50 Years of LSD

CURRENT STATUS AND PERSPECTIVES OF HALLUCINOGENS
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
CURRENT STATUS AND PERSPECTIVES OF HALLUCINOGENS
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

NEW YORK

LONDON

CONTENTS
List of principal contributors Preface A. Pletscher SECTION 1 1 HISTORICAL 7 vii 1

History of the discovery of LSD A. Hofmann PHARMACOLOGY

SECTION 2 2

5-Hydroxytryptamine receptor interactions of D-lysergic acid diethylamide S. J. Peroutka LSD and phenethylamine hallucinogens: common sites of neuronal action G. K. Aghajanian

19

3

27 43

4 Ethnopharmacology of LSD and related compounds L. Rivier SECTION 3 5 6 PSYCHOPATHOLOGY

Experience of time and space in model psychoses H. Heimann 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 Arylalkanamine-induced effects in normal volunteers: on the significance of research in hallucinogenic agents for psychiatry L. Hermle, M. Spitzer and E. Gouzoulis Psychological aspects of altered states of consciousness of the LSD type: measurement of their basic dimensions and prediction of individual differences A. Dittrich

59

67

7

87

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101

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50 YEARS OF LSD

SECTION 4 9

TRANSCULTURAL ASPECTS

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

121

SECTION 5

CLINICAL ASPECTS

10 Pharmacological standards for evaluation of clinical effects of hallucinogens M. Lader 11 Human psychopharmacology of LSD, dimethyltryptamine and related compounds R. J. Strassman

135 145

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 paradigm R. Yemen 14 Psychotherapeutic effects R. Richter 15 Methodological issues in the evaluation of a medication for its potential benefits in enhancing psychotherapy C. P. O'Brien and R. T.Jones

191 203

213

Conclusions, with special regard to clinical aspects D. Ladewig Appendix: List of invited participants Index

223 229 233

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LIST OF PRINCIPAL CONTRIBUTORS
G. K. Aghajanian Department of Psychiatry and Pharmacology Yale University School of Medicine and the Connecticut Mental Health Center 34 Park Street New Haven Connecticut 06508 USA A. Dittrich PSIN Psychologisches Institut für Beratung und Forschung Jupiterstrasse 49 Zürich Switzerland H. Heimann Psychiatrische Universitätsklinik Osianderstrasse 22 Tübingen Germany L. Hermle Fachkrankenhaus für Psychiatrie und Neurologie Christophsbad Göppingen Faurndauerstrasse 6-28 Göppingen Germany A. Hofmann Rittimatte 4117 Burg iL Switzerland H. Isernhagen Department of English University of Basel Nadelberg 6 Basel Switzerland

M. Lader Institute of Psychiatry The Maudsley Hospital De Crespigny Park Denmark Hill London SE5 8AF UK D. Ladewig Psychiatric University Clinic of Basel Wilhelm Klein-Strasse Basel Switzerland H. Leuner Eisenacher Strasse 14 Göttingen Germany C. P. O'Brien University of Pennsylvania Veteran Affairs Medical Center 3900 Chestnut Street Philadelphia Pennsylvania USA

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50 YEARS OF LSD

S. J. Peroutka Spectra Biomedical, Inc. 2465 E. Bayshore Road, Suite 301 Palo Alto California 94303 USA A. Pletscher Schweizerische Akademie der medizinischen Wissenschaften Petersplatz 13 CH-4051 Basel Switzerland R. Richter Sektion Psychoanalytische Methodik Abteilung Psychotherapie Klinikum der Universität Ulm Am Hochsträss 8 Ulm Germany L. Rivier University Institute of Legal Medicine Rue du Bugnon 21 Lausanne Switzerland

R. J. Strassman University of New Mexico Department of Psychiatry 2400 Tucker Avenue, NE Albuquerque New Mexico USA F. X. Vollenweider Psychiatric University Hospital Zürich Research Department Lenggstrasse 31 Zürich Switzerland R. Yensen Orenda Institute 2403 Talbot Road Baltimore Maryland USA

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Preface
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 classified 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 considerations: (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-hydroxytryptamine 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

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50 YEARS OF LSD

which later had to be amended) and some people thought it might help in the elucidation 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 disorders? (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

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2

Lysergic acid diethylamide (LSD)

Mescaline

Phencyclidine

PREFACE

_____ 3,4- Methylenedioxymethamphetamine

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3 (MDMA, 'Ecstasy')

Psilocin Psilocybin (= phosphate ester)

N,N-Dimethyltryptamine

Figure 1

Psychotomimetic drugs

50 YEARS OF LSD

other hallucinogens under well-controlled conditions, using modern experimental 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 Basel. Alfred Pletscher Symposium Chairman

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Section 1 Historical

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CHAPTE R 1

History of the discovery of LSD
A . HOFMAN N

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 extraordinary 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 - epidemics 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

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50 YEARS OF LSD

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 pharmacological 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 glycosides in the laboratory of Professor Stoll, with the elucidation of the chemical structure of the aglycon of the Scillaglycosides. I asked the professor for permission 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

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HISTORY OF THE DISCOVERY OF LSD

Figure 2 Munich)

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.

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50 YEARS OF LSD

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 'Methergine') 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 Pharmacology 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 pharmaceuticals: 'Hydergin' and 'Dihydergot'. Yet strangely enough I could not forget LSD-25, and 5 years later I decided to prepare another batch of this compound 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

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HISTORY OF THE DISCOVERY OF LSD

surprised, when in the afternoon of 16 April, 1943, after I had repeated the synthesis 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 uninterrupted 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 dichloroethylene, 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 substance have found its way into my body? Possibly some of the methanolic solution 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.
Self-experiments 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. Everything 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 poisoning. The dizziness and sensation of fainting became so strong that I could no

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50 YEARS OF LSD

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 restlessness. 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 breathing 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

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HISTORY OF THE DISCOVERY OF LSD

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 consciousness, 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, terrifying 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 investigations 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 analysis.

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50 YEARS OF LSD

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 abovementioned 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

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HISTORY OF THE DISCOVERY OF LSD

Propanolamin e iD ethly amin sergi yL c acid e

sergi yL c acid propanolamid e robasi Eg n

Coramin e

sergi yL c acid diethly amid e (LSD )

sergi yL c acid amid e

sergi yL c acid droxethly amid yh y

e

Constituents of ololiuqui

Psilocybi n

Psilocin

Serotonin

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 .

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50 YEARS OF LSD

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. REFERENCES
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)

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Section 2 Pharmacology

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CHAPTE R 2

5-Hydroxytryptamine receptor interactions of D -lysergic acid diethylamide
S . J . PEROUTKA

INTRODUCTION 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 , 3 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 observation 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-HTcontaining neurons of the dorsal and median raphe nuclei 5 . These early observations have been confirmed and extended by numerous other investigators. 5-HT RECEPTOR MULTIPLICITY More recently, molecular biological data have unequivocally confirmed the existence of multiple 5-HT receptors (Table 1). Indeed, the multiplicity of 5-HT

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50 YEARS OF LSD
Table 1 Overview of 5 - H T receptor subtypes

G protein-coupled receptors 5 - H T 1 'Family' 5 - H T 2 'Family' Others Ligand-gated ion channels Transporters

5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E,5-HT1F 5-HTdrol, 5-HTdro2A, 5-HTdro2B, 5-HTsnail 5-HT2, 5 - H T l c , 5-HT2F 5-HT5A, 5-HT5B, 5-HT6, 5-HT7 5-HT3 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 (approximately 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).

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20

5-HT RECEPTORS AND LSD
5-HT1B.mouse 5-HT1B.rat 5-HT1B.humon 5-HT1D.human 5-HT1D.rat 5-HT1D.canine 5-HT1F.mouse 5-HT1F.rat 5-HT1F.human 5-HT1E.human 5-HTlA.rat1 5-HT1A.rat2 5-HTIA.human 5-HT7.mouse 5-HT7.rat 5-HT5B.mouse 5-HT5B.rot 5-HT5A.mouse 5-HT5A.rat 5-HT2.mouse 5-HT2.rat 5-HT2.hamster 5-HT2.human 5-HTlC.mouse 5-HT1C.rat 5-HT1C.human 5-HT2F.mouse 5-HT2F.rot 5-HT6.rot

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).

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50 YEARS OF LSD
Table 2
D-LSD

interactions with G protein-coupled 5-HT receptor subtypes K i D-LSD (nmol/1) 0.74 12 2.4 270 21 4.0 0.99 na* 0.34 0.47 28 4.9 K d[125I]-LSD (nmol/1)

Receptor 5-HT1A 5-HT1b 5-HT 1 D 5-HT 1 E 5-HT 1 F 5-HT2 5-HT1C 5-HT2F 5-HT5A 5-HT5B 5-HT6 5-HT7

Species human human human human human human rat mouse mouse rat rat

Putative action agonist unknown agonist unknown unknown partial agonist agonist unknown unknown unknown unknown unknown

Reference ud† ud ud ud 15 16 ud 8 9 14 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 appears to display considerable agonist activity at 5-HT 1 receptor subtypes. 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 mediated 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.
D-LSD

5-HT 2 receptors A variety of past evidence has suggested that the effects of D - L S D may be mediated 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 phosphatidylinositol (PI) turnover is mediated by the 5 - H T 2 family of receptors.

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5-HT RECEPTORS AND LSD

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 turnover, 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 spiperone 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. Biochemical 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 receptor 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

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50 YEARS OF LSD

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

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24

5-HT RECEPTORS AND LSD

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 hallucinogenic agents produce their complex neuropsychiatric effects. ACKNOWLEDGEMENTS I thank Tiffany A. Howell for excellent editorial assistance. This work was supported in part by NIH Grant NS 23560-06. REFERENCES
1. Gaddum, J. H. and Hameed, K. A. (1954). Drugs which antagonize 5-hydroxytryptamine. Br. J. Pharm., 9, 240-8 2. Wooley, D. W. and Shaw, E. (1954). A biochemical and pharmacological suggestion about certain mental disorders. Proc. Natl. Acad. Sci. USA, 40, 228-31 3. Freedman, D. X. (1961). Effects of LSD-25 on brain serotonin. J. Pharmacol. Exp. Ther., 134, 160-6 4. Rosecrans, J. A., Lovell, R. A. and Freedman, D. X. (1967). Effects of lysergic acid diethylamide on the metabolism of brain 5-hydroxytryptamine. Biochem. Pharmacol., 16, 2011-21 5. Aghajanian, G. K., Foote, W. E. and Sherrd, M. H. (1968). Lysergic acid diethylamide: Sensitive neuronal units in the midbrain raphe. Science, 161, 706-8 6. Peroutka, S. J. (1992). Phylogenetic tree analysis of G protein-coupled 5-HT receptors: implications for receptor nomenclature. Neuropharmacol, 31, 609-13 7. Feng, D. F. and Doolittle, R. F. (1990). Progressive alignment and phylogenetic tree construction of protein sequences. Meth. Enzymol., 183, 375-87

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8. Plassat, J., Boschert, U., Amlaiky, A. and Hen, R. (1992). The mouse 5 - H T 5 receptor reveals a remarkable heterogeneity within the 5 - H T 1 D receptor family. EMBO J., 11, 4779-86 9. Matthes, H., Boschert, U., Amlaiky, N., Grailhe, R., Plassat, J., Muscatelli, F., Mattei, M. and Hen, R. (1993). Mouse 5-hydroxytryptamine 5A and 5-hydroxytryptamine 5B receptors define a new family of serotonin receptors: cloning, functional expression, and chromosomal localization. Mol. Pharmacol, 43, 313-19 10. Erlander, M. G., Lovenberg, T. W., Baron, B. M., DeLecea, L., Danielson, P. E., Racke, M., Slone, A. L., Siegel, B. W., Foye, P. E., Cannon, K. and Burns, J. E. (1993). Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain. Proc. Natl. Acad. Sci. USA, 90, 3452-6 11. Shen, Y., Monsma, F. J., Metealf, M. A., Jose, P. A., Hamblin, M. W. and Sibley, D. R. (1993). Molecular cloning and expression of a 5-hydroxytryptamine serotonin receptor subtype. J. Biol. Chem., 268, 8200-4 12. Plassat, J., Amlaiky, N. and Hen, R. (1993). Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase. Mol. Pharmacol, 44, 229-36 13. Peroutka, S.J. (1990). 5-hydroxytryptamine receptor subtypes. Pharmacol Toxicol, 67, 373-83 14. Monsma, J. F. J., Shen, Y., Ward, R. P., Hamblin, M. W. and Sibley, D. R. (1993). Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol. Pharmacol, 43, 320-7 15. Lovenberg, T. W., Erlander, M. G., Baron, B. et al. (1993). Molecular cloning and functional expression of 5 - H T 1 E - l i k e rat and human 5-hydroxytryptamine receptor genes. Proc. Natl Acad. Sci. USA, 90, 2184-8 16. Pierce, P. A. and Peroutka, S.J. (1989). Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex. Psychopharmacology, 97, 118-22 17. DeVivo, M. and Maayani, S. (1986). Characterization of the 5-hydroxytryptamine-lA receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J. Pharmacol. Exp. Ther., 238, 248-53 18. Conn, P. J., Sanders-Bush, E., Hoffman, B. J. and Hartig, P. R. (1986). A unique serotonin receptor in choroid plexus is linked to phosphatidylinositol turnover. Proc. Natl Acad. Sci. USA, 83, 4086-8 19. Conn, J. P. and Sanders-Bush, E. (1987). Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT-2) and (5-HT-IC) receptors. J. Pharmacol Exp. Ther., 242, 552-7 20. Sanders-Bush, E., Burris, K. D. and Knoth, K. (1988). Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine and partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J. Pharmacol Exp. Ther., 246, 924-8 21. Sanders-Bush, E. and Breeding, M. (1988). Putative selective 5 - H T 2 antagonists block serotonin 5 - H T l C receptors in the choroid plexus. J. Pharmacol Exp. Ther., 247, 169-73 22. Pierce, P. A. and Peroutka, S. J. (1988). Antagonism of 5-hydroxytryptamine-2 receptormediated phosphatidylinositol turnover by D-lysergic acid diethylamide. J. Pharmacol. Exp. Ther., 247, 918-25

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26

CHAPTE R 3

LSD and phenethylamine hallucinogens: common sites of neuronal action
G . K . AGHAJANIAN

INTRODUCTION 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 electrophysiological 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

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50 YEARS OF LSD

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 hallucinogens 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. SHARED ACTIONS OF HALLUCINOGENS 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 hallucinogens in anesthetized rats results in a decrease in spontaneous activity and, paradoxically, a facilitation of the activation of LC neurons by sensory

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NEURONAL ACTIONS OF LSD

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 receptors. 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 microiontophoresis. 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 hallucinogens 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 convergence 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 hallucinogens 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 synaptic inputs 26 . Intracellular recordings in vivo 27, 28 and in brain slices 29, 30 show that

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29

10 MΩ
LSD

lOnM 5-HT 1000μM

LSD l00nM

14 mV

50 YEARS OF LSD

Spikes/pulse

_____

_____

30

20

0

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

NEURONAL ACTIONS OF LSD

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 hyperpolarizing 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 electrical excitability of facial motoneurons. However, even at maximal concentrations, 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 apparent 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

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50 YEARS OF LSD

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 excitability, 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-4indophenyl)-2-aminopropane) produces effects similar to that of LSD, but with a slightly greater maximal depolarization. Thus, LSD and DOI appear to have relatively low intrinsic activity, relative to 5-HT, in decreasing a resting potassium conductance. A possible exception to this pattern is the ultra short-acting hallucinogen 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 potassium conductance, 5-HT produces an enhancement of the non-specific cationic current Ih to further increase the excitability of facial motoneurons 35 . Interestingly, 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, suggesting 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 different receptor/G protein complexes. In this case, the receptor/G protein complex rather than the receptor per se would confer differential intrinsic activity to different 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, pyramidal cells in various regions of the cerebral cortex have been found to respond to

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NEURONAL ACTIONS OF LSD
control -0.12 -0.49 5-HT

(a) LSD

I nA

(b)

1

nA

CONTROL

-0.04

5-HT LSD

1 nA

mV
(C)

-70
-120

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 piriform 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

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(mV)

50 YEARS OF LSD

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-dimethoxy4-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 pyramidal cells, which is blocked by ritanserin and spiperone. The blockade of the 5-HTinduced 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). 5-HT 2 RECEPTORS, HALLUCINOGENS AND SIGNAL TRANSDUCTION MECHANISMS G proteins A cloned 5 - H T 2 receptor from a rat brain cDNA library displays seven transmembrane 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 contrast, 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.

