angle, as I will elaborate later. Naturally, we tried to
duplicate the experiments of Osmond and Hoffer, but at that time, we
did not have the pure adrenochrome available. We, therefore, used,
perhaps not justifiably so, but for the time being, the stable semicarbazone of adrenochrome which was available in this country, and is being
widely used as a hemostatic in surgery.
Since then, however, we received pure adrenochrome from the Eli
Lilly Research Laboratories, with a report by Dr. Norbert Neuss,* of
the procedure and chemical identification of adrenochrome, and Dr.
Hoch received the same adrenochrome.
The adrenochrome was packed in ice and in vials each containing 20
mg. This was received on the morning of the experiment. I finally persuaded Dr. J. Jackson DeShon of the Boston Psychopathic Hospital, to
give me an injection of this substance.
Fremont-Smith: Subcutaneously ?
Rinke]: No, intravenously, because we had already had the same
experience as Dr. Osmond who stated that the subcutaneous injection
was very painful. He had suggested that it be injected intravenously,
*The adrenochrome
was prepared for this experiment
by Dr, N. Neuss using the method
of Sobotka and Austin (48) as modified by Kornfeld.
The spectral properties
(infrared and
ultraviolet
absorption)
were identical with those reported in the literature.
The material
was shown *o be free of epinephrine
by paper chromatography.

Research on Schizophrenia

207

and by withdrawing some blood and mixing it up in the syringe with

the adrenochrome, no pain would be experienced.
Kety: Dr. Osmond, did you give any of it intravenously and get
mental effects.
Osmond: Yes; we gave some intravenously and got mental effects,
but mostly on epileptic people about whom I am going to tell you later.
Rinkel: At that time, we followed the first publication on adrenochrome, and injected it according to Osmond and Hoffer's (22)
description: 1 mg. dissolved in 1 ml. of saline solution. Nothing happened to me when I took this dose.
I injected one more member of the hospital personnel who volunteered. I might say this young man approached it with terrific anxiety;
he was shaking, but no sooner had he received the adrenochrome than
he stopped shaking and felt perfectly fine.
Fremont-Smith: But your dosage was limited to 1 mg. ?
Rinkel: In the first experiments, yes. We planned to increase the
dose, although we were warned that a slight impurity of epinephrine in
the compound might have a rather serious consequence, especially if a
dose of from 25 to 50 mg. was injected.
Fremont-Smith: You mean that you have so far used only 1 rag. ?
Rinkel: Yes.
Fremont-Smith: And you got no results. Do you think this is a good
deal smaller dose than you used, Dr. Osmond ?
Osmond: Yes. As I will tell you, we came to the conclusion that probably the effective dose is somewhere between 10 and 50 rag. There
seems to be extraordinary individual variation with these things. Why
we do not know. We have a few clues, though, as to why this may be.
We did a few more experiments, and then we got a group of about 20
epileptics and gave them this substance intravenously in doses of from
10 to 50 rag. Hoffer and Szatmari (49) have published this work and
show that adrenochrome undoubtedly produces changes in the brain
waves; many slow waves can be altered by giving intravenous nicotinic
acid. I am not going to go into that very much as I do not know enough
about it.
Some interesting work has been done on rabbits at the Mayo Clinic
by Dr. B. Schwarz (50) who has given intraventricular adrenochrome
and adrenolutin.
John Smithies, my colleague in British Columbia, did some work with
cats and found nothing much. But shortly after that he reported that
his adrenochrome was turning black. Later it turned out to have much
silver in it so this work must be discounted. This was not using
Hutcheon's adrenochrome.

208

Neuropharmacology

Sherwood: Have you noticed any difference in onset of phenomena

in general with different modes of administration? For instance, how
long did onset of phenomena take if you put the substance in intravenously ?
Osmond: It appears to be about the same time. This was very curious.
I think that the EEG changes came on quite quickly, but the psychological changes, such as they were, came on quite suddenly. In work
we did on one epileptic, who was given approximately 20 rag. intravenously, there were fairly good indications that there was a reaction.
But unfortunately, that evening, she became acutely psychotic and she
remained that way for 4 months, after which she became better. Our
feeling was that it is possible to alter people who are balanced somewhere between, as it were, this world and the next.
Fremont-Smith: Did her convulsions stop during this time ?
Osmond: I do not know, unfortunately. She went away from us.
Sherwood: That is very important.
Fremont-Smith: It is very important, because this does happen.
Osmond: Yes; I know.
Fremont-Smith: I have seen that happen under psychotherapy. Was
she a paranoid ?
Osmond: I think she became acutely hallucinatory, almost, with many
paranoid phenomena. We moved along rather slowly because of lack of
material. We kept trying to get more adrenochrome, and we kept failing.
We then had Dr. _toodford* in Saskatchewan working on the _Xrarburg
apparatus and trying adrenochrome on rat brain. Here, I am afraid that
my information will be extremely unsatisfactory to the pharmacologists
and biochemists, because, of course, I simply do not know enough about
this to be really accurate. But what I understood happened was that he
showed that there is a very major inhibition in a rat brain on the Warburg apparatus. It is apparently something like up to 80 per cent, and
it is dramatic and impressive. That work will all be published. I believe
this has been shown before but in more detail and with different
substrates.
Ouastel: I would like to say that this effect of adrenochrome is fairly
well known, to us at any rate. Adrenochrome, or the oxidized product
of epinephrine, brings about a quite marked inhibitory effect on the
respiratory system of isolated brain tissue.
I would like to point out that the diketone group, as present in adrenochrome, is a very active group. Such groups have a very high affinity for
*xX,'oodford, V. R.: "Inhibition
of Carbc_hydratc Metab_dism
in Rat Brain by Adrcn_clnrome." Paper delivered at the 8th scientific session of the Western
Regi_,nal Group of
the Division of Medical Research NRC Winnipeg,
1954.

