Psilocybin Scientific Papers

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Psilocybin is a naturally occurring compound categorized as a psychoactive tryptamine that is found in some species of mushrooms. These mushrooms have ...
AEDMP Asociación para el Estudio y la Divulgación de la Medicina Psicodélica

Psilocybin Scientific Papers -2014Asociación para el Estudio y la Divulgación de la Medicina Psicodélica. Castellarnau, 11 2º 1ª 43004 Tarragona Spain Tel. 675 55 33 44 Email: [email protected] www.medicinapsicodelica.org Research conducted by: Fco. Miguel Ríos & Genís Oña

Content _____________________________________ 1. What is Psilocybin? 2. Scientific papers about Psilocybin arranged chronologically (1959-2014) -

A. Hofmann (1959). Chemical Aspects of Psilocybin, the Psychotropic Principle from the Mexican Fungus, Psilocybe Mexicana Heim

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S. Malitz et al. (1960). Some Observations on Psilocybin, a New Hallucinogen, in Volunteer Subjects

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L. E. Hollister (1961). Clinical, Biochemical and Psychologic Effects of Psilocybin

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M. Rinkel et al. (1961). Personality Patterns and Reaction to Psilocybine

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T. Leary et al. (1963). Reactions to Psilocybin Administered in a Supportive Environment

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J. Delay et al. (1963). The Therapeutic Implications of Psilocybine

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J. S. Da Fonseca et al. (1965). Evoked Potentials and Visual Information Processing Under the Action of Psilocybin in the Cat

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J. R. Flores (1965). Psicosíndrome Experimental con Psilocibina

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M. H. Keeler (1965). The Effects of Psilocybin on a Test of After-image Perception

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R. Metzner et al. (1965). The Relation of Expectation and Mood to Psilocybin Reactions: A Questionnaire Study

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R. Fischer & D. Warshay (1968). Psilocybin-induced Autonomic, Perceptual, and Behavioral Change

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O. Tosi et al. (1968). Quantitative Measurement of Time Contraction Induced by Psilocybin

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B. Clark (1968). Some Early Observations on the Use of Psilocybin in Psychiatric Patients

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R. Fischer et al. (1969). Effects of the Psychodysleptic Drug Psilocybin on Visual Perception. Changes in Brightness Preference

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P. H. Gwynne et al. (1969). Hypnotic Induction of the Interference of Psilocybin with Optically Induced Spatial Distortion

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K. Thatcher et al. (1971). An Electroencephalographic Analysis of Personality-dependent Performance Under Psilocybin

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R. M. Hill & R. Fischer (1973). Induction and Extinction of Psilocybin Induced Transformations of Visual Space

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C. Martindale & R. Fischer (1977). The Effects of Psilocybin on Primary Process Content in Language

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N. R. Peden et al. (1981). Clinical Toxicology of “Magic Mushrooms” Ingestion

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J. Koerner & J. B. Appel (1982). Psilocybin as a Discriminative Stimulus: Lack of Specificity in an Animal Behavior Model for “Hallucinogens”

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R. Doblin (1991). Pahnke’s “Good Friday Experiment”: A Long-term Follow-up and Methodological Critique

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M. Spitzer et al. (1996). Increased Activation of Indirect Semantic Associations Under Psilocybin

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F. X. Vollenweider et al. (1997). Positron Emission Tomography and Fluorodeoxyglucose Studies of Metabolic Hyperfrontality and Psychopathology in the Psilocybin Model of Psychosis

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R. Doblin (1998). Dr. Leary’s Concord Prison Experiment: A 34-Year Follow-up Study

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F. X. Vollenweider et al. (1998). Psilocybin Induces Schizophrenia-like Psychosis in Humans Via a Serotonin-2 Agonist Action

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K. S. Borowiak et al. (1998). Psilocybin Mushroom (Psilocybe semilanceata) Intoxication with Myocardial Infarction

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E. Gouzoulis-Mayfrank et al. (1999). Effects of the Hallucinogen Psilocybin on Habituation and Prepulse Inhibition of the Startle Reflex in Humans

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G. Sticht & H. Käferstein (2000). Detection of Psilocin in Body Fluids

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T. H. Lim et al. (2002). A Fatal Case of “Magic Mushroom” Ingestion in a Heart Transplant Recipient

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E. Gouzoulis-Mayfrank et al. (2002). Effects of the Hallucinogen Psilocybin on Covert Orienting of Visual Attention in Humans

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T. Passie et al. (2002). The Pharmacology of Psilocybin

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F. Hasler et al. (2004). Acute Psychological and Physiological Effects of Psilocybin in Healthy Humans: A Double-blind, Placebo-controlled Dose-effect Study

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O. L. Carter et al. (2004). Psilocybin Impairs High-level but not Low-level Motion Perception

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M. Espiard et al. (2005). Hallucinogen Persisting Perception Disorder After Psilocybin Consumption: A Case Study

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O. L. Carter et al. (2005). Modulating the Rate and Rhythmicity of Perceptual Rivalry Alternations with the Mixed 5-HT2A and 5-HT1A Agonist Psilocybin

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O. L. Carter et al. (2005). Using Psilocybin to Investigate the Relationship Between Attention, Working Memory, and the Serotonin 1A and 2A Receptors

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R. R. Griffiths et al. (2006). Psilocybin can Occasion Mystical-type Experiences Having Substantial and Sustained Personal Meaning and Spiritual Significance

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R. A. Sewell et al. (2006). Response of Cluster Headache to Psilocybin and LSD

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M. Wittmann et al. (2007). Effects of Psilocybin on Time Perception and Temporal Control of Behavior in Humans

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O. L. Carter et al. (2007). Psilocybin Links Binocular Rivalry Switch Rate to Attention and Subjective Arousal Levels in Humans

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C. S. Grob (2007). The Use of Psilocybin in Patients with Advanced Cancer and Existential Anxiety

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J. Wackermann et al. (2008). Effects of Varied Doses of Psilocybin on Time Interval Reproduction in Human Subjects

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R. R. Griffiths et al. (2008). Mystical-type Experiences Occasioned by Psilocybin Mediate the Attribution of Personal Meaning and Spiritual Significance 14 Months Later

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C. S. Grob et al. (2010). Pilot Study of Psilocybin Treatment for Anxiety in Patients with Advancedstage Cancer

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R. L. Carhart-Harris et al. (2010). The Administration of Psilocybin to Healthy, Hallucinogenexperienced Volunteers in a Mock-functional Magnetic Resonance Imaging Environment: A Preliminary Investigation of Tolerability

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E. Studerus et al. (2011). Acute, Subacute and Long-term Subjective Effects of Psilocybin in Healthy Humans: A Pooled Analysis of Experimental Studies

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J. van Amsterdam et al. (2011). Harm Potential of Magic Mushroom Use: A Review

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K. A. MacLean et al. (2011). Mystical Experiences Occasioned by the Hallucinogen Psilocybin Lead to Increases in the Personality Domain of Openness

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R. R. Griffiths et al. (2011). Psilocybin Occasioned Mystical-type Experiences: Immediate and Persisting Dose-related Effects

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B. B. Quednow et al. (2011). Psilocybin-induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers

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R. L. Carhart-Harris et al. (2012). Implications for Psychedelic-assisted Psychotherapy: Functional Magnetic Resonance Imaging Study with Psilocybin

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R. L. Carhart-Harris et al. (2012). Neural Correlates of the Psychedelic State as Determined by fMRI Studies with Psilocybin

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E. Studerus et al. (2012). Prediction of Psilocybin Response in Healthy Volunteers

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M. Kometer et al. (2012). Psilocybin Biases Facial Recognition, Goal-directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors

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M. W. Johnson et al. (2012). Psilocybin Dose-dependently Causes Delayed, Transient Headaches in Healthy Volunteers

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B. J. Catlow et al. (2013). Effects of Psilocybin on Hippocampal Neurogenesis and Extinction of Trace Fear Conditioning

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R. L. Carhart-Harris et al. (2013). Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

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C. Cummins & J. Lyke (2013). Peak Experiences of Psilocybin Users and Non-users

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F. Tyls et al. (2014). Psilocybin – Summary of Knowledge and New Perspectives

What is Psilocybin? ______________________________________ Psilocybin is a naturally occurring compound categorized as a psychoactive tryptamine that is found in some species of mushrooms. These mushrooms have been used for thousands of years by various cultures in order to achieve transcendent states of consciousness. In the 1960s, psilocybin was widely used in the experimental research of mental disorders and even in psychotherapy due to its therapeutic potential. However, psilocybin spread amongst the general public and became a popular recreational drug. Consequently, psilocybin was classed as a schedule I drug in 1970 and all human experiments were gradually discontinued. Since the 1990s, psychedelic research is being revived, and the properties of this substance have been rediscovered, becoming one of the most used psychedelics in human studies due to its safety.

Scientific papers about Psilocybin arranged chronologically

_.!-

200/III 60 PSI___52/(LSD) Oesamtl.546/Vari_ Chemie

Reprint_d/romNeuro-Psychopharmacology

Neuro-Psychopharmacology. Proceedings of the 1st International Congress of NeuroPsychopharmacology, Rome, September 1958. Ed. by: P.B. Bradley, P. Deniker, C. Radouco-Thomas. iElsevier, Amsterdam, London, New York, Princeton 1959, p. 446-448.

CHEMICAL THE MEXICAN

ASPECTS

PSYCHOTROPIC FUNGUS,

OF PSILOCYBIN, PRINCIPLE

PSILOCYBE

FROM

MEXICANA

THE HEIM

A. HOFMANN Pharmaceutical

Laboratories,

Sandoz

Ltd.,

Basle

(Switzerland)

Since the pre-Columbian era, the Indians of Mexico have made the eating of certain fungi a part of their religious rites; tribal soothsayers ate such fungi to acquire clairvoyance. An American ethnologist, R. GORDO_ WASSON, and his wife, made several mtpeditions into remote regions of Mexico between I953 and I955. They studied the References

p. 448.

Chemie 88

INVESTIGATIONS

IN NORMAL

447

HUMAN SUBJECTS

,

way in which these fungi are used today and described their experience of the hallucinatory states occurring in the rituals% ROGER HELM, Director of the Mus_e National d'Histoire Naturelle in Paris, accompanied R. G. WASSON on another expedition into the territories of the Mazatecs, Chat/nos and Aztecs in the summer: of I956. He was able to classify and describe these fungi_: the species were all pileate fungi (Basidiomycetes) belonging to the family of Strophariaceae. R. HElM succeeded together with R. CAILLEUXin growing cultures of several of these mushrooms in hi, :! Paris laboratory a. Material from a particularly active fungus, Psilocybe mexicanc ':: Heim, was sent to the Sandoz research laboratories in Basle for chemical investigation._: In spring I958, the psychotropic principle was isolated in crystalline form. It has?': been called psilocybin a. It occurs in the sporophores, mycelium and sclerotia of the; i fungus. A. BRAC_rand H. KOBEL in our laboratories developed an improved methoc of cultivating the mycelium and sclerotia on a larger scale 2. From this material several-; grammes of psilocybin have now been isolated--sufficient for chemical, pharmaco2:; logical and preliminary clinical investigations. _,!: The structure of psilocybin has recently been elucidated and confirmed b_}: synthesis 4.The following is a brief review of the chemistry of psilocybin. _ Psilocybin forms white crystals which are fairly soluble in water, but prachcallyi_ insoluble in the usual organic solvents. It is amphoteric, i.e. it forms salts with bot_-: acids and alkalis· Analysis of psilocybin and a study of its spectra and colour reactions, have revealed that it is an indole derivative, substituted in the benzene nucleus. It wa_ provisionally assigned the formula: C_3H_s(20)OaN2P2, but later degradation studiel}. have shown it to be C_2H_?O4N2P. On hydrolysis the psilocybin molecule is cleaved _ in two, giving: 4-hydroxy-dimethyltryptamine and phosphoric acid. Thus psilocybin possesses the structural[ formula I. O_,>/OH O/_

"O0

H

___(-.h, _CH

Oil

,C i_2 IN_C n 3

H_O

,_-..

(_)H

CH2CI-I2N/_ CHa +

H

It is the phosphoric ester of 4-hydroxy-dimethyltryptamine. been confirmed by the synthesis of psilocybin as demonstrated OH

OCH2C6H 5

_x-/CHa

4 steps

->

OCH2CoH5 x (COClh

[

[_'_NOa

2 HN(CH3)2

COCON_.CH

+

a

_'N H

O_OCt-I_C6H

H

LiA1H4 Pd/Hx

5

O _'* '"OCH2C6H 5 H _'-.N

This constitution hal by the following scheme; ·

O_1:_ OCH_C, CI _y "'-OCH_Ce

/CH3

H` H_

OH

4'

' ,/_'_--wr--CH_CH2N_.cH

/CH a

/

I H

I H

(n)

ai_ n_}

The synthetic compound was identical in every respect with natural psilocybin. ,o. Psilocybin is yet another example of the importance of the indole structI_ References

p. 448.

