Part I.

Psychotomimetic Agents: Clinical and Biochemical Aspects

A IiEVIEW OF THE CLINICAL EFFECTS

OF PSYCHOTOMIMETIC AGENTS*

By Humphry Osmond
The Saskatcliewan Ilospitui. U - e y b w n , Saskaiciiezean, Canada

The Psychotominiefic rlgepzls

We are using Gerard’s25 term “psychotomimetics” generically for com-
pounds that have been called schizogens, psychotica, psychotogens, phan-
tastica, hallucinogens, and elixirs. If one believes that the importance of
these compounds lies in their capacity to mimic the mental illnesses called
psychoses, psychotomimetics would be the term of choice. This capacity
alone would make these drugs the focus of psychopharmacological inquiry,
but this capacity is not their only, nor even, perhaps, their most important
quality. I t is but recently that the relationship between psychotomimetics
and schizophrenia has become somewhat clearer. Later in this presentation I
shall suggest a more inclusive term.
We are the latest of generations of experimenters who, from before the dawn
of history, in every part of the world, have sought for means by which man
could alter, explore, and control the workings of his own mind, thus enlarging
his experience of the universe. Until recently, however, science has shown
only sporadic interest in these matters.
Since there are few substances that, in large enough doses, will not produce
changes in body and mind resembling some mental illness, I shall try to limit
our field of inquiry by a definition that will prevent workers in this field from
being overwhelmed with an inconveniently large poitionof the pharmacopoeia.
This definition will be improved, and I make it in order to provoke such im-
provement : “Psychotomimetic agents are substances that produce changes
in thought, perception, mood and, sometimes, in posture, occurring alone or
in concert, without causing either major disturbances of the autonomic nervous
system or addictive craving, and although, with overdosage, disorientation,
memory disturbance, stupor, and even narcosis may occur, these reactions
are not characteristic.”
This rough and ready guide excludes morphine, cocaine, atropine, and
their derivatives. It also excludes anesthetics, analgesics, and hypnotics. I
expect, however, that there will still be some overlapping of these divisions.
Using this guide we have a sizable list, starting with the still-unidentified
soma?‘ imported from central Asia into India several thousand years ago and
ending with 3 , 4 , 5 ,trimethoxyphenyl-/3-aminopropane (TMA),55bufotenin,78
adren~chrome,~’ and a d r e n ~ l u t i n63~ ~whose
. qualifications for inclusion in
this classification are still being examined. As I list these treasures of 5000
*This paper is published with the approval of the Saskatchewan Committee for Schizophrenia Research
using funds provided by the National Department of Health and Welfare, Ottawa, Ontario; Psychiatric Service;
Branch, Department of Public Health, the Provincial Govenment of Saskatchewan, Regina, Saskatchewan; and
The Rockefeller Foundation, New York, N. Y.

418
 Osmond: Clinical Effects of Psychotomimetic Agents 419
years of perilous and sometimes fatal searching, think upon those nameless
discoverers and rediscoverers, Aztec and Assassin, Carib and berserker, Si-
berian and Red Indian, Brahmin and African, and many others of whose
endeavors even scholars do not know. We inherit their secrets and profit
by their curiosity, their courage, and even from their errors and excesses,
Let us honor them. They do not appear in any list of references.
There are such substances as soma, hashish, cohoba, ololiuqui, peyote, the
Syrian rue, the caapi vine, the fungus teonanacatl, the two Amanitas, pan-
therina and muscaria, the iboga bean, and the fierce virola snuff obtained
from a nutmeglike tree in Amazonia. Who knows what other compounds
await the keen inquiries of ethnobotanists such as R. E. Schultes or mycolo-
gists such as Gordon Wasson?
With our modern synthetics we are a little safer, though the ground quakes
beneath us. These synthetics include mescaline,2* introduced by Heffter in
1896, the first, I believe, of these agents to be synthesized; harmine or tele-
~ a t h i n ean
, ~ alluring
~ name whose significance I have never understood; Hoff-
man’s7” astonishing lysergic acid diethylamide (LSD), whose great activity
has made homeopathy seem less improbable; hashish, whose still-uncertain
active principles should surely be ascertained; TMA, synthesized by Scott and
his co-workers of Imperial Chemicals Ltd., Manchester, England, a synthetic
that lies in an area intermediate between mescaline and amphetamine and has
recently been the subject of a report by J. R. Smythies; bufotenin, isolated
from cohoba, a West Indian snuff; unstable adrenochrome; and the subtle
adrenolutin. What an array of substances for daring inquiry! What work
for generations to come!
We know little enough about the most familiar of these agents, and there
are only vague correlations between the physical and mental changes that
they cause. Considering their interest to medicine alone, our lack of infor-
mation is disquieting, but they are of more than medical significance. They
reach out to p s y ~ h o l o g y 64
, ~ s~o~~ i o l o g y philosophy,66
,~~ art,58,75 and even to
3*v 65 Surely we are woefully ignorant of these agents and this ig-
norance must be remedied.