Research on Schizophrenia

209

SH enzymes and bring about large inhibitions of their activities. I am

inclined to think that the changes you observed in the Warburg respiratory apparatus are largely due to the activity of the diketone groups.
Similar inhibitions may be obtained with a variety of orthoquinones. I
am, therefore, uncertain whether the respiratory inhibitions observed
with adrenochrome are more or less nonspecific effects caused by the
ketone groups or whether the molecule as a whole is specifically involved
and its effect possibly related to the psychological manifestations you
have discussed. You have mentioned, have you not, that you have had
samples with various activities ?
Osmond: Yes.
Quastel: What we would like to know is whether the psychological
effects of adrenochrome administration are caused by the activity of the
diketone moiety of the molecule, or by the molecule as a whole, acting
perhaps as a metabolite antagonist. Might it not be worthwhile injecting
a mixture of adrenochrome with an equimolar concentration of cysteine
or glutathione to bring about a reduction of the ketone to hydroxyl
groups? It is possible that injection of such reduced adrenochrome
would not result in the same psychological changes as are obtained with
adrenochrome
alone.
Abramson: Is the activity of those ketone groups dependent upon the
pH, and the oxidation reduction potential of the system, and so on ?
Ouastel: Their presence affects the entire enzymatic system. Once
they attack the SH enzymes present, the metabolic picture is changed.
I have been wondering whether adrenochrome enters the red cell ? Does
anyone know ?
Osmond: There is evidence that it does.
OQuastel: If it does enter the red cell, it may be reduced by the free
glutathione present. What adrenochrome does not enter the red cell
will be taken up by other tissues of the body where it will react with their
metabolic systems.
Osmond: Bacq (51) claims that it does get into the red cell.
O0.uastd; Then the problem is whether or not the reduced adrenochrome will emerge from the red cell and whether or not it is as
physiologically active as the oxidized form of adrenochrome. Presumably, if all the adrenochrome is absorbed by the red cells, it must emerge
from the cells in one form or another to take effect ?
Osmond: Yes.
Elmadjian." Does it get in the red cell systematically or was it done
in vitro ?
Ovmond: I do not know.
kfarrazzi: You have data on that ?

210

N euro pharmacology

Osmond: Yes.
Quasteh Here again we have labile groups to consider. In what form
are these groups ? I suppose you are sure of the structure of the molecule.
Osmond: I am not quite sure. I was merely assured by Dr. Hutcheon.
I understand it is a far from easy thing to be absolutely sure on this
thing.
Abramson: I should like to ask Dr. Osmond why he restricts his
chemical concept to this group of compounds. Clinically speaking, the
steroids, we know, do produce psychoses very often. I see them constantly. We know that they are natural products and know that the
psychoses they produce lead to suicide, to confusion, and, in fact, meet
all the requirements of change in thought, mood, perception, and posture. Why not stress the steroids with just as much interest as this group ?
Elmadjian: There may be close relations between the metabolism of
adrenal cortical and adrenal medullary hormones. Von Euler and his
associates (52) have demonstrated a reduction in the norepinephrine
excretion after ACTH and cortisone administration. We have been
able to confirm the effect of ACTH on norepinephrine excretion (53).
Furthermore, we have studied the effect of whole adrenal acetone
powder on the possible conversion of hydroxytyramine to norepinephrine-like material.
In the study of the physiological reactions to stress, we know that both
the adrenal medulla and the adrenal cortex play important roles. Attempts at studying together the adrenal-pituitary
and sympathicoadrenal systems have been delayed because of the lack of reliable techniques for the measurement of epinephrine and norepinephrine.
In
brief, the hypothesis may be stated in a general way that it is not just
by chance that these two portions of the adrenal gland, medulla, and
cortex happen to be together. There may be some functional and
metabolic relations between them.
Cleg,born: I would like to support that hypothesis.
Elmadjian: Table XII shows the results obtained by incubating 25 rag.
of whole adrenal acetone powder with hydroxytyramine in addition to
umarate, magnesium, and phosphate buffer. Control incubations included all factors except hydroxytyramine while the experimental
incubations contained 500 _g. of hydroxytyramine. In experiment 1,
ATP, DPN, and TPN were omitted. The control and experimental
results are the same. However, when these cofactors are added we
obtained an increase in the measurable norepinephrine-like
material.
The iodometric color reaction of von Euler and Hamberg (54) was of
limited value because hydroxytyramine gives a color approximately
15
per cent of that of norepinephrine.

Research

on Schizophrenia

TABLE
Incubation

of Adrenal

Acetone

211

XII
Powder

with

Hydroxytyramine*

Norepinephrine
Experiment

Cofactors

1. C
E

None
None

28.4
24.5

2. C
E

ATP DPN TPN

ATP DPN TPN

24.5
65.5

3. C
E

ATP DPN TPN

ATP DPN TPN

23.5
38.5

9. C
E

ATP DPN TPN

ATP DPN TPN

33.4
76.4

C__control

Bio-assay

_,g.

Iodometric

Color

22.0
159.2

36.0
192.0

without hydroxytyramine

Ezexperimental

with 500 t_g. hydroxytyramine

Courtesy of R. Ncri, M. Hayano, D. Stone, R. I. Dorfman,

and F. Elmadjian.

*Incubations were for 2 hours except for experiment 9, which was for 8 hours.

Cleghorn: What is the 3 in Table XII and the 9 ? What

ence between 3 and 2 ?

is the differ-

Elmadjian: They are exactly the same type of experiment.

Cleghorn: There is a different result, though.
Elmadjian." As indicated in the table, experiment
9, the incubation
period was for 8 hours, while all other experiments were incubated for
2 hours.
Quastel: May I interrupt you for a moment ? How far is ATP necessary for this reaction ? You have got all three together.
Elmadjian:
We cannot define the specific requirements
at this time.
The data support the idea that ATP is necessary. Of course we intend
to study these aspects in detail.
Cantonk What about DPN and TPN ?