_

448

A.HOFMANN

in psychotropic compounds. It is closely related to the biochemically important, naturally occurring hydroxy-tryptamine derivatives such as: serotonin (5-hydroxytryptamine), bufotenin (5-hydroxy~dimethyltryptamine), bufotenidin (quaternary base of bufotenin), dehydro-bufotenin and bufothionin. The structure analogy with bufothionin (formula II) which has been isolated from amphibian skin ? is striking. H o[ CH i

®OaSO_

(ii)

[_-CH=CH--N(CHaa

1 H

_Both compounds are acidic esters of a hydroxy-dimethyltryptamine derivative, the one being an ester of phosphoric acid, the other of sulphuric acid. As it is an indole derivative, psilocybin is furthermore related to the psychotropic indole alkaloids, such as tabernanthine, harmine and reserpine. A special relationship exists between psilocybin and lysergic acid diethylamide (LSD), hitherto the most potent psychotomimetic known. Both these compounds are indole derivatives substituted in position 4. Psilocybin and the ergot alkaloids, which include LSD, are unique in possessing this special structural feature. ; The discovery of a naturally occurring indole derivative with a phosphorylated hydroxyl group in position 4 may lead to a new concept of the biogenesis of the lysergic acid moiety of the ergot alkaloids. The proposals already put forward are not _ltogether satisfactory in that no explanation has been offered for ring closure in 'position 4 of the tryptamine moiety. As the phosphorylated hydroxyl group in the psilocybin molecule implies activation of position 4, it does not seem unreasonable to consider hydroxylation and phosphorylation at position 4 as an important step in the biogenesis of the ergot alkaloids. REFERENCES 1 R. HEm, Cornpt. rend. 242 (I956) I389; 244 (I957) 695; Rev. mycol., 22 (I957) 20, 36. I R. HELM, A. BRACK, H. KOBEL, A. HOFMANN AND R. CAILLEUX, Cornpt. rend., 246 (I958) I346. s R. HElM AND R. CAmLEUX, Compt. rend., 244 (I957) 3Io9; 245 (I957) 597, I76I. · A. HOFMANN, A. FREY, H. OTT, TH. PETRZlLKA AND F. TROXLER, Experientia, 14 (i958) 397& A. HOFMANN, R. HEIM, A. BRACK AND H. KOBEL, Experientia, 14 (r958) Io7. VALENTIA P. WASSON AND R. G. WASSO_, Mushrooms, Russia and History, Pantheon Books, New York, I957. · H. WIELAND AND F. V0CKE, Ann., 48I (I93 o) 216.

Printed

in The

Netherlands

25o?xtI 6o Ps!36/LSD !

[!'[

l_.eprinted from (_IIM PREll EN_qlVE I_SY_'II IA'tRY Vol. 1, No. 1, February, 196(i I'ri_tlcd i_ U.S.A.

Some Observations on l'sih)cybin, a New Hallucinogen, ill Volunteer Subjects By SIDNEY MALIrt'z,

M.D., ttal_oLI_ ESECOVER,M.D., BEaNam) AND PAUL H. Hoc_I, M.D.

WILKENS,

M.D.

Some Observations By SIDNEY MALITZ,

on Psilocybin, a New Hallucinogen, in Volunteer Subjects

M.D., HAROLD ESECOVEB, M.D., BERNARDWII.,KENS, aND PAuL H. HocH, M.D.

M.D.

T IS IRONIC that interest in hallucinogens like LSD-25 and mescaline has been recently heightened not by the published reports of a scientist, but of a banker. Gordon Wasson _" described the use of the "magic mushroom," psilocybe mexicana helm, by the priestesses or "curanderas" of certain remote Indian tribes in Southern Mexico. Wasson acquired his love of mushrooms from his late wife; with her he gained the confidence of these secretive people and was invited to participate in their solemn religious rituals. During these ceremonies, which outsiders had never before witnessed, the Wassons observed and experienced various hallucinatory phenomena. Subsequently, Hofmann 9 was able to isolate the active psychotropic principle from these mushrooms, which he named "Psilocybin." Psilocybin is a most interesting substance. It is a hydroxytryptamine derivative, closely related to serotonin. Much has been written in recent years of the latter's possible role in brain function and mental illness. ® Psilocybin also contains the indole ring structure found in many other hallucinogens (fig. 1). This paper describes our initial pilot study of clinical effects; in addition, we make a comparison between these observations and the findings of our previous experience with other hallucinogens, s'lm'-' IsbelP ° and Delay 2 had already reported briefly on Psilocybin but had not used more than 8 and 10 rog., respectively, in any of their subjects. We decided to start with these levels as our lower limits and study the effects of higher dosages. We chose paid vohmteers rather than patients for these studies in order to get a clearer picture of drug action unobscured by an overlay of previously existing and overtly manifest neurotic or psychotic: symptomatology. The studies were not clone in double blind fashion since we wanted first to familiarize ourselves with the drug and then to determine an optimal dosage level at which double blind studies could best be carried .ont. The subjects and attending nurses were not aware, however, whether an active hallucinogen or a placebo was to be administered, or whether the hallucinogen, if administered, would be LSD-25, one of its derivatives, or Psilocybin. MATERIAL

AND METtIOD

Fourteen student volunteers were chosen for the study after a psychiatric screening interview. All were paid for their services. &mong the criteria for selection were freedom from previous mental illness, adequate adaptive functioning in their present life situa-

From the Department New York, N. Y.

of Experimental

This research was supported #MY 1665 C2).

il* part

Psychiatry, IJq the

8

United

New

York

States

State

Public'

Psgchiatric tlealth

Service

Institute, (Grant

7

?

OBSERVATIONS ON PS1LOCYBIN, A NEW IIALLUCINOGEN

9

C2 H5 O---C

HO--_

'_

N H

/j

CH2CH2NH

2

_,

N_CH 3

SEROTONIN H

"

LYSERGIC

ACID

DIETHYLAMIDE

.... o. 0

H

I

I

,c.2

I H

PSILOCYBI Fig. 1.--Substances heavy black outline).

·'

containing

the

indole

CH 3

N

nucleus

(indole

nucleus

shown

in

tions, and the absence of overt evidence of neurosis or psychosis. Twelve men and two women, ranging in age from 20 to 27 years, comprised the series. The median age was 22.5 years. The volunteers selected were told only that they might receive a substance which could produce temporary changes in perception _nd bodily feelings, or an inert substance. On the day of the study the w_lunteers reported at 8 a.m. without breakfast. A baseline EEG, mental status and check list of symptoms were completed before the drug was administered. A previous publication describes the check list in detail. H This list contains an enumeration of autonomic, affective, cognitive and perceptual changes frequently observed after hallucinogen administration with provision for quantification of these modalities. The drug was administered orally. The experiment was conducted in a semidarkened room. A nurse, doctor or both were constantly in attendance. Verbatim statements of the subject's productions, as well as blood pressure, pnlse and respiration were recorded by the nurse. Every fifteen minutes the psychiatrist rated the subject's responses on the check list and conducted a mental status examination. A second EEG was recorded at the height of the drug action, usually 2 to 2 1/2 hours after ingestion. Observations were terminated between 3 and 5 p.m., depending on the subject's condition. Volunteers were told that they might

10

MALITZ, ESECOVER,WILKENS AND HOCH Table

1.--Dosage

Range

of Psilocybin

Dosage (mg.)

No.ofVolunteers Receiving Dosage

8 14 16 20 25 30 32 35 36 Total

1 1 1 1 1 3 2 3 1 14

be required to remain in the hospital for 24 hours, but in only two instances was this necessary. Within 24 to 48 hours following the procedure, the volunteers returned for a follow-up interview and were encouraged to write reports of their experiences. Several of the volunteers were requested to return for additional follow-up interviews from which further psychodynamic material was obtained. The dosage of Psiloeybin administered ranged from 8 to 36 lng. Table 1 lists the dosage range in detail. RESULTS A. Perceptual

Responses

1. Visual Hallucinations. By visual ihallucinations we mean a visual perception with eyes open or closed for which no external stimulus was present. Twelve of the fourteen subjects reported visual hallucinations. They consisted predominantly of abstract colored forms. Four subjects reported seeing conventional colored objects. One of these subjects reported "a scene like a Gauguin painting with green hills and a primitive ox cart moving slowly along a road." Another reported "a circus or carnival scene with animated objects like candy canes, waves of toys changing in kaleidoscope fashion, and presided over by a little elf. It was The Nutcracker ballet suite with vivid reds, yellows, oranges and blues." This same subject also saw "fields of waving red, green and blue scene "like the fun house

flowers like at a carnival

poppies." A third subject reported a with mirrors and the face of a laugh-

ing clown all in brilliant red and luminous fuchsia." Of the subjects listed in table 1, only those receiving 8 and 20 mg. of the drug, respectively, did not develop visual hallucinations. 2. Illusions. By illusion we mean a distorted or misinterpreted sense perception of an existing stimulus. Two types were observed: visual and auditory. Nine subjects reported visual illusions. These were usually seen in patients receiving higher levels of the drug, 30 mg. or above. Typical comments were, "People's faces appeared as if they had 6 or 8 eyes." "The nurse's face looked as if it were covered with green and blue pimples." Two subjects seemed to see their legs disconnected from _,heir bodies. Two experienced auditory illusions. One heard a "calliope-like sound" when a siren sounded in the vicinity; the other heard his own rhythmic breathing waterfall. The latter might also be considered a form

which sounded of hyperacusis.

like a

OBSERVATIONS

ON

PS1LOCYBIN,

3. Body Image Distortions. sonalization and derealization shape and size. the drug in the ing heavy, like Another stated,

A NEW

HALLUCINOGEN

11

Many of these were combinations of deperwith somatic delusions of distortions in body

Ten subjects reported these phenomena. All had received 14 to 36 mg. range. One subject described his body as "feel. the gravitational pull from a ride in an amusement park." "I felt like I was floating ,on a heavy but soft mass, like

mercury. My body felt peculiar." Another commented, "My body felt different. I almost forgot I had one. It was as if I had iust stepped out of my body." Other comments were, "I felt as if my legs were detached from my body." One subject felt his legs were shorter; another that they were longer. Another subject described the room as "unreal and different, like a strange and unfamiliar basement." 4. Temporal Distortions. Five subiects hour as 2 to 3 hours later than it actually date, place or person. B. A#ective

misiudged time by estimating was, but none were disoriented

the for

Responses

The predominant affective responses were euphoria, anxiety and depression, in that order. Ten subiects developed euphoria. In three, the reaction was marked; in five, moderate, and in two, slight. One euphoric response was followed by anxiety. Nine subiects developed anxiety. In three, the reaction was marked; in two, moderate, and in four, slight. In five subjects, the anxiety reactions were followed by euphoria. Depression of slight to moderate intensity developed in four subjects after the euphoria had subsided. One subiect became withdrawn and noncommunicative following a period of marked anxiety that had been characterized by near panic and sharp self reproach. C. Cognitive

Alterations

Four of the fourteen subiects exhibited marked impairment in verbalizing their thoughts with resultant blocking. Seven others suffered varying degrees of disorganized thinking, ranging from mild to severe. This was often expressed as "trouble concentrating." Distractibility, loosening of associations, pressure of speech and flight of ideas were noted, with clang associations. One example follows: "Doctor, where have you been? I'm Alabama bound! I'm carbamino bound. I suggested that to Bruce to use it in the show. BruceBrust. That's breast in German. Yeah. Bard Hall. Bard Hall. Leon M. Bard. Loeb. Loeb. Kuhn Loeb. I was at the Jewish Museum yesterday and all those people had medallions. Jones of microbiology used to say, 'No levity in the autopsy room.' I love to play tennis. Tennis. Tennis. Six love, love six. I love you!" Concrete responses to proverbs with inability to abstract after receiving thc drugs were noted in several patients. Before the drug, in response to "a stitch in time saves nine," one subject paraphrased it with the statement, "If a situation is getting worse, you should clear it up before it gets much worse." After the drug he said, "It's about sewing. I'm confused. What time is it? I'm mixed up about time." Another subject, in response to "People in

12

NSALI'I_Z,

ESECOVEI{,

;VILKENS

AND

HOCH

glass houses shouldn't throw stones," said, before the drug, "You shouldn't point out faults in others that might exist in yourself." After the drug he said, "At who? That depends on a lot of things." Then he blocked. Another subject who had given a satisfactory response before tile drug to "A rolling stone gathers no moss," replied after the drug, with obvious euphoric overtones, "A wandering we will go!" Some subjects felt that their thinking was slowed down; others that it was speeded up. One expressed it as, "My thoughts were racing at an incredible speed." Another stated, "My thoughts were uncontrollable. They came in such a rapid sequence I couldn't keep up with them." Another said, "They just seemed to flow." Four subjects gave definite evidence of paranoid ideation. One was grandiose, felt "very important" and thought that the study "was the most important thing going on at the hospital and everyone should be paying attention to it." One subject felt that his lunch was drugged and that he was being watched to see if he ate it. Another felt we were trying to prove he was "crazy" and consequently decided not to answer some of the questions since he felt they were geared to "test my sanity." One volunteer felt that the doctor was trying to trick him when he corrected one of the subject's distorted perceptions, and that the nurse was attempting to seduce him. D. Fantasy

Material

Fantasies were often of the wish fulfilment type and frequently could be understood in terms of individual psychodynamics. One subject fantasied lying passively on a tropical beach surrounded by attentive servants; another that he was the ruler of a tropical island, regally entertaining his appreciative fiancee. Only three admitted to sexual fantasies but it is interesting that all three related an associated lack of physical feeling or desire. This was succinctly described by one subject: "It was all in my thoughts. I knew I couldn't do anything. My body wasn't up to it." One subject described sexual fantasies about the nurse. Another fantasied having fellatio performed on him by a girl, and had homosexual fantasies as well. E. Autonomic

Responses

1. Pupillary Dilatation. All fourteen subjects showed pupillary dilatation beginning 30 minutes after ingestion of Psilocybin and lasting throughout the entire procedure, a period of 6 or more hours. 2. Nausea. Six subjects complained of slight to moderate nausea usually beginning 30 minutes after ingestion and lasting from 15 minutes to one and a quarter hours. There was no associated vomiting. 3. Dizziness. Six subjects complained of slight to moderate dizziness but only when changing suddenly from a prone to a sitting or standing position. 4. Flushing. Four subjects developed slight flushing of the face within 30 minutes to one hour and 15 minutes after receiving the drug, which persisted for 45 minutes to 3 hours.