To clinicians such as myself who daily encounter those crippling illnesses
that confine hundreds of thousands of unhappy people to dismal and obsolete
institutions flattered by the name of hospital, publication of a monograph
such as this one is heartening. Perhaps it means that apathy and neglect are
ending, and we may have a chance to apply the immense but often unused
knowledge that we already possess regarding the care of the mentally 31, and
that we shall get encouragement and support to seek for even more.
I n W h a t W a y A r e These Substances Important?
Nearly everyone who works with psychotomimetics and allied compounds
agrees there is something special about them. Such words as “unforgettable”
and “indescribable” abound in the literature. Few workers, however, have
emphasized that the unique qualities of these substances must be investi-
gated in many directions a t the same time, a consideration that makes work
420 Annals New York Academy of Sciences
in this field all the more difficult. I shall try to remedy this deficiency by
citing several reasons for ascribing importance to them, although in the at-
tempt I am sure to show my scientific shortcomings and imaginative limita-
tions.
(1) The primary interest of these drugs for the psychiatrist lies in their
capacity to mimic more or less closely some aspects of grave mental illnesses,
particularly of schizophrenia. The fact that medical men have been preoc-
cupied with transient states resembling mental illnesses that have been called
model psychoses, however, does not mean that the only use for these compounds
is in the study of pathological conditions. This misunderstanding, unless
corrected, can deprive us of much knowledge and prevent the growth of new
and fascinating researches. Model psychoses allow us to correlate human
experience with animal behavior. We can learn how to aggravate and allevi-
ate these model illnesses, and thus we can devise “model therapies” that may
later have wider application.
(2) Psychiatrists have found that these agents have a place in psycho-
therapy. This practice may sound like carrying the idea of “a hair of the
dog that bit rather far, but it seems to be justified.
( 3 ) Another potentiality of these substances is their use in training and
in educating those who work in psychiatry and psychology, especially in
understanding strange ways of the mind.
(4) These drugs are of value in exploring the normal mind under unusual
circumstances.
(5) Last, but perhaps most important: there are social, philosophical, and
religious implications in the discoveries made by means of these agents. T o
inquire more than superficially into any one of them would require more time
than I have available and more knowledge and wisdom than I possess.
The Model Psychoses
Over a century ago B. A. Morel, according to Ellenberger,14used hashish to
show his students the sort of world that might be endured by some mentally ill
people. It is remarkable how ignorant we still are as to the best way to con-
duct such experiments. We still do not know for certain the exact differences
between experiences produced by, for example, hashish, and those produced
by peyote, peyote and mescaline, or mescaline and LSD. Of course such com-
parisons have been made, but I know of none that has taken into account
obvious variables such as body type, height and weight, or skin and eye color,
let alone subtle personality or cultural, social, and biochemical factors that may
be very important. We are still unsure whether these substances differ quan-
titatively or qualitatively. Our work with o l ~ l i u q u i ,a~d~r e n o ~ h r o m e ,and
~~
a d r e n o l ~ t i n53~ has
~ , caused me to suspect that these drugs are qualitatively dif-
ferent from mescaline and LSD. The Aztecs who first used ololiuqui held the
same opinion. I have had a few reports of the results obtained from using
mixtures of these drugs, but I am unaware of any established facts about them.
From a11 account^,^^^ 45, 65 the cactus peyote is unpleasant to take, with the
result that the isolation and synthesis of mescaline by HeffteP encouraged
 Osmond: Clinical Effects of Psychotomimetic Agents 421
more work to be done. Beringer,6 R ~ u h i e rK, ~l U ~ ~ e rG.
, ~ Tayleur
~ Stocking,72
M a y e r - G r o ~ sand
, ~ ~Paul Hoch30 should be mentioned in this connection. The
introduction by HoffmanGgof LSD and subsequent investigation of this com-
pound by Stoll’l added an immensely potent weapon to our armory. The
minute concentration of it required to produce its effect and the fact that,
according to Cerletti,Io most of the drug is excreted from the body within 1
hour while its effects last 12 hours or more is an unsolved mystery. How does
the drug continue to act although it is no longer present?
Among many excellent papers on LSD, apart from St01l’s~~ original reports,
observations by Rinkel, Hyde, and Solomon57and by Anderson and Rawnsley2
are outstanding.
It is curious that in the lengthy and sometimes heated discussions about the
relationship of model psychoses to schizophrenia that smoldered for nearly 50
years, not until 195152was the difference between a transient, artificially in-
duced, experimental state in a volunteer under laboratory conditions and the
prolonged, insidious, creeping illness in an unsuspecting victim whose social
life progressively atrophied, clearly recognized.
There is one golden rule that should be applied in working with model
psychoses. One should start with oneself. Unless this is done, one cannot
expect to make sense of someone else’s communications and, consequently, the
value of the work is greatly reduced. StefaniukG8told me how much his at-
titude changed after he had himself taken LSD during the course of a series
of experiments.
