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50 Years

of LSD
A Symposium of the Swiss
Academy of Medical Sciences

Lugano-Agno (Switzerland)
October 21 and 22, 1993

Edited by
A. Pletscher and
D. Ladewig
50 Years of LSD
A Symposium of the Swiss
Academy of Medical Sciences

Lugano-Agno (Switzerland)
October 21 and 22, 1993

Edited by
A. Pletscher and
D. Ladewig

The Parthenon Publishing Group

International Publishers in Medicine, Science & Technology


List of principal contributors vii
A. Pletscher 1

1 History of the discovery of LSD
A. Hofmann 7

2 5-Hydroxytryptamine receptor interactions of D-lysergic acid
S. J. Peroutka 19
3 LSD and phenethylamine hallucinogens: common sites of neuronal
G. K. Aghajanian 27
4 Ethnopharmacology of LSD and related compounds
L. Rivier 43

5 Experience of time and space in model psychoses
H. Heimann 59
6 Evidence for a cortical-subcortical imbalance of sensory information
processing during altered states of consciousness using positron
emission tomography and [ 18 F]fluorodeoxyglucose
F. X. Vollenweider 67
7 Arylalkanamine-induced effects in normal volunteers:
on the significance of research in hallucinogenic agents for psychiatry
L. Hermle, M. Spitzer and E. Gouzoulis 87
8 Psychological aspects of altered states of consciousness of the LSD
type: measurement of their basic dimensions and prediction of
individual differences
A. Dittrich 101



9 Acid against established realities: a transcultural and transdisciplinary
view of LSD and related hallucinogens
H. Isernhagen 121


10 Pharmacological standards for evaluation of clinical effects of
M. Lader 135
11 Human psychopharmacology of LSD, dimethyltryptamine and
related compounds
R. J. Strassman 145
12 Hallucinogens as an aid in psychotherapy: basic principles and results
H. Leuner 175
13 Perspectives on LSD and psychotherapy: the search for a new
R. Yemen 191
14 Psychotherapeutic effects
R. Richter 203
15 Methodological issues in the evaluation of a medication for its
potential benefits in enhancing psychotherapy
C. P. O'Brien and R. T.Jones 213

Conclusions, with special regard to clinical aspects

D. Ladewig 223

Appendix: List of invited participants 229

Index 233


G. K. Aghajanian H. Isernhagen
Department of Psychiatry and Department of English
Pharmacology University of Basel
Yale University School of Medicine Nadelberg 6
and the Connecticut Mental Basel
Health Center Switzerland
34 Park Street
New Haven
Connecticut 06508
USA M. Lader
Institute of Psychiatry
The Maudsley Hospital
A. Dittrich
De Crespigny Park
PSIN Psychologisches Institut für
Denmark Hill
Beratung und Forschung
Jupiterstrasse 49
D. Ladewig
H. Heimann Psychiatric University Clinic of
Psychiatrische Universitätsklinik Basel
Osianderstrasse 22 Wilhelm Klein-Strasse
Tübingen Basel
Germany Switzerland

H. Leuner
L. Hermle Eisenacher Strasse 14
Fachkrankenhaus für Psychiatrie und Göttingen
Neurologie Germany
Christophsbad Göppingen
Faurndauerstrasse 6-28
C. P. O'Brien
University of Pennsylvania
Veteran Affairs Medical
A. Hofmann 3900 Chestnut Street
Rittimatte Philadelphia
4117 Burg iL Pennsylvania
Switzerland USA


S. J. Peroutka R. J. Strassman
Spectra Biomedical, Inc. University of New Mexico
2465 E. Bayshore Road, Suite 301 Department of Psychiatry
Palo Alto 2400 Tucker Avenue, NE
California 94303 Albuquerque
USA New Mexico
A. Pletscher
Schweizerische Akademie der F. X. Vollenweider
medizinischen Wissenschaften Psychiatric University Hospital
Petersplatz 13 Zürich
CH-4051 Basel Research Department
Switzerland Lenggstrasse 31
R. Richter
Sektion Psychoanalytische Methodik
Abteilung Psychotherapie R. Yensen
Klinikum der Universität Ulm Orenda Institute
Am Hochsträss 8 2403 Talbot Road
Ulm Baltimore
Germany Maryland
L. Rivier
University Institute of Legal
Rue du Bugnon 21

A symposium celebrating the 50th anniversary of a world-renowned drug, with
the active participation of its discoverer, is certainly a remarkable event. The drug
in question, lysergic acid diethylamide (LSD), was prepared by Albert Hofmann
from lysergic acid, the basic structure of the ergot alkaloids (e.g. ergotamine),
which occurs in the cereal fungus Claviceps purpurea (see Chapter 1). Somewhat
later, in 1943, Hofmann discovered the peculiar psychotropic actions of LSD.
This drug, an indolamine derivative like serotonin, has subsequently been classi-
fied as a hallucinogen or psychotomimetic drug because its principal effect in
humans is the generation of psychosis-like states, including hallucinations. The
history of LSD has been extraordinary, as is revealed in Chapter 1 by the
discoverer himself.
The decision of the Swiss Academy of Medical Sciences (SAMS) to organize a
symposium on LSD and other hallucinogens was based on the following
(1) LSD has been of worldwide interest, not only to pharmacology and
psychiatry but also to society at large.
(2) The 50 th anniversary of the discovery of LSD, which coincides with the 50 th
anniversary of the foundation of the SAMS, was thought to be a good
opportunity to review the experiences with LSD and related hallucinogens
which have been collected to date, and to reflect on the future potential of
these drugs.
(3) LSD was discovered in Basel, Switzerland, and the discoverer of the drug is
still with us.
What is so unusual about LSD? The first feature which intrigued pharmacologists
and psychiatrists was the extreme potency of the drug in inducing profound
psychic alterations. Whereas other drugs had to be applied in quantities in the
order of mg or g/kg, LSD already exhibits effects in doses below 1 µg/kg. This
represented a challenge for pharmacologists, who soon found the drug to be a
valuable research tool, since it showed high affinity, especially for 5-hydroxy-
tryptamine receptor subtypes, but seemed to act also on the dopamine system.
Secondly, LSD raised considerable hopes for psychiatrists. In the early days the
drug was thought to produce a model psychosis imitating schizophrenia (a view



which later had to be amended) and some people thought it might help in the elu-
cidation of the pathophysiology of this mental disorder. In addition, LSD found
application in psychiatric therapy as a psycholytic, psychodysleptic or psychedelic
agent. Thirdly, the drug also became of interest to ethnologists; an aspect which
has been included in the symposium.
Unfortunately, LSD did not remain in the scientific and medical scene, but fell
into the hands of esoterics and hippies and was used by hundreds and thousands
of people in mass-gatherings. This uncontrolled propagation of LSD had
dangerous consequences - for instance, prolonged psychotic episodes, violence
and suicide attempts. Therefore, the use of the drug was subjected to severe
restrictions by legal acts. It was placed into the same category of dangerous drugs
as opiates, although unlike the opiates it has virtually no physical dependence
liability. This development seriously curtailed pharmacological and clinical
research with LSD, but some activities in these domains are still continuing.
Pharmacological research is also proceeding with other hallucinogens. These
belong to various chemical classes, including those of the indolalkyl- and
phenethyl-amines (Figure 1). They differ in their mechanisms of action. A
hallucinogen whose biological action was known before that of LSD is mescaline,
a constituent of a Mexican cactus. Following the discovery of LSD, psilocin and
psilocybin were extracted from a fungus of a Mexican cactus and synthesized by
Albert Hofmann. Other compounds used paramedically to produce abnormal
mental states with occasional hallucinations include N,N-dimethyltryptamine,
phencyclidine and 3,4-methylenedioxymethamphetamine (MDMA). The latter is
also placed into the group of entactogens. All these substances are interesting
research tools, but have little or no therapeutic potential.
It is hoped that 50 years of LSD studies, and considerable research experience
with other hallucinogens, has enabled us, during this symposium, to answer some
open questions. Among these, the following are of particular interest:

(1) What has been learned about the mode of action of hallucinogens and have
they contributed to the understanding of the pathophysiology of psychotic

(2) Do hallucinogens, especially LSD, have a place in the treatment of mental

disorders and, if so, what are their main applications?

(3) Which direction should the work with hallucinogens take in the future?

Even partial answers to these questions are of interest to psychiatrists,

psychologists, pharmacologists and health authorities. Therefore, it was decided
to publish the proceedings of the symposium in book form and Parthenon
Publishing kindly agreed to assume the responsibility for its publication. It is
hoped that this book will help to stimulate further critical research on LSD and


Lysergic acid diethylamide (LSD) Mescaline Phencyclidine


Psilocin 3,4- Methylenedioxymethamphetamine

Psilocybin (= phosphate ester) (MDMA, 'Ecstasy') N,N-Dimethyltryptamine

Figure 1 Psychotomimetic drugs


other hallucinogens under well-controlled conditions, using modern experi-

mental and clinical methodologies. These symposium proceedings can also be
thought of as a contribution to the Decade of the Brain, which, in Switzerland, was
inaugurated in January 1994.
Finally, the SAMS expresses its thanks to those who have contributed to the
organization of the symposium, namely the program committee, including
J. Angst (Zürich), H. Dufour (Prilly), J. Gelzer (Basel); A. Hofmann (Burg), D.
Ladewig (Basel), D. Loew (Basel), L. Maître (Basel), W. Poeldinger (Basel); the
conference administrators M. Borer, I. Michel, G. Nussbaumer; and last but not
least the sponsors: the Swiss Federal Office of Health and the Sandoz company of
Alfred Pletscher
Symposium Chairman


Section 1


History of the discovery of LSD


Time and again I hear or read that LSD was an accidental discovery, that LSD was
discovered by chance. This is only partly true. LSD was already 5 years old when
chance came into play. I had prepared this compound in 1938 in the course of
planned research, but it was only in 1943 that I discovered, by chance, its extra-
ordinary psychical effects. I had planned to prepare an analeptic, a circulatory
stimulant, but then found a psychical stimulant of unprecedented potency. The
English vocabulary has a term for such discoveries - 'serendipity' - meaning a
kind of planned accident, or planned chance.
The source of LSD is ergot; in German, 'Mutterkorn' 1 . Ergot is produced by a
lower fungus (Claviceps purpurea) that grows parasitically on rye and on other
grain-producing species and also on wild grasses (Figure 1). Kernels infected with
the fungus develop into light-brown colored curved pegs that emerge from the
husk in place of the normal grain. Ergot is described botanically as a Sclerotium,
the form that the fungus takes in winter. Ergot of rye (Secale cornutum) is the
variety used medicinally.
Ergot, more than any other drug, has a fascinating history. Once dreaded as a
poison, in the course of time it has become a rich storehouse of valuable remedies.
It first appeared in the early Middle Ages, as the cause of mass poisonings - epi-
demics and affected thousands of people. Because members of the Order of St
Anthony treated these patients primarily, the disease was called 'St Anthony's fire'
(Figure 2). The connection of ergot with the illness was elucidated only in the
seventeenth century.
Since the Middle Ages, ergot has been used by midwives as a medicament to
precipitate childbirth. This accounts for its German name of 'Mutterkorn'.
Chemical investigation in order to isolate the active principle that influences
childbirth had already begun in the last century, but these studies remained
unsuccessful for a long time.
When Professor Arthur Stoll founded the pharmaceutical department of the


Figure 1 Ergot (Claviceps purpurea) on rye

Sandoz company in 1917, research on ergot became one of the main topics in his
laboratory. He was soon successful in isolating an alkaloid, which he named
ergotamin, which possessed the sought activity on the uterus, as well as other phar-
macological properties. The ergot problem seemed to be solved. However, it was
not until later, between 1932 and 1934, that the truly specific uterotonic ergot
alkaloid was isolated in several laboratories, in the USA, in England and in the
Sandoz laboratory. It was named ergobasin, ergometrine or ergonovine.
At that time, I had just finished my investigations in the field of cardiac glyco-
sides in the laboratory of Professor Stoll, with the elucidation of the chemical
structure of the aglycon of the Scillaglycosides. I asked the professor for permis-
sion to start working with ergot. He granted my request with some misgivings:
'I must warn you of the difficulties you will face in working with ergot alkaloids.
These are exceedingly sensitive, easily decomposing substances. But you are
welcome to try'.
So the switches were thrown and I found myself engaged in a field of research
that would become the main theme of my professional career. I remember for ever


Figure 2 St Anthony, surrounded by ergotism victims (Staatliche Graphische Sammlung,


the creative joy, the eager anticipation I felt in embarking on the study of ergot
alkaloids, at that time a relatively uncharted field of research. The first goal of my
new activity was the partial synthesis of ergobasin. The chemical structure of
ergobasin has been found to be lysergic acid propanolamide. Lysergic acid is the
common nucleus of all medicinally important ergot alkaloids. I was successful
after having developed a procedure for the production of amides of lysergic acid,
one which enabled lysergic acid to combine with amines. By linking lysergic acid
with propanolamine I obtained a compound that was identical with ergobasin.


Figure 3 Chemical structure of (a) D-lysergic acid L-isopropanolamide (ergonovine, ergobasin,

ergometrine, (b) LSD and (c) nicotinic acid diethylamide (coramine)

This was the first synthesis of a natural ergot alkaloid. If a chemist develops a
procedure for the synthesis of a natural product, he can use this procedure to
produce chemical modifications of the natural compound.
Amongst the many chemical modifications of ergobasin that I synthesized was
its higher homolog lysergic acid butanolamide, which proved to be superior to
ergobasin in its pharmacological properties. It was therefore introduced into
obstetrics and became the leading medicament (with the brand-name 'Mether-
gine') for the treatment of postpartum bleeding.
Another chemical modification of the natural alkaloid, the 25th of this series,
was lysergic acid diethylamide; in German: Lysergsäure-diäthylamid, abbreviated
'LSD-25' 2 . I had synthesized this compound in order to obtain an analeptic, a
stimulant for blood circulation and respiration. Such pharmacological properties
could be predicted, on the basis of the close structural relationship between
lysergic acid diethylamide and nicotinic acid diethylamide, the well-known
analeptic 'Coramine' (Figure 3).
The pharmacological tests with the new compound (carried out in the Pharma-
cology Department, headed at that time by Professor Ernst Rothlin) revealed a
strong effect on the uterus, amounting to 70% of the activity of ergobasin. The
research report noted also that the experimental animals became restless in the
narcosis. These results did not elicit special interest, and the testing of LSD-25 was
therefore discontinued.
In the subsequent years I worked on the isolation of new alkaloids from ergot.
I succeeded also in producing dihydro derivatives of these new alkaloids of the
ergotoxine type. These became the components of two successful Sandoz phar-
maceuticals: 'Hydergin' and 'Dihydergot'. Yet strangely enough I could not
forget LSD-25, and 5 years later I decided to prepare another batch of this com-
pound for a more extended pharmacological testing.
How dull would life be, if one of its dominating factors, what we call accident
or chance, were missing, and if we would never become surprised. I was very


surprised, when in the afternoon of 16 April, 1943, after I had repeated the syn-
thesis of LSD, I entered suddenly into a kind of dreamworld. The surroundings
had changed in a strange way, and had become luminous, more expressive. I felt
uneasy and went home, where I wanted to rest. Lying on the couch with closed
eyes, because I experienced daylight as unpleasantly glaring. I perceived an unin-
terrupted stream of fantastic pictures, with an intense kaleidoscopic play of colors.
After some hours this strange but not unpleasant condition faded away.
I presumed that an intoxication, by some substance I had been working with in
the laboratory, had been the cause of that strange, bizarre experience. In the first
place, I surmised that dichloroethylene (which I had used in the purification
process of LSD and which is related to the inebriating solvent chloroform) could
have been the intoxicating agent. In order to test this assumption, 3 days later
(after a weekend, on April 19) I carried out a self-experiment with dichloroethy-
lene, sniffing carefully the vapors of this solvent. But nothing happened. I
decided, therefore, to test also lysergic acid diethylamide as a possible cause of that
strange psychical experience. The question was, however, how could this sub-
stance have found its way into my body? Possibly some of the methanolic solu-
tion of lysergic acid diethylamide had come into contact with my fingertips
whereby a trace of the substance had been absorbed through the skin.
Exercising extreme caution, I began the experiment with the smallest quantity
that could be expected to produce any psychical effect: only 0.25 mg lysergic acid
diethylamide tartrate. Quoted below is the entry in my laboratory journal of 19
April, 1943.
19.IV. 16.20 h: 0.5 cc of 1/2 promil aqueous solution of diethylamide tartrate orally -
0.25 mg tartrate. Taken diluted with about 10 cc water. Tasteless.

17.00 h: Beginning dizziness, feeling of anxiety, visual distortions, symptoms of

paralysis, desire to laugh.

Here the notes in my laboratory journal cease. By now it was already clear that
lysergic acid diethylamide had been the cause of the extraordinary experience of
the previous Friday, for the altered perceptions were of the same type, but much
more intensive. I asked my laboratory assistant to escort me home. Having no car,
we went by bicycle.
On the way home my condition began to assume threatening forms. Every-
thing in my field of vision wavered and was distorted as if seen in a curved mirror.
I had lost the feeling of time which resulted in the sensation of being unable to
move from the spot, although my assistant told me later that we had travelled
very rapidly. At home I asked my companion to summon our family doctor and
request milk from our neighbor. In spite of my delirious condition I was still
capable of clear and effective thinking - milk is a nonspecific antidote for poison-
ing. The dizziness and sensation of fainting became so strong that I could no


longer hold myself erect and had to lie down on a sofa. My surroundings had now
transformed themselves in more terrifying ways. Everything in the room spun
around and familiar objects and the furniture assumed grotesque, threatening
forms. They were in continuous motion, animated, as if driven by an inner rest-
lessness. When the neighbor brought the milk, she was no longer Mrs Ruch, but
rather a malevolent witch with a colored mask.
Even worse than these demonic transformations of the outer world were the
alterations that I perceived in myself, in my inner being. Every exertion of my will
to put an end to the disintegration of the outer world, and the dissolution of my
ego, seemed to be wasted effort. The substance with which I had wanted to
experiment had become a demon who had vanquished me and who scornfully
triumphed over my will. I was seized by the dreadful fear of having become
insane. I was taken to another world, another place, another time. My body
seemed to be without sensation, lifeless, strange. Was I dying? Was this the
transition? At times I believed I was outside my body, and then perceived clearly,
as an outside observer, the complete tragedy of my situation. I had not even taken
leave of my family (my wife, with our three children, had travelled that day to
visit her parents in Lucerne). Would they ever understand that I had not
experimented thoughtlessly or irresponsibly, but rather with the utmost caution?
By the time the doctor arrived, the climax of my despondent condition had
already passed. He shook his head in perplexity after my attempts to describe the
mortal danger which threatened my body. He could not detect any abnormal
symptoms other than extremely dilated pupils; pulse, blood pressure and breath-
ing were all normal. He saw no reason to prescribe any medication. Instead he
conveyed me to bed.
Slowly I came back from a weird, strange world to reassuring everyday reality.
The horror softened and gave way to a feeling of good fortune and gratitude.
Now, little by little, I could begin to enjoy the unprecedented colors and plays of
shapes that persisted behind my closed eyes. It was particularly remarkable how
every acoustic perception became transformed into optical perceptions. Every
sound generated a vividly changing image with its own consistent form and color.
Late in the evening my wife returned from Lucerne. By now I had recovered
sufficiently to tell her what had happened. Exhausted, I then slept, to awake the
next morning refreshed and with a clear head, though still somewhat physically
tired. When I later walked out into the garden, in which the sun shone after a
spring rain, everything glistened and sparkled in an enchanting new light. The
world seemed as if newly created.
That was how the first planned experiment with LSD ended. It was a dramatic
one - a horror trip as one would say later, because I had not been prepared for such
an overwhelming experience and because the chosen dosage had been too high.
The next day I wrote a detailed report about my unexpected discovery to
Professor Stoll, with a copy to Professor Rothlin. As expected, the first reaction


was incredulous astonishment. Instantly a phone call came from the management;
Professor Stoll asked: 'Are you sure you made no mistake in the weighing? Is the
dosage you mention really correct?'. Professor Rothlin also called, asking the same
question. But I was certain of this point, for I had carried out the weighing and
dosage with my own hands. Yet the doubts of these gentlemen could be justified
because until that time no substance was known which produced, in such low
dosage, even the slightest psychical effects. A psychoactive compound of a
potency such as reported seemed almost unbelievable.
Professor Rothlin and his two assistants, Drs Aurelio Cerletti and Rudolf
Bircher, were the next three persons who had an LSD experience. In order to
check the data of my report they took for their experiment, quite cautiously, only
one-third of the dose I had applied. Nevertheless, even at that level, the psychical
effects they experienced were still extremely impressive and quite fantastic. All
doubts about the statements in my report were eliminated.
After the discovery of the deep effects of LSD on the human psyche and con-
sciousness, one could expect that such a substance would receive an important
place in pharmacology, neurology, psychology, psychiatry and brain research.
That these expectations were fulfilled in the years that followed is demonstrated
by the fact that 50 years later we gathered at this international congress to discuss
and evaluate the many results and aspects of LSD research.
What I never would have expected for the future of LSD was that it would ever
find application as a pleasure drug on a large scale, considering the demonic, ter-
rifying effects I had also experienced in my first self-experiment. Unfortunately,
however, that did happen. LSD was for some time the 'number one' drug in the
drug scene, especially in the USA, and became the subject of total prohibition.
A third, quite unexpected thing happened which I must report here also,
because without mentioning it, the topic of this chapter, the story of the history
of LSD, would not be complete. I refer to the discovery of the close relatives of
LSD in the 'magic' plants of Mexico 2 . This was an extremely important finding
because it revealed that LSD, which had been regarded as a synthetic product born
in a laboratory, belongs to the group of ancient sacred Mexican drugs. It was LSD
itself that directed these Mexican drugs into my laboratory for chemical analysis;
this happened with the sacred Mexican mushroom teonanacatl.
After the discovery, in the early 1950s, of an ancient mushroom cult in
the Southern mountains of Mexico, by the American ethnologists R. Gordon
Wasson and his wife 3, the 'magic mushrooms' were botanically identified by the
mycologist Roger Heim in Paris. They were then sent to some chemical
laboratories for the identification of the active principles. After these investiga-
tions had been pursued without success in three different places, Heim sent me
samples of the mushrooms, in 1957. He hoped that in the laboratory where LSD
had been discovered, the special skill would exist for a successful chemical


Figure 4 Psilocybe mexicana. (Photo: A. Brack)

He was right. We (myself and co-workers 4 ) were soon successful. We were able
to isolate, identify and also synthesize the psychoactive principles. They were
named psilocybin and psilocin, after the mushroom Psilocybe mexicana (Figure 4). It
transpired that these compounds are structurally closely related to LSD, since
both contained a 4-substituted tryptophane radical (Figure 5).
An even closer chemical relationship of LSD to another sacred drug of the
Mexican indians was discovered when, in collaboration with Wasson, ololiuqui
was investigated in my laboratory. Ololiuqui is the Aztec name for seeds of plants
of the morning glory family (Convolvulaceae)5. The result of the chemical
analysis was quite sensational. The psychoactive principles of ololiuqui were
found to be lysergic acid amide and lysergic acid hydroxyethylamide, nearly
identical with lysergic acid diethylamide, or LSD 6 .
Despite these findings, the LSD story is still not yet complete. The research on
LSD that made an essential contribution to solve the problem of the above-
mentioned Mexican drugs also helped to shed light on the famous Mysteries of
Eleusis (Figure 6). It was discovered that exactly the same alkaloids as those in


Constituents of ololiuqui

Constituents of teonanacatl

Figure 5 LSD and related compounds

ololiuqui (i.e. lysergic acid amide and lysergic acid hydroxyethylamide) were
found to occur in an ergot species (Claviceps paspali), which grows in Greece in the
surroundings of Eleusis. These findings led R. G. Wasson, C. A. P. Ruck and
myself to the hypothesis that the same LSD-like alkaloids which occur in the
sacred drug ololiuqui could also have been the psychoactive constituents of the
kykeon, the holy potion of Eleusis 7 .


Figure 6 The Eleusinian Goddess (Skyphos, 490-480 BC, British Museum)

In closing, I would remark that 50 years is a very young age for a compound
such as LSD which, as a substance, will never die. We cannot foresee its fate for
the next 50, 100 or 1000 years, but looking back to its development in the first 50
years we can make, it seems to me, some hopeful speculations for the future. If
notice had been taken of the thousand-year-old experiences of ancient cultures
about how to properly use drugs of the LSD type, drugs that affect the very core
of our being, our consciousness, then the incautious, profane application in the
drug scene would not have taken place, prohibition would not have succeeded,
and we, as participants in this conference would be discussing, I am convinced,
many more positive aspects of LSD research.

1. Hofmann, A. (1964). Die Mutterkornalkaloide. (Stuttgart: Ferdinand Enke Verlag)
2. Hofmann, A. (1993). LSD - Mein Sorgenkind. 2nd edn. (München: dtv)
3. Wasson, V. P. and Wasson R. G. (1957). Mushrooms, Russia and History. (New York: Pantheon
Books Inc.)
4. Hofmann, A., Heim, R., Brack, A., Kobel, H., Frey, A., Ott, H., Petrzilka, T. and Troxler, F.
(1959). Psilocybin und Psilocin:, zwei psychotrope Wirkstoffe aus mexikanischen Rauschpilzen.
Helv. Chim. Acta., XLII, 1557-72
5. Schuhes, R. E. (1941). A Contribution to our Knowledge of Rivea corymbosa. The Narcotic Ololiuqui
of the Aztecs. (Cambridge, USA: Botanical Museum of Harvard University)
6. Hofmann, A. and Tscherter, H. (1960). Isolierung von Lysergsäure-Alkaloiden aus der
mexikanischen Zauberdroge Ololiuqui. Experientia, 16, 1-3
7. Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis. (New York and
London: Harcourt Brace Jovanovich)

Section 2


5-Hydroxytryptamine receptor
interactions of D -lysergic
acid diethylamide


Neurotransmitter receptors consist of at least four distinct types of molecular

structures: G protein-coupled receptors, ligand-gated ion channels, transporters
and tyrosine kinases. At present, the greatest diversity exists within the molecular
'superfamily' of G protein-coupled receptors. The multiplicity of behavioral and
biological effects of D-lysergic acid diethylamide (D-LSD) is mirrored in its broad
range of receptor interactions. Within the group of G protein-coupled receptors,
D - L S D appears to exert its primary biological effects on 5-hydroxytryptamine
(5-HT) receptors. The most potent interactions of D - L S D have been observed at
5-HT receptors. The data reviewed here indicate that D - L S D acts differentially as
an agonist, partial agonist or antagonist at specific 5-HT receptor subtypes.
Due to the structural similarities between D - L S D and the 5-HT molecule, early
investigators hypothesized that D - L S D might exert its hallucinogenic effects
through the 5-HT system in the central nervous system ( C N S ) 1 , 2 . In the C N S ,
D - L S D has been found to increase levels of 5 - H T and to decrease levels of the
5-HT metabolite, 5-hydroxy-indoleacetic acid (5-HIAA) 4 . A significant observa-
tion was made in 1968 by Aghajanian and colleagues, who showed that systemic
administration of D - L S D caused a cessation of spontaneous firing of the 5-HT-
containing neurons of the dorsal and median raphe nuclei 5 . These early observa-
tions have been confirmed and extended by numerous other investigators.


More recently, molecular biological data have unequivocally confirmed the exis-
tence of multiple 5-HT receptors (Table 1). Indeed, the multiplicity of 5-HT


Table 1 Overview of 5 - H T receptor subtypes

G protein-coupled receptors
5 - H T 1 'Family' 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E,5-HT1F
5-HTdrol, 5-HTdro2A, 5-HTdro2B, 5-HTsnail
5 - H T 2 'Family' 5-HT2, 5 - H T l c , 5-HT2F
Others 5-HT5A, 5-HT5B, 5-HT6, 5-HT7
Ligand-gated ion channels 5-HT3
Transporters 5 - H T uptake site

receptor subtypes, both within and between species, has exceeded most of the
predictions that might have been made on the basis of pharmacological data. As
a result of these recent scientific findings, nearly all of the initial data on D - L S D
must be re-evaluated. It is now clear that very few studies, if any, of D - L S D have
ever been performed at 'pure' subpopulations of 5-HT receptors.
This review is intended to summarize the recent molecular biological data and
to present the available information concerning the ability of LSD to interact with
5-HT receptor subtypes. To place the multiplicity of G protein-coupled 5-HT
receptors into the context of molecular evolution, the relationships between the
known 5-HT receptor subtypes were determined by a phylogenetic tree analysis6.
The aligned sequences of all identified mammalian G protein-coupled 5-HT
receptors were compared and a phylogenetic tree was constructed (Figure l) 7 . The
length of each 'branch' corresponds to the evolutionary distance between receptor
subpopulations. Thus, G protein-coupled 5-HT receptors have differentiated into
three clearly discernible major branches. The low level of homology (approxi-
mately 25%) between the major branches suggests that 5 - H T 1 , 5 - H T 2 and 5 - H T 6
receptors diverged from a common ancestor gene early in evolution, prior to the
differentiation of vertebrates and invertebrates.
The 5 - H T 1 receptor 'family' or 'branch' includes 5 - H T 1 A , 5 - H T 1 B , 5 - H T 1 D ,
5 - H T 1 E and 5 - H T 1 F receptors, as well as 5 - H T 5 A , 5 - H T 5 B and 5 - H T 7
receptors 8 - 1 2 . The 5 - H T 5 and 5 - H T 7 receptors appear to have differentiated early
in evolution since they are more similar to each other than to the vertebrate 5-HT 1
receptors. The next evolutionary differentiation occurred when 5 - H T 1 A receptors
branched from a receptor group which subsequently evolved into 5 - H T 1 B ,
5 - H T 1 D , 5 - H T 1 E and 5 - H T 1 F receptors.
The 5-HT 2 -receptor family or branch includes 5 - H T 2 , 5 - H T l C and 5 - H T 2 F
receptors. These receptors share a significant number of molecular biological,
pharmacological and biochemical characteristics 13 , as might have been predicted
by their evolutionary similarity. However, their characteristics are quite distinct
from all other 5-HT receptor subtypes. For all identified members of the 5 - H T 2
receptor family, the interspecies variation is minimal (i.e. > 90% identity between
species homologs) as indicated by the very short branches that link these subtypes
in the phylogenetic tree (Figure 1).






























Figure 1 Phylogenetic tree of 5-HT receptors. The tree was constructed according to the method
of Feng and Doolittle 7 . The length of each 'branch' correlates with the evolutionary distance
between receptor subpopulations

In early 1993, the cloning and expression of a third major subtype of a G

protein-coupled 5-HT receptor was reported 14 . The 5 - H T 6 receptor has, thus far,
been identified only in the rat, but is likely to be present in the human. 5-HT
receptors have also been identified amongst the superfamilies of ligand-gated ion
channels (5-HT 3 ) receptors and the transporters (5-HT uptake site).


Table 2 D-LSD interactions with G protein-coupled 5-HT receptor subtypes

K i D-LSD K d[125I]-LSD
Receptor Species (nmol/1) (nmol/1) Putative action Reference

5-HT1A human 0.74 agonist ud†

5-HT1b human 12 unknown ud
5-HT 1 D human 2.4 agonist ud
5-HT 1 E human 270 unknown ud
5-HT 1 F human 21 unknown 15

5-HT2 human 4.0 partial agonist 16

5-HT1C rat 0.99 agonist ud
5-HT2F na* unknown
5-HT5A mouse 0.34 unknown 8
5-HT5B mouse 0.47 unknown 9
5-HT6 rat 28 unknown 14
5-HT7 rat 4.9 unknown 11

*na, not applicable; ud† = unpublished data

The ability of D - L S D to interact with each of these receptors is reviewed below.

Studies of D - L S D interactions with cloned human receptors have been limited; the
currently available data, including unpublished observations from the author's
laboratory, are presented in Table 2.

5-HT 1 receptors
D-LSD appears to display considerable agonist activity at 5-HT 1 receptor sub-
types. It has been shown to inhibit forskolin-stimulated adenylate activity in
guinea pig and rat hippocampal membranes 17 , an effect which is likely to be medi-
ated by 5-HT 1 receptors. D - L S D displays the highest (i.e. nanomolar) affinity for
human 5 - H T 1 A and 5 - H T 1 D receptors, and a slightly lower affinity for human
5 - H T 1 B receptors. Although D - L S D has never been analyzed at 5 - H T 1 F receptors,
the receptor can be labeled by [ 1 2 5 I]-LSD, which displays an affinity of 21 nmol/1
for the receptor 16 . D - L S D is least potent at the human 5 - H T 1 F receptor.

5-HT 2 receptors
A variety of past evidence has suggested that the effects of D - L S D may be medi-
ated by 5 - H T 2 receptors. These receptors comprise at least three distinct subtypes:
5 - H T 2 , 5 - H T l C and 5 - H T 2 F receptors. The extensive work of Sanders-Bush and
colleagues 1 8 - 2 1 have demonstrated convincingly that 5-HT-stimulated phos-
phatidylinositol (PI) turnover is mediated by the 5 - H T 2 family of receptors.


Pierce and Peroutka 21 demonstrated that nanomolar concentrations of D - L S D fail

to stimulate PI turnover directly, although nanomolar concentrations of D - L S D
inhibit the stimulatory effect of 1 0 - 5 m o l / l 5-HT significantly. The ability of
nanomolar concentrations of D - L S D to antagonize the effect of a 1000-fold higher
concentration of 5-HT is consistent with a 5-HT 2 -mediated effect. Sanders-Bush
and co-workers have also demonstrated that D - L S D antagonizes 5-HT-stimulated
PI turnover; however, their data indicate that D - L S D acts as a slight partial agonist
(25% efficacy, compared to 5-HT) in this system 20 . Both sets of data suggest that
the predominant effect of D - L S D is the antagonism of 5-HT 2 -mediated PI turn-
over, although D - L S D may also possess a slight partial agonist activity.
The 5 - H T j C receptor is also linked to the PI second messenger system. D - L S D
is a partial agonist (34% of maximal 5-HT effects) in this system, whereas spiper-
one acts as a weak antagonist (K i = 6200 nmol/1) 18, 19, 2 1 .

5-HT 5 receptors
The first detailed reports of the closing and characterization of the rat 1 0 and mouse 9
5 - H T 5 A receptor were published in early 1993. The mouse 5 - H T 5 A receptor
contains an intron that is located in the middle of the third cytoplasmic loop and is
situated on mouse chromosome 5, position 5B 9 . Mouse 5 - H T 5 A receptor mRNA
was found to be localized to the cerebral cortex, hippocampus, olfactory bulb and
granular layer of the cerebellum. The rat receptor was expressed transiently in
COS-M6 cells and labeled by [ 1 2 5 I]-LSD (K d = 1.7 nmol/1). 5-HT displayed
relatively moderate affinity for the receptor (K i = 240 nmol/1). The receptor also
displayed a moderate affinity for ergotamine and 5-carboxyamidotryptamine. Bio-
chemical studies showed that the 5 - H T 5 A receptor did not alter the levels of cyclic
adenosine monophosphate (cAMP) or inositol phosphates. Therefore, the second
messenger system of the 5 - H T 5 A receptor remains to be identified 8-10 . The human
5 - H T 5 A gene has been localized to chromosome 7, position 7q36 9 . No data have
been presented on the sequence of pharmacological characteristics of this receptor.
The first detailed report of the cloning and characterization of the rat 1 0 and
mouse 9 5 - H T 5 B receptor were published in early 1993. Anatomically, the 5 - H T 5 B
receptor is unique amongst 5-HT receptors in that it is located exclusively in the
CA1 field of the hippocampus, the habenula and the dorsal raphe 9 . The mouse
5 - H T 5 B receptor contains an intron located in the middle of the third cytoplasmic
loop and is located on mouse chromosome 1, position IF 9 . The rat 5 - H T 5 B recep-
tor was expressed transiently in COS-M6 cells and labelled by [ 1 2 5 I]-LSD
(K d = 4.8 nmol/1). It displayed a moderate affinity for ergotamine and 5-CT but
was reportedly 'insensitive' to both methysergide and sumatriptan. The mouse
5 - H T 5 B receptor was labelled with [ 1 2 5 I]-LSD (K d = 0.47 nmol/1) and displayed
a moderate affinity for 5-CT and ergotamine, but a very low affinity
(> 1000 nmol/1) for sumatriptan and ketanserin. Biochemical studies showed that


the rat 5 - H T 5 B receptor did not alter the levels of cAMP 1 0 . The human 5 - H T 5 B
gene has been localized to chromosome 2, position 2q11-13 9 . No data have been
presented on the sequence or pharmacological characteristics of this receptor.

5-HT 6 receptors
The rat 5 - H T 6 receptor was the first member of this family to be cloned and
expressed 14 . The reverse transcription polymerase chain reaction (PCR) technique
was used to amplify the receptor cDNA sequence from rat striatal mRNA. The
receptor is a 437-amino acid protein that is approximately 30% homologous to
other G protein-coupled 5 - H T receptors. The third cytoplasmic loop contains
only 57 residues, thus making it the shortest of all known 5-HT receptor sub-
types. The 117-residue carboxy-terminal intracellular tail of the receptor is the
longest of all identified 5 - H T receptor subtypes. These features are common
among receptors that are coupled to the stimulation of adenylate cyclase.
Northern blots indicated that the receptor is most densely expressed in the
striatum but is also present in limbic and cortical areas. The expressed receptor
was labeled with [ 1 2 5 I]-LSD (K d = 1.3 nmol/1) and displayed a moderate affinity
for 5-HT (K I = 1 5 0 nmol/1). The receptor also displayed a moderate affinity for a
number of tricyclic antidepressant and antipsychotic drugs. A stimulation of
adenylate cyclase activity was found when the receptor was expressed in human
embryonic kidney (HEK-293) cells. Thus, the 5 - H T 6 receptor was the first
mammalian G protein-coupled 5 - H T receptor that was linked to the stimulation
of adenylate cyclase.

5-HT 7 receptors
The rat 1 1 and mouse 1 2 5 - H T 7 receptor sequences were first reported in 1993. The
sequence was identified from rat kidney RNA using the PCR method. The full-
length clone encoded for a 404-amino acid protein which displayed the highest
homology to other 5-HT receptor subtypes. Expression of this clone in COS-7
cells produced specific radioligand binding of [ 3 H]-5-HT (K d = 1 nmol/1) and
[ 3 H]-LSD (K d = 5 nmol/1) 11 . The receptor displays a high affinity for a number of
antipsychotic and antidepressant drugs but its pharmacological profile differs
from all other 5 - H T receptor subtypes. The highest mRNA expression occurs in
the hypothalamus but is also dense in the hippocampus, mesencephalon and other
CNS regions. In the periphery, the mRNA is most abundant in the spleen. The rat
5 - H T 7 receptor is positively coupled to adenylate cyclase 11, 1 2 .

A variety of current evidence suggests that the prototypical hallucinogenic agent,
D-LSD, acts primarily through 5-HT receptor subtypes. For example, a number


of cloned 5 - H T receptors have now been identified which interact with D - L S D or

its close derivatives at nanomolar concentrations: 5 - H T 1 A , 5 - H T 1 D , 5 - H T 2 ,
5 - H T 1 C , 5 - H T 5 A , 5 - H T 5 B and 5 - H T V receptors. Moreover, it appears that
D - L S D displays differential interactions with 5 - H T receptor subtypes by acting as
an antagonist or partial agonist at 5 - H T 2 and 5 - H T 1 C receptors and an agonist at
multiple 5 - H T 1 receptors. It is also likely to interact with 5 - H T 5 A , 5 - H T 5 B and
5 - H T 7 receptors, although there are no data regarding whether it acts as an
agonist or antagonist at these sites. Therefore, it appears to be impossible, given
the current state of knowledge, to attribute the hallucinogenic effects of D - L S D to
any single 5-HT receptor subtype.
Previously, the 5 - H T 2 receptor was hypothesized to play an important role in
the mechanism of action of hallucinogenic agents. However, the more recent
experimental results discussed here suggest that hallucinogenic drug activity is not
derived from the direct activation of a single 5-HT receptor subtype. It is possible
that the effects of D - L S D on sensory perception during hallucinosis might be a
reflection of its unique ability to interact potently as either as agonist, partial
agonist or antagonist at a relatively large number of 5-HT receptor subtypes in
the somatosensory cortex 16 . Alternatively, the unique ability of D - L S D to interact
with a large number of 5-HT receptors may explain many of the current apparent
paradoxes about D - L S D action. Future studies are clearly needed to determine
more precisely the receptor-mediated mechanisms of action by which hallucino-
genic agents produce their complex neuropsychiatric effects.

I thank Tiffany A. Howell for excellent editorial assistance. This work was sup-
ported in part by NIH Grant NS 23560-06.

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LSD and phenethylamine

hallucinogens: common sites of
neuronal action


Early studies on LSD and serotonin (5-HT)

The modern era of research on the electrophysiological actions of LSD (D-lysergic

acid diethylamide) in the central nervous system began in the mid-1960s after the
discovery and mapping by histochemical fluorescence methods, of serotonergic
and other monoaminergic neuronal pathways in the brain 1 . Based on the
histochemical maps, it was possible for the first time to examine directly the elec-
trophysiological effects of LSD on identified serotonergic neurons. LSD and other
indoleamine hallucinogens were found to have potent, direct inhibitory effects
upon serotonergic neurons located in the raphe nuclei of the brainstem 2 - 4 . The
resulting reduction in impulse flow explained the previously observed increase in
5-HT levels detected in brain after LSD 5 . However, it was soon discovered that
mescaline and other substituted phenethylamine hallucinogens failed to share,
with the indoleamines, a raphe inhibitory effect 6.
The delineation of multiple 5-HT receptor subtypes by radiolabeled ligand
binding and molecular methods (see Chapter 2, by S. J. Peroutka) has helped to
explain the difference between the effect of the indoleamine and phenethylamine
hallucinogens on serotonergic neurons. LSD has high affinity as an agonist for
5 - H T 1 A receptors, thus accounting for its direct inhibitory actions on serotonergic
raphe neurons, which have a high density of these receptors. As they mediate
responses of the serotonergic neurons to their own transmitter, these receptors
have been termed somatodendritic autoreceptors. Mescaline and other
phenethylamines have very low affinity for 5 - H T 1 A receptors, explaining their


inability to inhibit serotonergic raphe neurons. In view of the fact that the action
of LSD on 5 - H T 1 A autoreceptors is shared by a number of selective 5 - H T 1 A
agonists which are not hallucinogenic 7,8 , there appears to be no correlation
between the activity of various drugs at 5 - H T 1 A receptors and the presence or
absence of hallucinogenic properties.

Common action of hallucinogens at 5-HT 2 receptors

In contrast to their disparate affinities for 5 - H T 1 A receptors, there is a very good
correlation between the affinity of both indoleamine and phenethylamine hal-
lucinogens for 5 - H T 2 receptors and their potency as hallucinogens in humans 9, 1 0 .
The 5 - H T 2 receptors are not located on serotonergic cell bodies but rather are
found upon subpopulations of neurons in postsynaptic regions. For example,
quantitative autoradiographic studies show high concentrations of 5 - H T 2 sites in
the neocortex (layers IV/V), piriform cortex, claustrum, nucleus accumbens,
olfactory tubercle, facial nucleus, and the n. tractus solitarius 11 . A high density of
5 - H T 2 receptor mRNA has been demonstrated by in situ hybridization in these
same regions 12 . Immunocytochemical studies also show the presence of 5 - H T 2
receptors in some of the same regions 13 .
This review focuses on the electrophysiological actions shared by LSD and the
phenethylamine hallucinogens in three different brain regions: the locus
coeruleus, the facial motor nucleus and the cerebral cortex. Each area exemplifies
a different level of organization and function within the central nervous system at
which hallucinogens can act: sensory, motor and associational.


Locus coeruleus
The locus coeruleus (LC) consists of two dense clusters of noradrenergic neurons
located bilaterally in the upper pons at the lateral border of the 4th ventricle. The
LC, which projects diffusely to virtually all regions of the neuraxis, receives an
extraordinary convergence of somatic, visceral and other sensory inputs from all
regions of the body and has been likened to a novelty detector 14, 1 5 . Thus, the LC
represents a unique nodal point both for the detection of significant changes in the
internal and external environment and for relaying this information to the
remainder of the central nervous system. It is not surprising that hallucinogenic
drugs, which produce such dramatic changes in perception, would alter either
directly or indirectly the function of LC neurons.
The systemic administration of LSD, mescaline, and other psychedelic hal-
lucinogens in anesthetized rats results in a decrease in spontaneous activity and,
paradoxically, a facilitation of the activation of LC neurons by sensory


stimuli 1 6 - 1 8 . Mediation by 5 - H T 2 receptors is suggested by the fact that the effects of

the hallucinogens on LC neurons can be reversed by low intravenous doses of
selective 5 - H T 2 antagonists such as ritanserin, LY-53857 18 and ketanserin 19 .
Antipsychotic drugs are also able to reverse the actions of hallucinogens in the
locus coeruleus independently of their actions at dopamine and adrenergic recep-
tors. The relative potencies of antipsychotic drugs in antagonizing hallucinogens
in the LC neurons correlate highly with their affinity for 5 - H T 2 receptors 20 . Of
particular note is the fact that spiperone, which has almost a 1000-fold greater
affinity for 5 - H T 2 than 5 - H T l C receptors, completely blocks the effects of the
hallucinogens at extremely low doses. Thus, the effects of hallucinogens on the
LC appear to be mediated by 5 - H T 2 rather than 5 - H T l C receptors.
The effects of systemically administered hallucinogens do not appear to be
mediated by an action directly upon LC cell bodies since these effects are not
mimicked by the direct application of the hallucinogens to LC cells by micro-
iontophoresis. Moreover, the systemic administration of mescaline or LSD does
not enhance the excitation of LC neurons evoked by the local application of
acetylcholine, glutamate or substance P 1 6 . These results imply that the hallucino-
gens are acting indirectly, perhaps via afferents to the LC. Consequently, the LC
itself cannot be used as a model for studying the direct cellular actions of
hallucinogens. Nevertheless, the effects of the hallucinogens upon the LC are
of interest because this nucleus receives such an extraordinarily widespread con-
vergence of sensory information, both somatosensory and visceral, and relays this
information to virtually all other parts of the neuraxis.

Facial nucleus
In addition to their well-known effects on perception and cognition, LSD and
other hallucinogens also have effects on motor function. Clinically, it has long
been known that motor reflexes are enhanced by LSD and other hallucinogens 21 .
In rodents, the head-twitch response has been used as a quantitative measure of
the behavioral effects of hallucinogens. The hallucinogen-induced head twitches
are blocked by selective 5 - H T 2 antagonists, indicating that they are mediated by
5 - H T 2 receptors 2 2 - 2 4 . Similarly, the limb-flick response produced by hallucino-
gens in cats can be blocked by 5 - H T 2 antagonists 25 . These behavioral effects of
hallucinogens are likely to be mediated, at least in part, by 5 - H T 2 receptors that
are located directly on motoneurons. Facial motoneurons have an especially high
density of 5 - H T 2 receptor binding sites and they also express a high level of
5 - H T 2 receptor mRNA 1 2 . Thus, facial motoneurons can serve as model system
for the study of the electrophysiology of 5 - H T 2 receptors at a cellular level.
The microiontophoretic application of 5-HT, whilst not itself inducing firing,
facilitates the excitatory effects of iontophoretically applied glutamate and synap-
tic inputs 26 . Intracellular recordings in vivo 27, 28 and in brain slices 29, 30 show that

10 MΩ

lOnM l00nM

14 mV


5 min
Figure 1 Effects of bath application of 5-HT and LSD on input resistance (upper trace), membrane potential (middle trace) and electrical
excitability (lower trace) recorded simultaneously in a rat facial motoneuron from an in vitro brain-slice preparation. Horizontal bars indicate
periods of drug application; see text for further explanation
control 5-HT

* **

2 nA
20 mV
0.1 s

Figure 2 Oscilloscope traces showing the effect of 5-HT on the electrical excitability of the facial
motoneuron shown in Figure 1. The spikes were evoked by a depolarizing pulse (+1.5 nA), the cell
is otherwise silent (resting potential, - 7 2 mV). Under control conditions (left trace) two spikes are
elicited by the depolarizing pulse (single asterisk denotes the time-point that the sweep was taken in
Figure 1). In the presence of 5-HT (100μmol/l) (right trace) the same pulse elicits 16 spikes (double
asterisk in Figure 1), thus indicating that 5-HT increases the electrical excitability of the cell. Note
also the increase in input resistance (i.e., greater voltage deflections in response to the hyperpolariz-
ing pulse) following 5-HT. (From ref. 35, with permission)

5-HT induces a slow depolarization in facial motoneurons by decreasing a resting

potassium conductance. Similar effects of 5-HT on potassium conductance have
been described in spinal motoneurons 31 and in nucleus accumbens 32 . The action of
iontophoretically applied 5-HT in the facial nucleus can be blocked by the classical
5-HT antagonists metergoline, methysergide, cyproheptadine and cinanserin 33 as
well as the selective 5 - H T 2 antagonist ritanserin 34 . In contrast, the selective 5 - H T 1 A
agonist 8-OH-DPAT (8-hydroxy-2-(di-«-propylamine)-tetralin) has no effect
when applied locally, either by microiontophoresis or bath application in brain
slices 34, 3 5 . However, 8-OH-DPAT does increase facial motoneuron excitability
when given in vivo by the systemic route, presumably due to an indirect action 34 .
The iontophoretic administration of a wide range of hallucinogens (e.g., LSD,
mescaline and psilocin) also enhances the excitability of facial motoneurons 36 .
Intracellular studies in brain slices show that LSD produces an increase in the elec-
trical excitability of facial motoneurons. However, even at maximal concentra-
tions, this increased excitability is associated with only a small depolarization
compared to that produced by 5-HT itself 35 . In the presence of LSD, the maximal
effect of 5-HT is suppressed, indicating a partial agonist effect (Figures 1 and 2).
Figure 1 shows that bath application of 5-HT (100μmol/l) produces an increase
in apparent input resistance, a depolarization (14 mV), and an increase in electrical
excitability of the cell (i.e., an increase in spikes induced by a constant current
pulse; note that the ratemeter trace shown in Figure 1 goes off the scale at the peak
of the response). Application of LSD (10 nmol/1) produces little change in appar-
ent input resistance or membrane potential, but there is a clear increase in electrical
excitability, which has a slow onset of action. Interestingly, LSD at this dose


slightly suppresses the response of the cell to 5-HT. A higher concentration of

LSD (100 nmol/1) again produces little change in apparent input resistance or
membrane potential, although there is a further increase in the electrical excitabil-
ity, also with a slow onset and very long duration (> 1-2 h, not shown in Figure
1). At this dose there is further suppression of the response of the cell to 5-HT.
Electrical excitability is measured by injecting the cell with a depolarizing pulse
(+1.5nA, 400 ms duration) which elicits one or two spikes under control
conditions. The phenethylamine hallucinogen DOI (l-(2,5-dimethoxy-4-
indophenyl)-2-aminopropane) produces effects similar to that of LSD, but with a
slightly greater maximal depolarization. Thus, LSD and DOI appear to have rela-
tively low intrinsic activity, relative to 5-HT, in decreasing a resting potassium
conductance. A possible exception to this pattern is the ultra short-acting hal-
lucinogen N,N-dimethyltryptamine (DMT) which approximates 5-HT in its
efficacy as a direct agonist in this system (Aghajanian, in preparation).
Recently, we have found that in addition to causing a decrease in resting potas-
sium conductance, 5-HT produces an enhancement of the non-specific cationic
current Ih to further increase the excitability of facial motoneurons 35 . Interest-
ingly, both LSD (Figure 3) and DOI produce a greater maximal enhancement of
I h than does 5-HT (LSD > DOI > 5-HT). Moreover, in contrast to 5-HT, DOI
and LSD have a slow onset and very long duration of action ( > l - 2 h ) . The
enhancement of I h by LSD and DOI is reversed by application of both the 5-HT 2 /
5 - H T 1 A antagonist spiperone and the 5-HT 2 /5-HT l C antagonist ritanserin, sug-
gesting that the increase in I h is mediated by 5 - H T 2 receptors. This appears to be
the first example of a direct 5-HT 2 -mediated electrophysiological response in the
brain in which hallucinogens have greater efficacy than 5-HT.
The high efficacy of LSD is increasing Ih and its low efficacy in decreasing
resting potassium conductance could be explained simply by supposing that the
5 - H T 2 receptor couples to the two different channels via two different G proteins.
Thus, the same 5 - H T 2 receptor could couple to potassium channels via one type
of G protein and to Ih channels via another type of G protein, yielding two differ-
ent receptor/G protein complexes. In this case, the receptor/G protein complex
rather than the receptor per se would confer differential intrinsic activity to differ-
ent agonists. A second possibility is that there are two or more different 5 - H T 2
receptor subtypes that independently confer differential intrinsic activity to 5-HT
and the hallucinogens.

