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

Psilocybin is a naturally occurring psychedelic and a partial agonist at serotonin receptors, principally 5-HT2A and 5-HT1A. Earlier clinical and preclinical studies have suggested psilocybin can produce rapid changes in mood and affect and may reduce symptoms in conditions such as treatment-resistant depression, anxiety in terminal illness, OCD and substance use disorders. However, much of the evidence to date has come from small, often open-label studies or trials lacking placebo control, and there remains limited systematic evidence about psilocybin's effects on cognitive functioning and longer-term emotional and social cognition outcomes. Rucker and colleagues set out to evaluate the safety, feasibility and cognitive and emotional effects of single oral doses of psilocybin (10 mg and 25 mg) compared with placebo in healthy volunteers. The study additionally explored a model of simultaneous administration — dosing up to six participants at once with individual psychological support — as a potentially more time- and cost-efficient approach to delivering therapy. The authors aimed to measure short- and longer-term changes in cognitive domains using the CANTAB battery and in emotional/social processing with multiple standardised tests, while systematically capturing adverse events over a 12-week follow-up.

This was a Phase I, randomised, double-blind, placebo-controlled, between-groups trial conducted at King's College London and sponsored by COMPASS Pathways. Healthy male and female volunteers aged 18–65 were recruited; the study planned to enrol up to 90 participants and randomised 89. Participants were stratified by sex and age group (18–35; >35) and randomised 1:1:1 to receive a single oral dose of 10 mg psilocybin, 25 mg psilocybin, or placebo. COMP360, a pharmaceutical-grade synthetic psilocybin formulation, was given as a five-capsule dose (placebo and active capsules combined to achieve the intended mg dose). Administration sessions lasted ~6–8 hours and were conducted with one-to-one psychological support from trained assisting therapists supervised by a lead therapist. Preparatory work included a 2-hour group preparatory session the day before dosing and brief individual discussion; integration occurred in one-to-one sessions the day after dosing. Participants underwent screening that included psychiatric interview (MINI), suicidality assessment (SSTS), physical exam, ECG, laboratory tests and urine drug/pregnancy screens. Cognitive and emotional processing assessments were performed at baseline (day -1) and at post-dose visits: primary cognitive comparisons were change from baseline to day 8 and day 29 on CANTAB measures (PAL-TEA for episodic memory; SWM-BE and SWM-S for working memory and executive function; RVP-A' for sustained attention) and a CANTAB global composite score. Emotional and social cognition were measured by a battery including the Pictorial Empathy Test (PET), Reading the Mind in the Eyes Test (RMET), Scale of Social Responsibility (SSR), Social Value Orientation (SVO) and Toronto Empathy Questionnaire (TEQ); these were assessed at day 8 and day 85 for longer-term change. PANAS was administered pre- and post-dose on the day of administration. Safety endpoints included treatment-emergent adverse events (TEAEs), suicidality (SSTS), vital signs and laboratory tests. Populations for analysis were defined as Safety (all dosed), modified intent-to-treat (mITT; Safety participants with at least one post-dose assessment) and Per-Protocol (PP; Safety participants without major deviations). The study was exploratory and not powered for formal hypothesis testing; p values were not reported. Change-from-baseline outcomes collected at multiple post-baseline time points were analysed using mixed models for repeated measures (MMRM) with fixed effects for treatment, visit and interactions and baseline as covariate; PANAS was analysed by ANCOVA. The MMRM used an unstructured covariance and Kenward–Roger denominator degrees of freedom; analyses assumed missing data were missing at random.