I am still unsure in what way patients should participate in these investiga-
tions. RinkeP has observed that mentally ill patients can be made worse by
LSD. One cannot be dogmatic, but an investigator might ask himself whether
someone who cannot communicate much a t best is likely to be very useful
during an experience that often silences healthy volunteers who have agreed
to do their ulmost to report. Changes in behavior can be noticed, but one
questions their value when their meaning is obscure.
After Smythie@ rediscovered the similarities in the structural formula of
mescaline and adrenalin we started to hunt for substances that might be psy-
chotomimetic and that lie in the enormous series between the 2 compounds.
We thought that we should find some of those intermediate compounds whose
activity would be nearer to that of adrenalin than that of mescaline. Clinical
information from asthmatics and from A ~ q u i t h an , ~ anesthetist, directed our
attention to adrenalin that has lost its pressor qualities. We first investigated
adrenochrome and, later, adrenolutin. We think that these 2 compounds are
psychotomimetics. FabingI7 has recently carried out trials with bufotenin.
While our work has still to be repeated in humans by independent investi-
gators, work with animals63 has been encouraging. An early attempt by
Rinkel, Hyde, and Solomon57 to reproduce our work with semicarbazone, a
more stable adrenochrome, failed, which suggests that there is something spe-
cific in the unstable molecule. Later attempts with adrenochrome from an-
other source have also been unsuccessful. The trouble seems to spring from
difficulties inherent in the synthesis of both adrenochrome and adrenolutin.
422 Annals New York Academy of Sciences
A recent letter from J. Harley Mason of Cambridge University, England, states
that the causes of these difficulties are not yet clear. I hope that this will be
a challenge to organic chemists to sort out and classify these indolic derivatives
of adrenalin whose very instability makes them excellent prospects for use as
natural psychotomimetic agents. The changes that they induce, although
sometimes very striking, are more subtle and less florid than those induced by
mescaline or LSD. Consequently, these changes are harder to detect, de-
lineate, and measure and, for persons who are used to mescaline and LSD, they
may seem very small. We are trying, however, to reproduce a cross section
of an illness that is insidious, that seeps into its victim over a period of weeks
and months, so that these characteristics that make the experiment so difficult
to perform are perhaps encouraging.
The more our psychotomimetics resemble the hypothetical endotoxin that
g ~ ~toxin-X and that we have called M (mescalinelike) substance,
Carl J ~ n called
the harder they will be to test and the more attention they will require in
experimental design. Since someone already loaded with M substance might
not respond to it at all, it would seem wise in this type of experiment to ex-
clude psychotics, neurotics, epileptics, alcoholics, and psychopaths and to rely
on normal volunteers. is bell'^^^ demonstration of the tolerance that is de-
veloped for a short time after taking LSD supports this suggestion.
There are other difficulties, such as finding regular supplies of a particular
agent, uncertainties about the proper route for administration, individual dif-
ferences in absorption and susceptibility, the dearth of subjects skilled in self-
observation, and the effects of placebo on both the observer and the observed.
Before all this comes the task of designing testing schedules to measure and
correlate physiological, electrophysiological, biochemical, psychological, and
social changes, and then the task of relating these changes to a naturally occur-
ring illness-schizophrenia. The work bristles with difficulties, yet it must
be done, for the rewards that it offers are large, even a t the soberest reckoning.
No account of model psychoses would be complete that did not relate those
that are induced chemically to those induced by other means, such as the
reduced or specialized environments described by Heron, Bexton, and Hebb29
and by L i l l ~ . These
~ ~ specialized environments have been used since antiq-
uity, and they raise a host of questions, one of which is of sufficient urgency
to discuss briefly.
Most people can adjust themselves to small changes in perception quickly
enough for these changes to be of no importance. There are a few situations
in which even these small changes can be dangerous and, unless they are ex-
pected and sought for, they might not be recognized. I n high-speed flying
and as they will in any flight into outer space, men suffer major psychophysio-
logical and psychochemical changes within a very short time (it is artificial to
separate these 2 categories, but the division is practically useful). We know
that damage to the liver, even though it has been sustained many years previ-
ously, may prolong the effects of both mescaline*?and a~lrenochrome~~ by hours
and even days in some people. Under great stress, in the special environment
of both the pressure suit and the cabin of an aircraft, a pilot’s liver, affected by
 Osmond: Clinical Effects of Psychotomimetic Agents 423
changes in gravitational pull and possibly by anoxia, might not work suffi-
ciently well to detoxicate the by-products of his own adrenalin. If this
happened the pilot might not be able to exert sufficient control to survive.
An aggravating factor in these circumstances would be the steady drinking
of alcoholic liquor, due to its known tendency to damage the liver. Low blood
sugar and inadequate niacin intake would certainly increase these tendencies.
Coffee and tobacco, in excess, would increase the danger.
Atropine derivatives especially should be avoided by men flying planes. It
has long been known that hashish42and dhatura make a very deadly mixture
that may well enhance endogenous psychotomimetics. T ~ n i n has i ~ ~shown
that Methedrine will prolong the effects of LSD-25 and will also intensify
them. Thought must be given to lights flashing at certain f r e q ~ e n c i e sand
~~
76 or cabin covers of particular colors that may be necessary a t great
altitudes.
