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Summary Sensory attenuation, a modified form of sensory deprivation where sensory inputs are controlled, is described as a method useful for the study of drug responses. The above is a preliminary report about a comparative study, using this technic, of the following three psychotomimetic drugs: o 1. Sernyl 1—(1-phenylcyclohexyl) piperidine monohydrochloride (May and Baker CI395) 2. Psilocybin, a tryptamine derivative: isolated active principle of Psilocybe Mexicana Heim, a Mexican mushroom. (Sandoz) 3. LSD-25, D. lysergic acid diethylamide. (Sandoz)

The extracts ofP. venenosus, P. sphrinctrinus, Psil. mexicana, Psil. cubensis, andPsil. caerulescens have been compared by paper chromatography. It was found that neither Panaeoli contain psilocybin, the main constituent of the threePsilocybe species. The extract fromP. venenosus has been chromatographed, and two of the three major constituents were purified and obtained crystalline. One of these compounds could be shown to possess the same chromophore as psilocybin, a 4-oxygenated indole system, and seems most likely to be the active compound of the mushroom.

This paper is a continuation of our experiments with LSD-25 and similar compounds that have been carried out for the last thirteen years.1 It employs the same technique described previously2 to compare these drugs on non-psychotic test subjects under suitable conditions. The conditions of the experiment are most important because under certain circumstances the experimental milieu produces so much anxiety that the environment may be said to affect the results as much as the drug itself. Of particular importance is the growing use of methysergide (Sansert) in the treatment of migraine. The frequent occurrence of side affects due to Sansert and the apparent development of tolerance to this derivative of d-lysergic acid has led us to explore the effects of methysergide (Sansert) in the same test subjects used in the study of psychotomimetic drugs for the past ten years. The present series of experiments comparing LSD-25, psilocybin, psilocin and methysergide were begun in 1958. This communication will report...

A sample of mushroom seized by the Royal Canadian Mounted Police in Vancouver was shown by morphological examination to be a species of Psilocybe , a genus known to contain psychotomimetic principles. Chemical tests proved the presence of psilocybin (1.5% of the dried mushroom) as well as several other indole alkaloids. Psilocin could not be detected. Procedures suitable for routine examination of similar samples are described.

The activity of tryptophan pyrrolase in rat liver was significantly increased by stress and by chlorpromazine administration. Adrenalectomy did not prevent the increase in enzyme activity produced by chlorpromazine, but hypophysectomy eliminated the enzyme induction. The effect of several hormones and of psychotropic drugs was also studied. It was indicated that the pituitary as well as the adrenal was involved in the regulation of rat liver tryptophan pyr. rolase activity. (Endocrinology 76:1190,1965)

The synthesis of 14 C-psilocin labelled in two different positions is described. The resorption, distribution, excretion and metabolism of psilocin in the rat was studied quantitatively with the labelled compounds.

Incubation of psilocybin with rat kidney homogenates caused a rapid liberation of its -OH congener, psilocin, through the action of alkaline phosphatase. The psilocin thus formed underwent further degradation to form a blue-colored product. This last step appeared to be catalyzed by an oxidative enzyme which was cyanide-sensitive, but not to β-phenylisopropylhydrazine, a monoamine oxidase inhibitor; its optimal activity was at pH 9.0. In many respects it resembles the characteristics of a phenolase type enzyme. The distribution of the phosphatase and oxidase enzymes in a number of tissues from several species of animals was also investigated. Psilocybin-dephosphorylating activity was highest in the rat and mouse kidney and the mucosa of the small intestine of guinea pig and rabbit. Oxidase activity was highest in the heart of all species and in the kidney of the rat and mouse. These experiments indicate that possibly in the intact animal psilocybin is rapidly dephosphorylated and is pharmacologically active as psilocin, while the duration of the effect might be controlled by the oxidation of the latter compound to an o-quinone type of structure.

d-LSD was employed as a discriminative stimulus in a two-lever, freechoice procedure involving water reinforcement with rats. The results indicated that 1. doses of 0.02-0.04 mg/kg of d-LSD were at the “threshold” level of discriminability from no drug (saline), 2. 0.08 mg/kg was clearly discriminable from no drug, 3. the same dose of d-LSD (0.08 mg/kg) was also discriminable from d-amphetamine, and 4. subjects could probably discriminate, albeit weakly, between d-LSD and two other hallucinogens, mescaline and psilocybin.