Cerebral cortex
The majority of 5 - H T 2 receptors in the brain are located in the cerebral cortex.
Accordingly, the effects of hallucinogens on perceptual and cognitive functions
are likely to be mediated predominantly by this structure. In brain slices, pyrami-
dal cells in various regions of the cerebral cortex have been found to respond to


control 5-HT

-0.12 -0.49

I nA 1 nA
(a) (b)

-0.04 5-HT


1 nA


(C) 400 ms

Figure 3 Effects of bath application of 5-HT and LSD on the hyperpolarization activated cation
current (Ih) in facial motoneurons, (a)-(c) are oscilloscope traces showing a single-cell intracellular
voltage-clamp recording from a facial motoneuron; (a) shows a progressive increase in the size of the
I h current in response to increased hyperpolarizing steps from - 7 0 mV to - 1 2 0 mV; (b) shows the
enhancement of Ih in the presence of 5-HT (100μmol/l); (c) shows that LSD (100 nmol/1) produces
a greater increase in Ih than 5-HT. The graph is a current-voltage plot obtained from the traces
(a)-(c) showing the difference between steady state and instantaneous currents in response to voltage
clamp commands in 10-mV steps from a holding potential of - 7 0 mV to - 1 2 0 mV. Note that LSD
produces a greater increase than 5-HT in Ih at all voltage steps. (From ref. 35, with permission)

5-HT by either a small hyperpolarization, a depolarization, or by no change in

potential 3 7 - 3 9 . It has been suggested that the depolarizations are mediated by
5 - H T 2 receptors, since they can be blocked by 5 - H T 2 antagonists.
Recently, we have observed a novel effect of 5-HT in pyramidal cells of the piri-
form cortex: the enhancement of spontaneous inhibitory postsynaptic potentials
(IPSPs) 39 . A similar induction of IPSPs by 5-HT has also been observed in the
prefrontal cortex (Aghajanian, unpublished observation). The IPSPs in the piriform
cortex have been shown to be blocked by the γ-aminobutyric acid (GABA)
antagonist bicuculline, suggesting that GABAergic interneurons are excited by
5-HT to give rise to IPSPs in the pyramidal cells. This finding led to the discovery
of a subpopulation of interneurons (at the border of layers II and III) that are excited


by 5-HT. The 5-HT2/5-HT 1C antagonist ritanserin blocks the 5-HT-induced

activation of interneurons 39 . The hallucinogens LSD and D O M (2,5-dimethoxy-
4-methylamphetamine) behave as partial agonists in this system, producing a
modest activation by themselves but occluding the full effect of 5-HT.
Another effect of 5-HT in the piriform cortex is a direct depolarization of pyram-
idal cells, which is blocked by ritanserin and spiperone. The blockade of the 5-HT-
induced activation of interneurons by ritanserin and spiperone occurs much more
readily than the blockade of pyramidal cell depolarization 39, 4 0 . Since ritanserin and
spiperone have a 10- and 1000-fold higher affinity, respectively, for the 5 - H T 2
receptor than for the 5 - H T l C receptor 41 , it has been hypothesized that the action of
5-HT on interneurons occurs through 5 - H T 2 receptors and that the action of 5-HT
upon pyramidal cells is through 5 - H T l C receptors. This hypothesis is consistent
with recent in situ hybridization 12 and immunocytochemical 13 studies which show
that the 5 - H T 2 receptor is located on cortical interneurons 12 , while the 5 - H T l c
receptor is on pyramidal cells 42 . To test this hypothesis further we studied the effect
of MDL 100,907, a new, highly selective antagonist with a 300-fold greater affinity
for 5 - H T 2 than for 5 - H T l c and α-adrenergic receptors. MDL 100,907 blocks the
5-HT-induced excitation of piriform interneurons with a pA 2 value close to its K i
for 5 - H T 2 receptor binding, further indicating that 5 - H T 2 rather than 5-HT 1 C
receptors, are responsible for the excitation of cortical interneurons by 5-HT
(Marek and Aghajanian, in preparation).


G proteins
A cloned 5 - H T 2 receptor from a rat brain cDNA library displays seven trans-
membrane regions that are typical of G protein-coupled receptors 43 . The 5 - H T 2
receptor behaves as a typical member of the G protein-coupled receptor family, in
that the binding of agonists is reduced by nonhydrolyzable GTP derivatives 44 .
The reduction in binding induced by GTP analogs results from a persistent state
of dissociation and activation of the G-protein α subunit. Non-hydrolyzable GTP
analogs have also been used to evaluate the role of G proteins in mediating the
electrophysiological effects induced by 5 - H T 2 receptor activation in facial
motoneurons 4 5 . The 5-HT induced inward current becomes largely irreversible,
in the presence of intracellular GTPγS, a hydrolysis-resistant GTP analog. In con-
trast, the 5-HT-induced inward current is reduced by intracellular GDPβS, which
renders the G protein resistant to activation by agonists. Taken together, these
electrophysiological observations strongly suggest a mediation of the 5 - H T 2
response by G proteins. The identity of the G proteins that couple to the 5 - H T 2
receptor remains to be determined.


Phosphoinositide second-messenger pathway

At a second messenger level, it has been shown that 5-HT stimulates phos-
phatidylinositol (PI) hydrolysis in brain through 5 - H T 2 and 5 - H T l C receptors 46
PI hydrolysis yields at least two major second messengers: inositol trisphosphate
(IP3) and diacylglycerol. The latter activates protein kinase C, thereby potentially
affecting many long term cellular responses through protein phosphorylation.
The hallucinogens share with 5-HT the ability to increase PI hydrolysis 47 .
However, compared to 5-HT, the hallucinogens are only partial agonists of this
effect. Thus, 5-HT itself shows the greatest maximal activation of PI turnover,
whereas hallucinogens such as DOB (l-(2,5-dimethoxy-4-bromophenyl)-2-
aminopropane), D O M and LSD act as partial agonists.
On the basis of these biochemical data, we have tested the effect of
protein kinase inhibitors on the response of facial motoneurons to serotonin 45 .
Two protein kinase inhibitors with different mechanisms of action
((l-(5-isoquinolylsulfonyl)-2-methylpiperazine (H7), a non-selective protein
kinase inhibitor, and sphingosine, a selective protein kinase C inhibitor) in
concentrations that have no effect of their own (100 and 10 μmol/l, respectively),
both enhance the excitation of facial motoneurons induced by 5-HT and LSD
(Figure 4). Conversely, phorbol esters that are known to activate protein kinase
C reduce the excitatory effect of serotonin. These results suggest that activation
of phosphatidylinositol turnover (possibly, through protein kinase C-induced
receptor phosphorylation) has a negative feedback effect on 5-HT-induced
excitations in the facial nucleus. Analogous studies on 5 - H T 2 receptor-mediated
responses in rat aorta also indicate that the activation of protein kinase C
desensitizes 5 - H T 2 receptors 48 .
An interesting implication of the negative feedback model is the possibility that
the partial agonist 47 or even antagonist 49 properties of hallucinogens, with respect
to 5-HT-stimulated phosphatidylinositol hydrolysis, may contribute to (rather
than interfere with) the electrophysiological response. Thus, the greater enhance-
ment of I h in facial motoneurons by hallucinogens relative to 5-HT, could be
explained by a combination of two factors: first, LSD has a high efficacy in this
transduction system and, second, LSD induces (to a lesser degree than 5-HT) the
negative feedback reduction in response through an activation of phos-
phatidylinositol hydrolysis.


5-HT 2 receptors and the action of hallucinogens
This review has described the electrophysiological actions shared by LSD and the
phenethylamine hallucinogens in three different brain regions: the locus
coeruleus, the facial motor nucleus and the cerebral cortex. In all these regions,



5 min
Figure 4 Enhancement by the protein kinase inhibitor H7 (l-(5-isoquinolylsulfonyl)-2-methylpiperazine) of the excitatory effect of 5-HT
and LSD on a facial motoneuron, shown by current clamp recordings. The initial application of 5-HT (100 μmol/1) produces a depolarization
(ca. 10 mV, middle trace), an increase in electrical excitability (as measured by the number of spikes induced by a depolarizing pulse through
the intracellular electrode: slower trace) and an increase in input resistance (upper trace). Following recovery from 5-HT, the application of
H7 (100μmol/l) by itself has no effect but the effect of a subsequent application of 5-HT (100 μmol/l) is markedly enhanced both in amplitude
and duration (note the number of evoked spikes goes off the scale). Subsequently, LSD application (100 nmol/1) produces a delayed increase
in electrical excitability approximating that induced by the first application of 5-HT (note that LSD causes only a slight depolarization).
Because of its long duration of action, LSD could not be tested prior to H7; however, the LSD response had evidently been enhanced by H7
since normally it would produce a maximal response of only half of that of 5-HT

pharmacological evidence indicates that the effects of both classes of hallucinogens

are mediated through 5 - H T 2 receptors. Since the effects of the hallucinogens can
be blocked by spiperone, which has almost a 1000-fold higher affinity for 5 - H T 2
than for 5-HT 1 C receptors, it is likely that these drugs are acting primarily at
5 - H T 2 receptors. However, a contributory role for 5-HT 1 C receptors in the action
of hallucinogens cannot be ruled out.

The role of 5 - H T 1 A receptors

In contrast to the phenethylamines, LSD and the other indoleamine hallucinogens
are more similar to 5-HT itself in having a broad spectrum of activity at multiple
5-HT receptors. This raises questions about how the indoleamines can be
hallucinogens if they simply act in the same way as the endogenous transmitter.
A possible answer may lie in the fact that LSD and the other indoleamine
hallucinogens are much more efficacious as agonists at somatodendritic 5 - H T 1 A
receptors than they are at post-synaptic 5 - H T 1 A receptors 3, 5 0 . By inhibiting the
firing of serotonergic neurons through their action upon somatodendritic 5 - H T 1 A
receptors (as well as by stimulating inhibitory 5 - H T 1 B presynaptic autoreceptors)
the indoleamine hallucinogens would reduce the tonic release of 5-HT onto post-
synaptic neurons. Since they are poor agonists at post-synaptic 5 - H T 1 A receptors,
their primary action post-synaptically would be upon 5 - H T 2 or 5-HT 1 C recep-
tors. Thus, the net effect on post-synaptic neurons would be similar for the
indoleamine and phenethylamine hallucinogens, namely an excessive stimulation
of 5 - H T 2 and 5-HT 1 C receptors, compared to other 5-HT receptor subtypes
(Figure 5).

Signal transduction mechanisms

The overall effect of 5 - H T 2 receptor stimulation is to produce an increase in neu-
ronal excitability through a G protein-coupled mechanism. The ionic mechanism
for the increased excitability is through a reduction in resting potassium conduc-
tance and/or enhancement of the hyperpolarizing-activated cationic current I h .
Biochemical studies show that 5 - H T 2 receptors are coupled to the phos-
phatidylinositol signal transduction pathway. Thus, it would appear that 5 - H T 2
receptors are coupled to at least three different transduction systems potassium
channels, cationic channels, and phosphatidylinositol hydrolysis. The coupling
could be through a single G protein or through multiple G proteins and multiple
5-HT 2 -receptor subtypes, one for each transduction pathway.
It should not be assumed that the electrophysiological effects of 5-HT and the
hallucinogens are mediated through the phosphatidylinositol/protein kinase C
second-messenger pathway. On the contrary, in the facial motor nucleus 45 and
piriform cortex (Marek and Aghajanian, in preparation) it has been found that



pyramidal cells
5-HT -
5-HT 1A

5-HT -
1A cortical
5-HT (+) 2
LC afferents
mescaline etc.
Figure 5 Schematic diagram showing the shared action of indoleamine (e.g., LSD and N,N-
dimethyltryptamine (DMT)) and phenethylamine hallucinogens (e.g. mescaline and 2,5-dimethoxy-
4-methylamphetamine (DOM)) upon 5 - H T 2 receptors on post-synaptic neurons and the non-shared
action at somatodendritic 5 - H T 1 A autoreceptors located on 5-HT neurons of the raphe nuclei where
only the indoleamine hallucinogens have direct activity. Post-synaptic neurons with 5 - H T 2 recep-
tors include a subpopulation of cortical interneurons, facial motoneurons, and unidentified afferents
to the locus coeruleus (LC). The arrow/dotted line connotes the low efficacy of indoleamine hal-
lucinogens at post-synaptic 5 - H T 1 A receptors (5-HT 1 A ) such as occur on hippocampal and cortical
pyramidal cells

activators of protein kinase C suppress 5-HT 2 -induced increases in neuronal

excitability, while inhibitors of protein kinase C enhance them. Thus, the phos-
phatidylinositol second-messenger system appears to serve as a negative feedback
loop, rather than as a mediator of the electrophysiological effects produced by
5 - H T 2 receptor activation.

Relationships between electrophysiology and behavior

How do the effects of hallucinogens at a single neuron level mediate the
behavioral effects produced by these drugs? We can now begin to formulate
regionally specific answers to this question. The enhancement of sensory respon-
sivity of locus coeruleus neurons may contribute to the characteristic intensifica-
tion of certain kinds of perceptual experience produced by hallucinogens in
humans. The increase in motoneuronal excitability produced by hallucinogens
would explain the hyperreflexia produced by these drugs. The persistent, and
presumably inappropriate, activation of a subpopulation of interneurons that
express 5 - H T 2 receptors in the cerebral cortex may underlie some of the cognitive
and perceptual distortions produced by the hallucinogenic drugs. Of course


5 - H T 2 receptors are expressed in neurons in other parts of the central nervous

system and it remains to be seen how these also contribute to the total hallucino-
genic response.

This chapter was prepared with support from National Institute of Mental Health
grant MH-17871 and the State of Connecticut.

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Ethnopharmacology of LSD and

related compounds


Ethnopharmacology aims to obtain and maintain a broad multidisciplinary per-

spective on the human use of crude drugs and poisons in a traditional context 1 .
Widely differing disciplines are involved, such as cultural anthropology, linguis-
tics, history, botany, zoology, chemistry, pharmacology, toxicology and medi-
cine. Irrespective of any practical medical relevancy, ethnopharmacology
broadens our general knowledge of mankind and places our own attitude towards
pharmacologically active agents into a cultural and historical perspective.
After the discovery of the pharmacological activity of LSD-25 in 1943, follow-
ing his studies of rye ergot (Claviceps purpurea) alkaloids, Albert Hofmann has con-
tributed immensely to ethnopharmacology. He was sufficiently open-minded to
agree to examine unusual plant material samples that mycologists or eth-
nobotanists forwarded to him for analyses. Two key discoveries were made.
Firstly, in the mid-1950s, the structure was determined of psilocybin and psilocin,
two hallucinogenic compounds isolated from teonanacatl, the magic Psilocybe
mushroom of the Mazatec Indians of Mexico. Secondly, in the late 1950s, the
characterization was made of the active principle, lysergic acid amide, in the
sacred Aztec ololiuqui, the narcotic Volubilis seeds, which demonstrated the
existence, for the first time, of a molecule very similar to LSD in a higher plant
On each occasion, Hofmann had carried out experiments on himself, ingesting
a small amount of the drug. He also travelled extensively to collect plant materials
for analyses with his colleagues Roger Heim, R. Gordon Wasson and Richard E.
Schultes. Together, they should be considered as the most significant ethnophar-
macologists to date, whose work has resulted in major contributions to the litera-
ture and knowledge of the field.



Amongst the plant species identified as 'major hallucinogens' that have played a
key role in the ritualistic and medicinal practices in indigenous societies, almost
100 genera from 20 families have been identified from the New World, in contrast
with only around 12 in the cultures originating from Eurasia 2 .
To explain such differences, it is generally agreed 3 that migrant nomads
travelled (at the end of the palaeolithic age) from Siberia to the New World
through the Bering Straits - at that time, possibly a continuous land bridge. These
populations brought with them a strong shamanistic tradition based on the ritu-
alistic utilization of Amanita muscaria, the fly-agaric. This mushroom could have
allowed them to reach stages of trance and stupor for divinitory or diagnostic pur-
poses. We know that the shamanism based on Amanita is very old indeed, its roots
originating in prehistoric times, even before the first nomadic tribes appeared on
the American continent. When these first immigrants reached the new continent,
they encountered a completely new flora as they approached the equator. In these
warm and humid areas, the density of plant species that have psychotropic
properties is higher than in any other part of the world. This is probably why
those living in these regions have attained the highest knowledge about the con-
sumption of magicoreligious substances. From our palaeolithic heritage, con-
vened by human natural curiosity, the field of psychopharmacological
experimentation is still a reality today. Schultes 4 has defined certain South Ameri-
can Indians as the best hallucinogen specialists in the world. They possess an
extraordinary knowledge of the preparation, cultivation, harvest and use of these
plants 4 .

In using a powerful hallucinogenic preparation, men are brought face-to-face
with visions and experiences of an overwhelming nature, which tends strongly to
reinforce their beliefs in the reality of the supernatural world 5 . In non-literate
societies, the experts who directly confront the supernatural are called 'shamans',
a Siberian word introduced by anthropologists. A shaman may be defined as a
man or a woman who claims to be in direct contact with the spirit world through
a trance state. Depending on his beliefs, he may influence the course of events in
his community. Contemporary anthropologists tend to view the shaman as a psy-
chotherapist, but in the culture of his own society, its people believe him able to
contact, through making a journey, and deal with an invisible spirit world. The
shaman is accorded considerable respect. The use of psychedelic agents is only one
of the ways of achieving the trance-like states that are conducive to the sensation
of seeing and living in a supernatural world. In many cultures, other methods are
used: fasting, sensory deprivation, breathing exercises, and ritual dancing and


drumming. A common psychophysiological basis for the similarity of effects

produced by all these methods may exist, but the use of hallucinogens appears to
be a widely used technique by most indigenous people.


Among the indigenous peoples of the tropics, there are generally two kinds of
plant medicines; those that are regarded as sacred and used exclusively by, and
under the strict surveillance of the shaman, and those known and used by the
general population. The latter are often (but not always) known and collected by
women. Hallucinogens are always related to the first type, which may explain
why it has been so difficult to discover them.
Not all South American shamans are 'medicine' men, but most of them do have
an extensive interest in the properties of plants and will prescribe them when their
superstitious diagnosis or treatments fail. In fact, all hallucinogens are tradition-
ally used as 'holy mediators' between man and his gods. For example, the prophe-
cies of the oracle of Delphi are thought to have been induced through
hallucinogens. However, hallucinogens are employed also during the initiation
rituals of adolescents: under the influence of the drug caapi, young Indians lose
their memory, and thus begin manhood by forgetting their past boyhood.
Ayahuasca, a plant-derived hallucinogenic drink, brings sensations of a separation
of body and soul which is used to journey to the world of the 'little people'.
Psychoactive plant preparations are also consumed to foresee the future, settle
disputes, decipher enemy plans, diagnose and cure diseases and placate good and
evil spirits. In brief, they help shamans to commune with the supernatural world.


As the use of hallucinogens linked with shamanism has great antiquity, Weil 6 has
argued that 'the desire to alter consciousness periodically is an innate, normal
drive in man, analogous to the hunger or sexual drive'. We can also postulate, but
not prove, that the practise of shamanism as an 'archaic technique of ecstasy' 7 may
have involved the psychodysleptic potential of the natural environment 8 from the
very first - that is, from the beginnings of religion itself. La Barre 9 demonstrated
that shamanism and this direct contact with the supernatural (in these altered
states of consciousness, that include hallucinations) is considered to be the de facto
source of all revelation, and ultimately of all religions. It is now realized that the
most important botanical hallucinogens are structurally related to biologically
active compounds that occur naturally in the brain. For example, some com-
pounds that Hofmann isolated are indole-tryptamine derivatives and thus are
similar in chemical structure to serotonin (5-hydroxytryptamine). Does it





Figure 1 Chemical formulae from representative constituents of American hallucinogenic plants.

All the compounds are hallucinogenic except bufotenine

suggest that the origin of religions shall be found in our brain chemistry? In any
event, hallucinogens - synthetic or natural - are tools of choice to understand the
biochemical mechanisms that might regulate the brain's activities.
Tryptamine and its psychotropic derivatives are formed from the amino-
acid tryptophane 10 . The simplest hallucinogenic derivative (Figure 1) is
N,N-dimethyltryptamine (DMT). Psilocybin is derived from DMT and has a
phosphoric acid moiety attached at position 4. Bufotenine, which is the 5-hydroxy
derivative of DMT is not hallucinogenic. Its name derives from its isolation from
the skin of some toads of the genus Bufo. On the other hand, 5-methoxy-
dimethyltryptamine (5-MeO-DMT) is a potent hallucinogen. If the tryptamine
side-chain is closed with an additional carbon atom, one obtains the beta-
carbolines 11 . Of these, several hallucinogenic products have been identified:
harmine, harmaline and tetrahydroharmine. All these compounds have been
isolated from various hallucinogenic preparations (e.g. drinks, snuffs) made by
certain Amazonian Indians 12 .


The natives of the Amazon Basin use Banisteriopsis caapi bark (Malpighiaceae) and
Psychotria viridis leaves (Rubiaceae) for prophetic, divinitory and magic purposes
and to fortify the bravery of male adolescents about to undergo the painful
ceremony of initiation. The narcosis of this brew, named ayahuasca, natema, yagé
or caapi, may be violent, with unpleasant after-effects, but these effects may be
due to certain admixtures or to the boiling of the bark of the liana and the leaves
of the shrub. Usually - especially when a cold bark infusion is ingested with
no resultant admixtures - the intoxication has no unpleasant after-effects. The
hallucinations, which are due to a mixture of harmine and DMT, may start after
30 min and last 2-3 h depending on the amount of the drink taken 13 . The effects
are characterized by a pleasant euphoria, followed by visual hallucinations that are
in color, but often initially tinged with blue or purple. In higher doses, it produces
frighteningly nightmarish visions and a feeling of extremely reckless abandon,
although consciousness is never lost.

Yopo, niopo or niopa snuffs are made from Anadenanthera seeds by the Piaroa
Indians of the Venezuelan Orinoco head waters. They have been found to contain
mainly bufotenin and traces of DMT and 5-MeO-DMT; in one snuff sample,
harmine has also been detected 14 . Known as ebena, parica or yakee, other types of
snuff are prepared in north-western Brazil from a red bark-resin of the myristi-
caceous genus Virola. The Indians usually strip the bark from the jungle tree and
scrape off the soft inner bark with its resinous exudation. This fresh tissue is
kneaded and squeezed in water, which is then strained and boiled to a thick syrup.
When the syrup is sun-dried, it is pulverized, sieved and mixed with the ashes of
the bark of a wild species of cacao. The snuff is then administered through a tube
by blowing the powder violently into a nostril. Virola intoxication varies, but
usually includes initial excitability, numbness of the limbs, muscular unco-
ordination, nausea, visual hallucinations and, finally, a strongly disturbed sleep.
The snuff contains mainly 5-MeO-DMT. The Bora and Witoto Indians of
Amazonian Colombia and Peru utilize resin-like bark exudate from Virola to
prepare pellets which they ingest. Hallucinogenic tryptamines and beta-carbolines
have been found in these preparations 15 .
The presence of beta-carboline alkaloids together with tryptamine derivatives
in hallucinogenic preparations is biochemically significant. The beta-carbolines
are monoamine oxidase inhibitors which may potentiate the activity of simple
indoles. This supports an early statement of Holmstedt and Lindgren 16 : 'once
again, one cannot but marvel at the ingenuity of the South American Indians who
relentlessly seem to be able to find their way to the right herb containing the most


active component'. In view of the most recent findings, one can now add: 'and to
form the most pharmacologically active mixture that is best suited for the chosen
route of administration'.

There is still much controversy about the value of bufotenine as a hallucinogen.
Current thinking amongst neurophysiologists is that it has little use. In contrast
to DMT, 5-MeO-DMT or psilocybin, bufotenine does not readily cross the
blood-brain barrier. Bufotenine can have profound effects on peripheral physio-
logical processes such as heart rate and blood pressure, and these effects may con-
tribute significantly to the total overall activity of hallucinogenic snuffs prepared
from species containing it. The history of its investigation in toads provides a
good example of the confusion which prevailed for many years. Bufotenine is a
major component of Bufo marinus venom. The latter is produced by a gland situ-
ated close to the eye. Toxic cardiac glycosides, bufogenin and bufotoxin are also
found in this toxic liquid. A species of toad called Bufo alvarius lives in the Sonoran
Desert, in south-eastern California and has prominent parotid glands that secrete
a viscous, milky-white venom, in the same manner as different, though morpho-
logically similar species. Their respective secretions, however, are chemically very
different: in B. alvarius, up to 15% of the dry weight of the parotid and tibial
glands consist of 5 - M e O - D M T 1 7 . Since 1987, Andrew Weil and Wade Davis,
both former students of Schultes, have investigated the smoking of the dried
venom of B. alvarius and have recently reported on self-experiments 18 ; a single
deep inhalation of vaporized venom proved to be powerfully psychoactive within
15 s. Consistent with the known effects of 5-MeO-DMT, the intoxication was
intense and short-lived, and marked by auditory and visual hallucinations. The
strongest effects dissipated after 5 min, but residual changes in perception per-
sisted for 1 h. No toxic effects were experienced during or after the experiments.
When smoked, the venom is effective in humans at doses from 3 to 5 mg. In other
words, a single toad can yield 15 or more doses 19 . This was the first documented
use of an hallucinogenic agent derived from the animal kingdom, although Euro-
pean Bufo bufo has been postulated to be one ingredient of the 'flying' ointment
made by witches during the Middle Ages 20 . Dried B. alvarius venom would have
been an excellent trading commodity transported along the extensive trade routes
known to occur through the Sonoran Desert to Mesoamerica. In this respect, the
puzzling issue of the distribution of Bufo bones (possibly of B. marinus, but also,
perhaps of B. alvarius) that are associated with ceremonial contexts at various
Mayan sites merits further study. Perhaps examination of the archaeological and
iconographic records, as well as the osteological remains at the sites, should be
made before concluding that the ancient people of Mesoamerica employed
B. alvarius venom as a sacred intoxicant.



Archaeological findings are instrumental in the study of the origin of the use of
hallucinogens. A few such studies have been made with promising results. Some
examples are presented below.

Although the present use of snuffs by native peoples is relatively well known, the
origin of such usage is still a matter of speculation. Recently, a major advance in
the understanding of the spread of snuff use has been made by a group of Chilean
archaeologists collaborating with some American specialists in botany and
chemistry. The San Pedro de Acatama archaeological remains in Chile are charac-
terized by the highest concentration of snuff-taking implements known from pre-
Columbian America. The most common of the snuff-taking kits consists of a
woollen bag containing a rectangular wooden snuff tray; a snuff-taking tube,
usually of wood or bone; a spoon or spatula; and a small mortar and pestle. A total
of 612 such kits have been found in approximately 5000 burial sites excavated
since the mid-1950s. Age determinations using radiocarbon and thermolumines-
cence dating methods on related ceramic samples indicated dates ranging from
AD 320 to AD 910 2 1 . Mass spectrometric analyses indicated the presence of DMT,
5-MeO-DMT and 5-hydroxy-DMT (bufotenine) in two of these snuffs from
Atacama archaeological sites. The presence of the bufotenine suggests that the
plant source of this material was a species of Anadenanthera, because this is the only
genus implicated in the hallucinogenic snuff complex that contains bufotenine.
The investigation of the origin of snuff-taking in South America has relied more
on ethnographic data than on controlled and well-documented archaeological
excavations. Snuff-taking equipment consisting of trays and tubes 2 2 has been
found more frequently in the Amazonian Basin, but previous to the period of
European contact, there is no clear chronology regarding snuff-taking in the
Amazon. Until the discovery of these Atacama snuffs, the practise was viewed as
originating in the northern Amazon Basin, suggesting a north-to-south migration
of the usage pattern. However, the gap of nearly two millennia between the
earliest evidence of snuff usage in the area and in the south-central Andes indicates
an earlier acceptance of hallucinogenic inhalants in the latter area. As northern
Chile and north-western Argentina have the highest concentration of snuff-
taking paraphernalia in pre-Columbian America, Anadenanthera-based snuff
preparations could, instead, have diffused from south to north.


Not only many species of Psilocybe (Strophariaceae) but other genera like Conocybe,
Pholiotina (Bolbitiaceae), Panaeolus, Copelandia (Coprinaceae), Gymnopilus, Inocybe


(Cortinariaceae) and Pluteus (Pluteaceae) 23 has been found to contain psilocybin 24 .

Generally, mushrooms containing psilocybin become blue or greenish, upon
cutting the flesh, especially around the lower part of the stalk. Sometimes, this
coloration spreads all around the carpophore. However, this is by no means a safe
method of identification. In archaeology, where living specimens are lacking,
chemical analyses are of course impossible, and coloration is not usually evident
in the remains. This has led to different interpretations, some of which are not
always convincing. There are however, a few exceptions that are worthwhile
mentioning below.

Figure 2 Known examples of postulated mushroom effigies on seven Swedish bronze razors dated
between 1100 BC and 700 BC. The general motifs may represent ship-figures in a mythic framework
or religious context. (Drawings modified from ref. 26)


Northern Europe
Rock carvings in Scandinavia are the expression of a rich religious tradition. They
are found mainly in agricultural areas and usually close to the sea. There, petro-
glyphs are the product of the Bronze Age culture. Contemporaneous with the
formation of these engravings, many of the same motifs appear on bronze objects
that are often found as grave goods - particularly flat, wide-bladed razors. Analy-
sis of the motifs suggests strongly that they were engraved as part of the ritual of
this worship 2 5 . Amongst the motifs, the ship-figure (Figure 2) is particularly
noteworthy as it occupies a central position in the ritual. Some imaginative people
have claimed to see the shapes of mushrooms (Amanita or Psilocybe?) in these
images 26 . It is postulated that the engravings are evidence of a mushroom cult,
which utilized the psychotropic properties of the fungi for ritual purposes. These
practises, still maintained by other northern groups in this century, died out by
the early Iron Age.

Another 'discovery' of an ancient mushroom painting in the Sahara Desert was
made recently 27 . The polychromic scenes are the work of a group of pre-Neolithic
Early Gatherers located in the Tassili region of Algeria. They may represent
scenes of harvest, adoration and the offering of mushrooms, leading to specula-
tion that again we are confronted with evidence of an ancient hallucinogenic
mushroom cult. Produced 7000-9000 years ago, these could indeed derive from
the most ancient human culture yet documented in which the ritual use of hal-
lucinogenic mushrooms is explicitly represented. At that time, the Sahara region
would still have been covered with an extensive layer of vegetation 28 . Belonging
to the 'Round Heads' period, the center of this style is in Tassili 29 . The Round
Head period is associated with palaeolithic populations that were gathering wild
plant foods. The rock paintings suggest that this art could have been influenced by
ecstatic or hallucinogenic states: images of enormous mythological beings of
human or animal form, side-by-side with a host of small-horned and feathered
beings in dancing stance cover the rock shelters, of which there are very many on
the high plateau of the Sahara. One of the most important scenes is a series of
masked figures approximately 0.8 m tall, who wear the typical mask of this pic-
torial style. Another common feature is the presence of mushroom symbols
sprouting from the forearms and thighs; others are hand-held (Figure 3). These
figures have been interpreted as the images of the 'spirit of the mushroom' that are
known to exist in other cultures characterized by the psychoactive use of
mushrooms. Pollen examination carried out at Tassili revealed that, during the
Round Head period, this area was characterized by a high-altitude (2000 m) flora
including coniferous trees and oaks. It may be presumed that some of the


Figure 3 Line drawing from a rock painting dating from ca. 7000-5000 BC and originally
designed by Lajoux (and adapted from ref. 31) of a rock painting in Tassili, Algeria. This illustration
represents a masked anthropomorph figure with its body outline entirely covered by mushroom
shapes, and might have been associated with an ancient ethnomycological cult in which fungi were
used as ecstatic media


mushrooms represented were indigenous to this woodland area, since they are
intimately associated with these types of trees. In short, this Saharan evidence
might well demonstrate that the use of hallucinogens originates in the palaeolithic
period and that this practise was invariably associated with mysticoreligious
contexts and rituals.


An excursion into the fungal world was also described in The Road to Eleusis:
Unveiling the Secret of the Mysteries 30, a book which Albert Hofmann co-authored
with R. Gordon Wasson, and Carl A. P. Ruck, a professor of Classics at Boston
University. Its theme offered the suggestion, based on a historical analysis of the
Greek literature, as well as botanical and chemical evidence, that the psychoactive
agent employed in the Eleusian Mysteries was a species of ergot growing on a
wild grass that was common at that time in Greece - a different ergot than the one
infecting rye. The chemicals involved might be the same as those known to occur
in ergot growing on the wild grass Paspalum distichum L. They comprise the water-
soluble lysergic acid amides, closely related to LSD, which have been isolated
previously from ololiuqui. This plant grows commonly all around the Mediter-
ranean basin and is often infected with Claviceps paspali. Other fungi might also
have been involved, but C. paspali is the most likely, as it contain only alkaloids
with hallucinogenic properties. It might be also that ergots growing on barley or
wheat would have been used with a water-extraction procedure. The water-
soluble alkaloids are psychoactive, in contrast to the non-water soluble alkaloids
(medicinally used alkaloids of the ergotamine and ergotoxine types). With the
techniques and equipment available to antiquity, it was therefore easy to prepare
a hallucinogenic extract from suitable kinds of ergots. Hofmann and his col-
leagues produced hard evidence, illustrated from ancient poetry, cultural patterns,
comparative religion, science and cultural anthropology and erected a persuasive
argument which suggested that this unknown sacramental substance imbibed at
Eleusis was obtained from a psychoactive fungus.

Through the selected examples presented here, the extraordinary richness of the
ethno-psycho-pharmacological field of investigation can be realised. Even though
the traditional use of hallucinogens is not recent, it is to the great merit of people
like Albert Hofmann that they have greatly contributed to its rediscovery.
To conclude, I cite the words of Albert Hofmann in the final chapter of his
book LSD - Mein Sorgenkind 31 (p. 228):
Meditation beginn in jener Tiefe der objektiven Wirklichkeit, bis zu der gegenständlisches
Wissen und Erkennen vorgedrungen ist . . .


and, later (p. 230):

In der Möglichkeit, die auf mystisches Erleben einer zugleich höheren und tieferen Wirklichkeis
ausgerichtete Meditation von der stofflichen Seite her zu untersstützen, sehe ich die eigentlische
Bedeutung von LSD. Eine solche Anwendung entspricht ganz dem Wesen und Wirkungscharak-
ter von LSD als sakraler Droge.

Is this not exactly the kind of effects that shamans are looking for when choosing
a hallucinogen from their natural environment - a true religious experience? The
more we learn about the ethnopharmacology of natural hallucinogens, the more
we may realize how LSD is similar to these alkaloids.

1. de Smet, P. A. G. M. and Rivier, L. (1989). A general outlook on ethnopharmacology. J.
Ethnopharmacol., 25, 127-38
2. Schultes, R. E. and Hofmann, A. (1980). The Botany and Chemistry of Hallucinogens, 2nd edn.
(Springfield: Charles Thomas)
3. Fürst, P. T. (1972). Flesh of the Gods (New York and Washington: Praeger)
4. Schultes, R. E. (1977). The botanical and chemical distribution of hallucinogens. J. Psychedel.
Drugs, 9, 247-63
5. Harner, M. J. (1973). Introduction. In Harner, M. J. (ed.) Hallucinogens and Shamanism. (Oxford:
Oxford University Press)
6. Weil, A. (1972). The Natural Mind. (Boston: Houghton Mifflin)
7. Eliade, M. (1964). Shamanism: Archaic Techniques of Ecstasy, Bollingen Series LXXVI. (New
York: Pantheon Books)
8. Fürst, P. T. (1976). Hallucinogens and Culture. (San Francisco: Chandler and Sharp)
9. La Barre, W. (1980). Culture in Context: Selected Writings. (Durham: Duke University Press)
10. Rivier, L. and Pilet, P. E. (1971). Composes hallucinogènes indoliques naturels. Année Biol, 3,
11. Allen, J. R. F. and Holmstedt, B. (1980). The simple beta-carboline alkaloids. Phytochemistry, 19,
12. Schultes, R. E. (1982). The beta-carboline hallucinogens of South America. J. Psychoact. Drugs,
14, 205-20
13. Rivier, L. and Lindgren, J. E. (1972). "Ayahuasca", the South American hallucinogenic drink:
an ethnobotanical and chemical investigation. Econ. Bot., 26, 101-23
14. de Smet, P. A. G. M. and Rivier, L. (1985). Intoxicating snuffs of the Venezuelan Piaroa Indians.
J. Psychoact. Drugs, 21, 93-103
15. Holmstedt, B., Lindgren, J. E., Plowman, T., Rivier, L., Schultes, R. E. and Tovar, O. (1982).
Indole alkaloids in Amazonian Myristicaceae: field and laboratory research. Bot. Museum Leaflets.
Harvard Univ., 28, 215-34
16. Holmstedt, B. and Lindgren, J. E. (1967). Chemical constituents and pharmacology of South
American snuffs. In Efron, D. H. (ed.) Ethnopharmacological Search for Psychoactive Drugs
(Washington: Public Health Service Publ. No. 1645)
17. Erspamer, V., Vitali, T., Roseghini, M. and Cei, J. M. (1965). 5-Methoxy- and 5-hydroxy-
indolealkylamines in the skin of Bufo alvarius. Experientia, 21, 504-9
18. Davis, W. and Weil, A. T. (1993). Identity of a New World psychoactive toad. Ancient
Mesoamerica, 3, 51-9


19. Weil, A. T. and Davis, W. (1994). Bufo alvarius: a potent hallucinogen of animal origin.
J. Ethnopharmacol., 41, 1-8
20. Hansen, H. A. (1978). The Witch's Garden. (Santa Cruz: Unity Press - Michael Kesend)
21. Torres, C. M., Repke, D. B., Cahn, K., McKenna, D., Llagostera, A. and Schultes, R. E. (1991).
Snuff powders from pre-hispanic San Pedro de Atacama: chemical and contextual analysis.
Curr. Anthropol, 32, 640-9
22. Wassen, H. (1985). Convergent approaches to the analysis of hallucinogenic snuff trays.
Årstryck Gothenburg Ethnographic Museum, 1983-84, 26-37
23. Allen, J. W., Gartz, J. and Guzman, G. (1992). Index to the botanical and chemical analysis of
the known species of the hallucinogenic fungi. Integration, 2, 91-7
24. Stijve, T. and Kuyper, T. W. (1985). Occurrence of psilocybin in various higher fungi from
several European countries. Plant Medica, 5, 385-7
25. Gellin, P. and Davidson, H. R. E. (1969). The Chariot of the Sun. (London: J. M. Dent)
26. Kaplan, R. W. (1975). The sacred mushroom. Man, 10, 72-9
27. Samorini, G. (1992). The oldest representations of hallucinogenic mushrooms in the world
(Sahara Desert, 9000-7000 BP). Integration, 2, 69-78
28. Samorini, G. (1989). Etnomicologia nell'arte rupestre Sahariana (Periodo delle "Teste
Rotondo"). Boll. Camuno Notizie, 6, 18-22
29. Muzzolini, A. (1986). L'art Rupestre Préhistorique des Massifs Centraux Sahariens. (Oxford: Bar)
30. Wasson, R. G., Ruck, C. A. and Hofmann, A. (1978). The Road to Eleusis Unveiling the Secret of
the Mysteries. Ethno-mycological Studies No 4. (New York and London: Harcourt Brace
31. Hofmann, A. (1979). LSD - Mein Sorgenkind (p. 228). (Stuttgart: Klett)

Section 3


Experience of time and space in

model psychoses

'Mind-expanding' is a term which has been used in discussions about 'psychodys-

leptic' drugs. In analogy to mystic absorption, the term refers indirectly to
experience of the borders of consciousness by means of mind-altering external condi-
tions such as stimuli withdrawal. These borders of consciousness are usually
acknowledged in a cultural restriction by our socialization. Therefore, the term
'mind-expanding' itself has a positive connotation. The borders of consciousness,
however, are psychobiologically based constants. They are determined by intra-
psychic constructs or structures and are approved by perceiving reality 1 .
In a discussion about realization of time and space during psychotic conditions
Pöppel's finding 1 that human senses have different temporal abilities seems
important. The threshold of missing coincidence of events is shorter in the acous-
tic field than the visual field. The differences of the threshold of temporal simul-
taneity for acoustic and visual events demonstrates a horizon of coincidence of
about 10 m. This distance is necessary to enable visual and acoustic stimuli to
reach the brain simultaneously. Therefore, the acoustic and visual dimensions
must be temporarily co-ordinated for an adequate sensation. In order to realize a
sensory stimulus of both qualities as a single event, the brain needs a time period
of 0.03-0.04 s. Pöppel 1 has shown that histograms of the choice reactions of
stimuli from different qualities have a multitopic distribution also of 0.03-0.04 s.
This suggests that there is a special timing mechanism in the brain which is
responsible for co-ordinating the decision process.
We are used to having our experiences in the past, the present and the future.
We do not recognize the present as a simple limit; the present always has a certain
duration. Pöppel 1 demonstrated that the human sensation of the present is limited
to 3 s, by observing problem-solving behavior with the Necker cube or by


temporally accentuating metronomic beats at different tempos. It is well known

that man is unable to perceive a single version of the Necker cube for a longer
time, because of the temporal organization of the attention span. We can also per-
ceive the 3-s limit when speaking; we stop between phrases of significance or
whilst reciting poems so that the rhyme is interrupted by a pause after about 3 s.
This is valid, as Pöppel has shown, for poems of different languages.
The described psychobiological constants represent limits of consciousness.
Furthermore, in the monistic concept this is equivalent to the central processes in
the brain. Without doubt, these limits change in a model psychosis. I will describe
these changes using examples of time and space experience. Additionally, I will
interpret them with respect to Gestalt psychology, as well as to developmental
psychology, with reference to systematic examinations with psilocybin and LSD
during the 1950s and 1960s with my co-worker Kaspar Weber 2 - 8 .
I examined the disturbances of facial, gestic and linguistic expression during
model psychoses by direct observation and film recordings of the subjects 6 . Within
this scientific frame I explored the drugs' effect on the tipping phenomenon of the
Necker's cube. However, the results were intra- and interindividually variable.
Because of this, any conclusions about a systematic effect of the experience of the
present during a model psychosis were not valid. However, Weber's experiments
about the disturbance of the experience of time and music in experimental
psychosis have been more informative.
The following self-report about the experience of 'time standstill' may be
important for the understanding of this phenomenon:
For that which came there existed no chronological sequence in my memory. There were only
some single images which appeared incoherently. Above all, I know that I was not able to rest
anywhere. As soon as I looked at something it disappeared. My arm shrank to a shapeless mass.
The experimenter's face disappeared and looked like colored structures as soon as I looked at it
for a short time. Furthermore, I had a terrible feeling that in myself every thing dissolved just as
the outer world did. This became even worse by the knowledge that this experience would never
end. Time seemed to stand still.

Related to this was a disability to perceive movements:

As I looked at a watch during a cognitive task, it seemed that the time stood still. By means of
the hand I tried to prove to myself that the time still continued, but to my fright the hand did not
move; then, after a while, it stood at quite a different position. Later, when the experimenter
came to me, I first saw him sitting at the desk, then, a moment later, I saw him standing half-way
toward, then suddenly beside me. He seemed no longer real.

In this self-report all elements of the experience of time-disturbance are men-

tioned: the subject could not perceive movements as they are, i.e. he could no
longer realize the temporal quality of a moving object or of a person as a series of
continuously changing images within a certain period of time. We must assume
that the brain mechanisms that are responsible for such a serial registration no
longer function adequately. The subject was unable to co-ordinate spatial and


temporal changes. This is the reason for the subjective experience of unreality - as
an experience of 'derealization' complementary to an additional experience of
depersonalization. The visual overflow, with its disintegration of sensual impres-
sions, convey to the subject the loss of intentional independence. He/she cannot
remain anywhere, and is threatened by pressing experiences of the disintegration
of structures, and so demonstrates an apathy and passivity or, as we have called
it, an absorption.
The disorder of casuality as a temporal experience is related to the serial co-
ordination of movement sequences. If the subject is no longer able to experience
movement sequences, the identity of objects becomes questionable for him or her
(derealization). Additionally, he/she no longer has the ability to determine causal
relationships correctly. The temporal disturbance - the 'standstill of time' - cor-
responds to an inner psychic state characterized by a loss of serial temporal order,
co-ordinated with the identity of objects and with insight into causal relation-
ships. At present, we are unable to localize the fundamental mechanisms of con-
sciousness in the brain or specify their functions more precisely. The experience
of time in the model psychosis points to a fundamental disorder of the serial
integration and co-ordination of movements. Therefore, the term 'mind-
expanding' describes a restriction of intentional degrees of freedom.
This can be demonstrated even more clearly in the acoustic field, an area which
until now has only played a minor role in the investigation of model psychoses.
The occidental music of the past centuries is based on Gestalt time melodies,
developing themselves within time. As a result of their Gestalt qualities they
produce tension and satisfaction for the musically educated subject.
Weber examined musicians after they had taken psilocybin and when actively
playing 2 or listening to music 3, 4 . Surprisingly, the technique of their performance
changed very little, but gave an immature shapeless impression. The musicians'
dominating subjective experience was the impression of having lost their musical
talent. The overview on the music they played, the tensions which should have
been accumulating and relaxing according to the music - all seemed to have dis-
solved into nothing.
In a report about the music 3 h after taking 16 mg psilocybin, one of the musi-
cians gave the following description:
The music I play seems to me completely unimportant, somehow trivial, not full and round as
usual. It seems for me that it almost belongs to the visible things, but as an unimportant appear-
ance at the border of the visual field. When I am playing notes the piece of paper dominates the
musical experience: a luminous white paper with an enlarged, very clear musical stave or grid.
When I play some music it seems that I outline figures along this grid. I do not see, in reality the
music as a graph, but when playing I feel like I am drawing.

In response to the experimenter's question regarding tempo and mood, the subject
answered, 'Tempo needs some inner excitement and this is missing. Nobody asks
what a tempo a picture has'.


When listening to music the same change was observed; by indicating the
themes of Bach's fugues, a subject reported:

At the beginning, when I was able to recognize the themes, I was also able to distinguish a
rhythm. As time went on, I had a lot of trouble with this. The tempo became completely unim-
portant, it was not quick, nor was it slow, but there was simply music. That music was almost
standing still, existing as a Ganzheit, without going on, without tempo . . . almost static . . . but
with a lot of sense . . . comparable to the content of a whole passion, the Matthew Passion.

