In a Phase 2, non-randomised open-label trial of 22 adults with PTSD, a single 25 mg dose of psilocybin administered with psychological support was generally well tolerated with no serious adverse events and mostly transient side-effects, and was associated with large, clinically meaningful reductions in PTSD symptoms and improvements in functioning and quality of life sustained to 12 weeks. These results indicate single-dose psilocybin may be safe and potentially efficacious for PTSD, warranting further controlled investigation.
Papers cited by this study that are also in Blossom
Aaronson, S. T., van der Vaart, A., Miller, T. et al. · JAMA Psychiatry (2024)
Background
Post-traumatic stress disorder (PTSD) is a debilitating condition for which there are few efficacious treatments. Psilocybin is being studied for use in treatment-resistant depression but has not yet been investigated in PTSD.
Aims
The trial’s primary outcome was to investigate the safety and tolerability of single-dose psilocybin in participants with PTSD.
Methods
This was a Phase 2, nonrandomized, open-label, multicenter trial. Secondary outcomes were changes in PTSD symptoms (Clinician-Administered PTSD Scale for DSM-5 (CAPS-5); PTSD Checklist for DSM-5 (PCL-5)), functional impairment (Sheehan Disability Scale; SDS) and quality of life (EQ-5D-5L index score).
Results
Amongst the 22 participants enrolled (63.6% female; mean (SD) age, 39.0 (7.91) years), there was a total of 117 treatment-emergent adverse events (TEAEs); 70 (59.8%) were reported on administration day, of which 64/70 (91.4%) resolved by the end of the next day. TEAEs commonly included headache ( n = 11; 50.0%), nausea ( n = 8; 36.4%), crying ( n = 6; 27.3%) and fatigue ( n = 6; 27.3%). There were no serious TEAEs or TEAEs leading to study withdrawal. Pre-post comparisons indicated a clinically meaningful change from Baseline in mean CAPS-5 total score at Week 4 (−29.9 (14.06)) and Week 12 (−29.5 (15.43)), which was associated with the intensity of psychedelic experience on Day 1. PCL-5 scores showed symptom reduction was rapid and sustained until Week 12. SDS total score and EQ-5D-5L index score showed similar improvements.
Conclusions
Psilocybin at a dose of 25 mg, administered with psychological support, may be safe, well-tolerated and associated with symptomatic improvement in adults with PTSD. Further investigation is warranted. Clinical trial registration: ClinicalTrials.gov Identifier: NCT05312151 (https://clinicaltrials.gov/study/NCT05312151)
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.
Participants were adult outpatients with PTSD resulting from a traumatic event experienced during adulthood, aged ⩾18 years, recruited from the community and referring healthcare providers. The Life Events Checklist for DSM-5 (LEC-5) and PTSD Checklist for DSM-5 (PCL-5) were used at Screening to identify eligible participants. Diagnosis of PTSD, according to DSM-5 criteria, was confirmed by an experienced clinician using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and participants were required to have at least moderate symptoms of PTSD determined by a total score of 25 or higher at Baseline. Comorbid psychiatric disorders were assessed via medical records and clinical assessment using the Mini International Neuropsychiatric Interview (MINI) version 7.0.2. Participants taking antidepressant or antipsychotic medications at Screening completed medication down-taper and discontinuation at least two weeks before Baseline. Concomitant psychological therapies were permitted, provided they were initiated at least 3 weeks before Baseline and remained stable throughout the duration of the trial. Exclusion criteria included a medical history of psychotic disorder, bipolar disorder, personality disorder, obsessive compulsive disorder, alcohol or substance use disorder (within last 12 months), a primary diagnosis of major depressive disorder (within last 6 months), exposure to a traumatic experience in past 3 months, significant suicidal risk (identified with the use of the Columbia Suicide Severity Rating Scale [C-SSRS] at Screening, within the past year, and Baseline, since last visit), and significant physical or sexual abuse during childhood based on clinician judgement with the use of the Childhood Trauma Questionnaire. Complex PTSD, a psychiatric disorder that is similar to PTSD but with the additional presentation of disturbances in self-organization symptoms (ie affective dysregulation, negative self-concept and disturbances in relationships), was also excluded. Complex PTSD is commonly associated with greater psychiatric symptom comorbidity and with prolonged or repeated exposure to traumatic stressors, often arising from a background of interpersonal abuse. As an initial study on the safety and feasibility of psilocybin in PTSD, this patient group and participants with a primary presentation involving childhood abuse were not enrolled to limit symptom heterogeneity and exclude individuals at risk of severe personality changes that commonly result from a background of chronic abuse. Dissociative symptoms were not exclusionary.