OBSEBVATIONS

ON

PSILO(:YBIN,

A NIq_'

ItALLUCIN()(;F.N

l_

5. Abdominal Complaints. Three subjects complained of "cramping," "tightness" and "tallness" ill the lower abdomen. One further described a pain extending into the groin and another into the base of his penis and scrotum. These complaints developed after 15 minutes to ()ne hour and 30 minutes, were of slight to moderate severity and lasted from I to 2 hours and 30 minutes. 6. Blood Pressure and Pulse Changes. Only three of the fourteen subjects showed any significant change in these modal/ties. In all three cases, the changes developed during a period of increased anxiety and motor activity. Two subjects showed temporary elevations of 20 to 40 mm., both systolic and diastolic. One subject's pulse increased[ from 60 to 110 per minute and then gradually returned to its baseline as his anxiety diminished. 7. Inhibition of Urination. One male subject described di/ficultv in startil_ to urinate, but during the follow-up interview described similar urinary difficulty in public toilets. In this case, the influence of prior conditioning and emotional factors may have played a greater role than any direct effect of the drug on the bladder musculature or sphincters. F. Electroencephalogram

Findings

Eight subjects had EEG's done before and during the drug administration. The second EEC was taken at the height of the subject's response, about 2 to 21/2 hours after drug ingestion. Disc electrodes were applied to the scalp and 8 channel recordings were obtained from a Grass instrument. Four of the subjects showed no change. The other four showed increases in alpha frequency with a range of 0.5 to 3.0 e.p.s. Our EEG findings were shnilar to those seen with LSD-25 hy Gestaut et al.,:' who observed an increase in alpha frequency of 0.5 to 4.0 c.p._ with an accentuation of beta rhythms, and Rinkel et al., _a who confirmed these observations and also noted "a reduced response to hyperventilation probably on the basis of decreased subject cooperation." Similar findings have also been observed with mescaline. Wikler 17 noted either no change, or intermittent or continuous low voltage fast activity, or an increase in alpha frequency. Denber and Merlis a described an acceleration of alpha frequency with a decrease in percentage time alpha, including its disappearance, and nonspecific random beta activity. G. Miscellaneous 1. Paresthesias. Five subjects complained of numbness and tingling in their extremities. One subject described "warm, pleasant tingling feelings in my arms and legs like one experiences just before an orgasm." 2. Yawning. Persistent yawning was observed in three subjects. In one the yawning was accompanied by drowsiness but in the other two it was not. We have reviewed the literature on this interesting phenomenon, going back over the last 20 years, and have found little information about its etiology, physiology or psychological significance. Anoxia has been reported as a common cause of yawning, as has suggestion. Yawning is associated with withdrawal from morphine. It may be that a more intensive study of yawning and related

14

MALITZ,

ESECOVER,

WILKENS

AND HOCH

symptoms which appear to involve a neurophysiologie substrate will offer additional clues as to the sites of action in the brain of Psilocybin and related hallucinogens. 3. "Reality Testing" Behavior. Four of our subjects displayed behavior which seemed to be a reparative device for holding on to reality. We have called this behavior "reality testing" because of its similarity to the reality testing employed by some schizophrenics. One volunteer clung to the headboard of his bed during intermittent attacks of panic and stated later, "I felt like I had to hold on to something. It was a way of anchoring myself. It seemed solid." Another subject began biting and gripping the side of the bed. Later he said, "I was having trouble distinguishing between what was real and what was not. This [the bed rail] was real." A third volunteer stood with his back to a radiator gripping it tightly during periods of extreme anxiety. "The radiator was something to hang on to." A fourth subiect kept asking for water and stated later that the feeling of the glass in his hand and the water on his lips, both familiar objects from "the real world," were very reassuring. H. Duration

of Drug Effects

Most subjects began experiencing drug effects 30 to 60 minutes after ingestion. Peak response was usually reached in 1% to 21/2 hours. Rapid subsidence of symptoms therafter was common, with a few subiects symptomfree in five to six hours. The majority of subiects reported post-drttg effects, however. Five volunteers complained of headache, three of drowsiness and lethargy, one of diarrhea and one of depression on the evening of the study or the following day. Wasson _ reported no post-drug effects following the use of the whole mushroom in religious rituals. Characteristically, after 4 to 5 hours under the influence of the drug, the Indians are reported to fall into a deep sleep lasting two hours from which they awake "refreshed and ready for work." Delay 2 reported the usual length of the Psilocybin response as from 2 to 4 hours "with subtle disturbances occasionally remaining for several more hours and in rare instances for several days," but he does not elaborate on these side effects. Henze? reported that in the Sandoz Laboratories, "The effect wore off in 4 to 5 hours at reasonable dose levels." These were usually doses ranging from 4 to 8 mg. It is possible that our consistently higher dosage levels might account for our greater incidence of post-drug effects. DISCUSSION

Qualitatively, the reactions observed in our present subiects were similar to the responses we observed previously in subjects given LSD-g5. s,n,_2 Both LSD-25 and Psilocybin vohmteers showed a similar pattern of autonomic reactions, perceptual distortions, and affective variations. In the cognitive sphere, we noted a greater disturbance of thinking with Psilocybin, expressed as blocking, associational impairment and flight of ideas, but these results might have been either a factor of dosage or related to basic personality variations from subject to subject.

OBSERVATIONS

ON PSILOCYBIN,

A NEW

HALLUCINO(;EN

15

Stoll's TM experience with LSD-g5 after-effects resembles very much the postdrug symptoms we observed with Psilocybin. He reported somatic disturbances the day after LSD-g5 ingestion consisting of "back pain, diarrhea and grippe-like symptoms," and in the psychic sphere, two cases of mild depression. The lack of sexual desire seen in our present subjects has also been observed by us with LSD-g5 and mescaline. _ Stoll t4 reports a similar experience with LSD-g5, and Guttman 6 commented on the anaphrodisiac qualities of mescaline in the Indians of the southwestern United States. Our experience with Psilocybin reinforces our impression that hallucinogenic agents act in two ways simultaneously. On the one hand, they behave like toxic agents producing autonomic disturbances and predominantly visual perceptual distortions, without marked disorientation or clouding of consciousness. On the other hand, they act as nonspecific psychic stresses on the total organism, to which the individual responds in a manner dependent on his basic personality structure, his previous life experiences and the techniques of adaptation he has developed throughout his life to handle these experiences. The affective responses of the subject to the drug, and the total behavior pattern emerging under its influence may be related to this nonspecific stress effect. Thus, a schizoid individual might become more withdrawn and even appear to be temporarily schizophrenic when under the influence of a hallucinogen, while an individual with a eycloth,vmie temperament might act more euphoric and demonstrate less blocking and associational disturbance than the former. This viewpoint might explain why one investigator emphasizes that the hallucinogenic effects in his ease material resemble closely a schizophrenic process, while anether investigator using the same drug and dosage level finds little or no resemblance to schizophrenia in his subjects. The stressing effect of hallucinogens is not limited to anv single agent since, in addition to Psilocybin, we have seen it with LSD-25 and mescaline. The e_avironmental setting in which the drug is administered als() affects the emerging behavior pattern. This factor may also account for variations in results with different invest{gators. Our hospital setting, with the subject, a paid volunteer, receivin_ an unknown agent in an experimental framework surrotmded by unfamiliar doctors and nurses, differs markedly from the mystical settin_ which Wasson observed, where the drug is part of a solemn religious ritual. Only one of our subiects reported what might be described as a transcendental experience resembling the religious ecstasies observed by Wasson. The differences in expectation and setting between these two grossly divergent groups may account in part for the disparity in their responses. Becently, the use of hallucinogens, specifically LSD-25, as therapeutic agents in psychiatric disorders has been proposed2 We feel that such a usage of these drugs, especially in an out-patient setting, is fraught with danger and should be undertaken only with the greatest of eaution. Psilocybin, LSD-25 and mescaline are extremely potent agents, capable of producing acute psvehotic behavior in many individuals. Depression, with the ever present risk of suicide, may develop during or after their administration. Additional post-drug effects als() occur. Once a patient has been entrusted with a hallucinogen, even when instructed to take the drug in small doses

16

MALITZ,

ESE(X)VER,

WILKENS

AND I-lOCH

below the hallucinogen threshold, we.' have no control over the numbers of pills he may take at any one time while at home. We believe that the use of hallucinogens should, for the present, be restricted to research in a hospital setting, where untoward reactions can be promptly managed with a maximum of safety. Further research is indicated regarding the site of action cf hallucinogens, the relationship between personality, dosage level and total behavior pattern, and the possible prognostic value of these drugs in assessing the likelihood of future emotional decompensation in specific individuals. SUMMARY

Fourteen paid vohmteers, screened by clinical interviews, received Psilocybin orally over a dosage range of 8 to 36 mg. The perceptual, affective, cognitive, behavioral and autonomic responses observed were qualitatively s;milar to those previously described with d-LSD25, but quantitatively, a greater impairment cf cognition with Psilocvbin was noted which may have been related to dosage or personality differences. EEG findings in four out of eight subjects were similar to those previously reported with d-LSD-g5 and mescaline. The use of psychctomimetic drugs as therapeutic agents in an out-patient setting may prove potentially hazardous. Acute states of excitement, depression with suicidal ideation and impairment of judgment may occur with these drugs, even in the most carefully supervised in-patient setting. With out-patients, the danger of self-administration and inadequate supervision could compound such occurrences. Further research is indicated regarding the site of action of hallucinogens, the relationship between personality, dosage level and total behavioral pattern, and the possible prognostic value of such drugs in assessing ego strength in specific individuals. ACKNOWLEDGMENT We are grateful to the Sandoz Pilarmaceutical Company, Hanover, New Jersey (R. Bircher, M.D., Medical Director), for supplying us with the Psilocybin used in this study. We also wish to thank Dr. Reginald Taylor for his assistance in reading the EEG's reported in this study. _REFERENCES 1. Cohen,

S.,

and

Eisner,

B.

G.:

The

4. Gaddnm,

J.

H.,

Hebb,

C.

O.,

Silver,

usc of LSD-25 in a psychotherapeutic setting. A.M.A. Arch. Neurol.& Psychiat. 81:615-619, 1959. 2. I)elay, J., Pichot, P., Lemperiere, T., Nieolas-Charle, P., and Helm, lq.:

A., and Swan, A. A. B.: 5-Hydroxytryptmnine; pharmacological action and destruction in perfused hmgs. Quart. J. Exper. Physiol. 38:255, 1953. 5. Gestaut, H., Ferret, S., and Castells, C.:

Effets psycho-physiologiqnes de la psiloeyhe. Compt. rend. Acad. Sc. 247: 1235-1238, 1958. 3. Denber, H., and Merlis, S.: Studies on mcscaline: I. Action in schizophrenic

Action de la diethylamide de l'acid:, d-lysergique (LSD-25) sur les fonttions psyehiques et l'eleetroencephalogramme. Confinia nenrol. 13:102120, 1953.

patients. Psychiat. 429, 1955.

Quart.

29:421-

6. Gnttman, duced

E.: Artifidal by mescal/ne,

psychosis proJ. Ment. Sc. 82:

OBSERVATIONS 203-221,

ON PSILOCYBIN,

A NEW

17

HALLUCINOGEN

1936.

W., and Solomon,

H. C.: Experimental

7. Henze, C.: Personal communication, 8. Hoch, P. H., Cattell, J. P., and Pennes, H. H.: Effects of mescaline and lysergic acid (d-LSD-25). Am. J. Psychiat. 108:579, 1952. 9. Hofmann, A.: Chemical aspects of

schizophrenic-like symptoms. Am. J. Psychiat. 108:572-578, 1953. 14. Stoll, W. A.: Lysergsaeure-Diaethylamid, ein Phantastikum aus der Mutterkorngruppe. Schweiz. Arch. Neurol. u. Psychiat. 60:279-323, 1947.

Psilocybin, the psychotropic principle from the Mexican fungus, Psilocybe mexicana Heim. Paper presented at First International Meeting of Neuro-

15. Wasson, R. G.: The hallucinogenic mushrooms of Mexico: An adventure in ethnomycological exploration. Presented at N. Y. Academy of Sciences,

Psycho-Pharmacology, Rome (Italy), September 8-13, 1958. 10. Isbell, H.: Comparison of the reactions induced by Psilocybin and LSD-25 in man. Psychopharmacologia 1:2938, 1959. 11. Malitz, S., Wilkens, S., Glusman, M., and Hoch, P. H.: Comparative study of blocking agents in model psychoses. In Pennes, H. H., Ed.: Psychopharmacology. New York, Hoeber-Harper, 1958. 12. --,

--., Roehrig, W. C., and Hoch, P. H.: A clinical comparison of 3 related hallucinogens. Paper presented at A.P.A., May 12, 1958.

13. Rinkel,

M., DeShon,

H.

J., Hyde,

R.

Division of Mycology, Jan. 23, 1959. Wasson, V. P., and Wasson, R. G.: Mushrooms, Russia and History. New York, Pantheon Books, 1957. 17. Wikler, A.: Clinical and electroencephalographic studies on the effects of mescaline, N-allylnormorphine and 16.

morphine in man. J. Nerv. & Ment. Dis. 120:157-175, 1954. 18. Wooley, D. W., and Shaw, E.: Evidence for the participation of serotonin in mental processes. Ann. New York 19. --:

Acad. Sc. 66:649, 1957. Neurologic and psychiatric changes related to serotonin. In Pennes, H. H., Ed.: Psychophannacology. New York, Hoeber-Harper,

1958.

Sidney Malitz, M.D., Acting Chief of Psychiatric Research, New York State Psychiatric Institute, and Assistant Clinical Professor of Psychiatry, College of Physicians and Surgeons, Columbia Univer.yity, New York, N. Y. Harold Esecover, M.D., Senior Research Psychiatrist, New York State Psychiatric Institute, and Assistant Psychiatrist, Vanderbilt Clinic, Presbyterian Hospital, New York, N. Y. Bernard Wilkens, M.D., Senior Research Psychiatrist, New York State Psychiatric Institute, and Instructor in Psychiatry, College crf Physicians and Sltrgeons, Columbia University, New York, N.Y. Paul H. Hoch, M.D., Commissioner of Mental Hygiene, New York State, and Clinical Professor of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, N. Y.

·

/

_eh._-t._rmoo_. VETERANS

L_

Al)MINISTRATION

CLINICAL,

42-52 (z_l).

ItOSPITAL,

BIOCHEMICAL EFFECTS

PALO

AI.TO,

PSX5_

(!ALIFORNIA

AND PSYCHOLOGIC

OF PSILOCYBIN

BY

LEO E. HOLLISTER,

(l) (Received

for

publication

I-7-196o).

