The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation

This Phase I RCT indicates that 10mg and 25mg doses of psilocybin are generally well-tolerated when administered to up to 6 participants simultaneously. Participants (n=89) each received one-to-one psychological support during the sessions. 511 treatment adverse events (TEAEs) were reported, 67% of which were resolved on the day of administration in the largest published trial with psilocybin to date.

Abstract

“Background: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin’s effects on cognitive function have not been widely or systematically studied.

Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring.

Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support – each participant having an assigned, dedicated therapist available throughout the session.

Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores.

Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing.”

Authors: James Rucker, Lindsey Marwood, Riikka-Liisa J. Ajantaival, Catherine Bird, Hans Eriksson, John Harrison, Molly Lennard-Jones, Sunil Mistry, Francesco Saldarini, Susan Stansfield, Sara J. Tai, Sam Williams, Neil Watson, Ekaterina Malievskaia & Allan H. Young

Notes

Ensuring drugs are safe for human consumption is one of the most important parts of the drug development process. Alongside proving their effectiveness in treating their target disorder, researchers must prove that their new drugs do not possess any threat to human health. To do so, new drug candidates must undergo rigorous testing in what is known as the clinical trial process. This process consists of various phases, with each phase having different requirements the drug under study must meet. Randomized-controlled trials (RCTs) have become the gold standard of this process. These trials tend to consist of large sample sizes to enhance the statistical significance and the overall generalizability of trial results.

In the realm of psychedelic research, the criterion set out by the gold standard RCTs is proving difficult to meet. Firstly, sample sizes in trials tend to be low given that psychedelics remain as Schedule I substances making them difficult and expensive to procure. Blinding and randomization are also difficult given the potency and effects psychedelics have once consumed. Despite these difficulties, as psychedelic research is progressing it slowly becoming more compliant with these gold-standard RCTs which are favoured by regulatory agencies like the FDA and EMA.

The present study is the largest study with psilocybin published in a peer-reviewed journal to date. One of the many trials sponsored by Compass Pathways, the overall aim of this study was to assess the safety and feasibility of the simultaneous administration of single doses of either 10 or 25 mg doses of psilocybin compared with placebo in healthy participants. The study also assessed the effects of psilocybin on some key aspects of cognitive function. This Phase I study saw 89 healthy participants being administered either 10mg or 25mg of psilocybin or a placebo simultaneously in groups of up to six people. Dosing took place in a controlled environment and each participant had one-to-one psychological support.

The main findings:

• 10mg and 25mg of doses of psilocybin were generally well tolerated by trial participants given their willingnes to undergo simulatenous administration and group preperation sessions.
• 511 treatment emergent adverse events (TEAEs) were reported during th 12 week study period: 217 in the 25mg psilocybin arm, 203 in the 10mg psilocybin arm and 91 in the placebo arm. 67% of TEAEs were resolved on the day of administration while no serious TEAEs were reported.
• The Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel assesseed measures of congitive function. Small differences in congitive measures were obsereved between groups but no clinically relevant negatvie findings were identified.
• Psilocybin was found to have no consistent short- or long-term effects on any measures of social cognition.

Overall, the findings of this study support the use of psilocybin for the treatment of mental health disorders such as depression. Furthermore, given that the administration of psilocybin took place in a group setting, the findings also support the use of psilocybin in this context providing there is adequate preparation and psychological support given in a supportive environment. If psilocybin-assisted therapies are to become available, the group context may prove to be both a cost- and time-effective method.

The authors do acknowledge several limitations to their study. Given that the efficacy of blinding was not assessed, it is not possible to rule out the unblinding of participants (i.e guessing their treatment) did not impact results. 37% of trial participants had previously used psilocybin so it is plausible to assume that these participants could have determined their treatment group. Practice effects may also have influenced results as a familiarisation session with testing procedures took place prior to treatment administration. While psychedelic research as a whole must overcome limitations such as these, the overall results of this trial are a positive step toward realizing the therapeutic potential of psychedelics.