With so many possible factors to take into consideration, much patient in-
vestigation is needed, and one suspects that many unexpected changes in
perception would escape notice simply because they cover so many fields.
Do such changes actually occur? I do not know. I do know, however, that
the only occasion on which I have ever been unable to relate time to distance
was after taking adrenochrome. The reaction made it impossible to drive a
car, and it even made being driven very unpleasant. I wonder what it would
have been like trying to land a jet plane?
Uses in Psycholherapy
I have read Sandison’s,GO Abramson’s,’ and Frederking’sZ3accounts of the
use of LSD-25 and mescaline in psychotherapy, but I have not been able to
see the reports of Busch and Johnson? I have done some work in this field
myself, and I have access to the records of a colleague who has conducted an
extended series of experiments in psychotherapy with these substances. Let
me emphasize again that those who have not themselves taken the particular
substance with which they wish to work, preferably several times, would be
wise not to use these agents in therapy. Possibly no one has done this, but
no paper that I have read has made it the essential precondition for such work.
Abramson,‘ using a modified psychoanalytical approach, gives small doses
of LSD-25 in repeated sessions. He aims to resolve early conflicts by abreac-
tion, free association, and re-education. SandisonG0gives a varying dose of
LSD-25 to chronic neurotic patients in a mental hospital. He uses the ex-
perience for group discussion and psychotherapy of a Jungian nature. Freder-
kinglZ3whose account is the most sophisticated, compares mescaline and LSD-
25, and he discusses about 200 treatments. He uses psychoanalytical methods.
Our work started with the idea that a single overwhelming experience might
be beneficial to alcoholics, the idea springing from James4’ and T i e b o ~ t . ~ ~
Thus far it seems that a high dose may be valuable, but that repeated treatment
is necessary. At this stage of our investigations we have not yet observed
enough patients to be able to give any hard and fast rules as to prescribing
these drugs.
424 Annals New York Academy of Sciences
Hubbard,36 whose large unpublished series of cases has been most kindly
placed a t my disposal, has treated a number of gravely ill alcoholics. All
seem benefited to some extent, and a number of them to a degree that the
patients themselves consider miraculous. Looking over the records it is hard
not to agree with the appraisal these patients gave of themselves.
All new therapies enjoy an early period of high success, so that cautious
optimisin seems to be our wisest attitude, yet there are exciting, indeed, ex-
traordinary possibilities available to the therapist who has himself endured
these experiences. The substances in question can be used to develop very
high degrees of that mysterious yet vital quality-empathy. Shall we find a
means by which the therapist will share, to a far greater degree than he com-
monly does now, his patient’s experience? J ~ n g , 4and
~ many othersll
have long been aware of transient happenings of this sort.
We should perhaps do well not to be too hidebound by old techniques when
using these new tools.
Psychotomimetics a d Trainiitg
I know of no study dealing specifically with the application of these sub-
stances to the training of the workers engaged in many different disciplines
who work together in psychiatry. Such training has resulted from experi-
mental work, but only incidentally. and others have used these sub-
stances to enlarge the sympathy of members of a psychiatric staff for patients
in their care. Such a journey of self-discovery may one day be obligatory for
those working in psychiatry. Although it might not always be pleasant, with
care and understanding this experience would be very useful to the trainee.
The Model Therapies a d the Reverse
Schueler6‘seems to have been the founder of model therapies when, in 1934,
he gave some of his mescalinized medical students sodium succinate by vein.
This treatment reduced their symptoms briefly, but the symptoms recurred
when the succinate was excreted, which happened quickly. Mayer-Gross,4s
using the LSD 25 model, showed that perceptual change is reduced when the
blood sugar is over 200 pg. per cent. Elkes13found that both chlorpromazine
and sodium amytal antagonised LSD. FabingI6 altered the LSD-25 model
with azacyclonal (Frenquel), but with mescaline it seems that the effects re-
curred after more than one half-hour. H ~ d e during, ~ ~ the course of some
elegant work, discovered that a social setting that is protective and nutritive
results in a reduction of paranoid tendencies and perceptual changes. Hoffer
and A g n e ~used~ ~ nicotinic acid to alter the LSD-25 model. Giberti and
Gregoretti2‘jused both reserpine and chlorpromazine in LSD-25 models, and
Schwarz, Bickford, and RomeG2found that LSD-25 models and 1 mescaline
model were much reduced by chlorpromazine.
Schueler7sG1 work has never, I think, been used in psychiatric treatment on
any scale, although Smythies6’ used sodium succinate on a few chronic
schizophrenics without any change. M,ayer-Gro~s’s~~ work may have a bearing
on insulin therapy and, if it does, a radical change in technique seems indi-
 Osmond: Clinical Effects of Psychotomimetic Agents 425
cated. It is said that schizophrenia and diabetes rarely occur together. This
may be a lead worth following. Chlorpromazine, reserpine, and Frenquel have,
of course, all been used extensively in therapy. Hoffer and I, with our asso-
ciates,32are preparing a paper on a large series of schizophrenics treated with
massive doses of niacin. At this stage, the results seem promising.