Another subject answered a question about how long she had heard a certain tone:
'As long as this table's edge - it is peculiar, I can see the duration of a tone on it'.
From this study, we can see a merging of the temporal experience and a fusion of
musical perception with visual perception. For example, a subject was able to listen
enthusiastically to one of Bach's fugues, but was no longer able to indicate the
beginning of each fugue's theme. The subject explained as follows: 'It is wonderful;
although I cannot follow the fugue, everything is interweaving with what I can see
outdoors - the sun, the branches, the trees - it is like in paradise'. Above all, this
example shows that the frequently mentioned deepening of musical perception
after drug intake does not rely on a perceived deepening of the dynamic musical
structure or its nature as temporal Gestalten which are now no longer recognized.
In this sense, music is only an unspecific stimulus, activating an existing mood.
In summary we can therefore state that in the model psychosis the musical
temporal Gestalten, or dynamic structures (whose parts for the musically formed
listener have a meaning dependent on the whole) become altered to an unrelated
sequence of tones which were heard in parallel. As Wellek has formulated 9 ,
complex qualities instead of Gestalt qualities become predominant - single
features of unstructured Ganzheiten which do not depend on the relation, but on
the sum of the features of its elements, for example the lightness of the sound or
its loudness. Lightness or loudness now impress as a figure, whereas the back-
ground relationships, depending on the melodies' structure, dissolve. The
perceiving person's inner state, the inner mood during the psychosis, becomes
more essential than the structure of the perceived object.
Similar to the experience in the visual field, there exists an acoustic disturbance
of the serial order of events. Melodies as temporal structures disintegrate into
single tones, much like movements, which are not perceived as serial optical
phenomena, but dissolve themselves into individual, static momentary images.
As well as these fundamental changes of the temporal experience, the experience
of space becomes split into single parts. The space is limited to that which can be
observed in the visual field. The visual field is no longer experienced, as usual, as
a part of a comprehensive structure. Illusions and hallucinations occur especially
in the near space or with closed eyes. When a subject is looking through a window
in the distance to, for example, the Swiss mountains or the Tübingen Castle,
the different landscape structures merge together into a sort of flat scenery,


with the impression of one element being directly behind the other. The changes
close to the observer, which are characteristic for behavior in one of several phases
of the model psychosis 6 may be associated with the above-mentioned coincidence
horizon of 10 m. However, it is possible that the coincidence horizon could limit
the illusionary experience of movements.
For a better understanding of the disturbed temporal and spatial experience in
the model psychosis Weber 4 pointed out the relationship to Jean Piaget's studies
of developmental psychology 1 0 , 1 1 . The concepts of time and space, as they are
perceived and self-evident for adults, are developed during the child's history. As
Piaget has shown, the child's intellectual development goes through different
stages, namely by 'assimilation' and 'accommodation'. Assimilation is the process
of the subject's use of the objects around him/her by assimilating the inherited or
acquired scheme, for example to suck, to see, to grasp and so on. Accommodation
on external objects is related to the resistances the environment puts up to the
assimilation. Piaget showed that the constructs of objects, space, causality, and
time in the developmental course are constituted only gradually and in correlation
to the development and differentiation of 'assimilation' and 'accommodation'.
This is achieved interactively with the environment and the child's sensorimotoric
behavior. Thereby, step-by-step, an active delimitation between environment and
subject is achieved.
Without considering the details of these developmental processes, an early
intellectual phase in the child's development can be observed where the child only
sees the surface of an object and is not able to distinguish environmental
phenomena from its own activity. For example, Piaget 11 asked children to work
quickly or slowly, respectively, during a time-period measured with an hour-
glass. He noticed that the children gave the impression that the sand would run
more quickly if they worked more rapidly. In another study he showed two little
cars to 5-year-olds. Both cars started and stopped at the same time, but one car
completed a longer distance. The children assumed that the car which had moved
a longer distance would have taken more time. Consequently, it was concluded
that the child is incapable of associating the two objects with their different speeds
to an objective time-period, that is valid for both cars. Furthermore, Piaget 11 con-
cluded that these 5-year-olds were unable to perceive movements of distant
objects without relation to their own movement. For instance, they assumed that
the stars or mountains follow them from far away. Only when they reach 7-9
years of age do children acquire the understanding of a uniform time-period and
space, valid for objects and other persons. Thereafter, the child acknowledges that
he/she is also integrated in this frame, and is able to correlate two independent
phenomena (e.g. the speed of the two cars or the running of the sand in the hour-
glass) with his/her own activity. The child is able to relate to an objective temporal
construct. These developmental steps correspond to the transition from an
'egocentric' thought process to an 'operational' one, through a progressive


decentralization. This 'operational' way of thinking enables the child to separate

the perceived surface of objects and events.
In the model psychosis a subject is no longer able to make a distinction such as
seen in the reports about disorders of temporal experience: loss of movement per-
ception in the visual field or loss of tempo in the musical one. During model psy-
chosis the subject returns to an early egocentric way of thinking, and a
homogeneous space does not exist any more. Changing environments related to
momentary experiences and to changing impressions do exist. There is no
homogeneous objective time where the self-experienced time can steadily be
referred to but individual changing time-periods that are again coupled with the
perception of experiences in which the subjects cannot distinguish between an
inner and an outer world. One subject reported, after drug-intake, that when
walking home he had seen the house situated far away from him, but he was not
capable of realizing the house's apparent movement when walking quickly. He
had the impression that the house was moving away with him and that he could
never arrive.
However, a regression to egocentric thinking during the model psychosis only
explains one part of the problem. An adult with LSD does not return to child-
hood. If we consider that subjects during model psychosis passively experience a
chaotic overflow of sensory internal and external impressions which would other-
wise be filtered, the regression to egocentric thinking could be understood as a
response of the organism. The recourse to early strategies seems to be an attempt
to cope with this subjective chaotic world. Adults still have the early stages of
their intellectual development available.
In conclusion, as a general pathophysiological principle for these psychoses we
first have a disturbance of the available cognitive and emotional filters as a conse-
quence of the drug intake. The subjects became overwhelmed by new somatosen-
soric, visual and acoustic impressions. Secondly, recourse to the egocentric
thinking mechanism can be interpreted as an apparently helpless endeavor to
reactualize strategies from earlier experience. The recourse or regression to earlier
thinking strategies in the model psychosis describes the borders of consciousness
and could lead to a positive experience. Normally hidden personality variables
and structures may become conscious and predominant.

1. Pöppel, E. (1985). Grenzen des Bewußtseins. Uber Wirklichkeit und Welterfahrung. (Stuttgart:
Deutsche Verlags-Anstalt)
2. Weber, K. (1966). Veränderungen des musikalischen Ausdruckes unter Psilocybinwirkung.
Schw. Arch. Neurol. Neurochir. Psychiat., 99, 176-9
3. Weber, K. (1977). Beobachtungen und Überlegungen zum Problem der Zeiterlebensstörungen
ausgehend von den Veränderungen des Musikerlebens in der experimentellen Psychose. Confin.
Psychiat., 20, 79-94


4. Weber, K. (1967). Veränderungen des Musikerlebens in der experimentellen Psychose

(Psilocybin). Confirm. Psychiat., 10, 139-76
5. Heimann, H. (1952). Die Scopolaminwirkung. Vergleichend psychopathologisch-
elektroencephalographische Untersuchungen. Bibl. Psychiatr. Neurol, 93, 1-80
6. Heimann, H. (1961). Ausdrucksphänomenologie der Modellpsychosen (Psilocybin). Vergleich
mit Selbstschilderung und psychischem Leistungsausfall. Psychiat. Neurol, 141, 69-100
7. Heimann, H. (1963). Beobachtungen über gestörtes Zeiterleben in der Modellpsychose.
Schweiz, med. Wochenschr., 93, 1703-11
8. Heimann, H. (1990). Biologische Aspekte des Zeiterlebens. In Ciompi, L., Dauwalder, H.-P.
(eds.) Zeit und Psychiatrie. Sozialpsychiatrische Aspekte, pp. 29-43. (Bern-Stuttgart-Toronto:
9. Wellek, A. (1963). Musikpsychologie und Musikästhetik. Grundriss der Systematischen Musikwissen-
schaft. (Frankfurt: Akademische Verlagsgesellschaft)
10. Piaget, J. (1955). Die Bildung des Zeitbegriffs beim Kinde. (Zürich: Rascher)
11. Piaget, J. (1974). Der Aufbau der Wirklichkeit beim Kinde. (Stuttgart: E. Klett)


Evidence for a
cortical-sub cortical imbalance of
sensory information processing
during altered states of
consciousness using positron
emission tomography and
[ 18 F ] fluorodeoxyglucose


The recent development of functional imaging techniques such as positron emis-

sion tomography (PET) and single photon emission computed tomography
(SPECT) now allows the direct exploration of physiological operations in the
living human brain. In particular, the measurement of glucose metabolism has
been one of the most frequent indicator variables to study the interactive organiza-
tion of the brain, because of the physiological coupling of cerebral glucose utiliza-
tion and neuronal activity. Its application to physiological conditions has shown,
for example, that visual stimulation results in a specific metabolic activation
pattern. The relationship between metabolic alterations and higher mental
activity, particularly under psychopathological conditions, is less well under-
stood, however 1 . The various metabolic findings seen in schizophrenic patients
gave rise to fundamental questions: to what extent do cerebral metabolic altera-
tions reflect disturbed mental activity and, in particular, psychotic phenomena?


The analysis of drug-induced altered mental states (model psychoses) has been
one of the most effective approaches for generating chemical hypotheses asso-
ciated with schizophrenic disorders. The predominant hypothesis of schizophre-
nia, the dopamine hypothesis, was derived from the observation that
amphetamine can induce psychotic symptoms resembling those of acute
schizophrenia by augmenting dopamine release. Whether a dysfunction of the
dopaminergic neurotransmission is the primary event in the pathogenesis of
schizophrenia, however, is not beyond doubt.
Alternative models of schizophrenia, based on the psychotomimetic and phar-
macological effects of phencyclidine (PCP) and ketamine, or the effects of LSD
and psilocybin, suggest that a deficient glutamatergic or excessive serotonergic
activity, respectively, may also be involved in schizophrenic disorders.
Model psychoses have a methodological advantage over clinical studies, in that
the same subject under investigation can be tested under various conditions,
allowing intra-individual control, and thereby minimizing the variability of the
data. To explore the relationship between cerebral metabolic activity and psy-
chopathological changes, we have begun to investigate the effects of psychotomi-
metic doses of ketamine and psilocybin on cerebral energy metabolism in a group
of selected, healthy volunteers. The practise and theory of 'model psychosis' as
employed at the Psychiatric University Hospital, Zürich, is used as an experimen-
tal paradigm of schizophrenia 2-4 . The in vivo measurement of cerebral glucose
utilization is realized using PET and the radioligand [ 18 F]-fluorodeoxyglucose 5,6 .
Based on a cortical-subcortical model of sensory information processing, and
on pharmacological mechanisms of psychedelic drug action, we hypothesized that
a common feature of the psychedelic states induced by ketamine and psilocybin is
a sensory overload of the frontal cortex, resulting in a hypermetabolic pattern
(hyperfrontality) 5,7 . The study aims, firstly, to investigate which brain regions
respond metabolically to ketamine and psilocybin stimulation, and secondly to
explore the complex interrelationships between cerebral metabolic changes and
psychological changes. Moreover, it is important to compare the metabolic data
('patterns') obtained from these model psychoses with the results of metabolic PET
studies of schizophrenic patients. Finally, we consider that such investigations will
be decisive in the foundation of biological models of altered states of consciousness.

Complex-loops controlling sensory information processing
Based on the recent characterization of functionally segregated cortico-striato-
thalamo-cortical (CSTC) feedback loops, which are thought to control cortical
information processing, and on the recent findings of psychedelic drug actions,
we have hypothesized that a corticostriatal neurotransmitter dysfunction may be a
common cause of the pathogenesis of psychedelic and psychotic mental states such


as schizophrenia 5 , 7 , 8 . Five principal CSTC loops have been identified and each
loop, functioning in parallel, is thought to mediate a different set of functions: the
motor, the oculomotor, the prefrontal, the association and the limbic loop (Figure
l) 9 . The limbic loop is involved in memory, learning and self-nonself discrimina-
tion by linkage of cortical categorized exteroceptive perception and internal stimuli
of the value system (homeostatic-autonomic and neuroendocrine brain functions).
The limbic loop originates in the medial and lateral temporal lobe and hippocampal
formation, projects to the ventral striatum including the nucleus accumbens, the
ventromedial portions of the caudate nucleus and putamen. Projections from these
nuclei then converge on the ventral pallidum (GPi) and feed back via thalamic nuclei
(dorsomedial, ventral anterior) to the anterior cingulate and orbitofrontal cortex.
In this model the thalamus acts as a 'filter' for sensory input from specific affer-
ents originating in the sense organs. Its filtering capability is under the control of
cortico-striato-thalamo feedback/re- entry l o o p s 1 0 , 1 1 . The 'filter' is postulated to
protect the cortex from exteroceptive sensory information, as well as from
internal hyperarousal mediated by non-specific afferents of the mesencephalic
reticular formation (DR). There is evidence that cortico-striatal neurotransmission
is mediated by the neurotransmitter glutamate which activates, at least in part, the
N-methyl-D-aspartate (NMDA) receptors 12 . In addition, the neuronal informa-
tion flow within CSTC loops is thought to be modulated by subsidiary circuits.
The mesostriatal and mesolimbic projections provide the dopaminergic input to
the caudate and the putamen, and to the nucleus accumbens. The reticular forma-
tion, which is activated by input from all sensory modalities, gives rise to
serotonergic projections to the components of the CTSC loops, namely the
cerebral cortex, cingulate cortex, striatum, thalamus, hippocampus, nucleus
accumbens and amygdala 13 .
Altered mental states, and in particular psychotic symptoms, can be considered
as complex disturbances that arise from more elementary deficits of sensory infor-
mation processing within CSTC loops. The model predicts that psychotic sym-
ptoms may be induced either by decreasing glutamatergic and/or by increasing
dopaminergic neurotransmission, resulting in an opening of the thalamic filter and
a subsequent sensory overload of the frontal cortex. Excessive activation of the
ascending serotonergic pathways may lead to a similar neurotransmitter
imbalance within CSTC loops which again results in cortical overload of sensory
information (Figure 2).

Role of hallucinogens in the CSTC-loop mediated neurotransmission and

the link to schizophrenia
The 'dopamine hypothesis' of schizophrenia has been derived from the observa-
tion that dopaminergic stimulants such as d-amphetamine can induce a psychotic
mental state resembling acute paranoid schizophrenia 1 0 , 1 4 and from the clinical

sensory assoc. cortex 1st proj. area

frontal medial/lateral temporal lobe GABA 3ABA

cortex glu?

hippocampus CM
glu input


ventral striatum ventral pallidum

VTA thalamus
Ach NE 5-HT SNc

NMDA receptor

Figure 1 The limbic cortico-striato-thalamo-cortical (CSTC) feedback loop is involved in memory, learning and self-nonself discrimina-
tion by linkage of cortical categorized exteroceptive perception and internal stimuli of the value system. The 'filter' function of the thalamus
which is under the control of CSTC feedback/re-entry loops, is postulated to protect the cortex from exteroceptive sensory information, as
well as from internal hyperarousal mediated by non-specific afferents of the mesencephalic reticular formation. Ach = acetylcholine;
CM = corpus mamillaria; DA = dopamine; GABA = y-aminobutyric acid; glu = glutamate; 5-HT = serotonin; LC = locus ceruleus;
NE = norepinephrine; NMDA = N-methyl-D-aspartate; SNc = substantia nigra pars compacta; VTA = ventral tegmental area
sensory assoc. cortex 1st proj. area

medial/lateral temporal lobe GABA

frontal glu?
cortex glu?

hippocampus CM
glu ket input

glu glu GABA GABA

central striatum ventral pallidum

VTA thalamus

5-HT 5-HT


Figure 2 The model predicts that psychedelic effects induced by ketamine may be caused either by decreasing NMDA receptor-mediated
glutamatergic (glu) and/or by increasing dopaminergic (DA) neurotransmission, resulting in an opening of the thalamic filter and a subsequent
sensory overload of the frontal cortex. Excessive stimulation of 5-HT2 receptors by psilocybin may lead to a similar neurotransmitter
imbalance within the cortico-striato-thalamo-cortical loops which again results in a cortical overload of sensory information. Abbreviations
as for Figure 1

efficacy of dopamine D2 receptor antagonists in the treatment of such artificial and

naturally occurring psychoses. Whether hyperactivity in central dopaminergic
pathways is the primary event in the pathophysiology of schizophrenia is, as yet,
unproven 1 0 . Classical neuroleptics (D 2 receptor antagonists) are effective only in
reducing positive symptoms (hallucinations, delusions, thought disorders, excite-
ment), but have little effect on the negative symptoms (flattened affect, poverty of
speech, apathy, social withdrawal) of schizophrenia. More recently, PET studies
have shown that atypical neuroleptics, such as risperidon, block not only
dopamine D 2 receptors in the striatum, but also antagonize serotonergic 5 - H T 2
receptors in the neocortex 15 .
The recent finding that atypical neuroleptics display antagonistic effects on
5 - H T 2 receptors, and the observation that LSD and related drugs have 5 - H T 2
receptor agonistic properties gave rise to a revival of the 'serotonin hypothesis' of
schizophrenia 1 6 - 1 8 . This hypothesis suggests that excessive serotonergic activity
is one of the causes of schizophrenia. The 5 - H T 2 agonist binding sites are found
to occur at a high density in the frontoparietal cortex, anterior cingulate gyrus,
nucleus accumbens, claustrum and putamen 1 9 . The distribution of these agonistic
binding sites is highly correlated with the LSD binding sites in human cortex 20 .
The serotonin hypothesis is supported by the observation of an increased 5-HT
content in postmortem studies of patients with schizophrenia, and by the finding
that schizophrenics have increased 5-HT levels in blood platelets 21 .
It has been discovered that PCP, ketamine and dizocilpine (MK-801) which
have psychotomimetic properties in man, selectively block the glutamatergic
NMDA receptor-associated ion channel at subanesthetic doses, supporting the
idea of a 'glutamate deficiency hypothesis' of schizophrenia 22-24 . A high density
of NMDA receptors are found in human brain regions implicated in the
pathophysiology of schizophrenia, such as the limbic system, the frontal and tem-
poral cortex and the basal ganglia. The finding in recent studies, of significant
changes in NMDA-receptor densities in the putamen and orbitofrontal cortex in
the schizophrenic postmortem brain strengthens the hypothesis of a frontostriatal
glutamatergic dysfunction in the pathophysiology of schizophrenia 25-28 .
In summary, the psychedelic effects of PCP and ketamine are thought to be
caused by the blocking of cortical and, in particular, frontostriatal NMDA
receptor-mediated neurotransmission, whereas the psychedelic effects of LSD,
psilocybin and related drugs result from excessive stimulation of 5 - H T 2 receptors,
preferentially of the frontal cortex and of further components of the CSTC loops.

Experimental tests: effects of ketamine and psilocybin on cerebral energy

metabolism in healthy volunteers
The CSTC model is an extremely oversimplified, yet testable hypothesis. I will
briefly summarize some preliminary evidence that supports the idea of a cortico-
subcortical dysfunction in psychedelic mental states.


The hyperfrontality hypothesis of psilocybin- and ketamine-induced mental

states has been investigated in healthy volunteers using P E T 7 , 2 9 , 3 0 . In order to
reduce risks and anxiety, subjects were given a preliminary exposure to the indi-
vidual psychoactive substances under clinical conditions (n = 15). Subsequently
each subject received, at monthly intervals, a magnetic resonance imaging (MRI)
scan, a baseline PET scan (without any drug), and a second and third PET scan
under psilocybin (15-20 mg p.o.) or ketamine (0.03-0.04 mg/kg/min i.v.) In addi-
tion, blood samples were taken to determine metabolites and the respective drug
levels. Psycho(patho)logical states and alterations were measured before and after
each PET scan. The following rating scales were used: the Altered States of Con-
sciousness questionnaire (APZ), the Ego-Psychopathology (EPP), the AMDP
(Association for Methodology and Documentation in Psychiatry) and the EWL
(mood state) rating scales 3 , 3 1 , 3 2 .

Absolute metabolic rates
Both ketamine and psilocybin treatment increased metabolic rates of glucose
(CMRglu: μmol/100 mg/min) in most of the brain regions examined. It should be
noted, however, that the average metabolic changes were not equally high in all
brain regions. Ketamine stimulated CMRglu markedly in the following regions
(Wilcoxon, p < 0.01, n = 10): bilaterally in the frontomedial (28%), frontolateral
(30%), temporal (28%) and parietal (26%) cortex, in the insula (29%) and the
thalamus (32%). Lower increases were found bilaterally in the caudate nucleus
and the putamen (18-23%). The ventral striatum was significantly stimulated
(16%) only in the right hemisphere. The smallest increase was found in the
occipitomedial cortex (14%). No significant changes of metabolic rates were
observed in either temporal pole.
A similar cortical activation 'pattern' was found under psilocybin (Wilcoxon,
p < 0.01, n = 10): psilocybin increased metabolic rates bilaterally in the fronto-
medial (28%), frontolateral (30%) and parietal (24%) cortex and in the thalamus
(23%). The temporal cortex (17%) and the insula (17%) were somewhat less
strongly activated as compared to ketamine. The putamen (21-23%) was stimu-
lated bilaterally in the same range as seen under ketamine. The smallest increase was
again found in the occipitomedial cortex (13-16%). In neither hemisphere were the
ventral striatum, caudate nucleus and temporal pole significantly stimulated.

Relative metabolic rates

The effects of ketamine and psilocybin on relative metabolic rates were also inves-
tigated. Relative metabolic rates were calculated by dividing absolute metabolic


values in a given region by global brain metabolism. This normalization allows us

to minimize the effect of the variance of the global metabolism on regional
changes from a first to a second scan. Figures 3 and 4 compare the mean changes
of rCMRglu from the baseline to ketamine or to the psilocybin treatment by brain
regions. Comparison of the two figures shows that the pattern of change in rela-
tive metabolism of the right brain hemisphere is very similar for the two treat-
ments. Ketamine affects metabolism equally in both hemispheres, while
psilocybin seems to stimulate metabolism preferentially in the right hemisphere.

Metabolic gradients and psychopathology

Ketamine and psilocybin induced significant psychedelic/psychotic mental states
as measured by the APZ questionnaire 2,3 . Ketamine induced somewhat more pro-
nounced psychotic effects than psilocybin as indicated by the mean of APZ-scores
for 'oceanic boundlessness' (OSE: 9.3 ± 2.5/7.3 ± 2.5), for 'visionary restruc-
turing' (VUS: 9.3 ± 3.8/7.6 ± 2.7), and for 'dread of ego-dissolution' (AIA:
7.6 ± 4.9/6.9 ± 2.6) or by the AMDP subscales (Figure 5). In particular, keta-
mine was more effective in inducing thought disorders, anxiety and apathy than
In order to compare metabolic patterns obtained in these model psychoses with
PET data from schizophrenic patients, ratios between metabolic rates of cortical
and subcortical regions were calculated (i.e. gradients). Ketamine altered cortico-
subcortical gradients significantly in both hemispheres, psilocybin preferentially
in the right hemisphere. In particular, ketamine increased the fronto-occipital
gradient and inverted the gradient from the frontal cortex to the ventral striatum
in both hemispheres, psilocybin only in the right hemisphere.
The significance of changes in metabolic gradients have been validated by
correlations to psychopathological syndromes. Figure 6 summarizes the correla-
tional analysis between significantly changed metabolic gradients and psy-
chopathological syndromes as measured by the AMDP subscales, hallucinatory
disintegrative, psycho-organic, manic depressive, and schizophrenic syndrome.
Gradients which showed no significant correlation to psychopathology have been
omitted from the figures.

The 'hyperfrontality hypothesis' of psychotic states were tested under ketamine
and psilocybin conditions using PET and the radioligand [ 18 -F]-fluoro-
deoxyglucose. The results of this study demonstrate that both ketamine and
psilocybin induce hyperfrontal metabolic patterns. The frontal cortex was one of
the most stimulated brain regions as indicated by increased absolute and relative


(n = 10, Wilcoxon: *:p < 0.05; **:p < 0.01)

left (s)
Change of rCMRglu (%)








right (s)
Change of rCMRglu (%)










Brain regions

Figure 3 Effect of ketamine on relative metabolic rates of glucose (rCMRglu): activation over
baseline (change of metabolic rates) by brain regions under ketamine (0.02-0.03 mg/kg/min, i.v. for
60 min). FRM = frontomedial; FRL = frontolateral; FRA = average of the frontal cortex; INS =
insula; TEB = temporobasal; TEL = temporolateral; TEP = temporal pole; TEA = temporal
average; OCMA = occipitomedial-anterior; OCMP = occipitomedial-posterior; O C M = average
of the occipitomedial cortex; OCL = occipitolateral; PAR = parietal cortex; VSTR = ventral
striatum, CAU = caudate nucleus; PUT = putamen; OCA = occipital average; THA = thalamus;
CER = cerebellum


(n = 10, Wilcoxon: *:p < 0.05; **:p < 0.01)


- 10
left (s)










Change of rCMRglu (9)

- 10
right (s)










Brain regions
Figure 4 Effect of psilocybin on relative metabolic rates of glucose (rCMRglu): activation over
baseline (change of metabolic rates) by brain regions under psilocybin (15-20 mg p.o.). Abbrevia-
tions as for Figure 3



















Figure 5 The interrelationship of the three dimensions of altered states of consciousness (APZ)
'oceanic boundlessness' (OSE), 'visionary restructuring' (VUS), and 'dread of ego-dissolution'
(AIA) under (a) ketamine and (b) psilocybin (n = 20). Ketamine induced somewhat more pro-
nounced psychedelic/psychotic effects than psilocybin. Thought disorders were concomitant with
anxiety under ketamine, but not under psilocybin

metabolic rates. Ketamine increased the fronto-occipital gradient bilaterally,

psilocybin only in the right hemisphere.

Ketamine effects
Surprisingly, the marked stimulation of the frontal cortex is thought to be due to
block of excitatory NMDA receptors, but may also result from an enhanced input


Percentage change of M6 vs. baseline

Percentage change of M6 vs. baseline


Figure 6 Correlational analysis between significantly changed metabolic gradients (M6) and
psychopathological syndromes as measured by the AMDP subscales: manic depressive
(MAN-DEP), hallucinatory disintegrative (HALL-DIS), psycho-organic (PSYCH-ORG), (n = 10)
and schizophrenic syndrome (SCHIZO) under (a) ketamine and (b) psilocybin. Gradients (R
refers to right hemisphere and L to left): FM-OA-R = frontomedial-occipitomedial anterior;
FM-OP-R = frontomedial-occipitomedial posterior; FM-CA-R = frontomedial-caudate; FM-
VSTR-R = frontomedial-ventral striatum; FL-OP-R = frontolateral-occipitomedial posterior;
FAV-OAV-R = frontal average-occipital average; TH-OA-R = thalamus-occipitomedial anterior;
TH-OP-R = thalamus-occipitomedial posterior; FM-TH-L = frontomedial-thalamus; FL-TP-L =
frontolateral temporal pole


from associational projections such as those originating in the parietal, temporal

and occipital cortex, which also showed increased metabolic rates with ketamine.
The thalamus was the only subcortical region that showed an increase in meta-
bolic rate comparable to that seen in the cortex, despite its lower NMDA-receptor
density. This is interesting, in that the CSTC model predicts that blockade of
cortical and, in particular, striatal NMDA receptors leads to an inhibition of the
cortico-striato-thalamo feedback loops, resulting in an opening of the thalamic
filter. Increased thalamic and frontocortical activity support the idea of such a
mechanism. This interpretation is underscored by the finding that blockade of
hippocampal (limbic loop) NMDA receptors by local injection of PCP increases
cell firing markedly in its projection areas, such as the thalamus and cingulate
cortex 33 .
Subcortical structures, such as the ventral striatum or putamen, showed smaller
absolute increases than cortical regions, and relative metabolic rates were even
decreased, supporting the idea that NMDA receptor blockade results in a dis-
turbance of the cortico-striatal neurotransmission. The dramatic change of the
frontostriatal gradient suggests that the ventral striatum is 'disconnected' from the
cortex. The occipital cortex was much less effectively stimulated than other
cortical regions. This may be because subjects had their eyes closed during the
experiment and did not receive visual stimulation.
The sites of ketamine-induced metabolic changes correlate with the distribution
and the density of NMDA receptors in the brain. Animal studies, using ketamine,
PCP or the high-affinity NMDA-receptor antagonist MK-801, show a similar
correlation 3 4 - 3 7 . In the rat, however, the most dramatic metabolic changes were
associated with subcortical brain structures, which have the highest NMDA-
receptor densities, while in humans, the highest NMDA-receptor densities are
found in the cortex. It is not possible to conclude from this experiment, however,
that the metabolic effects of ketamine are strictly due to NMDA-receptor block-
ade. Other neurotransmitter systems, such as γ-aminobutyric acid (GABA) and
dopamine are also candidates. MK-801 and PCP have been shown to inhibit
NMDA-induced GABA release and to modulate NMDA-mediated dopamine
release in various tissue preparations of the r a t 3 8 - 4 1 .
Several lines of evidence suggest that ketamine- (and PCP-) induced psychotic
symptoms may be due to interference with glutamatergic neurotransmission at
the level of the NMDA receptor complex. First, PCP, ketamine and MK-801
selectively block the NMDA receptor-associated ion channel 42 . Second, compari-
son of behavioral effects between competitive (e.g. AP-5, AP-7) and non-
competitive (e.g. PCP, MK-801 etc.) NMDA-receptor antagonists in animals
provides strong support for the idea that impairment of sensory and cognitive
functions may be the major event in the genesis of the behavioral response to MK-
801 and P C P 4 3 - 4 6 . Indeed, the high-affinity NMDA-receptor channel blocker
MK-801 can induce aberrant mental states in healthy volunteers 4 7 , 4 8 . Third,


NMDA-receptor densities are changed in the putamen and orbitofrontal cortex in

the schizophrenic postmortem b r a i n 2 6 , 2 7 .

Psilocybin effects
Psilocybin stimulation induced a hyperfrontal metabolic pattern and resulted in
similar activation of the cortex, the putamen and the thalamus. The thalamus
showed a substantial increase in metabolic rate, the occipital cortex showed a
moderate increase, and the ventral striatum and temporal poles showed no
increases. The bilateral hyperfrontality, together with activation of the thalamus,
similar to that seen under ketamine stimulation, can be interpreted in the context
of an analogous disturbance of the cortico-striatal neurotransmission and a tha-
lamic filter dysfunction. This metabolic activation pattern corresponds closely to
the serotonergic 5 - H T 2 receptor density in the human brain, with the exception
of the thalamus. A PET study using radiolabeled LSD reported the highest levels
of 5 - H T 2 receptors in the frontal and temporal cortex, intermediate levels in the
basal ganglia, and very low levels in the thalamus 20 . On the other hand,
antagonism of 5 - H T 2 receptors by LSD and related drugs as a possible cause of
psychedelic states has been questioned because selective 5 - H T 2 antagonists do not
induce hallucinations in h u m a n s 1 6 , 4 9 . In contrast, several physiological and
biochemical studies have demonstrated that LSD and related drugs, as well as
phenylakylamine hallucinogens, have agonist properties at the 5 - H T 2 A (and
5-HTlC) receptor16,19,50,52.
The psilocybin-induced metabolic pattern strongly suggests that both direct
5 - H T 2 receptor stimulation and indirect mechanisms contribute to the metabolic

Psychopathology and implications for schizophrenia

Both ketamine and psilocybin induce acute altered mental states that fall within
the broad nosological category of schizophrenia (Figure 5). Especially, ego-
disorders and perceptive changes of surroundings are prominent features of
psychedelic and 'endogenous' psychotic s t a t e s 4 , 3 2 , 5 3 , 5 4 . In general, loss of ego
boundaries and alterations in the perception of time and space (as measured by the
APZ questionnaire) occurred simultaneously with excessive activity of the frontal
cortex (hyperfrontality) in both ketamine- and psilocybin-induced psychedelic
mental states. This observation validates the assumption of the holonomic brain
theory, which suggests that the frontal cortex is involved in structuring episodes
by processing covariant external and internal sensory information 55 . The con-
ception of time within such an episode is based on a succession of images
(object-forms) in space and time (chronology), and on the redundant nature of
processing recurrent events (duration). Sensory overload of the frontal cortex


central sulcus

frontal lobe
parietal lobe

vision (V1)

occipital lobe

occipitolateral OR temporal pole

temporal lobe

Figure 7 Diagram illustrating the domain-specific covariant processing of the frontal cortex on
segregated spatial and non-spatial (object recognition) visual information (SP + OR). Stimulation of
the primary visual cortex (VI) by peripheral vision results in activation of the posterior parietal
cortex (SP) which is concerned with spatial perception (i.e. 'where'), and in the activation of the
inferior temporal cortex (OR) which is concerned with object recognition (i.e. 'what'). Distraction
of the content-context relationship (SP + OR) results in the inability to order processing stages;
time evolution ceases and spatial boundaries disappear. (Modified from ref. 55)

(hyperfrontality) as induced by psychedelic drugs leads to destruction of the

covariation, resulting in the inability to order processing stages: 'Time evolution
ceases and spatial boundaries disappear. An infinity of envisioned covariations
characterizes the episode, often referred to as spiritual or mystical experience' 55 .
The concept that the frontal cortex is involved in covariant perceptual processing
is further supported by clinical and experimental studies. Human and animal
studies show that there are regional specializations in the processing of spatial (i.e.
'where') visual information and visual object recognition (i.e. 'what') in the frontal
cortex (Figure 7 ) 5 5 , 5 6 . Dissociation of the content-context relationship ('what-
where' relationship) results in a distortion of the contiguity of time (and space);
patients with frontal cortex damage fail, for example, to temporally tag the serial
position of events within an episode 55 .
The relative prominence of certain psychotic syndromes induced by the two
drugs differs considerably, as measured by the APZ or AMDP subscales.
Ketamine was more effective in inducing thought disorders, loss of ego bound-
aries and apathy. Thought disorders were concomitant with anxiety under keta-
mine, but not under psilocybin. Moreover, ketamine-induced thought disorders
(included in the psycho-organic syndrome) were negatively correlated with the
change of the frontolateral-temporal pole gradient in the left hemisphere, two
brain regions involved in cognitive functioning (Figure 6).
Psilocybin and ketamine increased metabolic gradients associated with psycho-
pathological alterations in the right brain preferentially. Interestingly, mescaline,


which interferes with the 5 - H T 2 receptor, also induces a hyperfrontal pattern

with emphasis on the right hemisphere, which is positively correlated with
mescaline-induced psychotic symptoms 57 . Nevertheless, the ketamine- and
psilocybin-induced metabolic patterns are not identical.
Correlational analysis of significantly altered metabolic gradients and psycho-
pathological measurements (AMDP) revealed, first, that psychopathological
syndromes are associated preferentially with metabolic alterations of the right
hemisphere and, second, that the same brain regions can be involved in different
psychopathological syndromes. The right hemispheric frontostriatal gradient was
the only gradient which correlated positively with schizophrenic symptoms under
both ketamine and psilocybin. This important finding underscores the key role of
the frontostriatal pathway of the limbic loop in the pathogenesis of psychotic
disorders. The fronto-occipital gradient of the right hemisphere correlates with
the schizophrenic syndrome (including hallucinations) under psilocybin, but, in
contrast, with the hallucinatory syndrome under ketamine (Figure 6).
These findings indicate that the relationship between metabolic alterations and
mental processes cannot be described as a simple one-to-one correlation, but
rather that clusters of brain regions are involved in different mental operations.
Ketamine- and psilocybin-induced metabolic hyperfrontality corroborates the
PET findings as seen in acute and drug-naive schizophrenics, but stands in
contrast to the observed hypofrontality in chronic schizophrenics. Moreover,
hyperfrontality in acute hallucinating schizophrenics tend to correlate with
positive symptoms, while negative symptoms are associated with hypo-
frontality 1 , 5 8 , 5 9 . Ho w can this hypofrontality be explained? Blockade of the
NMDA receptor-mediated fronto-striatal neurotransmission might lead to a
sensory overflow into the cortex associated with increased glutamate release.
Glutamate, which is itself toxic to neurons in excessive amounts, might then lead
to the degeneration of fronto-cortical and striatal NMDA receptor-bearing
neurons. This hypothesis is supported by the fact that chronic PCP abusers have
shown decreased frontal metabolism 60 , that treatment with PCP and MK-801
results in a selective loss of cingulate neurons in the rat 6 1 , and that chronic
schizophrenics have structural alterations, such as reduced neuronal density, in the
cingulate cortex 62 . The etiological mechanism by which NMDA receptor
dysfunction of the cortico-striatal pathways may occur in schizophrenics remains
to be elucidated.

The study of altered mental states (model psychosis) using PET allows direct
investigation of pathophysiological hypotheses for schizophrenic disorders. Cor-
relational analysis has shown that clusters of metabolic activated brain regions
relate to one or more psychopathological syndromes. These preliminary results


remain to be further explored by multivariate statistics, increased sample size, and

other hallucinogens.
The finding of hyperfrontality stresses the involvement of the fronto-cortical
pathway in the generation of psychotic symptoms. Several lines of research will
help to clarify the role of the glutamatergic, serotonergic and dopaminergic
neurotransmitter systems as a cause of the observed hyperfrontality and the role
of 5 - H T 2 and NMDA-receptors in schizophrenia, including further metabolic
PET studies using specific 5 - H T 2 and NMDA receptor agonists and antagonists,
and specific radiolabeled 5 - H T 2 , NMDA and dopamine PET ligands.

I wish to thank my collaborators Prof. Dr J. Angst, Psychiatric University
Hospital Zürich, and PD Dr K. L. Leenders, PET Unit, Paul Scherrer Institute,
Villigen, for their interest and continuous support of this study. The author is
indebted to Prof. Dr D. Vonderschmitt, Chem. Inst. University Hospital Zürich
and PD R. Brenneisen, Pharm. Inst. University Bern for biochemical analyses,
Prof. Dr C. Scharfetter, Psychiatric University Hospital, Zürich, for psychiatric
screening of volunteers, and Dr R. Mettler, Anesth. Inst. University Hospital of
Zürich, for clinical support. Thanks are also due to PD Dr S. Thompson, Brain
Res. Inst. University Zürich, for proofreading the manuscript, and to Maggie
F. I. Vollenweider MD for statistical analysis. This investigation was supported
partly by a grant from the Swiss National Science Foundation (32-28746.90).

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Arylalkanamine-induce effects
in normal volunteers: on the
significance of research in
hallucinogenic agents for

Experimentally induced psychotic states have been described by various authors
during the last century in what might be called the pre-scientific stage of
hallucinogen research. By 1880 the German psychiatrist Kowalewsky discussed a
case of atropine intoxication, and stated that psychiatry possesses a means to
'induce psychoses at will'. Experimental investigations of peyote in volunteer
subjects were reported for the first time in 1895 by Prentiss and Morgan 1 and
Kraepelin 2 published his famous monograph: 'On the experimental manipulation
of simple mental processes by drugs' in 1892. From his writings it is very clear
that Kraepelin was one of the major proponents of experimental research on
psychoactive agents. Between the turn of the century and World War II, a number
of thorough investigations on mescaline was conducted, and high methodological
standards were implemented. These studies yielded the following main results.
Firstly, the reaction to a given drug by a single person on repetitive administration
can vary depending upon set and setting 3 . Secondly, psychopathological effects
were described in unsurpassed detail by Beringer 4 , who also introduced the term
'artificial model of psychosis'. A third result was that the advantages of
investigating experimentally induced psychotic states were clearly delineated.
Such states could be provoked in normal control subjects, who could be tested


before, during, and after intake of the agent, intra-individual comparisons could
be made. Fourthly, it became evident that in experimentally induced psychosis,
primary pathological mechanisms could be more readily discerned from secon-
dary reactions to, and coping mechanisms with, such pathology. Compared to the
use of samples of patients, the experimental approach was shown to lead to a
much greater homogeneity of data, and hence to more precise comparisons.
Fifthly, like Kraepelin before him, Beringer hoped to find access to the structure
of personality by means of psychoactive drugs. This aim, however, was not
achieved. Finally, it was shown that hallucinations produced by mescaline could
be distinguished from those due to endogenous psychoses 5 .
These findings set the stage for the further investigations, discussions and
controversies that characterized the period from the mid 1940s to the present. In
the 1950s and 1960s, hallucinogens were used widely to produce the changes of
perception, thought and mood, which were thought to resemble schizophrenia to
some extent. 6 Research in experimental psychoses, however, came to an abrupt
end in 1966, when the use of hallucinogenic substances was severely restricted by
law. Hence, in the last 25 years we have witnessed a tremendous increase in the
number and versatility of methodological tools for psychiatric research, whereas
the subject of psychiatric inquiry regarding psychosis was restricted to spontane-
ously occurring (endogenous) psychotic states. The aim of the present chapter is
to review some of our experimental findings on the important class of the
arylalkanamines (e.g. mescaline and 3,4-methylenedioxyethylamphetamine
(MDE)) using psychological and biological assessment strategies.


Notwithstanding the differences between endogenous and drug-induced psychotic

states, the similarities between substance-induced schizophrenic-like states and
(endogenous) schizophrenia quite possibly point to similar pathogenetic
pathways. In line with the vulnerability model of Zubin and Spring, 7 we
assume that various etiological factors contribute to a psychotic state. Hence, we
believe that it makes sense to use findings and research strategies that are
currently used for the investigation of schizophrenia in order to study
experimental psychoses. Furthermore, we consider that one way of validating
modern concepts in schizophrenia research (e.g. 'hypofrontality', 'laterality',
'vulnerability', 'limbic-system involvement', etc.) is to look for parameters
indicative of these concepts in experimentally induced psychotic states, using
psychoactive substances.
In this discussion, we focus on a few major issues: brain imaging techniques,
sleep electroencephalography and the different psychological effects of psycho-
active agents.



Mescaline study
In an open study, 12 carefully selected, physically and mentally healthy, right-
handed male volunteers received 0.5 g mescaline sulfate 8. All subjects were
examined by two experienced raters using, among other instruments, the Brief
Psychiatric Rating Scale (BPRS) 9 and the questionnaire 'APZ' for the assessment
of'altered states of consciousness' (ASC) with its dimensions of'oceanic bound-
lessness' (OSE), dread of ego dissolution (AIA), and visionary restructuralization
(VUS) 10 .
Regional cerebral bloodflow (rCBF) was assessed by single photon emission
computed tomography (SPECT) using the non-stable radioactive isotope of
techetium ( 9 9 m Tc) coupled to an organic molecule, which is taken up by active
sites of the brain ( 99m Tc-hexamethylpropyleneamineoxime; HMPAO as tracer
substance), 4½ h after mescaline intake. For final evaluation, 18 regions of interest
(ROIs) were drawn semi-automatically in each hemisphere on four adjacent
22-mm thick cross sections (Figure 1), according to Musalek and colleagues 11

SF 1 SF 2




Figure 1 Position of four transversal SPECT slices, each 22 mm thick. Slices 1-4 start, respectively
at 82, 60, 38 and 16 mm above the canthomeatal line. SF1-3, gyrus frontalis superior; C l - 2 , central
region; SP, sup. parietale region; MF, gyrus frontalis medialis; IP, inf. parietale region; SO, sup.
occipital region; IF, gyrus frontalis inferior; ST, sup. temporal region; IO, inf. occipital region; BG,
ant. basal ganglia; TH, thalamus; FB, frontobasal region; IT, inf. temporal region; HI, hippocampus;
CB, cerebellum


Table 1 Brief Psychiatric Rating Scale (BPRS) ratings (mean ± SD) before and after mescaline
intake in 12 male volunteers. Results of Friedman rank ANOVAs comparing t 0 to t 3 (df = 3)

Time before and after intake (min)

-60 30 90 210 x2

Total score 19.6 ± 1.4 27.0 ± 6.0 32.1 ± 9.3 33.5 ± 10.2 20.3 0.0001
Anergia 4.3 ± 0.7 5.3 ± 1.4 6.5 ± 3.1 6.1 ± 1.4 8.65 0.034
Anxiety and depression 4.8 ± 1.0 8.5 ± 2.4 7.5 ± 3.3 6.5 ± 2.6 9.47 0.023
Thought disorder 4.14 ± 0.3 4.68 ± 1.0 7.4 ± 4.7 10.1 ± 5.6 20.47 0.0001
Activation 3.4 ± 0.7 5.1 ± 2.1 6.9 ± 3.1 6.8 ± 3.2 12.92 0.004
Hostility 3.0 ± 0.0 3.5 ± 1.0 3.7 ± 0.8 4.0 ± 1.4 3.87 0.275

and Podreka and co-workers 12 . For evaluation of relative regional cerebral blood
flow (rCBF) distribution in the brain, a regional index (RI: ratio between
counts/voxel of one ROI and mean counts/voxel of all ROIs) was calculated.
SPECT scans produced under mescaline were then compared intra-individually
with SPECT scans of the same subjects under control conditions, which had been
obtained 14 days prior to the study.
Ingestion of 0.5 g mescaline resulted in psychotomimetic effects: the BPRS total
score (Table 1) changed significantly during the experiment (from 30 min before,
to 210 min after drug intake; measured by Friedman rank ANOVA, df = 3;
X 2 = 20.3, p < 0.001) with the most prominent increase in the subscales of
thought disorder (p = 0.0001) and of activation (p = 0.004). Furthermore,
significant changes were found in the subscales of anergia (p = 0.034) and of
anxiety/depression (p = 0.023). Data from the APZ questionnaire are discussed
Neurometabolic data are shown in Figure 2, and the results of a statistical
analysis are presented in Table 2. The significant interaction anterior-posterior x
left-right effect points to different rCBF indices in anterior vs. posterior cortical
regions. As illustrated in Figure 3, rCBF is more pronounced in right anterior
cortical regions, as opposed to higher rCBF in the left posterior cortical regions.
This effect is independent of ingestion of mescaline. The significant interaction of
mescaline x anterior-posterior shows that there is an increased HMPAO uptake
under mescaline in the frontal cortical regions, whereas posterior cortical regions
show a reduction of HMPAO uptake. The significant 3-way interaction of
mescaline X anterior-posterior X left-right effects reveals that in anterior cortical
regions HMPAO uptake is more pronounced in the right hemisphere, while there
is no difference in posterior cortical regions. In cortical and limbic regions there
are tendencies toward higher HMPAO uptake in the right hemisphere, which are
also independent of mescaline intake.


Figure 2 9 9 m Tc-HMPAO uptake in 36 single cortical and limbic regions of interest (ROIs); data
show differences between 'with' and 'without' mescaline values (n = 11 male volunteers; the data
of one volunteer was lost due to technical reasons). Abbreviations are as follows: cortical (frontal):
superior-frontal (SF 1-3); central (C 1-2); medio-frontal (MF); inferior-frontal (IF); fronto-basal
(FB); cortical (posterior): superior/inferior parietal (SP, IP); superior/inferior temporal (ST, IT);
superior/inferior (SO, IO); limbic: basal ganglia (BG), thalamus (TH); hippocampus (HI) and
cerebellum (CB)

Table 2 Cortical and limbic regional cerebral bloodflow (rCBF) patterns with and
without mescaline (n = 11; data of one volunteer was lost due to technical reasons)

F (1, 10) P

Cortical region effects

left-right 3.98 0.074
anterior 7.19 0.023*
mescaline X anterior-posterior 5.25 0.045*
mescaline x anterior-posterior X left-right 5.27 0.045*
Limbic region effects
right-left 4.34 0.064

*p < 0.05

MDE study
According to anecdotal evidence, 3,4-methylenedioxymethylamphetamine
(MDMA, known also as 'ecstasy', 'Adam', 'XTC') and 3,4-methylenedioxy-
ethylamphetamine (MDE, or 'Eve') exert a unique psychological effect on
humans, distinguishing them from classical hallucinogenic substances 1 3 , 1 4 .
MDMA was reported to possess antidepressant and anxiolytic properties, and for


10 5 105

100 100
left hemisphere
right hemisphere
95 95
Mean combined Rl

90 90

85 85

80 80
(a) frontal cortical posterior cortical limbic (b) frontal cortical posterior cortical limbic

Figure 3 9 9 m Tc-HMPAO uptake in cortical and limbic regions of interest (ROIs) (a) with and
(b) without mescaline. 'Combined RI' (x-axis) indicates the mean of ratios between counts/voxel of
combined ROIs and the mean counts/voxel of all ROIs

this reason has been used as an adjunct in insight-oriented psychotherapy 1 5 , 1 6 .

However, the psychological effects of these substances have not been demon-
strated using reliable, controlled scientific methodology. The data on psychologi-
cal effects of MDMA and MDE are limited. Although there are some reports of
panic reactions and 'bizarre and risky behavior' 17 during the peak of intoxication
with the drug, MDMA and MDE enjoy a reputation for producing a well
controlled emotional, peaceful experience with enhanced insight, empathy and
closeness to others, with only rare occasions of severe toxicity.
Nichols hypothesized that MDMA and MDE might belong to a novel pharma-
cological class, which he termed 'entactogenes' to indicate the particular nature of
their subjective effects as 'a touching within' 1 8 .
In order to further pursue the question of the specificity of the effects of these
drugs, we carried out two randomized, double-blind, placebo-controlled studies
on the effects of M D E 1 9 - 2 1 . The first study focused on neuroendocrine and
cardiovascular effects; the second evaluated the effects on sleep parameters.
Eight carefully screened physically and mentally healthy male volunteers took
140 mg MDE (2-3 mg/kg bodyweight), a dose commonly taken for recreational
and therapeutic use, or placebo. Among other inventories, the State Anxiety Scale
(STAI-X 1 ) and the Manic-State Rating Scale (MSRS) 22 were used for assessment.
With respect to the APZ questionnaire 10 , data from this study were pooled with
the second study on the effects of MDE on sleep parameters in six healthy




MSRS score


0 1 2 3 4

Figure 4 Ratings using the Manic-State Rating Scale (MSRS) for subjects under the influence of
MDE or placebo; **, p = 0.005

Table 3 APZ-scores (mean ± SD) under mescaline (n = 12), as evaluated some

days after drug intake, compared to 3,4-methylendioxyethylamphetamine
(MDE) and placebo. OSE, oceanic boundlessness; AIA, dread of ego-dissolution;
VUS, visionary restructuralization

Dimension Mescaline (n = 12) MDE (n = 14) Placebo (n = 14)

OSE 6.16 ± 3.63 3.92 ± 2.97 0.14 ± 0.36

AIA 7.08 ± 4.03 2.57 ± 3.08 0.07 ± 0.26
VUS 7.41 ± 3.65 1.64 ± 1.86 0.00 ± 0.00

In the Manic-State Rating Scale, a significant difference between MDE and

placebo was found 2 h after MDE intake (Figure 4).
In the State Anxiety Inventory, no significant differences between MDE and
placebo were found. The analysis of individual state anxiety scores, however,
showed a decrease of anxiety in seven of the eight subjects. One subject (No. 8),
however, displaced a marked increase of anxiety under MDE (Figure 5). As can
be seen from Table 3, MDE produced highly significant differences compared to




STAI-X1 score





-1 2 5 24 168
(a) baseline Time (h)



STA1-X1 score




-1 2 5 24 168
(b) baseline Time (h)

Figure 5 Time course of state anxiety as rated with the STAI-X 1 scale in (a) eight subjects under
MDE, and (b) eight subjects under placebo





APZ dimensions

Figure 6 Dimensions of the APZ questionnaire under mescaline and MDE (means ± SEM;
see Table 3); OSE, oceanic boundlessness; AIA, dread of ego-dissolution; VUS, visionary

placebo in all three APZ subscales. A comparison between the APZ-data on

subjective drug experience under both drugs, mescaline and MDE, revealed
highly significant differences between the two agents in the dimensions AIA
(df = 20; p = 0.005) and VUS (df = 15; p < 0.0001), whereas the difference in
the APZ-dimension OSE was not statistically significant (Figure 6).
It is worth mentioning that in the sleep study, MDE caused a clear-cut
deterioration of sleep parameters. After normal sleep onset latency and a sleep
duration of 30-90 min, all subjects awoke and stayed awake for at least 150 min.
Compared to placebo, there was a tendency towards an increased amount of slow
wave sleep under MDE. Rapid eye movement (REM) sleep was totally suppressed
under MDE.