Psilocybin has been isolated as an active principle of the mushroom, Heim Psilocybe mexicana, used by Mexican Indians in religious ceremonies for many centuries. Upon synthesis, psilocybin was found to STRUCTURAL FORMULAE OF PSILOCYBIN AND CHEMICALLY SIMILAR COMPOUNDS

HO_GHz-CI'_-NI_

5-hydroxvtryl)tomine (Serotonin)

HO_CI'IfCH_-

NH(GI'_)2 bufotenin

CHi-CHI_-N H (ella)it , psilocybin (I) The Mr.

author

I:.l.I ,_'IURM,

would and

E. [)At:I.%EN for secreening

like Mrs.

to

L'xprcss

["IIAN('I_$ the

voluntet,

National Institute of Mental I Jrahh. of ,Sandoz [_harnmcrulicals, Inc.

his

appreciation

MooRl.: ers.

'rhis

Matt*rial

for

to

technical study was

Mrs.

assistance

was sul}portct] furnishcd

by

N()RXtA and by Air.

ROSENQUis'r, to

grant [larry

Dr.

J._.Xll-.-,;

l_,!Y-3o3o. Althouse

I)NII.¢)('YIHN

43

have an indnle mlcleus substituted at thc 4-position with a phnsphoric acid grouping, making it unique among naturally-occuring indoles thus far known (6). Its structural rt:scmblancc to 5-hydr0xytryptaminc(serotonin) and bufotenin is shown in Figure i. Preliminary studies in mice revealed that strong doses produced sedation without loss of excitability in normals and alleviation of the circular movements lasting 2o to 4° minutes in waltzing mice. These effects were analogous to those of lysergic acid diethylamide (LSD-zs) but distinguished by earlier onset and almost complete absence of neurovegative reactions especially trembling, salivation, and pilomotor reactivity (4)Clinical studies in Europe and this country revealed psilocybin to be a potent material capable of producing many of the effects previously noted from other psychotomimetic drugs (3, I I). Although resembling closely LSD-z 5 in its pharmacologic action, the drug is considerably weaker, early estimates indicating that i 14 mcg/K of psilocybin was roughly equivalent in action to i mcg/K of LSD-z 5 (7)- In the present study, we shall describe some clinical, biochemical, and psychologic effects of the drug in normal volunteers.

METHOD

OF

STUDY

Psilocybin was used in 27 separate trials in volunteer subjects. Seven subjects took only oral doses (9 trials) ranging between 6o and zo9 mcg./K. Nine subjects took both oral and subcutaneous doses on separate occasions, oral doses varying between 6o and 2o 9 mcg/K, parenteral between 37 and 2o 5 mcg/K. In most cases, subjects received equal doses orally and parenterally, allowing a comparison of potency to be made between the two routes of administration. Most volunteer subjects were graduate students or professionals with a background in psychology. Although some subjects knew something of the clinical effects of the psychotomimetic agents, none had access to material concerning psilocybin. Despite a considerable degree of expectation on their part as well as a tendency to interpret all clinical phenomena in psychologic terms, the subjects had been trained to make objective observations and possessed descriptive ability. To minimize the factor of expectation, 7 of the 9 subjects receiving both parenteral and oral doses of the drug were "blind", not knowing which of several drugs they were receiving. Drugs were administered in the morning with subjects fasting. Ages varied between zz and 4z years, the median being

44

LEO E. HOLLISTER,M.I).

z6 years. All subjects were in good general health and had been screened to rule out overt psychiatric disorders. Each trial was conducted on a medical ward of a psychiatric hospital. For most subjects, this setting was familiar, though not necessarily conducive to ease. Subjects were placed in a private room, small and austerely furnished. 'Fo minimize the effects of external suggestion, they were visited by hospital personnel only for obtaining clinical or laboratory data. For the first 9° minutes of each trial, these interruptions were minimal. Three parameters were studied: i) Clinical Measures. -- Clinical effects were assessed in two ways. Each subject was provided with a tape recorder for verbal recording of subjective experiences. Time cues were provided so that the onset and duration of each reported symptom could be recorded. If subjects had difficulty using the tape recorder, one of the experimenters questioned him at the time some other measure was being taken. Each tape was carefully reviewed to transcribe a chronologic log. Following the trial, each subject completed a questionnaire of 43 questions. Twentyfive of these were questions most frequently answered positively in a questionnaire previously used in studies of psychotomimetic drugs; x8 questions regarding specific symptoms of psychopathology were derived from another similar questionnaire (x, 8). Data from questionnaires and the recorded logs were used to establish the full clinical syndrome experienced. Prior to each trial, measures were taken of blood pressure, pulse rate, pupillary size, deep tendon reflexes, and simple coordination tests (finger-nose, heel-knee, Romberg test). These tests were repeated approximately two hours after taking the drug. 2) Psychometric Tests. -- Two measures of mental functions were used (9)- One consisted of a series of simple arithmetic problems (Number Facility Test). The other consisted of linear drawings, each consisting of four lines which had to be copied from a completed drawing (Flexibility of Closure). Subjects were also tested for ability tv, estimate varying periods of time (5, 15, 3° and 6o seconds). Each of these tests were administered administration.

prior to the trial and hourly for 4 hours after drug

3) Biochemical Measures. -- Prior to administration of psilocybin and a hours later, blood was drawn fi_r determinatinn of fasting total eosinophil count, serum cholesterol, alkaline phosphatase and cholinesterase activity and serum glutamic oxalacetic transaminasc (S(;O-T) titer. A baseline electroencephalogram was also obtained, being repeated I ._ to z hours after the drug had been administered. A control urine sample

PSI I.()('Y Bi N

45

_'as collected fi_r determinations of total inorganic phosphorus and creatinine excretion. All urine wfided during the first 2 hours of the drug trial was collected for the same determinations.

RESULTS

OF STUDY

Clinical Syndrome. A fairly characteristic clinical syndrome was produced by effective doses of psilocybin. Although subjects varied in responses, a dose of il 5 to i6o mcg/K orally ordinarily sufficed to elicit an appreciable effect. Both the frequency and the intensity of clinical effects increased with tile dose. The threshold dose orally was about 6o mcg/K from which minimal but definite changes were produced. Comparisons of potency between oral and parenteral doses were difficult, the latter appearing to be 5© to Ioo percent more potent at the same dose in the same subject. The pattern of the syndrome in 18 trials of oral medication in i6 subjects was as follows: First 3 ° minutes: Dizzy, light-headed or giddy. Weakness, muscle aching and twitching, Nausea, abdominal discomfort. Anxiety, tension, restlessness. Numbness of the tongue, lips, or mouth. Heaviness or lightness of the extremities.

shivering.

30 to 60 minutes: Blurred vision, brighter colors, longer after-images, sharp definition of objects, visual patterns (eyes closed). Increased acuity of hearing. Yawning, tearing, facial flushing, sweating. Dreamy state, loss of attention and concentration, slow thinking, feelings of unreality, depersonalization. Incoordination, difficult and tremulous speech. 60 to 9o minutes: Increased visual effects (colored patterns and shapes, generally pleasing, sometimes frightening, most often with eyes closed, occasionally superimposed upon objects in field of vision). Undulation or wave-like motion of viewed surfaces. Distance perception impaired. Euphoria, general stimulation, ruminative state. Slowed passage of time.

46

LEO E. HOLLISTER,M,D,

O0 to 120

minutes:

Continuation

of many

of above

effects

in

varying

degrees,

especially

introspective

_tate.

increased bodily sensations and mental perceptions. x2o

to

Waning

z8o

minutes:

of previously

described

effects.

18o to 300 minutes: Nearly complete resolutionof drug-inducedeffects. Effects of parenteral psilocybin in 9 subjects were similar. Clinical effects began within 5 minutes following parenteral doses as contrasted with 2o to 3o minutes after oral administration. The same doses elicited a more intense and prolonged syndrome when given subcutaneously. These subjects complained more often of difficulty in thinking, uncontrollable laughter, paresthesias, and difficulty in breathing. Other effects reported by subjects from both forms of drug administration, though not as frequently as those noted above, were decreased salivation, decreased appetite, transient sexual feelings, and synesthesia. Psychotic symptoms were infrequent. None of the subjects experienced paranoid delusions or hallucinations of smell, taste, or feeling. A few described auditory hallucinations, these being either misinterpretations of meanings of environmental sounds or of actually hearing fantasied conversations. Neither type of auditory experience contained accusatory material. Four subjects reported changes in the body image, the extremities appearing larger than normal. These changes were concurrent with other visual effects. Two subjects had difficulty in maintaining temporal orientation and three in maintaining spatial orientation, these symptoms being brief and transient. A frequently reported psychologic effect of the drug was an unusual ability to perceive the feelings and motivations of people in the environment, as well as the subject's own reactions. Attempts to define more precisely what was experienced proved to be extraordinarily difficult, consisting mainly of speculative observations or tales of elusive insights. At times, subjects reported great empathy ("I feel that I could get inside another person's skin, experience all that he does."), while other observations were sometimes banal ("I noted fi_r the first time that thc laboratt_ry technician drawing my blood was a wontan."). The visual beauty of the colored images, especially when at,gmentcd by thc stroboscopic light during the electroencephalogram seemed to be a mystical experience to some. Few after-effects were reported. ()ccasionallv patients had headache or fatigue likened to a mild hang-over. Somc reported a contimwd con-

P_II,O('YBIN

47

templative or philos.phic state with unusual serenity. None had difficulty functionning, many resuming their usual activities (including driving a car) as soon as 5 hours after taking psilocybin. Changes in blood pressure or pulse rate were minimal. Significant elevation of blood pressure was considered to be 25 mm/Hg, over the control systolic or lo mm/Hg, over the control diastolic pressure. Three subjects had systolic elevation of this degree, two having unusually low control pressures. During three trials, diastolic blood pressure elevations were encontered, two of these being in the same individual, a borderline hypertensive. No decreases in blood pressure of similar degree were noted, and in no instance did the blood pressure either rise or fall beyond physiologic levels unless it had been abnormal on the control measure. Pulse rate was not changed appreciably in either direction, remaining within physiologic limits or close to the control values in all drug trials. Dilatation of the pupils was almost constantly encountered after effective doses. Average dilatation over 2-hour period was 3 mm. When dilatation was extreme, the pupillary reaction to light was often sluggish with hippus. Deep tendon reflexes were increased during 19 trials of the drug, often becoming clonic in character. Incoordination was more subjective than objective, as coordination tests were seldom impaired enough to be clinically detectable. A few patients were sloppy in performing the finger-nose or heel-knee test as well as swaying slightly on the Romberg test. Biochemical

Measures

Results of the biochemical

measures

are summarized

in Table

x.

Measures most changed by psilocybin were urinary excretion of inorganic phosphorus and total circulating eosinophils, both of which were significantly reduced. Urinary inorganic phosphorus was decreased in z8 trials and increased in 3. On the basis of milligrams of phosphorus excreted per milligram of creatinine, the mean control level was. 55 mg. P/mg. creatinine (standard deviation .18) and the mean treatment level was .38 mg. P/mg. creatinine (standard deviation .2o). These differences were statistically significant. Total eosinophil counts decreased during 17 trials, increased during 3, and remained the same in i. The mean control level was 2II eos/cu.ml. (standard deviation 133). The mean value 2 hours following drug was 126 eos/cu.ml. (standard deviation Io3), a statistically significant decrease. No remarkable changes were noted in the SGO-T titer, serum cholesterol, serum chulinesterase, or serum alkaline phosphatase activity.

42

LEO E. HOLLISTER,

M.D.

TABLE 1 Results of biochemical tests in - t trials with psilocybin in normal volunteers I Measure

Prior to drug

Urine rog. P/creatinine Mean S.D. Total eosinophils,

Serum

glutamic

.55 .18

'3 8{)) .2o

blood Mean S.D.

a!x 133

126(t) I°3

oxalacetic transaminase Mean S.D.

16units 4.2

i6 units 4-5

Serum alkaline phosphatase Mean S.D. Serum

Serum

z hrs. after

2.8 Bodansky unit .97

pseudocholinesterase Mean S.D.

2.8 Bodansky .9I

unit

204units 48

2_ounits 58

234mg. % 31

24zmg. % 35

cholesterol Mean S.D.

(l) p _ < .oz (_) p = < computation of the significance for small samples.

.o5 All tests of statistical significance of the difference between the standard

Electroencephalograms were comparable each of 20 trials of psilocybin.

Were based on error of means

to the baseline tracing during

Psychometric Tests Results of two psychometric tests (Flexibility of Closure and Number Facility) measured before and hourly for 4 hours fi_llowing psilocybin are shown in Table 2. The effects of oral psilocybin were to decrease significantly the number of problems completed on the Number Facility test during the first hour, but fi_llowing this, there were no significant differences. Parenteral psilocybin decreased significantly both the number of lines attempted on the Flexibility of Closure test during the first 2 hours and those correctly drawn during the first hour. Thc number of problems completed on the Number Facility test was significantly de-

PsiLocvm_4

49

'l'nm._: II

Results

of psychometric

Psychometric

tests in normal

test

volunteers

Before drug

treated

i hour after

with psilocybin

a hours after

3 hours after

4 hours after

_ 3I x4.2

i-Number Facility (con'ect solutions) Oral dose, N = 13 Mean S.D. Parenteral

dose, Mean S.D.

N

35 ia.6

a2Q) 9.4

28 t3.2

32 14.5

35 21

I3(1) i5.1

x9 x3.6

27 t8

30 al.4

69 t7

62 14.8

67 ao.a

71 so.3

68 aa.3

59 20.7

53 x6. I

57 22.6

62 21.5

56 28.3

80 19.a 71 24.9

53(x) 8.8 4aC) I5.3

61(l) 6.6 47 15-5

68 Ia.7 58 I9.3

80 I4.5 68 26.2

= 7

Flexibility of Closure Oral dose, N -- i i Lines

attempted

Lines

correct

Parenteral

mean S.D. · mean S.D.

dose,

N = 7

Lines attempted mean S.D. Lines correct mean S.D.

(1)

p

=


C_ extent

experience, with

Pleas'ant] Ecstatic I i [ 38% ] 320_; [ yourself and thc

were

import:mt,

intcrpersotzal

aspects

(sharing

of your

something

othe,'s)?

il{ i

_"_'

:Isi,t'ctsMany \spcctsS°me il As ects Into(pets. Interpcrs. Interpers.

