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COMPARISON OF THE REACTIONS INDUCED BY PSILOCYBIN AND LSD-25 IN MAN

By

Harris Isbell

From the
Natlonal Institute of Mental Health,
Addiction Research Center,
U. S, Public Health Service,
Lexington, Kentucky.

155

5 May 1959 Feli

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COMPARISON OF THE REACTIONS INDUCED BY PSILOCYBIN AND LSD-25 IN MAN

The use of certain intoxicating mushrooms by Indians in Mexico has been reviewed by Hofmann et al. (1958). V. P. and R. O. Wasson (1957) have reported the way in which the mushrooms are taken by the Mexican Indians and the hallucinatory experiences occurring foliowing their ingestion. Hofmann et-al. (1958a) have described the identification of the mushrooms and their successful cuiture by Heim, and by Helm and Cailleux. Hofmann et al. (1958) isolated a pure compound from the mushrooms which had the characteristics or an indoleamine and which contained phosphorus. Later the compound was identifled as 0-Phosphoryl-h-hydroxy-N-dimethyl tryptanine, was synthesized (Hofmann, 1958; Hofmann et al., 1958 a and b) and named psilocybli Preliminary studies in man (Hofmann et al, 1958a) showed that the compound, in doses of 4 to 8 mg, induced an abnormal mental state resembling that seen after LSD or mescaline. In animals (Cerletti, 1958), psilocybin caused neurovegetative symptoms although it had no high degree of activity on peripheral.

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autonomic structures. The autonomic effects of psilocybin seemed to be due to central sympathetic stimulation. It facilitated spinal reflexes and caused án "arousal" pattern in the EEG, although motor behavior was depressed.

Because of the chemical relationship of psilocybin to serotonin and to bufotenins, and because of the possible role of serotonin (5-hydroxy tryptamine} in the function of the central nervous system, s detailed comparison of the effects of psilocybin with those of the diethylamide of d-iysergic acid (LSD-25) in man was thought to be of interest.

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METHODS

Preliminary Experiments. In order to confirm the dose range reported by Hofmann et sl. (1958a), several preliminary experiments were done in which 7 volunteers ingested

psilocybin orally in doses ranging from C.5 to 8.0 mg/70 kg of body weight. Thesa experlments indisated that psllocybin caused definite mental effects in doses of 2 to 8 mg/70 kg which were accoapanled by pupillary dilatation, increased tendon refiexes, and increased blood pressure. The mental effects of psilocybin seemed to resenable those.of LSD. A more detallied experiment was then carried out utillzing 9 patlents.

Sublects. The subjects used in these experiments were all negro males who were former drug addicts and who were serving sentences for violation of the United States narcotic laws. Their ages .ranged botween 22 and l0 years. All wore in good physical health, and none presented evidence of any of the major psychoses. All had experienced the effects of LSD-25 in previous experiments.

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General Conditions. The experiments were all conducted in a special ward devoted to ciinical research. Observations were made by specially trained attendants with many years of experience in observing patients who have received various drugs. The patients entered this special ward on the night before the experiments were conducted. They ware awakened at 6:30 a.m. Each patient was free to mix and mingle with other patients in a coamon dayroom, or to remain in his own room, as he preferred.

solution in raspberry syrup. The syrup was used in order to mask the sllghtly bitter taste of psilocybin. Drugs were administered at 6 a.m. with the patients fasting. All patients received, in a randomized balanced order, a placebo, 1.0 and 1.5 mcg/kg of LSD, 57, 86, and 11h mcg/kg of ps1locybin (4.0, 6.0 and 8.0 mg/70 kg). The "single-blind" procedure was followed throughout.,The patients were not aware of the identity of the drugs given on a specific day but one of the attendants, for reasons of safety, did know what medication had been given.

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Observatlons. The following observations were made at houriy intervals from 7 a.m. to 4 p.m. after the patients had rested quietly for ten minutes in bed: rectal temperature, pulse rate, respiratory rate, systolic and diastolic, blood pressure, diameter of pupils, and thresholds for eliciting the kneejerk. Methods for making these neasurenents were those previously ccscribed (isbeil ut al, 195ó; isbell st al, 1958). At hourly intcrvals from 7:30 a.m. to 3:30 p.a. patients completed a questionnaire² modified from that of Abramson et al (1955), with the help of an aide. A short mental status examination was made one and one-half to two hours after the drug and a grade³ (scale 0-4) of the intensity of the reaction was assigned according to the system used in rating the intensity of the LSD reaction (lsbell et al, 1956).