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NEURONAL ACTIONS OF LSD

Phosphoinositide second-messenger pathway At a second messenger level, it has been shown that 5-HT stimulates phosphatidylinositol (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)-2aminopropane), 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 enhancement 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 phosphatidylinositol hydrolysis. SUMMARY AND CONCLUSIONS 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,

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LSD

50 YEARS OF LSD

Spikes/pulse

_____

_____

36

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

5 min

NEURONAL ACTIONS OF LSD

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 postsynaptic 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 receptors. 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 neuronal excitability through a G protein-coupled mechanism. The ionic mechanism for the increased excitability is through a reduction in resting potassium conductance and/or enhancement of the hyperpolarizing-activated cationic current I h . Biochemical studies show that 5 - H T 2 receptors are coupled to the phosphatidylinositol 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

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50 YEARS OF LSD
RAPHE POST-SYNAPTIC
pyramidal cells

5-HT
5-HT1A

(-)

5-HT 1A

etc.

(-)

5-HT 1 A

LSD DMT
cortical interneurons

5-HT mescaline DOM

(+)

5-HT2

motoneurons LC afferents etc.

Figure 5 Schematic diagram showing the shared action of indoleamine (e.g., LSD and N,Ndimethyltryptamine (DMT)) and phenethylamine hallucinogens (e.g. mescaline and 2,5-dimethoxy4-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 receptors 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 hallucinogens 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 phosphatidylinositol 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 responsivity of locus coeruleus neurons may contribute to the characteristic intensification 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

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NEURONAL ACTIONS OF LSD

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 hallucinogenic response. ACKNOWLEDGEMENTS This chapter was prepared with support from National Institute of Mental Health grant MH-17871 and the State of Connecticut. REFERENCES
1. Dahlstrom, A. and Fuxe, K. (1965). Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta. Physiol. Scand., 62, Suppl. 232, 1-55 2. Aghajanian, G. K., Foote, W. E. and Sheard, M. H. (1968). Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe. Science, 161, 706-8 3. Aghajanian, G. K. and Haigier, H. J. (1975). Hallucinogenic indoleamines: preferential action upon prosynaptic receptors. Psychopharm. Comm., 1, 619-29 4. Aghajanian, G. K., Haigier, H. J. and Bloom, F. E. (1972). Lysergic acid diethylamide and serotonin: direct actions on serotonin-containing neurons. Life Sci., 1, 615-22 5. Freedman, D. X. (1961). Effects of LSD-25 on brain serotonin. J. Pharmacol. Exp. Ther., 134, 160-6 6. Haigier, H.J. and Aghajanian, G. K. (1973). Mescaline and LSD: direct and indirect effects on serotonin-containing neurons in brain. Eur. J. Pharmacol, 21, 53-60 7. Sprouse, J. S. and Aghajanian, G. K. (1987). Electrophysiological responses of serotonergic dorsal raphe neurons to 5 - H T 1 A and 5 - H T 1 B agonists. Synapse, 1, 3-9 8. Sprouse, J. S. and Aghajanian, G. K. (1988). Responses of hippocampal pyramidal cells to putative serotonin 5 - H T 1 A and 5 - H T 1 B agonists: a comparative study with dorsal raphe neurons. Neuropharmacology, 27, 707-15 9. Glennon, R. A., Titeler, M. and McKennay, J. D. (1984). Evidence for 5 - H T 2 involvement in the mechanism of action of hallucinogenic agents. Life Sci., 35, 2505-11 10. Titeler, M., Lyon, R. A. and Glennon, R. A. (1988). Radioligand binding evidence implicates the brain 5 - H T 2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology, 94, 213-16 11. Pazos, A., Cortes, R. and Palacios, J. M. (1985). Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res., 346, 231-49 12. Mengod, G., Pompeiano, M., Martinez-Mir, M. I. and Palacios, J. M. (1990). Localization of the mRNA for the 5 - H T 2 receptor by in situ hybridization histochemistry. Correlation with the distribution of receptor sites. Brain Res., 524, 139-43 13. Morilak, D. A., Garlow, S. J. and Ciaranello, R. D. (1993). Immunocytochemical localization and description of neurons expressing serotonin 2 receptors in the rat brain. Neuroscience, 4, 701-17 14. Cedarbaum, J. M. and Aghajanian, G. K. (1978). Activation of locus coeruleus neurons by peripheral stimuli: modulation by a collateral inhibitory mechanism. Life Sci., 23, 1383-92 15. Foote, S. L., Aston-Jones and Bloom, F. E. (1980). Impulse activity of locus coerulus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc. Natl. Acad. Sci., 11, 33033-37

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16. Aghajanian, G. K. (1980). Mescaline and LSD facilitate the activation of locus coeruleus neurons by peripheral stimuli. Brain. Res., 186, 492-8 17. Chiang, C. and Aston-Jones, G. (1993). A 5-hydroxytryptamine 2 agonist augments γ-aminobutyric acid and excitatory amino acid inputs to noradrenergic locus coeruleus neurons. Neuroscience, 54, 409-20 18. Rasmussen, K. and Aghajanian, G. K. (1986). Effects of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5 - H T 2 antagonists. Brain Res., 385, 395-400 19. Gorea, E. and Adrien, J. (1988). Serotonergic regulation of noradrenergic coerulean neurons: electrophysiological evidence for the involvement of 5 - H T 2 receptors. Eur. J. Pharmacol, 154, 285-91 20. Rasmussen, K. and Aghajanian, G. K. (1988). Potency of antipsychotics in reversing the effects of a hallucinogenic drug on locus coeruleus neurons correlates with 5-HT 2 binding affinity. Neuropsychopharmacology, 1, 101-7 21. Wolbach, A. B. Jr, Miner, E.J. and Isbell, H. (1962). Comparison of psilocin with psilocybin, mescaline and LSD-25. Psychopharmacologia, 3, 219-23 22. Colpaert, F. C. and Jansen, P. A.J. (1983). The head twitch response to intraperitoneal injection of 5-hydroxytryptophan in the rat: antagonist effects of purported 5-hydroxytryptamine antagonists and pirenperone, an LSD antagonist. Neuropharmacology, 22, 993-1000 23. Green, A. R. (1984). 5-HT-mediated behaviour. Neuropharmacology, 23, 1521-8 24. Lucki, I., Nobler, N. S. and Frazer, A. (1984). Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat .J. Pharmacol Exp. Ther., 228, 133-8 25. Heym, J. and Jacobs, B. L. (1988). 5 - H T 2 agonist activity as a common action of hallucinogens. In Rech, R. and Gudelsky, G. (eds.) 5-HT Agonists as Psychoactive Drugs, pp. 95-106 (Ann Arbor, Michigan: NPP Press) 26. McCall, R. B. and Aghajanian, G. K. (1979). Serotonergic facilitation of facial motoneuron excitation. Brain Res., 169, 11-27 27. VanderMaelen, C. P. and Aghajanian, G. K. (1980). Intracellular studies showing modulation of facial motoneurone excitability by serotonin. Nature (London), 287, 346-7 28. VanderMaelen, C. P. and Aghajanian, G. K. (1982). Serotonin-induced depolarization of rat facial motoneurons in vivo: comparison with amino acid transmitters. Brain Res., 239, 139-52 29. Aghajanian, G. K. and Rasmussen, K. (1989). Intracellular studies in the facial nucleus illustrating a simple new method for obtaining viable motoneurons in adult rat brain slices. Synapse, 3, 331-8 30. Larkman, P. M., Penington, N. J. and Kelly, J. S. (1989). Electrophysiology of adult rat facial motoneurons: the effects of serotonin (5-HT) in a novel in vitro brainstem slice. J. Neurosci. Meth., 28, 133-46 31. White, S. R. and Fung, S.J. (1989). Serotonin depolarizes cat spinal motoneurons in situ and decreases motoneuron afterhyperpolarizing potentials. Brain Res., 502, 205-13 32. North, R. A. and Uchimura, N. (1989). 5-Hydroxytryptamine acts at 5 - H T 2 receptors to decrease potassium conductance in rat nucleus accumbens neurones. J. Physiol, 417, 1-12 33. McCall, R. B. and Aghajanian, G. K. (1980). Pharmacological characterization of serotonin receptors in the facial motor nucleus: a microiontophoretic study. Eur. J. Pharmacol, 65, 175-83 34. Rasmussen, K. and Aghajanian, G. K. (1990). Serotonin excitation of facial motoneurons: receptor subtype characterization. Synapse, 5, 324-32 35. Garratt, J. C., Alreja, M. and Aghajanian, G. K. (1993). LSD has high efficacy relative to serotonin in enhancing the cationic current I h : intracellular studies in rat facial motoneurons. Synapse, 13, 123-34

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36. McCall, R. B. and Aghajanian, G. K. (1980). Hallucinogens potentiate responses to serotonin and norepinephrine in the facial motor nucleus. Life Sci., 26, 1149-56 37. Araneda, R. and Andrade, R. (1991). 5-Hydroxytryptamine 2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience, 40, 399-412 38. Davies, M. F., Deisz, R. A., Prince, D. A. and Peroutka, S. J. (1987). Two distinct effects of 5-hydroxytryptamine on single cortical neurons. Brain Res., 423, 347-52 39. 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 Res., 506, 62-9 40. Sheldon, P. W. and Aghajanian, G. K. (1991). Excitatory responses to serotonin (5-HT) in neurons of the rat piriform cortex: evidence for mediation by 5 - H T l C receptors pyramidal cells and 5 - H T 2 receptors in interneurons. Synapse, 9, 208-18 41. Hoyer, D. (1988). Functional correlates of serotonin 5-HT 1 recognition sites. J. Receptor Res., 8, 59-81 42. Mengod, G., Nguyen, H., Lee, H., Waeber, C., Lubbert, H. and Palacios, J. M. (1990). The distribution and cellular localization of 5 - H T l C receptor mRNA in the rodent brain examined by in situ hybridization histochemistry. Comparison with receptor binding distribution. Neuroscience, 35, 577-92 43. Pritchett, D. B., Bach, A. W. J., Wozny, M., Taleb, O., Dal Toso, R., Shin, J. C. and Seeburg, P. H. (1988). Structure and functional expression of cloned rat serotonin 5-HT-2 receptor EMBO J ., 7, 4135-40 44. Lyon, R. A., Davis, K. H. and Titeler, M. (1986). 3 H - D O B (4-bromo-2,5-dimethoxyphenylisopropylamine) labels a guanyl nucleotide-sensitive state of cortical 5 - H T 2 receptors. Mol. Pharmacol, 31, 194-9 45. Aghajanian, G. K. (1990). Serotonin-induced inward current in rat facial motoneurons: evidence for mediation by G proteins but not protein kinase C. Brain Res., 524, 171-4 46. Conn, P.J. and Sanders-Bush, E. (1986). Regulation of serotonin-stimulated phosphoinositide hydrolysis: relation to the serotonin 5 - H T 2 binding site. J. Neurosci., 6, 3669-75 47. Sanders-Bush, E., Burris, K. D. and Knoth, K. (1988). Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J. Pharmacol. Exp. Ther., 246, 924-8 48. Roth, B. L., Nakaki, T., Chuang, D. M. and Costa, E. (1986). 5-Hydroxytryptamine 2 receptors coupled to phospholipase C in rat aorta: modulation of phosphoinositide turnover by phorbol ester. J. Pharmacol. Exp. Ther., 238, 480-5 49. Pierce, P. A. and Peroutka, S. J. (1988). Antagonism of 5-hydroxytryptamine 2 receptormediated phosphatidylinositol turnover by d-lysergic acid diethylamide, J. Pharmacol. Exp. Ther., 247, 918-25 50. Haigier, H. J. and Aghajanian, G. K. (1974). Lysergic acid diethylamide and serotonin: a comparison of effects on serotonergic neurons and neurons receiving a serotonergic input. J. Pharmacol. Exp. Ther., 188, 688-99

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CHAPTE R 4

Ethnopharmacology of LSD and related compounds
L . RIVIER

INTRODUCTION Ethnopharmacology aims to obtain and maintain a broad multidisciplinary perspective on the human use of crude drugs and poisons in a traditional context 1 . Widely differing disciplines are involved, such as cultural anthropology, linguistics, history, botany, zoology, chemistry, pharmacology, toxicology and medicine. 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, following his studies of rye ergot (Claviceps purpurea) alkaloids, Albert Hofmann has contributed immensely to ethnopharmacology. He was sufficiently open-minded to agree to examine unusual plant material samples that mycologists or ethnobotanists 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 species. 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 ethnopharmacologists to date, whose work has resulted in major contributions to the literature and knowledge of the field.

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THE ORIGIN OF THE USE OF HALLUCINOGENS 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 ritualistic utilization of Amanita muscaria, the fly-agaric. This mushroom could have allowed them to reach stages of trance and stupor for divinitory or diagnostic purposes. 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 consumption of magicoreligious substances. From our palaeolithic heritage, convened by human natural curiosity, the field of psychopharmacological experimentation is still a reality today. Schultes 4 has defined certain South American 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 . THE SHAMANS 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 psychotherapist, 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

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ETHNOPHARMACOLOGY OF LSD AND RELATED COMPOUNDS

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. PLANT MEDICINES AND HALLUCINOGENS 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 traditionally used as 'holy mediators' between man and his gods. For example, the prophecies 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. THE ORIGIN OF RELIGION 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 compounds that Hofmann isolated are indole-tryptamine derivatives and thus are similar in chemical structure to serotonin (5-hydroxytryptamine). Does it

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DIMETHYLTRYPTAMINE (DMT)

HARMINE

5-METHOXY-DMT

TETRAHYDROHARMINE

BUFOTENINE

N-METHYLTETRAHYDROHARMINE

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 aminoacid 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-methoxydimethyltryptamine (5-MeO-DMT) is a potent hallucinogen. If the tryptamine side-chain is closed with an additional carbon atom, one obtains the betacarbolines 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 .

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HALLUCINOGENIC DRINKS 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. HALLUCINOGENIC SNUFFS 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 myristicaceous 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 uncoordination, 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

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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'. ANIMAL HALLUCINOGENS 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 physiological processes such as heart rate and blood pressure, and these effects may contribute 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 situated 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 morphologically 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 persisted 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 European 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.