From the clinical point of view, hallucinogen-induced effects can be rather similar
to 'endogenous' psychoses, in some respects. However, the question as to whether
phenomenological similarities represent similar underlying causal mechanisms is
still unsolved.
As evident from the BPRS-data, mescaline produced an acute psychotomimetic
state. The APZ questionnaire showed that the psychotic effects were mainly
concerned with the dissolution of ego-boundaries, visual hallucinations and
dimensions of 'oceanic boundlessness', often mixed with anxious passivity
experiences. Compared to results from a study on MDE, mescaline produced
significantly more pronounced effects than MDE. Whereas this general effect
could be due to the particular doses used in these studies, the differential scores of
the two substances in the three APZ scales reveal genuine differences in the
psychological effects of the substances. In particular, mescaline is comparatively
more effective in producing visual changes than MDE. It also induces more
anxiety and passivity experiences.
Functional brain imaging using 9 9 m Tc-HMPAO SPECT showed an increase of
regional cerebral blood flow under mescaline in both anterior regions, as well as
an even more pronounced increase in brain metabolism in the right anterior
cortical regions. Hence, mescaline seems to produce a 'hyperfrontal' pattern with
an emphasis on the right hemisphere, which correlated with mescaline-induced
psychopathology. No statistically significant influence of mescaline intake on the
subcortical (limbic) system was found.
Our brain imaging data seem to conflict with results from other g r o u p s 2 3 , 2 4 ,
who found 'hypofrontal' patterns in endogenous schizophrenia. However, more
recent results from other imaging studies question the generality of the inter-
pretation of psychotic states as being associated with hypofrontality2 5 - 2 7. In
particular, acute endogenous psychosis has been associated with a hyperfrontal
cortical activation pattern. Moreover, a study using positron emission tomography
in ketamine- and psilocybin-induced psychotic states also showed a hyperfrontal
activation pattern .
The hitherto anecdotally reported powerful antidepressant and anxiolytic
properties of MDE seem to be different from the effects of standard antidepressant
and anxiolytic agents. According to our data, MDE produced a decrease in
anxiety and an increase of euphoric and depressed moods with an augmented
drive being present at the same time. This seemingly paradoxical finding of both
emotional states, a manic-like temper and depressed mood, may be regarded as
the result of a general increase of responsiveness to emotions. Under the influence
of MDE, these states were experienced in a calm and relaxed manner, almost
without accompanying anxiety. Furthermore, the fact that MDE does not lead to
a marked reduction of general sensitivity and cognitive functioning, may add to


the emotional responsiveness of the subjects. Our sleep data on MDE demonstrate
that this substance possesses similar effects to d-amphetamine.
The comparison between the psychological effects of MDE and the 'classic'
hallucinogen mescaline reveals similarities as well as differences: whereas both
agents lead to a positively experienced loss of ego boundaries, mescaline produces
more accompanying anxiety and, in particular, leads to much more pronounced
effects on the visual system.
From a general point of view, these studies have methodological and systematic
implications for research in experimental and endogenous psychoses. With respect
to methodology, it is important to bear in mind that the effects of hallucinogens
are highly dependent on the setting in which they are taken. In our studies the
technical, scientific setting interrupted the experience of the subjective drug
effects several times and prevented further elaborations of psychotic contents.
Possibly because of this, the subjective experiences become less pronounced the
more technically sophisticated the study design. Our subjects, for example,
reported the peak of their subjective reactions to mescaline during the SPECT
investigation which, contrary to psychopathological and neuropsychological
testing, required confinement to a horizontal posture without body movements.
With respect to the functional brain imaging method, it was important that in
the present study, relative rCBF patterns were measured intra-individually. A
subject thus serves as his own control, minimizing the variability of the data. Such
an approach might ultimately help to shed some light on the relationship between
objective, 'functional' brain images and subjective experience.
From a systematic point of view, research has to go beyond such diagnostic
categories as 'organic' and/or 'endogenous', especially if we take into account the
vulnerability model of psychoses.
In conclusion, the study of psychoactive substances under controlled laboratory
conditions represents a research strategy which merits further inquiry for several
reasons. Firstly, as a methodological tool, experimental psychosis can be studied
with a broad array of psychological as well as biological techniques. Secondly,
from a systematic perspective, the study of the effects of psychoactive substances
enhances our general understanding of psychiatric phenomena - from subtle
subjective psychopathological experiences to the underlying biological brain
mechanisms - and even allows correlational analyses, bridging the 'gap' between
the mental and the physical. Finally, from the point of view of public health, it is
of the utmost importance for society to have access to valid knowledge about the
effects of substances which are widely used by the general public.

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Psychological aspects of
altered states of consciousness
of the LSD type:
measurement of their basic
dimensions and prediction of
individual differences


This chapter attempts to summarize research performed or co-ordinated by us

concerning two basic questions on altered states of consciousness (ASCs). These
questions were first put forward nearly 150 years ago - an important starting
point of experimental studies in this field; in 1845 the French psychiatrist J.
Moreau de Tours 1 postulated (after having described his studies on hashish,
nitrous oxide, various narcotics and hypnagogic phenomena) that ASCs have a
common denominator, independent of their means of induction. Our first
question is whether or not this hypothesis can be corroborated using current
scientific methods.
In his experiments with hashish, Moreau found that his subjects reacted, at least
in intensity, quite differently to identical dosages. It seemed to him that
individuals with a 'bilieux-sanguin' temperament are 'les plus impressionables'
(Moreau de Tours 1 , p. 8). This leads to our second question, that asks which
variables predict these individual reaction differences, a topic of differential


General characteristics of ASCs

A major problem in testing the above hypotheses is that ASCs are not yet
operationally defined to a sufficient degree. Several definitions exist (e.g. by
Ludwig 2 ). At present, it seems useful to define these non-ordinary waking states,
in spite of conceptual pitfalls, in the following way:
(1) ASCs represent a sufficient deviation in subjective experience or psychologi-
cal functioning of a normal individual from her/his usual waking
(2) This deviation represents not only changes in mood or motor activity but
also an unusual experience of oneself and the surroundings; i.e. a more or less
'separate reality' in time and space.
(3) ASCs normally last only a few hours, as compared to psychiatric diseases.
(4) ASCs are self-induced, that is to say usually induced voluntarily, or may
occur in the 'normal way of life'. They are not the result of illness or adverse
social circumstances.
(5) ASCs are considered as being 'irrational', 'abnormal', 'exotic' or even 'patho-
logical' by the social norms of the mainstream of western society 3 .

ASC-inducing agents
There are various means of inducing ASCs. The most important ones can be
grouped into four types. Firstly, there are hallucinogens of the first order, a
prototype being LSD. Other compounds of this category are mescaline,
psilocybin, N,N-dimethyltryptamine (DMT) and also Δ9 -trans-tetrahydro-
cannabinol (THC) (cf. Leuner ). Hallucinogens of the second order produce a
stronger 'clouding of consciousness' and fewer scenic hallucinations or pseudo-
hallucinations. This category includes substances like scopolamine, nitrous oxide,
ketamine or muscimole. In the third category is the reduction of environmental
stimulation or contact in the broadest sense, which includes sensory deprivation,
some types of hypnosis, and autohypnotic techniques such as autogenic training
or meditation techniques. Similar conditions occur while falling asleep or awaken-
ing, when hypnagogic or hypnopompic phenomena appear. The fourth type of
ASC inducer is increased environmental stimulation or contact (sensory bom-
bardment) of which there are basically two different kinds: one consists of an
intense rhythmic stimulation of different sense organs, and the second is sensory
bombardment with extremely variable stimuli.
Further agents for the induction of ASCs, that do not fit in the above scheme,
are, for example, hyperventilation, sleep deprivation or combinations of different




Moreau's hypothesis of the common denominator of ASCs has, in the interim,

been accepted by several researchers studying ASCs and has been developed in
greater detail (e.g. by Ludwig 2 ). Based on this preliminary theoretical work we
have tried to formulate this hypothesis in such a way that it can be tested
empirically, according to viewpoints put forward by the critical rationalism 5,6 .
ASCs have, irrespective of their mode of induction, invariant features in
common, which simultaneously differentiate them from normal waking
consciousness. These etiology-independent characteristics form a structure of
mutual similarities which is maintained when ASCs are induced by different
means. On the dimensional level, (i.e. the methodological adoption of a similar
approach to that of dimensional theories of personality - e.g. Eysenck and
Eysenck 7 or Cattell 8 ) this means that ASCs have certain major dimensions in
common, irrespective of their induction means and intensity. This does not
exclude, of course, that etiology-specific dimensions exist, perhaps such as a
'clouding of consciousness', for hallucinogens of the second order.

Experimental studies

After pilot studies 9 , the above hypothesis on the common denominator was
tested, first in a series of 11 experiments with different induction means on 393
healthy volunteers, including control groups 1 0 . The experimental conditions are
summarized in Table 1.
The APZ questionnaire was used as the dependent variable 11 . It consists of 158
items presented in the first person singular, the response to which is either 'yes'
or 'no'. The items are a condensation of ~800 items formulated on the basis of
previously existing questionnaires on ASCs, free reports, psychiatric rating scales
and the author's personal experiences with ASCs. The APZ questionnaire was
given directly before and after an experiment to assess ASCs retrospectively.


The hypothesis stated above was tested using the experimental data as follows 10 .
Those items of the APZ were identified which at the same time occur (lower 95%
confidence limit >1%) in each of the four main groups of ASC-inducing agents,
and also significantly differentiate ASCs (p < 0.05: comparisons with control
groups and pre-experimental level) from the normal waking consciousness. A
total of 72 items were found that fulfilled both criteria (see below).


Table 1 Conditions of experimental studies

Pharmacological agents 120

Hallucinogens I. order:
(1) N,N-dimethyltryptamine (DMT) 26
(2) N,N-dimethyltryptamine (DMT) 15
(3) psilocybin 14
(4) Δ 9 -trans-tetrahydrocannabinol (THC) 18
(5) Δ9-trans-tetrahydrocannabinol (THC) 9
Hallucinogens II. order:
(6) nitrous oxide 38

Psychological agents 139

Sensory deprivation in a broader sense:

(7) perceptual deprivation
(8) hypnagogic states
(9) autogenic training
(10) hypnosis
Sensory overload:
(11) stimuli of high variety 60

Control groups 134

(12) placebo to (1) 12

(13) placebo to (2)
(14) placebo to (3)
(15) placebo to (4)
(16) control to (11) 39
(17) lecture on ASC 58

The correlation matrices of these 72 variables were computed for each of the
four main types of ASC-inducing agents. The statistical significance of the
similarity of the correlation matrices (six comparisons) was tested by four
different algorithms. Of a total of 24 comparisons, only one was not statistically
significant (p < 0.05). Thus the hypothesis was corroborated; that etiology-
independent characteristics of ASCs form a structure of mutual similarities which
is maintained when ASCs are induced by different means.
Analyses on the dimensional level, using factor analyses, cluster analyses and
multidimensional scaling, identified three primary and one secondary etiology-
independent dimension. These were subsequently used as the basis for the
construction of scales according to the classical theory of mental testing (see


International Study on Altered States of Consciousness (ISASC)

The main objects of the ISASC 12 were to test the external validity of the
experimental results in the field, to determine the level of their 'intercultural'
consistency, and to construct psychometrically equivalent scales in several
languages. The ISASC was carried out on a total of 1133 subjects in the following
six countries: German-speaking Switzerland (n = 184), Federal Republic of
Germany (n = 193), Great Britain (n = 175), Italy and Italian-speaking Switzer-
land (n = 185), Portugal (n = 164) and the United States (n = 232). Subjects were
asked whether or not they had experienced an ASC within the past 12 months.
They were invited to complete (anonymously) a questionnaire on general infor-
mation, as well as the APZ, on their most recent ASC.
In 499 (44.0%) of the cases the ASC was induced by hashish or marijuana. A
total of 96 (8.5%) reported LSD to be the induction method, whilst meditation
(n = 86; 7.6%) and hypnagogic states (n = 63; 5.6%) were the two most
frequently mentioned psychological ASC-inducing agents. The hypotheses of the
ISASC can be tested by any kind of sample, so no effort was made to gather
representative samples.

Results of the ISASC

To test the main hypotheses of the ISASC, the similarities of the seven correlation
matrices (experiments, six countries) of the 72 etiology-independent items (as
well as between ASCs and normal waking consciousness-differentiating items)
were first tested for statistical significance. All of the 21 comparisons were
statistically significant (p < 0.05). The comparison of the three-factor solutions of
the seven data-sets was performed by two different algorithms. Of the 42
comparisons, only one was not statistically significant.
Results of the scale constructions in comparison to those of the experimental
studies are described below.
In general, the results of the ISASC correspond well with those of the previous
experiments, in that the hypotheses of the ISASC were corrobated to a sufficient
degree. The external validity of the experiments was demonstrated in spite of
important differences between the two studies.


The 72 items which proved to be etiology-independent, and also differentiating
between ASCs and the normal waking state, comprise the secondary scale:
'Veränderter Wachbewusstseinszustand' (VWB) 'Altered State of Consciousness'
(ASC) - i.e. all items in Tables 2 to 5. It refers to alterations in thinking, a changed


Table 2 The APZ dimension of 'Ozeanische Selbstentgrenzung (OSE)' ('oceanic boundlessness';

Ni = 13)

Number in APZ Item

1 I had the feeling everything around me was somehow unreal

7 I felt as though I were floating
13 The boundary between myself and my surroundings seemed to blur
16 I felt totally free and released from all responsibilities
31 I had the feeling that I had been transferred to another world
34 It seemed to me that there were no more conflicts and contradictions in the
68 It seemed to me as though I did not have a body any more
84 I felt very happy and content for no outward reason
92 I could have sat for hours looking at something
95 I was completely indifferent toward everything
127 I experienced past, present and future as a oneness
129 It seemed to me that my environment and I were one
147 It seemed to me that I was dreaming

sense of time, a feeling of loss of control, intense emotions, body-image changes,

an altered visual perception including, (pseudo)-hallucinations, visions, illusions
or synesthesias and a change in the meaning of various percepts.
The three primary scales, which are positively correlated, are parts of the
secondary scale. The first subscale is designated as 'Ozeanische Selbstentgren-
zung' (OSE) ('oceanic boundlessness'). The scale contains 13 items (Table 2) and
describes a state similar to mystical experiences, according to the scientific
literature in this subject. The second subscale: 'Angstvolle Ichauflösung (AIA)
('dread of ego dissolution') is operationally defined by 22 items (Table 3) which
indicate a very unpleasant state, similar to what is called a 'bad trip' by drug-users.
The third primary scale is termed 'Visionäre Umstrukturierung (VUS) ('visionary
restructuralization') and includes the 14 items shown in Table 4. It includes items
on visual (pseudo)-hallucinations or visions, illusions and synesthesias. Other
items indicate a change in the significance of objects. Table 5 shows the 23 items
that belong only to the secondary scale and not to OSE, AIA or VUS.
With reference to Huxley 1 3 , it could be said that the three primary etiology-
independent aspects of ASCs correspond to 'heaven', 'hell' and 'visions'.
The correlations between the APZ scales are shown in Table 6. In the
experimental studies, medium to high positive correlations between OSE, AIA
and VUS were found. The results of the ISASC are similar except for OSE and
AIA whose correlation is lower in these studies. The reliabilities of the APZ scales
(internal consistency, formula KR 8) are shown in Table 7. The reliabilities are
sufficient for most purposes. In the ISASC the reliability for OSE is lower than in
the experimental studies but satisfactory, nevertheless. The validity of the APZ


Table 3 The APZ dimension of 'Angstvolle Ichauflösung (AIA)' ('dread of ego dissolution';
N i = 22)

Number in APZ Item

9 I had difficulty in distinguishing important from unimportant things

32 My thinking was constantly being interrupted by insignificant thoughts
40 My own feelings seemed strange to me, as though they did not belong to
44 I felt tormented without knowing exactly why
55 I felt like a robot
56 My surroundings seemed peculiarly strange to me
64 I felt threatened without realizing by what
66 I had the feeling that I no longer had a will of my own
71 I was afraid without being able to say exactly why
83 I felt like a marionette
91 Everything around me was happening so fast that I could no longer follow
what was really going on
105 I stayed frozen in a very unnatural position for quite a long time
107 I had difficulty making even the smallest decision
110 I felt as though I were paralyzed
131 Things around me appeared distorted to me
133 Time passed more slowly than usual
136 I was not able to complete a thought; my thoughts repeatedly became
141 I felt isolated from everything and everyone
148 It seemed to me that I no longer had any feelings
156 It seemed to me as though there was an invisible wall between me and my
157 I observed myself as though I were a stranger
158 I felt a total emptiness in my head

scales was assessed in the experimental studies by various means. In six of the
studies a control group was used; i.e. in four experiments with hallucinogens a
placebo group was included, and in two experiments with sensory overload the
non-manipulated original film and sound material was used as a control.
Statistically significant differences between experimental and control groups
were found for OSE and AIA in four of the six comparisons; for VUS in three out
of six and for VWB in all six comparisons.
Thus these studies show that the APZ scales differentiate well between the
normal waking consciousness and ASCs. As the type of differences found
depends on the ASC-inducing agent it may be concluded that the scales are not
redundant, despite high correlations between them. Later researchers 1 4 , 1 5 found
similar results.


Table 4 'Visionäre Umstrukturierung (VUS)' ('visionary restructuralization'; N i = 14)

Number in APZ Item

14 So many thoughts and feelings assailed me at once that I become confused

29 I saw lights or flashes of light in total darkness or with closed eyes
33 I saw scenes rolling by like in a film in total darkness or with my eyes
42 Objects around me engaged me emotionally much more than usual
43 Things around me appeared to be bigger than usual
51 Things around me had a new, strange meaning for me
70 I saw colors before me in total darkness or with closed-eyes
80 I saw things that I knew were not real
100 I saw regular patterns in complete darkness or with closed eyes
119 Something occurred to me and I did not know whether I had dreamt or
actually experienced it
120 I saw strange things, which I now know were not real
128 Everyday things gained a special meaning for me
134 Sounds seemed to influence what I saw
138 The colors of the things I saw were changed by sounds and noises

As a further study on validity, narrative reports of ASC experiences were

compared to the corresponding APZ scores. Fifty reports, from a total of 167 of
our experiments, were randomly selected and a content analysis was performed
by three independent raters concerning OSE, AIA and VUS, who were blind to
the APZ scores in the experiments. The inter-rater reliability was high. The rank
correlation values Rho between content analyses and the actual APZ scores were
0.62 for OSE, 0.45 for AIA and 0.55 for VUS, indicating a good agreement.
An analysis of the literature shows that the scores of most performance tests are
decreased when the subjects are under the influence of an hallucinogenic drug. In
experiment 4, with T H C (n - 30) and experiment 1 with DMT (n = 38), the
subjects were tested before the experiment and at the average maximum effect of
the drug with two tests of verbal fluency, a shortened version of the 'work curve',
a test of persistence, and two tests of concentration and memory. Of the 40
correlations (five tests, four APZ scales and two studies) between a decrease in
performance and the four APZ scales, 31 (78%) were statistically significant
(Rho = -0.39, SD - 0.17, range = 0.00--0.64), all of them having at least a
medium effect size.
To test the discriminant validity of the APZ scales, i.e. to assess what they do
not measure, two studies were performed. In all experimental studies on the 393
subjects, a personality test assessing the dimensions E (extroversion), N
(neuroticism), P (psychoticism) and O ('Offenheit', a 'lie'-scale) was given at the
beginning of each study. As the APZ is designed to assess specific states and not


Table 5 Additional items of the APZ secondary scale: 'Veränderter Wachbewusstseinszustand

(VWB)' ('altered state of consciousness'; N i = 23)

Number in APZ hem

2 Sounds and noises sounded different than usual

3 Time passed faster than usual
6 I simply could not get rid of some unimportant thought
11 I became conscious of another 'I' being hidden behind my usual T
19 The ground I was standing on seemed to be swaying
20 My ears were buzzing
22 I could not remember what had happened 2 h earlier
24 I had the vague feeling that something important would happen to me
28 Parts of my body seemed no longer to belong to me
39 I had the feeling my limbs were larger than usual
41 I was convinced that I had experienced the same situation before
57 Things around me had a different smell than usual
58 I was tired and exhausted but at the same time wide awake
63 It seemed that I had once dreamt what I was experiencing
65 I perceived peculiar relationships between widely diverging matters
87 I had trouble distinguishing between what I imagined and what I really
113 I no longer knew where I actually was
122 I had the feeling I could think faster or more clearly than usual
132 So many thoughts came to my mind that I was no longer able to organize
them properly
137 I was too wide awake and too sensitive
139 I had the impression that everything occurring around me was related to
146 I had the feeling that I could no longer control the movements of my body
152 I felt influenced by electric currents, rays, or hypnosis

personality traits, low correlations were predicted. The average correlation is

Rho = 0.07 (SD = 0.05, range 0.02--0.19). The highest correlations were found
between AIA and P (Rho = 0.19) and AIA and N (Rho - 0.19). Thus, our
prediction was corroborated. Furthermore, to test the hypothesis that the APZ
measures specific states, and not mood changes in general, an experiment on 59
healthy subjects was performed comparing, in a double-blind study, ethyl alcohol
(0.8-1.0‰ blood alcohol), chlorpromazine (average 37.5 mg per os) and placebo.
No statistically significant difference in the APZ scores was found between the
three experimental conditions.
In summary, we may conclude that the reliability and the validity of the APZ
scales are more than satisfactory for most purposes. The four APZ scales are now
available in psychometrically equivalent forms in English (UK, USA), German,
Italian and Portuguese. Versions exist in Dutch, Finnish, French, Greek, Spanish
and Russian, but these have not yet been psychometrically tested. A translation


Table 6 Correlations (Rho) between the APZ scales OSE, oceanic

boundlessness; AIA, dread of ego dissolution; VUS, visionary
restructuralization; VWB, altered state of consciousness

Rho SD min-max

This study (n = 393)

OSE/AIA 0.60 - -

OSE/VUS 0.56 - -

AI A/VUS 0.50 - -

VWB/OSE 0.87 - -

VWB/AIA 0.83 - -

VWB/VUS 0.74 - -

ISASC* (n = 1133)
OSE/AIA 0.39 0.16 0.18-0.62
OSE/VUS 0.56 0.10 0.44-0.72
AIA/VUS 0.51 0.12 0.38-0.72
VWB/OSE 0.72 0.08 0.60-0.83
VWB/AIA 0.80 0.05 0.76-0.88
VWB/VUS 0.82 0.06 0.74-0.91

* Six countries

Table 7 Reliability of the APZ scales (r tt , formula KR 8); OSE,

oceanic boundlessness; AIA, dread of ego dissolution; VUS,
visionary restructuralization; VWB, altered state of consciousness

SD min-max

This study (n = 393)

OSE 0.88 - -

AIA 0.88 - -

VUS 0.83 - -

VWB 0.95 - -

ISASC* (n = 1133)
OSE 0.76 0.04 0.72-0.83
AIA 0.86 0.03 0.83-0.89
VUS 0.83 0.02 0.81-0.87
VWB 0.92 0.01 0.92-0.93

* Six countries


into Hindi is in progress. A psychometrically improved version of the APZ exists

in German. This questionnaire ('OAV') uses visual analog scales as a response
instead of a 'yes' or 'no'. 'APZ' and 'OAV' scores can be transformed into each
other by multiple regression equations 1 6 , 1 7 . At least in Europe, the APZ question-
naire (or its follower, 'OAV') has become the standard instrument when assessing
ASCs, which helps to integrate the international research.


LSD was not used in the experiments described. The field study ISASC comprised
only 97 subjects (8.6% of the total sample) with LSD as an ASC-inducing agent.
Our general hypothesis predicts that the basic dimensions of the LSD
experience are theoretically identical to OSE, AIA and VUS as found in the
experimental studies. In order to test this hypothesis all available data on LSD
assessed by the APZ questionnaire were combined. In addition to the 97 cases of
the ISASC, a total of eight from a further study 1 6 were used. The average age of
the 105 subjects from six countries was 24.8 (SD = 6.2) years; 76 (72%) were
male. A total of 76 (72%) of the subjects reported that the time-span between the
LSD experience and completion of the APZ questionnaire was no greater than
6 months.
Our hypothesis was tested by a confirmatory factor analysis. The invariant,
hypothetical factor matrix is defined by the allocation of the 49 salient variables
to the three factors - i.e. the items of the three scales, OSE, AIA and VUS. The
rotation of the 3-factor matrix of the LSD data to the invariant matrix gives a
highest loading in one of three factors for each item. The comparison of the
hypothetical matrix with the empirically determined highest factor loadings is
shown in Table 8.
The agreement between the theoretically predicted and the empirically deter-
mined highest factor loadings was 85.7%. The kappa coefficient (k = 0.78, 95%
confidence interval; 0.41-1.00) was statistically significant. Thus, our hypothesis
on the common denominator of ASCs was corroborated again - despite using
data from six countries and four languages.
It can be concluded safely that the basic dimensions of the LSD experience are
in good agreement with those induced by other hallucinogenic compounds and
also (which seems scientifically more interesting) by those induced by non-
pharmacological agents such as sensory deprivation or certain types of sensory


As already observed by Moreau de Tours 1 , individual reaction differences
on ASC-inducing agents are high, even when experimental conditions are


Table 8 Comparison of theoretical and empirical (LSD, highest loading) factor structures; OSE,
oceanic boundlessness, AIA, dread of ego dissolution; VUS, visionary restructuralization

Theoretical matrix

OSE AIA VUS N i (total)

Empirical matrix (LSD)

item number in APZ 7, 13, 16, 34, 68, 42, 119, 128
84, 92, 95, 127,
129, 147
Ni 12 0 3 15
item numbers in APZ 1 9, 32, 40, 44, 55,
56, 64, 66, 71, 83,
91, 105, 107, 110, 14, 43
131, 141, 148,
156, 157, 158
Ni 1 21 24
133 2
item numbers in APZ
29, 33, 51, 70, 80,
Ni 0 1 100, 120, 134, 138
N i (total) 13 22 9 49

kept constant. Such reaction differences are considered to result from what is
called 'set' and 'setting'. A thorough analysis of the literature 18 , including reports
on non-pharmacological agents, revealed less than 60 methodologically sound
studies. Self-reported ASCs are predicted in these studies by personality traits,
mood dimensions, expectations, previous experiences with ACSs or setting vari-
ables. About 30 intercorrelated variables (including age) seem to be relevant to the
prediction of individual reaction differences. As a first stage in our empirical
studies 1 8 - 2 0 , we selected psychological tests in the German language that
operationally define some of these variables. Further psychometric tests were
constructed or revised for our purpose using the data of 245 normal subjects. The
31 predictor variables finally selected were used to test the main hypotheses in
three experimental studies on normal healthy volunteers:
(1) Our 31 variables predict the individual reaction differences of an ASC
globally and for each of the three dimensions.
(2) The equations between the predictor variables and the APZ dimensions
found for one ASC-inducing agent also hold true for all other induction


Experimental studies

In order to test the above hypotheses three experimental studies, each with 45
normal, healthy subjects were performed. The experimental conditions were:

(1) Sensory deprivation of 1.5 h in a 'Samadhi-tank'; i.e. floating on a warm

magnesium sulfate solution in total darkness and silence.

(2) N,N-Dimethyltryptamine (DMT), the dosage being 0.625 mg/kg, intra-


(3) Nitrous oxide, 3 1 N2O and 2.5 1 O2 per min for 15 min using a 'continuous-
flow' apparatus.

The age of the total (135) subjects (mean ± SD) was 32.2 ± 9.5 years; range
20-70 years. A total of 55 (41%) were female. The formal educational level of our
subjects was very high (82% 'Matura' (Swiss subjects) or 'Abitur' (German
In each of the three experiments the schedule was identical, involving first, tests
of the prediction variables; second, application of the experimental conditions;
and, third, retrospective assessment of the ASCs.


To test the above hypotheses, multivariate statistical procedures were used;

beginning with a factor analysis with Varimax rotation, extracting nine factors
(eigenvalues >1). The (orthogonal) factor scores were computed for each subject
in the nine factors. They were used as the predictor variables in multiple regres-
sion equations, the dependent variables being the three primary and the one
secondary scale of the questionnaire O A V 1 6 , 1 7 . Table 9 shows the multiple
regression coefficients (R) for each scale and experimental condition.

Table 9 Summary of multiple correlation coefficients (R); OSE,

oceanic boundlessness; AIA, dread of ego dissolution; VUS, visionary
restructuralization; VWB, altered state of consciousness

Experimental condition n OSE AIA VUS VWB

Sensory deprivation 45 0.72* 0.60* 0.55 0.65*

DMT 45 0.64* 0.65* 0.60* 0.67*
N2O 45 0.69* 0.42 0.60* 0.67*

* statistically significant (p < 0.05) with large effect size


All multiple R values are at least of a medium effect size. With two exceptions
(i.e. VUS in sensory deprivation (p - 0.13) and AIA in the experimental con-
dition 'N 2 O') the multiple correlation coefficients are statistically significant and
of a large-effect size. Thus, 10 out of 12 computations clearly corroborate our first
To test our second hypothesis, a cross-validation study was performed. The
multiple regression equations found for each dependent variable in one
experimental condition was used to predict the results of the other two condi-
tions. This gives, for each of the dependent variables, six comparisons between
predicted and measured values - i.e. DMT to sensory deprivation, DMT to N 2 O ,
sensory deprivation to N2O and vice versa. Of the six comparisons of the OSE
equations, five were statistically significant and at least of a medium-effect size.
The prediction of OSE under the DMT condition based on the equation found
with N 2 O was in the predicted direction but was not significant.
For AIA, our second hypothesis was refuted. Four of the comparisons were in
the predicted direction, but only one - DMT to sensory deprivation - being
statistically significant. On the other hand, the correlations between predicted and
measured values from DMT to N2O and vice versa were contrary to our
hypothesis, one even being statistically significant.
For VUS, all six comparisons were in the predicted direction. They were,
without exception, statistically significant and at least of a medium-effect size.
For the secondary scale VWB (ASC), all six correlation coefficients are in the pre-
dicted direction; five were statistically significant and at least of medium-effect size.
Summarizing, it is remarkable that our second hypothesis was more often con-
firmed when comparing sensory deprivation and DMT than when comparing the
two pharmacological agents.
It seemed appropriate to compute general regression equations for all those
experimental conditions and scales where the specific equations were sufficiently
similar. This was the case for OSE, VUS and VWB in all three conditions, while
the general equation for AIA could only be based on the sensory deprivation and
DMT data. Figure 1 shows the significant ß-weights for the computed general
On the left, in Figure 1, are listed the nine predictor variables found by factor
analysis. Each factor is operationally defined by the factor loading of our 31
measurement scores. On the right are shown the significant ß-weights for each
scale. Risking misunderstandings - only the actual equations are sufficiently
precise - our results can be summarized as follows.
Persons that tend to experience OSE during an ASC are characterized by
extroversion and an optimistic attitude towards life (mainly a trait; F3), a high
esthetic sensibility (mainly a trait; F4); non-dogmatic religiosity (mainly a trait;
F5) desactivity, i.e. calmness shortly before the ASC induction (a state; F7) and the
number of previous experiences with pharmacological or non-pharmacological


Predictor variables Scales

F1 Emotional lability

F2 Rigid conventionality

F3 Optimistic extroversion

F4 High esthetic sensibility

F5 Non-dogmatic religiosity
F6 Optimistic naivety

F7 Desactivity

F8 Previous experience

F9 Setting

Figure 1 Significant β-weights of multiple regression equations. Clear boxes = negative and
shaded boxes = positive values; OSE, oceanic boundlessness; AIA, dread of ego dissolution; VUS,
visionary restructuralization; VWB, altered state of consciousness. (See text for further explanation)

ASC-inducing agents (between state and trait; F8). The setting (F9) - as assessed
by us before the ASC induction with a semantic differential - is of no major
The likelihood of experiencing AIA increased with Fl (emotional lability, as a
trait and especially as a state) and F2 (rigid conventionality, mainly a state). Previ-
ous experiences with ASCs (F8) did not prevent the occurrence of AIA and the
setting was of minor importance.
The predictor-factors, F3, F4 and F7 for VUS were identical to those of OSE.
In contrast to OSE, the factors F5 and F8 had no major influence on the occur-
rence of VUS.
The general intensity of an ASC under identical experimental factors (i.e. dosage)
can be predicted quite well by a linear function of factors Fl, F3, F4, F5 and F7.

Concerning the topics discussed in this chapter, we perceive several main perspec-
tives for further research, as follows.
Certain types of ASCs probably have etiology-specific dimensions (e.g. a
'clouding of consciousness' or 'acoustic-hallucinatory phenomena') besides those
described. The identification and measurement of such specific dimensions might
allow a more comprehensive description of ASCs. Such studies are in progress 21 .
ASCs are defined as not being caused by illness or adverse social circumstances.
However, some psychopathological symptoms or syndromes (e.g. in schizophre-
nia or those due to solitary confinement) are similar to those of ASCs. Further
studies comparing ASCs and psychopathological phenomena with the same


self-rating scales might contribute to the understanding of some kinds of mental

illness 2 2 , 2 3 and of the effects of several adverse social circumstances 24 .
The further study of ASCs and psychopathological phenomena using an identi-
cal self-assessment procedure might lead to an empirically based classification
system of ASCs and related phenomena.
In the near future, it will be possible to analyze the complex interactions
between quantitatively assessed ASCs and important aspects of brain functioning
revealed e.g. by positron emission tomography 25 or single photon emission com-
puted tomography 1 4 .
The assessment scales developed might also be useful in further studies of the
psychology of religion, as far as ASCs are concerned 2 6 , 2 7 .
In ASC-assisted psychotherapy it has been hypothesized by several therapists
and researchers that 'peak experiences' contribute substantially to the therapeutic
outcome. This hypothesis can now be tested quantitatively using the correspond-
ing scale of 'Ozeanische Selbstentgrenzung' (OSE) (oceanic boundlessness).
In other fields of applied psychology our equations for the prediction of
individual reaction profiles might, for example, be useful for the selection of
personnel who are expected to function normally despite circumstances which
could induce ASCs.

The studies on the common denominator of ASCs were performed at the
Psychiatric University Clinic Burghölzli, Zürich, Research Department (Director:
Prof. Dr med. J. Angst). Daniel Lamparter and I conducted the research on the
prediction of individual reaction differences at his private psychiatric practice and
at the author's 'PSIN Psychologisches Institut für Beratung und Forschung',
Zürich. Several of the studies summarized here were supported by the Swiss
National Science Foundation (Grants No 1.958-079, 91.744.83, 1.612-87 and
11-25473.88) which is gratefully acknowledged. Special thanks are due to more
than 50 of my former students, as well as friends and colleagues who helped
substantially, especially Ines Bodmer, Martha Koukkou-Lehmann, Maja Maurer
and Christian Scharfetter. Finally, I thank all subjects who were willing to
experience the antipodes of everyday consciousness and to report on them.

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Hofmann, A. (eds.) Welten des Bewusstseins, Vol. 3.: Experimentelle Psychologie, Neurobiologie und
Chemie. (Berlin: Verlag für Wissenschaft und Bildung) in press
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N,N-Dimethyltryptamin und Stickoxydul. In Dittrich, A., Hofmann, A. and Leuner, H. (eds.)
Welten des Bewusstseins, Vol. 3.: Experimentelle Psychologie, Neurobiologie und Chemie. (Berlin: Verlag
für Wissenschaft und Bildung) in press
21. Schneiter, B. (1991). Akustisch-halluzinatorische Phänomene bei Gesunden: Eine experimentelle Unter-
suchung mit sensorischer Deprivation, Stickoxydul und N,N-Dimethyltryptamin. (Lizentiatsarbeit,
University of Zürich)


22. Maurer, M. (1994). Erleben in freiwillig ausgelösten aussergewöhnlichen Bewusstseinszustän-

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University of Zürich)

Section 4
Transcultural Aspects


Acid against established realities:

a transcultural and
transdisciplinary view of LSD
and related hallucinogens

The attempt to historicize LSD as a cultural icon that was prominent in the 1960s
and 1970s requires a transdisciplinary approach, which will here be literature-
based, but always with the intention of applying the methods of literary criticism
to a wider cultural topic. This broadening of perspective is necessary since the
literary events, even in America, where LSD and other drugs arguably acquired
greater cultural prominence than anywhere else1, are marginal in at least two
senses: authors writing and texts written under the influence of drugs were only
reluctantly, if at all, canonized and thus remained marginal, and such authors
tended to describe the impact of drugs on their finished texts as marginal,
emphasizing the need for control in the creation of the aesthetic product. Even
with Burroughs, for instance, the modernist ethos of artistic and social innovation
is, in a very 'classically' modernist way coupled with notions of control and objec-
tification; it may also be in this spirit that he separates the art process from the
drug experience, the latter becoming no more than one of several techniques to
transcend the barriers of convention, of automatic reaction 2 . In Bowles' autobiog-
raphy, too, the creative process is ultimately characterized by rigid control 3. Larger
claims (such as Timothy Leary's - that drug-induced experiences would take the
place of the various art forms 4) typically came from outside the arts, postulating
a type of rupture between traditional and innovative forms of expression that even
the most avant-gardist artists did not advocate.


The history so far adumbrated is ethnocentric: it applies to drug use in one

sector of highly modernized western civilization. A transcultural perspective
could be achieved by including other, and particularly more traditional, societies;
this would necessitate greater historical inclusiveness also, so as to cover the last
two hundred years or so. Obviously, this lies outside the scope of this brief essay.
What it can attempt is to say how and why we have, in this century, and particu-
larly under the spur of the excitement generated by the development of synthetic
drugs, understood drug use as a transcultural phenomenon and formed hypoth-
eses concerning possible transcultural functions of drugs. I can talk, in other
words, about the rhetoric that 'surrounds' and in a real sense makes the icon. This
is not in order to evade 'the thing itself, but in order to insist on a humanities per-
spective, according to which - particularly in these deconstructionist days - the
'thing' only constitutes itself culturally, in usage and in language. It is known only
through the forms in which it is culturally constructed.
One might begin by asking why drugs acquired such cultural significance in the
1960s and 1970s at all. In my view this was because there already existed a well-
established cultural tradition - that of aesthetic Modernism (ca. 1900/1910 - ?) -
which was searching for what one might term alternate realities: there also existed
a well-established language to express this search and its results. The basic gesture
implicit in both was an indictment of the limitations of 'normal' (conventionally
guaranteed) reality, a denial of the legitimacy of modes of perception that consti-
tute it, and a resulting desire to subvert or corrode them. The syntheticization of
drugs fell on this fertile ground, and the slang expression 'acid' must have had its
added symbolic attractiveness.
The term 'the establishment' pervasively denotes the opponent in the resulting
conflicts over sociocultural legitimation and over the proper ways of dealing with
areas of alterity such as the dream, the drug, and madness. If traditional western
civilization had, by and large, established hard solutions, policing all three areas
through marginalization and/or suppression - with the dream being designated as
not real, drugs being banned, and madness put away - aesthetic modernists,
listening well to Freud and Jung, tended to centralize the dream as an approach to
the real, to experiment with drugs, and to explore madness. As a secular move-
ment, it could not give these phenomena the full religious sanction they have in
many Native American cultures, for example, but it did at least designate them as
spiritual or spiritually relevant, and opposed them to the prevalent materialism of
'the establishment'. (Freedman 5 , quoting William James, reminds us of the coinci-
dental emergence of the modernist concern with alternate realities and the scien-
tific exploration of those outskirts of the mind where religious and drug-induced
experiences take place.)
The 1960s were heirs to this tradition and developed a specific variant of it.
Their dominant mode and mood were the same transgression of boundaries that
characterizes the twentieth century's other avant-gardist innovations, which


attempt to come to terms with the ever-accelerating process of modernization.

But the preceding decades were (in literature and other arts at least) in part also
motivated by a desire for order that made them return to older stabilities in
politics and culture. (T. S. Eliot, for instance, quite typically designated himself a
royalist and an Anglican.) In the 1960s such gestures were rare. They privilege a
revolutionary program that can be summarized thus:

By releasing and then controlling the energy flows, anonymous drives, condensations, pul-
sations, explosive semantics of the imaginary - the entire repertoire of primary process - the
revolution will have brought into the life of society what otherwise is lost, trapped, dispersed in
the unconscious: along with the fungus growth of repressed emotion, the fractious theatricality
of the factitious body. 6

LSD did not alone stand for such transgressions; there were other drugs. The most
influential drug-related anglophone writers were arguably Paul Bowles and
Carlos Castaneda, and their poisons were hashish and mescal, respectively. Also,
not even drugs were alone in representing the transgressive spirit; there were
other media and manifestations, from the Berkeley discussions of ideology, in
which Marcuse expressed his fears that our society - even then - might not permit
true difference any more, to the sexual revolution of the same time. But drugs
were taken to be symptomatic, and LSD became the cultural icon at the centre of
the discussion. In a sense it became the drug: it came to stand for the mind-
expanding capacities of drugs in general. It came to symbolize, in particular, the
irreducible ambivalence, between negation and affirmation, destruction and con-
struction, of any transgressive act or experience. This aspect becomes clear
enough in the literary evidence. Between fables of harmony like Brautigan's In
Watermelon Sugar and fables of power like the books of Castaneda, there arises an
image of alterity as danger. When Tennessee Williams called Bowles' first novel,
The Sheltering Sky of 1949, 'a mirror of what is most terrifying and cryptic within
the Sahara of moral nihilism, into which . . . man now seems to be wandering
blindly' 7 , he did not only recognize the quality that united Bowles with later
authors like Burroughs and the Beats, or like Mailer, and which made him their
well-recognized and well-resented forerunner, he also employed that same notion
of a threatening otherness that had been at the core of much modernist writing.
The search for alternate realities has traditionally been thoroughly ambivalent,
both constructive and destructive, permitted and forbidden, sacred and criminal,
and confronting the human with the abyss and the summit - the problem being
the inseparability of the two. It is always associated with a sense of crisis, which
demarcates experientially the borders between these opposed elements and their
transgression, as well as the interface between the familiar and the unfamiliar, the
known and the unknown. This is so because alterity is viewed as power-full, full
of power. The same ambivalent tremendum that modernist texts, both fictional and
poetic, attempt to recreate in what has variously been called a moment of being or


an epiphany appears when supposedly 'in the days of Early Man his whole world
was shot through with religious feeling and the unseen powers held him in thrall.
Our sacred "mushroom" must have been wondrous indeed, evoking awe and
adoration, fear, yes, even terror' 8 . Bowles can focus on the destruction, and he can
share the fascination of the Tangiers expatriate artist community with crime, with
the primitive as a fascinating realm of violence and the abominable 9 . But he can
also create perfect moments of quasi-mystical being:

The room was very quiet. I was alone in that part of the house. Suddenly the gold clock chimed
four times. As soon as the last stroke was stilled, I realized that something important was happen-
ing. I was four years old, the clock had struck four, and 'mug' meant mug. Therefore I was I, I
was there, and it was that precise moment and no other. A satisfying new experience, to be able
to say all this with certainty. . . . The following year there occurred a phenomenon similar to the
one involving the mug, but this time I was forewarned and savored the sensation voluptuously,
letting myself float in total awareness of the moment. I was at the Happy Hollow Farm. I sat on
the swing under one of the giant maples, bathing in the smells and sounds of a summer afternoon
in Massachussetts. And I let myself fall backward to hang with my head down, almost touching
the grass, and stayed that way. Then a clock in the house struck four. It began all over again. I
am I, it is now, and I am here. The swing moved a little, and I saw the green depths of maple
leaves and, farther out, the unbelievably blue sky 1 0 .

As has been indicated, the return to stable limits toward which earlier decades had
aimed does not appear possible any more in the literature of the 1960s; there is
only the attempt, after the transgression of boundaries, or the recognition that
they have become permeable, to keep them fluid, uncertain and shifting, but all the
same real. There emerges a principle of uncertainty: indeterminacy as a principle
not just of expression, but of living. The crisis becomes permanent. (One could
speculate on a relation between this development and the roughly simultaneous
widespread emergence and new prominence of intercultural literature, which
explores similar uncertainties.)
This is a state of affairs that may not truly be livable - a literary idea rather than
a prescription for living. Perhaps this is why, out of the 1960s and 1970s, came
two reactions in the general culture that were not unrelated: the attempt to isolate
and appropriate the positive aspect alone, in the manner of Bowles' 'awareness of
the moment', and a consumerist degradation reminiscent of Huxley's Brave New
World that we find already in the public reception of Bowles' A Hundred Camels in
the Courtyard (1962) - a reception that regarded the standard 'breaking down the
barriers of logic and reaching another level of consciousness' as a comparatively
simple and straightforward thing 1 1 . The spirit of the times seems to favor a coup-
ling of hedonism and anomie that leads to these reactions. A simultaneous expan-
sion and shrinkage of the real seems to have taken place in that everything has
become possible or believable, which leads to anomie, so that one begins to look
for shelter, for small enclaves of reality in which one can feel less exposed than in
the generally available reality, let alone the open field of potentiality that was the


aim of Brautigan, Castaneda, or Marcuse. Finally, there seems to occur less of a

search for alternate realities than a struggle over scarce ones. To put it somewhat
extremely: where the drug culture was characterized by a sense of plenitude, the
drug scene appears to be characterized by a sense of scarcity. This problem may
have (inadvertently) stood behind the ambivalence or vacillation between elitism
and egalitarianism in a book like The Road to Eleusis, where the privileged state is
supposed to be democratized, but remain a privilege 12 .
The connection with the modernist spirit of search has, however, been
preserved in purer form in the general academic discussion of the drug, of which
I shall, in the following, take texts like Freedman, Wasson and Schultes/Hofmann
to be representative. To analyze it is therefore at one and the same time to 'place'
this discussion historically and to fill in some of the white areas of my sketch of
this tradition in literature and the other arts.
This tradition, which has operated with a redefinition of the self as id and body,
and with a dislocation of interest from history to myth and from secularly pur-
poseful action to ritual, has attempted to include the hitherto excluded. The rhetoric
of alterity that it has thus developed is in itself once again transcultural in two
respects: it defines 'privileged' experiences as transcending the culturally or con-
ventionally given normalcies of a cultural situation, and as being or having been
available in and to all cultures - to a degree that in approaching them one may be
supposed to approach one of the sources of the human. The aspect of transcul-
turality was from the beginning inscribed (at least as a potential) in the project of
aesthetic modernism in so far as it aimed at an anthropological perspective that com-
bined an interest in the variety of the human with a profound search for its (sup-
posed) underlying essence. A statement of the type that Louis Lewin 'captured the
all-pervading significance of hallucinogens to the cultural evolution of the human
race' 1 3 indicates that specific discussions of the drug replicate the anthropological
gesture of modernism. There do exist statements that 'the psychoactive effects of
[x or y] preparations vary widely, depending on dosage, the preparation and the
type of plant used, the method of administration, personality of the user, and
social and cultural background' 1 4 , but such variation - and particularly its last-
named aspect - is rarely if ever of central interest; the aim of the discourse is 'the
human' transculturally seen:

Their [the drugs'] potential energy has covered the whole earth and established communication
between various races . . . These substances have formed a bond of union between men of oppo-
site hemispheres, the uncivilized and the civilized; . . . Here all kinds of human contrasts meet:
barbarism and civilization, with their various degrees of material possessions, social status,
knowledge, belief, age and gifts of body, mind and soul 15 .

When, for example, Grof and Grof attempt to recover original aspects of human
faculties 16, it appears that both tribal ('primitive') and ancient high cultures are
closer to the sources; the implication is that it is only or primarily modern western


civilization that has lost this 'originality', which may be recoverable 'more espe-
cially [in] the peripheral cultures, out of the main stream, where archaic forms and
beliefs survive longest: the Albanian, Frisian, Lappish, Basque, Catalonian and
Sardinian, Icelandic and Faroese, and of course the Hungarian and the Finnish' 1 7 .
In the search for the human universal or the universally human, the cultural
'Other' thus acquires prominence (cf. Jung's well-known discovery of the 'primi-
tive' in Africa). One might say that the threat of difference as a corollary of
modernization (social, economic, technological difference, which is associated
with notions of fragmentation) can be countered by the discovery of another kind
of difference (ethnic, racial) as a value, which is associated with notions of unifica-
tion. Faced with the internal complexities and complications of one's civilization,
one discovers the Other as a repository of unitary wholeness. The wish for wholes
is, however, in this act of the mind totally compatible with a recognition of the
systemic complexity of other beliefs. It is in this sense that the cultural icon 'LSD',
too, almost necessarily carries the index of 'transculturality' along, which is also
not surprising in view of the influence that the long history of ethnopharmacol-
ogy had on the development of synthetic drugs. Holmstedt 18 , for example, traces
the beginnings of ethnopharmacology, in drug-related areas, back to Moreau's
travels in the Near East in the late 1820s, and his subsequent work of the 1830s
and 1840s.
This discourse of the Other goes well with another comparative and holistic
impulse that arose from the syntheticization of hallucinogenic drugs: the search
for underlying principles that connect different drugs, for what one might call a
principle or principles of hallucinogenity. Freedman, for instance, who regards
LSD as the prototype of the then current psychoactive drugs, stresses the multi-
plicity of real and attributed effects and the importance of a search for some
underlying unity: 'Given an ample smorgasbord of effects, claims and usages, we
can eventually best gain perspective by concentrating on what - if anything - is
common to all of these varied drug effects' 19 . Also in Hofmann's personal
narrative, the connection between mushrooms as well as other natural, organic
hallucinogens (such as ergot) and LSD is given at least via his personal interests
and research procedures 20 .
The dominant focus of attention is a collective and undifferentiated totality of
human faculties, of which the psychological equivalent would appear to be the
archetype, and the generally medical one the psychosomatic (cf. the interest in
psychosomatic reactions like the trance-induced burn reported by Bowles 21 ). To
speak about it properly requires a holistic discourse - such as Wasson's 22 , for
instance, which brings together the ethnographic with the search for the archaic
and esoteric - which will almost necessarily also be transdisciplinary: it advocates,
or it constitutes itself by, a transgression of disciplinary borders 23 . One could
adduce here the recurrence of the old postulate of an original oneness of poetry
and religion 24 , and indeed of all characteristically human faculties, in a pristine


moment whose oneness becomes emblematic in synaesthesia, which is conceived

of as a pure state, or an experience of abstract pure form, and in which the world
appears as totally new 2 5 . That the recovery of 'the poetry of religion' is simultane-
ously an act of community formation, of bonding, is both part of traditional liter-
ary theory and a central experience in, for example, the report given in The Road
to Eleusis, which reads in part like the story of the rediscovery of an original
nuclear community, or of the principle of community 2 6 .
Behind all of this lies the transgression of the very rules and limits of discipli-
nary inquiry - namely of those internal discursive borders through which a
culture defines and regulates the various intellectual enterprises within it, and thus
constitutes itself as an ensemble of such enterprises. Like modernist literature, dis-
cussion of the drug encounters the problem of how to represent radical alterity,
or that which is defined as unrepresentable in the standard discourse of reality.
The solution, in both instances, is metaphor, but where literature establishes a
purely metaphorical world-in-the-text, discourses about the drug are frequently
characterized by a bidirectional permeation of the border between the literal and the
metaphorical. There occurs a metaphorization of the literal and a literalization of the
metaphorical, when, for instance, Wasson, Hofmann and Ruck report that they
'examined the common names for mushrooms in all these cultures, seeking the
fossil metaphors hiding in their etymologies, to discover what those metaphors
expressed . . , ' 2 7 .
If metaphor establishes connections that are supposed to lead one back to a
hidden original source, the question is which connections are legitimate, and
which are not. We encounter the problem already on the level of more or less pure
description, when similarities among alternate experiences are intuitively obvious
- at least to the point where typical experiences can be named, albeit only
metaphorically: 'His first mushroom experience represented dismemberment; his
second, meeting with the spirit' 2 8 - but when there does not seem to be any set
of rules on how to talk about them, where the limits of relevant similarity are.
This is obviously in part due to a real lack of verifiable knowledge about use of
drugs elsewhere and in other times: the arcanum could by definition not be
divulged, so that then and today surmise has to take the place of solid knowledge;
unavoidably, contradictions arise on which drug was used at Eleusis, or what soma
really was 2 9 . More generally, however, there appears to exist no criterion of
exclusion here - a state of affairs which violates the rules not only of science and
the academic, but of any civilization based on a division of labor.
The result is total, apparently unregulated eclecticism, of a type that one also
encounters in Burroughs' 'interest in mind control and the Mayan codices as well
as . . . drugs' or in Jane Bowles' characterization of Allen Ginsberg as 'a member
of the "Zen Buddhist-Bebop-Jesus Christ-Peyote g r o u p " ' 3 0 . Huxley, writing
about his first experience with mescalin, quite typically adds to the description of
his experience of original reality - 'I was seeing what Adam had seen on the


morning of his creation - the miracle, moment by moment, of naked existence' -

reflections that contain recollections of Meister Eckhart and Plato and refer to the
paradoxical union of opposites, unio mystica, and Zen 31. Graves, who, in The White
Goddess, is perhaps one of the most extreme exponents of a search for the origins
of poetry in an original myth that will at the same time provide access to an essen-
tially alternate reality, typically has an index that reads like a dictionary of
mythology 3 2 . In writing such as The Road to Eleusis, the principle of metaphorical
connection clearly operates via any trait in the object or event under consideration,
though among the preferred types appear to be etymology and Gestalt. The essays
of Burroughs, too, are full of what one might call 'metaphors formed by illicit
connection': non-resolvable metaphors in which the basis of connection between
two realms is neither guaranteed by convention nor supported by an intra-textual
argument, however implicit 33 . Also, sources are often not subjected to critique;
frequently, in Burroughs, for example, that someone has said something is valida-
tion enough. The discourse then tends to slide from question to cautious surmise
to the statement that X or Y 'must have been' the case, and on to hypostatizing
as fact what had, a short time previously, only been the merest suggestion. In the
same vein, history is written by moving from metaphor to metamorphosis, and
from metamorphosis to underlying identity: X is, or was, similar to Y; X must
have developed from Y; X is essentially identical with Y.
In violating basic rules of academic and other decorum, such texts associate
themselves with precisely what they are frequently about: a submerged or secret,
alternate and original tradition that has been falsified or betrayed by the official
civilization. A conspiracy view of history frequently goes with the charge, or at
least the view that our civilization has gone in the wrong direction - that it has
proceeded by reduction, elimination and selection, from the essentially manifold,
complex and multiple (and zweckfrei) to the essentially single and univocal (and
utilitarian) 34 - and that it needs to reverse its course. In The Road to Eleusis, there
quite typically emerges a background story according to which the original source
has been stopped up by Christianity.
Within the dominant literary and artistic culture, the trend may have become
obsolete, with this specific logic of transgression being reduced to 'outsider' or
'minoritarian' status. Its specific strategies of unification, too, have come under
attack; as Edwin Wilmsen has said in a hitherto unpublished manuscript, the
image (or imagery) of original oneness that one encounters, for instance, in Jung's
view of the primitive:

. . . is losing its potency. Its power seems to have run its course not so much because the image
has been shown to be flawed (indeed, flaws enhance metaphors by extending their ambiguity
and, thereby, the potential scope of their power), but because it is an image of universality, of
indivisible unity of human potential and purpose. In an increasingly polarized 'new' world order,
such unifying images dissolve in the rhetoric of primordial difference.