: Entirely i Personal

I llC_

'i

3')¢- _

295¢

' 6. To what extent was your (with abstrimt.?actual

M,,stly iMany Perceptual

im'tges

or

[ Images[Some

[

137_

[

; experience forms)

15%

, as

perecptu'd opposed

! Mostly

to

Fmtirely

Imagesi Abstract Abstract

, ___[ ! 18% 33% 2050 10% t 7. How about tnking the lnushroonls again undcr trustful, securc circumst,'mccs? 18%

Not 0%

[ Rati_erNot{Don'tCare LikeTo

Very

I

l_ager

,[

4%

6%

34%

56%

I

506

LEARY,

LITWIN

AND

High

sion S reported feeling before the 'experience and 2) how supportive he perceived tlle situation as being. Again, it must be cautioned that these two ratings might well be infiuenced by the experience itself; a suggestion which is born out by the clustering of pleas-

TABLE 2 Some Effects of Group Size* A Pleasantnc_

CroupSize Low Small (2-5) ............... Moderate (6-8) ........... Large (9-21) ..............

7 12

23 20

11

15

x 2 = 2.2; df := 2; Hsd.

B

.

.

Small (2-5) ................ Moderate (6-8) ............ Large x2 =

Little

Much

18

12

perceived

17

It can be seen in Table 2 that there was a slight non-significant tendency for small

15

(9-21) ...............

{

17

{

9

Croup Size

Supportiveness

L(-_---- H-igh

Small (2-5)...--.._. ......... Moderate (6-8) ............

{ I

8 14

{ {

22 18

(9-11) ...............

{

19

{

7

x a = 13.6; df _. 2; p
ns, thus citement ration of >ne may Lose seen

·:_

-.

a_·_._-,_·e_'_

_.........

_

..........

_

......

,

. _ ..............

,_

.......

:_.,

_: ........

___-

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

,

BY J. DELAY, P. P1CHOT AND T. LEMPERII_RE 41 doctor/patient relationship. The special character of oneiranalysis resides in tile fact that the patient can follow lucidly the progress of tile experiment and remain to a certain extent detached from it; his heightened capacity for selfanalysis allows him to perceive the rich symbolism of his phantasy and his hallucinatory reactions and their emotional implications. The emergence of childhood memories or unpleasant comlictual situations produces intense emotional reactions of cathartic value. Remembering well what has occurred during the experiment the patient can give a detailed report of it. It is in fact in the hours or days following the experiment that thc most fruitful processes of association and interpretation continue, in which tile patient readily links what he has just lived through with his past experiences. Again, the modifications of mood and afiZct bring about a change in the doctor/patient relationship. A transference relationship is established, which can be used therapeutically, since it allows the patient an easier externalization of his emotional needs and a better grasp of the meaning of the material brought up during the experiment.

BIBLICKiRAPHY

of events ninution Lions are

DELAY, J., PICHOT, P., and NICOLAS-CHARt[S, P., "Premiers Essais de la Psylocybine en Psychiatric", Premi;2re R6union lnternationale de Ncuro-psychopharmacologie, Rome, 8-13 Sept., 1958. Neu;:o-Psychopharmacoh,,c,y, 528-531. Amsterdam: Elzevier.

involved

DELAY, J., PICHOT, P., LEMP_R|imI'_', T., and NICOt. as-CHARLES, P., "Effects PsychoPhysiologiques de la Psilocybine', C.R. Acad. Sci., 1958, 247, 1235-1238. DELAY, J., PtCnOT, P., LEMPFIRIiiRE, T., NICOLAS-CHARLES,P., and QUETIN, A. M., "Etude Psychophysiologique ct Clinique de la Psilocybine', in: Les Champignons Hallucbmg_nes du A_exique (eds. R. Helm et R. G. Wasson). Editions du Mus&lm d'Histoire Naturelle de

:ntres

his or

aking neurosis heatrical

Paris, DELAY,

infantile with an minates, :. In the of

con-

com_ to _es, Il;on It CaSeS,

;es. For showed locybine mfirmed n a case reaction reed the ble per;pecially in some patients material in the

J.,

1958, 287-309. PICttOT,

P.,

LEMPERI/:,RE,

T.,

NICOLAS-CHAB.

LES,

P.,

and

QUETIN,

A.

M.,

"Les

Effets

Somatiques de la Psilocybine", AtiLt. mdd.-p.v'chol., 1959, 117 i, 891-899. DELAY, J., PICHOT, P., LEMPERIERE, T., NICOLAS-CHARLES. P., and QUETIN. A. M., "Les Effets Psychiques de la Psilocybine et les Perspectives Thdrapeutiques", Ann. mdd.-psychol., 1959, 117 i, 899-906. DEL^V, J., PlcBqo'r, P., LEMPrgm/m_-, T., and QUETIN, A. M., "Effets Thfirapeutiques de la Psilocybine surune N6vrose Compulsive", Ann. mdd.-psychol., 1959, 117 ii, 509-5i5.

_- .......

I'

....

i ........

,mli ill_l ...........................................

1)RU(;

'..........

]:.FFECTS

ON

AUI)ITORY

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

POTF.

N'I'IAI.

'

S

30¢)

as suggested by I'{ERN."_NIW. Z-I_I:6:'; 7 although there was no indication that harmacol. Exptl. Therap. ..f49. 425 (1065) 120_' r i k e. W. W., Anal. Chem. SS. 1%: (to66_ 12rl R . e I i u s . Il. W.. L e e, J. M., anti A I b u r n , Il. E., Arch. I_ [231 1241 [25]

Biod_em. Klm mci,Biophys. lt, B. 111. anti 376 Walkenstein, (It_)5} S. S., J. Pi,ar. Sci. s6, ,_s ,96?) 1/ i e d e r, J., Arzneim.-ForsdJ. (Drug Rcs.) 1_;,1148 (196'$) P i1bs ie IhI Ia.a gO., O ri_; e r,ibid. H., 15. V o1148 I k (1'}6_) c , J., Lira. G. T., and Frank, u., ibid. 16, 82 (t966) [261 inter al.: Sternbaeh. L. It., Kaiser. S., and Reeti S et er, r nE.,b J.a cAmer. h , L. Chen,, It. andSc,,'. H S2, c e d475 e r,(196051 E., J. erg. Chem. 26, ti:il (1961); s t e r n h a e h, L. lt.. R e c ,1 e r. E., K e 1 I e r, O., and ._l e ti e s i c s, W., il,id. 26, 448S (19615: s t e r nbS, aC.,c h,Sutkow_ki, L. II. and Il c eT.d S., e r, Gochma E., ibid. 26, Bell, nn, 4936 C.,(1961): and (: h

Sim-

Med. G.E.,

s n n s h i n e. I., Amer. J. Clin. Path. 40, 57(:;(19655 1' a u I u s, W.. II o c h. W.. and K e y m e r, I/., Arzneim.Fo,-sch. (Dr,,g lies.) 13, 60'} (1%35

I d r os

s , S. J.,

ibid.

27,

562

(19625:

n oa _1k I.S.e r, C,G.andN.,C ibid. It i I d27,r e1929 _ s ,(1962); S. .1., bid 27, 1961 (1962); W s t e r n b a e h, L. Il., F r y r e r, R. I., M e t 1 e s i c s. W;,

und versdticdencn pharmaze,,liadicn Zubercitungsfor-

kcine Unreinheiten.

A t I m a r k , M. G., Can. R. Ir . andS( ev ens,S,

Thc Analyst 87, 562 (1'5625 National Formulary XII, American Pharmaceat/cal Association, Washington D.C. 1965 p. 85 British 1966, Amendments, Pharmaceutical Pharmacopoeia Pre_, l.ondon, Addeadum, U.K., I September 1966 B ii u m I e r, J. and IIi p p s t o i n, S., Itel(. Chim. Acta 4_,

Isl 191

vcrwendct fiir (lie raSchc Dbcrpriifung yon Chlordiazepo,_id-ltCl-llohprodukt

men. Dic it, Phar,nakop/ien angegcbene, Grenzwcrte fiir das Vorhandcnsein tics Lactamhvdrolvscprod,kts · . yon Chlordiazepoxid .HC1 in pharmazeutisdlcn Pr[ipara(tn sd(cinch sidl ni&t' z,, de(ken mit dent,, gu(er pharn)azcl, tisd_cr Erzeughisse. Handclsm,stcr yon Diazcpam und Oxazepam,Rohprodukten nnd pllarnlazcutischc ZnbercitungeIl _-erden gcpriift. In den DiazepamProdt,ktcn a,tf derh kanadisdlen Mark( fanden sid)

555

R i c e . W. B., L u , F. C., anti Assoc. J. 92, 180 (1%551 B i rd,

2208

of thc lactam hydrolysis product of ddordiazepoxidc ' IICI in pharmaceutical preparations, do not appcar to be in accord with good pharmaceutical manufacturing practice. Commercial samples of diazepam anti oxazcpara bulk drug and pharntaccutical dosage forms arc s('rcened, l)iazepam products marketed in Canada were found it, I)e free of impurities, while oxazepanl I)ro -

PgI 223

Il e e d e r , E..

S a e It , G.,

S a u e y , G.,

anti

S t e m p e 1,

A.,

ibid. 27, 37s8 0962); S t e m p e 1, A.. and L aFry(er, n d g r a f, R., F. W., ihid. 27, 4674 (1962); Sternbac L. Il'.. Keller, O., MetI e s i c s, w., s a e h , G., and S t e i g e r, N., I. Med. Chem. s. 26! (19635: Bell, S, C., Goehman, C., and Child(ess, S. J., ]'. erg. Chem. 28, 3010 (10635: Canadian Patent 735 460 (J,,ne, 196651 ibid., 757934 (Inly, 196b) 12-1 G References I u c k m acited n. M. in I.,review J. Pharm. article, Sci: 53, C h 577 i 1¢1r (19645 e s s , S. J. and T2,} SPress. t a It I. E.. Thin-laver Chromatography, 1st Ecl.. Academic New York. N,¥., 1(165,p. 5 ff. 1291 B e e k s t e a d, H. D., F r e n c h , W. N., anti S m i t h , S. J., J. Chro,nato¢. 51, 226 (1%75 [-,0! S h e 1 1a r d. E. J., Lab. Practice 290 (19645 [';Il Dohman, K.,ibid. 80_ (1%35 ['_21 D a 1 1a s M.S.J., J. Chromatog. t7, 267 (19655 For fbe authors: Dr. S. J. Smith, Department o[ National ltealth and Welfare Food and Drag Directorate. Tunney's Pasture, Ottawa _, Ontario (Canada)

of Andiolo_y and Speed_ Scie,ces. Collea,, of Commt, oication Art.q. :ltidff_an Stale Uninersity. Mi_igan (U.S.A.) and from the Dioision of Behaoioral Sciences, Department o[ Psy&iatry; The College of Medicine, Olifo Slate Unioersity, Cohtmbus, Ohio _U.S.A.)

Measurement Bv Oscar

Test,

of Time Marsha

Contraction

A. Rockey,

In addition to paases of the syntactic and hesitation tyne. th(re are during speed_, short periods characterized l)v the emission of Iow acoustic energy. These short pcriods are i_{)ssil)lv rclated to the dynamics of the phonatory, articalator._', and respiratory structures. While hesi(alien pauses have been studied in spontaneous speech (Flanagan 1960: (;oldman-Eisler 19611 Boomer : and Dittman 19621 Goldman-Eisler, Skarbek, and Henderson 19651 etc.), it is only recently that an o,erational definition of pause has been introduced (Test 19665 whidi facilitates the detection and mcasnrement of the duration of these short intervals of low acoustic energy. The means, medians, and interquartiles _;_of the dnration and frequency distribution of both types

and

Induced Roland

by Psilocybin

Fiscller

of pauses might well servc as parameters which may reflect various physioh)gical tit)(] 1)sychoh)gical cond{tions. Inded, it has been fo, nd. for exanu)lc, that hesiration pauses in spontaneous speech are indicative o[ the differential effects of 2-dfioro-10-(3-dime(hylaminopropyl)phenothiazine (chlorpromazine) and sod/mn 5-isoamyl-5-ethy]barbituric acid (amol)arl)ital) ((;oldmanEisler, Skarbek, and Henderson 19655. Psy&otomimetic drags, sud_ tis 4-1)hosphory],_xy-o_N,N-dimethyltryptamine (psilocybin), 1)reduce an ex(iration syndrome (Hofmann 19615 which is charactcrized by an experience of time contraction or c h r o n o s y s t o I e, i.e. an increased data content anti [asler running of physiological clocks (F i s c h e r et al. 1966,

556

Test, Rodiey, Fischer / Psilocybin

1967)*). Verbalization garded as an external the coded expression It seemed reasonable effect of psilocybin through tile duration hesitation a n d low considered, Method

in the form of speed], can be remanifestation of thought, that is, of brain activity' (Z em a n 1963). to expect the time-contraction to be measurable during speech of pauses especially since both acoustic energy pauses could be

Results The results are s,mmarized in Table 1. The median pause duration most significantly indicates the effects of the drug and defines two subgroups. In the sub-group of ten subjects the median pause is shorter at drug peak, with a significance ;veil exceeding the 0 00t level using a one-tailed S t u d e n t' s t-test, while the sub-group of five subjects have significantly longer median pauses, p < 0.001 level. All fifteen subjects as a group show a significant

Twelve uuiversity students, 7 males and 5 females, served as subjeers fl_ree Each of them testedconsisted twice y/eldiag mental with sessions. session of reading altogether a selected,1_ expertneutral '_S-word passage from n book, under control conditions, that is, prior to oral ingestion of psilocybin, then, again, during the peak effect of the drug, 90 mtn after drug ingestion. Preceding the experiment by at.novelty least twoof weeks, each subject exposed experimentato psilocybiu to remove experience" from thew_ following

so recorded were processed through a pausimeter, definition of "pause" and the technique described

are

of T.

amplitudes _

Dnringof acoustical the present energy experimen, levels were

tation, defined the by pauses the para-or

medians,

and

means,

interquarfiles

tions the pauses for each ditions of and at the drug peak subjet were

standard

'fable

separately.

formula:

lion at drug

peak

gains

importance

in the light

of tile

fact that with the exception of one subject (N.G.), the total reading time changed less than 10%; specifically, three subjects, representing both sub-groups, took slightly less time to read the passage while the remaining eleven took slightly more. In other words, t h e t i m c to complete the reading of tile passage r e m a i n e d e s s e n t i a 11y u n c h a n g e d, w h i I e t h e 1e n g t h o f p a n s e s d e c r e a s e d. This dmngc

(pres-

I

1

}

e-ge PURE:TONE!i 6ENERATOR t !

f I

PuaEtone I.eUT

BLOCK I BLOCK 17 I BLOCK TIl s£ctiFIt0 DC COntROL ffj__ [ [ l--I CLIPPERS I PULSES SGINALI AMPLIFIER'ATT.W&VES 14V PEAI_ ON-OFF ELECTRONIC °u._"° / RECTIFIER SCHMITTTRIGGERS SWITCH I,Li........