212

N euro pharmac ology

Elmadjian: We can only answer that question when ATP is tried

alone.
Quasteh You mean, this reaction does not go without ATP ?
Elmadjian: I would say at the present time that in one experiment
conducted to date with DPN and TPN no conversion could be demonstrated. Of course this must be repeated. On this basis we are inclined
to believe that ATP is necessary.
Quasteh This involves a straight oxidation of a side chain of tyramine,
as you know.
Elmadjian: Yes.
Quasteh One can understand TPN or DPN entering the picture, but
I do not yet see the function of the ATP. Is it your point that ATP is
necessary ?
Elmadjian: Various molds were also shown to have the ability to
convert hydroxytyramine to norepinephrine-like material. When cultures of molds (Cunninghamella blakesleeana, Neurospora crassa, and
Rhizopus arrhizus) were extracted and assayed, there was no norepinephrine present. However, when the cultures of these molds were
grown with hydroxytyramine, norepinephrine activity was demonstrated
ranging from 0.50 to 1 per cent conversion. When DOPA was tried,
no conversion could be demonstrated. By studying the mechanisms of
biosynthesis or epinephrine and norepinephrine, we may be able to
show relations between the adrenal cortex and the adrenal medulla.
Cleghorn: They contained which ?
Elmadjian: These are the molds: Rhizo/_us, Neurospora, and Cunleheghamella. Cunnheghamella is quite clearly demonstrated to have 11-_3hydroxylase in the study with steroids. With Cunninghanzella, and
the mold alone gave no activity in the bio-assay. When 500 _g. of
hydroxytyramine was added, there was definite activity; with 250, there
was definite activity; at 250 again--and these are the volumes in which
the growth had occurred--2.78;
and then we tried DOPA, to see what
would happen to it; but it was inactive and nothing happened.
With our present Cunninghamella, we have done other experiments
on Rhizopus and NeurosDora , and both of these molds form material
which comes out active in the bio-assay of norepinephrine and, furthermore, when DOPA was used as an abstrate, no transformation to norepinephrine occurred.
Therefore, the story here is, from what Dr. Abramson said, that when
you do get these steroids, they may be doing something or being closely
involved and, as I said, we are working with epinephrine, norepinephrine, 17-K and other determinations under various conditions to see
just what relationship they have, one to the other.

Research on Schizophrenia

213

Osmond: We next began to search for a way to substantiate our

theory that there might be some substance of this sort in the body.
We have been trying with various methods, using paper chromatography
and things of that sort, and so far, we have not been very successful.
There was some work by Macht (55,56) in which he showed that
the growth of the lupine seed root point has been inhibited by various
sorts of sera, and particularly by schizophrenic serum. We therefore
thought that it would be quite logical, since adrenochrome is not unlike
the auxins or plant hormones, if something like this was around which
would interfere with the lupine mitosis. We also knew that there was
some evidence that adrenochrome interferes with the mitosis of mouse
skin.
We therefore began to think of some way by which we could find
out if this were so, and we were rather fortunate in that Dr. Rudolph
Altschul at the University of Saskatchewan Medical School has a colleague, Dr. S. Fedoroff, who works with cell cultures. He had a cell
culture known as the L cell culture, and he also had several others, but
this L culture, I understand, came originally from mouse cell. We
began to send up samples of acute schizophrenic serum, and later, of
a more chronic schizophrenic series F, to Dr. Fedoroff to work with on
his cultures. Roughly and briefly, this is what seemed to happen: There
is a big split between the sera of normal and the schizophrenic people.
At least 80 per cent of the sera of schizophrenic people also seem to
be toxic to the mouse cell. The normal people, or most of them, don't
do anything much to it, and a few of them do a little. Naturally he
doesn't know what the samples are; they are all done under coding;
but we do not think there is any question of his suggesting things here
and, indeed, the pictures that he shows don't look much like it.
In this intermediate group, who represent something like 10 per cent,
we have not yet characterized them. Naturally, we would like to make
our results more accurate. We have just started doing the same thing
with cerebrospinal fluid. The interesting thing is that both chronic and
acute schizophrenic patients show much the same pattern. The cerebrospinal fluids seem to be extremely toxic to the mouse cell. Dr.
Fedoroff has reported this at the recent anatomical meeting, and I hope
that we will press ahead and try to find out what fraction of the serum
cerebrospinal fluid does this. Clearly, if it is substantiated, it would be
extremely interesting.
Fremont-Smizh: How many experiments, roughly ?
Osmond: I think he has now worked with about 50 schizophrenic and
about 30 normal patients.
Fremont-Sn_ith: This is serum or cerebrospinal fluid ?

214

Neuropharmacology

Osmond. This is serum. With cerebrospinal fluid we did only about

10. Unfortunately, we ran into one of those snags which often occur
with cell cultures. They got one of their illnesses; the cells got some
"bugs" in them.
Leake: Who reported this ?
Osmond: Fedoroff (57,58).
Cantoni: Have any experiments been done with dialyzed serum ?
Osmond: That is the next thing to be done and preparations are
actually being made to do that now. Naturally we want to know
whether or not it is attached to the protein.
Fremont-Smith: Would you have an opportunity to measure the
cerebrospinal fluid pressure of schizophrenic patients by lumbar puncture ? In this way there could be a double check on this other matter.
Osmond: I will certainly try. It is being done in several places. I
rather fear that this is a thing where you need to have one man who
measures carefully all the time.
Fremont-Smith: That is right. Perhaps in one place, one man could
measure, and we could get ten or twelve reports after a while. We need
them.
Sherwood: I would like to add something to that. I think that lumbar
puncture pressure measurements are not necessarily the same as ventricular, and, second, if lumbar puncture is done in the same patient
often, it becomes insignificant.
Fremont-Smith: Because of leakage ?
Sheru, ood: Yes, because of leakage.
Fremont-Smith.. Quite right, but it is also of considerable importance
to look again at what the lumbar puncture pressure is, because we need
to know that, or we cannot possibly evaluate what there is or is not in
the other. The question of whether your patients had had previous
lumbar punctures which had been leaking would also come up. That
is why the ventricular pressure was low.
Osmond: We have also tried to look in the urine to see whether we
could find something else, assuming again that we were looking for
something that might be of this family. We have tried a number of
things and, so far, with only rather moderate success.
We tried, first, to see whether, if there was such a substance here,
we could produce some inhibition in plant growth. We did not really
succeed there immediately. Then, while paper chromatography was
still going on, following Dr. Roland Fischer's (59) suggestion that
indolic substances get picked up on wool, we thought we would try
to absorb these substances from urine; that is, soak special wool in
urine, then dry it under standard conditions and wait and see whether