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ARCHAEOLOGICAL REPRESENTATIONS OF HALLUCINOGENS 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. America 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 characterized by the highest concentration of snuff-taking implements known from preColumbian 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 thermoluminescence 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 snufftaking paraphernalia in pre-Columbian America, Anadenanthera-based snuff preparations could, instead, have diffused from south to north. ARCHAEOLOGICAL REPRESENTATIONS OF MUSHROOMS Not only many species of Psilocybe (Strophariaceae) but other genera like Conocybe, Pholiotina (Bolbitiaceae), Panaeolus, Copelandia (Coprinaceae), Gymnopilus, Inocybe

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(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)

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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, petroglyphs 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. Analysis 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. Africa 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 speculation 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 hallucinogenic 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 pictorial 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

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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

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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. SOLVING THE MYSTERIES OF ELEUSIS 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 watersoluble lysergic acid amides, closely related to LSD, which have been isolated previously from ololiuqui. This plant grows commonly all around the Mediterranean 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 watersoluble 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 colleagues 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. CONCLUSION 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 . . .

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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 Wirkungscharakter 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. REFERENCES
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, 129-49 11. Allen, J. R. F. and Holmstedt, B. (1980). The simple beta-carboline alkaloids. Phytochemistry, 19, 1573-86 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-hydroxyindolealkylamines 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

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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 Jovanovich) 31. Hofmann, A. (1979). LSD - Mein Sorgenkind (p. 228). (Stuttgart: Klett)

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Section 3 Psychopathology

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CHAPTE R 5

Experience of time and space in model psychoses
H . HEIMAN N

'Mind-expanding' is a term which has been used in discussions about 'psychodysleptic' drugs. In analogy to mystic absorption, the term refers indirectly to experience of the borders of consciousness by means of mind-altering external conditions 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 intrapsychic 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 acoustic field than the visual field. The differences of the threshold of temporal simultaneity 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

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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 perceive 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 mentioned: 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

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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 impressions, 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 coordination 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' - corresponds 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 relationships. At present, we are unable to localize the fundamental mechanisms of consciousness 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 'mindexpanding' 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 dissolved into nothing. In a report about the music 3 h after taking 16 mg psilocybin, one of the musicians 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 appearance 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'.

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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 unimportant, 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 background 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,

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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 hourglass. 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 concluded 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 hourglass) 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

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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 perception in the visual field or loss of tempo in the musical one. During model psychosis 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 childhood. If we consider that subjects during model psychosis passively experience a chaotic overflow of sensory internal and external impressions which would otherwise 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 consequence of the drug intake. The subjects became overwhelmed by new somatosensoric, 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. REFERENCES
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

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4. Weber, K. (1967). Veränderungen des Musikerlebens in der experimentellen Psychose (Psilocybin). Confirm. Psychiat., 10, 139-76 5. Heimann, H. (1952). Die Scopolaminwirkung. Vergleichend psychopathologischelektroencephalographische 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: Huber) 9. Wellek, A. (1963). Musikpsychologie und Musikästhetik. Grundriss der Systematischen Musikwissenschaft. (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)

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CHAPTE R 6

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

INTRODUCTION The recent development of functional imaging techniques such as positron emission 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 organization of the brain, because of the physiological coupling of cerebral glucose utilization 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 understood, however 1 . The various metabolic findings seen in schizophrenic patients gave rise to fundamental questions: to what extent do cerebral metabolic alterations reflect disturbed mental activity and, in particular, psychotic phenomena?

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The analysis of drug-induced altered mental states (model psychoses) has been one of the most effective approaches for generating chemical hypotheses associated with schizophrenic disorders. The predominant hypothesis of schizophrenia, 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 pharmacological 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 psychopathological changes, we have begun to investigate the effects of psychotomimetic 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 experimental 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. WORKING HYPOTHESIS Complex-loops controlling sensory information processing Based on the recent characterization of functionally segregated cortico-striatothalamo-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

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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 discrimination 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 afferents 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 information 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 formation, 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 information processing within CSTC loops. The model predicts that psychotic symptoms 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 observation 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

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sensory assoc. cortex
medial/lateral temporal lobe

1st proj. area glu? glu?
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Figure 1 The limbic cortico-striato-thalamo-cortical (CSTC) feedback loop is involved in memory, learning and self-nonself discrimination 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
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frontal cortex
glu?
hippocampus

medial/lateral temporal lobe

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sensory input

glu

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IMBALANCE OF SENSORY INFORMATION PROCESSING

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ket : ketamine blocks NMDA receptors psi: psilocybin activates 5-HT2 receptors

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

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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, excitement), 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 temporal 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 corticosubcortical dysfunction in psychedelic mental states.

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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 individual 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 addition, 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 Consciousness 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 . RESULTS 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 frontomedial (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 stimulated 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 investigated. Relative metabolic rates were calculated by dividing absolute metabolic

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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 relative metabolism of the right brain hemisphere is very similar for the two treatments. 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 pronounced 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 restructuring' (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, ketamine was more effective in inducing thought disorders, anxiety and apathy than psilocybin. 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 corticosubcortical 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 correlational analysis between significantly changed metabolic gradients and psychopathological 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. DISCUSSION The 'hyperfrontality hypothesis' of psychotic states were tested under ketamine and psilocybin conditions using PET and the radioligand [ 18 -F]-fluorodeoxyglucose. 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

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

left (s) Change of rCMRglu (%) 10

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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

FRM FRL FRA INS TEB TEL TEP TEA OCMA OCMP OCM OCL OCA PAR VSTR CAU PUT THA CER Brain regions
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(n = 10, Wilcoxon: *:p < 0.05; **:p < 0.01)

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- 10 right (s) FRM FRL FRA INS TEB TEL TEP TEA OCMA OCMP OCM OCL OCA PAR VSTR CAU PUT THA CER 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.). Abbreviations as for Figure 3

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0.947 1.895 2.842 3.789 4.737 5.684 6.631

(a )

7.579 8.526 9.473 10.421 11.368 12.315 13.262 14.210 15.157

(b)
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 pronounced 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

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(b)
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; FMVSTR-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

Percentage change of M6 vs. baseline

Percentage change of M6 vs. baseline

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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 metabolic 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 disturbance 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 NMDAreceptor 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 blockade. 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, comparison of behavioral effects between competitive (e.g. AP-5, AP-7) and noncompetitive (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 MK801 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,

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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 thalamic 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 changes. 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, egodisorders 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 conception 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

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central sulcus

parietal lobe SP SP+OR vision (V1 ) occipital lobe occipitolateral temporal lobe OR

frontal lobe

frontolateral (DL)

temporal pole

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 ('whatwhere' 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 boundaries and apathy. Thought disorders were concomitant with anxiety under ketamine, 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 psychopathological alterations in the right brain preferentially. Interestingly, mescaline,

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

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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. ACKNOWLEDGEMENTS 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).

REFERENCES
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Reynolds, G. P. and Cross, A. J. (1989). Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia. J. Neurochem., 52, 1781-6 27. Kornhuber, J., Mack-Burkhardt, F., Riederer, P., Hebenstreit, G. F., Reynolds, G. P., Andrews, H. B. and Beckmann, H. (1989). [ 3 H]MK-801 binding sites in postmortem brain regions of schizophrenic patients. J. Neuronal Transm., 77, 231-6 28. Simpson, M. D. C., Slater, P., Royston, M. C. and Deakin, J. F. W. (1992). Alterations in phencyclidine and sigma binding sites in schizophrenic brains. Schizophrenia Res., 6, 41-8 29. Vollenweider, F. X. Antonini, A., Leenders, K. L. and Angst, J. (1993). Evidence for a corticalsubcortical dysbalance in the ketamine model of schizophrenia using PET. Presented at the World Congress of Psychiatry, Rio de Janeiro, June 30. Vollenweider, F. X., Antonini, A., Angst, J. and Leenders, K. L. (1992). Zerebraler Energiemetabolismus (PET/FDG) bei gesunden Probanden während Ketamin- und Psilocybininduzierten Modell-Psychosen. Fortschr. Neurol. Psychiat., 60, 103 31. Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie AMDP (1981). Das AMDP-System. Manual zur Dokumentation Psychiatrischer Befunde, 4th edn., (Berlin: Springer-Verlag) 32. Scharfetter, C. (1986). Schizophrene Menschen, 2nd edn., Psychologische Verlags Union. (Munich: Urban & Schwarzenberg) 33. Marwaha, J. (1982). Candidate mechanisms underlying phencyclidine-induced psychosis: an electrophysiological, behavioral and biochemical study. Biol. Psychiatry, 17, 155-98 34. Nelson, S. R., Howard, R. B., Cross, R. S. and Samson, F. (1980). Ketamine-induced changes in regional glucose utilisation in the rat brain. Anesthesiology, 52, 330-4 35. Piercey, M. F., Hoffman, W. E. and Kaczkofsky, P. (1988). Functional evidence for PCP-like effects of the anti-stroke candidate MK-801. Psychopharmacology, 96, 561-62 36. Piercey, M. F. and Ray, C. A. (1988). Dramatic limbic and cortical effects mediated by highaffinity PCP receptors. Life Sci., 43, 379-85 37. Tamminga, C. A., Tanimoto, K., Kuo, S., Chase, T. N., Contreras, P. C., Rice, K. C., Jackson, A. E. and O'Donohue, T. L. (1987). PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent. Synapse, 1, 497-504 38. Drejer, J. and Honoré, T. (1987). Phencyclidine analogues inhibit NMDA-stimulated [ 3 H]GABA release from cultured cortex neurons. Eur.J. Pharmacol, 143, 287-90 39. Olney, J. W., Labruyere, J., Wang, G., Wozniak, D. F., Price, M. T. and Sesma, M. A. (1991). N M D A antagonists neurotoxicity: mechanism and prevention. Science, 254, 1515-18 40. Rao, T. S., Kim, S., Lehmann, J., Martin, L. L. and Wood, P. L. (1989). Differential effects of phencyclidine (PCP) and ketamine on mesocortical and mesostriatal dopamine release in vivo. Life Sci ., 45, 1065-72 41. Rao, T. S., Kim, H. S., Lehmann, J., Martin, L. L. and Wood, P. L. (1990). Interactions of phencyclidine receptor agonist MK-801 with dopaminergic system: regional studies in the rat. J. Neurochem., 54, 1157-62 42. Anis, N. A., Berry, S. C., Burton, N. R. and Lodge, D. (1983). The dissociative anesthetics, ketamine and phencyclidine selectively reduce excitation of central mammalian neurons by N -methyl-D-aspartate. Br. J. Pharmacol, 79, 565-75 43. Hiramatsu, M., Cho, A. K. and Nabeshima, T. (1989). Comparison of the behavioral and biochemical effects of the N M D A receptor antagonists, MK-801 and phencyclidine. Eur.J. Pharmacol, 166, 359-66 44. Jackson, A. and Sanger, D.J. (1988). Is the discriminative stimulus produced by phencyclidine due to an interaction with N -methyl-D-aspartate receptors? Psychopharmacology, 96, 87-92 45. Tricklebank, M. D., Singh, L. S., Oles, R. J., Preston, C. and Iversen, S. D. (1989). The behavioural effects of MK-801: a comparison with antagonists acting non-competitively at the N M D A receptor. Eur.J. Pharmacol, 167, 127-35

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46. Tang, A. W. and Ho, P. M. (1988). Both competitive and non-competitive antagonists of N -methyl-D-aspartate acid disrupt brightness discrimination in rats. Eur. J. Pharmacol, 151, 143-6 47. Reimherr, F. W., Wood, D. R. and Wender, P. H. (1986). The use of MK-801, a novel sympathomimetic, in adults with attention deficit disorders, residual type. Psychopharmacology Bull, 22, 237-42 48. Troupin, A. S., Mendius, J. R., Cheng, F. and Risinger, M. W. (1986). MK-801. In Meldrum, B. S. and Porter, R.J. (eds.) Epilepsy, pp. 191-201. (London: John Libbey & Co.) 49. Aghajanian, G. K., Sprouse, J. S. and Rasmussen, K. (1987). Physiology of the midbrain serotonin system. In Meitzer, H. Y. (ed.) Psychopharmacology: The Third Generation of Progress, pp. 141-9. (New York: Raven Press) 50. Peroutka, S.J. (1993). 5-Hydroxytryptamine receptors. J. Neurochem., 60, 408-16 51. Pierce, P. A. and Peroutka, S. J. (1990). Antagonist properties of d-LSD at 5-hydroxytryptamine 2 receptors. Neuropsychopharmacology, 3, 5-6 52. Titeler, M., Lyon, R. A. and Glennon, R. A. (1988). Radioligand binding evidence implicates the brain 5 - H T 2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology, 94, 213-16 53. Javitt, D. C. and Zukin, S. R. (1991). Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry, 148, 301-8 54. Leuner, H. (1981). Halluzinogene Psychische Grenzzustände in Forschung und Therapie, (Bern: Hans Huber) 55. Pribram, K. H. (1991). Brain and Perception. (New Jersey: Lawrence Erlbaum Associates) 56. Wilson, F. A. W., Scalaidhe, S. P. O. and Goldman-Rakic, P. S. (1993). Dissociation of object and spatial processing domains in primate prefrontal cortex. Science, 260, 1955-8 57. Hermle, L., Fünfgeld, M., Oepen, G., Botsch, H., Borchard, D., Gouzoulis, E., Fehrenbach, R. A. and Spitzer, M. (1993). Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol. Psychiatry, 32, 976-91 58. Cleghorn, J. M., Garnett, E. S., Nahmias, C., Brown, G. M., Kaplan, R., Szechtman, H., Szechtman, B., Franco, S., Dermer, S. W. and Cook, P. (1990). Regional brain metabolism during auditory hallucinations in chronic schizophrenia. Br. J. Psychiatry, 157, 562-70 59. Cleghorn, J. M., Garnett, E. S., Nahmias, C., Firnau, G., Brown, G. M., Kaplan, R., Szechtman, H. and Szechtman, B. (1989). Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia. Psychiatry Res., 28, 119-33 60. Wu, J. C., Buchshaum, M. S., Potkin, S. G., Wolf, M.J. and Bunney, W. E. Jr. (1991). Positron emission tomography study of phencyclidine users. Schizophrenia Res., 4, 415 61. Olney, J. W., Labruyere, J. and Price, M. T. (1990). Phencyclidine, dizocilpine, and cerebrocortical neurons. Science, 221 62. Benes, F. M. and Bird, E. D. (1987). An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients. Arch. Gen. Psychiatr., 44, 608-16

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Arylalkanamine-induce effects in normal volunteers: on the significance of research in hallucinogenic agents for psychiatry
L . HERMLE , M . SPITZER AND E . GOUZOULIS

INTRODUCTION 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

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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 secondary 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 spontaneously 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.

RESEARCH 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 psychoactive agents.

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METHODS AND RESULTS Mescaline study In an open study, 12 carefully selected, physically and mentally healthy, righthanded 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 boundlessness' (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 CI SP SF 2 MF C2 IP SO

SLICE 1
SF 3 BG IF ST TH 10

SLICE 2
FB IT HI CB

SLICE 3

SLICE 4

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

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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 Total score Anergia Anxiety and depression Thought disorder Activation Hostility 19.6 4.3 4.8 4.14 3.4 3.0 ± ± ± ± ± ± 1.4 0.7 1.0 0.3 0.7 0.0 27.0 5.3 8.5 4.68 5.1 3.5 30 ± ± ± ± ± ± 6.0 1.4 2.4 1.0 2.1 1.0 32.1 6.5 7.5 7.4 6.9 3.7 90 ± ± ± ± ± ± 9.3 3.1 3.3 4.7 3.1 0.8 210 33.5 6.1 6.5 10.1 6.8 4.0 ± ± ± ± ± ± 10.2 1.4 2.6 5.6 3.2 1.4 x2 20.3 8.65 9.47 20.47 12.92 3.87 0.0001 0.034 0.023 0.0001 0.004 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 below. 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.

