Investigating the safety and tolerability of single-dose psilocybin for post-traumatic stress disorder: A nonrandomized open-label clinical trial

PTSD is a common and disabling psychiatric disorder marked by intrusion, avoidance, negative alterations in cognition and mood, and heightened arousal. Existing first-line treatments—principally trauma-focused psychotherapies and selective serotonin reuptake inhibitors (SSRIs)—have important limitations: psychotherapies are time-intensive, often poorly tolerated, and suffer high dropout, while SSRI efficacy is modest with remission rates below 30% and high levels of polypharmacy and non-adherence in clinical practice. These gaps have driven interest in novel interventions that may be more tolerable and act more rapidly. This study evaluated COMP360, a pharmaceutical-grade synthetic psilocybin formulation, which has shown promise in treatment‑resistant depression but had not previously been studied in clinically confirmed PTSD. Mcgowan and colleagues designed a Phase II trial to assess the safety and tolerability of a single 25 mg dose of COMP360 psilocybin, with secondary aims to characterise changes in clinician‑rated and self‑reported PTSD symptoms, functional impairment and health‑related quality of life over 12 weeks. The trial also explored whether the qualitative features of the acute psychedelic experience related to clinical outcomes.

This was a 12‑week, Phase II, multicentre, nonrandomised open‑label clinical trial conducted at one UK and two US sites between June 2022 and February 2024. The primary objective was to assess safety and tolerability following a single oral dose of 25 mg COMP360 psilocybin. The trial complied with Good Clinical Practice and ethical approvals were obtained in both countries; all participants provided written informed consent. Eligible adults had DSM‑5 PTSD arising from adult trauma, confirmed by the Clinician‑Administered PTSD Scale for DSM‑5 (CAPS‑5), and scored at least 25 on the PTSD Checklist for DSM‑5 (PCL‑5) at baseline. Key exclusions included current psychotic or bipolar disorder, recent substance use disorder, primary major depressive disorder within 6 months, recent traumatic exposure, complex PTSD or significant childhood physical/sexual abuse by clinician judgement. Participants taking antidepressant or antipsychotic medications completed a medication washout at least two weeks before baseline; concomitant psychological therapies were allowed if initiated ≥3 weeks before baseline and remained stable. Procedures included a 2–6 week run‑in with three preparatory sessions delivered by trained therapists following the Compass Psychological Support Model. On Day 1 participants received a single 25 mg dose in a 6–8 hour administration session attended by two therapists in a dimly lit, nonclinical environment; a standardised music playlist and eyeshades were used. Integration sessions were provided on Day 2 and during Weeks 1 and 2. Participants were followed through scheduled in‑clinic visits at Day 2, Week 1, Week 2, Week 4 and Week 12, with additional Week 6 and Week 9 contacts that could be remote. Participants were requested to remain off PTSD medications until after Week 4 as clinically appropriate. The primary outcome was safety and tolerability, assessed as treatment‑emergent adverse events (TEAEs) coded via MedDRA and monitored at each visit; suicidality was assessed with the Columbia Suicide Severity Rating Scale (C‑SSRS). Vital signs, ECG, laboratory tests and the Brief Psychiatric Rating Scale positive subscale (BPRS+) were also collected. Secondary outcomes included change from baseline on CAPS‑5 at Weeks 4 and 12, PCL‑5 at each visit, functional impairment via the Sheehan Disability Scale (SDS) and quality of life via EQ‑5D‑5L index score. The 5‑Dimensional Altered States of Consciousness Rating Scale (5D‑ASC) captured acute psychedelic experience on Day 1; post hoc Spearman correlations tested associations between 5D‑ASC dimensions and CAPS‑5 change. No inferential hypothesis testing was performed. Safety analyses included all participants who received COMP360; efficacy analyses used the same Full Analysis Set. Descriptive statistics summarised outcomes; no imputation was applied for missing efficacy data. EQ‑5D‑5L values were mapped to a UK EQ‑5D‑3L value set via cross‑walk. Cohen’s d was used to report effect sizes where presented.