Research on Schizophrenia

215

there was any difference in what was picked up. Dr. Fischer has suggested that since wool is an ectodermal tissue and most of the central
nervous system is ectodermal in origin, wool may be a useful and easily
handled model of the central nervous system.
We pressed on and certainly at the moment, it does seem that you
can get differences in what is picked up on wool from schizophrenic
people and what is picked up from nonschizophrenic people.
Fremont-Smith: Measured by weight ?
Osmond: Yes, measured by weight.
Fremont-Smith: You mean, more in the schizophrenic people ?
Osmond: Yes, more in the schizophrenic people and less from nonschizophrenic people. It is an extremely tedious process, not wholly
satisfactory, and technically difficult.
Fremont-Smith: Does the urine have the same specific gravity?
Osmond: I understand all these points have been carefully considered
and allowed for. But this technique is tedious and it is affected by all
sorts of things like humidity. I am not satisfied with it, and we want
to get rid of it. But I thought I would mention it as one thing that we
have been doing.
Mirsky: Dr. Osmond, did you or did you not confirm Macht's
work (56) ?
Osmond: We never confirmed Macht's work (55,56) because we
decided not to go into this lupine seed work. We decided on the cell
once we knew we had the cell culture available and found it worked.
We were thinking of going to see Macht and learning his technique,
but we decided not to because it seemed too tricky.
Mirsky: Incidentally, has anyone confirmed this work or attempted
to confirm it ?
Osmond: I think Dr. Jacques S. Gottlieb, now I believe at the University of Michigan, said that many years ago, he attempted it but he
did not have any success; he said it was a difficult technique and he
was not certain that he had got it. It sounded difficult to us. I feel
that our wool work is in this category. I think that there are certain
techniques that a few people can do but are too tedious or too boring
for anyone else to do. These things, of course, are often of no practical
use because some more straightforward technique is called for, for
general use. Therefore, from the wool work, we went on to see, if we
got that substance or if we thought that some substance has absorbed,
whether we could grow various things on the wool and see if their
rate of growth were changed.
We had considerable satisfaction from this and got marked differential growth in wheat seedlings and in oat seedlings. Then, we

216

Neuropharmacolo

gy

ran into some difficulty and, for the last months, we have had whole
batches going wrong. We don't understand it, but we are trying to
find out why this is happening.
Fremont-Smith:
growth ?

You

mean

you

are

not

having

the

differential

Osmond:
No differential growth, and some dying off. We originally
thought that we had copper in the water, which is one of the things
that often happens in Saskatchewan.
We are now trying to avoid this.
Therefore,
I don't know what happened to that. Certainly, initially,
the results were promising.
Now, they are far less promising.
The
wool work itself is still standing up fairly well.
A4arrazzi: Do you have any idea what absorbed onto the wool ?
Osmond:
No. We think indolic substances, but our tests have been
very gross, and I would not say. I think it can go on the record as being
gross, but I do not think it should be accepted as being that.
However, this area of the work is going on, and we are trying now
to find out what this substance is that deals with cell cultures.
Apparently, the evidence so far suggests that if the serum is heated to about
56 C. the toxic substance is destroyed and the cells are unaffected.
But I understand that it is not thought to be a virus.
Then, the next area in which we are particularly
interested
is in
exploring some other substances.
The first one that we explored was
largely a matter of personal
interest, I think. I got some ololiuqui
seeds by the kindness of Dr. I. D. Clement, Director of the Atkins
Memorial
Laboratory
and the Harvard
Botanical
Gardens
in Cuba.
I was very much interested in these and started to investigate them.
Briefly, they are interesting
from several points of view: The first is
that there is a magnificent
monograph
on them by Richard
Evans
Schultes (35), so you start off with the advantage
of a fascinating
story of how this thing got lost for so long. It is one of the apparently
celebrated
ethno-botanical
cases of a substance getting lost for many
years amid great differences of opinion, and Schultes did this very able
bit of work in identifying it. Then the Indian accounts, both ancient
and modern, have proved to be accurate. Finally, it is queer in itself;
the seeds are very hard and must be chewed. Eventually,
we invented
a little machine for breaking them up, as they taste rather unpleasant.
Ololiuqui
produces minor changes in visual perception
but major
changes in affect and volition.
When given a close of this substance,
the subject does not want to do anything, won't do anything, and gradually he becomes more and more inactive. Then a kind of alert watchfulness supervenes.
I found
seeds, this is quite a feature.

that with 60 seeds and finally with 100

I sat, noting everything but not cnoving.

Research on Schizophrenia

217

It is quite difficult to decide whether I did not want to move or was not
able to. I also found that when I did move there was a tendency, once
I got going, to keep going. If I stopped, I remained where I was. For
example; if I started writing, I would keep on writing; if I stopped
writing, there I would stop. But I didn't write the same syllable over
and over again.
Fremont-Smith: But you kept on writing ?
Osmond: Yes; I kept on writing. There were several curious and
interesting things. Again, I had this detachment from human beings,
but a feeling of great comfort from small animals. We had a little
Chihuahua dog, who was particularly comforting and friendly. This
makes one wonder how many psychotic people may get great pleasure
from small animals.
Fremont-Smith:
Do they have pets? Do they like pets? Do we
know ?
Osmond: We know of many strange old people who live alone with
pets, and the death of the pet is a terrible catastrophe for them. They
may well be right, and the great comfort obtained from this little animal
is really extraordinary.
I noted in the hospital that many of the patients want to have pets
but for administrative reasons many do not have them. I often wonder
of how much we are depriving them. Pets were a feature of the
famous Retreat at York, England, about 1800. It was considered
therapeutic for patients to have helpless creatures depending on them.
In retrospect, I found this an intriguing idea because it may be of
great clinical interest. As far as I know, the capacity to form relationships with animals has received little attention except in the medicolegal field. Nevertheless, it is of some importance. For instance, the
human relationship with the dog is immensely old, and not only hunters
but many others form a very close reciprocal attachment to these excellent creatures. It seems odd that this survived when human beings
were terribly tiresome. I found my little dog far less difficult to relate
to than my small daughter then aged 4 and very active. She was darting
about, and couldn't understand what was happening. This was annoying to me so I thought I would give her a little shove, but without
meaning to I knocked her absolutely fiat. Here was an example of an
almost all-or-none response. Also, I got one of my arms up in the
air and found myself unable to get it down. Eventually, however, I
got it down by pulling it with the other arm. This, I would say was
a so-called catatonic phenomenon.
Fre/,ont-Smith., You mean, you had a sense of helplessness about
getting ),our arm down ?

218

N euroDharmacolo gy

Osmond: Yes. I couldn't move it one way or the other.