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6 4 2 Mean Rl differenc e 0 -2 -4 -6
99m

left hemisphere (LH ) right hemisphere (RH) SF1 SF2 SF3 C1 C2 MF IF FB SP IP ST IT SO IO BG TH HI CB

Figure 2 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) Cortical region effects left-right anterior mescaline X anterior-posterior mescaline x anterior-posterior X left-right Limbic region effects right-left *p < 0.05 3.98 7.19 5.25 5.27 4.34 P 0.074 0.023* 0.045* 0.045* 0.064

MDE study According to anecdotal evidence, 3,4-methylenedioxymethylamphetamine (MDMA, known also as 'ecstasy', 'Adam', 'XTC') and 3,4-methylenedioxyethylamphetamine (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

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10 5 105

100

100 left hemisphere (LH) right hemisphere (RH)

Mean combined Rl

95

95

90

90

85

85

(a)

80

frontal cortical

posterior cortical

limbic

80 (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 demonstrated using reliable, controlled scientific methodology. The data on psychological 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 pharmacological 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 volunteers.

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40

MDE Placebo
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MSRS score 20 10 t0
t1 t2 t3 t4

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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 OSE AIA VUS Mescaline (n = 12) 6.16 ± 3.63 7.08 ± 4.03 7.41 ± 3.65 MDE (n = 14) 3.92 ± 2.97 2.57 ± 3.08 1.64 ± 1.86 Placebo (n = 14) 0.14 ± 0.36 0.07 ± 0.26
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

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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

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10
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6 Score
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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 restructuralization

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.

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DISCUSSION 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 interpretation 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
28

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

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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. REFERENCES
1. Prentiss, D. W. and Morgan, A. (1895). Anhalonium lewinii (mescal buttons): a study of the drug with especial references to the physiological action upon man with report of experiments. Ther. Gazette, 9, 9

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2. Kraepelin, E. (1892). Über die Beeinflussung einfacher psychischer Vorgänge durch einige Arzneimittel (Jena: Fischer) 3. Knauer, A. (1912). Psychologische Untersuchungen über den Meskalinrausch. Z. ges. Neurol. Psychiat., 4, 37-9 4. Beringer, K. (1927). Der Meskalinrausch. Seine Geschichte und Erscheinungsweise. Monograph. Neurol. Psychiatr., vol. 49. (Berlin-Heidelberg: Springer) 5. Zucker, K. (1930). Versuche mit Meskalin an Halluzinanten. Z. Neurol. Psychiatr., 127, 108-61 6. Hermle, L., Gouzoulis, E., Oepen, G., Spitzer, M., Kovar, K. A., Borchardt, D., Fünfgeld, M. and Berger, M. (1993). Zur Bedeutung der historischen und aktuellen Halluzinogenforschung in der Psychiatrie. Nervenarzt, 64, 562-71 7. Zubin, J. and Spring, B. (1977). Vulnerability - a new view of schizophrenia. J. Abnorm. Psychol., 86, 103-26 8. Hermle, L., Fünfgeld, M., Oepen, G., Botsch, H., Borchardt, D., Gouzoulis, E. and Spitzer, M. (1992). Mescaline-induced psychopathological, neuropsychological and neurometabolic effects in male volunteers. Experimental psychosis as a tool for psychiatric research. Biol. Psychiatry, 32, 976-91 9. Overall, J. E. and Gorham, D. R. (1976). BPRS. Brief Psychiatric Rating Scale. In Guy, W. (ed.) ECDEU Assessment Manual for Psychopharmacology, pp. 157-69. (Maryland: Rockville) 10. Dittrich, A., von Arx, S., Staub, S., in collaboration with Cochrane, R., Cordero, M., Davenport, D., Davenport, R. H., Deters, H., Dierse, B., O'Callaghan, M. A. J., Pollonio, P., Pusterla-Longoni, C., Ratti, A., Simmen, R. and Simoes, M. (1985). International Study on Altered States of Consciousness (ISASC). Summary of the results. German J. Psychol, 9, 319-39 11. Musalek, M., Podreka, I., Suess, E., Nutzinger, D., Passweg, V., Stobl, R., Walter, H., Baumgartner, C. and Lesch, O. M. (1988). Neurophysiological aspects of auditory hallucinations. Psychopathology, 21, 275-80 12. Podreka, I., Suess, E., Goldenberger, G., Steiner, M., Bruche, T., Muller, C., Lang, W., Neirinckx, R. D. and Deecke, L. (1987). Initial experience with Tc-99m-hexamethylpropylene-amine oxime (Tc-99m-HMPAO) brain SPECT. J. Nucl. Med., 27, 1657-66 13. Shulgin, A. T. and Nichols, D. E. (1978). Characterization of three new psychotomimetics. In Stimman, R. C. and Willette, R. E. (eds.) The Pharmacology of Hallucinogens. (New York: Pergamon Press) 14. Shulgin, A. T. (1986). The background and chemistry of MDMA. J. Psychoactive Drugs, 18, 291-304 15. Grinspoon, L. and Bakalar, J. M. (1986). Can drugs be used to enhance the psychotherapeutic process? Am. J. Psychotherapy, 60, 393-404 16. Greer, G. and Tolbert, R. (1990). The therapeutic use of MDMA. In Peroutka, S.J. (ed.) The Clincial, Pharmacological and Neurotoxicological Effects of the Drug MDMA, pp. 21-35. (Boston: Kluwer) 17. Dowling, G. P., McDonough, E. T. and Bost, R. O. (1986). "Eve" and "Ecstasy": a report of five deaths associated with the use of MDEA and MDMA. JAMA, 257, 1615-17 18. Nichols, D. E. (1986). Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogenes. Identification of a new therapeutic class: entactogenes. Psychoactive Drugs, 18, 305-13 19. Hermle, L., Spitzer, M., Borchardt, D., Kovar, K. A. and Gouzoulis, E. (1993). Psychological effects of MDE In normal subjects: are entactogens a new class of psychoactive agents? Neuropsychopharmacology, 8, 171-6 20. Gouzoulis, E., Steiger, A., Ensslin, M., Kovar, K. A. and Hermle, L. (1992). Sleep EEG effects of 3,4-methylenedioxyethamphetamine (MDE, "Eve") in healthy volunteers. Biol Psychiatry, 32, 1108-17

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21. Gouzoulis, E., Bardeleben, U. V., Rupp, A., Kovar, K. A. and Hermle, L. (1993). Neuroendocrine and cardiovascular effects of MDE in healthy volunteers. Neuropsychopharmacology, 8, 187-93 22. Beigel, A., Murphy, D. L. and Bunney, W. E. (1971). The Manic-State Rating Scale. Arch. Gen. Psychiatry, 25, 256-62 23. Ingvar, D. H. and Franzen, G. (1974). Distribution of cerebral activity in chronic schizophrenia. Lancet, 2, 1484-6 24. Farkas, T., Wolf, A. P., Jaeger, J., Brodie, J. D., Christman, D. R. M. and Fowler, J. S. (1984). Regional brain glucose metabolism in chronic schizophrenia: a positron emission transaxial tomographic study. Arch. Gen. Psychiatry, 14, 293-300 25. Cleghorn, J. M., Garnett, E. S., Nahmias, C., Firnau, G., Brown, G. M., Kaplan, R., Szechtman, H. et al. (1985). Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia. Psychiatry Res., 28, 119-33 26. Wiesel, F. A., Wik, G., Sjögren, J., Bomqvist, G., Greitz, T. and Stone-Elander, S. (1987). Regional brain glucose metabolism in drug free schizophrenic patients and clinical correlates. Acta Psychiatr. Scand., 76, 628-41 27. Szechtman, H., Nahmias, C., Garnett, S., Firnau, G., Brown, G. M., Kaplan, R. D. and Cleghorn, J. M. (1988). Effect of neuroleptics on altered cerebral glucose metabolism in schizophrenia. Arch. Gen. Psychiatry, 45, 523-32 28. Vollenweider, F. X. (1992). Die Anwendung von Psychotomimetika in der Schizophrenieforschung unter besonderer Berücksichigung der Ketamin/PCP-Modellpsychose. Sucht, 38, 398-409

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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
A . DITTRIC H

INTRODUCTION 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 psychology.

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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 psychological functioning of a normal individual from her/his usual waking consciousness. (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 'pathological' 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-tetrahydro4 cannabinol (THC) (cf. Leuner ). Hallucinogens of the second order produce a stronger 'clouding of consciousness' and fewer scenic hallucinations or pseudohallucinations. 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 awakening, when hypnagogic or hypnopompic phenomena appear. The fourth type of ASC inducer is increased environmental stimulation or contact (sensory bombardment) 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 techniques.

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BASIC DIMENSIONS OF ASCs Hypotheses 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.

Results 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).

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Table 1 Conditions of experimental studies n Pharmacological agents Hallucinogens I. order: (1) N,N-dimethyltryptamine (DMT) (2) N,N-dimethyltryptamine (DMT) (3) psilocybin (4) Δ 9 -trans-tetrahydrocannabinol (THC) (5) Δ9-trans-tetrahydrocannabinol (THC) Hallucinogens II. order: (6) nitrous oxide Psychological agents Sensory deprivation in a broader sense: (7) perceptual deprivation (8) hypnagogic states (9) autogenic training (10) hypnosis Sensory overload: (11) stimuli of high variety Control groups (12) placebo to (1) (13) placebo to (2) (14) placebo to (3) (15) placebo to (4) (16) control to (11) (17) lecture on ASC 38 139 22 29 22 6 60 134 12 7 6 12 39 58 120 26 15 14 18 9

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 etiologyindependent 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 etiologyindependent dimension. These were subsequently used as the basis for the construction of scales according to the classical theory of mental testing (see below).

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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 Switzerland (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 information, 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. DESCRIPTION OF THE APZ - SCALES 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

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Table 2 The APZ dimension of 'Ozeanische Selbstentgrenzung (OSE)' ('oceanic boundlessness'; Ni = 13) Number in APZ 1 7 13 16 31 34 68 84 92 95 127 129 147 Item I had the feeling everything around me was somehow unreal I felt as though I were floating The boundary between myself and my surroundings seemed to blur I felt totally free and released from all responsibilities I had the feeling that I had been transferred to another world It seemed to me that there were no more conflicts and contradictions in the world It seemed to me as though I did not have a body any more I felt very happy and content for no outward reason I could have sat for hours looking at something I was completely indifferent toward everything I experienced past, present and future as a oneness It seemed to me that my environment and I were one 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 Selbstentgrenzung' (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 etiologyindependent 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

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Table 3 The APZ dimension of 'Angstvolle Ichauflösung (AIA)' ('dread of ego dissolution'; N i = 22) Item I had difficulty in distinguishing important from unimportant things My thinking was constantly being interrupted by insignificant thoughts My own feelings seemed strange to me, as though they did not belong to me I felt tormented without knowing exactly why I felt like a robot My surroundings seemed peculiarly strange to me I felt threatened without realizing by what I had the feeling that I no longer had a will of my own I was afraid without being able to say exactly why I felt like a marionette Everything around me was happening so fast that I could no longer follow what was really going on I stayed frozen in a very unnatural position for quite a long time I had difficulty making even the smallest decision I felt as though I were paralyzed Things around me appeared distorted to me Time passed more slowly than usual I was not able to complete a thought; my thoughts repeatedly became disconnected I felt isolated from everything and everyone It seemed to me that I no longer had any feelings It seemed to me as though there was an invisible wall between me and my surroundings I observed myself as though I were a stranger I felt a total emptiness in my head

Number in APZ 9 32 40 44 55 56 64 66 71 83 91 105 107 110 131 133 136 141 148 156 157 158

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.

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Table 4 'Visionäre Umstrukturierung (VUS)' ('visionary restructuralization'; N i = 14) Item So many thoughts and feelings assailed me at once that I become confused I saw lights or flashes of light in total darkness or with closed eyes I saw scenes rolling by like in a film in total darkness or with my eyes closed. Objects around me engaged me emotionally much more than usual Things around me appeared to be bigger than usual Things around me had a new, strange meaning for me I saw colors before me in total darkness or with closed-eyes I saw things that I knew were not real I saw regular patterns in complete darkness or with closed eyes Something occurred to me and I did not know whether I had dreamt or actually experienced it I saw strange things, which I now know were not real Everyday things gained a special meaning for me Sounds seemed to influence what I saw The colors of the things I saw were changed by sounds and noises

Number in APZ 14 29 33 42 43 51 70 80 100 119 120 128 134 138

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

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Table 5 Additional items of the APZ secondary scale: 'Veränderter Wachbewusstseinszustand (VWB)' ('altered state of consciousness'; N i = 23) Number in APZ 2 3 6 11 19 20 22 24 28 39 41 57 58 63 65 87 113 122 132 137 139 146 152 hem Sounds and noises sounded different than usual Time passed faster than usual I simply could not get rid of some unimportant thought I became conscious of another 'I' being hidden behind my usual T The ground I was standing on seemed to be swaying My ears were buzzing I could not remember what had happened 2 h earlier I had the vague feeling that something important would happen to me Parts of my body seemed no longer to belong to me I had the feeling my limbs were larger than usual I was convinced that I had experienced the same situation before Things around me had a different smell than usual I was tired and exhausted but at the same time wide awake It seemed that I had once dreamt what I was experiencing I perceived peculiar relationships between widely diverging matters I had trouble distinguishing between what I imagined and what I really experienced I no longer knew where I actually was I had the feeling I could think faster or more clearly than usual So many thoughts came to my mind that I was no longer able to organize them properly I was too wide awake and too sensitive I had the impression that everything occurring around me was related to me I had the feeling that I could no longer control the movements of my body 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

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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 This study (n = 393) OSE/AIA OSE/VUS AI A/VUS VWB/OSE VWB/AIA VWB/VUS ISASC* (n = 1133) OSE/AIA OSE/VUS AIA/VUS VWB/OSE VWB/AIA VWB/VUS * Six countries 0.39 0.56 0.51 0.72 0.80 0.82 0.16 0.10 0.12 0.08 0.05 0.06 0.18-0.62 0.44-0.72 0.38-0.72 0.60-0.83 0.76-0.88 0.74-0.91 0.60 0.56 0.50 0.87 0.83 0.74
-

SD

min-max

-

-

-

-

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 This study (n = 393) OSE AIA VUS VWB ISASC* (n = 1133) OSE AIA VUS VWB * Six countries 0.76 0.86 0.83 0.92 0.04 0.03 0.02 0.01 0.72-0.83 0.83-0.89 0.81-0.87 0.92-0.93 0.88 0.88 0.83 0.95
-

min-max

-

-

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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 questionnaire (or its follower, 'OAV') has become the standard instrument when assessing ASCs, which helps to integrate the international research. BASIC DIMENSIONS OF ASCs AND THE LSD EXPERIENCE 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 determined 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 nonpharmacological agents such as sensory deprivation or certain types of sensory overload. PREDICTION OF INDIVIDUAL REACTION PROFILES As already observed by Moreau de Tours 1 , individual reaction differences on ASC-inducing agents are high, even when experimental conditions are

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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 Empirical matrix (LSD) OSE item number in APZ AIA VUS N i (total)

Ni

7, 13, 16, 34, 68, 84, 92, 95, 127, 129, 147 12

42, 119, 128

0 9, 32, 40, 44, 55, 56, 64, 66, 71, 83, 91, 105, 107, 110, 131, 141, 148, 156, 157, 158 21 133

3

15

AIA item numbers in APZ 1

14, 43 24 2 29, 33, 51, 70, 80, 100, 120, 134, 138 9 14

Ni VUS item numbers in APZ Ni N i (total)

1

0 13

1 22

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 variables. 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 globally and for each of the three dimensions. of an ASC

(2) The equations between the predictor variables and the APZ dimensions found for one ASC-inducing agent also hold true for all other induction means.