Summary

Introduction

Psilocybin, a naturally occurring psychoactive alkaloid, is a partial agonist of serotonin (5-HT) receptors and belongs to a class of drugs called ‘psychedelics’.

Psilocybin has been used in sacred ceremonies by Central and South American native groups for thousands of years, and was first isolated and synthesised by Albert Hofmann in 1957 and 1958, respectively.

Psilocybin has been reported to reduce clinical symptoms of depressive disorders.

A phase 1 randomised controlled trial of psilocybin in healthy participants found that 511 treatment-emergent adverse events (TEAEs) were reported, with a median duration of 1.0 day. There were no serious TEAEs, and no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores.

Psilocybin was generally well tolerated and had no detrimental effects on cognitive functioning or emotional processing.

Clinical Trial Registration: EudraCT number: 2018-000978-30.

Psilocybin produces a non-ordinary state of consciousness, which is mainly attributable to partial agonism of the 5HT2A receptor subtype.

Studies of psilocybin’s efficacy in treatment-resistant depression, major depressive disorder, terminal-cancer – related anxiety, obsessive-compulsive disorder and alcohol and nicotine dependence have reported encouraging efficacy findings, with minimal adverse events.

Recent studies demonstrated that psilocybin modulates neural circuits implicated in affective disorders, with potential to reduce clinical symptoms of depression.

Current interventions for mental health problems include psychosocial techniques, pharmacological treatments, and social environment and role interventions. Psilocybin may be able to improve social and emotional functioning and may improve real-world functioning across various settings.

The serotonin system has been reported to represent a promising target for pharmacological modulation of social and emotional functioning. Psilocybin, a preferential partial agonist of the 5-HT2A and 5-HT1A receptors, has been shown to enhance mood, empathy, prosocial behaviour and attenuate processing of negative facial expressions and social pain. Psilocybin’s acute effects indicate that serotonin receptor stimulation is a promising target for improvement of emotional processing, but it has not yet been investigated whether its prosocial effects persist post-acutely.

This study aimed to evaluate the safety and feasibility of administering psilocybin to healthy participants simultaneously with psychological support, and to assess the short- and long-term effects of psilocybin on key domains of cognitive functioning.

Study design

This was a phase 1 study of healthy participants given single doses of psilocybin compared with placebo.

Participants

The study recruited healthy participants aged 18-65 years with no psilocybin experience within 1 year prior to enrolment. Participants were recruited via online advertisements and word of mouth.

Procedures

Participants were followed up for 12 weeks after study drug administration, and underwent assessments of cognitive functioning and emotional processing on the day before study drug administration. They also attended a 2-h group preparatory session and had a short (5 – 15 min) individual discussion with their assigned assisting therapist.

On day 1, participants were instructed to eat a light breakfast 2 hours before arriving at the clinic, and underwent a screening, assessment, and treatment session (SSTS, EV, and AEs). Psilocybin was administered to up to six participants as a single 5-capsule oral dose.

Psilocybin was administered to participants in private rooms by assisting therapists, who were supervised by a lead therapist. Participants were encouraged to wear eyeshades, earplugs and/or earphones during the administration sessions.

After at least 6 h, participants were assessed for safety, AEs were collected, and a PANAS was completed. They were subsequently discharged and asked to return the following day for safety assessments and a discussion.

Funding and ethical approval

The study was approved by the London-Brent Research Ethics Committee and conducted in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice.

Study endpoints

Cognitive function, suicidality, AEs and serious AEs were measured in participants taking the study drug. A higher CANTAB global composite score indicates better cognitive function.

The primary efficacy endpoints were short-term change in cognitive measures, short-term change in social cognition, emotional processing scales, and long-term change in social cognition, emotional processing scales.

Psilocybin had cognitive effects at baseline, day 8 and day 29, psychological effects at baseline, day 8 and day 85, and differences in PANAS after study drug administration on day 1.

Statistical analyses

The Safety Population comprised all participants who received study drug and were monitored for adverse events and cognitive performance. The modified Intent-to-Treat Population was used for emotional processing endpoint analyses.