Sherwood: You were fully aware, with respect to body image, where
the arm was ?
Osmond: Yes; I knew exactly where it was, and I knew exactly
what I wanted to do. I had previously had, with mescaline, disturbances
in the perceived body but this was not the same thing.
Sherwood: There was no Parkinsonian feature about it ?
Osmond: No, none at all, which is curious; there were no tremors
or that sort of thing. At any rate, this is one small exploration that
we have made. All I think we can suggest is that, really, it is worth
looking into.
Fremont-Smith: Did you do more than one experiment at this level ?
Osmond: We have done four of them.
Fremont-Smith: With this dose ?
Osmond: No; I took up to 100 seeds and then, for other reasons,
I had to stop. I got up to 60 seeds and got a rather similar thing. Sixty
and a hundred seeds seem to be a sort of limit. I am hoping to go back
to this work.
Leake: How large are these seeds ?
Osmond: About the size of a sweet pea.
Leake: That includes the shell ?
Osmond: Yes. They have a hard shell. I took the shells and all,
because there wasn't any way of shelling them very easily.
Cantoni: Is there any information as to what material is in these
seeds? I mean, what one could attribute these reactions to? Do you
have any idea ?
Osmond: Yes. Santesson (60) did quite a bit of work on this. He
apparently got only a very short distance and, with his mice, found
that there are some different fractions which work in different ways.
But the work is all in Richard Evans Schultes' monograph (35) and,
because we were not able to start systematically on it, we did not go
any further. But I am hoping to carry out some more psychological experiments with the seeds themselves, and I hope that somebody may get
interested in this and may start sifting out what the active fraction is.
Ololiuqui comes from Rivea corymhosa (61), which is a morning
glory.
Fremont-Smith: Where is it available ?
Osmond: The only place I know is from Atkins Memorial Botanical Gardens in Cuba. Dr. Clements, who is extremely obliging, sent
it to us. A great authority on it is Richard Evans Schultes at Harvard.
Marrazzi: How disturbed were you by the arm incident ?
Osmond: I did not like it. But the most peculiar thing was the way

Research on Schizophrenia

219

this reaction went away. I am quite used to adrenochrome and the way
these reactions go away, but this time I had the impression that with
ololiuqui the reaction can go away extremely quickly. I was very much
impressed by Dr. Cerletti's dogs which made a very sudden recovery.
My impression with the ololiuqui is, and this is borne out by the tapes,
that in about 20 minutes, one moves from being really extremely inefficient to being thoroughly active and interested, with insight and all
these things, and one is left in a very curious condition of well-being.
After mescal, and certainly after adrenochrome and adrenolutin, I did
not have a feeling of well-being. But, after ololiuqui, I felt very relaxed, cheerful, active, and able to think very clearly and well.
Fremont-Smith: For how long?
Osmond: This feeling of well-being lasted for about 24 hours.
Another interesting thing was that sleep was not interfered with by
this substance; I was able to go to sleep, and when I was awakened in
the night by my daughter, which normally would make me very irritable,
I felt relaxed and calm. I would like to know whether this happens to
other people. It seems to me that these little points are interesting in
that they may throw light on the very many curious properties of these
things.
In continuing to look around, we came upon adrenolutin. Abram
Hoffer asked Harley Mason at Cambridge for some suggestions which
he gave us. Dr. D. Hutcheon in Saskatchewan had worked with this
initially and had done with Dr. N. Eade some experiments on mice.
The great advantage of it from our point of view is that it is stable
and can be stored quite easily. We didn't know how it had to be given,
but we didn't feel it was going to deteriorate. This allowed us to work
with it more easily, because, after our experience with adrenochrome,
which we were still trying to get, we were hoping to find something a
bit more stable.
Leake: Doesn't this turn color in solution ?
Osmond: No; it just goes yellow. It will after you leave it long
enough, but we found that it didn't go dark quickly. It meant that we
could bring it over from England in a little bottle without having to
have it very carefully prepared.
At the moment we have done about eight or nine experiments with
adrenolutin. In the first one, I took 5 rag. of the lot that Harley Mason
gave us. This was the original lot we got from England. I certainly
did not expect it to have an effect because we started at what we
thought was as low a dosage as possible. I did, however, have certain
changes from this.
The lot had never been meant for intravenous use. We thought it

220

NeuroDharmacology

wouldn't act, and therefore we took it by mouth, assuming this to be

safe. Then, we worked up to 15 mg. in different preparations, because
we ran out of our first lot. So far, we have used doses up to 50 rag.
on different people, and in two of them, we had no effect at all; one
was with 50 and one with 25 rag. In five of them, with doses from 5
to 25 mg. we have had different effects. In one, we have had quite a
major change in EEG, with slow waves appearing that did not appear
with adrenochrome and did not appear with hyperventilation in this
subject. They are quite interesting. We do not know what they mean.
We have a suspicion that blondes are more easily affected than brunettes; that is, people with dark skin, brown eyes and black hair are
much less affected than very fair people. We have rather more than
an impression, although I cannot prove this, that in some people at
least this substance will go on producing reactions at times for longer
than 24 hours, and that it will recur under stress.
Fremont-Smith: What kind of reactions ?
Osrnond: I will give you some examples. Hoffer took adrenolutin
and was quite clearly very different from his normal self. He was withdrawn, irritable, edgy, but the next day, he felt fine. The day after,
he became very gloomy and paranoid, that is, in this sense: He came
to the conclusion from a letter that he had received that he wasn't very
much liked. We looked at the letter and found it to be perfectly noncommittal. He even came to the conclusion that it might be a good idea
to give up his job on this account. He is not normally a temperamental
man, but he became extremely irritable and, finally, he stopped work
in the afternoon and went home, which was also unusual for him.
This continued for about 2 days. He didn't immediately relate it to
anything in particular but ascribed it to outside influences. Finally, he
went to bed. When he got up again later that day he was feeling quite
different, and only then did he think that this might have some conceivable relationship to the adrenolutin.
At that time, one of our colleagues had been urging us to do some
double-dummy experiments and we were saying that we would want
to know what reaction the substance produced first. Some months previously, I had taken it, and for about 10 days, had had periods of great
uneasiness. I also became very anergic and I had periods, particularly
under stress, in which I would get something that seemed to me to be
derealization, but I am not quite sure what it was.
The end of this reaction was very odd, and it is not easy to interpret.
I may have been merely ill, but I did not feel ill in the ordinary sense.
One morning I got up and while washing felt faint and sick. I feared
I might be gravely ill and become quite hypochondriacal, but in a