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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. (DMT), the dosage being 0.625 mg/kg, intra-

(2) N,N-Dimethyltryptamine muscularly.

(3) Nitrous oxide, 3 1 N2O and 2.5 1 O2 per min for 15 min using a 'continuousflow' 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 subjects)). 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.

Results 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 regression 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 Sensory deprivation
DMT N2O

n 45 45 45

OSE 0.72* 0.64* 0.69*

AIA 0.60* 0.65* 0.42

VUS 0.55 0.60* 0.60*

VWB 0.65* 0.67* 0.67*

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

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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 condition '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 hypothesis. 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 conditions. 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 predicted direction; five were statistically significant and at least of medium-effect size. Summarizing, it is remarkable that our second hypothesis was more often confirmed 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 equations. 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

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PSYCHOLOGICAL ASPECTS OF ASCs Predictor variables
OSE
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

Scales
AIA VUS VWB

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 importance. 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). Previous 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 occurrence 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. PERSPECTIVES Concerning the topics discussed in this chapter, we perceive several main perspectives 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 schizophrenia or those due to solitary confinement) are similar to those of ASCs. Further studies comparing ASCs and psychopathological phenomena with the same

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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 identical 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 computed 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 corresponding 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. ACKNOWLEDGEMENTS 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. REFERENCES
1. Moreau de Tours, J. (1845). Du hachisch et de l' aliénation mentale - Etudes psychologigues. (Paris: Librairie de Fortin, Masson). [Translation, (1973), Hashish and Mental Illness. (New York: Raven Press)] 2. Ludwig, A. M. (1966). Altered states of consciousness. Arch. Gen. Psychiatry, 15, 225-34 3. Weber, M. (1920). Gesammelte Aufsätze zur Religionssoziologie, Vol. 1. (Tübingen: Mohr) 4. Leuner, H. (1981). Halluzinogene. Psychische Grenzzustände in Forschung und Therapie. (Bern: Huber)

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5. Popper, K. (1976). Logik der Forschung, 6th edn. (Tübingen: Mohr) 6. Lakatos, I. (1974). Falsifikation und die Methodologie wissenschaftlicher Forschungsprogramme. In Lakatos, I. and Musgrave, A. (eds.) Kritik und Erkenntnisfortschritt, pp. 89-189. (Braunschweig: Vieweg) 7. Eysenck, H. J. and Eysenck, S. B. G. (1969). Personality Structure and Measurement. (San Diego: Knapp) 8. Cattell, R. B. (ed.) (1966). Handbook of Multivariate Experimental Psychology. (Chicago: Rand McNally) 9. Dittrich, A., Bättig, K, Woggon, B. and Zeppelin von, I. (1972). Entwicklung einer Selbsteinschätzungsskala (DAE - Skala I) zur Erfassung von Cannabis-Effekten. Pharmakopsychiatrie Neuro-Psychopharmakol. , 5, 255-68 10. Dittrich, A. (1985). Atiologie-unabhängige Strukturen veränderter Wachbewusstseinszustände - Ergebnisse empirischer Untersuchungen über Halluzinogene I. und II. Ordnung, sensorische Deprivation, hypnagoge Zustände, hypnotische Verfahren sowie Reizüberflutung. (Stuttgart: Ferdinand Enke) 11. Dittrich, A. (1975). Zusammenstellung eines Fragebogens (APZ) zur Erfassung abnormer psychischer Zustände. Z. Klin. Psychol. Psychother., 23, 12-20 12. Dittrich, A., von Arx, S., Staub, S., in collaboration with Cochrane, R., Cordero, M., Davenport, D., Davenport, R. H., Deters, H., Dierse, B., O'Callaghan, M. A. J., Polonio, P., Pusterla-Longoni, C., Ratti, A., Simmen, R. and Simoes, M. (1985). International Study on Altered States of Consciousness (ISASC). Summary of the results. German J. Psychol, 9, 319-39 13. Huxley, A. (1956). Heaven and Hell. (London: Chatto and Windus) 14. Hermle, L., Fünfgeld, M., Oepen, G., Botsch, H., Borchardt, D., Gouzoulis, E., Fehrenbach, R. A. and Spitzer, M. (1992). Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: Experimental psychosis as a tool for psychiatric research. Biol Psychiatry., 32, 976-91 15. Hermle, L., Spitzer, M., Borchardt, D., Kovar, K, and Gouzoulis, E. (1993). Psychological effects of MDE in normal subjects. Neuropsychopharmacology, 8, 171-6 16. Bodmer, I. (1989). Konstruktion des Fragebogens OAV zur quantitativen Erfassung aussergewöhnlicher Bewusstseinszustände (ABZ). (Lizentiatsarbeit, University of Zürich) 17. Bodmer, I., Lamparter, D. and Dittrich, A. (1994) Aussergewöhnliche Bewusstseinszustände ihre gemeinsame Struktur und Messung. 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 18. Lamparter, D. and Dittrich, A. (1994). Differentielle Psychologie aussergewöhnlicher Bewusstseinszustände - Literaturübersicht und methodische Probleme. In Dittrich, A., Leuner, H. and Hofmann, A. (eds.) Welten des Bewusstseins, Vol. 3.: Experimentelle Psychologie, Neurobiologie und Chemie. (Berlin: Verlag für Wissenschaft und Bildung) in press 19. Dittrich, A. and Lamparter, D. (1991). Experimentelle Untersuchung zur Differentiellen Psychologie aussergewöhnlicher Bewussteinszustände. Wissenschaftlicher Schlussbericht zum Nationalfondsprojekt., No. 11-25473.88 20. Dittrich, A. and Lamparter, D. (1994). Differentielle Psychologie aussergewöhnlicher Bewusstseinszustände - Ergebnisse experimenteller Untersuchungen mit sensorischer Deprivation, 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 Untersuchung mit sensorischer Deprivation, Stickoxydul und N,N-Dimethyltryptamin. (Lizentiatsarbeit, University of Zürich)

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22. Maurer, M. (1994). Erleben in freiwillig ausgelösten aussergewöhnlichen Bewusstseinszuständen und schizophrenen Erkrankungen: Eine vergleichende empirische Untersuchung. 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 23. Simoes, M. (1992). Consciencia do Eu na Esquizofrenia Paranoide. (Dissertacao à Faculdade de Medicina da Universidade de Lisboa) 24. Volkart, R., Dittrich, A., Rothenfluh, T. and Paul, W. (1983). Eine kontrollierte Untersuchung über psychopathologische Effekte der Einzelhaft. Schweiz. Z. Psychol. Anwend., 42, 25-46 25. Vollenweider, F. X. (1992). Die Anwendung von Psychotomimetika in der Schizophrenieforschung unter besonderer Berücksichtigung der Ketamin/PCP-Modell-Psychose. Sucht, 38, 117-18 26. Bodmer, I., Braun, H.-J. and Dittrich, A. (1990). Ozeanische Selbstentgrenzung, angstvolle Ichauflösung, visionäre Umstrukturierung und Mystik - zwischen Empirie und Theologie. In Leuner, H. and Schlichting, M. (eds.) 4. Symposion des Europäischen Collegiums für Bewusstseinstudien, pp. 49-60. (Göttingen: ECBS) 27. Jacobowitz, E. S. (1994). Religiöse Erlebnisse bei Pfingstlern - Eine empirische Untersuchung zur differentiellen Psychologie aussergewöhnlicher Bewusstseinszustände. (Unpublished dissertation; University of Zürich)

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Section 4 Transcultural Aspects

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CHAPTE R 9

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

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 literaturebased, 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 objectification; 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' autobiography, 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.

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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 particularly under the spur of the excitement generated by the development of synthetic drugs, understood drug use as a transcultural phenomenon and formed hypotheses 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 perspective, 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 wellestablished 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 constitute 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 movement, 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 coincidental emergence of the modernist concern with alternate realities and the scientific 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

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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, pulsations, 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 mindexpanding capacities of drugs in general. It came to symbolize, in particular, the irreducible ambivalence, between negation and affirmation, destruction and construction, 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

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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 happening. 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 coupling of hedonism and anomie that leads to these reactions. A simultaneous expansion 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

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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 purposeful 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 conventionally 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 transculturality 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 combined an interest in the variety of the human with a profound search for its (supposed) 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 lastnamed 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 opposite 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

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civilization that has lost this 'originality', which may be recoverable 'more especially [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 'primitive' 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 unification. 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 ethnopharmacology 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 multiplicity 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

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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 simultaneously an act of community formation, of bonding, is both part of traditional literary 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 disciplinary 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, discussion 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

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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 essentially 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 validation 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.

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The transgressive impulse, though, persists elsewhere - for example in (discussions 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 tautological: 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 mystical 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. REFERENCES AND NOTES
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)

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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 Books] 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 Comparative 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 Press] 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)]

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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 [quotation 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)

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Section 5 Clinical Aspects

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CHAPTE R 10

Pharmacological standards for evaluation of clinical effects of hallucinogens
M . LADER

INTRODUCTION The hallucinogenic drugs are characterized by their ability to induce disturbances of perception, thought and mood. LSD, although not the oldest of these compounds, is the most representative. Descriptions of its actions in human subjects vary greatly, depending on such factors as whether normal volunteers or psychiatric 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 difficulty 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.

ANIMAL STUDIES 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).

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Table 1 Validity face concurrent predictive Biochemical models serotonin Behavioral models Therapeutic focus any bizarre behavior probably none really possibly none indirect e.g. alcoholism, obsessive-compulsive disorder Value of animal studies

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 psychopathological 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. DOSE The careful construction of dose-effect curves is a necessary part of the standardization 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.

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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. Furthermore, 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 overfrequent administration. FACTORS IN THE SUBJECT 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 Expectation if subject expects psychedelic experience, response will be different from the naive subject Motivation reason for volunteering needs documenting Personality factors broad, e.g. 'neuroticism' narrow, e.g. 'obsessionality' Education level of verbal facility is important in order to describe experience Age Sex

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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 Multiphasic 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 perceptual 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 physical 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. FACTORS IN THE PATIENT 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 conditions can be ascertained using a standard diagnostic schedule. More detailed profiles of psychopathology within each diagnosis can also be drawn up using standard instruments. 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

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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. FACTORS IN THE THERAPIST 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

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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. FACTORS IN THE ENVIRONMENT More than with most psychotropic drugs, environmental factors must be carefully selected and standardized in the study of hallucinogenic effects. The surroundings 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 avantgarde! 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. OUTCOME VARIABLES 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 questionnaires 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 syndrome, 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 treatment 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

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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. BODILY CHANGES 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 frequently, especially at higher doses. Autonomic effects are invariably present; blurring 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 hallucinogen. 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 comparisons 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 fascinating 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. ADVERSE EFFECTS 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

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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. CONCLUSIONS Half a century on, the hallucinogens remain among the most fascinating of psychotropic drugs and LSD is the best understood of the group. After initial uncritical 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 psychoanalysis. 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.

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50th
Basel April 19th 1943 Cycling

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!

REFERENCES
1. Aaronson, B. and Osmond, H. (eds.) (1971). Psychedelics, The Uses and Implications of Hallucinogenic 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,IndustrialandClinicalPerspectives. (Cambridge: Cambridge University Press) 7. Abramson, H. A., Jarvik, M. E. and Hirsch, M. W. (1955). Lysergic acid diethylamide (LSD25): VII. Effect upon two measures of motor performance. J. Psychol, 39, 455-64

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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 hallucinogenic 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 Association) 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, 566-74 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. Psychopharmacology, 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 admission (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, 884-9 24. Institute for the Study of Drug Dependence (ISDD). (1993). Drug Misuse in Britain. (London: ISDD)

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CHAPTE R 11

Human psychopharmacology of LSD, dimethyltryptamine and related compounds
R . J . STRASSMAN

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 tryptamines, 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,

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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.

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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 psychopharmacologic 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.

EARLY APPROACHES TO HUMAN HALLUCINOGEN RESEARCH The discontinuation of human hallucinogen research coincided with the beginnings of both a more sophisticated approach to human psychopharmacology, 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 neuropharmacologic hypotheses may be validated, refuted or extended.

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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 descriptive/clinical clustering of questions that emphasized somatic and emotional effects. The Linton-Langs scale clustered items based on psychoanalytical theories of consciousness. The ARCI is now the standard rating scale for psychoactive drug effects in humans. After undergoing extensive field trials using multiple drugs and populations, 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.),

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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 volunteers. 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.

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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-ethylamphetamme (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. NEURO/PSYCHOPHARMACOLOGY: ANIMAL-HUMAN CORRESPONDENCES Serotonin 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 opposing 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

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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-2methyl-5-methoxytryptamine), failed to demonstrate acute pretreatment reduction 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 antagonistic to the effects of LSD 8 0 .

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Meitzer and co-workers 81 and Demisch and Neubauer 8 2 generated neuroendocrine 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 administration, 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, SaiHalasz 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. Reserpine 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

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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 metachloropiperazine (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.

Dopamine 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 presynaptic 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

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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 autonomic 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 humans. Norepinephrine 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-methylpara-tyrosine, which decreases brain levels of norepinephrine, prevented the behavioral and sympathomimetic effects of LSD, whilst leaving intact hyperthermic 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. Acetylcholine 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

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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 neurotransm 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 pretreatment studies in which progesterone was administered to men demonstrated a robust inhibition of LSD effects 3 2 , 1 2 6 . TOLERANCE AND CROSS-TOLERANCE 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 . Crosstolerance 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)

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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 . ENDOGENOUS HALLUCINOGENS 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 cumulative exposure to endogenous DMT. In addition, the metabolism of DMT is of interest, because so little is excreted

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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. CURRENT HUMAN RESEARCH 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 psychodynamic 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

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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 behavioral 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 generalizations 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 subculture'. 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.

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Subjects 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 professional 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 interview 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 medication 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.

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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 sessions. Studies are carried out at the inpatient unit of a National Institute of Healthfunded 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

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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 dosedependent 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.

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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 mediating 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.

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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 pretreatment 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.

DIRECTIONS FOR FUTURE RESEARCH 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-electroencephalography, and radically new tools such as magnetic resonance spectroscopy 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

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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 (hallucinogenic 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, posttraumatic 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,

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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 potentially 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.

CONCLUSION 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.

ACKNOWLEDGEMENTS 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., UCLA.