The transgressive impulse, though, persists elsewhere - for example in (discus-

sions of) postmodern performance; e.g.:
According to Lacan, the imaginary is limited to individuals, a limit that cannot be surpassed
except by means of symbolic mediation. But if we could restore the performative to society we
would regain the collective imaginary. This imaginary, the universal immanent, is realer than
real. This universal immanent can be reached only by means of performance 35 .

It is legitimate, finally, to raise the question of why the logic discussed has, in a
general way, been the permanent 'underbelly' of western civilization. One
answer, I think, is that out of the deficits and discontents of our civilization,
we have constructed its other - as an eternal other. One can perhaps pinpoint this
relationship through reference to the way in which the alternate logic deals with
time: in a sense making time irrelevant or at least a minor dimension, where
western civilization has arguably made it the major dimension of its thought. If
the drug experience denies time and history - 'Place and distance cease to be of
much interest. The mind does its perceiving in terms of intensity of existence,
profundity of significance, relationships within a pattern. . . . an indefinite
duration or alternatively . . . a perpetual present made up of one continually
changing apocalypse' 36 - this must appear as a major sin to the historical mind of
the West. Furthermore, that discourses about drugs often waver between past and
present, placing the action of the drug in a timeless past-present 37 , does not help
to integrate them into the official universe of discourse.
Another possible answer to why we do not cease thinking about alternatives to
our dominant rational culture has to do with the logic of cultural constructions of
reality in general. Such constructions are self-validating, autotelic and tautologi-
cal: the real is the self-evident, which is nothing but the culturally guaranteed.
(This also applies to literary constructions of reality, and to hallucinatory or mys-
tical ones.) Cultures are aware of the self-enclosedness of the resulting systems
and attempt to transcend them. They have a tendency to search for an intertextual
or intercultural basis for a discourse about the similarities and differences among
them, and about their relative validity. Eclecticism and syncretism provide such a
basis; it is a shaky one: it fails to interrelate the different systems rationally,
because it cannot limit itself and has a built-in tendency to end in arbitrariness.
But there does not seem to be anything else, and it is at least an expression of a
human desire to transcend limitations that refuses to go away. LSD, as a cultural
icon, focused this desire on itself and gave it cultural prominence.


1. Cf. Hoffman, D. (ed.) (1979). Harvard Guide to Contemporary American Writing. (Cambridge,
Mass.: Harvard University Press) [especially the chapter on 'Experimental Fiction']
2. Burroughs, W. (1984). The Job: Topical Writings and Interviews, pp. 27. (London: John Calder)
3. Bowles, P. (1972). Without Stopping: An Autobiography, pp. 347-50. (New York: Ecco Press)


4. Cf Green, M. (1991). The Dream at the End of the World: Paul Bowles and the Literary Renegades in
Tangier, pp. 241. (New York: Harper Collins)
5. Freedman, D. X. (1967). Perspectives on the Use and Abuse of Psychedelic Drugs. In Efron, D.
H. Flolmstedt, B., Kline, N. S. (eds.) Ethnopharmacological Search for Psychoactive Drugs: Proceedings
of a Symposium, San Francisco, January 28-30, 1961, pp. 77-102. (Washington: Public Health
Service ) [specifically pp. 85ff]
6. Blau, H. (1991). The surpassing body. The Drama Review, 35, 74-98 [quotation p. 75]
7. Green, M. (1991). The Dream at the End of the World: Paul Bowles and the Literary
Renegades in Tangier, p. 74. (New York: Harper Collins) [quoting from The New York Review of
8. Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis: Unveiling the Secret
of the Mysteries, p. 16. (New York & London: Harcourt Brace Jovanovich)
9. Green, M. (1991). The Dream at the End of the World: Paul Bowles and the Literary Renegades in
Tangier, passim. (New York: Harper Collins)
10. Bowles, P. (1972). Without Stopping: An Autobiography, pp. 9-10. (New York: Ecco Press) [Cf.,
on the use of terms: Gillespie, G. (1986). Epiphany: notes on the applicability of a modernist
term. In Riesz, J., Boerner, P. and Scholz, B. (eds.) Sensus Communis: Contemporary Trends in Com-
parative Literature/Panorama de la situation actuelle en litterature comparee (Festschrift for Henry
Remak), pp. 255-66. (Tübingen: Narr); and Nichols, A. (1987). The Poetics of Epiphany:
Nineteenth-Century Origins of the Modern Literary Moment. (Tuscaloosa: University of Alabama
11. Green, M. (1991). The Dream at the End of the World: Paid Bowles and the Literary Renegades in
Tangier, p. 257. (New York: Harper Collins)
12. Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis: Unveiling the Secret
of the Mysteries, pp. 18f., 20ff. (New York & London: Harcourt Brace Jovanovich)
13. Schuhes, R. E. and Hofmann, A. (1980). Plants of the Gods: Origins of Hallucinogenic Use, p. 184.
(London: Hutchinson)
14. Ibid., p. 101
15. Ibid., p. 184 [quoting Louis Lewin]
16. Grof, S. and Grof, C. (1980). Beyond Death: The Gates of Consciousness, pp. 12ff. (London:
Thames and Hudson) [cf. pp. 28, 210]
17. Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis: Unveiling the Secret
of the Mysteries, p. 14. (New York & London: Harcourt Brace Jovanovich)
18. Holmstedt, B. (1967). Historical survey. In Efron, D. H., Holmstedt, B. and Kline, N. S. (eds.)
Ethnopharmacological Search for Psychoactive Drugs: Proceedings of a Symposium, San Francisco, fanuary
28-30, 1967, pp. 3-32. (Washington: Public Health Service)
19. Freedman, D. X. (1967). Perspectives on the use and abuse of psychedelic drugs. In Efron, D.
H., Holmstedt, B., Kline, N. S. (eds.) Ethnopharmacological Search for Psychoactive Drugs: Proceedings
of a Symposium, San Francisco, fanuary 28-30, 1967, pp. 77-102. (Washington: Public Health
Service) [quotation p. 78]
20. Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis: Unveiling the Secret
of the Mysteries, p. 29. (New York & London: Harcourt Brace Jovanovich)
21. Bowles, P. (1972). Without Stopping: An Autobiography, p. 268. (New York: Ecco Press)
22. In Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis: Unveiling the Secret
of the Mysteries. (New York & London: Harcourt Brace Jovanovich)
23. Cf. Schuhes, R. E. and Hofmann, A. (1980). Plants of the Gods: Origins of Hallucinogenic Use.
(London: Hutchinson) [e.g. pp. 102, 185]
24. Elliott, R. C. (1960). The Power of Satire: Magic, Ritual, Art. (Princeton: Princeton University
Press) [following Francis M. Cornford's The Origin of Attic Comedy (1914)]


25. Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis: Unveiling the Secret
of the Mysteries. (New York & London: Harcourt Brace Jovanovich) [especially pp. 18-23]
26. Wasson, R. G., Hofmann, A. and Ruck, C. A. P. (1978). The Road to Eleusis: Unveiling the Secret
of the Mysteries, p. 22 et passim. (New York & London: Harcourt Brace Jovanovich)
27. Ibid., p. 14
28. Schultes, R. E. and Hofmann, A. (1980). Plants of the Gods: Origins of Hallucinogenic Use, p. 85.
(London: Hutchinson)
29. Ibid.
30. Green, M. (1991). The Dream at the End of the World: Paul Bowles and the Literary Renegades in
Tangier, pp. 127, 182. (New York: Harper Collins) [cf. p. 126]
31. Huxley, A. (1954). The Doors of Perception, pp. 11 ff. (London: Chatto & Windus)
32. Graves, R. (1961). The White Goddess: A Historical Grammar of Poetic Myth. (London: Faber)
[amended and enlarged edition]
33. Burroughs, W. (1984). The Job: Topical Writings and Interviews. (London: John Calder)
34. Huxley, A. (1954). The Doors of Perception, pp. 16f. (London: Chatto & Windus)
35. Kitazawa, M. (1992). Myth, Performance, and Politics. The Drama Review, 36, 160-73 [quota-
tion p. 172]
36. Huxley, A. (1954). The Doors of Perception, pp. 14f. (London: Chatto & Windus)
37. Schultes, R. E. and Hofmann, A. (1980). Plants of the Gods: Origins of Hallucinogenic Use, p. 61.
(London: Hutchinson)

Section 5
Clinical Aspects


Pharmacological standards for

evaluation of clinical effects of


The hallucinogenic drugs are characterized by their ability to induce disturbances

of perception, thought and mood. LSD, although not the oldest of these com-
pounds, is the most representative. Descriptions of its actions in human subjects
vary greatly, depending on such factors as whether normal volunteers or psy-
chiatric patients are involved, set, motivation, expectations, etc. The psychotic
features induced led to the concept in research of the 'model psychosis' 1 .
However, it was the therapeutic claims for LSD that made the greatest impact 2, 3.
Conversely, the dangers of LSD therapy have been stressed repeatedly.
The purpose of this paper is not to review the evidence for and against the
efficacy and risks of LSD therapy. Rather, I shall review the areas of especial diffi-
culty in assessing these attributes of LSD and of any future drugs falling under the
same rubric of hallucinogen. The need for carefully controlled double-blind
studies, usually involving a placebo, is discussed in Chapter 16 by Drs O'Brien
and Jones. Pharmacokinetic considerations will not be considered here, as these
are not special to this class of drugs.


In the development of psychotropic drugs, animal studies play a more limited role
than in, for example, the cardiovascular field. The reliability of drug effects on
animal behavior is not in question, but the predictive validity is sometimes
tenuous. Nowhere is this more apparent than with the hallucinogens (Table 1).


Table 1 Value of animal studies

face any bizarre behavior
concurrent probably none really
predictive possibly none
Biochemical models
serotonin indirect
Behavioral models
Therapeutic focus e.g. alcoholism, obsessive-compulsive disorder

These drugs have a wide range of effects in animals 4 . However, the effects vary
between species and with dose, biphasic dose-response curves having been
reported. No reliable predictive test has evolved since the early work on the
effects of LSD on animal behavior. Biochemical models involving serotonin
provide an alternative approach which may ultimately prove more successful.
A more focused approach would be to utilize animal models of the psy-
chopathological conditions for which LSD is advocated as a therapy. An example
concerns experimental neuroses of Pavlovian and other types. For example,
Marazzi 5 found that LSD inhibited conditioned approach behavior rather than
conditioned avoidance behavior. With the recent careful development of various
behavioral models of anxiety, panic and other neurotic disorders 6 , a re-evaluation
of the effects of LSD would be timely. Whether predictive animal models would
eventuate remains unlikely.

The careful construction of dose-effect curves is a necessary part of the standardi-
zation of usage of an hallucinogen. The minimal effective dose must be sought;
with LSD this is about 20-30 μg. The median effective dose must be established
and this varies widely between subjects, and will overlap with the minimal toxic
dose. Because of this, dose-ranging studies within an individual may be useful in
this context. For example, Abramson and colleagues7 used five dose-ranges of
LSD in 31 non-psychotic subjects and found a correlation between psychotic and
perceptual changes across dose but not between dose and neurotic symptoms.
However, De Marr and co-workers 8 found that subjects could distinguish
between 25, 50 and 100 μg doses, the number of symptoms being linearly related
to dose. It is important to establish the slopes of the dose-effect curve in different
individuals. If these slopes are similar, then the ratio of maximal effective dose to
minimal effective dose is a constant; if these slopes differ, then the dosing schedule
would have to be established ab initio in every subject to whom the putative
hallucinogen is administered.


The phenomenon of tolerance complicates the issue. This can develop very
quickly if LSD is administered with too short an interval between sessions. Thus,
100 jug of LSD will produce an intense reaction on first administration, but the
effects soon disappear on daily repetition. At least a week must elapse between
tests. Therefore, the time-interval between doses must be carefully specified. Fur-
thermore, if a series of different doses is to be given to each individual, it is safer
to randomize the dose-schedules rather than to have an escalating scheme.
However, use of a test dose may be wise to avoid an over-reaction to an initially
large dose.
The parameters of tolerance may need evaluation in their own right. Thus, it is
important to establish the minimum intervals between doses to avoid over-
frequent administration.


The expectations in the subject are major factors governing the response (Table 2).
When subjective experiences induced by hallucinogens have been described in
such terms as 'pure contemplation at its height' 9 or 'an enlargement of
experience' 10 , it is clear that their psychotropic effects can be influenced by the
prior knowledge of the individual and his attitudes and expectations. Placebo
control will not compensate for the elaboration of the psychedelic experience,
unless the subject is abnormally over-suggestible. The naive subject volunteering
for yet another study to earn some money to eke out his or her student grant will
react in a different and more muted way than the sophisticate who seeks new
experiences with drugs.

Table 2 Factors in the subject

Previous experience
first LSD experience may be atypical
if subject expects psychedelic experience, response will be different
from the naive subject
reason for volunteering needs documenting
Personality factors
broad, e.g. 'neuroticism'
narrow, e.g. 'obsessionality'
level of verbal facility is important in order to describe experience


Previous experience will also have a profound influence. The first LSD
experience is often atypical, with more anxiety and anticipation. Later experiences
may be more stereotyped. Therefore, careful attention must be paid to properly
balanced treatment sequences, or the first exposure can be regarded as a separate
training session.
The personality of the subject influences the LSD reaction. Measurement of
personality profiles such as obsessionality (e.g. by use of the Minnesota Multi-
phasic Personality Inventory (MMPI)) may help establish predictive factors for
particular patterns of response. At a secondary level, personality factors such as
neuroticism may also be informative predictors of hallucinogenic reactions.
Education will affect the subjective reporting acumen of the subjects. The per-
ceptual experiences are often so bizarre and complex that a well-developed verbal
facility is needed to convey their essence. The occupation of the subject will also
influence the response; objective scientists provide very different accounts from
creative artists.
Neither age nor sex seem to be major modifying influences. The state of physi-
cal health is important and ill subjects should not be subjected to the possible
hazards of a psychedelic experience. The use of psychotropic agents should be
documented, in particular the use of alcohol. Subjects should be drug-free at the
time of testing.


All of the factors listed as affecting the response to an hallucinogen operate in the
patient, but there are additional and often important considerations in the
therapeutic context. The use of LSD has been advocated in a wide range of usually
ill-defined psychiatric and other patients, sometimes on the basis of single
case-reports. A typical example is a careful description of the use of LSD in some
patients with migraine, and individual cases of 'writer's block', frigidity, sexual
perversion, pathological gambling, immaturity, character disorder, anxiety, and
psoriasis 11 . Manifestly there is a need to specify, in generally recognized terms, the
characteristics of the patients treated. This can be done at several levels.
Firstly, formal diagnostic criteria can be applied using DSM-III-R 1 2 or ICD-10 1 3
criteria, as in the case of establishing indications for any psychotropic drug. LSD
has been used to treat alcoholics, drug addicts, and schizophrenics, all conditions
with a fluctuating course and variable prognosis. It has also been used in rather
refractory conditions such as obsessive-compulsive disorder. All of these condi-
tions can be ascertained using a standard diagnostic schedule. More detailed profiles
of psychopathology within each diagnosis can also be drawn up using standard
Psychotropic drugs can also be used on a symptomatic basis, e.g. to treat
anxiety or delusions in whatever context they occur, and this presents greater


Table 3 Factors in the therapist

Objectives of therapy and therapist

(1) Abreactive experience
(2) To facilitate blocked progress in psychoanalysis
(3) Repeated use as adjunct to individual or group psychotherapy
(4) To induce a single overwhelming psychedelic experience 14
Therapist - client relationship (specify)
Potential or actual transference
Attitudes of therapist: what have his own experiences been? Does he
have an evangelic approach?

difficulties. Although these symptoms can be detected, their quantification

presents some problems. For example, although well-developed scales (both
objective and subjective) exist to rate the severity of anxiety in a patient with an
anxiety disorder, these scales are often poorly validated with respect to anxiety in
an alcoholic or in a victim of sexual abuse. Nevertheless, some attempt should be
made to quantify the target symptoms.
On yet another level LSD therapy has several objectives. The problems of
specifying the common characteristics of patients selected for such therapeutic
procedures are similar to those which bedevil psychotherapy research where
traditional classificatory schema seem inadequate or inappropriate.


It is necessary to pay some attention to factors in the therapist or investigator
(Table 3). The effects of LSD can be modified profoundly by the patient-therapist
interaction in a manner that is more akin to psychoanalytic transference processes
than to other psychotropic drug experiences. The objectives of the therapist or
investigator need to be carefully specified. The prime aim may be to investigate
the effects of an hallucinogen on a psychological test, or to reactivate childhood
experiences, to effect a symptomatic improvement or, more vaguely, to provide
a psychedelic experience which he believes will widen the subject's horizons. Such
objectives may be covert or communicated to the subject in a subtle way, during
of a frank discussion between subject and therapist. For ethical reasons, it is
important that the investigator/therapist is clear in his/her own mind whether the
person taking the drug is an experimental subject for whom no therapeutic benefit
is expected or a client/patient in whom potential adverse effects are balanced by
possible therapeutic benefit.
One factor which should be specified is whether the therapist has had personal
experience of an hallucinogen's effects, and his attitude to those experiences. If he


is cautious about potential benefits, the eventual outcome may be very different -
i.e. better or worse - than if he is a less critical enthusiast.


More than with most psychotropic drugs, environmental factors must be care-
fully selected and standardized in the study of hallucinogenic effects. The sur-
roundings and milieu (e.g. wallpaper) must be standardized, for example. Such
factors do, however, depend on the purpose for which the hallucinogen is being
administered. If the purpose is to induce a psychedelic experience, then all the
factors of space, color, sound and comfort need to be specified and implemented.
This is less important if a more indirect therapeutic goal is envisaged.
For the induction of a psychedelic experience, additional material may be
provided. This could include photographs, paintings, colorful curtains and rugs
and music of various types. The subject's preferences must be considered. It may
not be helpful to play pop music to someone who finds Palestrina too avant-
garde! Nor will abstract art elicit much of a response from a subject who enthuses
over high Victorian realism!
The number of people present may be important 15 . The ideal number is three -
patient, therapist and nurse. More than four may be disconcerting to the subject,
unless the object is to study group dynamics. The drug administration should not
be interrupted by constant comings and goings - strangers may profoundly
influence the experience.

The LSD experience itself is so variable that it is important to keep standardized
records of the sessions themselves. This can take the form of a time-diary filled in
by the therapist and by the patient (if he/she is capable of it) or a series of question-
naires each addressing a different aspect, e.g. emotional and perceptual responses.
Detailed behavioral records are helpful and a video recording is probably the most
convenient means of providing this. The responses of the therapist to the patient
should also be logged. Semantic analysis of speech content is useful.
The more traditional outcome variables comprise measures of symptomatic
improvement. The choice of these will depend on the target symptom or syn-
drome, as will the time focus of the assessment. Interest may lie in the immediate
effects of an LSD session or on the longer-term outcome. As with all evaluations
of treatment in poorly defined and fluctuating conditions, follow-up after treat-
ment with comprehensive evaluations is essential.
Assessments of other psychological features than subjective symptoms and
objective behavior have been used. For example, Barr and her colleagues 16 used
a questionnaire and observed the behavior of their subjects, but also utilized


cognitive tests such as digit span and comprehension, a color-word test, theme
lists and projective tests. In particular, the Rorschach Test has been popular,
despite the unreliability of its interpretation. The assessment of the quality of
creative work produced during and after LSD sessions is even more controversial.

With LSD, somatic changes commence about 30 min after the drug is given.
Nausea, loss of appetite, and vomiting are common, but hunger and stomach
cramps may occur instead. Headache, dizziness, chest pains, sweating, tremor of
the extremities, hyper-reflexia, inco-ordination and ataxia are all reported fre-
quently, especially at higher doses. Autonomic effects are invariably present; blur-
ring of vision, palpitations, urinary frequency, pupillary dilatation and increases in
blood pressure. These latter effects usually persist during the perceptual effects
and may be the last to disappear.
Such bodily effects can provide a useful correlate in the investigation of an hal-
lucinogen. Thus, Isbell 17 used pupil size as an index of drug action in comparing
psilocybin with LSD in a bioassay procedure. He calculated that 121 μg/kg of
psilocybin was equivalent to 1 μg/kg of LSD, with 0.05 fiducial limits of 103 and
156μg/kg, which is quite precise for a human psychotropic drug comparison.
Nevertheless, there are pitfalls in this approach. The bodily changes may not
necessarily be an intrinsic property of an hallucinogen so that misleading compari-
sons could be made. Even somatic effects attributable to perturbations in serotonin
mechanisms, such as nausea and headache, may be inconstant between drugs. Thus,
although a precise measure of autonomic effects such as pupil size and sweating can
be made, care must be taken in the interpretation of the results, which must be
done in the light of the known basic pharmacology of the compound.
Central measures, namely the electroencephalogram (EEG) and its responses,
have been widely used in the investigation of new psychotropic compounds. The
EEG generally shows an activated pattern and this can easily be quantified using
modern techniques. In view of the perceptual changes which may dominate the
hallucinogenic experience, event-related potentials (ERPs) would provide a fas-
cinating method of investigation. The sophistication of these techniques and the
sensory, perceptual and cognitive data which they are capable of producing
suggest a fruitful area of research with, perhaps, the development of standard
evaluative procedures for new hallucinogens.

A clear distinction must be made between the adverse effects of LSD used in a
carefully controlled therapeutic context and the toxicity that arises during abuse.
We are concerned with the former. During the LSD session, affective changes


may be marked with feelings of terror and depression, as described by

Hofmann 18 . This is the 'bad trip', and sufferers appear nowadays in casualty
departments of hospitals. Also during this phase, the patient can be a danger to
himself or to others 19 . The assessment of immediate unwanted effects can be done
in the usual way with checklists, although the wide range of LSD effects may
necessitate specially-designed instruments.
The longer-term adverse effects are more problematic. Several studies have
reported the onset of psychotic illnesses following LSD administered in clinical
settings. Cohen 2 0 described a survey of 44 users of LSD therapy covering 5000
patients given a total of 25 000 doses. Eight cases of prolonged psychosis were
reported. Malleson 21 calculated a rate of nine cases per thousand patients in the
UK. Some individuals became psychotic after a single dose, suggesting an
idiosyncratic susceptibility. The commonest symptoms of the psychosis are mood
swings, visual hallucinations, grandiosity and religiosity. Although some of these
cases could be interpreted as an intensification of pre-existing psychopathology,
many were not predictable from the prior psychiatric state.
The other belated sequel of LSD use is the perceptual 'flashback' disorder. This
can be common and often persistent 22 . The phenomena are predominantly visual,
with transient altered perceptions, geometric pseudohallucinations, flashes of
color and often imagery 23 .
These long-term adverse effects need careful documentation using present-day
techniques of pharmacovigilance. They constitute definite and important hazards
which must be entered into the estimation of the risk-benefit ratio of any putative
hallucinogen advocated in therapy.

Half a century on, the hallucinogens remain among the most fascinating of psy-
chotropic drugs and LSD is the best understood of the group. After initial uncriti-
cal enthusiasm, a more sober mood has resulted in a careful re-evaluation of its
effects. Factors influencing response include dose, dose intervals, tolerance,
expectations and experience in the subject/patient and the experimenter/therapist.
The goals of therapy need careful definition, as does the diagnostic status of the
patient. Some therapeutic goals suffer the same imprecision as those of psy-
choanalysis. Finally, as the hallucinogenic experience is so stimulus-bound,
factors in the environment must undergo standardization.
When the clinical and psychological effects of LSD are quantified more exactly
than hitherto, the exciting possibility arises to relate them to the advances in our
knowledge concerning the biochemical pharmacology of this group of drugs.
Neuro-imaging with positron emission tomography and single photon emission
computed tomography is also very promising. In these ways, truly fundamental
advances will be made in our understanding of brain function.


Basel April 19th 1943


Figure 1 Design on illicit LSD sheet, 1993

Unfortunately, LSD is a common drug of illicit use and mini-epidemics occur

periodically. In the UK, we are suffering one at the present time of writing, with
up to 10% of our young adults claiming some experience of LSD 2 4 . The drug is
produced illicitly as sheets of paper impregnated with multi-doses of LSD, about
125 μg per small square, and these sheets are overprinted with various designs. As
can be seen from one of these designs (Figure 1), we are not the only people
celebrating 50 years of LSD!

1. Aaronson, B. and Osmond, H. (eds.) (1971). Psychedelics, The Uses and Implications of Hallucino-
genic Drugs. (London: Hogarth)
2. Cohen, S. (1964). Drugs of Hallucination. The Uses and Misuses of Lysergic Acid Diethylamide.
(London: Seeker and Warburg)
3. Hoffer, A. and Osmond, H. (1967). The Hallucinogens. (New York: Academic Press)
4. Weckowicz, T. (1967). Animal studies of hallucinogenic drugs. In Hoffer, A. and Osmond, H.
(eds.) The Hallucinogens. (New York: Academic Press)
5. Marazzi, A. S. (1962). Synaptic and behavioral correlates of psychotherapeutic and related drug
actions. Ann. NY Acad. Sci., 96, 211-26
6. Willner, P. (1991).BehaviouralModelsinPsychopharmacology:Theoretical,IndustrialandClinicalPer-
spectives. (Cambridge: Cambridge University Press)
7. Abramson, H. A., Jarvik, M. E. and Hirsch, M. W. (1955). Lysergic acid diethylamide (LSD-
25): VII. Effect upon two measures of motor performance. J. Psychol, 39, 455-64


8. De Marr, E. W. J., Williams, H. L., Miller, A. I. and Pfeiffer, C. C. (1960). Effects in man of
single and combined oral doses of reserpine, iproniazid and d-lysergic acid diethylamide. Clin.
Pharmacol. Ther., 1, 23-32
9. Huxley, A. (1960). The Doors of Perception. (London: Chatto and Windus)
10. Mortimer, R. (1963). The moral, religious and social significance of experience under hallucino-
genic drugs. In Crocket, R., Sandison, R. A. and Walk, A. (eds.) Hallucinogenic Drugs and their
Psychotherapeutic Use pp. 167-8. (London: Lewis)
11. Ling, T. M. and Buckman, J. (1963). Lysergic Acid (LSD 25) and Ritalin in the Treatment of Neurosis.
(London: Lambarde Press)
12. Diagnostic Criteria from DSM-III-R. (1987). (Washington DC: American Psychiatric
13. The ICD-10 Classification of Mental and Behavioural Disorders. (1992). (Geneva: World
Health Organization)
14. Osmond, H. (1957). A review of the clinical effects of psychotomimetic agents. Ann. NY Acad.
Sci ., 66, 418-34
15. Cheek, F. E. (1963). Exploratory study of drugs and social interaction. Arch. Gen. Psychiatry, 9,
16. Barr, H. L., Langs, R. J., Holt, R. R., Goldberger, L. and Klein, G. S. (1972). LSD: Personality
and Experience. (New York: Wiley)
17. Isbell, H. (1959). Comparison of the reactions induced by psilocybin and LSD-25 in man. Psy-
chopharmacology, 1, 29-38
18. Hofmann, A. (1980). My Problem Child. (New York: McGraw Hill)
19. Elkes, C., Elkes, J. and Mayer-Gross, W. (1955). Hallucinogenic drugs. (Letter), Lancet, 1, 719
20. Cohen, S. (1960). LSD: side effects and complications J. Nerv. Ment. Dis., 130, 20-40
21. Malleson, N. (1971). Acute adverse reactions to LSD in clinical and experimental use in the
United Kingdom. Br. J. Psychiatry, 118, 229-30
22. Holsten, F. (1976). Flashbacks: clinical and social significance 1½-4 years after the 1st admis-
sion (in Norwegian). Tidsskrift For Den Norske Laegeforening, 96, 875-8
23. Abraham, H. D. (1983). Visual phenomenology of the LSD flashback. Arch. Gen. Psychiatry, 40,
24. Institute for the Study of Drug Dependence (ISDD). (1993). Drug Misuse in Britain. (London:


Human psychopharmacology of
LSD, dimethyltryptamine and
related compounds

Hallucinogenic drugs elicit a complex syndrome of effects in humans. These

include alterations in emotional, perceptual, cognitive, somatic and volitional
function. Visual and auditory illusions and hallucinations; rapidly shifting, highly
polarized emotional states; the suffusing of novelty and meaning to otherwise
mundane thoughts and percepts; bodily dissociation and other distortions of
physical experience; and striking changes in the ability to interact with one's self
or environment, are often described.
The 'classic' hallucinogens can be placed into chemical families, such as the
lysergamides, phenethylamines and tryptamines, of which respectively, LSD,
mescaline and psilocybin are examples 1 . They also may be considered within the
context of their time course, i.e.: onset, peak effect and duration of action. These
parameters are, naturally, dependent on route of administration, but for our
purposes will refer to those seen with their usual route of administration.
'Ultra-short acting' drugs have an onset of 1-5 min, peak effects occur within
15-30 min, and duration is 1 h or less. They include the parenterally active trypta-
mines, such as dimethyltryptamine (DMT) 2 . 'Short-acting' hallucinogens' onset is
between 15 and 30 min, peak effects are within 30-90 min, and duration is
between 1 and 3 h; diethyltryptamine (DET) 3 and dipropyltryptamine (DPT) 4 are
examples. 'Intermediate-acting' hallucinogens include orally active tryptamines
such as psilocybin 5 , and CZ-74 and CY-19 6 , and the botanical hallucinogen
'ayahuasca' 7 . Onset begins within 30-60 min and peak effects occur within 2-3 h,
with a duration of 4-6 h. 'Long-acting' hallucinogens include LSD and mescaline,


with onset at 30-90 min, peak effects at 3-5 h, and duration of 8-12 h 8 .
'Ultra-long-acting' compounds include the selective 5-HT 2 / 1 C agonist
2,5-dimethoxy-4-methyl-amphetamine 9 (DOM), and the poorly characterized
African plant drug 'ibogaine' 10 . Duration of action may last 18-24 h.
The birth of 'biological psychiatry' is said to have occurred with the discovery
of the antipsychotic effects of milligram doses of chlorpromazine. However, the
contemporaneous discovery of the thousandfold more potent effects of LSD in
eliciting certain symptoms of endogeneous psychoses is arguably as important. A
polarized debate developed, however, over how best to use and study LSD and
related compounds. This was never the case for drugs that treated commonly
accepted psychiatric disorders, i.e. antipsychotics, antidepressants, and lithium.
Thus, the free exchange of interfacing data between basic and clinical investigators
necessary for advances in the brain sciences and clinical practice, could not proceed
after hallucinogens were placed into highly restrictive regulatory classifications.
Nevertheless, the scientific and greater public communities remain fascinated
by the hallucinogens. Highly restrictive regulatory policies 11 concerning
manufacture and possession have not greatly hindered the hallucinogens' utility as
behavioral and pharmacological probes of the mammalian central nervous system
by two generations of basic scientists. Nor has their legal status prevented
'psychedelic' drugs from being taken by a consistent minority of the population 12 .
The reason for the continued interest in the hallucinogens can be inferred from
the many names for this class of drugs. These include: 'psychedelic',
'psychodysleptic', 'phantasticant', 'psychotogen', 'oneirogen', 'entheogen',
'phanerothyme', 'psychotomimetic', and 'schizotoxin' 13 . How many other drugs
can claim so many different epithets?
The elicitation of some symptoms seen in psychiatric patients, particularly the
psychoses, prompted the terms 'psychotomimetic', 'psychotogenic' and
'psychodysleptic'. A case has been made for the naturally occurring short-chain
tryptamines being endogenous 'schizotoxins'. Although many investigators have
compared the naturally occurring psychoses (particularly schizophrenia) with the
effects of hallucinogens, questions regarding similarities and differences
remain 1 4 , 1 5 . Although studies often remark on the preponderance of visual
hallucinations in drug-induced states, and the relative lack of these in
schizophrenia, there are data that suggest a high incidence of visual effects in
schizophrenics, if these effects are carefully s o u g h t 1 6 , 1 7 .
'Hallucinogen', 'phanerothyme ("making visible feelings")', 'oneirogen
("producing dreams")' and 'phantasticant' point out salient features of the
intoxication, using an individualistic, clinical, but less pathological perspective.
Psychotherapists, particularly the psychoanalytic, noted the ability of
hallucinogens to affect volitional, memory and emotional functions, prompting
attempts to harness these effects for therapeutic use. 'Psycholytic' and
'psychedelic' forms of psychotherapy were researched and practiced.


The initial descriptions of hallucinogen effects excited the religious, as well as

clinical, imaginations. Rites and ceremonies in several non-Western cultures,
observed and recorded by early botanists and anthropologists, suggest their use as
aids to spiritual exercises 18 . That certain combinations of drug, 'set' and 'setting'
elicited similarly interpreted experiences was not missed in the West 19 , giving rise
to the quasi-religious term 'entheogen'.
Freedman referred to the hallucinogens as 'cultogenic' 20 , referring, at least, to
the strikingly different but similarly firmly held beliefs of the proponents of any
of the above terms. Stephen Szara's recently introduced term 'psychoheuristic' can
be considered in a similar vein, namely that the explanatory power of the drugs
may relate as much to the philosophy and psychology of the investigator as to the
effects being studied!
Public health issues also keep these drugs in the public eye. The consequences
of unsupervised use of hallucinogens by young adults often require clinical
intervention. The treatment of exacerbations of pre-existing psychopathology,
accidental injuries and death, and precipitation of de novo symptomatology in
susceptible individuals 21 utilize scarce public resources.
Finally, we are witnessing a second opportunity for clinical investigators to use
these compounds as probes of the mind-brain interface. The psycho-
pharmacologic approach takes advantage of a number of technological advances
that were not anticipated when the first stage of human research ceased. A much
keener eye now can be turned towards the relevant brain mechanisms underlying
such phenomena as hallucinations, dissociation, emotional dysregulation and
other aspects of hallucinogen intoxication in humans. This is an admirable goal of
the Decade of the Brain, in the 1990s, as inaugurated by the American Congress.
Within the context of re-emerging human studies, investigations can continue
into whether and how hallucinogens may shorten the length, or enhance efficacy,
of psychotherapeutic treatment. New psychotherapy research protocols are
ideally suited for this work, with their emphasis on limited treatment course, and
standardized psychotherapy protocols and outcome measures.


The discontinuation of human hallucinogen research coincided with the

beginnings of both a more sophisticated approach to human psycho-
pharmacology, and the burgeoning field of serotonin receptor physiology. Thus,
there are meager interfacing data bridging the gap between clinical and basic
science. Most of the early human studies used outcome measures that lack the
specificity of current clinical research. Nevertheless, this work will guide current
human studies so that psychopharmacologic or contemporary neuro-
pharmacologic hypotheses may be validated, refuted or extended.


The first descriptions of hallucinogenic drug effects in humans took the form of
careful clinical descriptions, often using a psychoanalytic perspective 22 . Reports
from self-experiments also were used routinely 23 . Some clinical observational
studies used quantitative scores, but generalization of these scoring methods
between different research sites was difficult 24.
The acute psychological effects of hallucinogens also were quantified using the
validated questionnaires then in use 2 5 . In addition, two rating scales (the
Abramson et al. scale8 and Linton-Langs scale) 26 were developed specifically
for LSD effects; a third (the Addiction Research Center Inventory (ARCI)), for
multiple drugs, used LSD as a reference compound. The former two instruments
quantified the effects of hallucinogens on several statistically- or clinically-derived
groupings of questions. The scale of Abramson and co-workers used descrip-
tive/clinical clustering of questions that emphasized somatic and emotional effects.
The Linton-Langs scale clustered items based on psychoanalytical theories of con-
The ARCI is now the standard rating scale for psychoactive drug effects in
humans. After undergoing extensive field trials using multiple drugs and popula-
tions, the ARCI determines the degrees of similarity between test and reference
drug(s) - i.e. whether a novel drug is more or less 'LSD-like', or shares any
characteristics of, for example, morphine-benzedrine drugs 2 7 . There are
difficulties with the short-form ARCI (47, rather than >500 items) with respect
to drug similarity to LSD, alluded to by the LSD-scale being referred to as the
'dysphoria' scale. For example, sumatripan, a selective 5 - H T 1 D agonist,
demonstrated 'LSD-like' effects using the ARCI, but no volunteer rated it as
'similar to LSD' 2 8 . Thus, although the ARCI can give adequate 'first
approximations' of 'hallucinogenic' effects, more sensitive means of making valid
comparisons are necessary.
Also of interest, with respect to rating scale scores, is the importance of
standardizing whether or not subjects receive hallucinogens alone or in groups of
other intoxicated subjects, and whether doses within a group are the same. The
experience of 'contact highs', whereby subjects are affected by the experiences
shared with others, verbally or otherwise, has been verified repeatedly 2 9 , 3 0 .
Other studies of human hallucinogen effects used 'psychophysiological'
measures. However, they were relatively far removed from the clinically relevant
subjective effects of these d r u g s 3 1 , 3 2 . Of note were investigations assessing the
effect of LSD on the perception of time passage, which bridged arcane
psychophysiology and inner experience 33 .

Route of administration
Rarely was the administration route made the primary focus of investigations.
Hoch 3 4 compared onset, peak and duration issues using oral, intramuscular (i.m.),


intravenous (i.v.) and intraspinal LSD, while Freedman reported on 'rapid i.v.
push' administration 35 . Rapid i.v.-push LSD effects were noted 'within minutes',
while onset of effects with intraspinal LSD was 'nearly instantaneous'. In spite
of the differences in onset, duration was quite similar for all parenteral routes,
i.e. 9-10 h. Whilst i.m. DMT, DET and DPT all showed onset of effects within
3 to 15 min, the lack of 'nearly instantaneous' effects still raised questions
regarding immediate versus 'downstream' effects. However, as is evident from
our DMT data, discussed below, rapidity of onset may relate as much to the
pharmacokinetic as to the pharmacodynamic properties of specific drugs.

Hallucinogens administered to psychiatrically ill patients

Acutely and chronically ill psychiatric patients were also administered

hallucinogens, and responses compared to healthy volunteers. These studies were
designed with the aim of elucidating functional differences in different diagnostic
groups. They foreshadowed the current approach of studying presumed
neurotransmitter dysfunction by comparing responses in patients with
hypothesized abnormalities of the system of interest, with those of healthy
Furthermore, whilst LSD was believed to mimic certain features of psychoses
in normal volunteers, the true nature of these similarities remained elusive.
Administering hallucinogens to schizophrenic patients, and assessing similarities
and differences between endogenously- and exogenously-derived symptoms, was
used to further explicate these questions.
Most studies demonstrated that schizophrenics who had LSD administered to
them worsened, usually with an exacerbation of their pre-existing characteristic
symptoms 3 6 , 3 7 . Despite a worsening of symptomatology, the more verbal and
communicative patients were able to distinguish between the effects of the
hallucinogens and those of their pre-existing disorder 3 8 , 3 9 . Interestingly, patients
with successful outcomes to psychosurgery showed a recrudescence of their
presurgery pathology when administered either LSD or mescaline 3 6 , 4 0 . Another
relatively consistent finding was that the more 'chronic' or 'burned out' patients
showed a blunted psychological response to LSD compared to n o r m a l s 3 6 , 4 1 , 4 2 , a
finding also confirmed with D M T 4 3 . However, a general decrease in the patients'
ability to communicate their inner state tempers the validity of these data. More
objective measures of responsivity, such as neuroendocrine factors, may shed
further light on these issues.
Some preliminary data suggested a salutary effect of LSD on psychiatric
disorders, including autism 44 and melancholic depressions 45 , using daily doses of
LSD over several weeks to months.


A note on early human structure-activity relationship studies

Many congeners of the classic hallucinogens have been synthesized. However,
only a small number of these have been assessed in a very limited number of
human studies. These included the tryptamines DET, DPT, CZ-74, CY-19; the
lysergamides L-methyl-D-lysergic acid diethylamide (MLD), D-L-acetyl lysergic
acid diethylamide (ALD), D-lysergic acid dimethylamide (DAM), D-lysergic acid
monoethylamide (LAE), D-lysergic acid pyrrolidide (LPD), and D-lysergic acid
morpholide (LSM) 46 ; and the phenethylamines 2,5-dimethoxy-4-ethylampheta-
mme (DOET) 4 7 and D O M 9 . For example, ALD-52 was found to be quite similar
to LSD in potency and duration, while MLD-41 was about one-third as potent,
and showed a shorter duration of action. D-L-Methyl-2-brom-lysergic acid
diethylamide (MBL), which was five times as potent in animal models of anti-5-HT
effects was, however, inactive in humans at doses up to 175 μg/kg 4 6 . With their
history of safe use in humans, the psychopharmacology of these compounds could
be studied, and correlations made with their neuropharmacological properties.
Regulatory agencies may require less rigorous documentation regarding clinical
safety issues, as these drugs were administered to humans without adverse sequelae.

Hallucinogens have multiple effects on central neurotransmission. Serotonin
(5-HT) mechanisms are of greatest current interest, and there are descriptions of
LSD's antagonism of several 5-HT-stimulated effects 48,49 . LSD was also shown
to affect central 5 - H T parameters uniquely, with 5-HT levels in the brain rising
whilst metabolite 5-hydroxyindole acetic acid (5-HIAA) levels dropped 5 0 .
Radioligand binding studies of hallucinogens, which initiated the wave of
intensive study of 5 - H T systems 51 , reveal binding at nearly every 5-HT subtype,
with 5 - H T 1 C , 5 - H T 2 and 5 - H T 1 A sites being of greatest interest. Interactions
between these subtypes is being explored further, with electrophysiology 52 ,
behavioral pharmacology 53 , and human neuroendocrine 54 data suggesting oppos-
ing roles for 5 - H T 1 A and 5 - H T 2 / 1 C sites.
Studies using a variety of 5-HT agonist/antagonist compounds support the
importance of 5-HT mechanisms in modulating a number of physiological
variables. Peripheral sympathetic effects include hyperthermia 55 , hypertension 56 ,
tachycardia 57 and mydriasis 58 . Neuroendocrine activation is seen with
adrenocorticotrophic hormone (ACTH) β-endorphin, prolactin, growth
hormone, renin and vasopressin release 59 .
Behavioral pharmacology has invested great effort in attempting to develop
animal models for hallucinogenic drug effects. The 5-HT 2 / 1 C subtype is currently


the most intensively studied one. Affinity for this site is correlated with the (often
meager) available data on human potency 6 0 . Ritanserin, a selective 5 - H T 2 / 1 C
antagonist, blocks the behavioral effects of different chemical classes of
hallucinogens 6 1 , 6 2 .
Reducing presynaptic 5-HT, for example by reserpine 63 , lowers threshold
doses for eliciting hallucinogenic effects in animals. Conversely, and consistent
with a post-synaptic mechanism of action, chronic antidepressant exposure raises
this threshold 64 . Also supporting a post-synaptic effect, a tolerance regime of LSD
induces downregulation of 5-HT 2 receptors 65 .
The contribution of the 5 - H T 1 A subtype is less certain. D M T and LSD have
almost equal affinities for the two subtypes 6 6 , 6 7 , whilst 5 - M e O - D M T has greater
affinity for the 5-HT 1 A site 68 . A trained animal perceives the discriminate effects
of 5 - M e O - D M T as similar to LSD 6 9 and D O M (with no 5 - H T 1 A affinity) 70,
while the 5-HT 1 A antagonist pindolol blocks 5-MeO-DMT's interoceptive
effects 71. Thus, we believe that the importance of the 5 - H T 1 A site in contributing
to the characteristic effects of hallucinogens needs to be ascertained more carefully.
The role of 5-HT in mediating LSD's effects was made the focus of many of
the early human studies, assessing effects of manipulating this newly discovered
neurotransmitter's function, and building upon early basic research findings.

Serotonin antagonism studies

Although both bromo-LSD (BOL) and LSD potently inhibited 5-HT-induced
uterine contractions, BOL was found at first to be essentially non-psychoactive 72 .
However, at doses greater than 70μg/kg orally, or i.v. doses of 18 mg or more,
effects were L S D - l i k e 4 6 , 7 3 , 7 4 . The logical next step - to assess the blockade of
LSD's effects by non-psychoactive doses of BOL in normal humans - was
generally successful 74-76 . BOL, although ineffective in treating endogenous
psychoses, prevented LSD's effects in schizophrenics 38 . Another study assessing
the effect of the (poorly characterized) 5-HT antagonist (BAS - 1-benzyl-2-
methyl-5-methoxytryptamine), failed to demonstrate acute pretreatment re-
duction of LSD effects 77.
Frenquel (azacyclonol) has had a checkered history as an LSD-antagonist, and
pharmacological characterization of this compound is deserved. Frenquel's
previous manufacturer suggested there are 5-HT 2 antagonistic effects, although
there are no published references to this, to the author's knowledge. The
'anti-LSD' effects of Frenquel heralded its brief term as an anti-psychotic
medication in endogenous disorders 78 . It was initially reported that a week of
pretreatment with Frenquel prevented the effects of LSD in normal volunteers,
and i.v. administration aborted an ongoing LSD experience 79 . However, an
almost identical study demonstrated that neither of these regimes were antagonis-
tic to the effects of LSD 8 0 .


Meitzer and co-workers 81 and Demisch and Neubauer 8 2 generated neuroendo-

crine data for DMT and mescaline, respectively. The former study demonstrated
that cyproheptadine, a relatively specific 5 - H T 2 / 1 C antagonist 83 , blocked the
psychological and growth hormone effects in two-thirds of the subjects studied.
However, only in the subject without psychic antagonism did cyproheptadine
inhibit the DMT-induced rise in Cortisol and prolactin. Interestingly, the effects of
DMT were markedly enhanced by the use of methysergide, a potent anti-5-HT
lysergamide 84 .
Building upon the hypothesis that LSD antagonizes the effects of 5-HT, 5-HT
precursor loading studies attempted to overcome this blockade. However, the
results of these studies were highly variable. For example, the infusion of
5-hydroxytryptophan (5-HTP) into humans, shortly before i.v. LSD administra-
tion, resulted in reduced rating-scale scores, but clinical interviews and subjective
responses showed that patients could not distinguish between 5-HTP and placebo
pretreatment 8 5 , 8 6 .

Monoamine oxidase inhibitor (MAOI) treatment

Careful attention to dose and duration is necessary to determine the effects of
enhancement or reduction of hallucinogen effects in humans. This is especially
important for MAOI or reserpine studies. A single dose of isocarboxazide had no
effect on LSD responses in humans 8 7 . However, 2-5 weeks' treatment with
isocarboxazide markedly reduced the acute effects of LSD 8 8 . Paradoxically, Sai-
Halasz demonstrated that the effects of DMT were robustly enhanced after a 4-day
treatment with iproniazid, even after a 2-day washout was provided to eliminate
any residual circulating M A O I 8 9 . This may relate as much to the inhibition of
DMT metabolism by M A O I 9 0 as it does to downstream receptor adaptation.

Duration of treatment is perhaps nowhere as relevant as studies with reserpine.
Reserpine, administered immediately before LSD, did not modify effects in
humans 8 7 , but when given 20 h before LSD, the latter's effects were enhanced 91 .
A high, single dose of reserpine administered to schizophrenics markedly
augmented LSD's effects 2 days later 92 , whilst a more adequate 'up-regulating'
2-week exposure to reserpine increased the acute psychological effects of LSD 8 7 .
In general, it appears that higher doses or longer duration of treatment with
reserpine can enhance LSD's effects, in some cases, inducing some of the
symptoms of a 'serotonin syndrome'-like delirium 80 .

'Downregulation'-induced decreased sensitivity to hallucinogens

Field reports of recreational users of hallucinogens also support the view that
5-HT mechanisms mediate these drugs' effects. For example, fluoxetine and


allopurinol both reduced the effects of hallucinogens in two experienced users.

This effect may devolve from post-synaptic 5-HT-receptor changes secondary to
enhanced synaptic 5-HT levels 93 .