Various modifications were made in the molecular structure of the natural psychotropic substances psilocybin (I) and psilocin (11) to obtain an insight into the relationship between structure and psychotropic action of this group of substances. A description is given of the synthesis and properties of the position isomers of I and II with a phosphoryloxy or hydroxy group in position 5, 6 or 7, of the four isomeric hydroxygramines, and of a series of further derivatives of 4-hydroxy-indole in which the structure of II was systematically modified, i.e. psilocin derivatives with other substitution at the ω-nitrogen; derivatives of II substituted at the indole nitrogen; psilocin derivatives with one additional methylene group in the side-chain or with a methyl-substituted or hydroxylated side-chain; phosphoric acid esters of some derivatives of II; esters of II with organic carbonic and sulfonic acids, with methylcarbaminic and with sulfuric acid; position isomers of psilocin with the dimethylaminoethyl side-chain in position 1 or 2.

(1960). Production of Cross-Tolerance to Psychosis-Producing Doses of Lysergic Acid Diethylamide and Psilocybin. The Journal of Psychology: Vol. 49, No. 1, pp. 151-154.

Mescaline, LSD-25, psilocybin, and a combination of these three drugs were each administered in moderate doses at 7-day intervals to 24 volunteer subjects according to a latin square design. Primary suggestibility, that type closely related to hypnosis, was measured both before and 2 hrs following each administration of drugs, using the 17-item Stanford Suggestibility Scale. A Trance Indicator Score was also obtained, representing both behavioral observations and subjective reports concerning the degree of trance-like or hypnotic-like experiences which may have accompanied each suggestibility testing session. Major findings were that mescaline, LSD-25, and the combination of drugs each produced an average enhancement in primary suggestibility closely comparable to that produced by an induction of hypnosis, the latter being tested for each subject after the completion of the drug series. Psilocybin did not enhance primary suggestibility. Associated trance phenomena were also substantially increased during all of the drug trials, but significantly less so for psilocybin. Significant correlations were obtained between suggestibility and Trance Indicator Scores following each drug and after induction of hypnosis, although psilocybin produced substantially less correlation. Although these results confirm speculations previously made in the literature that LSD-25 may increase suggestibility, it must be emphasized that they cannot be generalized beyond the specific type of suggestibility measured. Second, the differences between psilocybin and the other drugs on primary suggestibility restrict generalizations regarding the action of otherwise similar psychotomimetic drugs.

It was found that ergotropic arousal inducing drugs, such as psilocybin, a Ditran®-type ‘glycolate’ andd-amphet-amine, significantly lower human spatial distortion thresholds, i.e. these drugs, interfere with counter-adaptation to optical distortion, or the expectation to see the world undistorted. The trophotropic arousal inducing chlorpromazine® on the other hand promotes such counter-adaptation, i.e. the optimization of visual information. Optimization is independent from the rat at which the distorting stimulus is presented.

The relative effectiveness of N,N-dimethyltryptamine derivatives and amphetamine derivatives was evaluated in seven squirrel monkeys, trained to discriminate between two black discs of different sizes. After the animals learned the task, they were injected intraperitoneally with the test compounds and then retested. The dose-response curves showed that debilitating effects of the compounds were a function of dose. The median effective doses ( ED 50 ) that disrupted their performance were calculated according to the graphic logarithmic probit method. The descending rank order of effectiveness of the compounds, according to the ED 50 was: 2,5-dimethoxy-4-ethyl-amphetamine; 2,5-dimethoxy-4-methyl-amphetamine; psilocybin; 4-methoxy-N,N-dimethyltryptamine; N,N-dimethyltryptamine; and 6-hydroxy-N,N-dimethyltryptamine.

It is demonstrated in double-blind conditions that Psilocybin significantly changes an objective measure of after-image perception and that the occurrence of these changes is highly correlated with reports of altered visual experience. A hypothesis of how this effect and the findings of others can be explained on the basis of decreased inhibitory function in visual mechanisms involved in the perception of color and detail is presented with the caution that other explanations are possible. This study, and others, indicate the importance of knowing the nature of any subjective visual disturbance at the time that objective visual functions are performed to facilitate understanding of the mechanisms involved in hallucinogenic effect.

Resume Les effets electrophysiologiques de la psilocybine ont ete etudes chez le cercopithecinae Papio papio 1. 1. Les reponses visuelles (electroretinogramme, potentiels evoques au niveau du corps genouille lateral et du cortex visuel) ont ete etudiees seuls les potentiels evoques au niveau du cortex visuel primaire subissent une modification importante, constante et durable. 2. 2. L'action sur les potentiels evoques somesthesiques est variable d'un animal a l'autre, faible, se traduisant le plus souvent par une legere diminution d'amplitude. 3. 3. La psilocybine n'a aucun effet durable sur l'EEG. Une action specifique de la psilocybine sur le cortex visuel primaire peut etre consideree comme le support des manifestations hallucinatoires provoquees par la drogue chez l'homme.