Analysis of Data. The chalge after drugs in rectal tenperature, pulse .and respiratory rates, systolic and diastolic blood pressures, pupillary size, and threshold for elicitation of the kneeJerk were calculated by subtracting the figures ohtained at various hours after the drugs from the average of the two pre-drug observations. The areas under the time-actlon curves for each subject, and for each dose of each medicatlon for the various mcasurements, vere then calculated by the

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method of Winter and Flataker (1950). This procedure converts all the data on a particular measurement for an Individual receiving a given dose of a drug to one figure. The number of positive responses on the questionnaires after the drugs were counted over the entire cbservatlon period, eliminating answerg which were also scored positively before the drugs. Meang and standard errors of means were calculated according to standard statistical techniques. The t=test for palred observations was used in evaluating the significance of differences in the "objective" (temperature, pupils, etc.) signs (Edwards, 1946). Nonparanetric tests (Wilcoxon, 19h9) were used in evaluating the significancs of differences in the aumber of positive responses on the questionnaire and on the clinical grade. Measurements of pupillary diameter (an "objective" measure nnta /lan "ohlecttua" measure and number of positive responses on the questionnaire ( a "subjective" measure) were tabulated and averaged at each observation time before and after the drugs, in order to obtain time-action curves.

Regression lines for dose-effect curvss, calculations of relative potency and confidencs limits were calculated by the methods described by B1iss (1952).

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In order to compare the pattern of subjective response, the 57 questions constituting the questionnaire were classified The questionnaires were then scored by counting the number of patients responding positively to a given question two or more times after edministration of the drug, after which the number of patients responding positively to a given category of questions was determined by adding the totals for all the questions constituting the particular category.

RESULTS

General Clinical Description of the Psilocvbin Reaction. This description of the reaction occurring after psilocybin is based primarily on the data obtained with the 1l4 mcgm/kg dose. Foilowing administration of psilocybin orally the patients usually spontancously reported the first subjective effects within 1o to 15 minutes.., These effects consisted of vague sensations that things looked, felt, or seemed peculiar, and were accompanled by mild anxiety. After 30 minutes, anxiety becane quite definite and was expressed as consisting of fear that something evil was going to happen, fear of insanity, or of death. At this time, changes in mood, usually in the direction of elation (despite the anxiety) and sometimes In the direction of depression, occurred. The patients reported

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increasad keenness of hearing, paresthesia, and blurring of vision.. Cao hour after the drug the rsaction was well developad. Anxiety becama more marked and, in some cases was intense. Elation, when present, was great and in some patients was expressed by almost continuous gales of laughter.. Alterations in practically all sensory modalities were mentioned, particularly in touch, hearing and vision. As is the case with LSD, distortion of visual perception was outstanding, and invelved distance, depth, size, shape and color, Visual distortion usually varied rapidly from mcment-to-moment. Perception of elementary visual hallucinations were commonly reported. These entoptic phenomena consisted of colored lights which flickered and coalesced to form patterns varying in a kaleidoscopic fashion, or of shadows that seemed to dancs on the wali. In sensitive patients, the lights or shadows were perceived as s definite person, object, or animal which the indlvidual could nate. The patlents reported inereased difficulty ia thinking, difficulty in concentration, and in carrying out simple arithmetical calculations or reading. They reported a "rush of thorghts," with one thought replacing another before the first was completed. A fealing of alteration in the individual's own body occurred consistently and varled

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from simple feeling of being light or heavy to marked. alterations in size, shape or color. Some patients felt they had become very large, or had shrunk to the size of children. Their hands or feet did nct seem to be their own, and sometimes took on ths appearance of animal paws. At times, patients had the sensation that they could see the blood and bones in their own body or in that of another person. They reported many fantasies or dream-like states in which they seemed to be elsewhere. Fantastic experiences, such as trips to the moon or living in gorgeous castles, were occasionally reported. Despite these striking subjective experiences, the patients remained oriented in time, placs and person. In moat inatances the patients did not lose their insight, but realized that the effects wore due to the drug. Two of tho 9 patients, howevers did lose insight and felt that their experiences were caused by the experimenters controlling their minds. Reaction usually reached its peak one and one-half hours after the drug was given and remained intense for two to thres hours. It subaided almost completely five to six hours after the drug was given. The subjects most frequently compared the subjective experiences after psilocybin to thoss occurring after LSD or merihuana.