Ways of aggravating model psychoses are equally important, though we
know little about them. found that cold and, particularly, inquisi-
torial attitudes increase perceptual disorders and paranoid trends. Atropine
and its derivatives aggravate the effects of hashish42and also those of schizo-
~ h i - e n i a .The
~ ~ effect of dhatura on hashish has been known for many years
in India, and is said to have been used by professional robbers in that country
to produce temporary madness in their victims. Methedrine, as I have al-
ready indicated, prolongs and reactivates the LSD-25 model. According to a
drug addict, benzedrine in large doses, dissolved in black coffee, is very like
~ ~ that 30 per cent COZ and 70 per cent
mescaline in effect. H ~ b b a r dreports
oxygen will both exaggerate and reactivate the LSD-25 model when inhaled.
Srnythies,‘j7using a stroboscope and, latterly, a variable-speed shutter, finds
that this enhances some aspects of the mescaline model. I have mentioned
earlier in this paper that some people who have had infective hepatitis many
years previously endure greatly prolonged responses to mescaline and adreno-
chrome.
I should like to see these models combined with a reduced or specialized
environment. We also need to know within what limits hypnosis can elimi-
nate, aggravate, and facilitate these psychic changes.
Psychotomimetic Agents and Psychology
Heinrich K l i i ~ e has
r ~ ~pioneered so many trails that it will be no surprise to
discover that nearly 30 years ago he was emphasizing the importance of mes-
caline to psychology in an admirable book now unhappily out of print.
The advances in our understanding of the hallucinatory, the illusional, and
the delusional that Kliiver considered could be made by studying the effects
of mescaline and similar experiences are, for the most part, still undone. During
an experiment with adrenochrome I found myself an “it,” a thing. The sensa-
tion was not one of unreality. It might be called “depersonalization,” but I
am not sure that a great variety of self-perceptions is not subsumed under
that label. Only comparison and careful classification will tell us.
Let us consider empathy, that feeling for, in, or with other creatures or even
things that seems to be so poorly described in psychological texts. Yet when
it is lacking to any great degree something essentially human is lost. Em-
pathy, I know, can increase until one is “involved in mankinde,” something
that most of us feel only when deeply in love. Saints have had such experience
sustained for a lifetime, but for the rest of us a few moments of it are ever
remembered as supreme exaltation. When members of the Native American
peyote takers, say that in their meetings this happens frequently, I
believe them. I t may seem unlikely that the usually insensitive can become
acutely and exquisitely aware of the feelings of others, but they can do so.
42 6 Annals New York Academy of Sciences
The development of synesthesia, that strange fusing of 2 or more sensory
modalities, has received some attention, but we know little about minor de-
grees of this sort of perception and the problems of communicating them.
How might this affect schizophrenics? Bleuler7 in an account of the existen-
tialist psychotherapy gives a hint of the possibilities here.
There is also the matter of thought blocking. I have noticed 3 different
varieties of this phenomenon that appear similar to an outside observer. In
one of them, so great is the press of associations that they rupture the chain of
thought. I n another, illusions and even hallucinations distract one’s atten-
tion. I n the third type it is as if the power of concentration fails and thought
fades out. This third type seems to spring from a physiological level. Those
who have been able to see in themselves will, I believe, devise better means of
inquiry than we now possess.
For the social psychologist there are group studies springing from observa-
tions already made with peyote takers. We have made tentative explorations
of the experiences of group use of LSD-25. The effects are strange and im-
pressive. We seem to have almost no language suitable for communicating
them. I t is as if new dimensions of human relationship are revealed. Such
work can be done only by those who are used to these substances.
Other Inquiries drising from This W o r k
It is encouraging that many are joining in the hunt now that the question of
psychotomimetic indoles has been raised again. Federoff,ls, *O at the Uni-
versity of Saskatchewan, is pursuing the matter of blood toxicity in schizo-
phrenia, with interesting results. We need much more detailed information
about these derivatives of adrenalin and other related compounds, so that we
can obtain regular supplies of those that have known, predictable psycho-
tomimetic activity. At the moment there seems to be a considerable differ-
ence in potency between various batches of these drugs, and no one knows the
precise reason. There is an urgent need for vigorous research in this area of
psyc hopharmacology .
We also need a means of temporarily enhancing the effect of psychotomi-
metics so that while avoiding a model psychosis we can nevertheless spot their
presence in the volunteer. Smythie~,~’ using the stroboscope, has given us a
valuable clue here, and he is following this lead a t Cambridge University,
Cambridge, England.
If we are to succeed, close cooperation between many varied disciplines will
be necessary.
I hope that foundations, governments, and large firms will keep this thought
continually in mind. Let us encourage people from distant and often hostile
groups to meet, talk, and listen together. Let us lure them into making those
essential friendships. The attempt will be worth it.