Research on Schizophrenia

221

martyr-like way decided to go to work. In about a half hour I felt very

good. Then I knew that I was different.
This has now happened with two people. Of course, with our third
subject, we took great care to watch him and not let him know something would happen. It is not easy. You do not want to suggest anything. Yet over a period of several days it is not easy to keep a really
close watch on them and yet you do not want them to run into grave
difficulties either. Our third subject had another perceptive change.
He had great difficulty in telling the size of objects, until we let him
know he was making mistakes. He judged distances very queerly.
For instance, when I held up this pen, he announced that it was 21/_
inches long. We did about six tests of that sort. When we told him
he was wrong, then he began to correct very quickly. It comes out quite
clearly on the record. He alleged that the floor was sloping downward,
but of course it was not. He went home, and he came back the next
day and said that he was perfectly well. However, people who work
with him said that he was odd and irritable and "bossy." He is normally
a rather quiet man.
His wife asked what we did to him, and she said that he was so
different. The difference, apparently, was that he was extremely irritable
and "bossy," which, again, is not like him.
Therefore, we have seen some evidence that the effect of adrenolutin
may last a little longer than 24 hours, and that this effect may be
brought about by tiredness and stress. We are now pressing ahead
on this, working with certain changes in the urinary chemicals, and
we are trying to see whether there is any constant change with it. We
are also trying to relate it to skin color, to see whether there is, in fact,
some specific difference in people of different color. This, then, is our
work in that direction.
In the other direction, my own particular interest lies in seeing the
psychological effects of mescaline on gifted people who can describe
what has happened. I was lucky enough to be able to give it to Mr.
Aldous Huxley, who wrote of it in his book The Doors of PerceHion
(62), and I have given it to a few other gifted people, who undoubtedly, are able to make great use of this experience and who believe that
it is of both esthetic and psychological interest.
Leake: Are you responsible for the suggestion that it be substituted
for alcohol ?
Osl_ond: No; I do not think Mr. Huxley means that exactly. I
think what he means is that we require less dangerous institutionalized
narcotics than alcohol, and that mescaline shows us another possibility.
Personally, I feel, and I know that Mr. Huxley agrees, that this is a

222

Neuropharmacology

field in which we should proceed rather slowly. I do not think that

we can ignore the fact that it is at present a largely ignored deep
human craving.
Marrazzi: May I go back a moment, Dr. Osmond ? Why have you
confined yourself to oral administration of adrenolutin?
Osmond: Because we have not yet had our substance biologically
standardized. We are just having that done now. We had a chemically
pure but unstandardized substance.
Leake: You didn't want any pressor agent ?
Osmond: No; nor did we know what the substance might do. We
were told by Hutcheon, in the original work he did, that it was quite
as toxic as adrenochrome. We only started giving it by mouth because
we had not obtained any substance that we thought was sufficiently
pure to give by intravenous injection.
Abramson: I would like to bring up a very important point from
a methodological point of view. I know that Dr. Osmond is fully aware
of the usefulness of the placebo experiment in this kind of work. However, we have found (63,64) it very wise not to avoid inoculating our
subjects ahead of time. Actually we revised our original questionnaire
technique to acquaint our subjects ahead of time with the possible
symptoms they might have with the drug. We have also studied unknowns. For example, we studied successfully many other compounds,
the response to which was unknown with our questionnaire method.
Abramson: To continue apropos of Dr. Osmond's remarks that
there was some fear of inoculating his subjects with what they might
be expected to show following an unknown drug, we, in our work at
Mount Sinai and at the Biological Laboratory, have taken the reverse
point of view. We found it expedient to structure the whole experiment
in such a way, using a rather large number of placebos, that the subjects
know exactly what they may expect.
I have passed around a type of questionnaire (Table XIII) which
we found very useful for a period of 3 years. We have had no trouble
detecting unknowns at all. We have always been right when an unknown sample of LSD-25 was given to us. We could say with our
method whether or not a threshold dosage of LSD-25 was present and,
approximately how much the threshold dose had been exceeded.
Fremont-Smith: By the answers to the questionnaire?
Abramson: Yes. But we always did reject as our test subjects, and
this is extremely important, those on placebo dosage who gave more
than three or four positive responses consistently. For example, an
individual's heart might be faster or his palms might get moist without
necessarily excluding him as a subject. We used this first technique,

Research on Schizophrenia

223

therefore, to screen out people who were "suggestible" and only then
did we use our screened test subjects to test our unknowns.
However, we found that even this was not inoculation enough. Dr.
Jarvik and Mrs. Hirsch improved the questionnaire (Table XIV). Instead of having the first question given half an hour after, we give the
questionnaire to the subject and he is asked to say ahead of time whether
or not he has any symptoms. Table XV illustrates a marked response
to zero dosage. This subject would be unsuitable for screening purposes.
This, then, will prepare for the part of the work on tolerance which
will follow Dr. Rinkel's presentation, because none of our work is
done on subjects unless they have been screened and found to be
satisfactory. This screening must be done on the same subjects periodically. We always introduce a placebo from time to time.
I found one very interesting thing. Mr. B. has been used as a subject
for 2 years. At first, I allowed Mrs. B. who helped in the experiments,
to know in certain critical experiments whether or not he and other
subjects were getting the drug. But by her facial expression and attitude,
he could often guess what was going on, even though she did not say
a word. So the problem of unconscious communication between the
observer and his subject is very important.
I think the experiments
should be run as blind as possible.
Leake: In connection with the experiments described by Dr. Osmond,
all of us were impressed by the extraordinary quality of the description
of subjective symptoms, and this would suggest the value of a battery of
projective tests, establishing for subjects a base line personality profile,
as it were, which then could be run almost routinely in connection with
the subsequent effect under drugs.
Fremont.SmBh: Especially of the normal subjects.
Leake: Yes, especially of the normal subjects, of course, and that
would give a considerable amount of information that is pretty well
standardized as to significance and interpretation, with regard to the
sort of projections that are made.
Osmond: We have done that with our LSD work modified by niacin,
and we have had a lot of work done on this. We found that so far-we started to work with rather high doses of LSD--our tests have not
shown any that worked very well during the procedure, because they
are too long, but we are trying to get a series of much shorter tests,
such as Lehman* was developing at one time.
Leake: Or the Zondi is extremely rapid, and that shows as quick
changes in projective personality.
*Unpublished

data.