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Oblective veasurements. The data on the objectiva measurenents are shown in table 1. Significant changes as compared with the placabo were observed after both doses of LSD and after ona or mor: of the doses of psilocybin in the cases of rectal temparature, pulse and respiratory rates, systolic blood pressure, pupillary size, and threshold for elicitation of the kneejerk. Tus, psilocybin induced a patteru of autonomic and central nervous system excitation similer to that caused by LSD, but was, or course, less potent than the latter drug.

Sublective Measurements. Significant changes, as compared with placebo, occurred efter all doses of both drugs, with respect to number of positive raspensss on the queationnaire and to the clinical grade. Data on the "pattern of responses is shown in table 2. when the patterns after the tuo drugs are comparad at the most neariy equlvalent doses (l.0 mcgm/kg of LSD, end 1l4 mcgm/kg of psiloeybin) it is evident that the patterns after the tro 'drugs are very similar, except in incidance of "trus hallucinations."

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The time=course after placebo and the various doses of the two drugs is shown in tables 3 and 4. The time of onset is very similar after both drugs. This result may be, to some extent, an artefact of the fixed observation times, since patients consistently began to report subjective changes sooner after psilocybin than after LSD. Definite pupillary dilatation cccurred one hour after both drugs, with the peak effect occurring at one hour after psilocybin and two hours after LSD. As Judged by number of responses on the questionnaire, the reaction was beginning to subside by the third to the fourth hour after both drugs, reaching insignificant levels five end one-half hours after psilocybin and six and one-half hours after LSD. The length of action of psilocybin seems definitely shorter than that of LSD.

Comparative Potency of LSD and Psilocybin. From the data, a number of dose-effect curves comparing the potency of LSD and psilocybin can be constructed. Those based on the total course (pupillary diameter, number of positive responses and clinical grade) yielded estimates that LSD is approxlmately l00-l50 times as potent as psilocybia. Sinca the total course of ths psilocybin reaction was shorter than that of the LSD reaction these estimates of potency couid be misleading. For this reason, change in pupillary diameter at two hours and the

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number of positive responses at one and one-half hours were calculated and used in constructing the dose-effect curves shown in figure 1.- Analysis of these data at approximately peak effect for both drugs gave potency estimates with 5 per cent confidence limits of 1 mcgm/kg of LSD being equivalent to 121 (103-156) mcgm/kg of psilocybin in the case of pupillary change, and to 110 (60-218) mcgm/kg in the case or responses on the questionnaire. These two dose-effect curves met the usual tests for parallelism and slope. Unfortunately, the preliminary experiments gave a somewhat high impression of the potency of psilocybin, so that the highest dose of psilocybin used (ilh mcga/kg) corresponded approximately to the lowest dose of LSD (1 mcgm/kg). A dose of psilocybin higher than ll4 mcgm/kg and a dose of LSD.lower than 1 mcgm/kg would have ylelded a more elegant estimate of comparative potancy.

DISCUSSION

The reactions obsèrved after oral adninistration of LSD-25 nnd psilocybin are remarkably similar. After both drugs, there is evidence of autonomic excitation (elevated temperature, dilated pupils, increased blood pressure and increased respiratory rate) and of increased hyper-irritabiiity in the central

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nervous system (decreased threshold for elicitation of the
kneejerk). After both drugs, anxiety, dirficulty in concen
tration and thiaking, sense of strangeness, marked sensory
perceptual distortion (especially visual), alterations in body
Image (depersonalization), and eiementary and true hallucinations
occurred. It is, of course, possible that the methods of
measurement and the situation in which the experiments were
conducted contributs in some degree to this similarity. The
subjects had already experienced the effects of LSD. and very
1ikely wouid expect similar symptoms from any drug given in
this particular testing situation. The uss of a questionnaire
may also suggest certain symptoms. On the other hand, patterns
of effects similar to those seen after LSD have not been
observed after administration of amphetamine, scopolamine,
barbiturates, opiates, chlorpromazine and many other drugs with
marked effects on the central nervous system. Thus it seems likely that the similarity between the reactions induced by LSD and psilocybin is a real phenomenon, and suggests that some common biochemicai or physiological mechanism is responsible for the effects of the two drugs. Experiments in which 分 subjects tolerant to LSD are challenged with pailocybin and y
vice versa ("eross tolerance") might help settle the question of the blological identity of the reactions caused by the two drugs.