Non-hallucinogenic 5-HT agonists

A discussion of the human psychopharmacology of hallucinogens would be

incomplete without referring to the effects of newly developed compounds with
similar neuropharmacological characteristics. That is, are other serotonin agonists,
with similar binding profiles to those of the hallucinogens, 'hallucinogenic'?
The best characterized compound in such use today is probably meta-
chloropiperazine (mCPP) which has a mixed receptor binding profile, with
5 - H T L C agonism, and 5-HT 2 antagonism 94 . mCPP elicits increases in positive
symptoms in schizophrenic patients 95 , and these effects are blocked by the
5 - H T 1 C / 2 antagonist ritanserin 96 . However, psychotic responses are not seen in
normals. This suggests a greater sensitivity to 5-HT agonist effects in
schizophrenia, contrary to descriptions of reduced sensitivity in early studies
where hallucinogens were administered to schizophrenic patients. MK-212
[6-chloro-2-(l-piperzinyl)pyrazine] has a high affinity for 5 - H T 3 , 5 - H T 1 A ,
5-HT 1 C and 5-HT 2 receptors and has been administered to normals and
psychiatric patients 97 . Alcoholics show an 'LSD-like' response, while normals do
not 9 8 . If altered sensitivity to these 5-HT active drugs is contentious, perhaps
higher doses in normals would produce more classic psychedelic responses.


Questions regarding the role of dopamine were raised during the first generation
of human hallucinogen work. Results from animal studies suggested
hallucinogen-mediated dopamine release 99 , which may be mediated by pre-
synaptic autoreceptor effects 100 . In addition, binding to haloperidol- and
apomorphine-binding sites was described for both LSD and D M T 1 0 1 . LSD, but
not DMT, elicited dopamine-like contralateral turning behavior 1 0 2 , but the
former compound also demonstrated antidopaminergic properties 1 0 3 .
Contradictory data exist in humans. For example, the dopamine agonist
methamphetamine (20-40 mg i.v.), especially in combination with 200-500 mg
i.v. amobarbital, briskly curtailed the duration of LSD's effects in humans 3 4 .
There are considerable data on the 'dopamine antagonist' chlorpromazine's
interactions with LSD. However, the anti-5-HT and anti-adrenergic effects of
chloropromazine complicate any facile interpretation of these data. Early results
from animal studies suggested that the doses of LSD and chlorpromazine were
crucial in determining whether an enhancement or reduction of LSD's effects


were s e e n 1 0 4 , 1 0 5 . Chlorpromazine also has inhibiting or potentiating effects on

LSD in humans, depending upon timing and dose, supporting the results from
field reports of a chlorpromazine enhancement of hallucinogen effects in the
emergency-ward setting 1 0 6 .
Murphree demonstrated a 'shift to the right' in the dose-response curve for
LSD after chlorpromazine pretreatment, but only for threshold, low doses of
LSD 1 0 7 . Hoch showed that intravenous chlorpromazine ameliorated the auto-
nomic and psychic effects of LSD in humans 3 4 , as did Abramson for intramuscular
administration 108 . However, the latter study reported increased LSD effects
if chlorpromazine were administered orally during the LSD reaction. Finally,
some investigators have found no effect of chlorpromazine pretreatment 109 .
Preclinical studies also showed (anti-dopamine) neuroleptic enhancement of
DMT's effects 110 . In support of these data, Meitzer described (in one subject)
enhancement of the hallucinogenic and growth hormone effects of DMT after
acute intramuscular haloperidol pretreatment 81 .
The importance of the simultaneous blockade of 5-HT and dopamine receptors
is supported by the higher potency of risperidone versus ritanserin in abolishing
the discriminative cue of LSD in rodents 1 1 1 . No corresponding data exist in

Early basic research suggested a role for norepinephrine in mediating some of
LSD's effects. For example, phenoxybenzamine (an α-adrenergic antagonist with
central effects) blocked behavioral effects in cats 1 1 2 . The compound a-methyl-
para-tyrosine, which decreases brain levels of norepinephrine, prevented the
behavioral and sympathomimetic effects of LSD, whilst leaving intact hyper-
thermic responses 113 . Later preclinical work established that LSD and mescaline
enhanced the noradrenergic responses of locus coeruleus neurons to peripheral
stimuli 114 , while hallucinogens also enhanced norepinephrine's effects on facial
motor nucleus neurons 1 1 5 .
Human data on adrenergically mediated effects of hallucinogens have been
contradictory and deserve further investigation. For example, Murphree found
that the effects of a threshold LSD dose (20 μg) could be blocked by acute
pretreatment with a dose of phenoxybenzamine that was inactive by itself 107 .
However, Isbell and colleagues 77 , and Bertino and co-workers 1 1 6 found only that
phenoxybenzamine pretreatment reduced the mydriasis of higher doses of LSD.

As with the noradrenergic system, cholinergic mechanisms have been studied
only superficially for salient human-hallucinogen interactions. Animal data have
suggested a role for acetylcholine in mediating some of the effects of D M T 9 9 , 1 1 7


and LSD 1 1 8 . However, Isbell and colleagues found no moderating effect of acute
pretreatment with scopolamine on LSD intoxication 77 . On the other hand, Forrer
and Goldner found that atropine enhanced the euphoric properties of LSD in
schizophrenics 119 .

Sex differences
There are abundant data regarding the importance of sex-steroid milieux for
modulating 5-HT function 1 2 0 , 1 2 1 and whole-animal responses to 5-HT-active
agents 1 2 2 . Human data also suggest a role for sex steroids in 5-HT neurotrans-
m i s s i o n 1 2 3 , 1 2 4 . This line of inquiry, using hallucinogens as probes of the gonadal
axis in humans, may shed light on the different prevalence rates of hallucinogen
use between male and female young adults 1 2 5 . Perhaps a changing sensitivity over
the menstrual cycle dissuades casual use in women.
Although receptor and monoamine metabolite effects of sex steroids usually are
believed to require sub-acute exposure to the relevant hormones, acute pretreat-
ment studies in which progesterone was administered to men demonstrated a
robust inhibition of LSD effects 3 2 , 1 2 6 .


Tolerance to the psychic effects of hallucinogens is of heuristic and clinical
interest. Understanding tolerance in pharmacological systems provides insights
into receptor homeostasis, uncoupling of second-messenger systems, and
dynamics of the metabolism of neurotransmitters and exogenous substances.
Human tolerance to hallucinogens' 'psychotomimetic' effects could be turned to
therapeutic use if endogenous hallucinogens contributed to the functional
psychoses. That is, if schizophrenics were made tolerant to the effects of
pharmacologic doses of endogenous hallucinogens, would there be less naturally
occurring symptomatology?
Hallucinogen tolerance has been demonstrated in neuropharmacologic 127 ,
electroencephalographic 128 , and whole animal behavioral 129 assays of
hallucinogen effects. However, raphe inhibition does not show tolerance to a
dosage regime that induces behavioral tolerance in the whole animal 1 3 0 . Cross-
tolerance occurs when different drugs produce tolerance to each other, and
supports a similar mechanism of action 1 3 1 .
Tolerance to the behavioral effects of DMT has been notoriously difficult to
demonstrate in lower animals 132 , and even heroic regimes (every 2 h for 21 days)
failed to produce complete tolerance to a bar-pressing paradigm in lower
animals 133 . The difficulty in demonstrating behavioral tolerance to the effects of
DMT in animals raises questions regarding the role of half-life in the development
of tolerance - i.e. is tolerance elicited by longer-acting (and not shorter-acting)


drugs because of differential lengths of exposure to relevant receptors, or because

of unique pharmacodynamic properties.
The opposite effect - sensitization - also can occur, depending on dose and
administration intervals. This phenomenon has been noted for DMT's
electroencephalographic 134 , 5-MeO-DMT's neuroendocrine 135 and DOM's
behavioral 136 effects.
Human data regarding tolerance and cross-tolerance to hallucinogens are
tantalizingly incomplete and could be strengthened with little difficulty by using
current methodologies systematically to confirm, refute, or modify hypotheses
generated by the first generation of human hallucinogen researchers.
Robust tolerance develops after 3-4 daily exposures to psychoactive doses of
L S D 1 3 7 and D O M 1 3 8 . However, tolerance may be either less complete, or more
difficult to attain with psilocybin 1 3 9 , 1 4 0 and mescaline 141 . Consistent with animal
data, DMT tolerance is difficult to demonstrate. A fully hallucinogenic dose of
DMT twice a day for 5 days did not evoke tolerance in humans 1 4 2 . In addition,
field reports of closely spaced, repetitive smoking of DMT free base have
produced conflicting results 143 .
Cross-tolerance studies in humans have yielded complex data. LSD responses
in mescaline-tolerant subjects may be less inhibited than mescaline responses in
LSD-tolerant individuals 1 4 1 , 1 4 4 , although the opposite finding has also been
reported 1 0 6 . Psilocybin and LSD develop cross-tolerance with each other 1 4 5 ,
although whether LSD responses in psilocybin-tolerant subjects are less 1 4 6 or
m o r e 1 4 0 than those seen in LSD-tolerant subjects, is uncertain. Even more striking
is the finding that humans who are completely tolerant to LSD show no
cross-tolerance to a fully hallucinogenic dose of D M T 1 4 7 . Only a few lysergamide
congeners have been assessed for cross-tolerance to LSD, and suggest that
cross-tolerance develops 148 .

The search for the endogenous schizotoxin/hallucinogen once nearly attained the
status of that for the Holy G r a i l 1 4 9 , 1 5 0 . Two leading candidates for this position
were D M T 1 5 1 and 5 - M e O - D M T 1 5 2 .
DMT has been found repeatedly in human body fluids 153 . Precursors and
enzymes exist for its synthesis in vivo and in vitro, in blood 1 5 4 and brain 1 5 5 . Before
this research ended, emphasis had shifted from the suggestion of absolutely higher
peripheral levels of DMT in psychoses compared to normals, to the correlation of
DMT levels with acute symptomatology in endogenous psychoses 156 . Less robust
responses to DMT in psychotic patients 43 also supported its role in endogenous
hallucinatory states, perhaps reflecting a degree of tolerance from greater cumula-
tive exposure to endogenous DMT.
In addition, the metabolism of DMT is of interest, because so little is excreted


unchanged after administration of pharmacological doses. Szara found that 3-IAA

is probably the primary metabolite 157 , while suggesting that 6-hydroxylation was
relevant to its mechanism of action. However, Rosenberg and colleagues found
no psychoactivity from 6-hydroxy-DMT 7 5 . Later studies determined that
oxidative deamination is the primary route of metabolism, yielding
D M T - N - O H , while 3-IAA is the breakdown product of D M T - N - O H 9 0 .
Although inconclusive evidence dissuaded investigators from pursuing the
DMT-model of endogenous psychoses 142 , the very small amount of DMT found
in the circulation even after pharmacological doses 1 5 8 suggests that blood levels
are a poor reflection of endogenous central production or sensitivity in discrete
brain areas.
The role of endogenous DMT in normal and abnormal mental states in humans
thus remains undetermined.


We now are seeing the beginning of the next phase of human hallucinogenic drug
research. Several converging forces have contributed to the establishment of these
nascent projects. Recent advances in serotonin receptor physiology provide a firm
scientific backdrop against which the study of these agents can take place. In
addition, the tumultuous social, cultural and political forces which often found
regulatory, research and activist communities at odds with each other have had
nearly a quarter century to resolve themselves (or be forgotten!) to each other's
satisfaction. The reflex reactions of interested parties are being replaced by more
measured responses to issues regarding the study of these drugs.
Our European colleagues have begun several important research projects. The
Swiss have embarked on the sophisticated mapping of brain effects of tryptamine
hallucinogens within the psychotomimetic model. They also are using the
hallucinogens within the context of traditional individual and group psycho-
dynamic psychotherapy. The Germans also have taken the psychotomimetic
approach, using phenethylamine hallucinogens. Modern electroencephalographic,
neuroendocrine and cardiovascular response data are being generated.

Human DMT studies

Our group, at the University of New Mexico, has been studying DMT in humans
since November 1990, in a clinical research setting. DMT was chosen for several
reasons. First, its presence in human body fluids has not been adequately
explained. If DMT were involved in endogenous hallucinatory states, then
compounds that block its psychological effects might prove useful in the
treatment of these disorders. For example, ritanserin has had some success as an
antipsychotic agent 1 5 9 , and blocks the discriminative properties of the classic


hallucinogens. Amperozide, another relatively selective 5-HT 2 antagonist, is also

a useful antipsychotic agent 1 6 0 .
Second, DMT is a rapidly acting drug, better suited to the demanding
environment of a modern clinical research center, than the 10-12 h long effects of
LSD. It was considered that potential dysphoric reactions to DMT would be less
difficult to manage because of their brief duration.
Third, DMT meets electrophysiological 161 , pharmacological 67,68 , and be-
havioral 1 6 2 criteria of a 'classical' hallucinogen. Although some pecularities of its
effect pose intriguing questions (e.g. the difficulties encountered in demonstrating
cross-tolerance with LSD), the similarities are sufficiently great to enable generali-
zations to be made from our data to the effects of better-known compounds.
Fourth, DMT is a relatively obscure drug; it was first determined in
hallucinogenic Amazonian snuffs 163 . Due to the highly controversial nature of
LSD use, we consider that a DMT study would be less likely to attract undue
media attention. This may change, however, as the use of DMT (in the form of
ayahuasca, mentioned above) is growing in popularity within the 'psychedelic
The acquisition of the requisite licenses for performing a human hallucinogen
research project took almost 2 years 11 . Future American studies should be less
impeded in their approval, as this precedent has been established.
Our initial protocol obtained dose-response data for D M T 1 6 4 , 1 6 5 . Several
biological, dependent variables were chosen for measurement because of their
putative modulation by 5-HT systems. These included neuroendocrine,
cardiovascular, and autonomic responses. Additionally, we were interested in
developing a new rating scale for DMT effects, one that could also be applied to
studies of other hallucinogens.

Hallucinogen Rating Scale development

The development of a new instrument, the Hallucinogen Rating Scale (HRS),
began with interviews of 19 experienced DMT users who had also taken a wide
variety of other hallucinogens. Most were highly educated, well-functioning
individuals who were able to provide detailed and candid descriptions of the
effects of DMT free base when smoked, the usual route of recreational use 1 4 3 .
Negative, positive, and neutral experiences were elicited, although as expected,
positive effects predominated in these descriptions. Thus, our scale differs from
previous ones in that no particular theoretical framework overlaid its
development, and it was drafted using responses from individuals who sought
and enjoyed the effects of hallucinogens. A first draft of the scale was developed
and refined during the early stages of our dose-response work. Although the
original version used in the initial dose-response study required over 230
responses, our current version has less than half this number.



The subjects chosen were experienced hallucinogen users, for several reasons.
First, it was anticipated that such users would be less prone to panic at the sudden
intense onset of hallucinogenic effects of DMT, particularly in the potentially
stressful clinical research setting. Second, experienced subjects were likely to be
more capable of describing the effects of DMT, because of their familiarity with
the effects of hallucinogens in general. Third, we were concerned about liability
issues, and considered that previous users would be less able to sustain a claim of
damage resulting from our study.
The issue of self-experimentation by the research team was discussed. There are
advantages to being personally exposed to the effects of a drug used in research,
as long as clinical protocol decisions are made relying on more than these data
alone. However, because of the controversial nature of this work, the stifling
effects on research of highly publicized recreational use by previous investigators,
and the vulnerability to charges of a loss of scientific objectivity, we were
dissuaded from this approach.
Recruitment was by 'word of mouth' within local communities. Twelve
subjects began our dose-response project, and nearly 50 have participated in this
and subsequent protocols. Over three-quarters of the volunteers are men, and
most are white. The majority are at least college educated, and many have profes-
sional degrees. Ages range from the early 20s to the mid-50s. There is a heavy
loading of past personal and family histories of depression in these volunteers. In
addition, the first 12 subjects had nearly 20 divorces among them, suggesting a
high degree of impulsivity. Thus, our findings, although rigorous in their
measurement of relevant variables, should be considered within the context of the
subjects not being 'psychiatrically normal'.
The subjects go through a well-established screening process. Information
packs are sent to interested individuals, who contact a member of the research
team. The principal investigator then interviews all prospective subjects, briefly
screening for medical and psychiatric conditions, and assesses the quality and
quantity of experience with hallucinogens. Those with very limited experience, or
with poorly integrated, acute adverse reactions to the drugs, are excluded from
further consideration. A medical history and physical examination (including
multiple laboratory screening tests) are performed, and if the results are within
normal limits, subjects then receive a standardized psychiatric diagnostic inter-
view for DSM-III-R diagnoses. A subject with a prior history of major depression
is allowed to participate if he/she has been in remission and has not required medi-
cation for at least 2 years, has understood the nature and course of the disorder,
and was not in circumstances conducive to a re-occurrence of this mood disorder.
The final decision to accept subjects into the study, however, is based upon the
research team's discretion.


Intravenous versus intramuscular DMT

DMT fumarate, dissolved in sterile saline, is administered intravenously, rather
than intramuscularly as in previous clinical research studies, because of our early
experience in dose-finding pilot work. The experienced DMT smoker who was
our initial subject stated that the onset of effects of 1.0mg/kg i.m. DMT were
slower and less intense, and the peak effects were less overwhelming than he was
accustomed to after smoking DMT freebase. As our research focus required the
elicitation of effects found desirable by recreational users, we decided to
administer the drug by intravenous push, over < 1 min. This approximated the
rapid absorption of DMT resulting from exposure to the pulmonary vascular bed
by the smoking route.
Two experienced DMT smokers volunteered for intravenous dose-finding
work. We determined that 0.6 mg/kg i.v. DMT produced a delirious state, from
which subjects could not recall much of the early effects. A dose of 0.4 mg/kg
produced effects comparable to that of a 'full dose' of smoked DMT, with little if
any confusion. Our low dose, 0.05 mg/kg, produced barely perceptible effects,
and was considered a sub-clinical dose. Intermediate doses were 0.1 and
0.2 mg/kg. Sterile saline was the inactive placebo.

Dose-response studies: methods and results

All subjects received 0.05 mg/kg of DMT on a given day, and 0.4 mg/kg DMT on
another, as 'screening' doses. We found that subjects with high normal resting
blood pressures occasionally showed a robust diastolic response to this low dose,
which then precluded them from future studies. The 0.4 mg/kg 'test' dose was,
firstly, to acquaint subjects with maximal DMT effects; secondly, to provide an
opportunity for their withdrawal from further, more intensive data-gathering
studies, if drug effects were intolerable; and, thirdly, to allow the research team
and volunteer the opportunity to become accustomed to each other's personalities
and behavior styles before commitment to the more demanding double-blind
Studies are carried out at the inpatient unit of a National Institute of Health-
funded General Clinical Research Center. This unit contains beds for clinical
research subjects, in addition to oncology patients, many of whom are receiving
experimental chemotherapy treatments. Both clinical populations require nursing
expertise in establishing and maintaining venous access, and intensive nursing
involvement in human research studies. One nurse was assigned to this study, an
important requisite in enhancing the consistency necessary for subjects who often
found themselves regressed and helpless during high-dose DMT sessions.
Although these DMT studies were carried out previously in any one of the
single rooms of the unit, one room in particular is currently being remodelled to
provide a less sterile, high-technology atmosphere, which we hope is more


comfortable for our volunteers. The ward-wide intercom system is temporarily

switched off and a 'no-entry' sign placed on the door of the room, immediately
before sessions begin.
One intravenous line is set in place for DMT administration, and another in the
opposite arm for drawing blood. A flexible rectal thermistor is inserted, and a
blood pressure cuff placed on the arm used for DMT injection. DMT is
administered over 30 s, and the line flushed with 3 ml sterile saline over a further
15 s, and samples are collected for up to 1 h afterwards. The research team, a
psychiatrist and a nurse, sit on either side of the subject, and remain quiet but
attentive to verbal and nonverbal communication. As the acute effects of the drug
begin resolving, and when the volunteer indicates a readiness to begin talking,
focus is primarily on descriptive issues, rather than overtly therapeutic ones. The
Hallucinogen Rating Scale (HRS) is completed, generally within an hour after
DMT/placebo administration, and after all acute drug-effects have resolved.
Subjective effects of DMT begin almost immediately, usually while the saline
flush is being given, and peak effects are attained within 90-120 s after
administration. Nearly all psychological effects have resolved by 30 min. The
time-course of subjective responses parallels that of DMT blood-levels, peak
concentrations being seen at the first (2-min) blood sampling. Hypertensive and
tachycardic responses also follow this time course, as do pupillary dilatory effects.
Blood levels of ACTH and β-endorphin peaked 5 min after injection, while
prolactin and Cortisol responses lagged 5-15 min. Stimulation of growth hormone
levels in blood and hyperthermic effects did not begin until the psychological
effects had nearly resolved, at 15 min, and were continuing to rise at the end of
data collection, at 60 min.
All of these variables, except for growth hormone levels, showed dose-
dependent stimulatory effects of DMT. Growth hormone responses for all DMT
doses were greater than those seen with placebo, but could not be separated by
dose. The threshold for significant effects of DMT relative to placebo was that for
full hallucinogenic effects: 0.2 mg/kg or above.

Subjective effects Doses of 0.2 mg/kg DMT, or higher, elicited a very rapidly
developing, powerful and somewhat anxiety-provoking 'rush'. This then led to
an intensely colored, rapidly moving visual display of images, experienced usually
with eyes closed, that completely replaced previously existing mental contents. At
the higher doses of DMT, dissociation occurred, and subjects were no longer
aware of their physical bodies. Rapidly shifting mood-effects were seen, ranging
from euphoria to terror. Despite the sense that the reality of these images and
feelings was more compelling than waking or dreaming awareness, subjects
generally were able to observe the sequence of events and report upon them in
some detail. Doses of 0.1 and 0.05 mg/kg produced effects that were primarily
emotional and somatic, with minimal perceptual effects.


The HRS questions were clustered, using upon both an 'empirical, mental
status' approach, and a principal components factor analysis method with a
varimax rotation. The clinical clusters contained questions referring to effects on
the following mental functions: perception (visual, auditory, tactile, olfactory and
gustatory); cognition (process and content of thought); affect (emotional
condition/mood); volition (wilful interaction with self and the experience);
somesthesia (visceral and exteroceptive somatic cues); and intensity (global
measure of 'quantitative' effects). Both methods of grouping items (clinical
clustering and factor analysis) demonstrated that there were dose-dependent
effects of DMT relative to placebo; their sensitivity was comparable, and both
showed better separation of dose effects than did the biological variables.
These data were interpreted in the light of findings from lower animal studies,
and were proposed to be mediated by 5-HT mechanisms. The majority of our
results suggest a 5 - H T 2 / 1 C mechanism of action although, in several cases, 5 - H T 1 A
effects were also proposed. In addition, the rapidity of onset of DMT effects was
hypothesized to reflect the rapid access of DMT to the brain, seen in lower
animals, perhaps reflecting an active transport of DMT across the blood-brain
b a r r i e r 1 6 6 , 1 6 7 . This hypothesis is also supported by data which suggest that rapid
onset of LSD effects via 'fast i.v. push' 3 5 or a direct route into the lumbar spinal
fluid 34. The slower onset of phenethylamine hallucinogens, even in cortical slice
models, indicates the relevance of lipid solubility, in addition to entrance across
the blood-brain barrier 1 6 8 .
Once these normative data were generated, more experimental protocols were
designed. These included, first, an attempt to develop tolerance to DMT; second,
pretreatment with the mixed β-adrenergic agonist-antagonist and potent 5 - H T 1 A
antagonist pindolol 1 6 9 , in order to assess the role of this receptor subtype in medi-
ating DMT's effects in humans; third, a similar study using a 5 - H T 2 / 1 C antagonist;
and, fourth, a direct comparison of DMT's effects with the longer-acting, orally
active tryptamine, 4-phosphoryloxy-N,N-DMT (psilocybin).

Tolerance study
Thirteen subjects participated in the tolerance study. On a specified day, four
half-hourly injections of 0.3 mg/kg i.v. D M T were administered; on the other,
four doses of saline placebo were given. The decision to use a 30-min interval was
based on our initial study; ACTH, prolactin, and cardiovascular effects were
resolved by this time, and DMT levels were almost undetectable. This was also
the shortest time-interval in which subjects were able to fill out an abbreviated
version of the HRS, based upon pilot work. Prolactin and ACTH were chosen as
the neuroendocrine markers, based upon the dose-response study. The separation
of response by dose of DMT for these was reasonable, and the difference in the
response course over time suggested a different mechanism by which DMT
stimulated their release.


Biological variables showed inconsistent tolerance: heart rate, ACTH and

prolactin responses dropped significantly from the 1st to the 4th DMT session,
while only the ACTH responses reached placebo response-values. Mean arterial
blood pressure showed no tolerance, and temperature data could not be
interpreted because baseline effects between DMT sessions were greater than
responses within individual sessions.
HRS clinical clusters were also compared across DMT sessions, and the results
provide little evidence for the development of tolerance to the psychological
effects of DMT. There was a trend only for 'volitional' effects to decline from
DMT session 1 to session 4, although 4th session values were still greater than
those for placebo. Clinical interviews also supported the conclusion that little, if
any, reduction in subjective effects was evident across sessions.
Thus, both 'psychology' and 'biology' demonstrate highly divergent responses
to repeated DMT administration, suggesting that the location or characteristics of
5-HT sites mediating the biological and psychological effects of DMT differ.

Pindolol antagonism study

We have begun preliminary work with a pindolol 5 - H T 1 A antagonism pretreat-
ment protocol. Responses in three individuals suggest there is an enhancement of
DMT's cardiovascular and subjective responses when it is administered 90 min
after 30 mg oral racemic pindolol. This may be evidence for a 'buffering' or
antagonistic effect of 5 - H T 1 A agonism on 5-HT 2 responses. This is a tantalizing
possibility, in support of basic findings, but requires completion of the entire
study, using placebo-controlled, double-blind conditions.


Newly developed imaging methods that assess in vivo brain metabolism should
continue to be used to assess the effects of hallucinogens in humans. These
include refinements of older techniques, such as topographic pharmaco-electro-
encephalography, and radically new tools such as magnetic resonance spectro-
scopy functional imaging, single photon emission computed tomography, and
positron emission tomography. Our European colleagues are leading the way in
this regard.
There remain questions regarding the mechanisms of action of hallucinogenic
drugs in humans. More selective and potent antagonists for relevant receptors
need to be developed for clinical research, such as a pure 5 - H T 1 A antagonist and
selective 5 - H T l c versus 5-HT 2 drugs. Earlier human studies which supported a
role for 5-HT, such as reserpine, 5-HTP, and MAOI conjoint treatments need to
be confirmed and developed more fully. The newly developed strategy of acute


tryptophan depletion enhances 5-HT agonist neuroendocrine effects 170. If

hallucinogens' effects were similarly enhanced, it would strengthen support for
5-HT's role in mediating hallucinogen effects in humans.
Also of psychopharmacologic interest is the upsurge in popularity of the
Amazonian botanical brew known as 'ayahuasca', or 'yage' 7 , composed of plants
containing DMT and the β-carboline reversible monoamine oxidase inhibitors
harmine and harmaline 1 7 1 , 1 7 2 . The enhanced oral activity of DMT in this
preparation suggests that oxidative deamination, probably by type A MAO
(5-HT-preferring) 173 is the primary reason for the lack of oral efficacy of DMT.
Systematic approaches to this problem can be taken in the modern clinical
research setting, using recently developed selective MAO A and B subtype
inhibitors such as 1-deprenyl and selegeline.
Analogs of the lysergamides, tryptamines and phenethylamines, some of which
were administered in small clinical trials, could be investigated more thoroughly,
after safety and receptor binding profiles are established. Additionally, the
psychological properties of non-hallucinogenic 5-HT agonists may be assessed
using the HRS, and data compared to those generated by classic hallucinogens and
their analogs. A structure-activity-relationship database could then be established
upon which decisions regarding development of novel psychoactive (hallucino-
genic or other) compounds could be based. Novel psychoactive drugs, appearing
either 'on the street' or in the academic/industry laboratory, could be assessed
using reference data from the studies of classical drugs.
Continuing use and abuse of these drugs require that specific, safe, and effective
antidotes to adverse effects of acute intoxication be found. Pretreatment blockade
strategies will provide suggestions, as regards 'interruption' studies, whereby the
ongoing intoxication could be reversed with selective blockading agents. Chronic
users may also find a viable treatment option in preventive, blockade-type
strategies similar to those available for opiate addicts.
Suggested abnormalities in 5-HT systems in several psychiatric disturbances,
such as obsessive-compulsive disorder, schizophrenia, affective disorder, post-
traumatic stress disorder, and disorders of impulse control, can be studied using
hallucinogens as psychopharmacologic probes of central function.
Advances in model-development for psychoses, both in humans and animals,
could be used to further assess the similarities and differences between
hallucinogen-induced and naturally-occurring altered information processing.
Examples include prepulse inhibition of startle, evoked-response abnormalities,
and performance on well-characterized neuropsychological continuous
performance tasks.
Research on the role of hallucinogens in time-limited, medical psychotherapy
has relevance. The loss of psychiatry's role as primary provider of psychotherapy
has stimulated research into more refined medical psychotherapeutic techniques.
Additionally, the cost-effectiveness of psychotherapy is under increasing scrutiny,


with emphasis on time-limited approaches. Current psychotherapy research

protocols are designed to investigate these issues. Additionally, the presumptive
psychotherapeutic utility of hallucinogens may be assessed from the vantage point
of 5-HT systems, in addition to more psychological measures.
For example, it is suggested that treatment with the African hallucinogen
ibogaine will prevent withdrawal and craving in humans addicted to a variety of
psychoactive compounds. Before such claims can be tested, however, careful
dose-response data must be generated to assess the effects in non-addicted
humans. Once these normative data are available, the necessary interaction studies
with other drugs of abuse could proceed before beginning the costly and poten-
tially dangerous clinical trial phase of research.
This discussion may become dated by its emphasis on 5-HT mechanisms. The
role of other neurotransmitters and neuromodulators (such as dopamine,
γ-aminobutyric acid, endogenous opioids, acetylcholine and norepinephrine, both
alone and in interaction with the 5-HT system) should be assessed.


The hallucinogens are some of the most fascinating drugs known to medicine.
They provide insight into states as disparate as schizophrenia and religious
ecstasy. They are also powerful tools to assess brain-mind relationships, one of
the most pressing issues facing modern science. After a generation of neglect,
advances in basic science can now be tested in humans, and many of the questions
left unanswered by the first generation of researchers into human hallucinogen
effects can be addressed. Prudent, systematic, hypotheses-based research has the
potential to generate a wealth of information of both clinical and heuristic utility.


This research was supported in part by NIH General Clinical Research Center
grant RR-00997; National Institute on Drug Abuse grants R03-06524 and
R01-08096; the Scottish Rite Schizophrenia Research Foundation, NMJ; and
University of New Mexico, Department of Psychiatry Research Committee and
Scott Rogers Fund support. The author would like to thank the nursing,
laboratory, biostatistical and dietary support staff of the GCRC; Cynthia Geist,
RN; Laura M. Berg, MSN; Clifford R. Quails, Ph.D; Eberhard Uhlenhuth, M.D.;
Robert Kellner, M.D., Ph.D; the Pilot Drug Evaluation staff at FDA; David
Nichols, Ph.D, Purdue University, and the late Daniel X. Freedman, M.D.,



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Hallucinogens as an aid in
psychotherapy: basic principles
and results

This paper is a retrospective report on the research on LSD-aided psychotherapy

performed between 1953 and 1972 before LSD therapy became illegal. Methodo-
logically, the studies do not meet the standards of modern psychotherapy
research. Consequently, this presentation can only have an orientational character.

The term 'psychedelic' was coined by Osmond 1 and refers to 'enriching the mind
and enlarging the vision'. This concept has two different roots:
(1) The anthropologists Henley (cited in Josuttis and Leuner 2 ) and William
James 3 , as well as Slotkin 4 reported concurrently that religious conversion
with the aid of peyote could cure alcoholics.
(2) In his Good Friday experiment at Harvard (which has since become a classic
in the field) Pahnke 5 showed, using a double-blind design, that hallucino-
genic substances could induce so-called cosmic-mystic experiences.
According to a compilation by Stace6, these descriptions show great similarity to
those which mystics of all ages and religions have described. Stace found that
mystic experiences all have certain fundamental culture- and religion-independent
characteristics in common. From the nine categories which he listed as being at
the core of every mystic experience, I have chosen several which substantiate their
psychotherapeutic value:


(1) The perceived outer diversity is experienced as the 'unity of all things' - i.e.
'all things are one'.
(2) The transcendence of time and space, i.e. 'experiencing the present as a
timeless moment', which is clothed in terms like 'infinity' and 'eternity'.
(3) A deeply felt positive mood in the context of overwhelming feelings of
happiness, blissfulness, reconciliation and freedom.
(4) The unspecific 'feeling of holiness', clothed in feelings of astonishment and of
awe in view of an inspiring reality. However, this occurs outside the context
of religious belief.
(5) 'The experience of an ultimate reality' with the certainty that there is another
dimension beyond everyday life.
I have omitted the next categories 6, 7 and 8 with the keywords 'paradox', 'in-
expressibility' and 'fleetingness', and to emphasize category 9, which is especially
relevant for the therapeutic action of psychedelic therapy. These dimensions of
Stace describe the lasting positive action of humans on themselves toward their
fellow human beings, as well as toward life, and the mystic experience itself.
All types of psychotherapy, even that performed under the influence of
hallucinogens, are supported by the interaction between the patient and the
therapist, as well as the patient's experience. The interpersonal medium is under-
standing, a category which lies outside of the sphere of quantitative measurement.
For this reason, I believe that it is essential here to first quote two exemplary
passages taken from psychedelic therapy sessions. Stace's categories of mystic
experience evidently reappear in them. Compared with other psychotherapeutic
methods, they have an inherent character which is especially important in an
existential context.

Passage 1
A 21-year-old woman with a severe neurotic disorder, in her first psychedelic
session with a 300-µg dose of LSD, reported:

The doctor showed me several pictures, a mother and her child. I recognized myself and began
to cry, 'I can love my baby after all the many doubts and fears.' . . . At this point I felt as if God
were holding me in his arms and revealing himself to me. I laughed and said, 'I have found him,
I have found him'. I had an extraordinary feeling of peace and well-being. After so many years
of wandering lost and alone, now God was with me. It was wonderful. . . . I also found reasons
for everything. God's place in the universe, in the world and in myself appeared so clear to me.
It is life and love. He is present in everything and finally after such a long time he was also
in me. . . .

Passage 2
This passage is taken from a tape recording of a therapy session with a 23-year-
old medical student under the influence of 10 mg of CZ 74, a psilocin derivative:

. . . a heavenly state. I consist of nothing but love, a purely mental being. God appears, a father
figure, I wave to him amiably as he floats by and he returns my greeting. An overwhelming
cosmic feeling: I feel the eternal spirit, who stretches back through all the primeval times, and fills
the universe and all living beings with his aura. I myself am only a grain of sand in the eternity
of time. Everything I experience touches on the evident truth of human existence. Then I was
driven out of that paradise, I don't know why.

Before I begin my consideration of the results of psychedelic therapy, let me take

you on a short excursion into the new psychic dimensions which present them-
selves in these patient reports. In them a series of completely different scientific
concepts manifest themselves in a downright dramatic manner. In some cases they
complement each other; in others they are incompatible. The individual reports
occasional conflict with the observed collective experience. This experience is
abstract in Stace's dimensions, in the questionnaire of Pahnke's 5 Good Friday
study, and in the three-dimensional questionnaire on altered states of conscious-
ness by Dittrich 7 - defined as 'oceanic boundlessness', 'dread of ego dissolution'
and 'visionary restructuralization'. These dimensions prove to be the basis of
cosmic-mystic experience, which is, to some extent, the unspecific core of
experience common to all religions. In addition, as early as 1961, the philosopher
Maslow 8 , in a statistical study, found the frequency of occurrence of these peak
experiences to be 70% among his students.
In the context of a psychodynamic concept, the fundamental principle of the
psychedelic treatment method can be understood as a regression to the level of a
child's experiential state. For the clinical observations and psychometric evalua-
tion of this regression, I must thank my former co-workers Bolle 9 , for the
administration of ketamine, and Schlichting (unpublished observations) for
determining the influence of phenethylamide, known as 2 C D 1 0 .
The research on fundamental perinatal experiences in humans has meanwhile
been received with great investigative interest, as shown by the publications of
Janus 1 1 and Fedor-Freyberg and Vogel 12 for psychoanalysis and Grof 1 3 for the
theory of transpersonal psychology, which he represents. The fundamental
perinatal experience expands deeply into the sphere of religious psychology 14 .
Using the observational methods of natural science, one confronts a schism in
our society, when considering this or similar subjects. In a noteworthy book by
Hübner 1 5 on The Truth of the Myths, however, humankind is confronted with the
fact that, more or less unadmittedly, our encounters with nature and people, love,
birth and other important occurrences still anchor us with scarcely conscious
roots in mystic thinking. This near subconscious knowledge builds a critical

Table 1 Publications on the application of psychedelic therapy.

(From ref. 20, with permission)

General discussions 7
Chronic alcoholism 22
Autistic children 5
Cancer patients (including pain therapy) and euthanasia 4
Addiction to narcotics 1
Sexual perversion 1
Total 40

bridge between natural science's causality and the non-causality common to

mystic experience. The importance of statistical dependence has meanwhile been
demonstrated to us by chaos research.
As regards the results of psychedelic therapy: for the period between 1954
and 1971 there exists a bibliography of 40 publications concerning this type of
therapy. The main topics covered in these papers are indicated in Table 1. It is
noteworthy that the emphasis of these research programs was placed on the
treatment of chronic alcoholism. This disease has an extremely poor treatment
prognosis: the majority of such patients cannot be reached by conventional
psychotherapeutic methods.


The Spring Grove Hospital in Baltimore has conducted a series of methodically
well-designed studies as part of its research program. They include investigations
on the treatment of chronic alcoholics, severely disturbed neurotics as well as on
conducting psychedelic sessions with terminally ill cancer patients 1 6 , 1 7 . Their
research team, headed first by Phanke and later by Grof, was funded by the
National Institute for Mental Health (NIMH) in Washington with more than
4 million dollars. In the course of an expert-opinion contract, I had the oppor-
tunity to become familiar with and critically assess a series of research projects
which were in progress. Methodologically, they were of a very high standard.
Indeed, it was extremely informative to see how attempts were made to fit the
requirements of formal stringency to the activation of the individual patients'
The results of a study on the psychedelic treatment of 175 chronic alcoholics
were reported by Kurland and colleagues 18 . The practical administration of the
treatment method appears straightforward. Firstly, there is normally only a single
LSD session (seldom a second one). The dose is substantially greater than the
average for psycholytic treatment. Secondly, the goal of the therapy is to impart
a cosmic experience which lasts for many hours and to achieve this, an intensive

90 90
85 before 85
80 80
75 75
70 70

65 65

60 60
55 55

50 50

45 45
40 40

0 L F K Hs D Hy Pd Mf Pa Pt Sc Ma Si 0
MMPI scales

Figure 1 Comparison of the MMPI (Minnesota Multiphasic Personality Inventory) profiles of

the high-dosage and low-dosage (the control group) psychedelic treatment groups after com-
pletion of the 18-month follow-up investigations for 114 alcoholics. L = lie score; F = unusual
answer; K = dissimulation; Hs = hypochondria; D = depression; Hy = hysteria; Pd = psycho-
pathology; Mf = masculinity/femininity; Pa = paranoia; Pt = psychoasthenia; Sc = schizophrenia;
Ma = hypomania; Si = introversion. (From ref. 18, with permission)

4-week-period of psychotherapeutic preparation of the patient is undertaken.

Finally, the therapists continually apply suggestion during the 8-10-h LSD
session, influencing the patient toward the goal of cosmic mystic experience.
According to the statistics reported by the Spring Grove Hospital, 70% of their
treated patients achieve a peak experience.
The study was conducted using a double-blind design. A dose of 150 µg LSD
served as an active placebo and the dosage of the active treatment group was
between 300 and 500 ßg. The initial results are presented as an MMPI profile
(Figure 1). Figure 2 shows the results after the conclusion of the 18-month
follow-up investigation of both the active and the placebo groups. There was no
difference between two profiles. The data for the drinking behavior (Figure 3)
confirm this. Subsequently, 12 and 18 months after conclusion of the treatment,
there was no significant difference between the results. Clearly, the 4-week
psychotherapeutic pretreatment, combined with the active placebo, led to a sub-
stantial improvement in the subjects' drinking behavior.
Thus, the effect of the high LSD dose is only relevant to the immediate success
of 51%, but not for the period of the follow-up investigation.

90 90
low dose
85 85
high dose
80 80
75 75
70 70

65 65

55 55
50 50
45 45
40 40

0 L F K Hs D Hy Pd Mf Pa Pt Sc Ma Si 0 A R
MMPI scales

Figure 2 Comparison of the profiles of the MMPI test for 81 alcoholics before and after
psychedelic therapy using high doses; abbreviations explained in Figure 1. (From ref. 18, with

Percentage of patients with score > 8







before 6 12 18
treatment (n = 114) (n = 94) (n = 91)
(n = 114)
Months after treatment

Figure 3 The drinking behavior of 114 (psychedelically) treated chronic alcoholics 6, 12 and 18
months after completion of the follow-up examinations: a comparison of the high- (solid line) and
low- (dotted line) LSD-dosage groups; *p < 0.05. (From ref. 18, with permission)


After the discovery of the hallucinogenic properties of LSD-25 by Hofmann 1 9 (see
Chapter 1), psychoactive substance-aided psychotherapy gained an unexpectedly
large importance. In his monograph on LSD Psychotherapy, Caldwell 20 listed 193
publications in the bibliography.
Psycholytic therapy has two sources:
(1) The publications of the English psychiatrists Sandison, Spencer and
Whitelaw 21 in 1954.
(2) The presentation of my own results on the support of 'guided affective
imagery' at the International Congress for Psychotherapy in Barcelona in 195922,23.

The interest of psychiatrically trained psychotherapists in psycholytic therapy

increased greatly within a short period of time. For this reason I invited them to
a European symposium in Göttingen in 1960. Participants from England, Italy,
Austria, Switzerland, Scandinavia and Czechoslovakia agreed unanimously to
Sandison's suggestion to call the new method 'psycholytic therapy'. From this
group, the European Medical Society for Psycholytic Therapy (EPT), of which I
was the chairperson, developed. Until 1971, when research was prohibited, the
EPT held five international symposia, and its representatives were leading con-
tributors at symposia of the International Congresses for Psychotherapy and also
those for psychopharmacology.
The performance of psycholytic therapy is similar to the imaginative techniques
of psychotherapy, such as guided affective imagery 22 , in terms of the setting, the
interaction between the patient and therapist, and the occurring phenomena. The
phenomenological difference between psycholytic therapy and the imagination
methods was expressed by a female patient as follows: 'It is more straightforward
and comes more out of one's self. Nothing is given by the therapists, nothing is
controlled, nothing is demanded of me'. In other words, the therapeutic process
continues relatively autonomously under positive transference by the patient, and
often with strong emotional engagement. However, at the same time it is accom-
panied by cognitive insights into the developing psychodynamic interactions.
Indeed, the insights gained are often extremely convincing for the subjects.
This experience and the emergence of self-knowledge may be illustrated using
the records from two psycholytic sessions with a 23-year-old female university
lecturer; after her fifth session with a low dose of LSD-25, which had lasted
several hours, she wrote:

My thoughts then turned to Queen Elizabeth of England. I projected myself into the Queen. Her
gaze, which was full of authority, appealed to me. I loved the idea that a woman has power over
so many men. From the Rock of Gibraltar I looked down upon the British fleet, which was just
winning a battle, . . . as if her men fought against Hitler's power.


Comment: her powerful, masculine, ideal ego identified itself with the Queen and
linked itself with her majestic role against the gestalt which the patient identified
with Hitler and in which she obviously sees her father, whom she experienced
as brutal.
After the following session, she wrote:
In this treatment session I realized that I have an inferiority complex. I did not wish to accept this.
I like to see things in the extremes, i.e. in such a way that when I appear to be occupied with a
difficult problem, I immediately desire to die to free myself from the hardness of life. It is true
that I wish to have a life which is like a continuous Christmas . . . This treatment session was very
depressing: the most unpleasant I have ever experienced.

Comment: this is the first insight into her narcissistic rejection of the requirements of
reality and her tendency toward resignation with flight into depressive withdrawal.
These two psychotherapeutic vignettes were part of a treatment consisting of
12 psycholytic sessions. To understand the case of this young woman some
background information is essential. Since the age of 14 she had suffered from
periodically occurring depressive conditions. She came to me with a severe
depression after the loss of her boyfriend. After 3 months of treatment, inter-
spersed with 12 psycholytic sessions, she remained free of complaints. The final
follow-up, after 10 years, confirmed this result.
Statistical comparison studies have shown that such a combination of individual
psychotherapeutic treatment sessions, interspersed with scattered psycholytic
ones, achieves the best results 24 . To state this more simply: psycholytic therapy is
not an autonomous treatment method, but a psychodynamically oriented therapy
aided by a hallucinogen 25 .


A synopsis of the indications for psycholytic therapy from 42 publications by 28
therapists on a total of 1603 patients has been compiled by Mascher 24 (Tables 2
Table 2 Synopsis of the indications of psycholytic therapy from 40 publications by
28 therapists (after Mascher, 1967) 24
Number of Indications:
Rank Diagnoses publications very good/good (%)

1 Anxiety neuroses 9 70.0

2 Irritable depression 4 62.0
3 Character neuroses and sociopathies 10 61.0
4 Borderline cases 4 53.0
5 Perversions and homosexuality 7 50.0
6 Compulsive neuroses 10 42.0
7 Hysteria and conversion 2 31.5
8 Dependency on alcohol and tablets 6 31.0


Table 3 Forms of application (after Mascher, 1967) 24

Number Clinical results:

Groups of cases * Applications very good/good (%)

Group I 87 a single LSD session after intensive psychoanalytic 56.0

Group II 701 repeated LSD sessions combined with individual 56.0
Group III 452 several LSD sessions combined with individual and 62.5
group psychotherapy
Group IV 363 several LSD sessions, only in the group 40.0

* Total = 1603

and 3). The author is well aware of the problematical nature of a comparison of
these results which were obtained under very different prerequisites. Nevertheless,
they allow a first preliminary clinical overview. Comparing the original papers
has led to the development of certain indication groups. Table 2 shows the
indication spectrum and the results of the synopsis.
From the published studies it seems noteworthy that approximately two-thirds
of the subjects were classified as severe or chronic cases. Even in our own
statistical investigation, 70% of the patients were considered psychotherapeutically
untreatable and had often had a very long patient career. The group of psycho-
therapy-resistant patients were divided into three groups by Arendsen-Hein 26 :
(1) Alexithymia patients.
(2) Rationalizing intellectuals.
(3) Silent, tense and extremely reserved people.
As Mascher's synopsis 24 and our data show, the great majority of these therapists
applied psycholytic therapy to resistant patients.
Table 3 allows comparison of the applied methods with their results. The best
results (as a percentage) were shown by Group III, which received a combination
of individual and group psychotherapy with the psycholytic treatment: improve-
ment in 62.5% of cases. These results support the arguments of Fontana 27 ,
Leuner 28 and Mascher 29 as well as Perez-Morales 3 0 , 3 1 , that the LSD sessions
require a therapeutic basis of individual and group treatment. In a comparison
study, Hausner and Dolezal 32 demonstrated that an increase in the number of
individual sessions is an alternative. Group IV, (i.e. LSD administration in
combination with group therapy alone) shows the least favorable results, with
40% improvement.
In 25 publications, follow-up studies over an average of 2 years were reported.
According to the patients' own estimates, 62% of them remained stable; 35% had
slightly worsened; and 3% reported that they had regressed in this period.



A meticulous recent study was conducted by Leuner and co-workers 33 in the
Department of Psychosomatics and Psychotherapy at the University of Göttingen.
Between 1968 and 1985, 123 chronically ill patients were treated with LSD- and
psilocybin-aided therapy. The diagnosis groups correspond very closely to those
given in Table 2, so that their repetition is unnecessary. The therapeutic method
consisted of a combination of individual and group therapy sessions among which
psycholytic sessions were interspersed (cf. also Table 3, Group III).


120 n = 44 n = 96




n = 83
Number of patients






n = 31
20 (24.4%)


Sample Results

Figure 4 Results of psycholytic therapy of 127 chronically ill patients in; 77% of them were
incurable with conventional psychotherapeutic methods; catamnesis occurred after an average of 2.5
years. The patient sample (left) were from studies by Schultz (clear bar) and Mascher (shadow bar)
and the results (right) indicate patients who shared 'very good' or 'good' improvement (clear bar)
or who were not influenced (shaded bar), (Data from Leuner and co-workers, 1992) 33


The admission of the patients into the therapy program was dependent on their
meeting specific criteria in our endeavor only to accept the severely disturbed and
the chronically ill. Due to their long patient careers before beginning our treat-
ments, and also to their pathology, 77% of the patients were chronically ill and
severely disturbed, and could not be treated with conventional psychotherapeutic
The assessment of the treatment efficiency is illustrated in the main results of the
follow-up investigation (Figure 4) after an average of 2.5 years. They demon-
strated 'good' to 'very good' improvement, with a regained ability to work in
75.6% of the treated patients (Figure 4).
The first part of the study was carried out by Mascher 29 , who conducted
follow-up investigations on 83 chronically disturbed patients. Figure 5 shows the
results as the relationship between improvement and the number of LSD sessions.
The best result was shown by Group 3, with an average of 38 LSD sessions.

1 (2-15) 28 7

2 (16-30) 36 23
Group variance of the sessions

3 (31-45) 50 38

4 (46-60) 37.2 52

5 (61-75) 27.4 70

60 50 40 30 20 10 0 10 20 30 40 50 60 70 80
Improvement according to Average number of LSD
Boehm's Index (%) sessions

Figure 5 Results from a study by Mascher 29 showing the percentage improvement in follow-up
studies of 83 chronically disturbed patients after an average of 2.5 years as a function of the number
of LSD sessions. (Reproduced with permission)


3.56 3.6
Boehm's Index values



2.67 2.54 2.6 2.5

2.5 2.4 2.4
2.3 2.3

2 1.9

1 2 3 4 5

pretreatment = immediate values after treatment = values for catamensis

Figure 6 Changes in the values of Boehm's Complaint Index in the five groups shown in Figure
5 (pretreatment; immediate value; post-treatment improvement or deterioration) in a catamnesis
after 2.5 years (after Mascher, 1967) 24

In contrast, Groups 4 and 5, with 52 and 70 LSD sessions, respectively, showed

no improvement in their percentage values, even with a greater treatment effort.
Thus, despite an extension of the therapy in accordance with the patients' own
wishes, achievement of a degree of improvement which would have justified the
treatment effort invested in them was not possible. In parallel to this, other
indications for this restriction were also seen in the spontaneous post-treatment
improvement (shown in Figure 6) for Groups 1 and 3. In contrast, the catamnesis
of Group 5 showed definite deterioration, and Group 4 demonstrated only a
minimal post-treatment improvement. It seems justified to conclude that further
treatment - beyond 45 hallucinogen sessions - would scarcely have resulted in
commensurate improvement.
A controlled design for this investigation was not possible for external reasons,
so that the study is considered to have an orientational character only. It is a
post hoc evaluation using Boehm's complaint index 3 4 to estimate the behavioral
disturbances of neurotic and psychosomatic patients before therapy and
after catamnestic investigation. A parametric evaluation known as BARS
('Behaviorally Anchored Rating Scales') 3 5 , 3 6 is primarily used in clinical and social


studies*. One of the major factors considered is whether or not the patient's
rehabilitation enables him to return to work. Because of the above-mentioned
selection, nearly 80% of the patients have been classified as especially severe and
chronically ill subjects. The results are discussed critically elsewhere 33 , in terms of
methodology and with regard to the question of control design in the psycholytic
Leary 37 stated that 'the notion of a double-blind study with hallucinogens is
ridiculous. Both the experimental subject and the experiment's director see within
a short time who has received the active substances and who the placebo'.
Consequently, in the United States at that time, a number of researchers decided
not to continue their LSD programs since neither double-blind nor blind studies
were possible.
In connection with the relatively favorable success of the psycholysis on psycho-
therapy-resistant patients, an examination of the statistics on the provisions for
psychotherapeutic care of the German population is of interest. According to a
recent compilation by Meyer and colleagues 38 , 65% of the people needing psycho-
therapeutic care cannot be treated with the concrete therapy methods available at
the present time. In addition, these patients are chronically ill: they have an
average treatment career of 7 years. Consequently, a re-examination of the results
of this pilot study with the methods of modern psychotherapy research to
consider aspects of treating psychotherapy-resistant persons is of great interest.

