This pooled analysis (n=110) of 8 double-blind studies investigated the effects and risks of different doses of psilocybin. It was found that most subjects described the experience as pleasurable, enriching, and non-threatening and there was no long-term impairment of functioning in any of the subjects. This suggests that the administration of moderate doses of psilocybin to healthy subjects in a research environment is associated with an acceptable level of risk.
Abstract
“Psilocybin and related hallucinogenic compounds are increasingly used in human research. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We therefore analysed acute, short- and long-term subjective effects of psilocybin in healthy humans by pooling raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008. The analysis included 110 healthy subjects who had received 1–4 oral doses of psilocybin (45–315µg/kg body weight). Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects. All acute adverse drug reactions were successfully managed by providing interpersonal support and did not need psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects. The results suggest that the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk.”
Authors: Erich Studerus, Michael Kometer, Felix Hasler & Franz X. Vollenweider
Summary
Psilocybin and related hallucinogenic compounds are increasingly used in human research, but due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We analysed eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008 and found no adverse effects in healthy humans.
Introduction
Psilocybin is an indoleamine-like hallucinogen found in fungi of the genus Psilocybe. It has been used in medical and religious rituals for centuries.
Modern psychopharmacological research with psilocybin began in 1955 with the discovery of the cultic use of Psilocybe mushrooms by Mesoamerican Mazatec Indians. Psilocybin and psilocin were identified at Sandoz Laboratories in 1958 and synthesized.
Psilocybin produces an altered state of consciousness similar to LSD, characterized by perceptual hypersensitivity, illusions, and pseudohallucinations, as well as intensification of affective responses, enhanced ability for introspection, and regression to primitive and childlike thinking.
Psilocybin has a shorter duration of action than LSD (4 – 6h instead of 8 – 12h) and milder vegetative side effects than LSD. Hence, many hallucinogen researchers valued psilocybin as a useful substitute for the earlier discovered LSD.
Throughout the 1960s, LSD and related drugs were associated with cultural rebellion, and were scheduled in the most restrictive category in most countries.
In the 1990s, human hallucinogen research in Europe re-emerged, with many laboratories using psilocybin to study the neural underpinnings of psychotic symptom formation, including ego disorders and hallucinations, as well as cognitive and visual processes, time perception, and sensory gating.
Recently, several studies have explored the acute and long-term subjective effects of psilocybin in hallucinogen-nave healthy subjects, and it has also been shown that the selective 5-HT2A receptor antagonist ketanserin blocks the hallucinogenic effects of psilocybin in human subjects.
Although serotonergic hallucinogens such as psilocybin are considered relatively safe physiologically, there is limited information on the acute tolerability and long-term psychological effects of psilocybin.
This paper presents data from eight double-blind placebo-controlled psilocybin studies that were conducted in our laboratory during the past 10 years. The data report on various aspects of consciousness, mood, psychological and physical side effects.
Study description
Eight psilocybin studies were conducted at our research facility between 1999 and 2008, with psilocybin doses ranging from 45 to 315 mg/kg body weight. The studies were approved by the Ethics Committee of the University Hospital of Psychiatry, Zurich, and the use of psilocybin was authorized by the Swiss Federal Office of Public Health.
Subjects were instructed to have a light breakfast prior to the experiments, to have their blood pressure and heart rate monitored, and to contact the research staff if any adverse events occurred.
Subjects
All subjects were recruited through advertisement from local universities and hospital staff. They were informed of the study aim, procedures, and possible risks, and gave their written consent. To assure health and minimize potential risk factors for adverse psilocybin reactions, all subjects underwent a psychological assessment with standard psychometric instruments Freiburg Personality Inventory (FPI) and the Symptom Checklist SCL-90. Subjects with high scores in the ’emotional lability’ scale of the FPI were also excluded.
Psychometric ratings of acute and post-acute effects
Eight studies used the Altered States of Consciousness Rating Scale (5D-ASC) and six studies used the Adjective Mood Rating Scale (AMRS) to assess acute and subacute subjective drug effects.
A self-rating scale consisting of 94 items measures five primary dimensions and one global dimension of ASC. The primary dimensions are Oceanic boundlessness (OB), Anxious Ego Dissolution (AED), and Mania like experience. The 5D-ASC measures 5 dimensions of altered states of consciousness, including: alterations in perception and meaning, auditory illusions and pseudo-hallucinations, reduced alertness and impaired cognitive function, and drowsiness.
The AMRS is a self-rating scale that can be used to assess 15 different mood states and conditions. It was administered at one to four time points during an experimental session and between 60min and 24h after drug administration.
Psychometric rating of subacute side effects
Six studies assessed acute side effects by the List of Complaints (LC). The LC is a self-rating scale that consists of 65 common somatic and psychological ailments.