PuaE ton(gal.

con-

.. Fig.

t:

Block diagram of pausimeter and associate instruments.

Si&;P_

I '

_

J

DIGITALCOUNTER .... _ll_._ii__ _,_

RECORDER 2

f.._

(la G e 1 p k e' s experiential intertorrential flood of inner sensat/on' or terminology: th,e subjec!t overestimatime. I

PRINTINGRECORDER i

., 771

L- -

_

_-_ '._,

1: Median, semi-interquartile, arid mean pause duration with standard deviation as well as t/me contraction or chronosTstolc in */* of the median pause; from the. recorded reading of a selected lP..8-word passage. Twelve subjects, three of whom were twice, were contrasted under control condRions mad at the peak of a psilocybm experience. *) Second session alter at least [ MPe--MP, month interval. **) Chronosysio[e of the Median Pause duration C.S. x_' -- 100 \.

Sex No.

Subject '

Dosage Psilocybin in ga/kg

1. 2. ). 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

of

(msec) MedianP_aseDuration MP_ ] (control) [MP_ (peak)

165 t34 15i 169 157 174 163 158 157 t42 1'57 125 157 165 153 S's

1--10

S's 11--1_

5t.8 46.6 36.7 41.3 43.8 42.3 _3.8 36.3 33.5 36.7 38.6 60.3 40.4' 46.4 38.2 t _

t

16.8

at

devia-

under control computed.

*) Chronosystole or time contraction. From the observer's point of view: a subject's experience of an increased data content within a chrono,logical time unit unaccompanied by an increase in data processing. pretatiou: "the m an objective les chronological

duration

c---------q [ 'ram: l RECSItOER I

The detection of "pauses" from durations a sample ofmay speech and the measuring of their be made by meads of an electronic device and asseelate instruments, called the "paasimeter". The pausimeter responds to the proposed definition of pause; adequate controls of its RC circuits allow meters Lr, and T.. Fig. I is a bio& diagram of the pansimeter and associate instruments, when used the setting of a wide range of values for the par. ato detect and measure defined the duration of pauses from a sample of speech, at predetermined lcvels of L, and T..

pause

C S Mp = 100 M_pc--MP, ' ' MPc and listed in the table. Thc magnitude of time contrac-

according by T o si

the is

considered

basis of the

A "pause" is a flow of acoustic energy of which the amplitudes remain b e 1 o w a predetermined value of a parameter called .,pause-maximum amplitude, L.", provided the duration of such levels of amplitude is more than a predetermined amount of time, indicated by another parameter called .pause-minimum duration, Tp". The parameter L,, is expressed as a percentage sure or voltage) of the rectified waves sample of sound analyzed. The parameter expressed in milliseconds.

of the median

A Der cent of time contraction or c h r o n o s y s t o I e was calculated from the median pause duration on the

(1966).

or dB ratio with respect to the average peak

shortening

the same level of significance as when the two subgroups

tion. Drug dose ranged from lg'I to 174 pa/kg psilooybin taking into account a subject's "drug sensitivity" estimated on the basis of his taste sensitivity ( F i s c h e r, K n o p p, and G r i f f i n 1965) and the experiential intensity of the previous exposure to l_ilocybin. Control and drug peak readings were tape-recorded on Uher Model 40005, the average of recorded speechof monitored3,75 inches/see in order towithmaintain it as intensity almost constant. Samples speech to the

Heft 5

Duration (reset) IPause Semi-interquartile [ I control peak

41.9. 57.2 )i.6 3b.l 38.7 7_7.3 30.8 33.3 31.2 34.8 40.9 6,4.5 &4.5 _4.3 45.3 a _

one-tailed 5.3 a

27.1 25.8 39.2 26.2 46.1 20.4 24.9 2i.5 18.7 t9.5 21.5 24.2 43.4 22.6 19.8

0.001

t = 2.60

' O,OOt

t

Mean control

22.1 22,0 2i.i 19.3 26.i 18.5 22.2 21.I 15.3 19. t 19.2 2b.9 57.2 22.9 28.3 a -- 0.0!

one-tailed 1.50 a = O.iO

(msec) Duration Pause

112.0 8/1.3 i10.8 93.3 120.2 85.2 55.4 74.8 _.O 94.8 64.3 87.3 127.2 7'J.1 89.4 t _ 3.28

t

peak 80.0 78.5 60.3 60.5 100.5 79.8 53.4 69.3 58.2 89.3 72.3 100.t 12:8.1 85,4 101.2 a _ O.0(D

one-t&/led 4.01 n = 0.005 .

(rosco) Standard control 209.8 156.1 t81.5 134.5 144.4 129.6 100.6 97.7 131._ 103.3 109.2 105.8 17,8.3 iOl.l 129.2

(C.S.) tested a one

ofDeviation Means

C.S.MP

peak

in '/***)

140.5 _7.2 110.4, 140.2 97.9 120.1 105.5 169.5 12D.3 159.3 120.2 104.5 I _/ '

20.2 20.0 13.9 12.6 lt.6 11.6 8.9 8.3 6.8 5.2 --5.9 --7.9 --10.1 - 17.1 _18.6

1;._ ,

{ '

"

j

t".

18.]ahrgang..........

Wcinges:_ Bfihr.Kl?ss !_(;inK'gobilol,a 1,.

_i_; in length of pauses is also reflected in the semi-inter'_ _ quartile paltse duration as well as mean panse duration. ' _'. :' ' These two measures were significant for ed& of the two sub-groups. Variability, as indicated by standard de, , elations, increased for seven subjects and decreased for ' ':_ _ tile other eight with the direction of change in variability _>_ distributed over both sub-groups. '_ ' ,i '_ i] Discussion We can hypothesize that the contraction of "pause" '.: duration at {he peak action of thc excitatory-exaltatory . s';; _ drug, psilocybin, is due to a faster grasp of tile infor% mati°n conveyed by eadt successive word or phoneme. _ We cannot cinnpare our data with those of Goldin a n - E i s 1 e r (1961, 1965) due to differences in metho· dology: we measured rate of data processing, i.e. informotion, whereas G o I d m a n - E i s I e r focussed on the quality of cognitive processes, i.e. meaning. _ H°nigfeld was able to demonstrate a decrement in lite performance of norlnal subjects under the influence of psilocvbin (1963) and Lysergic acid diethyiamide (LSD) (1965) in terms of "understandability" of spontaneous speedt. Data obtained from subjects'of our second sub-group, i.e. those who react to psiloeybin with an expansion of pause durations, approximate most closely the above findings. We assess these subjects as sensitive reactors whose deerelnent in performance could be accounted for by greater intensity and irequency of distracting halhlcinations due to their stronger drug experience (Fischer and Rockey 1967. 1968). We should like to emphasize that irrespective of dianges in tile median "pause" duration, no matter whidl direction they take, the total reading time is basically unaltered, i.e. it changes less than 10%. It may be frui{ful tO speculate about this phenomenon as another example of invariance. It is known that allophonie sonnds of specd_ are invariant with dmnges of pitch. · hntdness, and duration (Gibson 1966). It appears, then, that the total reading time of a given text is another invariant, in spite of lite reported changes in pause and word d.ration. Under the influence of tranquilizers, ii eonld be expected, then, that pause durations ill general would extend bnt within the invariance of the total '

reading time. Summary Alt increased data content during a chronologic time, in other words a time contraction or chronosvstole. · ;vas induced in 12 normal vohmteers in 15 tests by oral administration of 125--174 pg/kg 4-phosphorvloxy, 5 _,

P logy !ependent'. t¢ so_same employ pendence isjudg_es not

test..." me ,flher behold he most t which postural ment tder our

ther table _per comes fis is ncel in the t which lit, Cthis tbin ( 1 2). t he cted ual. iltncelled ion in lature

263

of such extinction phenomena*, which under more severe conditions may have survival value. One may then view proprioceptive and vestibular disorientation as arising from the conflicting psychological and physical frames of reference. At its worst, such disorientation may be compared to a 'jammed computer' state, a condition which may not be conducive to the survival of the ot_,;anism. The 'unjamming' of the computer by erasing or cancelling tile conflicting informational state may be functionally analogous to the "kick in the behind" under our experimental conditions. Acknowledgements: These studies (IND 3530 to R.F.) were supported by NIMH general research support funds. Our sincere thanks are due to Sandoz Pharmaceuticals, Basel, who thorugh the courtesy of Dr. M. Braude, FDA-NIMH Psychotomimetic Agents Advisory Committee, provided the psilocybin. References 1 Hill, ILM., IL Fischer: Effects of excitatory and tranquillizing drugs on visual perception. Spatial distortion thresholds. Experientia 25 (1969) 171 2 Gwynne, P.H., IL Fischer, R.M. Hill: Hypnotic induction of the interferenceof psilocybin with optically induced spatial distortion. Pharmakopsychiat. NeuroPsychopharmak. 2 (1969) 223 3 Fischer, IL, R.M. Hill, Ix, Thatcher, J. Scheib: Psilocybin induced contraction of nearby visual space. Agents and Actions I (1970) 190 4 Fischer, R.: Psychotomimetic drug-induced changes in space and time. Proceedings4th International Congress on Pharmacology, July 14-18, 1969 in Basel, Switzerland, Vol. Ill, Schwabe und Co. Publishers, Basel/Stuttgart, pgs. 28-61. See discussions followingby H.E. Lehman, pgs. 61-68 and by R.M. Hill,pgs.68-74. 5 Hill, R.M., IL Fischer: Psilocybin-induced transformations of visual space. Pharmakopsychiat. Nemo-Psychopharmak. 3 (1970) 256 6 WitMn, H.A., S.E. Asch: Studies in space orientation, Iil. Perceptionof the upright

in the absence of a visual field. Journ. Experiemental Psychol 38 (1948) 603 7 Witkin, H.A.Y.,_K. Oltman: Cognitive style.Inter.Journ. Neurok6 (1967) 119 8 Witkin, H. A.: Personal communication to R.F. Dated June 14, 1971. 9 Ovid[us, P.N.: Metamorphoses I, 84-85; as quoted by Straus, E.W., in Tijdschr. voor Filosofie 27e 4 (1965) 659 in the translation of Erling Eng. 10 ttoward, I.P., W.B. Ternpleton: Human spatial orientation. John Wiley & Sons, NewYork(1966)seep. 175 11 Day, R.H., N.J. [fade: Visual spatial aftereft¥ct from prolonged head-tilt. Science 154 (1966) 1201 12 Fischer, IL, ILM. Hill: To be published. 13 b2scher, R.: Out on a phantom limb; variations on the theme: Stability of body imageand the golden section. Persp. Biol. and Med. 12 (1969) 259 14 Fischer, IL: Unpublished. 15 Nyborg, H.: Tactile stimulation and perception of the vertical. Scand. J. Psychok 12 (1971) 1

Prof. Richard M. Hill, Ph.D., College of Optometry, The Ohio State University, Columbus, Ohio 43210/USA. Prof. Roland Fischer, Ph.D., The Maryland Psychiatric Research Center, Box 3235, Baltimore, Maryland 21228/USA

*Nyhorg reports a more accurate perception of the vertical after specific tactile stimulation (in analogy to our strong body distortion) by using the Rod-and-Frame Test in conjunction with whole body support during tilt (15).

Confinia psychiat. 20: 195-202 (1977)

The Effects of Psilocybin on Primary Process Content in Language Colin Martindale and Roland Fischer Department of Psychology, University of Maine, Orono, Me. and Maryland Psychiatric Research Center, Baltimore, Md.

Abstract. The hypothesis that psilocybin induces primary process thinking was assessed. On four separate occasions, a subject was asked to write before, during, and after the hallucinogenic experience induced by doses ranging between 80 and 200 IJ.g/kgof psilocybin. Texts produced at the drug peak contained significantly more primary process content and were significantly more stereotyped on several measures than those written before or after the drug peak.

The term drug 'trip' to describe the effects of psychotomimetic drugs may be seen as the usage of a spatial metaphor to describe what is really an alteration in state of consciousness, a 'movement' along the perception-hallucination continuum delineated by Fischer (1971). Some themes of the journey in literature can be interpreted in a similar light. Martindale (1974) has proposed that literary journeys to hell and other fabulous destinations are in fact extended metaphors describing alteration in state of consciousness. They are, in a sense, retrospective accounts of their own creation. This follows from the notion that the act of creation involves an initial stage of inspiration, wherein the creator undergoes an alteration in state of consciousness, and a subsequent stage of elaboration, wherein there is a return to a more normal state of consciousness (Kris, 1952). One may ask whether the destinations of the drug 'trip' and the 'fabulous voyages' of literature are the same. That is, do they involve a movement to the same or a similar state of consciousness? There is some theoretical reason to believe that they might. Both Fischer (1971) and Martindale (l975b) have demonstrated that creativity is connected with changes in level of arousal. Psychotomimetic drugs, such as psilocybin, LSD, and mescaline raise level of

Martindale/Fischer

196

arousal. Several theorists (e.g., Blum, 1961; Martindale, 1975b) have proposed that arousal is connected with what Freud (1938) labelled primary process thinking. We may see the fundamental continuum of states of consciousness as ranging from secondary process (abstract, analytic, purposeful, reality-oriented) to primary process (concrete, free associative, drive-dominated, autistic) states. We assume that normal or secondary process states are based upon a medium or 'normal' level of cortical arousal. When arousal is increased or decreased, primary process thought results in connection with an altered state of consciousness. Martindale (1975a) has developed a content analytic measure of primary process thinking presented later in this article. Using this measure, several studies (Martindale, 1974; Martindale and Hasenfus, 1975) have shown that primary process content rises to a peak and then declines across the course of narratives (such as The Tibetan Book of the Dead, Book VI of The Aeneid, and the first part of the Divine Comedy) that describe a journey to hell and a subsequent return. The purpose of the study described in this paper was to investigate whether this same pattern would be found in verbal material of a subject across the course of experiences induced by psilocybin. The volunteer subject used in this study, W.L., was a 28-year-old instructor of comparative literature at the time of his participation as a volunteer in psilocybin research. On a task tapping perceptual-behavioral stability or variability W.L. emerges as a 'variable' subject (Landon and Fischer, 1970; Fischer and Landon, 1972).