Participants and dosing: Eighty-nine participants were randomised: 30 to 25 mg psilocybin, 30 to 10 mg psilocybin and 29 to placebo. The mean age was 36.1 years and the sample comprised 41 females and 48 males. The extracted text reports that 33 participants (37.1%) had prior psilocybin experience, although a later passage in the extracted text refers to thirtyfive participants reporting prior use, so the exact count is inconsistent in the source material. Twenty-five administration sessions occurred, with up to six participants dosed simultaneously; most sessions had multiple participants and all participants in the psilocybin arms completed the study, while four placebo participants did not complete all visits. Adverse events and safety: Across the 12-week follow-up there were 511 TEAEs: 217 in the 25 mg arm (reported by 29/30 participants, 96.7%), 203 in the 10 mg arm (29/30 participants, 96.7%) and 91 in the placebo arm (26/29 participants, 89.7%). Investigators judged 208, 188 and 77 TEAEs as potentially related to study treatment in the 25 mg, 10 mg and placebo arms, respectively. There were no serious TEAEs and no TEAEs led to study withdrawal. Typical psychedelic-type acute events were reported: hallucination (86 reports), mood altered (57), illusion (56), euphoric mood (15) and altered time perception (11). Four participants experienced anxiety AEs on the day of administration (2 in 25 mg, 1 in 10 mg, 1 in placebo). Overall, 67% of TEAEs started and resolved on the day of dosing and the median AE duration was 1.0 day. A single event coded as substance-induced psychotic disorder occurred during the acute experience; the participant received 2.5 mg oromucosal midazolam, recovered without sequelae and was discharged ~11 hours after dosing. Clinical laboratory testing produced four clinically significant findings recorded as AEs (two at screening, two the day after administration), but none prevented continuation; there were no clinically significant vital sign findings. Suicidality: All participants had SSTS scores of 0 at baseline. No participant in the 25 mg arm recorded an SSTS score > 0 during follow-up. One participant in the 10 mg arm had a highest SSTS score of 1 and reported a mild, possibly related TEAE of suicidal thoughts that started and resolved on day 19. In the placebo arm one participant reported multiple suicidal ideation/thought events (four events in total) of moderate severity, considered possibly related to study drug. Cognitive outcomes: Mixed-model analyses of CANTAB measures showed small, non-definitive trends but no clinically relevant detrimental effects attributable to psilocybin. For RVP-A' (sustained attention), trends indicated improved performance on average for both psilocybin doses by day 29 versus baseline, yet there were no differences between either psilocybin dose and placebo, nor between doses. For SWM-BE and SWM-S (working memory, executive function/planning) there were trends to improved performance for 25 mg (and for placebo on SWM-BE) by day 29 versus baseline, but again no differences between active doses and placebo. PAL-TEA (episodic memory) showed no change versus baseline in any group and no between-group differences. The CANTAB global composite showed increasing trends for the 10 mg and 25 mg groups by day 29 versus baseline, but no differences versus placebo. At day 8 the 10 mg group appeared worse than placebo on the composite score, which the authors attribute to a larger placebo improvement at that timepoint; by day 29 the 10 mg group's performance approximated placebo. Analyses stratified by prior psilocybin experience and in the PP population showed similar patterns, though subgroup sizes were small and imbalanced, particularly in the 25 mg and placebo arms. Social cognition and emotional processing: There were no differences between either psilocybin dose and placebo on any of the social cognition or emotional processing measures (PET, RMET, SSR, SVO, TEQ) at day 8 or day 85 relative to baseline. PANAS: On the Positive and Negative Affect Schedule assessed immediately after dosing, placebo showed a trend towards reduced positive affect from baseline (LS mean change = -5.0), which was not seen in the psilocybin groups. Conversely, the 25 mg group showed a trend toward increased negative affect (LS mean change = 1.3) that was not observed in the 10 mg or placebo groups.

Rucker and colleagues conclude that single doses of psilocybin (10 mg and 25 mg) administered with one-to-one psychological support were feasible and generally well tolerated when given to up to six participants simultaneously. The absence of serious TEAEs and of withdrawals for adverse events is presented as consistent with prior smaller trials of supervised psilocybin administration. Most adverse events were transient and resolved on the day of dosing, and the acute psychedelic effects reported were as expected. With respect to cognition, the authors report small trends towards improved performance on several CANTAB domains by day 29 in the psilocybin groups, but emphasise there were no clinically relevant negative effects on cognitive functioning or on the CANTAB global composite score when compared with placebo. Measures of social cognition and emotional processing showed no consistent short- or long-term effects attributable to psilocybin, leading the authors to suggest no detrimental impact on the assessed domains. The PANAS results indicated a placebo-associated reduction in positive affect post-dose that was not seen with psilocybin, while the 25 mg group showed a trend to increased negative affect immediately post-dose; the authors note these mixed acute affect findings in interpreting emotional outcomes. Key limitations acknowledged by the authors include the exploratory nature of the trial and the lack of statistical power to detect efficacy differences, potential lack of generalisability due to a typically highly educated sample and a higher-than-population prevalence of prior psilocybin use among participants (the extracted text contains an inconsistency regarding whether 33 or thirtyfive participants reported prior use). The investigators also note potential unblinding given the distinctive acute effects of psilocybin and that the efficacy of the blind was not formally assessed. Practice effects on cognitive testing were addressed by a familiarisation session at screening but cannot be fully excluded. The authors recommend larger, more diverse samples, formal assessment of blinding and longer follow-up including more acute and more distal timepoints to characterise longer-term effects and rare adverse events more fully. Overall, the study team interpret these findings as supportive of further investigation of psilocybin therapy in supervised clinical settings, including exploration of simultaneous administration models, while emphasising the need for continued safety monitoring and efficacy trials in clinical populations.

This Phase I randomised, double-blind, placebo-controlled study demonstrated the feasibility of supervised simultaneous administration of single doses of psilocybin (10 mg and 25 mg) with one-to-one psychological support in healthy volunteers. No serious adverse events occurred, and there were no clinically relevant detrimental short- or long-term effects on cognitive functioning, social cognition or emotional regulation compared with placebo in this sample. The authors state that further investigation of simultaneous therapeutic psilocybin administration in clinical populations is warranted.