Tlze Exploralion of Experience
Our interest, so far, has been psychiatric and pathological, with only a hint
that any other viewpoint is possible, yet our predecessors were interested in
these things from quite different points of view. I n the perspective of history,
 Osmond: Clinical Effects of Psychotomimetic Agents 427
our psychiatric and pathological bias is the unusual one. By means of a variety
of techniques, from dervish dancing to prayerful contemplation, from solitary
confinement in darkness to sniffing the carbonated air a t the Delphic oracle,
from chewing peyote to prolonged starvation, men have pursued, down the
centuries, certain experiences that they considered valuable above all others.
The great William James41endured much uncalled-for criticism for suggest-
ing that in some people inhalations of nitrous oxide allowed a psychic disposi-
tion that is always potentially present to manifest itself briefly. Has our
comparative neglect of these experiences, recognized by James and Bergsons
as being of great value, rendered psychology stale and savorless? Our preoc-
cupation with behavior, because it is measurable, has led us to assume that
what can be measured must be valuable, and vice versa. During the 20th
century we have seen, except for a few notables such as Carl Jung, an abandon-
ing of the psyche by psychologists and psychiatrists. Recently they have
been joined by certain philosopher^.^ Pavlov, Binet, Freud, and a host
of distinguished followers legitimately limited the field to fit their requirements,
but later expanded their formulations from a limited inquiry to embrace the
whole of existence. An emphasis on the measurable and the reductive has
resulted in the limitation of interest by psychiatrists and psychologists to
aspects of experience that fit in with this concept.
There was and is another stream of psychological thought in Europe and in
the United States that is more suitable for the work that I shall discuss next.
James, in the United States, Sedgwick, Myers,s1 and Gurney in Britain, and
Carl Jung in Switzerland are among its great figures. Bergsons is its philos-
opher and Harrisonz7 its prophet. These and many others have said that in
this work, as in any other, science is applicable if one defines it in Dingle’sI2
term, “the rational ordering of the facts of experience.” We must not fall
into the pitfall of supposing that any explanation, however ingenious, can be
a substitute for observation and experiment. The experience must be there
before the rational ordering.
Work on the potentialities of mescaline and the rest of these agents fell on
the stony ground of behaviorism and doctrinaire psychoanalysis. Over the
years we have been deluged with explanations, while observation has become less
sharp. This will doubtless continue to be the case as long as the observer and
the observed do not realize that splendor, terror, wonder, and beauty, far from
being the epiphenomena of “objective” happenings, may be of central im-
portance.
Accounts of the effect of these agents, ranging in time from that of Havelock
Ellisls in 1897 to the more recent reports of Aldous H ~ x l e y ,~38’ .are many, and
they emphasize the unique quality of the experience. One or more sensory
modalities combined with mood, thinking and, often to a marked degree,
empathy, usually change. Nost subjects find the experience valuable, some
find it frightening, and many say that it is uniquely lovely. All, from Slot-
kin’s65unsophisticated Indians to men of great learning, agree that much of it
is beyond verbal description. Our subjects, who include many who have
drunk deep of life, including authors, artists, a junior cabinet minister, scientists,
a hero, philosophers, and businessmen, are nearly all in agreement in this
42 8 Annals New York Academy of Sciences
respect. For myself, my experiences with these substances have been the
most strange, most awesome, and among the most beautiful things in a varied
and fortunate life. These are not escapes from but enlargements, burgeonings
of reality. I n so far as I can judge they occur in violation of Hughlings
principle, because the brain, although its functioning is impaired,
acts more subtly and complexly than when it is normaI. Yet surely, when
poisoned, the brain’s actions should be less complex, rather than more so?
I cannot argue about this because one must undergo the experience himself.
Those who have had these experiences know, and those who have not had them
cannot know and, what is more, the latter are in no position to offer a useful
explanation.
Is this phenomenon of chemically induced mental aberration something
wholly new? I t is not, as I have suggested earlier. It has been sought and
studied since the earliest times and has played a notable part in the develop-
ment of religion, art, philosophy, and even science. Systems such as yoga
have sprung from it. Enormous effort has been expended to induce these
states easily so as to put them to use. Although occasionally trivial and
sometimes frightening, their like seems to have been a t least part of the ex-
perience of visionaries and mystics the world over. These states deserve
thought and pondering because until we understand them no account of the
mind can be accurate. It is foolish to expect a single exploration to bring
back as much information as 20 of them. It is equally foolish to expect an
untrained, inept, or sick person to play the combined part of observer, ex-
periencer, and recorder as well as a trained and skilled individual. Those who
have no taste for this work can help by freely admitting their shortcomings
rather than disguising them by some imposing ascription.
This may seem mere nonsense but, before closing hismind, the reader should
reflect that something unusual ought to seem irrational because it transcends
those fashionable ruts of thinking that we dignify by calling them logic and
reason. We prefer such rationalized explanations because they provide an
illusory sense of predictability. Little harm is done so long as we do not let
our sybaritism blind us to the primacy of experience, especially in psychology.
Psychoanalysts claim that their ideas cannot be fully understood without a
personal analysis. Not everyone accepts this claim, but can one ever under-
stand something one has never done? A eunuch could write an authoritative
book on sexual behavior, but a book on sexual experience by the same author
would inspire less confidence. Working with these substances, as in psycho-
analysis, we must often be our own instruments.