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The similarity in chemical structure of psilocybin and 5-hydroxytryptamine naturally leads one to speculate that psilocybin may cause an abnormal mental state by interfering with the actions, synthesis, disposition or metabolic degradation of 5-hydroxytryptamine. Others have hypotheslzed that LSD-25, bufotenine and other paychosomimetic druga might act through such mechanisms. Since psilocybin is a much simpler compound than LSD, it may prove to be an important tool for blochemical studies bearing on the role of serotonin in brain function. Investigations in animais will be necessary to shed light on these possibilities.

SUMMARY

1. The reaction induced by oral administration of 57 to 114 mcga/kg of 0-Phosphoryl-h-hydroxy-N-dimethyitryptamine (psllocybin) has been compared with that induced by a placebo and LSD-25 (1.0 to 1.5 mcgm/kg) in 9 subjects.

2. Both LSD and psilocybin caused elevatlons in body temperature, pulse and respiratory rates, and systolic blood pressure. Threshold for elicitation of the kneejerk was decreased by both drugs.

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3. After both drugs, abnormal mental states characterized by feelings of strangeness, difficulty in thinking, anxiety, altered sensory perception (particularly visual), eiementary and true visual hallucinations, and alterations of body image were reported by the subjects.

4. The effects of psilocybin did not persist as long as those of LSD.

5. LSD is 100 to 150 times as potent as psilocybin.

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REFERENCES

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FOOTNOTE 1.

Footnote 1. We are indebted to Drs. R. Bircher and C. Henze of the Medical Department, Sandoz Pharmaceuticals, Hanover, New Jersey, for generous supplies of LSD-25 and psilocybin.

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FOOTNOTE 3.

Footnote 3. The clinical grege was bascd on the mental status examination and grades assignod according to the following schene:

Grade C: No reaction,

Grade l: Anxiety and nervousness without perceptuai distortion or hallucinations,

Grade 2: Anxiety, nervousness and visual perceptual distortion without "true" hallucinations,

Grade\_3: Anxiety, nervousness, perceptual distortion and "true" hallucinations but with insight maintained (patients rsport' that effecta are duc to drugs), and

Grade i: Seme as grade 3, excopt that insight (realization that the effects ars due to the drug) -is lost.

The grading system has the' cisadvantage that the varicus grades may not forn a continuous scale. It gives no information concerning the quantitative aspects of the symptoms which go into determining the grades. Like the questionnaire, however, it yields peproducible data on repeated administration of the same dose of LSD, and good dose-effect responses are obtained.

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FOOTNOTE 4.

Footnota 4. The nine categories are shown in table 2. It is of course evident that'a large number of other categories could be devised and that there might be many ways of classifying a particular questlon. There appears to be no easy way out of this difficulty, so the classification must be regarded as completely arbitrary.

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TREATMENT

2 - Means f standard errors of number of questions scored positively in the 71 hours after the drug which were not scored positively before the drug.

3 - Meang t atandard errors of intensity of mental reaction based on a scale of O-4. - Significantly different from placebo (P <0.05).

\- Significantly different from placebo (P <O.05, non-parametric test).

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Table 2

Comparigon of pattern of "mental" response after psilocybin and LSD in 9 subjects.

1 - Refers to type of questions, e.g., "feeling strange" (general); "feet look old" (depersonalization); "an happy" (mcod); "things look small" (visual distortion); "is difficult to concentrate" (thinking), etc.

2 - Number of subjects tines number of questions in the category.

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Figures are means of pupillary diameter in millimeter on 9 subjects.

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LEGEND FOR FIGURE 1.

Figure 1. Relationship of dose of LSD-25 and psilocybin to change in size of pupils and to number of positive responses on the questionnaire.

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FIGURE l. Comparison of the reactions induced by psilocybin and LSD-25 in man. By Harris Isbell, M. D.