Visual, tactile and intermodal sensory magnitude estimations were performed by college students prior to and after the oral administration of either 160 μg/kg psilocybin or 30 mg Δ9-THC. Although the drugs induce inversely related changes in the exponent of the psychophysical power function (R=kSn), the straight line relationship between log S (Stimulus) and log R (Response) is altered by neither psilocybin nor Δ9-THC. The remarkable consistency of magnitude estimations in the face of a changing exponent and constant may be interpreted as a demonstration of ‘state boundness’ (i.e., performance that is consistently changed and characteristic of a particular state of consciousness).

Summary Mescaline, lysergic acid diethylamide (LSD-25) and psilocybin were studied in 20 screened subjects, 18 receiving all three drugs. Drugs were administered under similar test conditions, doses were constant between drugs and subjects, assignments to drug followed a latin-square sequence, and subjects were unaware of the drug given on each trial. Clinical syndromes were assessed by a questionnaire completed by the subjects following each drug trial. Color perception was studied by means of both adequate and inadequate stimuli for eliciting color phenomena, measurements being taken before and two hours after drug was administered. A number of selected biochemical and physiologic measurements were also made at similar times. Clinical syndromes were comparable in kind and degree from all three drugs, that from mescaline being most pronounced. Somatic manifestations predominated, psychotomimetic symptoms (other than visual hallucinations) being relatively uncommon. Color perception was not much altered when adequate stimuli were used, but color phenomena were appreciably enhanced from inadequate stimuli. Minor differences in color perceptual effects were noted between the three drugs, but similarities were greater. Each of the three drugs significantly decreased urinary excretion of inorganic phosphorus, increased plasma free fatty acids and decreased total circulating eosinophils. Of the other biochemical measurements made, only one other significant change was noted; an increase in copper oxidase activity after psilocybin. The three psychotomimetic drugs were quite comparable in the areas studied. One might assume that they have many common mechanisms of action despite their chemical differences.

1. Reactions induced by LSD, mescaline, psilocin, and psilocybin are qualitatively similar. 2. The time course of the psilocin and psilocybin reactions are shorter than those of LSD or mescaline reactions. li 4. Psilocin is approximately 1.4 times as potent as psilocybin. This ratio is the same as that of the molecular weights of the two drugs.

REACTIONS TO PSILOCYBJN ADMINISTERED IN A SUPPORTIVE ENVIRONMENT TIMOTHY LEARY;GEORGE LITWIN;RALPH METZNER; The Journal of Nervous and Mental Disease

The psychotropically active principles of the Mexican hallucinogenic fungus Psilocybe maxicana HEIM have been isolated and obtained in crystalline form. The two new substances, which have been called psilocybin and psilocin, are present in the fruit bodies, the artificially cultivated mycelium and in the sclerotia. The dried mushroom contains 0.2 to 0.4 per cent psilocybin. Psilocin is present, at the most, in trace amounts only.

The distribution of14C psilocin was studied in 74 regions of the rat brain, using autoradiograms of sagittal serial sections 1, 30 and 60 min, 2, 4, 8 and 24 hours after intravenous injection.

A fixed-ratio schedule of milk reinforcement (FR 30) was used to study tolerance to the effects of d-LSD, l-LSD, BOL, psilocybin, mescaline, and d-amphetamine in the rat. A decrease in the amount of disruption of bar-pressing occurs with repeated daily administration of appropriate doses of all of the “psychotomimetic” compounds, and cross-tolerance was also demonstrated.