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108. Abramson, H. A., Rolo, A. and Stäche, J. (1960). Lysergic acid diethylamide (LSD-25) antagonists: chlorpromazine. J. Neuropsychiatry, 1, 307-10 109. Clark, L. D. and Bliss, E. L. (1957). Psychopharmacological studies on lysergic acid diethylamide (LSD-25) intoxication. Arch. Neurol. Psychiatry, 78, 653-5 110. Moore, R. H., Hatada, K. and Domino, E. F. (1976). Effects of N,N-dimethyltryptamine on electrically evoked responses in the cat visual system and modification by neuroleptic agents. Neuropharmacology, 15, 535-9 111. Meert, T. F., de Haes, P. and Janssen, P. A.J. (1989). Risperidone (R 64, 766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology, 97, 206-12 112. Elder, J. T. and Dille, J. M. (1962). An experimental study of the participation of the sympathetic nervous system in the lysergic acid diethylamide (LSD) reaction in cats. J. Pharmacol. Exp. Ther., 136, 162-8 113. Horita, A. and Hamilton, A. E. (1969). Lysergic acid diethylamide: dissociation of its behavioral and hyperthermic actions by DL-α-methyl-p-tyrosine. Science, 164, 78-9 114. Aghajanian, G. K. (1980). Mescaline and LSD facilitate the activation of locus coeruleus neurons by peripheral stimuli. Brain Res., 186, 492-8 115. McCall, R. B. and Aghajanian, G. K. (1980). Hallucinogens potentiate responses to serotonin and norepinephrine in the facial motor nucleus. Life Sci ., 26, 1149-56 116. Bertino, J. R., Klee, G. D., Collier, D. and Weintraub, W. (1960). Clinical studies with dibenzyline and lysergic acid diethylamide. J. Clin. Exp. Psychopathol, 21, 293-9 117. Gillet, G., Ammor, S. and Fillion, G. (1985). Serotonin inhibits aceylcholine release from rat striatum slices: evidence for a presynaptic receptor-mediated effect. J. Neurochem., 45, 1687-91 118. Cervoni, P., Bertino, J. R. and Geiger, L. E. (1963). Medullary vagal effects of d-lysergic acid diethylamide in the decerebrate cat. Nature (London), 199, 700-1 119. Forrer, G. R. and Goldner, R. D. (1951). Experimental physiological studies with lysergic acid diethylamide (LSD-25). Arch. Neurol. Psychiatry, 65, 581-8 120. Biegon, A., Bercovitz, H. and Samuel, D. (1980). Serotonin receptor concentration during the estrous cycle of the rat. Brain Res., 187, 221-5 121. Fischette, C. T., Biegon, A. and McEwen, B. S. (1983). Sex differences in serotonin-1 receptor binding in rat brain. Science, 222, 333-5 122. Dickinson, S. and Curzon, G. (1986). 5-Hydroxytryptamine-mediated behaviour in male and female rats. Neuropharmacology, 25, 771-6 123. Dinan, T. G., Barry, S., Yatham, L. N., Mobayed, M. and O'Hanlon, M. (1990). The reproducibility of the prolactin response to buspirone: relationship to the menstrual cycle. Int. Clin. Psychopharmacol., 5, 119-23 124. O'Keane, V., O'Hanlon, M., Webb, M. and Dinan, T. G. (1991). d-Fenfluramine/prolactin response throughout the menstrual cycle: evidence for an oestrogen-induced alteration. Clin. Endocrinol, 34, 289-92 125. Johnston, L. D., O'Malley, P. M. and Bachman, J. G. (1991). Drug Use Among American High School Seniors, College Students and Young Adults, 1975-1990, vols. 1 and 2. (Rockville, MD: US Department of Health and Human Services) 126. Krus, D. M., Resnick, O. and Raskin, M. (1966). Apparent eye level tests. Its background and use in psychopharmacology. Arch. Gen. Psychiatry, 14, 419-27 127. Halaris, A. E. and Freedman, D. X. (1975). Plasma corticoids and brain tryptophan after acute and tolerance dosage of LSD. Life Sci., 203, 575-86 128. Wallach, M. B., Friedman, E. and Gershon, S. (1972). 2,5-Dimethoxy-4-methylamphetamine (DOM). A neuropharmacological examination. J. Pharmacol Exp. Ther., 182, 145-54

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129. Freedman, D. X., Aghajanian, G. K., Ornitz, E. M. and Rosner, B. S. (1958). Patterns of tolerance to lysergic acid diethylamide and mescaline in rats. Science, 127, 1173-4 130. Trulson, M. E., Ross, C. A. and Jacobs, B. L. (1977). Lack of tolerance to the depression of raphe unit activity by lysergic acid diethylamide. Neuropharmacology, 16, 771-4 131. Appel, J. B. and Freedman, D. X. (1968). Tolerance and cross-tolerance among psychotomimetic drugs. Psychopharmacology, 13, 267-74 132. Cole, J. M. and Pieper, W. A. (1973). The effects of N,N-dimethyltryptamine on operant behavior in squirrel monkeys. Psychopharmacology, 29, 107-12 133. Kovacic, B. and Domino, E. F. (1976). Tolerance and limited cross-tolerance to the effects of N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) on food-rewarded bar pressing in the rat. J. Pharmacol. Exp. Ther., 197, 459-502 134. Gillin, J. C., Kaplan, J., Stillman, R. and Wyatt, R. J. (1973). Failure of N,Ndimethyltryptamine to evoke tolerance in cats. Biol. Psychiatry, 7, 213-20 135. Simonovic, M. and Meitzer, H. Y. (1979). Repeated administration of 5-methoxy-N,Ndimethyltryptamine to male rats potentiates stimulation of prolactin secretion by serotonin agonists. Eur. J. Pharmacol., 58, 399-405 136. Darmani, N. A., Martin, B. R. and Glennon, R. A. (1992). Behavioral evidence for differential adaptation of the serotonergic system after acute and chronic treatment with ( ± l - ( 2 , 5 methoxy-4-iodophenyl)-2-aminopropane (DOI) or ketanserin. J. Pharmacol. Exp. Ther., 262, 692-8 137. Isbell, H., Belleville, R. E., Fraser, H. F., Wikler, A. and Logan, C. R. (1956). Studies on lysergic acid diethylamide, I: effects in former morphine addicts and development of tolerance during chronic intoxication. Arch. Neurol. Psychiatry, 76, 468-78 138. Angrist, B., Rotrosen, J. and Gershon, S. (1974). Assessment of tolerance to the hallucinogenic effects of D O M . Psychopharmacology, 36, 203-7 139. Hollister, L. E. (1961). Clinical, biochemical and psychologic effects of psilocybin. Arch. Int. Pharmacodyn., 80, 42-52 140. Balestrieri, A. (1960). Studies on cross tolerance with LSD-25, UML-491 and JB-336. Psychopharmacology, 257-9 141. Wolbach, A. B. Jr., Isbell, H. and Miner, E. J. (1962). Cross-tolerance between mescaline and LSD-25, with a comparison of the mescaline and LSD reactions. Psychopharmacology, 3, 1-14 142. Gillin, J. C., Kaplan, J., Stillman, R. and Wyatt, R. J. (1976). The psychedelic model of schizophrenia: The case of N,N-dimethyltryptamine. Am. J. Psychiatry, 133, 203-8 143. Stafford, P. (1992). Psychedelics Encyclopedia, 3rd edn., revised, pp. 308-331. (Berkeley: Ronin Press) 144. Balestrieri, A. and Fontanari, D. (1959). Acquired and cross-tolerance to mescaline, LSD-25, and BOL-148. Arch. Neurol. Psychiatry, 1, 279-82 145. Isbell, H., Wolbach, A. B. Jr., Wikler, A. and Miner, E. J. (1961). Cross-tolerance between LSD and psilocybin. Psychopharmacology, 2, 147-59 146. Abramson, H. A., Rolo, A., Sklarofksy, B. and Stache, J. (1960). Production of cross-tolerance to psychosis-producing doses of lysergic acid diethylamide and psilocybin. J. Psychol, 49, 151-4 147. Rosenberg, D. E., Isbell, H., Miner, E. J. and Logan, C. R. (1964). The effect of N,Ndimethyltryptamine in human subjects tolerant to lysergic acid diethylamide. Psychopharmacology, 5, 217-27 148 Abramson, H. A., Sklarofksy, B., Baron, M. O. and Fremont-Smith, N. (1958). Lysergic acid diethylamide (LSD-25) antagonists. II. Development of tolerance in man to LSD-25 by prior administration of MLD-24 (1-methyl-d-lysergic acid diethylamide). Arch. Neurol Psychiatry, 79, 201-7

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149. Kety, S. S. (1967). Current biochemical approaches to schizophrenia. N. Engl. J. Med., 276, 325-31 150. Mehl, E., Ruther, E. and Redemann, J. (1977). Endogenous ligands of a putative LSDserotonin receptor in the cerebrospinal fluid: Higher level of LSD-displacing factor (LDF) in unmedicated psychotic patients. Psychopharmacology, 54, 9-16 151. Christian, S. T., Harrison, R., Quayle, E., Pagel, J. and Monti, J. (1977). The in vitro identification of dimethyltryptamine (DMT) in mammalian brain and its characterization as a possible endogenous neuroregulatory agent. Biochem. Med., 18, 164-83 152. Mandel, L. R. and Walker, R. W. (1974). The biosynthesis of 5-methoxy-N,Ndimethyltryptamine in vitro. Life Sci., 15, 1457-63 153. Franzen, F. and Gross, H. (1965). Tryptamine, N,N-dimethyltryptamine, N,N-dimethyl-5hydroxytryptamine and 5-methoxytryptamine in human blood and urine. Nature (London), 206, 105-2 154. Wyatt, R. J., Saavedra, J. and Axelrod, J. (1973). A dimethyltryptamine-forming enzyme in human blood. Am. f. Psychiatry, 130, 754-60 155. Saavedra, J. and Axelrod, J. (1972). Psychotomimetic N-methylated tryptamines: Formation in brain in vivo and in vitro. Science, 175, 1365-6 156. Murray, R. M., Oon, M. C. H., Rodnight, R., Birley, J. L. T. and Smith, A. (1979). Increased excretion of dimethyltryptamine and certain features of psychosis. A possible association. Arch. Gen. Psychiatry, 36, 644-9 157. Szara, S. (1956). Dimethyltryptamine: Its metabolism in man; the relation of its pyschotic effect to the serotonin metabolism. Experientia, 12, 441-2 158. Kaplan, Mandel, L. R., Stillman R., Walker, R. W., Vandenheural, W.J. A., Gillin, J. C. and Wyatt, R.J. (1976). Blood and urine levels of N,N-dimethyltryptamine following administration of psychoactive dosages to human subjects. Psychopharmacology, 38, 239-45 159. Vinar, O., Molcan, J., Nahunek, K., Svestka, J. and Zapletalek, M. (1989). Ritanserin in schizophrenic patients. Activitas Nervosa Superior, 31, 107-9 160. Axelsson, R., Nilsson, A., Christensson, E. and Björk, A. (1991). Effects of amperozide in schizophrenia. An open study of a potent 5 - H T 2 antagonist. Psychopharmacology, 104, 287-92 161. Aghajanian, G. K, Foote, W. and Sheard, M. (1970). Action of psychotogenic drugs on single midbrain raphe neurons. J. Pharmacol. Exp. Ther., 171, 178-87 162. Geyer, M. A., Light, R. K., Rose, G. J., Peterson, L. R., Horwitt, D. D., Adams, L. M. and Hawkins, R. L. (1979). A characteristic effect of hallucinogens on investigatory responding in rats. Psychopharmacology, 65, 35-40 163. Fish, M. S., Johnson, N. M. and Horning, E. C. (1955). Piptadenia alkaloids. Indole bases of P. peregrina (L.) Benth. and related species. J. Am. Chem. Soc., 77, 5892-5 164. Strassman, R. J., Quails, C. R., Uhlenhuth, E. and Kellner, R. (1994). Dose-response study of N,N-dimethyltryptamine in humans, II: Subjective effects and preliminary results of a new rating scale. Arch. Gen. Psychiatry, 51, 98-108 165. Strassman, R.J. and Quails, C. R. (1994). Dose-response study of N,N-dimethyltryptamine in humans, I: Neuroendocrine, autonomic, and cardiovascular effects. Arch. Gen. Psychiatry, 51, 85-97 166. Yanai, K., Ido, T., Ishiwata, K., Hatazawa, J., Takahashi, T., Iwata, R. and Matsuzawa, T. (1986). In vivo kinetics and displacement study of carbon-ll-labeled hallucinogen, N,N[ 11 C]dimethyltryptamine. Eur. J. Nucl. Med., 12, 141-6 167. Sangiah, S., Gomez, M. V. and Domino, E. F. (1979). Accumulation of N,Ndimethyltryptamine in rat brain cortical slices. Biol. Psychiatry, 14, 925-36 168. Sheldon, P. W. and Aghajanian, G. K. (1990). Serotonin (5-HT) induces IPSPs in pyramidal

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layer cells of rat piriform cortex: evidence for the involvement of a 5-HT 2 -activated interneuron. Brain Res., 506, 62-9 169. Lesch, K.-P., Sohnle, K., Poten, B., Schoellnhammer, G., Rupprecht, R. and Schulte, H. (1990). Corticotropin and Cortisol secretion after central 5-hydroxytryptamine-1A (5-HT 1 A ) receptor activation: Effects of 5-HT receptor and beta-adrenoceptor antagonists. J. Clin. Endocrinol. Metab., 70, 670-4 170. Delgado, P. L., Charney, D. S., Price, L. H., Landis, H. and Heninger, G. R. (1989). Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects. Life Sci ., 45, 2323-32 171. McKenna, D. J., Towers, G. H. N. and Abbott, F. (1984). Monoamine oxidase inhibitors in South American hallucinogenic plants: Tryptamine and ß-carboline constituents of ayahuasca. J. Ethnopharmacol., 10, 195-223 172. McKenna, D. J., Towers, G. H. N. and Abbott, F. (1984). Monoamine oxidase inhibitors in South American hallucinogenic plants Part 2: constituents of orally-active myristicaceous hallucinogens. J. Ethnopharmacol, 12, 179-211 173. Buckholtz, N. S. and Boggan, W. O. (1977). Monoamine oxidase inhibition in brain and liver produced by ß-carbolines: structure-activity relationships and substrate specificity. Biochem. Pharmacol, 26, 1991-6

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CHAPTE R 12

Hallucinogens as an aid in psychotherapy: basic principles and results
H . LEUNE R

This paper is a retrospective report on the research on LSD-aided psychotherapy performed between 1953 and 1972 before LSD therapy became illegal. Methodologically, the studies do not meet the standards of modern psychotherapy research. Consequently, this presentation can only have an orientational character. PSYCHEDELIC THERAPY 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 hallucinogenic 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:

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(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', 'inexpressibility' 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 understanding, 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. . . .

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Passage 2 This passage is taken from a tape recording of a therapy session with a 23-yearold 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 themselves 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 consciousness 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 evaluation 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

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Table 1 Publications on the application of psychedelic therapy. (From ref. 20, with permission) General discussions Chronic alcoholism Autistic children Cancer patients (including pain therapy) and euthanasia Addiction to narcotics Sexual perversion Total 7 22 5 4 1 1 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 BALTIMORE STUDIES 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 opportunity 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' psychodynamics. 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

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T scores

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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 completion 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 = psychopathology; 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 substantial 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.

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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 permission)

Percentage of patients with score > 8

70 60 50 40 30 20 10 0
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6
(n = 114)

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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)

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PSYCHOLYTIC THERAPY 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 contributors 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 accompanied 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.