The results of the hallucinogen-aided psychotherapy which have been presented
here can only give an overview of this complex treatment field. The prevention,
by legislation, of continued therapeutic research in 1972 put an end to its normal
development and the possibilities of developing new approaches from the results
obtained. At the time of writing, it has just been announced that the Food and
Drug Administration (FDA) in the US is prepared again to allow research with
hallucinogens and endactogens on humans - especially for therapeutic purposes.
Thus, we can hope that funding can soon be made available for meticulously
designed, scientifically acceptable research programs. These programs should pay
careful attention to the double character of scientific responsibility in this area of
research; the specific emotional relationships between the therapist and his patient
must, on the one hand, be maintained whilst, on the other, the observance of the
methodological considerations must still be fulfilled. An appropriate compromise
will have to be made.

* For that reason, Bortz stated: 'In many, especially new, areas of research in which the conceptual
construction of a theory has just begun, . . . the investigators would be badly advised (if they were)
to completely dispense with this important survey instrument'.


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Academic Press)
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Perspectives on LSD and

psychotherapy: the search for a
new paradigm


This paper offers interdisciplinary perspectives, with the purpose of introducing

a new paradigm to study the effects of psychedelics on human consciousness.
Prior scientific work has been affected by paradigms that are not inclusive of
sufficient factors to logically account for all the observed objective and subjective
phenomena induced by psychedelics in humans. The proposed new paradigm
would encompass previous partial understanding of the effects of psychedelics on
human consciousness and offers a super-ordinate view.

Fifty years ago Albert Hofmann discovered LSD, the most potent psychoactive
compound known to humanity*. This revelation gave Western medicine and
science a substance as unique in its power as it is startling in its mind-altering
effects. The modern pharmaceutical laboratory where this epiphany occurred
gave no clue as to the long cultural history of humanity's relationship with the
botanical relatives of LSD. These plants had been used since prehistoric times
(documented as long ago as 8000 BC2) and were usually sacred to the cultures that

* Until very recently, LSD's reign as the most potent psychoactive substance was unchallenged. Nichols and
Hoffman of Purdue University have produced several compounds which, when tested on a group of rats trained
to discriminate the effects of intraperitoneal injections of saline from LSD (a method held to be reliable), seem
to have greater activity. Two LSD analogs ('ETHLAD' and 'ALLAD') appear to be more potent than LSD1.


used them. The journey in consciousness that Hofmann began, as he bicycled

home, was the outcome of a profound new discovery, yet its roots were as old as
human history. LSD, Hofmann's 'problem child', was born - a new drug, the
precocious offspring of modern science, without knowledge or connection to
long-lost human traditions and cultural contexts 3 .
The relationship of human beings, mystical experience and psychedelics had not
merely been forgotten. Wherever the veil of secrecy around such rites had been
lifted, they had been ground into repression under the boots of conquerors. In the
New World, when the Spanish found the peoples of Central America using
psychedelic mushrooms and cacti in sacramental rites, they violently opposed this
as devil worship. The distorted accounts of Spanish priest-historians reflected
their horror and revulsion at a powerful alien culture. Tales of cruelty and
satanism were based on projection, fear and hearsay. These lurid accounts were
themselves buried in history 4 . In the West, the secret of the 'wine' used for the
mysteries at Eleusis had long been forgotten and the rites themselves remained
truly mysterious 5 .


Cleansed of past condemnations, LSD was born into a brave new world. Mid-
twentieth century science was just beginning to question the limits of its new
frontiers of prediction and control. Uncertainty had been postulated as a principle
in quantum physics. This principle held that attempts to measure the sub-atomic
realm would be so intrusive as to disturb the outcome. The notion that there
might be a limit to what could be known through science was revolutionary. The
recent discovery of antibiotics had given medicine 'wonder drugs' to cure
infections that otherwise killed. Surely scientific scrutiny of something as
powerful and unique as LSD would yield a deeper understanding of the brain and
its relation to the mind.
Fifty years later, LSD and all other psychedelics are beset with repressive
government regulations in most of the world. Perhaps the greatest problem stems
from portrayal of psychedelic drugs in the mass media. In the confused
atmosphere of fear, propaganda and social controversy there is an educational
vacuum. Most psychiatrists and psychologists know more about psychedelics
from television, newspaper articles and drug-abuse propaganda than from the
scientific literature. Many of the best and brightest among professionals are,
unfortunately, as full of misinformation about this powerful family of compounds
as is the public at large.
We live in the polarized wake of a social movement that brewed the power of
LSD and the authority conflicts of two early researchers with free love, sexual
revolution and a youthful rebellion against US military involvement in the
Vietnam War. The United States reacted to these events with a repressive stance


taken out of fear - fear of losing the country's youth to a 'tune in, turn on and
drop out' movement; of losing future generations to chromosome damage or
madness, and perhaps any government's deepest fear, that of losing control. The
chromosome damage scare has subsequently proven to be unfounded 6 and the
fears of madness and mayhem seem to have been grossly exaggerated 7 .
The potential of psychedelics to change belief and alter behavior, even to propel
social movements, so alarmed the governments of the world that possession
became a crime. The strategy of prohibition curtailed legitimate research by
qualified investigators severely and had little effect on the ill-advised abuse it
purported to eliminate 8 . In contrast to this horrified panic, when our forebears
and Neolithic contemporaries found similar properties in certain plants, they
named them with reverence: semen of the sun, vines of the serpent, the tracks of
the deer, plant of the tomb, vine of the soul, mainstay of the heavens, herb of
divination and flesh of the gods 9 .
Such an extreme contrast in attitudes among human beings living on the same
planet can be understood by examining the cognitive framework that underlies
both the powers of scientific thinking and of world views.

The culture of science, indeed the way we think about what we are studying, has
played a limiting role in our understanding the effects of psychedelics on human
consciousness. In The Structure of Scientific Revolutions, Thomas Kuhn described the
power of certain fundamental ideas to open up new vistas in science 10 . One
example is the revolution from Newtonian physics to Einsteinian physics, which
led to the creation of the atomic bomb and atomic energy. A paradigm organizes
the process of thinking by exerting Hermetic influence on the perception of the
investigators in the field defined by that paradigm. For this reason the paradigm
itself is most clearly seen for what it is only when replaced by another, usually
more encompassing, view (a concept beautifully explained in mathematics by
Gödel's theorem 11 ). Until a revolutionary breakthrough takes place, the all-
encompassing principle goes unseen or unquestioned in its definitive role. Most
investigators in a field of study do not concern themselves with the paradigm they
are using or with paradigmatic perspectives at all. Instead they conduct research
that concerns itself with logical nuances within a paradigmatically defined view.

The first paradigm applied to psychedelics represents the oldest healing strategy
adopted by human beings, the shamanic paradigm. Although not scientific, the
shamanic paradigm has many of the elements of a scientific paradigm.


In tribal societies, the spiritual leader of the group is usually referred to by

anthropologists as the shaman. This individual serves the society in a multifaceted
role that encompasses much of what we consider to be the separate, if perhaps
related, provinces of the psychotherapist, the clergyman and the physician. The
shaman is at once the myth bearer, myth maker, ecstatic mystic, spiritual guide
and healer for the social group.
Among many native groups in the Americas, shamans employ plants that are
regarded as having spiritual power or as sacred. Most of these plants fall into the
pharmacological category of hallucinogenic, psychedelic or 'mind-manifesting'
substances. The shamans, however, prefer to conceive of these unusual plants as
powerful in a spiritual sense 12 .
The attitudes or perceptual paradigms of cultures using psychedelic plants
include the following elements. First, the plants are held to be sacred. Second,
they are used in specific ceremonies or rituals that support and renew the world
view of the culture. Third, there exists a world apart from this one to which the
plants give access. Useful experiences take place in this hidden realm of existence
and valuable knowledge may be gained there. Fourth, the use of these substances
is an acknowledged part of membership in the group or some significant sub-
group, for instance the shamans. Fifth, and finally, these plants can be used by
those adept in their application to heal and to effect other changes in the ordinary
The ritual in which sacred plants are used provides a psychosocial framework
for experiencing healing and mystical effects. The shaman is charged with using
the available technology of the culture to create the most effective environment
possible for the culture's collective ends. A variety of stimuli may be employed:
candles, drums, chants, various forms of art, etc. The stimuli are used, ingeni-
ously, to enhance and guide the experience along an accepted or desirable course.
With great sensitivity, the shaman uses much practical knowledge, the validity
of which has only recently been confirmed by scientific research. The ethnocentric
view suggests that shamans are 'witch doctors' using superstition to influence
their 'patients'; yet they exhibit sophistication on every level of clinical practice
with psychedelics, except in the application of the scientific method. We miss a
great deal when we judge other cultures prematurely. What seems simple-minded
may be elegant. What at first glance seems primitive emerges as a beautiful
summary of centuries of practical experience.


The fundamental paradigm that has been applied to LSD is the drug paradigm.
This way of thinking about the effect of a substance fits well for compounds that
have an unambiguous chemotherapeutic action. An important factor in the drug


paradigm is that a drug's effects occur independently of the expectations of both the
doctor and the patient.

Since LSD was discovered in a drug laboratory, scientific methods were applied
to quantify and characterize its effects. LSD produced such a profound upheaval
in mental functioning that it was thought to induce a toxic psychosis. This
suggestion led to the resurrection of the endogenous psychotogen hypothesis and,
ultimately, to the conclusion that the effects of LSD mimicked psychosis.
This psychotomimetic paradigm allowed researchers to study the 'properties of
the LSD state' objectively. Many apparently excellent research studies ignored
important subjective factors, but employed quantitative and qualitative measures.
Researchers in laboratories, wearing white coats and other badges of cultural
authority, told subjects both directly and indirectly that they would be
experiencing madness. This suggestion influenced and, in fact, usually determined
the subjective response to LSD. The insight that the madness might be at least as
much a product of the frame of investigation as of the substance under study
eluded many serious researchers.
The psychotomimetic paradigm for the actions of psychedelic drugs remains a
seductive belief because it assumes we are dealing with a drug known to produce
a major effect - psychosis. The origin of the model psychosis may be pursued on
the molecular level or on the psychodynamic level. If LSD were simply
psychotomimetic it would offer us much as a tool to understand the biochemical
concert of brain function and its relationship to consciousness. LSD can be
psychotomimetic, but it is so much more!

The psycholytic paradigm emerged from the psychotomimetic view of LSD. In
1950 this new experimental paradigm began with the publication in the United
States of an article by Busch and Johnson 1 3 , who suggested that LSD might help
in psychotherapy. They had observed that psychotic patients in a delirium were
sometimes able to verbalize repressed components of their conflicts. Such a
delirium might be provoked by a high fever. They interviewed patients under the
effects of sodium pentothal and amytal, during recovery from insulin shock and
electroshock therapy. A few dramatic successes, amid many failures, led them to
investigate new drugs that might induce a temporary state of delirium. Sandoz
offered LSD as a possibility. Bush and Johnson reported:
On the basis of this preliminary investigation, LSD-25 may offer a means for more readily
gaining access to the chronically withdrawn patients. It may also serve as a new tool for
shortening psychotherapy. We hope further investigation justifies our present impression 13 .


In 1953 Frederking published one of the first European articles on LSD as an

adjunct to psychotherapy 14 . He used low doses of LSD (30-60µg) or mescaline
(300-500 mg) to shorten the course of therapy, ease feeling or memory blocks and
to promote emotional catharsis. When combined with ongoing psychoanalytic
treatment, this approach produced positive results. In 1954 Sandison and his
group in England published an article emphasizing the abreactive qualities of LSD
for therapy with neurotics 15 . Therapists began to notice that most patients had a
clear memory of their experiences under the effects of LSD. The recall of the
altered state experience was crucial for the therapeutic integration of new insights
into normal consciousness. This unclouded recall is not a characteristic of delirium.
In this light, LSD seemed the perfect adjuvant to psychotherapy. Researchers were
slow to recognize and describe the difference between the effects of LSD,
psychosis and delirium, because of the effects of the psychotomimetic paradigm
on their thinking.
Sandison, Frederking, Leuner, Alnes, Arendsen-Hein and others in Europe
formed an association of psycholytic therapists. Psycholytic therapy is the use of
LSD and similar substances in low to moderate doses (generally 30-200 fig) with
the aim of shortening and facilitating psychoanalysis and psychoanalytically
oriented psychotherapy. This involves multiple (2-100) drug sessions within the
framework of an ongoing therapeutic relationship.
The psycholytic paradigm gained considerable support in Europe in the late
1950s and acquired some adherents among therapists in the US in the early
1960s 1 6 - 2 4 .

An interesting transition occurred in Canada when large doses of LSD were given
to alcoholics. The hope was that the ensuing psychosis would be frightening. Use
could be made of such a terrifying encounter with madness in an aversive therapy.
It was suggested to these persons that if they continued to abuse alcohol they
would surely enter once again the realms of madness that LSD had shown them,
only this time it would be due to delirium tremens. In this study, the persons able
to change their lifestyles were motivated, not by experiences of madness in the
horrific sense, but instead by experiences of transcendent beauty and meaning.
The patients described insights reminiscent of accounts from mystical prophets
and teachers. It seemed to be contact with a divine dimension of being that
persuaded them to change their destructive addiction and inspired them to live
more noble lives 25 . Humphrey Osmond eventually coined the term 'psychedelic'
to characterize effects that he felt were excluded by the psychotomimetic view.
Osmond found that LSD, mescaline and psilocybin were useful, not only in
studying psychopathology, but also in that they shed new light on the greatest
philosophical enigma of human existence: the purpose and meaning of life:


Our subjects, include many who have drunk deep of life, authors, artists, a junior cabinet
minister, scientists, a hero, philosophers, and businessmen . . . Most find the experience valuable,
some find it frightening, many say that it is uniquely lovely. If mimicking mental illness were the
main characteristic of these agents, psychotomimetic would indeed be a suitable generic term. It
is true that they may do so, but they do so much more . . . I have tried to find a more appropriate
name 2 6 .

In the psychedelic paradigm, there is a decisive orientation toward the production

of a mystical-religious experience. Large doses of LSD are used to facilitate
dramatic changes in consciousness that have an overwhelming quality, and to
bring subjects into transpersonal and collective dimensions of awareness. The
physical environment is prepared to be aesthetically pleasing and music that has
been carefully selected for its evocative and religious qualities may be used. The
therapist's communication to the subject is weighted in a mystico-religious
Unfortunately, the term psychedelic, literally 'mind manifesting', quickly
became associated with the hysteria of the Harvard drug scandal, the chromosome
damage hypothesis and the 'hippie' movement. Psychedelic became synonymous
with wild colors, flamboyant art, irreverent dress and outrageous lifestyle.
In the vastly different claims and aims of the shamanic, psychotomimetic,
psycholytic and psychedelic paradigms we can see the effects of each and notice
that our point of observation is separate from what we observe. This points to the
need for a new view that integrates insights from these past efforts.
A new paradigm must include the drug paradigm but be more encompassing by
including both objective and subjective phenomena. In addition, this new
paradigm would also integrate the pragmatic knowledge of shamanic cultures,
whilst making use of burgeoning new technologies for measuring and recording
responses at new levels.
The fundamental pillars of the scientific endeavor are objectivity and
impartiality. Respect is accorded to the researcher who designs and conducts
studies objectively that cleverly unlock the underlying principles of the phenome-
non under study. This investigation is to be accomplished with neutrality and
objectivity. Psychedelics present a powerful lens through which we may observe
the effects of a scientist's belief upon his or her investigation. The belief that
psychedelics create certain effects seems to maximize the occurrence of the
expected effects! Beliefs affect perception. Beliefs can direct attention away from
the mechanisms by which scientists unwittingly influence their subjects and,
hence, their results. The assumption that the researcher must be unbiased is a
virtual impossibility that has led to hidden and denied biases. The very posture of
denial and fear gives unconscious attitudes unbridled power to influence percep-
tion and results. The proper investigation of the effects of psychedelics on human
consciousness challenges scientists to become more revealing of their beliefs, more
humble about their objectivity, and more humanitarian toward their subjects.


LSD presents a challenge to science. It challenges the assumption of easy

progress - that current scientific methods will lead us to unlock the secrets of
the universe, without themselves changing in the process. The effects of LSD
on humans challenge our subject-object dichotomies not only because of its
subjective effects, but also because of its remarkable susceptibility to experimenter
Switzerland is unique among the advanced countries of the world in its liberal
traditions concerning medical research. In the field of psychedelics, its authorities
have issued permissions that support the importance of naturalistic research
through individual practitioners. It is only within a healing relationship that
informed consent for this kind of research can take place and individual
well-being be safeguarded. The often strangling grip of prematurely rigid
methodologies is avoided by this enlightened attitude toward qualified physicians.
The ethical safeguards of having clinicians whose focus is on healing their patients
as front-line practical researchers will lead to enhancement of our clinical
understanding of psychedelics.
When approaching a new frontier (and use of psychedelics in humans remains
a scientific frontier) it is not possible a priori to determine what are the important
variables. Instead we must perform the demanding task of meticulous description
and recording, not only of our subjects and their experiences but also of ourselves,
our own experiences and the surroundings of the experiment. Although some
literature exists describing the importance of set and setting, almost no reports
have been published in which the experimenter divulges his or her own
assumptions and beliefs about the subject and field of study. We assume that
personal biases, likes and dislikes, loves and hates are abolished in their potential
effects by the impartiality of our method, but past research with psychedelics has
illustrated that this is simply not true.
Rather than completely invalidating the methods of science, it seems to me that
psychedelics call upon researchers to be both open and cautious in their
application. Uncertainty is a scientific principle applicable to attempts at measure-
ment when instruments are unwieldy and of an inappropriate scale for their task.
The premature characterization of LSD's drug properties has produced confused
results. When its properties are characterized more appropriately, what emerges is
a clear understanding and flexibility, an intellectual framework that encompasses
and understands salutary effects and how to achieve them. This could replace a
rigid, judgmental narrowing of perception. The proper scientific study of
psychedelics requires tools and methods to account for a wide range of variables
that lead beyond the existing drug research paradigm. The creative solution to this
problem may truly expand our science and our consciousness 27 .
I have the privilege of representing the group with the longest tradition of
scientifically studying psychedelics as adjuncts to psychotherapy in the USA. At
Spring Grove and the Maryland Psychiatric Research Center we have given


psychedelic sessions to over 750 subjects in over 30 years of research. Most of the
sessions involved LSD. The patients and subjects ranged from severe alcoholics
and heroin addicts to neurotics, professionals and terminal cancer patients. There
have been no reported long-term complications or negative effects in our
subjects 2 8 - 4 9 .
My own patients included: an electrician, a nurse, a physician's assistant, a
miner, a short order cook. In their therapy there were times when they journeyed
deeply into their lives and took me with them; crying in the pain and trauma,
raging at the helplessness, laughing joyously at the fulfillment. Some enter a time-
less realm, one beyond the usual ken of human experience; a place beyond time
and space, of stunning beauty, where they feel both loved and loving in a deep
reverence for life. They tell me that this domain is more real for them than any
previous experience. Here they find inspiration and motivation to give all they
can; to be the best and most complete people they can possibly be. I have been told
that our feeble language can never contain the beauty, awe and love of these
moments - their effects are felt for a lifetime.
The great Swiss analytical psychologist Carl Jung saw modern man as searching
for lost soul. Through the efforts of another great Swiss pioneer an ancient factor
has been rediscovered. The question is how to regard this wonder?
In my country psychedelics have been labelled as without recognized medical
use, although there is compelling evidence that they can heal people in despair.
What does this attitude - that healing of the soul is beyond the boundaries of
medical practice - say about our profession and my country?
I pray that our science and medicine have not painted themselves into a corner
where there is no place for this kind of wonder and meaning.
Profound uncertainty surrounds peak experiences. It has often played havoc
with attempts at measurement. Yet when these numinous moments occur there is
great healing. To meet the challenge of understanding this potentiality, we need
a broader frame of analysis, a new paradigm, one that forces us to describe all the
variables in the clinical situation to understand what the relevant ones are.
We do not yet know when or whether peak experiences will occur, or with
whom, but we do know that this is the highest order of human experience, as
testified by the greatest sages and mystics of all religious and philosophical
traditions throughout history. We must safeguard the potential for this kind of
experience among our subjects as we continue careful scientific work on every
level possible, from the molecular frontiers of understanding the brain and its
relationship with consciousness to the philosophical and scientific study of the
mystical, as pioneered by Walter Pahnke 50 .
We cannot now, and may never, be able, to predict and control perfectly the
effects of psychedelics in humans. Yet, they are gateways to such precious and
forgotten realms that I do not believe any culture that aspires to full humanity can
afford to shut them out.



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Psychotherapeutic effects

There is no doubt that psychotherapists can influence the psychotherapeutic

process decisively. However, in psychoanalytic practice, the autonomous course
of psychotherapy is an essential. In 1913, Freud described the independence of the
transference neurosis from the analyst's influence as follows:
The analyst . . . sets in motion a process, that of the resolving of existing repressions. He can
supervise this process, further it, remove obstacles in its way, and he can undoubtedly vitiate
much of it. But on the whole, once begun, it goes its own way and does not allow either the
direction it takes or the order in which it picks up its points to be prescribed for it. 1

The development and the analysis of the transference neurosis constitute this
process, which is summarized in Freud's Remembering, Repeating and Working-
Through. The therapeutic goal is to explore the circumstances of the original
development of the neurosis. According to a causal understanding of therapy, past
and obsolete wishes and anxieties, being still expressed in symptoms, should be
repeated in a pure form, i.e. uninfluenced by the therapist. This repetition of
traumatic affects within the therapeutic relationship is the basis and the motor of
the therapeutic process, and although it 'goes its own way', it is vulnerable to both
external and internal disturbances, mainly to influences by the psychotherapist. In
addition, the therapeutic process depends on psychotherapeutic technique, as
Waelder 2 stated: 'As the full development of transference is the consequence of
analytic situation and analytic technique, changes of this situation or technique can
considerably alter the transference phenomena'.
In the classic technique of analytic psychotherapy 'interpretation remains the
exclusive or leading or prevailing tool', as Eissler 3 postulated. However, the same
author admits that 'no patient has ever been analysed with a technique in which
interpretations alone have been used'. Therefore, Eissler introduced the concept
of the 'parameter', which describes everything beyond interpretation. To remain
a psychoanalytic treatment, in order to analyze unconscious conflicts within a


therapeutic working alliance, a parameter has to satisfy four criteria 4 . 'Firstly, it

must be introduced only when it is proved that the basic model technique does not
suffice; secondly, it must never transgress the unavoidable minimum; thirdly, a
parameter is to be used only when it finally leads to its self-elimination (i.e., the
final phase of the treatment must always proceed with a parameter of zero) and,
fourthly, the effect of the parameter on the transference relationship must never be
such that it cannot be abolished by interpretation' 4 .
Parameters are changes in the psychotherapeutic setting, suggestive or suppor-
tive interventions, or contraventions of the rules of abstinence or neutrality.
According to this definition, the prescription of a drug, especially a psychoactive
drug, is a parameter as well. Several authors (e.g. Leuner 5 and Yensen 6 ) consider
LSD should be used as an adjuvant to psychoanalysis or psychoanalytically
oriented therapy. Thus, the use of LSD in psychoanalytic therapy is a parameter,
which alters the classic treatment technique, if at least one criterion is not fulfilled.
In the first case, in most of the LSD studies that have been described in the
literature, psychotherapists decided to introduce LSD at an early phase of the
therapeutic process or even before the beginning of the treatment. Only in a very
few studies was the parameter introduced only when the basic technique did not
suffice. Therefore, the first criterion is not satisfied.
In the second instance, frequency and dose of LSD are rather low, often
minimal in psycholytic therapy, whereas in psychedelic therapy high doses are
used. At best, criterion 2 is satisfied for psycholytic techniques but not for
psychedelic settings.
In the third case, most of the studies stopped using LSD in the final phase of
treatment; criterion 3 is satisfied.
The last criterion deals with transference and counter-transference. I am unable
to decide whether the last criterion is satisfied in everyday psychotherapeutic
practice. However, among the large number of published clinical studies I did not
find any suggestions for psychoanalytic interpretations of the introduction and
the application of LSD. Therapists often describe 'classic' transference processes
('good' or 'bad' mother transference, etc.), but they almost ignore the effects of
the prescription of the drug on transference. The assumption that the introduction
of the psychoactive drug into treatment could have caused more problems that it
has solved is directly associated with the fact that counter-transference has never
been described or interpreted in any of these clinical publications.
Godfrey 7 , who evaluated an LSD-treatment program for alcoholics at Topeka
V.A. Hospital, pointed out that 'LSD treatment by a therapist with a paranoid,
destructive, angry, psychological set towards his patients resulted in some patients
committing suicide'. What he and other practitioners call 'set' used to be termed
counter-transference. Clearly, even those psychiatrists who profess to work on a
psychoanalytic background do not reflect counter-transference processes and
problems. Rather, they discovered counter-transference as a new dimension in


psychotherapy that should be considered systematically. Again, Godfrey 7 can be


My conclusion . . . is that as medical . . . scientists we must dedicate ourselves first, and con-
tinuously to a most difficult task - to know ourselves . . . We are an integral part of the therapeutic
procedures we seek to evaluate. We must know ourselves in a way that will allow us to
effectively design and apply scientific methods of evaluation, with regard for all significant
extrinsic and intrinsic variables, including ourselves and our co-workers.

A psychiatrist who, in 1969, came to this conclusion, which is undoubtedly true,

shows that he ignores completely basic psychoanalytic writings and knowledge
on counter-transference and the importance of training analysis. In 1910, 59 years
before Godfrey, Freud emphasized: 'No psychoanalyst goes further than his own
complexes and internal resistances permit'. Several other LSD advocates showed
the same ignorance of such basic knowledge. Abramson 8 , for example, published
verbatim recordings of what he called psychoanalytic therapy of an asthmatic
woman, and Buckman 9 reduced the problem (and chance) of counter-transference
feelings to the problem of abstinence, when he warned of the erotic transference
of young female patients. Perhaps Grinspoon and Bakalar 10 , of the Harvard
Medical School, are correct when they said: 'In psycholytic therapy patients might
be asked to concentrate . . . on regression with the psychotherapist as a parent
surrogate'. Psycholytic and even more psychodelic therapy should be considered
as a surrogate therapy, where the therapist serves as a real partner who fulfills
wishes, reacts, and acts out his own aggressive and sexual impulses, instead of
working on transference and counter-transference on an exclusively verbal
non-acting level, where only fantasies are the grain for the psychoanalytic mill.
Consequently, surrogate therapy has been proposed for the treatment of sexual
In conclusion, the dissatisfaction of at least one of the criteria mentioned above
clearly demonstrates that most of the LSD psychotherapists had abandoned or had
never practiced basic psychoanalytic technique.
In a sophisticated discussion of the theoretical concept of Stanislav Grof's
transpersonal psychotherapy, Springer 11 demonstrates the close relationship of
psychodelic therapy to suggestion. Springer argued that the same objections to
suggestion and catharsis which Freud had already made are relevant to LSD
psychotherapy: first symptoms improve very quickly. However, these often
surprising improvements after suggestion do not last. Springer refers to the results
of the only controlled follow-up study of medical LSD use: the data published by
McGlothlin and Arnold 1 2 did not support the hypothesis of 'lasting personality,
belief, value, attitude or behavior changes' after the application of LSD within and
without a psychotherapeutic setting.
Undoubtedly, LSD facilitates regression and the reproduction of repressed
material from the patient's personal history, eases affects or memory blocks and


even insight and 'helps to overcome resistance'. Although these effects of LSD
could be useful in psychotherapy, they are not sufficient for therapeutic change.
Abreaction, cathartic experiences, oceanic feelings and transcendental experiences
- the return to primary processes, as they are called in psychoanalytic theory - are
usually not the factors that are essential for the recovery of the patient from neu-
rotic behavior, depressive states or psychosomatic symptoms. This is common
knowledge in psychotherapy research and has been proven for LSD treatment by
one of the very rare studies with a control-group design (Robinson and
colleagues 13 ). Insight, per se, does not usually modify behavior, or help the patient
to make a better adjustment to life. It is the often painful analysis of resistance (and
not the process of overcoming it), the analysis of the transference and its resolu-
tion, and the working through which enable corrective emotional experience in
the therapeutic relationship.
Ignorance or misunderstanding of transference and counter-transference is
neither harmful nor abject nor ineffective, by itself. Psychotherapeutic techniques
using LSD in psycholytic or psychedelic treatments, however, should not be con-
sidered as psychoanalytic techniques. Nevertheless, psycholytic and psychedelic
therapy could be effective in the treatment of psychiatric and psychosomatic
disorders. However, this has to be proven by clinical evaluation of the treatment,
starting with toxicological studies and ending with large-scale therapeutic studies
with representative patient groups.
I would like to summarize the findings on the effectiveness of LSD in therapeutic
applications from my point of view, which differs slightly from the belief of
Drs Leuner and Yensen. There are several critical reviews about LSD in psycho-
therapy (e.g. those of Ditman 1 4 , Hollister 15 , Yensen 6 and Springer 11 ). Therefore,
there is no need to review the literature here again, because the conclusions that
have been drawn by several authors are quite similar: 'Most of this literature is
based on clinical impressions, rather than controlled studies' 6 and the very few
controlled studies yield largely negative outcomes 12 .
It has been maintained that LSD is useful in the treatment of neurosis, socio-
pathic disorders, alcoholism, sexual perversions and other non-psychotic
psychiatric disturbances. Levine and Ludwig 1 6 pointed out that much of the
enthusiasm for the therapeutic use of LSD stems from its 'purported ability to
accelerate the process of psychotherapy by facilitating abreaction and the
emergence of previously repressed material, increasing the transference reaction,
stimulating the production of fantasy material, intensifying affectivity, diminish-
ing excessive intellectualization, dissolving the patient's customary defenses, and
by that allowing him to face his problems more honestly'. However, this
enthusiasm was based upon uncontrolled and seldom-replicated studies, so it was
not possible to separate with certainty the effects of the drug from those of the
therapeutic arrangements, or from the suggestion and pseudo-religious inter-
course that were part of the treatment. In most of the studies, either the dependent


Table 1 Number of publications on LSD and psychotherapy, 1965-1991

(source: Medline and Psyndex)

Year Publications Year Publications

1965 3 1979 3
1966 8 1980 1
1967 6 1981 0
1968 10 1982 0
1969 7 1983 2
1970 5 1984 0
1971 6 1985 2
1972 4 1986 1
1973 7 1987 0
1974 0 1988 0
1975 0 1989 0
1976 1 1990 0
1977 2 1991 1
1978 3

variables and the therapeutic outcome remained vague or, if clear-cut criteria for
improvement were specified and patients met the criteria, it was impossible to
decide which of the many variables of the setting and the set were responsible in
producing the therapeutic effects.
Psycholytic therapy involves the administration of low doses of LSD over a
rather long period to patients undergoing psychotherapy. The psychiatrists who
conduct these studies almost always claim excellent results. This enthusiastic
attitude, combined with the low methodological level of research, is typical of the
earliest phase of psychotherapy research in general, which began with the first
psychoanalytic writings and lasted until 1952, the year of Eysenck's harsh criti-
cism and which has been characterized by the American Psychiatric Association 17
as follows:

Among psychotherapists there was the general belief that what they were doing was usually
effective, and support for this belief was provided predominantly through reports of individual

Unfortunately, most of the research on LSD and psychotherapy did not overcome
this 'early phase of discovery'. Even in the late 1960s, i.e. before the legal
prohibition, many studies suffered from this methodological handicap.
Table 1 shows the consequences of this interference into scientific activities:
Since the early 1970s there have been only a very few publications on LSD and
psychotherapy in scientific journals and most of them are review papers, or
comments which present no new data.


Clearly, this interruption of scientific progress is the main cause for the lack of
knowledge today: the early claim of LSD research, the proof of psychotherapeutic
effectiveness, cannot be evaluated now, the results are too inconclusive. To the
author's knowledge, no study has yet been published which demonstrates clearly
the superiority of psycholytic therapy in comparison to a well-established
efficient psychotherapy without the use of LSD, where patients suffering from a
well-described psychiatric or psychosomatic disorder have been assigned at
random to either treatment.
Many psychiatrists (mainly from the US) have studied psychedelic therapy in
which one or more high doses of LSD are given to the patient. As Cole and Katz 18
stated, psychedelic therapy seems to be an amalgamation of drug therapy, brief
psychotherapy, elements of psychodynamic insight-oriented psychotherapy,
mystical-religious experience 6 , and strong suggestions in combination with
pressure on the patient to confront his problems head on, and all this during one
or more prolonged 8-10-h sessions during which the patient experiences the LSD
effects and is confronted with his pre- and sometimes unconscious wishes,
conflicts and impulses. At the end of the LSD session he discusses his problems,
needs, and experiences with the therapist or with his/her assistant intensively.
This complex mixture of variables apparently helps some patients. However,
there is no empirical evidence on which of these many variables may be effective
in producing the improvement. Psychedelic therapy has been introduced
systematically into the treatment of alcoholics. In their review, Grinspoon and
Bakalar 10 concluded that 'The authentic emotional power [of psychedelic
experiences] is not a guarantee against backsliding when the old frustrations,
limitations, and emotional distress have to be faced in everyday life. Even when
the experience does seem to have lasting effects, it might have been merely a
symptom of readiness to change rather than a cause of change'.
In summary, the enthusiastic belief of several authors who practice psycholytic
or psychedelic therapy has not yet been clearly supported by empirical data. There
is evidence to suggest that some of the many interventions and factors in LSD
therapy may be effective and helpful in the treatment of certain types of neurotic
patients. However, there are also some indications of adverse and even harmful
effects that have been attributed to LSD. In their follow-up study on 247 persons
(about 50% of whom received LSD during psychotherapy during the period
1955-1961, in comparison to a control group), McGlothlin and Arnold 1 2 found
that about 10% of the respondents reported harmful effects of LSD; 24%
experienced what they termed a 'bad trip'. Two-thirds of these bad trips occurred
in the psychotherapeutic setting, but 50% of those experiencing them viewed
them as beneficial in retrospect. Seven suicides occurred among the patients
receiving LSD in psychotherapy, although none took place during the treatment.
The side-effects seem to be neither dramatic, nor necessarily attributable to LSD
intake. However, it could be asked why these controlled follow-up studies, which


used questionnaires and interview techniques, have never been replicated subse-
quently, either in the US or Europe. Such lack of scientific activity cannot be
explained by the banishment of LSD from use under penalty of law. One could ask
why it was that those researchers who complained of the legal prohibition of LSD
research after 1966 hesitated to run systematic follow-up studies of those thousands
of patients which had been treated with psycholytic or psychedelic therapy.
In 1986, Grinspoon and Bakalar 10 complained that 'efforts to make use of drugs
directly to enhance the process of psychotherapy - diagnosing the problem,
enhancing the therapeutic alliance, facilitating the production of memories,
fantasies and insights - have been very limited'. Indeed, to use drugs in order to
improve the process itself could initiate a fascinating new development in
psychiatry. LSD has been proven to speed up regression and to facilitate fantasies
and emotions. However, its influence on the therapeutic alliance itself, on process
factors which have been shown to be relevant for the therapeutic outcome, or on
the process of differential diagnosis, have not been investigated yet.
The relevance of research on the psychotherapeutic approach can be illustrated
using an analogy that has been proposed by Kurland and colleagues 19 : 'It should
be emphasized that LSD is not conceived to have any inherent beneficial effects,
i.e. its use is different from that of other drugs or chemotherapeutic agents . . . The
analogy that we have sometimes used to try to convey the role of LSD in therapy
is that of a scalpel in surgical intervention: the scalpel is helpful, but without the
skilled surgeon it is merely a dangerous instrument'. During the early phase of
discovery, psychotherapists described the use of this new instrument, the scalpel
called LSD, with enthusiasm. In the next phase, which Kachele and Kordy 1 7 called
the 'justification' phase, the surgeons (as the new profession of those using the
scalpel was called) had to demonstrate the effects of this new treatment; they had
to demonstrate the advantage of the invasive technique over the non-surgical
non-invasive treatments of illness. As already mentioned, research on LSD
psychotherapy has not yet reached this phase.
The leading question of process-outcome research, which is the third phase of
psychotherapy research, may be framed as follows: which treatment (i.e. which
method at which time) is best for this particular individual given a specific
problem and conditions? Characteristically, these kind of studies - the first of
which dates from the 1970s - tried not only to identify a more effective kind of
treatment, but also studied carefully the conditions of success and failure. The
focus on patients' conditions or treatment modalities from earlier phases shifted to
the features of the therapeutic process 17 .
One cannot criticize the LSD researchers of the 1960s for the lack of studies that
satisfy the current standards of psychotherapy research, because at that time
systematic research on psychotherapeutic process variables had only just begun.
Nevertheless, a first approach was the longitudinal investigation of Natale and
co-workers 20 on figurative language during extended psychotherapy. They


showed that LSD increases, in two out of three cases, the patient's use of novel
figurative language during psychoanalysis.
At present, we know much more about the relevant factors of the therapeutic
alliance and its relevance to outcome. Thus, if one really assumes that LSD enhances
the therapeutic alliance itself in an effective way, one should begin high-level
research studies on this question, rather than quoting 30-year-old pilot studies or
referring to the anecdotal evidence of enthusiastic practitioners and healers. The
reply to such a proposal can be predicted. Some of my colleagues will object that it
would be nearly impossible, at least in Germany, to obtain the official permission
for research on the effects of LSD in human subjects. It is evident that the pathway
through the ethics committee and the federal health administration is a stony one.
However, it is possible, as the study of Dr Hermle on MDA (methylenedioxy-
amphetamine) demonstrates (see Chapter 7). Recently, I asked the Bundesgesund-
heitsamt, the responsible German administration, how many such applications they
have refused within the last 10 years. They could not answer this question, but they
asserted that, since 1988, there has been no application for a scientific LSD study
in humans.
As mentioned above, there is a great lack of controlled follow-up studies on
those patients who have been treated with LSD during psychotherapy. A group
of Swiss psychiatrists are working legally with LSD, however and some of them
were participants in this conference. I would like to propose that these colleagues
evaluate their psychotherapies systematically, i.e. to describe and rate the psycho-
therapeutic process and outcome of their actual and former patients and to ask
these patients to participate in this follow-up study. This would involve com-
pletion of questionnaires which have been proven useful for recording psycho-
therapeutic change and to participate in an interview with an independent
psychotherapist, who is trained for this special purpose.
I am convinced that the objective reality represented by empirical research will
cause enough frustration to bring the conflict between the narcissistic wishes of
the therapist and the demands of our health care system to a head.
Considering the lack of newer studies and the difficulties in obtaining official
permission, I propose to re-analyze those older data that are available.
Recently psychologists have developed a number of new methods to describe
emotions in psychotherapeutic dialogs (see, for example, Greenberg and
Pinsof 21 ). At least some of the older investigations (e.g. those of Leuner 2 2 , 2 3 )
where psychotherapeutic dialogs have been tape-recorded, might dispel some of
our ignorance of the psychotherapeutic processes that take place under LSD.

1. Freud, S. (1913). On beginning the treatment. Standard Edition, 12, 121-44
2. Waelder, R. (1956). Introduction to the discussion on problems of transference. Int. J.
Psychoanal., 37, 367-8


3. Eissler, K. R. (1958). Remarks on some variations in psychoanalytic technique. Int. J. Psychoanal.,

39, 222-9
4. Eissler, K. R. (1953). The effect of structure of the ego on psychoanalytic technique. J. Am.
Psychoanal. Assoc., 1, 104-43
5. Leuner, H. (1981). Halluzittogene-psychische Grenzzustände in Forschung und Psychotherapie. (Bern:
6. Yensen, R. (1985). LSD and psychotherapy. J. Psychoactive Drugs, 17, 267-77
7. Godfrey, K. E. (1971). LSD in Forschung und Therapie. In Ammon, G. (ed.) 'Beivußtseinser-
weiternde' Drogen in Psychoanalytischer Sicht, pp. 72-115 (Berlin: Pinel)
8. Abramson, H. A. (1977). Reassociation of dreams. III. LSD analysis of a threatening
male-female dog dream and its relation to fear of lesbianism. J. Asthma Res., 14, 131-58
9. Buckman, J. (1969). Psychedelic drugs as adjuncts to analytic psychotherapy. In Hicks, R. R.
and Fink, P. J. (eds.) Psychedelic Drugs, pp. 210-16.(New York: Grune and Stratton)
10. Grinspoon, L. and Bakalar, J. B. (1986). Can drugs be used to enhance the psychotherapeutic
process? Am. J. Psychotherapy, 3, 393-404
11. Springer, A. (1978). LSD-psychotherapie. Eine kritische Revision an Hand von Stanislav Grof's
Topographie des Unbewußten. Wiener Zeitschrift für Suchtforschung, 2, 21-32
12. McGlothlin, W. H. and Arnold, D. O. (1971). LSD revisited. Arch. Gen. Psychiatry, 24, 35-49
13. Buckman, J. (1966). An outline of psycholytic therapy. In Brill, H., Cole, J. O., Deniker, P.,
Hippius, H. and Brandley, P. B. (eds.) Neuro-Psycho-Pharmacology, pp. 417-21. (Amsterdam:
Excerpta Medica Foundation)
14. Ditman, K. S. (1968). The value of LSD in psychotherapy. In Ungerleider, J. T. (ed.) The
Problems and Prospects of LSD, pp. 45-60 (Springfield: Thomas)
15. Hollister, L. E. (1968). Chemical Psychoses (Springfield: Thomas)
16. Levine, J. and Ludwig, A. M. (1964). The LSD controversy. Comprehensive Psychiatry, 5, 314-21
17. Kachele, H. and Kordy, H. (1994). Outcome research. In von Uexküll, Th. (ed.) Psychosomatic
Medicine (Stuttgart: Urban and Schwarzenber) in press
18. Cole, J. O. and Katz, M. M. (1964). The psychotomimetic drugs: an overview. J . Am. Med.
Assoc., 187, 758-61
19. Kurland, A. A., Savage, Ch., Shaffer, W. and Unger, S. (1967). The therapeutic potential of
LSD in medicine. In De Bold, R. C. and Leaf, R. C. (eds.) LSD, Man and Society, pp. 20-35.
(London: Faber and Faber)
20. Natale, M., Kowitt, M., Dahlberg, C. C. and Jaffe, J. (1978). Effect of psychotomimetics (LSD
and dextroamphetamine) on the use of figurative language during psychoanalysis. J. Consult.
Clin. Psychol, 46, 1579-80
21. Greenberg, L. and Pinsof, W. (eds.) (1986). The Psychotherapeutic Process. A Research Handbook
(New York and London: The Guilford Press)
22. Leuner, H. (1966). Basic functions involved in the psychotherapeutic effect of psycho-
tomimetics. In Brill, H., Cole, J. O., Deniker, P., Hippius, H. and Bradley, P. B. (ed.)
Neuro-Psycho-Pharmacology, pp. 445-9 (Amsterdam: Excerpta Medica Foundation)
23. Leuner, H. (1987). Außergewöhnliche Bewußtseinszustände in der westlichen Psychotherapie.
Die Psycholytische Therapie: Durch Halluzinogene unterstützte tiefenpsychologische Psycho-
therapie. In Dittrich, A. and Scharfetter, C. (eds.) Ethnopsychotherapie, pp. 151-61 (Stuttgart:


Methodological issues in the

evaluation of a medication for its
potential benefits in enhancing

Novel ideas in science are typically met with skepticism. An inherent conservatism
is fostered by the scientific method. In its true sense the scientific method is com-
pletely open to new ideas but it requires that those ideas be presented in the form
of testable hypotheses. There is no place in the scientific method for 'beliefs' and
for serious discussion of ideas that are 'too complex to be tested'. Our job as scien-
tists is to find a way to test new ideas, instead of simply rejecting them because
they are too complex or accepting them on the basis of testimonials rather than
evidence derived from the proper testing of an hypothesis.
Nowhere is this tension between novelty and the scientific method more appar-
ent than in medical science where new treatments may save lives and alleviate
suffering. Claims for new but not completely proven treatments for cancer and
for diseases such as AIDS have become commonplace and there is public pressure
to allow them to be prescribed without appropriate testing. Any student of
medical history, however, knows that there have been many 'wonderful new
treatments' that were later found to be useless at best and harmful at worst. The
general public is quick to criticize the so-called 'medical establishment' and claim
that new treatments are being delayed needlessly. However, a balance has to be
struck between protecting the public against ineffective treatments and depriving
them of new developments that might be better than existing treatments. In this
context, the self-reports of scientists and therapists who have ingested LSD are


interesting clinical reports from keen observers, but their observing organ - their
brain - has surely been influenced by the presence of the drug itself. Reports of the
results of one's own treatment or observations of one's own patients can hardly
be objective.
Psychotherapy research techniques have progressed considerably in the past 20
years. Using controlled study designs, we have been able to show efficacy for a
variety of psychotherapeutic techniques. Measuring efficacy for combinations of
medications and psychotherapy has proven more difficult but not impossible.
Claims that medications such as LSD enhance the effects of psychotherapy can be
evaluated using modern psychotherapy research techniques. Certainly there have
been efforts at such evaluation in the past but they occurred at a time when the tech-
nology was less highly developed and when there was great controversy about the
safety of LSD itself. This controversy was emotional and entangled with the politics
of the day. However, these issues led medical researchers to become aggressive and
extreme in their arguments on each side of the issue. For example, one proponent 1
of the benefits of LSD charged in print that the controlled study of Ludwig and
colleagues2 which used LSD in the treatment of alcoholism was biased, consciously
or unconsciously, against LSD. Perhaps today's climate is calmer and more con-
ducive to dispassionate study of the case reports, suggesting that LSD or other
hallucinogenic drugs might have therapeutic benefits in the treatment of some
mental disorders or in the enhancement of psychotherapy for these disorders.
In reviewing the available evidence according to modern standards, one would
have to conclude, as did the late Daniel Freedman in an article published in 1992
that the evidence for therapeutic efficacy is wanting: 'Patients with varied dis-
orders were not improved or worsened. Freud's mapping of the unconscious was
not enhanced. Psychiatric residents offered the drug by some teaching centers
were not thereby more notably sensitive nor skilled psychotherapists.' 3


At this conference, we have been charged with presenting observations on the
essentials of an adequate study on the issue of psychotherapeutic benefits from
hallucinogenic drugs (Table 1). Such a study must begin with clearly defined
objectives. Hypotheses should be set forth as explicitly as possible. Sample size
will always be a problem. It is extremely difficult to obtain an adequate sample
size to meet scientific standards and statistical significance in any single treatment
clinic. With a small sample size, it is more likely that several well-designed studies
would show the same 'non-significant' trend. This would perhaps be encouraging
enough to obtain funding for the study of a larger group, perhaps in a multi-clinic
trial. The study is much more likely to obtain statistically significant results if
hypotheses can be stated in advance, rather than to have a 'fishing expedition'
after the end of a study that searched for differences among groups.


Table 1 Essentials of an adequate study

Specific diagnosis
Severity measures
Informed consent: risk vs. benefits
Placebo control group
Random assignment
Standardized psychotherapy
manual guided
measure 'dose' of psychotherapy
Objective 'blind' raters
Importance of follow-up

Ample precedent exists for the evaluation of complex treatment methods. Psy-
chotherapy itself was once thought to be too complicated for objective and quan-
titative evaluation.
More recently there have been double-blind studies of neuroelectrostimulation
for the treatment of opiate withdrawal 4 . Ongoing studies are evaluating acupunc-
ture treatment for various disorders 5 . There are studies of antidepressant medica-
tion combined with psychotherapy for depression 6 and methadone treatment
combined with psychotherapy for opiate dependence 7 . Ardent supporters of
hallucinogenic drug enhancement of psychotherapy should not expect to have this
proposed new treatment examined any differently from any other medication,
nutritional regimen, vitamin, or device that is claimed to have therapeutic potential.
An adequate study should be one that is not unduly influenced by the
enthusiasm of the proponents of the new treatment nor by any negativism on the
part of those who are skeptical. A homogeneous patient population is essential.
This means that the patients must be diagnosed using commonly accepted diag-
nostic criteria. The Diagnostic and Statistical Manual of the American Psychiatric
Association (latest revision, DSM-IV) 8 has gained wide international acceptance
and has been revised in accordance with the international classification of diseases
(ICD-X). A specific diagnosis is essential. For example, a study of patients charac-
terized simply as having drug dependence or alcoholism would not be acceptable.
One would have to specify the type of drug and whether or not there were any
additional drugs involved with each patient. Currently, in some parts of the
United States, at least 50% of the alcoholics in treatment also abuse cocaine. Diag-
nosis according to standard diagnostic criteria ideally should be applied by an
observer who is not one of the therapists in the study.


The same objectivity should be applied to severity measures. Simply having the
same diagnosis does not impart the same prognosis. Prognosis depends on many


factors, such as duration of illness and degree of social impairment. This was
recognized implicitly by Dr S. Grof 1 a well-known researcher of the therapeutic
effects of LSD when he wrote the following: 'The best candidates for LSD psy-
chotherapy seem to be subjects who have a good intellect and adequate interper-
sonal and professional adjustment, but lack zest for life and a sense of meaning.
Although they might appear to be highly successful by the standards of the
society that surrounds them, they cannot connect emotionally with their achieve-
ments and enjoy them'. Of course, patients who fit that description would prob-
ably do well in any form of therapy.
Most of the reported efforts that have used LSD as a form of psychotherapy
enhancer have been directed at patients who are dependent on alcohol or other
drugs 9 . Since these studies were published, diagnosis has become much more
precise, and a severity measure for addictive disorders has been developed. In the
substance-abuse field, the Addiction Severity Index 1 0 has become recognized
internationally in both clinical work and treatment-outcome research. An instru-
ment such as this is useful in studying changes produced by various therapies for
addiction and to ensure that treatment groups are comparable at the start.