Twenty‑two participants received psilocybin and comprised the analysis sample (14 female; 63.6%; mean age 39.0 [SD 7.91] years). Baseline CAPS‑5 indicated substantial symptom severity (mean 47.5 [SD 9.78]) and the mean duration of PTSD was long (88.2 [SD 68.65] months). Nine participants (40.9%) underwent antidepressant washout prior to dosing; seven (31.8%) were receiving stable psychological therapy at study entry. Safety: All participants experienced at least one TEAE, with 117 events reported in total. Seventy events (59.8%) began on the day of administration; most of these resolved the same day or by the following day (56/70 [80.0%] resolved on dosing day; 8/70 [11.4%] resolved the day after). The most frequent TEAEs were headache (n = 11; 50.0%), nausea (n = 8; 36.4%), crying (n = 6; 27.3%) and fatigue (n = 6; 27.3%). Three participants (13.6%) experienced severe TEAEs comprising eight events (two instances of euphoric mood and one each of nausea, chills, muscle twitching, visual hallucination, auditory hallucination and synesthetic hallucination); all occurred on administration day and seven resolved the same day. There were no treatment‑emergent serious adverse events and no withdrawals. Two TEAEs of suicidal ideation occurred: one moderate transient episode on administration day (deemed related to drug) in a participant who later met response and remission criteria at Week 4 and response at Week 12; and one mild event at Week 7 in a non‑responder that resolved within a month and was considered possibly related. No clinically concerning trends were reported in mDESS, vital signs (limited by sparse on‑treatment data for most participants), ECG, laboratory tests or BPRS+. Efficacy and related outcomes: CAPS‑5 total score decreased from a baseline mean of 47.5 to yield a mean change at Week 4 of −29.9 (SD 14.06; 95% CI −36.1 to −23.7; Cohen’s d = 2.13) and a comparable reduction at Week 12 (95% CI −36.4 to −22.7; Cohen’s d = 1.92). Using the prespecified definitions (response = ≥15‑point CAPS‑5 reduction; remission = CAPS‑5 ≤20), response rates were 81.8% at Week 4 and 77.3% at Week 12; remission rates were 63.6% at Week 4 and 54.5% at Week 12. Reductions were observed across all four PTSD symptom clusters. Self‑reported PCL‑5 scores showed a rapid reduction by Day 2 that was sustained through Week 12 (Day 2 change reported with 95% CI −39.8 to −27.1; Cohen’s d = 2.34; sustained effects at later visits with 95% CIs −42.4 to −26.3; Cohen’s d = 1.89). Functional impairment (SDS) improved markedly from a baseline mean total of 22.7 (SD 5.38), with mean reductions of −11.7 (SD 8.41; 95% CI −15.5 to −8.0; Cohen’s d = 1.39) at Week 4 and −14.4 (SD 8.21; 95% CI −18.1 to −10.6; Cohen’s d = 1.75) at Week 12. EQ‑5D‑5L index data were available and showed improvements (data reported as index change in figures/tables). CAPS‑5, PCL‑5 and EQ‑5D‑5L were available for all 22 participants at all follow‑up visits; one participant had missing SDS at Week 12. Acute experience correlations: On the 5D‑ASC, Oceanic Boundlessness (OB) scores correlated with greater CAPS‑5 reductions (Week 4 rs = −0.442; Week 12 rs = −0.394), indicating that higher OB was associated with larger symptom improvement. Other 5D‑ASC dimensions demonstrated positive or negligible correlations with change in CAPS‑5 (Anxious Ego Dissolution Week 4 rs = 0.396; Reduction of Vigilance Week 4 rs = 0.425; Visual Restructuralization Week 12 rs = 0.327); most other correlations were rs < 0.3.

Mcgowan and colleagues report that a single 25 mg dose of COMP360 psilocybin, given with psychological support, was not associated with any treatment‑emergent serious adverse events or study withdrawals in this sample of adults with DSM‑5 PTSD. Most adverse events occurred on the day of dosing and resolved quickly; common events (headache, nausea, fatigue, crying) align with prior psilocybin studies in healthy volunteers and in treatment‑resistant depression. The occurrence of suicidal ideation in two participants highlights the necessity for clinical vigilance when conducting psychedelic trials in populations with serious mental illness. On secondary endpoints, the investigators observed large, clinically meaningful reductions in clinician‑rated PTSD severity (CAPS‑5) that were evident at Week 4 and sustained to Week 12, with similarly rapid and durable decreases on self‑reported PCL‑5 scores. Functional impairment and quality of life also improved substantially. The authors note these response and remission rates compare favourably with historical SSRI trials and—using the protocol’s CAPS‑5 thresholds—appear substantial relative to results reported from MDMA‑assisted psychotherapy trials, but they emphasise the methodological differences that limit direct comparisons, including dosing schedules, trial length and inclusion criteria (for example, exclusion here of complex PTSD and childhood abuse). The study found that the Oceanic Boundlessness dimension of the acute psychedelic experience, a measure linked to mystical‑type positive states and network desynchronisation, correlated with greater PTSD symptom reduction, suggesting the qualitative nature of the acute experience may be a proximal pharmacodynamic predictor of outcome. By contrast, dimensions reflecting anxious ego dissolution and reduced vigilance showed correlations in the opposite direction, a pattern the authors contrast with findings in treatment‑resistant depression and which they propose warrants further investigation in PTSD where somatic and emotional reactivity are prominent. The authors acknowledge important limitations: the small sample size, the open‑label, uncontrolled design, exclusion of people with complex PTSD or significant suicidal risk, and limited on‑treatment vital sign data in most participants. They conclude that while COMP360 psilocybin was generally well tolerated and associated with rapid, sustained symptomatic and functional improvements over 12 weeks, larger controlled trials are needed to determine safety and efficacy definitively and to explore how the character of the psychedelic experience influences outcomes in PTSD.