This study was exploratory and not adequately powered to detect statistical significance. The effects of psilocybin on each outcome variable were evaluated as change from baseline scores (observed case), using a mixed-model for repeated measures (MMRM) analysis with factors for administration group, former psilocybin experience (FPE), visit, and treatment-by-visit interaction as fixed effects, and baseline value as a covariate.

Safety analyses were performed on CANTAB global composite score, AEs, vital signs and clinical laboratory assessments. Treatment-emergent AEs were defined as AEs that occurred on or after the dose of study drug.

Participants

The study randomised 89 healthy participants, 30 were randomised to receive 25 mg psilocybin, 30 – 10 mg psilocybin and 29 to placebo. Twenty-five administration sessions were completed, with up to six participants dosed simultaneously per session.

Safety outcomes

Adverse events were reported by 29 (96.7%) participants in the 25 mg psilocybin arm, 203 participants in the 10 mg psilocybin arm, and 91 participants in the placebo arm. There were no serious TEAEs.

Four participants reported anxiety-related AEs on the day of study drug administration, and 57 AEs of ‘mood altered’ were reported. Two AEs were negative alterations in mood, which started on day 3 and lasted for 9 days.

Psilocybin induced expected, transient psychedelic experiences, including hallucination, mood altered, illusion, 15 of euphoric mood and 11 of time perception altered. 92% of these experiences resolved on the administration day.

A participant who became disinhibited during the acute drug experience recovered with no sequelae and was discharged 11 h after receiving the study intervention.

Clinical laboratory assessment findings included two clinically significant findings at screening and two clinically significant findings on day after administration.

All participants recorded an SSTS score of 0 at baseline, and none reported an SSTS score > 0 during follow-up. One participant in the 10 mg psilocybin arm reported a TEAE of suicidal thoughts, which was mild in severity and possibly related to study drug.

Cognitive and emotional processing outcomes

There were trends indicating better performance on average for 25 mg psilocybin compared with placebo on measures of sustained attention, working memory, and executive function, but no difference was observed between 25 mg and 10 mg psilocybin on measures of episodic memory.

The global composite (safety outcome) score increased for 10 mg and 25 mg psilocybin by day 29 compared with baseline, but no difference was observed when compared with placebo, or between 25 mg and 10 mg psilocybin by day 29.

The CANTAB assessments suggested no difference of interest between psilocybin-naive and psilocybin-experienced participants, and the results were similar to what was observed in the overall analysis in the Safety Population.

Social cognition and emotional processing were not different between psilocybin groups, but positive affect was reduced in the placebo group and increased in the 25 mg psilocybin group.

Discussion

This phase 1, double-blind, randomised, placebo-controlled study demonstrated the safety and feasibility of psilocybin administration in healthy participants, with no serious TEAEs reported. Psilocybin elicited expected, transient psychedelic effects, which in previous studies have correlated with antidepressive/ anxiolytic efficacy.

Small differences in cognitive outcomes were seen between the groups, but no clinically relevant negative findings were identified. There was no consistent trend to suggest that either psilocybin dose had a short- or long-term effect on any social cognition scale.

Strengths and limitations

This was the first study to systematically study the longer-term effects of psilocybin on cognition in healthy volunteers. It did not detect statistically significant differences in psilocybin efficacy between groups.

Although psilocybin was generally well tolerated, previous literature has reported a few incidences of serotonin syndrome, hallucinogen persisting perception disorder and substance-related exogenous psychosis. More research is necessary to gain a clearer picture of the acute and longer-term adverse events associated with psilocybin.

3% of the UK population reported lifetime use of psilocybin, but 35 participants reported previous use in this study. This means that the results should be interpreted with caution when generalising to other populations.

The efficacy of the blinding was not assessed in this study, and it is possible that participants could have guessed their treatment assignment. However, a familiarisation session was conducted to minimise the small but consistent improvements in performance due to practice effects.

Conclusions

This study demonstrated that a single dose of psilocybin 10 mg or 25 mg did not cause any clinically relevant adverse effects in healthy volunteers.