Psychoanalysis resembles Galileo’s telescope, which lets one see a somewhat
magnified image of an object the wrong way round and upside down. The
telescope changed our whole idea of the solar system and revolutionized navi-
gation. Psychotomimetic agents, whose collective name is still undecided, are
more like the radar telescopes now being built to scan the deeps of outer,
invisible space. They are not convenient. One cannot go bird watching with
them. They explore a tiny portion of an enormous void. They raise more
questions than answers, and to understand those answers we must invent new
languages. What we learn is not reassuring or even always comprehensible.
 Osmond: Clinical Effects of Psychotomimetic Agents 429
Like astronomers, however, we must change our thinking to use the poten-
tialities of our new instruments.
Freud has told us much about many important matters. However, I believe
that he and his pupils tried illegitimately to extrapolate from his data far beyond
their proper limitsin an attempt to account for the whole of human endeavor and,
beyond this, into the nature of man and God. This was magnificent bravado.
It is not science, for it is as vain to use Freud’s system for these greatest ques-
tions as it is to search for the galaxies with Galileo’s hand telescope. Jung,
using what I consider the very inadequate tools of dream and myth, has shown
such skill and dexterity that he has penetrated as deep into these mysteries as
his equipment allows. Our newer instruments, employed with skill and
reverence, allow us to explore a greater range of experience more intensively.
There have always been risks in discovery. Splendid rashness such as John
Hunter’s should be avoided, yet we must be prepared for calculated risks such
as those that Walter Reed and his colleagues took in their conquest of yellow
fever. The mind cannot be explored by proxy. To deepen our understanding,
not simply of great madnesses but of the nature of mind itself, we must use our
instruments as coolly and boldly as those who force their aircraft through other
invisible barriers. Disaster may overtake the most skilled. Today and in
the past, for much lesser prizes, men have taken much greater risks.

How Should We Name Them?

If mimicking mental illness were the main characteristic of these agents,
“psychotomimetics” would indeed be a suitable generic term. It is true that
they do so, but they do much more. Why are we always preoccupied with the
pathological, the negative? Is health only the lack of sickness? Is good
merely the absence of evil? Is pathology the only yardstick? Must we ape
Freud’s gloomier moods that persuaded him that a happy man is a self-deceiver
evading the heartache for which there is no anodyne? Is not a child infinitely
potential rather than polymorphously perverse?
I have tried to find an appropriate name for the agents under discussion: a
name that will include the concepts of enriching the mind and enlarging the
vision. Some possibilities are: psychephoric, mind-moving ; psychehormic,
mind-rousing ; and psycheplastic, mind-molding . Psychezymic, mind-ferment-
ing, is indeed appropriate. Psycherhexic, mind bursting forth, though difficult,
is memorable. Psychelytic, mind-releasing, is satisfactory. My choice, be-
cause it is clear, euphonious, and uncontaminated by other associations, is
psychedelic, mind-manifesting. One of these terms should serve.

Epilogue
This, then, is how one clinician sees these psychedelics. I believe that these
agents have a part to play in our survival as a species. For that survival
depends as much on our opinion of our fellows and ourselves as on any other
single thing. The psychedelics help us to explore and fathom our own nature.
We can perceive ourselves as the stampings of an automatic socioeconomic
process; as highly plastic and conditionable animals; as congeries of instinctive
430 Annals New York Academy of Sciences
strivings ending in loss of sexual drive and death; as cybernetic gadgets; or
even as semantic conundrums. All of these concepts have their supporters
and they all have some degree of truth in them. We may also be something
more, “a part of the main,” a striving sliver of a creative process, a mani-
festation of Brahma in Atman, an aspect of an infinite God imminent and
transcendent within and without us. These very different valuings of the self
and of other people’s selves have all been held sincerely by men and women.
I expect that even what seem the most extreme notions are held by some
contributors to these pages. Can one doubt that the views of the world de-
rived from such differing concepts are likely to differ greatly, and that the
courses of action determined by those views will differ?
Our beliefs, what we assume, as the Ames9 demonstrations in perception*
show, greatly influence the world in which we live. That world is in part, a t
least, what we make of it. Once our mold for world making is formed it most
strongly resists change. The psychodelics allow us, for a little while, to divest
ourselves of these acquired assumptions and to see the universe again with an
innocent eye. I n T. H. H u x l e y ’ ~words,
~ * ~ we may, if we wish, “sit down in front
of the facts like a child” or, as Thomas Traherne, a 17th-century English
mystic puts it, “to unlearn the dirty devices of the world and become as it were
a little child again.”? Mystic and scientist have the same recipe for those
who seek truth. Perhaps, if we can do this, we shall learn how to rebuild our
world in another and better image, for our extraordinary technical virtuosity
is forcing change on us whether we like it or not. Our old faults, however,
persisting in our new edifice, are far more dangerous to us than they were in
the old structure. The old world perishes and, unless we are to perish in its
ruins, we must leave our old assumptions to die with it. “Let the dead bury
their dead” tells us what we must do.