This study was undertaken to evaluate the ion-exchange paper technique and rapid direct extraction methods for obtaining drugs of abuse from urine and the subsequent identification of these drugs or metabolites by thin-layer chromatography coupled with sequential chemical reagent spraying. Recoveries from urine ± S.D. of 21.7 ± 5%, 2.4 ± 0.8% and 21 ± 1% were obtained for labeled morphine, pentobarbital and amphetamine, respectively, using the ion-exchange paper technique. With this method most narcotic analgesics could be detected at a level of 1 μg/ml urine (50 ml urine sample). The method in general was unacceptable for detecting either barbiturates, amphetamines or certain psycho-active drugs (psilocybin, glutethamide, chlorpromazine, marihuana). Percentage recoveries obtained with direct extraction from urine ± S.D. were 61 ± 4% for morphine- 14 C, 86 ± 6% for pentobarbital- 14 C, and 61 ± 21% for amphetamine- 3 H. Utilizing direct extraction methods almost all the drugs of abuse could be detected at levels ranging from 1 to 2 μg/ml of urine (15 ml of urine sample). The methods described in this report provided some specificity through differential pH extraction. The subsequent use of thin-layer chromatography and sequential spray reagents allowed identification of specific drugs or metabolites. All methods and techniques could be completed within 24 h. The direct extraction in all cases and the ion-exchange technique for narcotics were sufficiently sensitive to provide detection of drug usage 24 h after last administration of drug. Both techniques were extremely simple to perform and did not require expensive equipment thus keeping the cost of analysis at a minimum. These techniques may readily be adapted to a urine monitoring program screening for drugs of abuse, provided the limitations as described are well understood.

Antibodies to D-lysergic acid have been produced in rabbits and guinea pigs and a radioimmunoassay for the hapten was developed. The specificity of this lysergamide-antilysergamide reaction was determined by competitive binding with unlabeled lysergic acid diethylamide (LSD), psychotomimetic drugs, neurotransmitters, and other compounds with diverse structures. LSD and several related ergot alkaloids were potent competitors, three to seven times more potent than lysergic acid itself. The N , N -dimethyl derivatives of several compounds, including tryptamine, 5-hydroxytryptamine, 4-hydroxytryptamine, 5-methoxytryptamine, tyramine, and mescaline, were only about ten times less effective than lysergic acid, even though these compounds lack some of the ring systems of lysergic acid. The pattern of inhibition by related compounds with various substituents suggests that the antibody receptor site recognizes structural features resembling the LSD molecule. In particular, the aromatic nucleus and the dimethylated ethylamine side chain in phenylethylamine and tryptamine derivatives may assume in solution a conformation resembling ring A and the methylated nitrogen in ring C of LSD. Among the tryptamine derivatives, a large percentage of the most potent competitors are also psychotomimetic compounds.

Die in gesunden, jungen Volontaren durch Psilocybin hervorgerufene, reversible Veranderung der bevorzugten Helligkeit kann mit der Stabilitat der Wahrnehmungspersonlichkeitsstruktur, nicht aber mit der mydriatischen Wirkung der Droge in Beziehung gebracht werden.

Twenty subjects were given three psychotomimetic drugs (mescaline, LSD-25 and psilocybin) in fixed doses, 18 receiving all three. Color experience was tested by applying stimuli involving color perception, stimuli eliciting subjective colors, and stimuli usually devoid of visual experience.

In order to assess the functional significance of a high-affinity binding of 5-HT to nerve ending particles the effects of lysergic acid derivatives and other pharmacological antagonists of 5-HT on the binding have been investigated. The non-hallucinogenic l -lysergic acid diethylamide was found to inhibit the 5-HT binding, whereas the hallucinogenic d -1-acetyl-lysergic acid diethylamide was only a weak inhibitor of the binding. There is therefore no consistent correlation between the hallucinogenic potency of lysergic acid diethylamide derivatives and their ability to inhibit 5-HT binding to nerve ending particles. The action of d -2-brom-lysergic acid diethylamide was found to be erratic, and evidence is presented of its breakdown under mild conditions. Reserpine and some other compounds which release 5-HT from its storage sites in vivo were found to be inhibitors of the 5-HT binding. However the 5-HT binding component inhibited by reserpine was shown to be different from that inhibited by d -lysergic acid diethylamide. The functional significance of these two 5-HT binding components present in nerve ending particles is discussed.

1. Different initial affective responses occurred in identical twins under the influence of d-LSD-25 and psilocybin. 2. These affective displays were related to the differences in personality between the twins. 3. It was possible for the affectivity of each twin to influence the affective response of the other at various times during the studies. 4. This communication of affect substantiates the hypothesis that affective responses associated with hallucinogen administration are personality specific rather than drug specific(1, 2, 3, 4, 5). 5. The drug specific changes in the autonomic, proprioceptive and perceptual spheres were similar in both twins and not modified to any noticeable extent by environmental influences. 6. Because of their profound effects, hallucinogens should be restricted to research use exclusively in a hospital setting. In our opinion, their use at this time for any other purpose or in any other setting is dangerous.