This task involves having a subject copy a standard 28-word passage several times and then computing the standard deviation on handwriting area. 'Variable' subjects - those who exhibit a large range of standard deviations - turn out to be those who are maximally susceptible to the effects of psychotomimetic drugs (Fischer, 1971). Variable subjects display significantly higher resting heart rates than do stable subjects. It is apparently this difference in arousal baseline level that is related to differential reactivity to hallucinogenic drugs. Under conditions of sensory attenuation stable subjects tend to maximize sensory input at drug peak while variable subjects tend to minimize it. Under these conditions the stable maximizers have no opportunity to maximize their optimal sensory input and hence will never be sure whether they have obtained a placebo or the drug. Variable minimizers, on the other hand, do not have to further minimize the already attenuated sensory input which prevails in the sensory attentuation chamber and, therefore, will have optimum conditions for an intense hallucinogenic drug experience (Panton and Fischer, 1973). These studies confirm in humans the experiments of Bradley and Key (1963) performed on a variety of animals. After 5 p.g/kg of hallucinogenic drug, EEG activating effects were found to depend upon a minimum amount of stimulation.

Effects of Psilocybin on Language

197

Landon and Fischer (1970) compared a sample of W.L.'s non-drug prose with a sample of prose written while under the effects of an 80l1g/kg dose of psilocybin. They found that the drug had effects on several linguistic dimensions: there was a movement toward the use of more concrete (as opposed to abstract) noun phrases; length of sentences, clauses, and T-units (independent clauses and subordinate clauses dependent upon them) decreased; use of subordination gave way to simple concatenation of clauses; and topical organization of subject matter broke down. In addition, standard deviations for most of these measures were appreciably smaller for drug than for control texts, indicating increased stereotypy of language produced under the influence of the drug. The findings of increased concreteness and of breakdown of syntactic and rhetorical integration are consistent with the hypothesis that the drug induces a primary process state. The findings of increased stereotypy are consistent with the idea that it induces heightened arousal.

Method Texts Texts were obtained during four separate sessions with the subject. Several months elapsed between each session. In each session, an attempt was made to obtain a sample of his writing during the three phases of the drug experience: the ascending branch (0-60 min after drug ingestion), the drug peak (60-120 min after ingestion), and the descending branch (over 120 min after ingestion). During the ascending branch, the drug has not yet fully taken effect, while during the descending branch its effects are wearing off. In several cases, not enough was written to allow meaningful analysis. At least 100 words of text are necessary for the methods to be expected to yield reliable results. Table I presents information on the texts obtained.

Table I. Dates of sessions, dosages of psilocybin, and number of words in textual samples Date

February 7 AprilS June 25 October 24

Dosage IJ.g/kg

160 80 80 200

Number of words in sample ascending

peak

descending

387 609 220 664

256

306 328

286

Martindale/Fischer

198

During the sessions of April 5 and June 25, the subject was asked to recall and write about a previous 80 tJ.g/kgpsilocybin experience. In the February 7 session, he was asked to write in reply to the question, 'Who are you and on what spiritual voyage are you embarking?' In the October 24 session, he was asked to write about a woman with whom he was in love.

Content Analysis Textual samples were keypunched and analyzed with the Regressive Imagery Dictionary (Martindale, 1975a). The Regressive Imagery Dictionary is a content analysis coding scheme implemented with a computer program called COUNT (Martindale, 1973a). COUNT accepts keypunched natural language texts and, after punctuation and suffix removal, looks up each text word in a dictionary that contains information as to which categories a list of up to 4,000 words is to be assigned. A running total of category occurrences is kept and the final output consists of a printout of the categories and the percentage of words in a document that were assigned to each category. The Regressive Imagery Dictionary contains 3,647 words assigned to 29 categories designed to measure primary process content. These categories were derived from the theoretical and empirical literature on regressive thought (Martindale, 1975a). The rationale behind the dictionary is that psychological processes operant at the time of a text's composition will be reflected in the content of the text. Thus, for example, the more primary process the thought involved in producing a text, the less abstract and the more drive- and sensation-oriented words it should contain. The primary process categories and examples of the words in each are given in table II. The dictionary yields a measure, primary process, derived by summing the word-based percentage occurrence scores of the component categories. Primary process words are listed under the summary categories Drive, Regressive Cognition, Defensive Symbolization, Sensation, and Icarian Imagery in table II. Primary process is measured by the percentage of words in a text that are classified into any of the primary process categories. Martindale (1975a) reports detailed evidence concerning the reliability and validity of the Regressive Imagery Dictionary. Evidence for the construct validity of primary process as an index of regressive or dedifferentiated thought comes from a number of studies where the measure has behaved as theoretically predicted. Significantly more primary process content has been found in the poetry of poets exhibiting signs of psychopathology than in that of poets not exhibiting such signs (Martindale, 1975a) and in fantasy stories of creative as opposed to uncreative subjects (Hines and Martindale, 1973). Unpublished research by Martindale has revealed more primary process content in verbal products of schizophrenic and anxious subjects as compared with control subjects. Martindale (1976) in a crosscultural study found, as predicted from the 'primitive mentality' hypothesis of Levy-Bruhl (1966) and Werner (1948), that amount of primary process content in folktales is negatively correlated with degree of sociocultural complexity in preliterate societies. Finally, the measure has varied as predicted in several studies of historical change in the content of poetry (Martindale. 1973b, 1975a). Thus, the Regressive Imagery Dictionary does seem to yield a reliable and valid index of primary process or dedifferentiated thought in a variety of contexts.

-_._-._----------

Effects of Psilocybin on Language

199

Table II. Regressive imagery summary categories, categories, and examples of words in each category Summary category Category

Example of words in category

Drive Oral Anal Sex

breast, drink, lip sweat, rot, dirty lover, kiss, naked

Regressive cognition Unknown Timelessness Consciousness alteration Brink-passage Narcissism (bodyparts) Concreteness (spatial references)

secret, strange, unknown eternal, forever, immortal dream, sleep, wake road, wall, door eye, heart, hand at, where, over

Defensive symbolization Passivity Voyage Random movement Diffusion Chaos

die, lie, bed wander, desert, beyond wave, roll, spread shade, shadow, cloud wild, crowd, ruin

Sensation General sensation Touch Taste Odor Sound Vision Cold Hard Soft

fair, charm, beauty touch, thick, stroke sweet, taste, bitter breath, perfume, scent hear, voice, sound see, light, look cold, winter, snow rock, stone, hard soft, gentle, tender

Icarian imagery Ascend Height Descend Depth Fire Water

rise, fly, throw up, sky, high fall, drop, sink down, deep, beneath sun, fire, flame sea, water, stream

200

Martindale [Fischer

o

16

x o

*

14 w

~ to LSD, psilocybin has no dopaminergic effect.699 In small doses, psilocybin evokes psychostimulation and anorexia, and experiments have used them in the therapy of body dysmorphic In toxic doses, psilocybin causes symptoms due to inhibition of CNS muscarinic receptors. Panic, schizophrenic, and obsessive-compulsive disorders have been d e s ~ r i b e d . ~ ' Psilocybin '~~ acts almost immediately, its biological activity continuing for 2-4 hours, with characteristic, repeated episodes of intoxication symptoms up to 24-48 End-stage renal failure and neurotoxic effects are described in users of natural hallucinogens .3*7-10 We describe a case of a myocardial infarct in an 18-year-old man with psychodysleptic intoxication. The clinical observations suggest the possibility of cardiac damage related to psilocybin. The mechanisms of cardiovascular toxicity by psilocybin are complex. Indole alkaloids are agonists at the 5-HT receptors in the CNS. Peripherally, the sympatho-

Psilocybin Intoxication mimetic stimulation is manifest as tachycardia and h y p e r t e n ~ i o n .Use ~ of serotonin agonists in migraine has caused myocardial infarction due to coronary vasoconstriction. The 5-HT receptors agonists can also lead to platelet hyperaggregation and occlusion of small coronary a r t e r i e ~ . ~ Both of these mechanisms may have caused myocardial infarction in our patient.

'

Clinical Toxicology Downloaded from informahealthcare.com by Univ Rovira I Virgili on 01/17/14 For personal use only.

REFERENCES 1. Lassen JF, Lassen NF, Skov F. [Consumption of psilocybin-containing hallucinogenic mushrooms by young people]. Ugeskr Laeger 1992;154:2678-2681. 2. Schwartz RH,Smith DE. Hallucinogenic mushrooms. Clin Pediatr Phila 1988;27:70-73. 3. Spitzer M, Thimm M, Hermle L, et al. Increased activation of indirect semantic associations under psilocybin. Biol Psychiatry 1996;39:1055-1057. 4. Hanes KR. Serotonin, psilocybin, and body dysmorphic disorder: A case report. J Clin Psychopharmacol

1996;16:188-189.

49 5. Gartz J. Extraction and analysis of indole derivatives from fungal biomass. J Bm'c Microbiol 1994;M:

17-22. 6 . Buckholtz NS, Zhou DF, Freedman DX, Potter WZ.

Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain. Neuropsychopharmacology 1990;3:137-148. 7. Franz M, Regele H, Kirchmair M, et al. Magic mushrooms: Hope for a "cheap high" resulting in end-stage renal failure. Nephrol Dial Transplant

1996;11 :2324-2327. 8. Dreisbach RH, Robertson WO. Vademecum intoxications. In: Handbook of Poisoning: Prevention, Diagnosis and Treatment, 3rd Polish ed. (translation). [Norwalk, CT: Appleton & Lange, 19871, Warsaw: PZWL, 1995:451-452. 9. Craig CR, Stitzel RE. Modern Pharmacology. Boston: Little Brown Co, 1982592-595. 10. Raff E, Halloran PF, Kjellstrand CM. Renal failure aRer eating "magic" mushrooms. Can Med Assoc J 1992;147:1339-1341. 11. Kostkowski W,Puzynski S . Experimental Psychopharmacology. Warsaw: PZWL, 1992:422-428.

Forensic Science International 113 (2000) 403–407

www.elsevier.com / locate / forsciint

Detection of psilocin in body fluids ¨ G. Sticht*, H. Kaferstein ¨ ¨ , Germany 60 -62, D-50823 Koln Institute of Forensic Medicine, University of Cologne, Melatengurtel

Abstract Active compounds of some mushrooms e.g. Psilocybe cubensis, Paneolus subalteatus or Stropharia coronilla, the psychotropic agents psilocybin and psilocin, have hallucinogenic effects. In one case of ‘magic mushroom’ intake, we had to analyse blood and urine. Psilocin was detected in the urine with REMEDi HS. Most of the psilocin was excreted as the glucuronide. Therefore an enzymatic hydrolysis should be the first step in analysis. Free psilocin was determined at a concentration of 0.23 mg / l while the total amount was 1.76 mg / l urine. The concentration of psilocin in serum was too low for detection with REMEDi HS. We proved a GC–MS-method with d 3 -morphine as internal standard and silylation with MSTFA. Similarly to urine, most of the psilocin in serum was found in the conjugated form. The concentration of free psilocin was 0.018 mg / l, that of total psilocin, 0.052 mg / l serum.  2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Psilocin; Psilocybin; Body fluids; Magic mushrooms

1. Introduction In recent years so called ‘magic mushrooms’ play a growing role among controlled substances. For instance, the species Psilocybe cubensis is offered as a set for cultivation (Fig. 1). At a corresponding time of the year in our region, mushrooms like Paneolus subalteatus or Stropharia coronilla can be collected [1]. Active components are the psychotropic substances psilocybin and psilocin (Fig. 4). The content of psilocybin is normally far higher than that of psilocin which does not have the protecting phosphorous ester group in its molecule. The mushrooms are consumed because of their hallucinogenic effects. They are illegal drugs with no accepted medical use but a high abuse potential (schedule I controlled substances). A rapid dephosphorylation of psilocybin to psilocin takes place in the organism [2], and it can *Corresponding author. Tel.: 149-221-478-4291; fax: 149221-478-4261.

be assumed that psilocin is similar to morphine glucuronidated to a high degree. Additionally psilocin should have comparable extraction properties as morphine because of the presence of a phenolic and a tertiary amino group. Symptoms after intake of psilocybin containing mushrooms can be very pronounced as the following example demonstrates.

2. Case report Two young male people drove from Cologne to The Netherlands to buy narcotic drugs. Among others, mushrooms were offered. Each of the men consumed 4 to 5 g of mushrooms. Subsequently they doubled up with laughter. Sometime later the house wall seemed to come up to the persons. After the effects had worn off and the persons felt fit again, they started homeward. During the trip on the

0379-0738 / 00 / $ – see front matter  2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0379-0738( 00 )00213-9

404

¨ / Forensic Science International 113 (2000) 403 – 407 G. Sticht, H. Kaferstein

Fig. 1. In a journal, a set for cultivation of mushrooms was offered.

highway the driver stopped his car because he turned sick. Then policemen came, confiscated the rest of the drugs and forbade further driving of the car. Twenty min later the policemen observed the car again but with insecure driving and they stopped it. The reaction ability of both occupants was retarded, stability in standing was insecure and the eyes were glassy and reddened. Two h later, 5 to 6 h after consuming the mushrooms, the doctor taking blood noted the following observations concerning the driver: insecure and sluggish walk, inarticulate speech, strongly enlarged pupils, delayed pupillary reaction, dazed consciousness, retarded behaviour, depressive mood, illogical thinking, slight problems of naming time and local position.