224

N europharmacolo gy

Abramsom
We have had considerable experience with projective
tests (65,66,67). In any test situation, what you get depends not only
on the personality structure, but also on the dosage. That must be
considered constantly. You may get no change with a given test with
50 _g. but important changes on 75 _g.
Beecber: I would like to say that there is another way of handling
this questionnaire problem. It is hardly fair to put in a question, "Do
you feel weak," because there is a suggestion there. Of course some
suggestion is unavoidable, but you can minimize the effect of suggestion
by presenting two opposites simultaneously.
TABLE

XIII

Questionnaire
i.
Half
tions are

Section I

an hour after administration

and at hourly
intervals
thereafter,
put to the subject.
His rating
is accepted_
if possible on a +
Up TO
Up To
Up To
QUESTION
Y_Hr.
1_/_ Hrs. I 2 Hrs.

1.

Do you feel ill in any way?

2.

Are you

3.
4.

Have
you a feeling
of choking?
Is salivation
increased?

the following
direct
questo + + + + + basistUp To
Up To
Alter
3Y2 Hrs.
4 Hrs.
4Y_ Hrs.

nauseated?

6. Or
Is your
appetite
5.
decreased?

..................

_.

increased?

...
i

7.

Or decreased?

8.

Do you have a "dry" taste in your mouth?

9.

Do you have a funny taste in your mouth?

i
J

]
--[,

lB.

Is it a bitter taste?

11.

Are your lips numb?

12.

Or drawn back as if you were smiling?

"(i

13.

Does your

]4.

Are things moving around

15.

Do you feel dizzy?

16.

Or

1"

head ache?
you?

unsteady?

17. Is there difl3culty in breathing?

18. Do you pass more urine than usual?
19. Are you aware of your heart heat?
20.

Is it faster than usual?

21.

Are you sweating?

22.

Are you hot?

23.

Or

24.

Are your palms moist?

2.5. Or

cold?

dry?

26.

Or'cold?

27.

Is your

28.

Do you have funny feellngs on your skin?

skin sensitive?
/

Research

on Schizophrenia

Up To
Hr.

QUESTION
29.

Do your handJ and feet feel peculiar?

30.

Do they feel heavy?

31.

Or

32.

Is there pressure in your ears?

33.

Is _our bearing abnormal?

34.

Is _t more acute than usual?

35,

Is your eyesight blurred?

36.

Do you have dit_cul_in

37.

Do you see double?

38.

Are shapes & colors altered in any way?

39.

Does light bother you?

40.

Do things seem too close?

41.

Or too far away?

42.

Do you tremble inside?

43.

Do yOU feel weak?

44.

Or

45.

Do you feel drowsy?

46.

Do you feel as if in it dream?

47.

Are you anxious?

'Up To
I% Hrs.

225

Up To
2% Hrs.

Up To
$ Hrs.

Up To
4_/2 Hrs.

After
4 Hrs.

.....

light?

focming your vislon ?

fatigued?

The

following

are

tested

and

rated

QUESTION

by the

experimentor,

Up "to
Y7 Hr.

Up _o
IE/2Hrs.

and
]
,

scored

Up To
2J/_ Hrs.

normal
Up To
3Y: Hrs.

- -; abnormal
t
r

1.

PalIor

2.

Flushing

3.

Restlessness

4.

Tremors

5.

Twitching

6.

Fasiculation

7.

Fibrillation

-I

8.

Pupillary

9.

Visual Fields (to confrontatlon)

Reactions

10.

Hearing

11.

Respiration

12.

Pulse

13.

Perspiration

14.

Blood

15.

Tendon

16.

Coordination

(Decreased)

Pressure
Reflexes

t8.
19. Handwriting
_llusions

(Increased)

(Impaired)

Up To
4 firs.

+
j
t

+.

After
4 Hrs.

TABLE

XIII

(Continued)

Questionnaire--Section

|.

Molo_ Bdmvi0_

II

The _ol]owil_ are tested by the experimentor's

oblervatJonp
plus the subject's statementL Rating is qualitative.
6. Atdlude to Envit<mmlmts

_4 Hour:

.,,

2 Hour*:

Hour:

2 H'oen:

3 Hours:

3_ Horn's:

4_ Hours:

4 Horn.st

Late_

Late_:

s+ Comtroh

7. O-"+_,,,t_mt

Hour:
!% Hours:

J'

2_ Hours:

2% Hours:
3 Houri:

4% Hours:

4 Hours:

Later:

Later:

3. Omsciommtu:

8. Memory:

Hour:

Hour:

1 Hours:

1 Hours:

2 Hours:

2% Hours:

3 Hours:

3 Hours:

4 Hours:

4_ Hours:

L
.....
Hour:
1 Hours:

_}
/
/
_

9.

Ha|lucinatiom:

L
.....

g Hours:
4% Hours:

_. Mood (Euphoria . Depression):

V2 Hour:
1 Hours:
2V_ Hours:

4_/_Hours:
3 Houri:
Later:

11/I Hours:

4% Hours:
_

% Hour:

3V_ Hours:

Later:
2 Hours:

l Hours:

_/

S Ho..:

4. Concentration:

>

Hour:

Later:
2 Hours:

TABLE
Revised

XIV

Questionnaire

Subject

Dose

Data

Time of Administration
Indicate time you first feel any kind of changes
Answer the fallowing questionswith "O" if your answer il "no"; "1'"
for slight; "'2" for moderate; and "3" for severe positive answers.
HOURSAFTERDRUG
QUESTION

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
] 1.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
2_.
24.
25.
26.
27.
28.
29.
30.

PRI_

2t/t

Do you feel peculiar in any way?

is your eyesight blurred?
Does it take long to focus your eyes?
Do colors seem changed?
Do shapes seem changed?
Do things look too dose?
Do things feel too close?
Do things look,too for away?
Do things feel too far away?
Do objects look distorted?
Do you see anything which isn't there?
Do you have visual hallulootions?
Are things moving to and from you?
is your hearing abnormal?
Do you have auditory hallucinations?
Is your hearing lessacute than usual?
Is your skinsensitive?
Do you have funny feelings on your skin?
Do your clothes feel peculiar?
Doyour arms foel peculiar when you move them?
Do your legs feel peculiar when you move them?
Do you feel dizzy?
Do you feel unsteady on standing?
Do things seem to move?
Does the room seemto move around you?
Do you feel ill?
Are y
coted?
Do you fee[ abnormal4y hungry?
Are you hat?
Are you cold?