The influence of personality structure on the stability of perceptual performance, specifically the degree of reproducibility under hypnotic induction of the psilocybinproduced lowering of spatial distortion thresholds, was investigated in two “variable” and two “stable” psilocybin reactors, that is, subjects who displayed variable and stable MMPI profiles under both control conditions and the influence of 160–200 µg/kg psilocybin. The results indicate that degree of stability in perceptual performance is a personality invariant with or without drug and also during the hypnotically-induced psilocybin experience. Moreover, susceptibility to hypnotic induction and ability to replicate exactly the hypnotically induced perceptual task are unrelated. Der Einflus der Personlichkeitsstruktur auf die Stabilitat der Wahrnehmungsleistung – im besonderen die hypnotisch-induzierte Reproduzierbarkeit der durch Psilocybin hervorgerufenen Erniedrigung des Raum-Verbiegungsschwellenwertes – wurde bei variablen und stabilen Vpn., d. h. bei solchen, die ohne Droge oder aber auch unter Psilocybineinwirkung variable und stabile Minnesota Multiphasic Personality Inventory (MMPI)-Profile aufweisen, untersucht. Die Resultate zeigen, das die Stabilitat der Wahrnehmungsleistung unter allen Bedingungen, d. h. unter Drogeneinwirkung, ohne Droge sowie auch wahrend des hypnotisch induzierten Drogen-Experimentes, durch die Personlichkeitsstruktur bedingt ist. Hypnotisierbarkeit und die Fahigkeit unter Hypnose einen Wahrnehmungstest exakt durchzufuhren, sind zwei voneinander unabhangige Phanomene.

1. The reactions caused by intramuscular administration of 0.75 mcg/ kg and 1.5 meg/kg of LSD-25 have been compared in the same 10 subjects with those induced by 2.5 mg/kg and 5.0 mg/kg of mescaline. 2. Both LSD and mescaline caused dilatation of the pupils, increase in body temperature, elevation of pulse rate and increase in systolic blood pressure. Both drugs decreased the threshold for elicitation of the kneejerk. 3. After both drugs, similar abnormal mental states characterized by anxiety, difficulty in thinking, alteration in mood (generally euphoric), altered sensory perception (particularly visual), elementary and true visual hallucinations and alterations of body image were reported by the subjects. 4. The effects of mescaline appeared more slowly and persisted somewhat longer than did the effects of LSD. 5. LSD tartrate is 2400–4900 times as potent as mescaline hydrochloride. On a molecular basis, LSD is 4500 to 9275 times as potent as mescaline. 6. Patients receiving LSD daily developed direct tolerance to LSD; such patients were also cross tolerant to mescaline. Likewise patients receiving mescaline daily became tolerant to mescaline and cross tolerant to LSD. 7. It was inferred that LSD, psilocybin and mescaline probably share common mechanisms of action or some common final pathway.

The administration of psilocybin (4-phosphoryl-N,N-dimethyltryptamine) to mice resulted in the accumulation of its 4-hydroxy analog, psilocin, in the kidney, liver, and brain. Highest concentrations in kidney and liver were found within 10–20 minutes and brain levels reached a peak at 25–30 minutes after administration of psilocybin. Behavioral effects, characterized by piloerection, exophthalmos, and motor incoordination, closely followed the increase in brain levels of psilocin. In mice pretreated with large doses of sodium β-glycerophosphate, a substrate of alkaline phosphatase, the administration of psilocybin resulted in much lower increases in tissue psilocin levels as compared to controls, and the behavioral effects were correspondingly attenuated. The accumulation of tissue psilocin after administration of psilocin did not differ significantly in control or β-glycerophosphate-pretreated mice. Correspondingly, no difference in the intensity of the behavioral effects could be observed in control and glycerophosphate-pretreated mice. The results of this study demonstrate the rapid dephosphorylation of psilocybin by the intact mouse. Evidence is also presented that the central nervous system effects of psilocybin are exerted only after its transformation to the 4-hydroxy analog, psilocin.

An electroencephalographic analysis of personality-dependent psychomotor performance was investigated in 11 volunteers under 160 μg/kg psilocybin-induced ergotropic arousal. Significant psilocybin-induced changes in mean energy content of EEG, reaction time, and latency and duration of alpha attenuation to photic stimuli were noted in all subjects, as well as significant correlations between EEG parameters, personality types and psychomotor (handwriting) test results. Moreover, a ‘clustering’ of certain EEG, personality, and handwriting characteristics in specific subjects seems to justify their classification into two general groups.