Long-term follow-up
Subjects were asked whether the experiment with psilocybin had caused changes in their world view, values, awareness of personal problems, relationships to other people, professional relationships, and aesthetic experiencing.
Subjects were asked whether they changed their drug consumption habits after the experiments, and whether they considered these changes to be a consequence of their drug experience.
Subjects were asked to report any experienced negative changes in psychological well-being and/or mental functions after the experiments.
Statistical analysis
All statistical analyses were performed using the freely available statistical package Rß (version 2.8). Mixed-effects models were used to account for observational heterogeneity and the lack of balance, and all available data from drop-outs were included in the statistical analyses.
Data from eight studies were pooled to assess the acute effects of drug dose on the five ASC dimensions. Linear mixed-effects models were used to analyse the data, and Akaike’s Information Criterion values were used to decide on appropriate correlation structures of random effects in model specifications. In each fitted mixed-effects model, orthogonal polynomial contrasts and one-tailed Dunnett contrasts were used to evaluate the shape of the psilocybin dose – response relationship and to determine the proportions of subjects experiencing strong subjective drug effects.
Subacute side effects measured by the LC were analysed on the total scale as well as on the item level. The frequency of single complaints was compared between three different doses of psilocybin using Cochran Q tests and McNemar tests.
All participants had received psilocybin, so responses to the long-term effects questionnaire were analysed with descriptive statistics only.
Sample characteristics and drop-outs
Of the 110 subjects included in the pooled analysis, seven subjects prematurely dropped out after having received at least one dose of active psilocybin. Two subjects were excluded due to technical reasons, two were excluded due to safety considerations, and two subjects prematurely terminated the study of their own accord.
Acute psychological effects
Psilocybin significantly increased scores of all 5D-ASC scales. The dose-dependent effects of psilocybin on the sub-scale level are illustrated in Figure 1, and the dose – response relationships were reasonably well approximated by linear functions in all 5D-ASC scales.
The proportions of subjects experiencing strong drug effects were clearly dose dependent, with 22% of subjects experiencing strong OB at the highest dose, whereas only 5.7%, 7.8%, and 0% of subjects experienced strong AED at the 250 – 260 mg/kg and 115 – 125 mg/kg dose conditions, respectively.
Short-term side effects
The global scores of the LC were dependent on drug condition, and the single complaints registered 24h after psilocybin administrations were summarized in Table 2. Item-level comparisons between three different psilocybin doses and placebo revealed significant differences for the items fatigue, headaches, lack of energy, difficulty concentrating, ‘gone feeling’, lack of appetite, and heavy or tired legs.
Long-term follow-up
Most subjects reported unchanged consumption habits for all drugs, and most subjects who reported changes reported decreased consumption. Of the three subjects who reported increased psilocybin consumption, two subjects consumed it twice a year and one three times per year.
Spontaneous alterations of consciousness and flashbacks were reported by 10% of subjects before and 9% of subjects after the experiments. These alterations were not experienced as threatening and did not interfere with subjects’ everyday lives.
All subjects reported that spontaneous ASC after the experiments could not be distinguished from those before with respect to frequency, duration and intensity. They were non-threatening and occurred only after specific triggers, such as listening to music, meditating, falling asleep, deeply concentrating, or being in a calm environment. Five subjects answered yes when asked if their spontaneous ASC was a flashback-like re-experiencing of drug effects. However, their descriptions of these events were very broad and did not meet the criteria for HPPD.
Eleven subjects reported negative changes in psychological well-being and/or mental functions after the psilocybin experiment.
Only one subject reported symptoms severe enough to seek help, and he was a 23-year-old medical student with no indication of above average emotional lability. The subject experienced strong feelings of unity and loneliness after taking a high dose of psilocybin, but calmed down considerably after receiving strong personal support and reassurance by the study manager. However, the subject felt uncomfortable over the next couple of weeks and was referred to an experienced psychotherapist.
Six subjects reported negative changes in well-being and/or mental functions after the experiments: concentration problems, mood swings, reactivation of old problems, memory problems, and being pensive and introverted.
Acute psychological effects
The present work showed that psilocybin dose-dependently induces an ASC in healthy human subjects, which is characterized by marked alterations in all mental functions. Psilocybin-induced ASCs were characterized by alterations in visual perception, followed by positively and negatively experienced alterations of self-awareness and loosening of ego boundaries. The AED scale was only moderately affected, and most subjects sustained critical distance to their own subjective experience. Psilocybin dose-dependently increased the RV scale, but this effect was relatively small and reflects the psilocybin-induced state of dreaminess, contemplativeness, and reduction of attentiveness, rather than true sedation or clouding of consciousness.
The cumulative distributions of the 5D-ASC major scales revealed widely varying individual responses to psilocybin. Other pharmacological variables, such as plasma levels of the active metabolite psilocin, as well as non-pharmacological variables, likely play a very important role.