31. Are you sweating?

32. Are your palms moist?

33. Are you aware of your heartbeat?

34. Have you a headache?
35. Do you tremble inside?
36. Is breathing difficult?
37 Is swallowing difficult?
]8. Do you have trouble moving about?
)9.
40.
41.
2.
43.
44.
|5.
46.
47.
t8.
t9.
50.
$1.

Do you feel weak?

Do you feel muscular fatigue?
Do you feel drowsy?
Do your movements lack control?
Are your movementsincoordinated?
Are you laughing more than usual?
Are you crying more than usual?
Do you feel more happy than usual?
Do you feel more sad than usual?
Are you unsure of where you are?
Do you have difficulty in concentrating?
Do strange things seem familiar?
Do famihar things seem strange?

S2.
$3.
54.
55.
$6.
57.
58.
59.
SO

Do you feel as if in a dream?

Are you anxious?
Does time seem to be passing more quickly than usual?
Does t me seem o be passing more slowly than usual?
Do thoughts crowd your mind?
Do unpleasant thoughts occur more often?
Doyou feel friendlier?
Do you have dimcuity expressing yourself as clearly as usual?
_syour memory different for recent events?

51

Is it difi:erent Forpast even!s?

_____

_l

4th

228

N euro pharmacology

TABLE XV
A Completed Questionnaire on a Subject with Zero
Dosage LSD-25
FoodPrior:_-,'_?_

Food

During

I.
Half
tions
arc

_'."_-o _

an hour after administration

and at hourly
intervals
thereafter,
put to the subject.
His rating is accepted,
if possible
on a +
Up lo
Up io
Up To
QUFSTION
VI Hr.
|=/_ Hrs. ] 2*/'=Hrs,

|.

Do you feel ill in ny way?

2.

A ...........

Is your ppetlte
Or

d_creased

'

+'+ I|
4

incr,,,d?

++ ]

"

8.

Do you have "dw/"

9.

D ....

10.

Is it bitter taste?

It.

Are your

lips numb?

12.

Or drawn

back ,, if you w_re trailing?

!........

+ I *+' I ]1
4

....... i
1

tas.te in _/our mouth?

lay ......

h?

++

+_.
"

II

i
* it i ]I+*+

..
14.

Ate things moving round you_

t
;

15.

Do you

feeldi_ty?

16. Or unsteady?
..!,7.

.Ib

"_+

h....

the following
direct
questo + + + + + basis:Up To
Up To
Af(er
3_/I Fir*.
4'/_ Hrs.
4Vt HH. ,.
'4'

ed?

Ord......d?
6.
I174

_A_ ,q._

_3..,_
or_ho_ing:
,.,.,tio_ f.liog
.......
d

_.e_.

h there diff*culty in breathing, )

18.

][_,, you p_SSmore urine _n

19.
20.

_re you ware o| your heart beat?

]J it laster *kan wtml?

.1renal?
I

21. Are you sweating?

_').

Are you hot?

23.

Or

25.

Or dry_

cold?

_.
Or cold?
..
2,.,,,_.._,.._.?
_, _,_.., .... ,......

" i
+-I
a.?l ++ I

'"

+ I

+ It
+ II

Research on Schizophrenia
Up To

QUr.STION
Do

Mrh_dt--,,_,..

30.

Do they feel heavy?

31.

Or lillhtP

32.

I,

33.

I, your h_lrin,

Up To"

+* r-.
4'4'

there pressure in yo4ir .e._.rs.

?

* I

Up To
4% Hrs.

After
4% Hn:.

+* J|

+4"
++

abnorm81_ .

34.

I* it more acute than usual?

++

$5.

Is your e,#eilght blurred?

36,

Do you have dlffic_ihy in |m:liiuil yoll vlii_l ?

37.

Do _ou tee do u.hJe?

'
"

_r

+++

...

++

Ji

++
,,.

',

._

Are shapes & "c?lon altered,in

39.

Does light bother you?

40.

Do things seem too c|o6e?

41.

Or too far nwsy?

42.

Do you Urembie inside?

43.

Do you feel weah?

44.

Or

45.

Do you feel drowsy?

46.

Do you feel al if in a driim?

47.,

Are you .nxlout,

fatJil_ed?

UpTo

38.

" Up To

229

wly?

++

J
+

4"4'

4'

++_

|
=

.--

**

The followlng are tested and rated by the exper[mentor, and scored normal- -; sbnonnkl + +.
upHr.
To
.%

QUESTION
I.

Pallor

2.

Flushing

3.

R_tlemne_

4.

"]l'remorl

5.

Twlicbin#:

6.

Fm_uhttion

7.

Fibrillation

8.

Pupillm7

9.

VisualFie!dl

UpHrs.
To
2V=

_pfl_.
To
SVs

4_I_,.

_-rHrs.
4YI

Reaetlom

10.

Hearing

11.

Resplrmtiom

12_. Pulle

upHrs.
To
IVs

(tocoulromafion)

(_)

.....

15.

Persplnti_t

14.

Blood

15.

Tendms

Premure
Refletes

(I_)

IS. Coo,,,tnJtioe
(.l_lm_l
' )
18.

Hamdwri_

17.
ll.

Articulation
illusion,,

._.
...........
t

....

230

N euro pharmacology

Abramson:
We thought of that.
Beecher: We have used, for example, "sad . . . happy", 3, 2, 1, 0,
1, 2, 3. You check the point which applies most accurately.
You get
opposite suggestions at the same time, and, at least in our experience,
this is a better way of handling the thing.
Abramson:
We weren't looking for the best way. We were looking
for a useful way. In our hands this has proven very useful over a period
of years, with slight modifications.
Beecher:
You should, I think, present opposites
simultaneously:
"strong-weak,"
"happy-sad."
Abramson:
Yes; we could. There are many ways of setting up a
questionnaire.
Sherwood: Would it be worth-while
to try to establish the basic personality characteristics,
such as Dr. Osmond mentioned?
Should we
determine if the subject rarely sees hypnagogic shapes. I always do,
so I assume that if I took LSD, I would probably get these things much
sooner and it would be much less significant than if he sees them.
Fremont-Smith:
You might not get them at all, but it would be
worthwhile.
That is the purpose of this suggestion of Dr. Leake's, to
establish the personality profile to some extent in advance.
Abramson:
We have done that in all our subjects,
Dr. Leake
(65,66,67).
REFERENCES
i.
2.
3.
4.
5.
6.
7.
8.

9.
1.0.

BRONOWSKI,J.: William Blake, 1757-1827;

a ]_Ian Without a
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