Informed consent for such a study is essential. The consent process must spell out
the risks and the potential benefits. The risks for LSD are small but they are
greater than zero. Attack rates for psychosis after experimental administration
have ranged from 0.89 to 4.6% (median, 2.7%). Higher rates have been reported
for psychiatric patients than for healthy volunteers 1 1 - 1 8 . The attack rate asso-
ciated with LSD that is administered experimentally is believed to be significantly
less than the risk for LSD used 'on the street' without supervision, but reliable
data are impossible to obtain. The risk is believed to be dose-related and there may
be individuals who have a special vulnerability to unpleasant effects. There is also
the risk of post-hallucinogenic perceptual disorder 19 . This was first described in
1958 as involving spontaneous recurrences of LSD-like perceptual states in sub-
jects in the days or weeks following use. More recent intensive study of repeated
LSD users by Abraham 18 has detected a visual perceptive disorder that persisted
over a 5-year period in 50% of the sample. Precipitants included stress, fatigue,
emergence into a dark environment, marijuana, neuroleptics and anxiety states.
Clearly, the causality for these symptoms is difficult to attribute because the
patients in Abraham's study were not studied prior to using LSD. From the per-
spective of an independent committee charged with protecting human subjects,
reports such as those of Abraham 1 9 must be considered. These reports of persist-
ent drug effects must somehow be communicated to potential research subjects.
The consent form must be written in plain language that is readily understood by
a lay person.


The consent form itself is not without disadvantages because of the possibility
that symptoms will be suggested to the patient. This is another reason for having
a placebo group as discussed below.


A placebo control group is an essential in any study of treatment-effectiveness in
psychiatry, whether the treatment involves diet, medication, an electronic device
or behavioral intervention. This applies whether one is studying an Axis I diag-
nosis such as an affective or schizophrenic disorder, or a drug-use disorder such
as alcoholism or cocaine dependence. Psychiatric disorders have varying courses.
Too often have investigators approached addiction as though it were a form of
terminal cancer, so that any beneficial outcome could be considered a treatment
success without the need for a control group. There are numerous studies
showing that substance-use disorders have a variable outcome, with some
patients doing well no matter what the treatment. An obvious difficulty with
evaluating a treatment such as an hallucinogen is that the patients and the raters
will probably know who is receiving placebo and not the active medication.
However, this may not be entirely unavoidable. First, there is the possibility of
using an active placebo design, as was applied by Reginald Smart and colleagues 20
when methylphenidate and LSD were compared in the treatment of alcoholics.
Another possibility is to use a very low dose of the active medication.
The informed consent process itself may be responsible for some remarkable
placebo effects because potential side-effects of the medication must be explained
to the patient before beginning the study. Thus, those patients who receive the
placebo may actually report hallucinations or very beneficial effects which,
without a placebo group, would have been incorrectly attributed to the medica-
tion. In the study reported by Grof 1 , 50 µg LSD was given as an active placebo
to a group of alcoholics and compared with the effects of 450 µg given to the
experimental group. Since an apparent therapeutic effect was observed at both
dose levels, the authors called this 'an interesting and unexpected research finding'
because of the 'dramatic improvement in some patients in the control group who
received only 50 µg LSD on a double-blind basis . . .'
This is often the response of investigators who attribute placebo effects to the
small dose of the active medication, when in fact it may be a pure placebo effect.
This response on the part of the investigator bears a striking similarity to the
response regarding another novel treatment. A study was conducted at our Center
for the Study of Addictions involving the use of neuroelectrostimulation in the
treatment of opiate withdrawal 4 . In this study, the placebo control treatment
involved connection of the patient to an impressive-looking stimulator that
produced only a few seconds of perceptible stimulation at the beginning of treat-
ment, after which the computer program automatically decreased the stimulation


to zero. In contrast, for the active treatment group, the stimulation continued,
though at a subperceptible level that was considered to be therapeutic, based on
prior uncontrolled studies. The controlled study produced apparent and some-
times remarkable benefits for many of the patients. The staff (who were very
experienced in treating addictive disorders) were quite impressed; some of the
patients who were well-known to them said that this was the best treatment that
they had ever experienced. The patients reported that they felt wonderful, with
more energy and enthusiasm and positive thinking than they had experienced in
any previous rehabilitation program. However, when the study was concluded
and the patients' treatments were decoded, it was found that those receiving the
placebo stimulation were just as likely to have reported these wonderful effects as
those receiving the active stimulation at full doses throughout the entire treatment
period! To an objective observer, this meant that the testimonials that were
reported for this treatment were simply a placebo effect. However, the enthusias-
tic proponents of the stimulation treatment suggested that a few seconds of stimu-
lation at the beginning must have produced these remarkable results.
Another benefit of including a placebo group is that it is the only means of
obtaining a true measure of the side-effects of the medication. When we were
studying cyclazocine in the early 1970s, the possibility of hallucinations as a side-
effect had to be included in the consent form. This information apparently
produced some remarkable hallucinatory experiences in patients who actually
received nothing but an inert placebo. More recently, we have been studying
naltrexone for the treatment of alcoholism, and the possibility of unexpected
penile erections produced by naltrexone was included in the consent form. As the
reader may have guessed, a remarkable incidence of spontaneous penile erections
were reported by alcoholics assigned randomly to placebo.
The most important reason for including a placebo control group is that this is
the only way to determine whether or not the medication is really effective. There
are spontaneous changes in all of the mental disorders that we treat and for
unknown reasons patients will sometimes respond to almost any treatment that is
given. In the case of giving medication to enhance the effects of psychotherapy,
there is an even more complex problem. In this case, an interaction between two
treatments that may both have their own independent effectiveness is sought.
Ideally, these should be a placebo-only condition; the putative psychotherapy
enhancer alone; psychotherapy plus placebo; and psychotherapy plus putative
psychotherapy enhancer. This results in more treatment cells, a larger sample size
and greater difficulty in executing the study. However, if the study is done
without the appropriate controls, the entire effort may be wasted.

Random assignment to treatment conditions in any study of this type is absolutely
essential. Consequently, all patients must be carefully screened and be willing to


be treated with a drug that may produce hallucinations. A corollary of this is that
some patients who are willing, and perhaps even eager to receive the hallucinogen
will receive only placebo. The promise of later treatment on an open basis (if
patients wished) could be made. For the study to be valid, however, it must
include a group of patients who are willing to receive the active medication, but
in fact receive a placebo assigned by chance on a double-blind basis.

There have been many advances in psychotherapy research over the past 25
years 21 . Psychotherapy must be described carefully and administered in a standard
way. This can be accomplished using treatment manuals that have operationalized
the application of the specific form of psychotherapy. Each therapist must have
demonstrated standard levels of competence in pilot studies prior to the beginning
of the trial. Therapists should receive regular supervisory sessions and some of
their sessions should be tape-recorded so that they can be analyzed by an indepen-
dent judge. In effect, the 'dose' of psychotherapy must also be quantified as care-
fully as the dose of medication 22 . These techniques have been well established in
the psychotherapy research literature. They cannot be neglected in a study that
focuses mainly on an hallucinogenic adjunctive medication.


An appropriate protocol should have, at a minimum, clinical assessments made by
independent observers before and after the experimental treatment. These
observers should not know which patients were given the control exposure and
which the active hallucinogenic experience. Clearly, it is possible that the patients
would themselves divulge to the observer the group to which they thought they
belonged, but these reports may or may not be accurate. As indicated above, the
informed consent process has been known to suggest hallucinogenic experiences
in patients given placebos. In any case, the independent observers would not
know for certain which patients had been given the experimental drug, and they
would be in the best position to evaluate the benefits of the treatment objectively.
The need for objective observers does not mean that the researchers might be
intentionally dishonest, but merely that none of us can be truly and completely
objective about the results of our own work.
The raters must rate the changes in patients according to the same criteria
used at baseline, prior to initiating therapy. Follow-up, 6-12 months after the
termination of treatment is also very important. Ideally, a study should have
hypotheses that can be tested in a prospective way. For example, one hypothesis
might be that those patients who had received the active medication and had had
a series of hallucinatory experiences might have more insight, more relief of


psychological symptoms associated with their substance abuse. Such a result

would be an important finding, even if there were no differences in relapse to sub-
stance abuse.


There appears to be much less controversy about research involving hallucino-
genic drugs during the 1990s than during the tumultuous 1960s and even the
1970s. However, it should be noted that at the time of writing there has been a
recent rise in the popularity of LSD among young people in the United States.
Lifetime LSD use among adolescents increased from 4.4% in 1985 to 5.7% in
1989, and to 6.8% in 1993. In some localities up to 19% of Caucasian adolescents
reported having used LSD. Thus, while use is still at relatively low levels, there is
a decrease in the perception of the dangers of LSD with the concomitant increase
in experimentation by adolescents with this drug. As physicians and health care
providers, we have the responsibility to 'first do no harm'. Consequently, articles
about the potential benefits of LSD and other hallucinogens in the popular press,
unless carefully written, could result in a further upsurge in the illicit use of this
substance. Even the most ardent supporters of the potential benefits of LSD and
other hallucinogens for enhancing psychotherapy would probably agree that
unsupervised use of LSD in 'street' doses is dangerous. Thus, we have a responsi-
bility to design our studies carefully and make certain that public statements are
worded thoughtfully.
In conclusion, this commentary on the methodological challenges that are faced
in studies of drugs that may enhance the effects of psychotherapy, is not meant to
discourage research in this area. We simply wish to set forth some guiding princi-
ples that must be followed if the results of a study in this area are to gain accept-
ance in the scientific community. There is no reason for the exemption of
medications of this type from the normal standards of scientific scrutiny that are
properly applied to all other therapeutic claims. If an appropriately designed study
produces positive results, this could represent a significant advance for use with
difficult patients who have not responded well to psychotherapy alone.

1. Grof. W. (1980). LSD Psychotherapy, p. 237. (Pomona, California: Hunter House)
2. Ludwig, A. M., Levine, J. and Stark, L. H. (1970). LSD and Alcoholism: A Clinical Study of Treat-
ment Efficacy. (Springfield: Thomas)
3. Freedman, D. X. (1992). LSD and psychiatry: a personal trip. In Kales, A., Pierce, C. M. and
Greenblaltt, M. D. (eds.) The Mosaic of Contemporary Psychiatry in Perspective, pp. 182-90. (New
York: Springer Verlag)
4. Gariti, P., Auriacombe, M., Incmikoski, R., McLellan, A. T., Patterson, L., Dhopesh, V.,
Mezochow, J., Patterson, M. and O'Brien, C. P. (1992). A randomized double-blind study of
neuroelectric therapy in opiate and cocaine detoxification. J. Substance Abuse, 4, 299-308


5. Bullock, M. L., Culliton, P. D. and Olander, R. T. (1989). Controlled trial of acupuncture for
severe recidivist alcoholism. Lancet, 1435-9
6. Kupfer, D. J., Frank, E., Perel, J. M., Cornes, C., Mallinger, A. G., Thase, M. E., McEachran,
A. B. and Grochocinski, V.J. (1992). Five-year outcome for maintenance therapies in recurrent
depression. Arch. Gen. Psychiatry, 49, 769-3
7. Woody, G. E., Luborsky, L., McLellan, A. T., O'Brien, C. P., Beck, A. T., Blaine, J., Herman,
I. and Hole, A. (1983). Psychotherapy for opiate addicts: does it help? Arch. Gen. Psychiatry, 40,
8. American Psychiatric Association (1993). DSM-IV Draft Criteria (Washington: APA Press)
9. Abuzzahab, F. S., Sr and Anderson, B. J. (1971). A review of LSD treatment in alcoholism. Int.
Pharmacopsychiatry, 6, 223-5
10. McLellan, A. T., Luborsky, L., O'Brien, C. P. and Woody, G. E. (1980). An improved diagnos-
tic instrument for substance abuse patients. The Addiction Severity Index. J. Nerv. Ment. Dis.,
168, 26-33
11. McLellan, T., Woody, G. E. and O'Brien, C. P. (1979). Development of psychiatric illness in
drug abusers. N. Engl. J. Med., 301, 1310-13
12. Bowers, M. (1972). Acute psychosis induced by psychotomimetic drug abuse, 1: clinical find-
ings. Arch. Gen. Psychiatry, 27, 437-40
13. Breakey, W., Goodell, H., Lorentz, P. and McHugh, P. (1974). Hallucinogenic drugs as
precipitants of schizophrenia. Psychol. Med., 4, 225-61
14. Fink, M., Simeon, J., Haque, W. and Itil, T. (1966). Prolonged adverse reactions to LSD in psy-
chotic subjects. Arch. Gen. Psychiatry, 15, 450-4
15. Frosch, W. A., Robbins, E. S. and Stern, M. (1965). Untoward reactions to lysergic acid
diethylamide (LSD) resulting in hospitalization. N. Engl. J. Med., 273, 1235-9
16. Malleson, N. (1971). Acute adverse reactions to LSD in clinical and experimental use in the
United Kingdom. Br. J. Psychiatry, 118, 229-30
17. Strassman, R. (1984). Adverse reactions to psychedelic drugs: a review of the literature. J. Nerv.
Ment. Dis., 172, 577-95
18. Abraham, H. D. and Aldridge, A. M. (1993). Adverse consequences of lysergic acid diethyla-
mide. Addiction, 88, 1327-34
19. Abraham, H. D. (1983). Visual phenomenology of the LSD flashback. Arch. Gen. Psychiatry, 40,
20. Smart, R. G., Storm, T., Baker, E. F. W. and Solursh, L. (1967). Lysergic Acid Diethylamide (LSD)
in the Treatment of Alcoholism, pp. 1-121. (Toronto: University of Toronto Press)
21. O'Brien, C. P. and Woody, G. E. (1989). Psychotherapy research. In Kaplan, H. I. and
Saddock, B.J. (eds.) Comprehensive Textbook of Psychiatry Fifth Edition, pp. 1568-73. (Baltimore:
Williams and Wilkins)
22. Kraemer, H. C. and Teich, C. F. (1992). Selection and utilization of outcome measures in psy-
chiatric clinical trials. Neuropsychopharmacology, 7, 85-92

Conclusions, with special regard
to clinical aspects
Natural sources of LSD-related hallucinogens have been used ritualistically for
hundreds of centuries by shamans to access non-ordinary states of consciousness
(see Chapter 4, by Rivier). In the ensuing decades since Albert Hofmann dis-
covered lysergic acid diethylamide, his 'problem child' has raised hopes about its
therapeutic potential, which unfortunately led to an epidemic of abuse, but
inspired a generation of scientists to ask ever more sophisticated questions about
its actions in the nervous system. Competing claims of benefit and harm have
resulted in controversies. This symposium covered a full spectrum of information:
data, experiences, explanations and beliefs. In a way it was a consensus con-
ference, both looking back and toward the future. The following topics have been
and will be the most important ones:
(1) What is the mode of action of LSD?
(2) What is the place of LSD in treatment?

(3) What are the topics and directions of future research?

LSD was used to develop new insights into the mechanisms of nerve cell trans-
mission, visual hallucination (although the latter term is misleading; see chapters
by Dittrich and Heimann, this volume) and the phenomenology of schizophrenia
- although again the term 'model psychosis' is misleading.
With the beginning of the worldwide abuse of psychoactive compounds
(including LSD and related substances) in the 1960s, clinical research became
increasingly difficult because of legal restrictions. This was signified by a decreasing
number of research applications to the corresponding national health authorities
correspondingly and by a general decreasing interest (see Chapter 14, by Richter).
In 1968, Freedman surveyed the dangers of hallucinogens and concluded that the
harm arising from the use of LSD outweighed the benefits 1. It is noteworthy,
in examining the literature (see Chapter 14), that the early 1960s produced a


preponderance of favorable reports, which abruptly reversed in 1968 1 and, from

then on, such reports appeared less frequently. Hopefully we will once again have
data that stimulate new research!
Clinical use has been directed towards neurosis, autistic children, schizophrenia,
alcoholism, and as an adjunct therapy for the terminally ill. Treatment of
alcoholism with LSD was considered to be particularly effective, but controlled
studies failed to favor LSD above other therapies (see Chapter 12, by Leuner and
Chapter 15, by O'Brien and Jones). It is inconceivable that controlled studies, as
a standard in clinical science, have been neglected in other areas of clinical use.
LSD was combined with psychotherapy at many different doses and frequencies
of administration. In Europe, 'psycholytic' therapy became predominant, whereas
North American psychiatrists tended towards the opposite approach, giving a
small number of LSD doses exceeding 200µg, termed 'psychedelic' therapy, with
the intention of creating a 'psychedelic peak'. It is difficult to find compelling
evidence that demonstrates a positive outcome from the combination of LSD with
psychotherapy, and it is questionable if the 'concepts' of psycholytic/psychodelic
therapy as a special kind of psychoanalytical therapy should be used in the future
(see Chapter 14, by Richter). The effect of LSD still concerns that subgroup of
patients in which a single dose of a drug appears capable of effecting major
psychobiological alterations in the subject.
It is perhaps ironic to note that in the past 50 years, although our understanding
of the mechanisms of action of LSD has vastly increased, we have yet to clarify
any conclusions from the original debate as to whether hallucinogens are clinically
useful. The prospect of new insights into the molecular mechanisms of hallucino-
gens is increasing today. We know that they play a significant role in delineating
the family of serotonin receptor subtypes (see Chapter 2, by Peroutka). With
current advances in ligand-specific neuroimaging, molecular genetics, tissue
culture and the dissection of the mechanisms of signal transduction, hallucinogens
promise (as never before) to assist in the search for at least some of the key factors
involved in mental illness. There are advantages in using hallucinogens experi-
mentally. In humans, the preservation of a relatively clear sensorium under LSD
facilitates the study of psychological processes caused by the drug. In animals,
access to neurons, membranes and genes is possible. The challenge to integrate
these approaches still remains. Why is it that many individuals can use these sub-
stances with impunity, while others become adversely affected? What is the basis
of such vulnerability? What kind of patients may be treated, in which therapeutic
setting, and with which kind of hallucinogen?

The continued endemic use of hallucinogenic drugs, and of LSD in particular, still
raises concern regarding their short- and long-term adverse consequences. The


epidemiology of LSD abuse concerns a constant minority of populations in

Europe and the USA, although with some peaks, reflecting a changing popularity.
In addition, the evidence supports an association of LSD use with panic reactions,
and post-hallucinogen perceptual disorder. There is a great variation in the
response to LSD both between individuals and in the same individual at different
times. This is related, in part, to the instructional set, setting, and personality of
the individual. Following multiple doses, tolerance develops and cross-tolerance
also is seen between LSD, psilocybin and mescaline.

Glennon and colleagues2 correlated the affinity of hallucinogens for various
receptors with their potency in humans. Affinity for the 5 - H T 2 receptor related
most closely with hallucinogenic potency. The evidence for agonism at the 5 - H T 2
receptor is derived from discrimination studies, in which rats are conditioned to
recognize the administration of an hallucinogen. Specific 5 - H T 2 antagonists are
then used to block hallucinogen discrimination. Agonist and partial-agonist
activity has been favored by Sanders-Bush and co-workers 3 and by Sheldon and
Aghajanian 4 while some antagonism has been favored by Pierce and Peroutka 5 .
LSD has a high affinity as an agonist for the 5 - H T 1 A receptor. This is shared
by a number of selective 5 - H T 1 A agonists without hallucinogenic properties. In
contrast, there is a good correlation between both indoleamine and phenethyl-
amine hallucinogens for 5 - H T 2 receptors and their potency as hallucinogens in
humans. Recently, Sanders-Bush and Breeding 3 have reported a potent effect of
hallucinogens at the 5 - H T l c receptor.
Peroutka (Chapter 2) summarized by saying that it appears that D - L S D seems
to display differential interactions with 5-HT receptor subtypes by acting as an
antagonist or partial agonist at 5 - H T 2 and 5-HT 1 C receptors and an agonist at
multiple 5-HT 1 receptors.
Knowledge of the relationships between electrophysiology and behavior (see
Chapter 3, by Aghajanian) is important. The enhancement of sensory responsivity
of locus ceruleus neurons are supposed to contribute to the characteristic
intensification of perceptual experience. The increase of motoneuronal excitability
(e.g. facial nucleus) and the activation of a subpopulation of interneurons that
express 5 - H T 2 receptors in the cerebral cortex may explain cognitive and
perceptual distortions.

Strassman (Chapter 11) argued that we are seeing the beginning of a new phase
of human hallucinogenic drug research. This is based on the aforementioned


advances in serotonin receptor physiology. In addition, a new psychopharmaco-

logical approach takes advantage of a number of new technologies that were not
anticipated when the first stage of human research ceased. A much keener eye can
now be turned towards brain mechanisms - an admirable goal in the 'Decade of
Brain.' Fruitful results of this kind of research have been presented by Hermle
(Chapter 7) and his group and by Vollenweider (Chapter 6). In the last 25 years
we have witnessed a tremendous increase in the number and versatility of
methodological tools for psychiatric research, e.g. brain imaging techniques, sleep
electroencephalography, as well as methods for studying differential psycho-
logical effects of hallucinogens (see Chapter 8, by Dittrich). Single photon
emission computed tomography (SPECT) scans produced under mescaline and
then compared intraindividually with SPECT scans made under controlled con-
ditions demonstrated clearly the localization of possible points of attack of the
drug. The mescaline effect could be located in the frontal cortical region, espe-
cially in the right hemisphere, whereas in posterior cortical regions there was no
difference within the treated individuals.
Vollenweider (Chapter 6) who is studying psilocybin and ketamine, presented
very interesting results using positron emission tomography in connection with
measures of psychological and psychopathological dimensions. These findings
again stressed the importance of the right hemisphere (cortex, thalamus). Hyper-
frontality might be seen as an hallucinogenic effect, as well as in psychotic states.
In his broad studies, Dittrich (Chapter 8) has developed a psychological
instrument for measuring and for differentiating substance-related and non-
substance-related altered states of consciousness.
Three associated syndromes can be measured precisely: 'oceanic boundlessness',
'dread of ego-dissolution' ('bad trip') and 'visionary restructuralization'. This
progress in methodology is important, but we should nevertheless be reminded
that the phenomenological description of personality traits, substance effects and
environment still remains a very helpful source of information (see Chapter 5,
by Heimann).


Therapy research with LSD and related compounds in human subjects is beset
with considerable methodological difficulties. Most of the literature is based on
clinical impressions and uncontrolled studies. It may be that some of this material
could be re-evaluated to look for more specific effects.
Lader (Chapter 10) mentioned the necessity of dose-effect, dose-response and
dose-ranging studies within individuals, including aspects of tolerance. Most
studies were done 30 years ago and new studies should include new hallucinogens.
For future therapy research, Lader stressed the need for:


(1) Specification of diagnoses according to DSM IV-R/ICD-10;

(2) Use of standardized instruments for measuring psychopathology;
(3) Specification of variables concerning therapist and environment;
(4) Operationalization of outcome variables; and
(5) Description of adverse effects.
New psychotherapy research protocols, suitable for the study of how hallucino-
gens may modulate psychotherapeutic treatment, will be welcome. The confusion
associated with the use of hallucinogens within a psychoanalytical approach (see
Chapter 14, by Richter) needs to be clarified.
Yensen (Chapter 13), in his broad philosophical treatment, outlined different
paradigms. He stressed once more the importance of the subject in the therapeutic
process. His criticisms concerning the more biological approach should be taken
seriously, but I consider that only a well-controlled approach can promote
research. Restrictive administrative obstacles that block clinical research have to
be dismantled.
As an example of the new psychopharmacological data, Hermle (Chapter 7) and
his collaborators presented some results from their studies on the effects of
methylenedioxyethylamphetamine (MDE), which seem worthwhile continuing.
Strassman (Chapter 11) used dimethyltryptamine (DMT); 3,4-methylenedioxy-
methylamphetamine (MDMA) has been mentioned as another substance (see
Chapter 2, by Peroutka). MDMA has mood-altering properties in humans; it
shares the dopamine-releasing properties of amphetamine but has been found to
be a more potent releaser of serotonin (5-HT). Pretreatment with the selective
5-HT uptake inhibitors fluoxetine, sertraline and zimelidine has shown to inhibit
MDMA-induced locomotor hyperactivity. The mechanisms are dependent on the
release of central 5-HT and are qualitatively different from the mechanism of the
action of amphetamine 6 .

Prompted in part by the accumulated research findings and by the historical
discovery of the psychological effects by Albert Hofmann, this symposium
allowed a number of leading scientists to discuss the status of research on LSD and
the related hallucinogens that produce similar mind-altering effects.
Whilst considerable progress has been made in animal studies, the human
hallucinogen research issue needs new data. Currently, animal and human studies
are attempting to further clarify the mechanisms of hallucinogenic drug actions; to
determine whether and how the mechanisms are linked to the behavioral and
physiological effects of these drugs; to identify the primary sites in the brain where


LSD and related hallucinogens work; and to determine which pathways control
the effects these drugs have on vision, cognition and emotions.
Both the mode of action and the target of treatment remain to be further
clarified. Hallucinogens are still drugs scheduled for Early Therapy Studies. A
better understanding of the ways in which these drugs affect basic brain functions
could lead to the development of new medications, firstly for treating some of the
short- and long-term adverse effects of LSD and other hallucinogens and, more
importantly, for syndromes within personality disorders or drug abuse, anxiety-
syndromes, depression and schizophrenia.
The actual case-oriented therapeutic use of hallucinogens needs a re-evaluation.
It has been very important that Swiss authorities have been open-minded about
this kind of therapeutic approach for many years, and it is hoped that with a
better methodology and standardization and, hopefully, with international co-
operation, a protocol on psychotherapeutic/psychopharmacological procedures
will allow this work to continue. It would be desirable that health authorities in
other countries will also consider research topics and strategies to study the
psychopharmacology of hallucinogens once more.

1. Freedman, D. X. (1968). On the use and abuse of LSD. Arch. Gen. Psychiatry, 18, 330-47
2. Glennon, R. A., Teitler, M. and McKenney, J. D. (1984). Evidence of 5-HT 2 involvement in the
mechanism of hallucinogenic agents. Life Science, 35, 2505-11
3. Sanders-Bush, E. and Breeding, M. (1991). Choroid plexus epithelial cells in primary culture: a
model of 5 H T 1 C receptor activation by hallucinogenic drugs. Psychopharmacology, 105, 340-6
4. Sheldon, P. W. and Aghajanian, G. K. (1990). Serotonin (5-HT) induces IPSPs in pyramidal layer
of rat piriform cortex: evidence for the involvement of a 5-HT 2 -activated interneuron. Brain
Research, 506, 62-9
5. Pierce, P. A. and Peroutka, S.J. (1990). Antagonist properties of d-LSD at 5-hydroxytryptamine 2
receptors. Neuropsychopharmacology, 3, 503-8
6. Wing, L. L., Tapson, G. S. and Geyer, M. A. (1990). 5HT 2 mediation of acute behavioral effects
of hallucinogens in rats. Psychopharmacology, 100, 417-25

Dieter Ladewig
Psychiatric University Clinic


H. Abraham, St Elisabeth's Hospital, Department of Psychiatric Research, 736 Cambridge Street,

Boston, MA 02135, USA
G. K. Aghajanian, Department of Psychiatry and Pharmacology, Yale University School of
Medicine and the Connecticut Mental Health Center, 34, Park Street, New Haven, CT 06508,
J. Angst, Psychiatrische Universitätsklinik Zürich, Forschungsabteilung, Lenggstrasse 31,
CH-8029 Zürich, Switzerland
O. H. Arnold, Psychiatrische Universitätsklinik, Stiftgasse 21, A-1070 Wien VII, Austria
R. Battegay, Psychiatrische Universitätspoliklinik, Kantonsspital, Petersgraben 4, CH-4031 Basel,
W. Böker, Psychiatrische Universitätsklinik Bern, Bollingenstrasse 111, CH-3072 Ostermundigen,
R. Brenneisen, Pharmazeutisches Institut der Universität Bern, Baltzerstrasse 5, CH-3012 Bern,
D. Bourquin, Pharmazeutisches Institut der Universität Bern, Baltzerstrasse 5, CH-3012 Bern,
A. Calanca, Clinique psychiatrique universitaire, Hopital de Cery, CH-1008 Prilly-Lausanne,
C. Calanchini, FMH psichiatria e psicoterapia, Via Luvini 7, CH-6900 Lugano, Switzerland
A. J. Cowling, Parthenon Publishing, Casterton Hall, Carnforth, Lanes LA6 2LA, UK
A. Dittrich, PSIN - Psychologisches Institut für Beratung und Forschung, Jupiterstrasse 49,
CH-8032 Zürich, Switzerland
R. Doblin, MAPS, 1801 Tippah Avenue, Charlotte, NC 28205, USA
U. Drews, Grienstrasse 28, CH-4055 Basel, Switzerland
H. Dufour, Departement Universitaire de Psychiatrie Adulte, Hopital de Cery, CH-1008 Prilly-
Lausanne, Switzerland
B. Eisner, 2314 La Mesa Drive, Santa Monica, CA 90402, USA
S. J. Enna, Department of Pharmacology Toxicology and Therapeutics, School of Medicine,
University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, 66160-7417 KA,
H. U. Fisch, Psychiatrische Universitäts-Poliklinik Bern, Murtenstrasse 21, CH-3010 Bern,
R. Forte, P.O. Box 322, Santa Cruz, CA 95061, USA
P. Gasser, Externer Psychiatrischer Dienst, Dornacherplatz 19, CH-4500 Solothurn, Switzerland
J. Geizer, Schweizerische Akademie der medizinischen Wissenschaften, Petersplatz 13, CH-4051
Basel, Switzerland
M. A. Geyer, Department of Psychiatry, University of California, San Diego School of Medicine,
La Jolla, CA 92093, USA
F. Gnirss, Seltisbergerstrasse 44, CH-4059 Basel, Switzerland
E. Gouzoulis, Psychiatrische Klinik der RWTH, Pauwelstrasse 30, D-52074 Aachen, Germany
C. Hänni, Bundesamt für Gesundheitswesen, Abteilung Pharmazie und Betäubungsmittel,
Postfach, CH-3001 Bern, Switzerland


A. Haynal, Departement de Psychiatrie, Universite de Geneve, 16-18 Bid St. Georges, CH-1205
Geneve, Switzerland
H. Heimann, Psychiatrische Universitätsklinik, Osianderstrasse 22, D-72076 Tübingen, Germany
H. J. Helmlin, Pharmazeutisches Institut der Universität Bern, Baltzerstrasse 5, CH-3012 Bern,
L. Hermle, Fachkrankenhaus für Psychiatrie und Neurologie, Christophsbad Göppingen,
Faurndauerstrasse 6-28, D-73035 Göppingen, Germany
P. Hess, Städtisches Krankenhaus Frankenthal (Pfalz), Psychiatrische Reha- und Tagesklinik,
Foltzring 20, D-67210 Frankenthal, Germany
W. Hitzig, Schweiz. Akademie der medizinischen Wissenschaften, Zentrale Ethik-Kommission,
Petersplatz 13, CH-4051 Basel, Switzerland
H. J. A. J. M. Hoes, Department of Psychiatry Ziekenhis Rivierenland, P.O. Box 6024, NL-4000
Ha Tiel, The Netherlands
A. Hofmann, Rittimatte, CH-4117 Burg i.L., Switzerland
E. Hösli, Department of Physiology, University of Basel, Vesalgasse 1, CH-4051 Basel,
L. Hösli, Department of Physiology, University of Basel, Vesalgasse 1, CH-4051 Basel,
D. Hoyer, Sandoz Pharma Ltd., 360/604, CH-4002 Basel, Switzerland
T. Illmaier, Augustastrasse 32, D-42119 Wuppertal, Germany
H. Isernhagen, Englisches Seminar der Universität Basel, Nadelberg 6/8, CH-4051 Basel,
O. Janinger, 138 Ocean Way, Santa Monica, CA 90402, USA
R. Jones, Department of Psychiatry, University of California, 401 Parnassus Avenue, San
Francisco, CA 94143-0984, USA
H. Konzett, Pharmakologisches Institut der Universität, Reithmannstrasse 18, A-6020 Innsbruck,
M. Lader, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
D. Ladewig, Psychiatrische Universitätsklinik, Wilhelm Klein-Strasse 27, CH-4025, Basel,
H. Leuner, Eisenacher Strasse 14, D-37085 Göttingen, Germany
G. C. Lin, National Institute on Drug Abuse, Division of Preclinical Research, Biomedical Branch,
5600 Fishers Lane, Rockville, MD 20857, USA
D. Loew, Head Group Medical Operations, Sandoz Pharma LTD, 409/415, CH-4002 Basel,
L. Maitre, Ciba AG, Pharma, K-125.1550, CH-4002 Basel, Switzerland
H. R. Marti, Schweiz. Akademie der medizinischen Wissenschaften, Petersplatz 13, CH-4051
Basel, Switzerland
M. Maurer, Kinder -und Jugendpsychiatrische Poliklinik der Universität Bern, Effingerstrasse 12,
CH-3011 Bern, Switzerland
H. J. Möbius, Ciba AG, Pharma, K 147, CH-4002 Basel, Switzerland
A. F. Muller, Präsident der Schweizerischen Akademie der medizinischen Wissenschaften,
Fondation pour recherches medicales, 64 avenue de la Roseraie, CH-1205 Geneve, Switzerland
P. Netter, Fachbereich 06 Psychologie, Universität Giessen, Otto-Behaghel-Strasse 10, D-35394
Giessen, Germany
R. Oberholzer, Schweiz. Akademie der medizinischen Wissenschaften, Petersplatz 13, CH-4051
Basel, Switzerland
C. P. O'Brien, University of Pennsylvania, Veteran Affairs Medical Center, 3900 Chestnut Street,
Philadelphia, PA 19104-6178, USA


C. Pellerin, Institution of Independent Reporting, 1108 North Pitt Street, Alexandria, VA

22314-1403, USA
S. Peroutka, Spectra Biomedical Inc., 2465 E. Bayshore Road, Suite 301, Palo Alto, CA 94303,
A. Pletscher, Chairman, Program Committee of the SAMS-Symposium 1993 on LSD,
Schweizerische Akademie der medizinischen Wissenschaften, Petersplatz 13, CH-4051 Basel,
W. Pöldinger, Psychiatrische Universitätsklinik, Wilhelm Klein-Strasse 27, CH-4025, Basel,
J. Püschel, Psychiatrische Universitätsklinik, Postfach 68, CH-8029 Zürich, Switzerland
R. Richter, Sektion Psychoanalytische Methodik, Abteilung Psychotherapie, Universität Ulm-
Klinikum, Am Hochsträss 8, D-89081 Ulm, Germany
L. Rivier, Institut universitaire de médecine légale, 21 rue du Bugnon, CH-1005 Lausanne,
M. Smrekar, Redaktion GAIA, Münsterplatz 6, CH-4051 Basel, Switzerland
O. Smrekar, AMI - Analytical Methods and Instrumentations, Münsterplatz 6, CH-4051 Basel,
A. Springer, Ludwig Boltzmann-Institut für Suchtforschung, Mackgasse 7-9, A-1237 Wien,
J. Schädeli, Psychiatrie und Psychotherapie, Gerechtigkeitsgasse 45, CH-3011 Bern, Switzerland
C. Scharfetter, Psychiatrische Universitätsklinik, Forschungsdirektion, Postfach 68, CH-8029
Zürich 8, Switzerland
M. Schlichting, Jüdenstrasse 33, D-37073 Göttingen, Germany
K. Schneider, St Alban-Vorstadt 80, CH-4052 Basel, Switzerland
P. Schulz, Division de psychopharmacologie clinique I.U.P.G., CH-1225 Chene-Bourg,
R. Stohler, Psychiatrische Universitätsklinik, Wilhelm Klein-Strasse 27, CH-4025, Basel,
J. Strang, The Bethlem Royal Hospital, Department of Psychiatry, Addiction Research Unit,
National Addiction Centre, Addiction Sciences Building, 4 Winsor Walk, London SE5 8AF,
R. J. Strassmann, Department of Psychiatry, University of New Mexico, 2400 Tucker Avenue,
NE, Albuquerque, NM 87131-5326, USA
J. Styk, Schweiz. Aerztegesellschaft für Psycholytische Therapie, Birmannsgasse 39, CH-4055
Basel, Switzerland
S. Szàra, 10901 Jolly Way, Kensington, MD 20895, USA
R. Verres, Ruprecht-Karls-Universität Heidelberg, Psychosomatische Klinik, Abt. 3.2.2-
Psychotherapie und med. Psychologie, Bergheimerstrasse 20, D-69115 Heidelberg, Germany
F. X. Vollenweider, Psychiatrische Universitätsklinik, Forschungsabteilung, Lenggstrasse 31,
CH-8029 Zürich, Switzerland
P. Waser, Oberer Heuelsteig 12, CH-8032 Zürich, Switzerland
R. Yensen, Orenda Institute, 2403 Talbot Road, Baltimore, MD 21216, USA


acetylcholine items 109

and hallucinogen responses 154-155 archaeological representations of
acoustic disturbances hallucinogens
in model psychoses 61-62 Africa 51-53
Addiction Research Center Inventory (ARCI) America 49-50
scale 148 Northern Europe 51
adenylate cyclase activity arylalkanamines (see also MDE, mescaline)
and 5-HT receptors 24 and experimental psychoses 87-97
administration route ASCs see altered states of consciousness
in hallucinogen research 148-149, 160 ayahuasca, hallucinogenic drink 45, 47
alcoholism, chronic DMT activity 164
psychedelic therapy 178-180, 196-197
altered states of consciousness (ASCs)
Baltimore Studies, of psychedelic therapy
(see also APZ questionnaire)
basic dimensions 103-111
Banisteriopsis caapi
and LSD 111,112
use in hallucinogenic drinks 47
experimental 87-89
blood flow, regional cerebral
spatial and temporal perception 59-64
mescaline effects 89-91
general characteristics 102
Bora Indians
inducing agent types 102, 104
use of hallucinogenic pellets 47
prediction of individual reactions
Brief Psychiatric Rating Scale (BPRS)
Amanita muscaria (fly-agaric) in mescaline study 89-90
Bufo alvarius venom
ritualistic use 44
hallucinogenic properties related to
Amazonian Indians
5-MeO-DMT 48
hallucinogen use 46-47
Bufo marinus venom, and bufotenine 48
amperozide, as antipsychotic agent 158
bufotenine 46
Anadenanthera seeds
hallucinogenic significance 48
use in hallucinogenic snuffs 47, 49 in snuffs from archaeological remains
animal hallucinogens 48 49
animal studies in development of LSD
structure of 46
therapy 135-136
APZ questionnaire (see also altered states
of consciousness) caapi, hallucinogenic drink 45, 47
and basic dimensions of altered states of ß-carbolines 46
consciousness 103 in hallucinogenic preparations 47
in MDE study 93, 95 cerebral blood flow, regional
in mescaline study 89, 93, 95 mescaline effects 89-91
in prediction of individual reaction cerebral cortex
profiles 111-115 5-HT electrophysiological effects 32-34
primary scales 105-111 cerebral metabolism
dread of ego-dissolution 77, 106, 107 in altered states of consciousness 67-68
oceanic boundlessness 77, 106 ketamine effects 72-82
visionary restructuralization 77, 106, 108 psilocybin effects 72-77, 80-82
reliability 109-110 childbirth, ergot applications 7
secondary scale 105-111 chlorpromazine, LSD interactions 153-154


Claviceps paspali 'Ecstacy' see

in holy potion of Eleusis 15 3,4-methylenedioxymethamphetamine
Claviceps purpurea ergot Eleusis, mysteries of 14-16, 53
as source of LSD 7, 8, 43 ergobasin (lysergic acid propanolamide) 8
consent, informed structure of 10, 15
significance in psychotherapeutic studies synthesis of 9-10
216-217 ergometrine 8
Convolvulaceae (morning glory) structure of 10
in ololiuqui 14 ergonovine 8
Coramine 10 structure of 10
structure of 15 ergot
cortico-striato-thalamo-cortical (CSTC) Claviceps paspali, and mysteries of
feedback loops 70-71 Eleusis 15
and schizophrenia 69-72 Claviceps purpurea, as source of LSD
control of cortical information 7-10
processing 68-69 ergot alkaloids 8-10
hallucinogen effects on 69-72 ergotamin isolation 8
cultural aspects of LSD 121-129 ethnopharmacology 43-54
and legislation 193-194

Delphi, oracle of facial nucleus

and hallucinogens 45 hallucinogen effects 29-32, 33, 35, 36
derealization, during model psychoses 61 mediation by 5-HT 2 receptors 29, 32-33
diacylglycerol 5-HT-induced excitation 29-32
in phosphoinositide second-messenger role of protein kinase 35, 36
pathway 35 fly-agaric (Amanita muscaria)
N,N-dimethyltryptamine (DMT) ritualistic use 44
endogenous 156-157 forskolin-stimulated adenylate activity
in hallucinogenic drinks and snuffs LSD effects related to 5-HTi receptors
47, 49 22
psychopharmacology 145-165 frontal cortex, sensory overload
human studies 157-163 in psychoses 68-69
tolerance 156 in schizophrenia 80-83
structure of 3, 46
study of induced psychosis 113-115 G proteins
dopamine hypothesis of schizophrenia 68
and 5-HT receptors 19, 20
CSTC loop model 69-72 5-HT 2 receptor response mediation 34,
dopaminergic neurotransmission 37-38
and behavioral pharmacology of LSD interactions 22
hallucinogen responses 153-154 in facial nucleus 32
changes during altered states of glucose metabolism, cerebral
consciousness 69 in psychoses 67-68
dosage, in LSD therapy 136-137 ketamine effects 72-82
dread of ego-dissolution, subscale of psilocybin effects 72-77, 80-82
APZ questionnaire 77, 106-111 glutamate deficiency hypothesis of
items 107
schizophrenia 72
drinks, hallucinogenic 47
glutamatergic neurotransmission
and hyperfrontality 82-83
ebena, hallucinogenic snuff 47 changes in psychoses 69


ketamine and PCP effects on 79-80 response mediation by G proteins 34

Gottingen study 184-187 signal transduction mechanisms 37-38
5-HT5 receptors
Hallucinogen Rating Scale (HRS) development characteristics 23-24
158 phylogenetic relationships 20-21
hallucinogenic preparations 47-48 5-HT 6 receptors
hallucinogens and adenylate cyclase stimulation 24
early approaches to research 147-150 phylogenetic relationships 20-21
studies with psychiatrically ill 5-HT 7 receptors
patients 149 characteristics 24
evaluation of clinical effects 135-143 phylogenetic relationships 20-21
origins of use 44 multiplicity of receptor types 19-25
harmaline 46 phylogenetic tree 20-21
harmine 46 5-hydroxy-indoleacetic acid (5-HIAA)
in hallucinogenic drinks and snuffs 47 levels, and LSD 19
structure of 46 5-hydroxytryptamine see 5-HT
history of discovery of LSD 7-16 hyperfrontality
5-HT in psychotic states 68, 73-83
and behavioral pharmacology of mescaline effects 81-82, 96
hallucinogen responses 150-152
and phosphoinositide second-messenger ibogaine, potential uses 165
pathway 35 indoleamine hallucinogens
and schizophrenia 72 and 5-HT 2 receptors 28, 35, 37-39
levels, and LSD 19 effects on raphe nuclei 27
neurophysiological effects electrophysiological actions 27-39
in cerebral cortex 33-34
information processing
in facial nucleus 30-32
imbalance during altered states of
non-hallucinogenic 5-HT agonists
consciousness 67-83
psychopharmacology 153 role of CSTC loops 68-69
structure of 15 inhibitory postsynaptic potentials (IPSPs)
5-HT receptors 5-HT effects in cerebral cortex 33
5-HTi receptors
inositol trisphosphate (IP3)
characteristics 22
in phosphoinositide second-messenger
hallucinogen interactions 37
pathway 35
phylogenetic relationships 20-21
International Study on Altered States of
5-HT 2 receptors
Consciousness (ISASC) 105
and phosphatidylinositol (PI)
turnover 22-23, 35
and schizophrenia 72 ketamine
common action of hallucinogens 28 psychosis induction 68
electrophysiology in cerebral cortex mechanisms 72
32-34 effects on cerebral energy metabolism
LSD interactions 22-23 72-82
mediation of hallucinogen responses 37 implications for schizophrenia 80-83
in facial nucleus 29, 32, 33 mechanisms 77-80
in locus coeruleus 29 kykeon, holy potion of Eleusis 15
mechanisms 37-39
phylogenetic relationships 20-21 legislation and LSD 193-194
psilocybin effects on 80 locus ceruleus

hallucinogen effects 28-29 5-methoxydimethyltryptamine (5-MeO-DMT) 46

mediation by 5-HT2 receptors 29 in Bufo alvarius venom 48
LSD see lysergic acid diethylamide in hallucinogenic snuffs 47, 49
LSD therapy see therapy structure of 46
lysergic acid 9 N-methyl-D-aspartate (NMDA) receptors
structure of 15 and hyperfrontality 82-83
lysergic acid amide blocking in schizophrenia 72
from ololiuqui 14 ketamine effects 77-80
structure of 15 3,4-methylenedioxyethylamphetamine (MDE)
lysergic acid butanolamide (methergine) 10 study of induced psychosis 91-97
lysergic acid diethylamide (LSD) 3,4-methylenedioxymethylamphetamine (MDMA,
abuse 224-225 'Ecstasy')
cultural aspects 121-129 psychological effects of 91-92
evaluation of clinical effects 135-143 structure of 3
history of discovery 7-16 N-methyltetrahydroharmine 46
interdisciplinary perspectives 191-199 monoamine oxidase inhibitor (MAOI)
psychopharmacology 145-165 effect on hallucinogen responses 152
structure of 10, 15 morning glory (Convolvulaceae)
synthesis of 10 in ololiuqui 14
therapeutic use see therapy movement perception
tolerance 156 in experimental psychoses 60-61
lysergic acid hydroxyethylamide mushrooms
from ololiuqui 14 archaeological representations 49-53
structure of 15 magic 13, 14, 43
lysergic acid propanolamide (ergobasin) music perception
in experimental psychoses 61-62
Mutterkorn (ergot) 7
magic mushroom 13, 43
Manic-State Rating Scale (MSRS) natema, hallucinogenic drink 47
in MDE study 93 Necker cube
Mazatec Indians and temporal perception 59-60
and magic mushrooms 43 neurotransmission dysfunction during
MDE see 3,4-methylenedioxyethylamphetamine altered states of consciousness 68-83
MDMA see 3,4-methylenedioxymethylampheta- nicotinic acid diethylamide (Coramine) 10
mine niopa (niopo), hallucinogenic snuff 47
medicines, plant norepinephrine
and hallucinogens 45 LSD interactions 154
and hyperfrontality 81-82 oceanic boundlessness, subscale of APZ
effects on locus ceruleus 28-29 questionnaire 77, 106-111
effects of raphe nuclei 5-HT neurons items 106
27-28 ololiuqui, hallucinogenic preparation
structure of 3 14, 43
study of induced psychoses 89-91, 96-97 constituents 15
metabolic alterations oracle of Delphi, and hallucinogens 45
in psychoses 67-68
ketamine effects 72-82 parica, hallucinogenic snuff 47
psilocybin effects 72-77, 80-82 phencyclidine (PCP)
methergine (lysergic acid butanolamide) 10 and schizophrenia 68

mechanisms 72 psychotherapy see therapy

effects on glutamatergic Psychotria viridis
neurotransmission 79-80 use in hallucinogenic drinks 47
structure of 3 pyramidal cells
phenethylamine hallucinogens 5-HT electrophysiological effects in
electrophysiological actions 27-39 cerebral cortex 32-34
and 5-HT 2 receptors 28, 35, 37-39
effects on raphe nuclei 27-28 random assignment
phosphatidylinositol (PI) turnover significance in psychotherapeutic
hallucinogen effects 35 studies 218-219
5-HT stimulation 35, 37-38 raphe nuclei
and 5-HT 2 receptors 22-23, 37-38 5-HT neurons, LSD effects on 19, 27
LSD antagonism 23 religion, origins of 45-46
phosphoinositide second-messenger pathway reserpine effects on LSD responses 152
35 ritanserin as antipsychotic agent 157-158
5-HT stimulation 35, 37-38 route of administration
LSD effects on 35, 37-38 in hallucinogen research 148-149, 160
Piaroa Indians rye (Secale comutum), and ergot 7, 8
use of hallucinogenic snuffs 47
pindolol, and DMT response 163 St Anthony's fire 7, 9
piriform cortex San Pedro de Acatama archaeological
5-HT effects in pyramidal cells 33-34 remains, snuff-taking implements 49
placebo control group schizophrenia
significance in psychotherapeutic studies altered metabolism 67-68
217-218 CSTC loop model 69-72
plant medicines, and hallucinogens 45 dopamine hypothesis 68
prohibition of LSD 193-194 ketamine study implications for 80-83
protein kinase C LSD effects on 149
and excitatory effects of 5-HT 35, 36 psilocybin study implications for 80-83
in phosphoinositide second-messenger serotonin hypothesis 72
pathway 35, 37-38 Secale comutum (rye), and ergot 7, 8
psilocin sensory information processing imbalance
isolation from mushroom 14 during altered states of consciousness
structure of 3, 15 67-83
Psilocybe mexicana (magic mushroom) 14, 43 sensory overload in frontal cortex
psilocybin in psychoses 68-69
and psychoses 61-64, 68 in schizophrenia 80-83
mechanisms 72 serotonergic neurons in raphe nuclei
effects on cerebral energy metabolism comparative effects of hallucinogens
72-77, 80-82 27-28
implications for schizophrenia 80-83 serotonergic neurotransmission
mechanisms 80 changes in psychoses 69
psychedelic therapy 175-180, 208 psilocybin effects on 80
Baltimore studies 178-180 serotonin see 5-HT
psycholytic therapy 181-182, 207-208 serotonin hypothesis of schizophrenia 72
psychopharmacology of hallucinogens severity of illness measures 215-216
145-165 shamans
psychoses, experimental see altered states and origins of hallucinogen use 44-45,
of consciousness 194-195

signal transduction mechanisms bodily changes 141

and 5-HT2 receptor stimulation 37-38 dosage 136-137
sleep parameters, in MDE study 95 evaluation methodology 213-220
snuffs, hallucinogenic 47-48 outcome variables 140-141
archaeological representations 49 psychotherapeutic effects 203-210
South American Indians psychedelic 175-180
use of hallucinogens 43-49 psycholytic 181-182
spatial perception tolerance to hallucinogen effects 155-156
in model psychoses 59-64 in human DMT study 162-163
State Anxiety Scale (STAI-Xi) tyrosine kinase type receptors 19
in MDE study 93-94
Virola, use in hallucinogenic snuffs and
temporal perception pellets 47
in model psychoses 59-64 visionary restructuring, subscale of APZ
teonanacatl, sacred Mexican mushroom questionnaire 77, 106-111
13, 43 items 108
constituents 15 visual perception
tetrahydroharmine 46 in model psychoses 62-64
thalamic filter Volubilis seeds 43
control of sensory input 69
role in altered states of consciousness Witoto Indians
79-80 use of hallucinogenic pellets 47
therapy, hallucinogen-aided
Gottingen study 184-187 yage, hallucinogenic drink 47
LSD 135-143, 195-197 DMT activity 164
adverse effects 141-142 yakee, hallucinogenic snuff 47
animal studies 135-136 yopo, hallucinogenic snuff 47