While we are Iearning, we may hope that dogmatic religion and authoritarian
science will keep away from each other’s throats. We need not put out the
visionary’s eyes because we do not share his vision. We need not shout
down the voice of the mystic because we cannot hear it, or force our rationaliza-
tions on him for our own reassurance. Few of us can accept or understand the
mind that emerges from these studies. Kant once said of Swedenborg,
“Philosophy is often much embarrassed when she encounters certain facts she
dare not doubt yet will not believe for fear of ridicule.” Sixty years ago ortho-
dox physicists knew that the atom was incompressible and indivisible. Only a
few cranks doubted this, yet who believes in the billiard-ball atom now?
In a few years, I expect, the psychedelics that I have mentioned will seem
as crude as our ways of using them. Yet even though many of them are
gleanings from Stone Age peoples they can enlarge our experience greatly.
Whether we employ these substances for good or ill, whether we use them with
skill and deftness or with blundering ineptitude depends not a little on the
* “ .. . the principle that what we are aware of is not determined entirely by the nature of what is out there
or by our sensory processes, but that the assumptions we hrins from past experience, because they have gener-
ally proved reliable, are involved in every perception we have.”g
t Also Francis Bacon, the father of modern scientihc method, in Novum Organum wrote “The entrance into
the Kingdom of man, founded on the sciences, being not much other than th; entrance into the King-
dom of Heaven, whereinto none may enter except as a little child.”
 Osmond : Clinical Effects of Psychotomimetic Agents 43 1
courage, intelligence, and humanity of many of us who are working in the
field today.
Recently I was asked by a senior colleague if this area of investigation lies
within the scope of science and, if it does not, should not religion, philosophy,
or politics take the responsibility for it? But politics, philosophy, religion,
and even art are dancing more and more to the tune of science and, as scientists,
it is our responsibility to see that our tune does not become a death march,
either physical or spiritual.
We cannot evade our responsibilities.
So far as I can judge, spontaneous experience of the kind we are discussing
has always been infrequent, and the techniques for developing it are often
faulty, uncertain, clumsy, objectionable, and even dangerous. Our increas-
ingly excellent physical health, with the steady elimination of both acute and
chronic infections; the tranquilizers that enable us to neutralize unusual chemo-
electrical brain activity; our diet, rich in protein and, especially, B-complex
vitamins whose antagonism to LSD I have already discussed; all of these com-
bined with a society whose whole emphasis is on material possessions in a
brightly lit and brilliantly colored synthetic world, will make spontaneous
experiences of the sort I have mentioned ever fewer. As we grow healthier
and healthier, every millimeter that we budge from an allotted norm will be
checked.
I believe that the psychedelics provide a chance, perhaps only a slender one,
for homo jaber, the cunning, ruthless, foolhardy, pleasure-greedy toolmaker to
merge into that other creature whose presence we have so rashly presumed,
homo sapiens, the wise, the understanding, the compassionate, in whose four-
fold vision art, politics, science, and religion are one. Surely we must seize
that chance.
Summary
After indicating that there are a number of substances a t present subsumed
as psychotomimetic agents I have indicated that these are not yet clearly
defined, and I have suggested that while mimicking psychoses is one aspect of
these agents, it is not the only or even the most important one. 1 have dis-
cussed their great antiquity and have shown how they have attracted man since
the dawn of history. Since many drugs produce changes in both body and
mind,, I consider that some working definition is required that will exclude
anesthetics, hypnotics, alcohol, and the derivatives of morphine, atropine, and
cocaine. I have suggested as a definition: “psychotomimetic agents are sub-
stances that produce changes in thought, perception, mood and sometimes
posture, occurring alone or in concert, without causing either major disturbances
of the autonomic nervous system or addictive craving, and although, with
overdosage, disorientation, memory disturbance, stupor, and even narcosis
may occur, these reactions are not characteristic.”
This definition, of course, will be modified as knowledge grows.
I have discussed model psychoses induced by means of these agents and have
indicated the existence of many gaps in our understanding. I believe that the
432 Annals New York Academy of Sciences
lack of such information has delayed the development of the sort of inquiry
that has recently led to work with adrenochrome, adrenolutin, and bufotenin,
mentioning some of the difficulties that beset those who work with the newer
and truer psychotomimetics. I have suggested how model therapies modifying
model psychoses and the study of means of aggravating or prolonging them
provide useful information, and have touched on some of their uses in psycho-
therapy, emphasizing how much is still unknown.
I believe that there is a place for the use of these substances in the training
of psychiatrists, psychologists, nurses, and others working with the mentally
ill. I have linked these agents with recent work on the reduced and specialized
environment by Hebb and Lilly, and I have discussed some psychological, so-
cial, and philosophical implications inherent in this inquiry, relating them to
the newer work on perception.
In view of all these considerations, I have suggested that “psychotomimetic”
is far too narrow a generic term, and I have suggested several that imply altera-
tions in the normal mind. Among these proposed designations are “psyche-
hormic,” “psycherhexic,” and “psychezymic,” my own preference being
“psychelytic,” or “psychedelic”-mind-manifesting.
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