Varian Bond Elut LRC Certify 300 mg per 10-ml ¨ columns (Phenomenex / Hosbach) Reagent Kit and other supplies for drug determination with REMEDi HS.

3.2. Instrumentation REMEDi HS drug profiling system (Bio-Rad). Hewlett-Packard 5995A gas chromatograph / mass spectrometer connected to a 59970A Workstation. Split ratio, 1:10. Injector temperature, 2508C; detector temperature 2008C, and the oven temperature was programmed from 2008C at 58C / min to 2508C. An HP Ultra-1 capillary column (12 m30.2 mm I.D.3 0.33 mm film thickness) was used. Carrier gas: helium 5.0.

3. Experimental

3.3. Performance of analysis

3.1. Reagents

3.3.1. REMEDi One ml of urine was prepared as recommended for drug analysis with REMEDi HS. Cleavage of the glucuronide in a second sample was performed in a water bath at 458C during 1 h after addition of 10 ml of glucuronidase solution.

Psilocin (100 mg / ml methanol) was obtained from Sigma–Aldrich. d 3 -Morphine was synthesised in our laboratory. b-Glucuronidase from E. coli K 12 (Boehringer / Mannheim). MSTFA (N-Methyl-N-trimethylsilyltrifluoroaceta¨ mide) (MachereyNagel / Duren).

3.3.2. GC–MS A solution of 25 ng of d 3 -morphine in 40 ml

¨ / Forensic Science International 113 (2000) 403 – 407 G. Sticht, H. Kaferstein

methanol was added to 0.5 ml of serum or urine, to a parallel sample, additionally 10 ml of glucuronidase solution for hydrolysis of the glucuronide as described above. The samples were diluted with 5 ml of phosphate buffer pH 8. Column conditioning: the following solutions were aspirated through Varian Certify LRC 300-mg columns: 2 ml of methanol, 2 ml of phosphate buffer pH 8. Sample addition: the prepared samples were aspirated through the columns at 1 to 2 ml / min until the columns went to dryness. Column wash: 2 ml water, 2 ml acetate buffer pH 4, 2 ml methanol / water (30% v / v). The columns were then dried under vacuum for 2 min. Sample elution: the elution was performed with methanol / conc. ammonium hydroxide (9812 v / v) at slight vacuum, first with 2 ml and then with 1 ml. Derivatization: The solution was evaporated under nitrogen at 408C and after addition of 50 ml MSTFA the tube was closed with parafilm and heated for 15 min at 808C. The injection volume was 10 ml. The detector was used in the electron impact mode (El) at 70. Mass spectra were recorded in the mass range of m /z 50–550. Qualitative and quantitative analyses were performed using single-ion monitoring (SIM) mode by comparison of retention times and relative abundance of three ions (psilocin-di-TMS 290, 291, 348) resp. four ions (d 3 -morphine-di-TMS 404, 417, 432, 433).

405

The retention indices were calculated to 2099 for psilocin-di-TMS and 2520 for d 3 -morphine-di-TMS.

4. Results The calibration ranges were from 1 to 10 ng psilocin and d 3 -morphine as di-TMS-derivatives corresponding to concentrations of 10 to 100 ng / ml serum or urine. There was linearity within these ranges (R 2 .0.99). Recoveries of psilocin and d 3 morphine after addition of 25 ng / ml to 0.5 ml serum were nearly complete. Recovery of psilocin related to d 3 -morphine as internal standard amounted to 98% with a standard deviation of 12% (n53). The limit of detection was about 5 ng / ml serum. After a conceded intake of Psilocybe cubensis blood and urine were available for investigation. Using REMEDi HS drug profiling system psilocin could be detected in urine. By GC–MS analysis in both body fluids psilocin was detectable. In urine a complete mass spectrum was to achieve as Fig. 2 demonstrates. The library search of the system led to psilocybin but it is considered that the phosphorous ester group is cleaved by the derivatization reaction. Fig. 3 shows ion chromatograms of the serum sample. The characteristic mass peaks 290, 291, and 348 of psilocin-di-TMS are present at a retention time of 4.54 min in expected relative intensities.

Fig. 2. Comparison of mass spectra of psilocybin-TMS-derivative and of a compound from an urine extract.

¨ / Forensic Science International 113 (2000) 403 – 407 G. Sticht, H. Kaferstein

406

Fig. 3. Ion chromatograms of a serum extract (psilocin-di-TMS derivative marked with an arrow).

The following concentrations were measured (Table 1).

5. Discussion Keller et al. [3] have recently described a GC– MS-method for the detection of psilocin in mushrooms after derivatization with MSTFA. In our procedure for estimation of morphine and benzoylecgonine, we use the same derivatization technique [4]. Protection of the two polar groups of psilocin, a phenolic and a NH-group, by trimethylsilyl (TMS) may avoid thermal decomposition. The structure of psilocin–di-TMS is confirmed by the occurrence of the molecular peak m /z 348 and the typical fragment m /z 290 formed by loss of m /z 58 in the mass spectrum. Psilocybin, the main active component of ‘magic mushrooms’ is transformed into psilocin by rapid dephosphorylation which is indicated by a short period between oral and a very short interval between intravenous administration of psilocybin and Table 1 Psilocin concentrations in serum and urine after consumption of ‘magic mushrooms’

Psilocin (free) (mg / l) Psilocin (total) (mg / l)

Serum

Urine

0.018 0.052

0.23 1.76

maximum plasma levels, 105 resp. 1.9 min [2]. Hasler et al. [2] found peak plasma levels of 8.262.8 ng / ml psilocin after oral administration of 0.22460.02 mg / kg (10–20 mg) psilocybin. Our investigations demonstrate that psilocin can be detected in body fluids after consumption of corresponding mushrooms. Glucuronidation seems to be an important detoxification step (Fig. 4). In the presented case, the free part of psilocin in serum is 35% and in urine only 13%. Similar high parts of bound psilocin in blood, urine and bile of two individuals are referred by Wennig [5]. The REMEDi HS system is suitable for screening of urine for psilocin. But in spite of an expected obviously higher yield a general enzymatic hydrolysis is not to recommended because by far more interfering substances appear in the chromatogram which can overlap the internal standard 1. In serum, not even after hydrolysis concentration of psilocin is high enough for a detection with REMEDi HS and therefore GC–MS analysis is the method of choice. Extraction and derivatization are successful in the same way as with morphine. Psilocin can be detected therefore by the procedure used for opiate and cocaine detection without problems. Morphine or deuterated morphine can serve as internal standards because of similarities with psilocin in the structure and properties in the extraction procedure. For screening of blood or urine with GC–MS an enzymatic hydrolysis is recommended because the

¨ / Forensic Science International 113 (2000) 403 – 407 G. Sticht, H. Kaferstein

407

detectable amounts of psilocin increase remarkably by this procedure.

References ¨ [1] A. Bresinsky, H. Besl, Giftpilze mit einer Einfuhrung in die Pilzbestimmung, in: Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1985, pp. 112–118. [2] F. Hasler, D. Bourquin, R. Brenneisen, T. Bar, F.X. Vollenweider, Determination of psilocin and 4-hydroxyindole-3acetic acid in plasma by HPLC–ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man, Pharm. Acta. Helv. 72 (1997) 175–184. [3] T. Keller, A. Schneider, P. Regenscheit, R. Dimliofer, T. ¨ Rucker, J. Jaspers et al., Analysis of psilocybin and psilocin in Psilocybe subcubensis GUZMAn by ion mobility spectrometry and gas chromatography–mass spectrometry, For. Sci. Int. 99 (1999) 93–105. ¨ [4] H. Kaferstein, G. Sticht, Immunchemische und gaschromatographisch massenspektrometrische Befunde im Blut bei Verdacht auf Drogenkonsum-1. Mitteilung: Opiate Kokain, Cannabis und Amphetamine, Rechtsmed 8 (1998) 173–177. [5] R. Wennig, Personal communication (1999).

Fig. 4. Structures of psilocybin, psilocin and psilocin glucuronide.

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airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004; 169: 361–6. 16 Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007; 49: 2028–34.

17 Brack T, Thuer I, Clarenbach CF, Senn O, Noll G, Russi EW et al. Daytime Cheyne-Stokes respiration in ambulatory patients with severe congestive heart failure is associated with increased mortality. Chest 2007; 132: 1463–71.

18 Roebuck T, Solin P, Kaye DM, Bergin P, Bailey M, Naughton MT. Increased long-term mortality in heart failure due to sleep apnoea is not yet proven. Eur Respir J 2004; 23: 735–40. 19 Becker HF. Bigger numbers needed! Eur Respir J 2004; 23: 659–60.

L E T T E RS T O T H E E D I T O R

Clinical-scientific notes A fatal case of ‘magic mushroom’ ingestion in a heart transplant recipient A 24-year-old heart transplant recipient presented to hospital following a cardiac arrest 2–3 h after ingesting an unknown quantity of magic mushrooms. The patient received a heart transplant 10 years previously for end-stage rheumatic heart disease. Her posttransplant progress was uncomplicated. At her last clinic review before death (9 years post-transplant), she was well with no physical limitations. Six months later, 2–3 h after consuming magic mushrooms, she collapsed. She received no bystander cardiopulmonary resuscitation and was cyanosed and pulseless on ambulance arrival. With resuscitation, she had intermittent return of spontaneous circulation interspersed with ventricular fibrillation/ventricular tachycardias/bradyarrythmias. Resuscitation continued for 100 min before she was declared deceased. Autopsy confirmed a healthy cardiac allograft (no allograft vasculopathy). Plasma toxicology revealed a psilocin level of 30 mg/L (consistent with magic mushroom toxicity) and a tetrahydrocannabinol level of 4 mg/L. No alcohol or other common drugs of abuse were detected. The cause of death was determined by court-appointed experts to be psilocin toxicity. Many species of toxic mushrooms exist. This report focuses on mushrooms with hallucinogenic effects (Psilocybe genus). Psilocybin and psilocin are the two main compounds responsible for hallucinogenic effects and act as partial agonists at 5HT1A, 5HT2A, dopaminergic and adrenergic receptors. Psilocybin is absorbed from the gastrointestinal tract. Psychological effects begin 10–30 min after ingestion (at 1268

a plasma concentration of 4–6 mg/L) and last for 2–6 h. The toxicity of psilocybin is low (LD50 = 280 mg/kg in rats), a 60-kg person would need to ingest up to 17 kg of fresh mushrooms to reach this dose. Acute effects involve all organ systems – cardiovascular (tachycardia, hypertension), neurological (headache, confusion, euphoria, muscle weakness, hallucinations, panic attacks), respiratory (transient hypoxaemia), gastrointestinal, renal, ocular and haematological. Only two deaths have been previously reported directly attributable to magic mushroom ingestion, one because of neurological sequelae (somnolence and convulsions) 6–8 h after ingestion of an unknown quantity of magic-mushrooms.1 Post-mortem toxicology revealed very high plasma psilocin concentration (4000 mg/L). Details of the second are scanty.2 Other deaths reported are as a result of accidents or self-harm following mushroom ingestion.3 Reported toxicity is variable and includes cardiovascular toxicity (arrhythmia,4 acute coronary syndromes5 and catecholamine-associated cardiomyopathy), multiorgan failure6 and syndromes consistent with excessive catecholamine stimulation. Injury related to the psychological effects of mushroom intoxication is also described. No specific antidote is available, and treatment is supportive. To our knowledge, this case is the first reported death from a cardiac arrest because of ingestion of psilocybe mushrooms. Control of heart rate is dependent on interplay between the sympathetic and parasympathetic nervous system. In the context of heart transplantation, cardiac adrenergic receptors remain intact after denervation and become supersensitive to exogenous catecholamines. Partial sympathetic reinnervation may occur © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians

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Letters to the Editor

postoperatively in transplanted hearts; however, parasympathetic control remains absent in the majority of patients. We postulate that in this case excessive sympathetic stimulation of the transplanted heart as a result of Psilocybe mushroom toxicity led to fatal ventricular arrythmias.

References 1 Gerault A, Picart D. Intoxication mortelle a la suite de la consommoation volontaire et en groupe de champignons hallucinogenes. Bull Soc Mycol France 1996; 112: 1–14. 2 Buck RW. Mushroom poisoning since 1924 in United States. Mycologia 1961; 53: 537–8. 3 Van Amsterdam J, Opporhuizen A, van den Brink W. Harm potential of magic

Received 22 April 2012; accepted 30 May 2012. doi:10.1111/j.1445-5994.2012.02955.x

T. H. Lim,1 C. A. Wasywich3 and P. N. Ruygrok2 1

Greenlane Cardiovascular Service and 2Department of Cardiology, Auckland City Hospital, 3New Zealand Heart and Lung Transplant Service, Auckland, New Zealand

mushroom use: a review. Regul Toxicol Pharmarcol 2011; 59: 423–9. 4 Borowiak KS, Ciechanowski K, Waloszczyk P. Psilocybin mushroom (Psilocybe semilanceata) intoxication with myocardial infarction. J Toxicol Clin Toxicol 1998; 36: 47–9. 5 Nef HM, Möllmann H, Hilpert P, Krause N, Troidl C, Weber M et al. Apical regional wall motion abnormalities reminiscent to

Disseminated herpes simplex virus infection following epidermal growth factor tyrosine kinase inhibitor therapy for non-small-cell lung carcinoma A 77-year-old man with metastatic non-small-cell lung carcinoma (NSCLC) presented with symptoms of dehydration and haematuria in the setting of 3 weeks of diarrhoea following commencement of a novel epidermal growth factor receptor tyrosine kinase (EGFR TK) inhibitor, afatinib. His NSCLC was initially managed with gefitinib before disease progression warranted commencement of afatinib. The patient had not received any myelosuppressive chemotherapy or corticosteroids. He was Eastern Cooperative Oncology Group performance status grade 0 prior to hospital admission. On presentation, his neutrophil count was 6.99 ¥ 10-9/L (normal 2.0 to 7.5 ¥ 10-9/L), his lymphocyte count was 0.77 ¥ 10-9/L (1.0 to 4.0 ¥ 10-9/L), and his creatine was 141 mmol/L (60–130 mmol/L). Urinalysis identified >1000 ¥ 10-6/L isomorphic red blood cells (normal