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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, interspersed 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 . SYNOPTIC OVERVIEW OF RESULTS 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 Rank 1 2 3 4 5 6 7 8 Diagnoses Anxiety neuroses Irritable depression Character neuroses and sociopathies Borderline cases Perversions and homosexuality Compulsive neuroses Hysteria and conversion Dependency on alcohol and tablets Number of publications 9 4 10 4 7 10 2 6 Indications: very good/good (%) 70.0 62.0 61.0 53.0 50.0 42.0 31.5 31.0

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Table 3 Groups Group I Group II Group III Group IV Forms of application (after Mascher, 1967) 24 Number of cases * Applications 87 701 452 363 a single LSD session after intensive psychoanalytic preparation repeated LSD sessions combined with individual psychotherapy several LSD sessions combined with individual and group psychotherapy several LSD sessions, only in the group Clinical results: very good/good (%) 56.0 56.0 62.5 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 psychotherapy-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: improvement 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.

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THE GOTTINGEN STUDY 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).
130 120 110 100 90 80 Number of patients n = 83 70 60 50 40 30 20 10 0 n = 31 (24.4%) n = 44 n = 96 (75.6%)

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

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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 treatments, and also to their pathology, 77% of the patients were chronically ill and severely disturbed, and could not be treated with conventional psychotherapeutic methods. 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 demonstrated '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

Group variance of the sessions

2 (16-30)

36

23

3 (31-45)

50

38

4 (46-60)

37.2

52

5 (61-75)

27.4

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60

30 50 20 10 40 Improvement according to Boehm's Index (%)

0

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20 30 40 50 60 70 Average number of LSD sessions

80

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)

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4 3.56 3.6

4 3.84 3.7

Boehm's Index values

3.5

3 2.67 2.5 2.3 2
1.9

3

2.54 2.4 2.4

2.6

2.5

2.3

1.5

1

2

3

4

5

Groups 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

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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 therapy. 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 psychotherapy-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 psychotherapeutic 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. CONCLUSIONS 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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REFERENCES
1. Osmond, H. (1967). In Hoffer, A. and Osmond, H. The Hallucinogens, p. 132. (New York: Academic Press) 2. Josuttis, M. and Leuner, H. (1972). Religion und die Droge. (Stuttgart: Kohlhammer) 3. James, W. (1902). The Varieties of Religious Experience. (New York: Longmans Green) 4. Slotkin, J.S. (1956). The Peyote Religion. (Glencoe: Free Press) 5. Pahnke, W.N. (1962). Drugs and Mysticism. An Analysis of the Relationship between Psychedelic Drugs and the Mystical Consciousness. (Cambridge: Ph.D thesis, Harvard University) 6. Stace, W. T. (1961). Mysticism and Philosophy. (London: McMillan) 7. Dittrich, A. (1985): Aetiologie-unabhängige Strukturen veränderter Wachbewußtseinszustände. Ergebnisse empirischer Untersuchungen über Halluzinogene I. und II. Ordnung, sensorische Deprivation, hynagoge Zustände, hypnotische Verfahren sowie Reizüberflutung. (Stuttgart: Enke) 8. Maslow, A. H. (1964). Religions, Values and Peak-experience. (Columbus: Ohio State University Press) 9. Bolle, R.H. (1964). Ursprung der Sehnsucht. (Berlin: Verlag Wissenschaft und Bildung) 10. Shulgin, A. T. and Carter, M. F. (1975). Centrally active phenethylamides. Psychopharmacol. Commun., 1, 93-8 11. Janus, L. (1986). Vorgeburtliche Lebenszeit und Geburtserleben. (Heidelberg: Bischoff) 12. Fedor-Freyberg, P. and Vogel, M. L. V. (eds.). (1987). Prenatal and Perinatal Psychology and Medicine: Encounter with the Unborn. (Carnforth, UK: Parthenon Publishing) 13. Grof, S. (1985). Beyond the Brain. Birth, Death and Transcendence in Psychiatry. (Albany: State University of New York Press) 14. Josuttis, M. and Leuner, H. (1972). Religion und die Droge. (Stuttgart: Kohlhammer) 15. Hübner, K. (1985). Die Wahrheit des Mythos. (München: C. H. Beck'sche Verlagsbuchhandlung) 16. Pahnke, W. N., Kurland, A. A., Unger, S., Savage, Ch. and Grof, St. (1970). The experimental use of psychedelic (LSD) psychotherapy.J. Am. Med. Assoc., 212, 1856 17. Pahnke, W. N., Kurland, A. A., Unger, S., Savage, Ch., Wolfe, S. and Goodman, L. E. (1970). Psychedelic therapy (utilizing LSD) with cancer patients. J. Psychedelic Drugs, 3, 63 18. Kurland, A. A., Savage, C., Pahnke, W., Grof, St. and Olssen, J. E. (1971). LSD in the treatment of alcoholics. Pharmacopsychiatra, 4, 83 19. Hofmann, A. (1955). Die Geschichte des LSD-25. Triangel, 2, 117 20. Caldwell, W. V. (1968). LSD Psychotherapy. (New York: Grove Press) 21. Sandison, R. A., Spencer, A. M. and Whitelaw, J. D. A. (1954). The therapeutic value of lysergic acid diethylamide in mental illness. J. Ment. Sci ., 100, 491 22. Leuner, H. (1984). Guided Affective Imagery. (New York: Thieme-Stratton Inc.) 23. Leuner, H. (1959). Psychotherapie in Modellpsychosen. In Speer, E. (ed.) Kritische Psychotherapie. (München: Lehmann) 24. Mascher, E. (1967). Psycholytic therapy: statistics and indications. In Brill, H., Cole, J. O., Hippius, H. and Bradley, P. B. (eds.) Neuropsychopharmacology. (Amsterdam: Excerpta Medica Foundation) 25. Leuner, H. (1967). Present state of psycholytic therapy and its possibilities. In Abramson, A. (ed.) The Use of LSD in Psychotherapy and Alcoholism, pp. 101-16. (New York: Bobbs-Merrill) 26. Arendsen-Hein, G. W. (1963). Psychotherapeutische Möglichkeiten zur Überwindung einer Behandlungsresistenz unter Berücksichtigung der psycholytischen Methode. Z. Psychother. Med. Psychol, 13, 81 27. Fontana, A. (1961). El uso clinico de las drogas alucinogenas. Acta Neuropsychiatr. Argent., 7, 94 28. Leuner, H. (1965). Effects of psychotomimetic drugs. In Kline, H. S. and Lehmann, H. E. (eds) Psychopharmacology. International Psychiatric Clinics, Vol. 2. No. 4, pp. 214-36. (Boston: Little Brown)

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29. Mascher, E. (1966). Katamnestische Untersuchungen von Ergebnissen der psycholytischen Therapie. (Göttingen: Unpublished Medical Dissertation) 30. Morales, F. P. (1963). El LSD-25 en psicoterapia I, II. Acta Psiciat. Psicol. Amer. Lat., 9, 136 31. Morales, F. P. (1963). El LSD-25 en psicoterapia III. Acta Neuropsiquiat. Argent., 9, 228 32. Hausner, M. and Dolezal, V. (1963). Catamnestic evaluation of results of psychotherapy combined with LSD. Activ. Ner. Sup. (Prague), 5, 215 and 7, 308 33. Leuner, H., Mascher, E. and Schultz-Wittner, Th. (1992). Die Effiziens der durch psychoaktive Substanzen gestützten Psychotherapie (psycholytische Behandlung). In Leuner, H. and Schlichting, M. (eds) Jahrbuch des Europäischen Collegiums für Bewußtseinsstudien 1992. (Berlin: Verlag für Wissenschaft und Bildung) 34. Boehm, F. (1942). Erhebung und Bearbeitung von Katamnesen. Zentralblatt Psychotherapie, 14, 17 35. De Cortiis, T. A. (1978). A critique and suggested revision of behaviorally anchored rating scales developmental procedures. Educational and Psychological Measurement, 38, 681 36. Bortz, J. (1984). Lehrbuch der Empirischen Forschung. (Berlin: Springer) 37. Leary, T. (1964). The religious experience: its production and interpretation. Psychedelic Rev., 1, 325 38. Meyer, A. E., Richter, R., Grawe, K., Graf, V. D. and Schulenburg, Schulte, B. (1991). Forschungsgutachten zu Fragen eines Psychotherapeutengesetzes, p.29. (Hamburg-Eppendorf: University Krankenhaus)

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CHAPTE R 13

Perspectives on LSD and psychotherapy: the search for a new paradigm
R . YENSEN

INTRODUCTION 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. HISTORY 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.

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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 . SOCIAL MOVEMENT AND LEGISLATIVE RESPONSE Cleansed of past condemnations, LSD was born into a brave new world. Midtwentieth 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

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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. HERMENEUTICS OF SCIENCE 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 allencompassing 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. SHAMANIC PARADIGM 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.

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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 subgroup, 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 world. 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, ingeniously, 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 DRUG PARADIGM: EFFECTS ON RESEARCH 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

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

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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 . PSYCHEDELIC PARADIGM 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:

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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 direction. 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 phenomenon 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 perception 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.

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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 effects. 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 measurement 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

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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 timeless 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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REFERENCES
1. Hoffman, A. J. and Nichols, D. E. (1987). Synthesis and LSD-like discriminative stimulus properties of d-lysergic acid diethylamide (LSD). Psychopharmacology, 91, 67-93 2. Furst, P. T. (1972). Flesh of the Gods - the Ritual Use of Hallucinogens. (New York: Praeger Publishers) 3. Hofmann, A. (1980). LSD: My Problem Child. (New York: McGraw-Hill) 4. Wasson, R. G. (1980). The Wondrous Mushroom. (New York: McGraw-Hill) 5. Wasson, R. G., Ruck, C. A. and Hofmann, A. (1978). The Road to Eleusis - Unveiling the Secret of the Mysteries. (New York: Harcourt Brace Jovanovich) 6. Tjio, J. H., Pahnke, W. N. and Kurland, A. A. (1969). LSD and chromosomes. J. Am. Med. Assoc., 210, 849-56 7. McGlothlin, W. H. and Arnold, D. O. (1971). LSD revisited. A ten-year follow-up of medical LSD use. Arch. Gen. Psychiatry, 24, 35-49 8. Dahlberg, C. C., Mechaneck, M. A. and Feldstein, S. (1968). LSD research: the impact of lay publicity. Am. J. Psychiatry, 125, 685-9 9. Schuhes, R. E. and Hofmann, A. (1979). Plants of the Gods: Origins of Hallucinogenic Use. (New York: McGraw-Hill) 10. Kuhn, T. S. (1970). The Structure of Scientific Revolutions. (Chicago: University of Chicago Press) 11. Hofstadter, D. R. (1979). Gödel, Escher, Bach: An Eternal Golden Braid. (New York: Basic Books) 12. La Barre, W. (1972). Hallucinogens and the shamanic origins of religion. In Fürst, P. T. (ed.) Flesh of the Gods - the Ritual Use of Hallucinogens, pp. 261-78. (New York: Praeger Publishers) 13. Busch, A. K. and Johnson, W. C. (1950). LSD-25 as an aid in psychotherapy. Dis. Nerv. Sys. 11, 243 14. Frederking, W. (1953). Ueber die Verwendung von Rauschdrogen (Meskalin und Lysegsaurediaethylamid) in der Psychotherapie. Psyche, 7, 342 15. Sandison, R. A. and Whitelaw, J. D. A. (1954). The therapeutic value of LSD in mental illness. J. Ment. Sci. 100, 491-507 16. Abramson, H. A. (1967). The Use of LSD in Psychotherapy and Alcoholism. (New York: Bobbs Merrill) 17. Butterworth, A. T. (1962). Some aspects of an office practice using LSD-25. Psychiatric Q. 36, 734-53 18. Chandler, A. and Hartman, M. (1960). LSD-25 as a facilitating agent in psychotherapy. Arch. Gen. Psychiatry, 2, 286-99 19. Eisner, B. G. and Cohen, S. (1958). Psychotherapy with LSD J. Nerv. Ment. Dis. 127, 528-39 20. Frederking, W. (1955). Intoxicant drugs (mescaline and lysergic acid diethylamide) in psychotherapy. J. Nerv. Ment. Dis. 121, 262-6 21. Ling, T. M. and Buckman, J. (1960). The use of LSD in individual psychotherapy. Proc. R. Soc. Med. 53, 927-9 22. Martin, A. J. (1957). LSD treatment of chronic psychoneurotic patients under day hospital conditions. Int. f. Social Psychiatry 3, 188-95 23. Rolo, A., Krinsky, L. W., Abramson, H. A. and Goldfarb, L. (1964). Multitherapist interviews utilizing LSD. J. Psychol. 58, 237-9 24. Sandison, R. A. and Whitelaw, J. D. A. (1957). Further studies in the therapeutic value of LSD in mental illness. J. Ment. Sci. 103, 332-43 25. Osmond, H. (1969). Psychedelic drugs in the treatment of alcoholism. In Hicks, R. E. and Fink, P. J. (eds.) Psychedelic Drugs: Proceedings of a Hahneman Medical College and Hospital Symposium sponsored by the Department of Psychiatry, pp. 217-25. (New York: Grune and Stratton)

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26. Osmond, H. (1957). A review of the clinical effects of psychotomimetic agents. Ann. N. Y. Acad. Sci ., 66, 418-34 27. Yensen, R. (1989). From mysteries to paradigms: humanity's journey from sacred plants to psychedelic drugs. In Rätsch, C. (ed.) Gateway to Inner Space: Sacred Plants, Mysticism and Psychotherapy, pp. 11-53. (Dorset: Prism Press) 28. Berendes, M. (1979). Formation of typical dynamic stages in psychotherapy before and after psychedelic drug intervention. J. Altered States of Consciousness, 5, 325-38 29. Cholden, L. S., Kurland, A. A. and Savage, C. (1955). Clinical reactions and tolerance to LSD in chronic schizophrenia. J. Nerv. Merit. Dis., 122, 211-21 30. Grof, S., Goodman, L. E. and Kurland, A. A. (1973). LSD-assisted psychotherapy in patients with terminal cancer. Int. Pharmacopsychiatry, 8, 129-44 31. Grof, S., Soskin, R. A., Richards, W. A. and Kurland, A. A. (1973). DPT as an adjunct in psychotherapy of alcoholics. Int. Pharmacopsychiatry, 8, 104-15 32. Harari, C. and Kashoff, S. A. (1972). Guided psychedelic experience: subjective report. Voices: The Art and Science of Psychotherapy, 8, 45-59 33. Kurland, A. A., Savage, C., Pahnke, W. N., Grof, S. and Olsson, J. E. (1971). LSD in the treatment of alcoholics. Pharmakopsychiatrie Neuro-Psychopharmakologie, 4, 83-94 34. Kurland, A. A., Unger, S., Shaffer, J. W. and Savage, C. (1967). Psychedelic therapy utilizing LSD in the treatment of the alcoholic patient: a preliminary report. Am. J. Psychiatry, 123, 1202-9 35. McCabe, O. L., Savage, C., Kurland, A. A. and Unger, S. (1972). Psychedelic (LSD) therapy of neurotic disorders: short term effects. J. Psychedelic Drugs, 5, 18-28 36. Pahnke, W. N., Kurland, A. A., Goodman, L. E. and Richards, W. A. (1969). LSD-assisted psychotherapy with terminal cancer patients. In Hicks, R. E. and Fink, P. J. (eds) Psychedelic Drugs, pp. 33-42. (New York: Grune and Stratton) 37. Pahnke, W. N., Kurland, A. A., Unger, S., Savage, C. and Grof, S. (1970). The experimental use of psychedelic (LSD) Psychotherapy. J. Am. Med. Assoc., 212, 1856-63 38. Pahnke, W. N., Kurland, A. A., Unger, S., Savage, C., Wolf, S. and Goodman, L. E. (1970). Psychedelic therapy (utilizing LSD) with cancer patients. J. Psychedelic Drugs, 3, 63-75 39. Rhead, J. C., Soskin, R. A., Turek, I., Richards, W. A., Yensen, R., Kurland, A. A. and Ota, K. Y. (1977). Psychedelic drug (DPT)-assisted psychotherapy with alcoholics: a controlled study. J. Psychedelic Drugs, 9, 287-300 40. Richards, W. A. and Berendes, M. (1977). LSD-assisted psychotherapy and dynamics of creativity: a case report. J. Altered States of Consciousness, 3, 131-46 41. Richards, W. A., Rhead, J. C., Di Leo, F. B., Yensen, R. and Kurland, A. A. (1977). The peak experience variable in DPT-assisted psychotherapy with cancer patients. J. Psychedelic Drugs, 9, 1-10 42. Richards, W. A., Rhead, J. C., Grof, S., Goodman, L. E., Di Leo, F. B. and Rush, L. (1979). DPT as an adjunct in brief psychotherapy with cancer patients. Omega, 10, 9-26 43. Savage, C. and McCabe, O. L. (1973). Residential psychedelic (LSD) therapy for the narcotic addict: a controlled study. Arch. Gen. Psychiatry, 28, 808-14 44. Savage, C. (1969). Psychedelic therapy. Res. Psychother., 3, 512-20 45. Savage, C., Hughes, M. A. and Mogar, R. (1967). The effectiveness of psychedelic (LSD) therapy: a preliminary report. Br.J. Soc. Psychiatry, 2, 59-66 46. Savage, C., McCabe, O. L., Kurland, A. A. and Hanlon, T. (1973). LSD-assisted psychotherapy in the treatment of severe chronic neurosis. J. Altered States of Consciousness, 1, 31-47 47. Soskin, R. A., Grof, S. and Richards, W. A. (1973). Low doses of dipropyltryptamine in psychotherapy. Arch. Gen. Psychiatry, 28, 817-21 48. Turek, I. S., Soskin, R. A. and Kurland, A. A. (1974). Methylenedioxyamphetamine (MDA) subjective effects. J. Psychedelic Drugs, 6, 7-13