The 5D-ASC showed a linear dose-response relationship, and higher doses may have produced even stronger subjective drug effects. Furthermore, in the highest dose condition, only 22% of subjects exceeded the cut-off value of the OB scale suggestive of deep mystical or transcendent experiences. In addition to the higher drug doses in Griffiths et al.’s study, several other factors might have contributed to these differences, such as the fact that subjects in our studies were engaged in performing tasks for a considerable amount of time during their whole psilocybin session.
Griffiths et al. reported more acute adverse reactions than our studies, although these reactions were confined to the acute phase and were readily managed by providing interpersonal support without psychopharmacological intervention.
The results of our analysis indicate that the effects of psilocybin follow differential time courses, and that the effects on emotional excitation, sensitivity, heightened mood, and concentration reach their maximum in an early phase, whereas the effects on dreaminess, dazed state, inactivation, and introversion are more pronounced in a later phase.
Short-term side effects
Psilocybin caused only few subacute side effects, including tiredness and exhaustion. The results suggest that psilocybin is usually well tolerated and that normal functioning is almost completely restored within 24h after drug intake.
Long-term follow-up
The majority of subjects were still positively impressed by the psilocybin experience 8 – 16 months after the last experimental session, and over 60% rated the experience as very enriching. Several subjects rated the experience as very enriching even though they had experienced significant distress during the acute phase.
Anecdotal reports and preliminary evidence suggest that hallucinogenic drugs can lead to sustained positive changes in personality, attitudes, and values, particularly in those subjects who have experienced profound personal insights and transcendent or mystical-type experiences.
Subjects reported the most positive changes in attitudes toward ASC, the relationship to the environment/nature, and aesthetic experiencing. Furthermore, behavioural changes were observed, such as increased number of records bought and time spent in museums.
Although some subjects reported positive changes in attitudes and values, the results should be considered exploratory, because validated questionnaires have not been used, and no attempt has been made to correlate subjective changes with behavioural measures or information provided by close relatives and friends.
The results indicate that psilocybin administration to healthy volunteers does not increase the risk for subsequent abuse of psilocybin or other illicit drugs. Classical hallucinogens have a very low abuse potential because they do not produce compulsive drug-seeking behaviour or physical withdrawal symptoms. Epidemiological evidence suggests that classical hallucinogens lack addictive qualities, and that the use of hallucinogenic mushrooms is unlikely to become regular because of tolerance to the effects and because it does not consistently produce any of the pleasurable effects of addictive drugs. Although psilocybin can evoke highly valued and in some cases even mystical-type experiences, subjects occasionally are confronted with frightening and unpleasant thoughts, memories, and emotions. Moreover, most subjects describe the psilocybin effects as tiring.
Our findings are in line with a study by McGlothlin and Arnold (1971) that found that most subjects who had taken LSD discontinued or reduced their frequency of hallucinogenic drug use after 10 years.
‘Flashbacks’ are a common long-term sequelae of hallucinogenic drug use. The present study avoided methodological inconsistencies of earlier follow-up studies and contributes to a better understanding of flashback phenomena after psilocybin administration by using operational criteria consistent with those of DSM-IV and ICD-10.
HPPD and other troubling perceptual abnormalities rarely occur in a therapeutic or research context, where subjects are carefully screened and monitored and judicious doses of pharmaceutical quality drugs are given. The clinical relevance of flashback phenomena has been a matter of controversial debate for several decades.
The majority of Abraham’s research was focused solely on LSD use, and there are very few case reports on flashback phenomena experienced by individuals who have used psilocybin, DMT or mescaline exclusively.
We have found no prolonged adverse reactions to psilocybin in 110 well-adjusted subjects in a controlled experimental setting. However, one subject experienced symptoms of emotional instability, anxiety, and depression, which lasted several weeks and were severe enough to seek professional help.
Limitations
The relatively low occurrence of adverse events in our studies is likely due to the careful selection, preparation, and monitoring of subjects as well as the administration of predominantly moderate drug doses. The subjects who volunteered for our studies had prior knowledge that experiments would involve psilocybin administration. They had a positive attitude towards hallucinogenic drugs and a personal interest in experiencing drug-induced ASC, which may have contributed to the low occurrence of adverse events. We excluded subjects who had some experience with hallucinogenic drugs, unless they used them on a regular basis, because safety and tolerability considerations were more important than methodological rigor.
Our investigation has limitations, including the lack of representativeness and the use of an investigator-constructed follow-up questionnaire whose reliability and validity is not known.
Conclusion
Taken together, the experimental data from 227 psilocybin administrations have demonstrated safety and tolerability not only acutely, but also in the long run. The most common adverse reactions were transient emotional instability and bad or horror trips, which resolved with strong interpersonal support.
Study details
Participants
110