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49. Yensen, R., Di Leo, F. B., Rhead, J. C., Richards, W. A., Soskin, R. A., Turek, B. and Kurland, A. A. (1976). MDA-assisted psychotherapy with neurotic outpatients: a pilot study. J. Nerv. Ment. Dis., 163, 233-45 50. Pahnke, W. N. (1963). Drugs and Mysticism: An Analysis of the Relationship Between Psychedelic Drugs and Mystical Consciousness. Doctoral Dissertation (Harvard University)

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CHAPTE R 14

Psychotherapeutic effects
R . RICHTER

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 WorkingThrough. 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

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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 supportive 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

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psychotherapy that should be considered systematically. Again, Godfrey 7 can be quoted:
My conclusion . . . is that as medical . . . scientists we must dedicate ourselves first, and continuously 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 dysfunctions. 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

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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 neurotic 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 resolution, 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 considered 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 psychotherapy (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, sociopathic 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, diminishing 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 intercourse that were part of the treatment. In most of the studies, either the dependent

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Table 1 Number of publications on LSD and psychotherapy, 1965-1991 (source: Medline and Psyndex) Year 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 Publications 3 8 6 10 7 5 6 4 7 0 0 1 2 3 Year 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 Publications 3 1 0 0 2 0 2 1 0 0 0 0 1

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 criticism 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 cases.

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.

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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

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used questionnaires and interview techniques, have never been replicated subsequently, 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

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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 (methylenedioxyamphetamine) demonstrates (see Chapter 7). Recently, I asked the Bundesgesundheitsamt, 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 psychotherapeutic process and outcome of their actual and former patients and to ask these patients to participate in this follow-up study. This would involve completion of questionnaires which have been proven useful for recording psychotherapeutic 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. REFERENCES
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

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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: Huber) 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.) 'Beivußtseinserweiternde' 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 psychotomimetics. 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 Psychotherapie. In Dittrich, A. and Scharfetter, C. (eds.) Ethnopsychotherapie, pp. 151-61 (Stuttgart: Enke)

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CHAPTE R 15

Methodological issues in the evaluation of a medication for its potential benefits in enhancing psychotherapy
C . P . O'BRIE N AND R . T . JONE S

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 completely 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 scientists 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 apparent 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

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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 technology 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 conducive 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 disorders 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 ESSENTIALS OF AN ADEQUATE STUDY 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.

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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 supervision measure 'dose' of psychotherapy Objective 'blind' raters Importance of follow-up

Ample precedent exists for the evaluation of complex treatment methods. Psychotherapy itself was once thought to be too complicated for objective and quantitative evaluation. More recently there have been double-blind studies of neuroelectrostimulation for the treatment of opiate withdrawal 4 . Ongoing studies are evaluating acupuncture treatment for various disorders 5 . There are studies of antidepressant medication 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 diagnostic 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 characterized 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. Diagnosis according to standard diagnostic criteria ideally should be applied by an observer who is not one of the therapists in the study. SEVERITY OF ILLNESS MEASURES The same objectivity should be applied to severity measures. Simply having the same diagnosis does not impart the same prognosis. Prognosis depends on many

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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 psychotherapy seem to be subjects who have a good intellect and adequate interpersonal 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 achievements and enjoy them'. Of course, patients who fit that description would probably 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 instrument 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 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 associated 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 subjects 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 perspective of an independent committee charged with protecting human subjects, reports such as those of Abraham 1 9 must be considered. These reports of persistent 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.

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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. PLACEBO CONTROL GROUP 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 diagnosis 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 medication. 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 treatment, after which the computer program automatically decreased the stimulation

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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 sometimes 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 enthusiastic proponents of the stimulation treatment suggested that a few seconds of stimulation 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 sideeffect 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 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

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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. STANDARDIZED PSYCHOTHERAPY 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 independent judge. In effect, the 'dose' of psychotherapy must also be quantified as carefully 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. OBJECTIVE BLIND RATERS 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

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psychological symptoms associated with their substance abuse. Such a result would be an important finding, even if there were no differences in relapse to substance abuse. PUBLIC HEALTH CONSIDERATIONS There appears to be much less controversy about research involving hallucinogenic 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 responsibility 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 principles that must be followed if the results of a study in this area are to gain acceptance 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. REFERENCES
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 Treatment 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

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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, 639-45 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 diagnostic 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 findings. 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 psychotic 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 diethylamide. Addiction, 88, 1327-34 19. Abraham, H. D. (1983). Visual phenomenology of the LSD flashback. Arch. Gen. Psychiatry, 40, 884-9 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 psychiatric clinical trials. Neuropsychopharmacology, 7, 85-92

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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 discovered 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 conference, 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?

TOPICS OF CONTROVERSY LSD was used to develop new insights into the mechanisms of nerve cell transmission, 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

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

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CONCLUSIONS

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. NEUROBIOLOGY 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 phenethylamine 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. CLINICAL RESEARCH 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

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advances in serotonin receptor physiology. In addition, a new psychopharmacological 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 psychological 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 conditions demonstrated clearly the localization of possible points of attack of the drug. The mescaline effect could be located in the frontal cortical region, especially 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). Hyperfrontality 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 nonsubstance-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 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:

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CONCLUSIONS

(1)

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

(2) Use of standardized instruments for measuring psychopathology; (3) (4) Specification of variables concerning therapist and environment; Operationalization of outcome variables; and

(5) Description of adverse effects. New psychotherapy research protocols, suitable for the study of how hallucinogens 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-methylenedioxymethylamphetamine (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 . CONCLUSION 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

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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, anxietysyndromes, 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 cooperation, 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. REFERENCES
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 Basel

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APPENDIX: LIST OF INVITED PARTICIPANTS
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, USA 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, Switzerland W. Böker, Psychiatrische Universitätsklinik Bern, Bollingenstrasse 111, CH-3072 Ostermundigen, Switzerland R. Brenneisen, Pharmazeutisches Institut der Universität Bern, Baltzerstrasse 5, CH-3012 Bern, Switzerland D. Bourquin, Pharmazeutisches Institut der Universität Bern, Baltzerstrasse 5, CH-3012 Bern, Switzerland A. Calanca, Clinique psychiatrique universitaire, Hopital de Cery, CH-1008 Prilly-Lausanne, Switzerland 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 PrillyLausanne, 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, USA H. U. Fisch, Psychiatrische Universitäts-Poliklinik Bern, Murtenstrasse 21, CH-3010 Bern, Switzerland 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

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50 YEARS OF LSD
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, Switzerland 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, Switzerland L. Hösli, Department of Physiology, University of Basel, Vesalgasse 1, CH-4051 Basel, Switzerland 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, Switzerland 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, Austria 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, Switzerland 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, Switzerland 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

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PARTICIPANTS
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, USA A. Pletscher, Chairman, Program Committee of the SAMS-Symposium 1993 on LSD, Schweizerische Akademie der medizinischen Wissenschaften, Petersplatz 13, CH-4051 Basel, Switzerland W. Pöldinger, Psychiatrische Universitätsklinik, Wilhelm Klein-Strasse 27, CH-4025, Basel, Switzerland J. Püschel, Psychiatrische Universitätsklinik, Postfach 68, CH-8029 Zürich, Switzerland R. Richter, Sektion Psychoanalytische Methodik, Abteilung Psychotherapie, Universität UlmKlinikum, Am Hochsträss 8, D-89081 Ulm, Germany L. Rivier, Institut universitaire de médecine légale, 21 rue du Bugnon, CH-1005 Lausanne, Switzerland M. Smrekar, Redaktion GAIA, Münsterplatz 6, CH-4051 Basel, Switzerland O. Smrekar, AMI - Analytical Methods and Instrumentations, Münsterplatz 6, CH-4051 Basel, Switzerland A. Springer, Ludwig Boltzmann-Institut für Suchtforschung, Mackgasse 7-9, A-1237 Wien, Austria 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, Switzerland R. Stohler, Psychiatrische Universitätsklinik, Wilhelm Klein-Strasse 27, CH-4025, Basel, Switzerland J. Strang, The Bethlem Royal Hospital, Department of Psychiatry, Addiction Research Unit, National Addiction Centre, Addiction Sciences Building, 4 Winsor Walk, London SE5 8AF, UK 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. 3.2.2Psychotherapie 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

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

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50 YEARS OF LSD
Claviceps paspali in holy potion of Eleusis 15 Claviceps purpurea ergot as source of LSD 7, 8, 43 consent, informed significance in psychotherapeutic studies 216-217 Convolvulaceae (morning glory) in ololiuqui 14 Coramine 10 structure of 15 cortico-striato-thalamo-cortical (CSTC) feedback loops 70-71 and schizophrenia 69-72 control of cortical information processing 68-69 hallucinogen effects on 69-72 cultural aspects of LSD 121-129 and legislation 193-194 Delphi, oracle of and hallucinogens 45 derealization, during model psychoses 61 diacylglycerol in phosphoinositide second-messenger pathway 35 N,N-dimethyltryptamine (DMT) endogenous 156-157 in hallucinogenic drinks and snuffs 47, 49 psychopharmacology 145-165 human studies 157-163 tolerance 156 structure of 3, 46 study of induced psychosis 113-115 dopamine hypothesis of schizophrenia 68 CSTC loop model 69-72 dopaminergic neurotransmission and behavioral pharmacology of hallucinogen responses 153-154 changes during altered states of consciousness 69 dosage, in LSD therapy 136-137 dread of ego-dissolution, subscale of APZ questionnaire 77, 106-111 items 107 drinks, hallucinogenic 47 ebena, hallucinogenic snuff 47 'Ecstacy' see 3,4-methylenedioxymethamphetamine Eleusis, mysteries of 14-16, 53 ergobasin (lysergic acid propanolamide) 8 structure of 10, 15 synthesis of 9-10 ergometrine 8 structure of 10 ergonovine 8 structure of 10 ergot Claviceps paspali, and mysteries of Eleusis 15 Claviceps purpurea, as source of LSD 7-10 ergot alkaloids 8-10 ergotamin isolation 8 ethnopharmacology 43-54 facial nucleus hallucinogen effects 29-32, 33, 35, 36 mediation by 5-HT 2 receptors 29, 32-33 5-HT-induced excitation 29-32 role of protein kinase 35, 36 fly-agaric (Amanita muscaria) ritualistic use 44 forskolin-stimulated adenylate activity LSD effects related to 5-HTi receptors
22

frontal cortex, sensory overload in psychoses 68-69 in schizophrenia 80-83 G proteins and 5-HT receptors 19, 20 5-HT 2 receptor response mediation 34, 37-38 LSD interactions 22 in facial nucleus 32 glucose metabolism, cerebral in psychoses 67-68 ketamine effects 72-82 psilocybin effects 72-77, 80-82 glutamate deficiency hypothesis of schizophrenia 72 glutamatergic neurotransmission and hyperfrontality 82-83 changes in psychoses 69

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INDEX
ketamine and PCP effects on 79-80 Gottingen study 184-187 Hallucinogen Rating Scale (HRS) development 158 hallucinogenic preparations 47-48 hallucinogens early approaches to research 147-150 studies with psychiatrically ill patients 149 evaluation of clinical effects 135-143 origins of use 44 harmaline 46 harmine 46 in hallucinogenic drinks and snuffs 47 structure of 46 history of discovery of LSD 7-16 5-HT and behavioral pharmacology of hallucinogen responses 150-152 and phosphoinositide second-messenger pathway 35 and schizophrenia 72 levels, and LSD 19 neurophysiological effects in cerebral cortex 33-34 in facial nucleus 30-32 non-hallucinogenic 5-HT agonists psychopharmacology 153 structure of 15 5-HT receptors 5-HTi receptors characteristics 22 hallucinogen interactions 37 phylogenetic relationships 20-21 5-HT 2 receptors and phosphatidylinositol (PI) turnover 22-23, 35 and schizophrenia 72 common action of hallucinogens 28 electrophysiology in cerebral cortex 32-34 LSD interactions 22-23 mediation of hallucinogen responses 37 in facial nucleus 29, 32, 33 in locus coeruleus 29 mechanisms 37-39 phylogenetic relationships 20-21 psilocybin effects on 80 response mediation by G proteins 34 signal transduction mechanisms 37-38 5-HT5 receptors characteristics 23-24 phylogenetic relationships 20-21 5-HT 6 receptors and adenylate cyclase stimulation 24 phylogenetic relationships 20-21 5-HT 7 receptors characteristics 24 phylogenetic relationships 20-21 multiplicity of receptor types 19-25 phylogenetic tree 20-21 5-hydroxy-indoleacetic acid (5-HIAA) levels, and LSD 19 5-hydroxytryptamine see 5-HT hyperfrontality in psychotic states 68, 73-83 mescaline effects 81-82, 96 ibogaine, potential uses 165 indoleamine hallucinogens and 5-HT 2 receptors 28, 35, 37-39 effects on raphe nuclei 27 electrophysiological actions 27-39 information processing imbalance during altered states of consciousness 67-83 role of CSTC loops 68-69 inhibitory postsynaptic potentials (IPSPs) 5-HT effects in cerebral cortex 33 inositol trisphosphate (IP3) in phosphoinositide second-messenger pathway 35 International Study on Altered States of Consciousness (ISASC) 105 ketamine psychosis induction 68 mechanisms 72 effects on cerebral energy metabolism 72-82 implications for schizophrenia 80-83 mechanisms 77-80 kykeon, holy potion of Eleusis 15 legislation and LSD 193-194 locus ceruleus

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

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

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

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