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Anderson, B. T., Danforth, A. L., Daroff, R. et al. · EClinicalMedicine (2020)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Goodwin, G. M. · Journal of Affective Disorders (2023)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · Journal of Affective Disorders (2025)
Kirlic, N., Lennard-Jones, M., Atli, M. et al. · American Journal of Psychiatry (2025)
Madsen, M. K., Stenbaek, D. S., Arvidsson, A. et al. · European Neuropsychopharmacology (2021)
Mitchell, J., Ot’alora G, M., van der Kolk, B. et al. · Nature Medicine (2023)
Passie, T., Seifert, J., Schneider, U. et al. · Addiction Biology (2002)
Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)
Rucker, J. J., Marwood, L., Ajantaival, R. L. J. et al. · Journal of Psychopharmacology (2022)
Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)
Nielson, E. M., Tai, S. J., Lennard-Jones, M. et al. · Frontiers in Psychiatry (2021)
Papers in Blossom that reference this study
Modlin, N. L., Williamson, V., Goodwin, G. M. et al. · EClinicalMedicine (2025)
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.
No inferential statistical analyses were performed for this openlabel study. Safety analyses were performed on the Safety Analysis Set, which included all participants who received COMP360. Efficacy analyses were performed on the Full Analysis Set, which included all participants in the Safety Analysis Set. Descriptive summaries were used to evaluate the safety data and secondary efficacy endpoints. There were no imputations for missing efficacy data; only observed data were analyzed. To obtain index values using the UK value set, EQ-5D-5L data were mapped to the available EQ-5D-3L value set via the cross-walk method (NICE, 2019). Spearman's rank correlation coefficients (r s ) were calculated in post hoc analyses to assess the correlation between each 5D-ASC dimension and change from Baseline in CAPS-5 total score at Week 4 and Week 12. Effect sizes are measured using Cohen's d and reported as absolute values throughout.
COMP360 psilocybin at a dose of 25 mg was not associated with any serious adverse events or adverse events resulting in study withdrawal in participants with PTSD. Secondary outcomes (PTSD symptom severity, functional impairment and quality of life) revealed consistent and durable pre-post treatment improvements. To our knowledge, this is the first clinical trial to report on the safety and tolerability of psilocybin in participants diagnosed with PTSD. There were no treatment-emergent serious adverse events observed and no withdrawals over the 12-week trial period. Most TEAEs observed during the trial started on the day of dosing, resolved on the same or following day, and commonly included headache, nausea and fatigue, which is a pattern consistent with other trials examining psilocybin in healthy volunteers and in patients with treatment-resistant depression. Most AESIs observed during the trial were as expected and described previously in psilocybin studies, including hallucinations, paraesthesia, mood alteration (eg crying) and euphoric mood. Suicidal ideation experienced by two trial participants emphasizes the need for clinical vigilance in trials involving participants with serious mental illness. Suicidality is not uncommon amongst individuals with PTSD broadly. Indeed, for this reason, appropriate treatment access assumes importance. Single-dose psilocybin was associated with a clinically meaningful reduction in CAPS-5 total score (clinician-rated PTSD symptom severity over the past month). This reduction was observed across all four symptom clusters and sustained until the end of the trial. The patient-rated equivalent measure (PCL-5) indicated a rapid onset of this improvement, observed the day after treatment and similarly sustained throughout the trial. A reduction in PCL-5 scores was reported previously in a psilocybin feasibility study in a sample of older long-term acquired immunodeficiency syndrome survivors who had experienced demoralization and traumatic loss. The current secondary outcome results suggesting efficacy for PTSD align with this previous work and are the first in a psilocybin trial to demonstrate this finding in clinically-confirmed PTSD. These data suggest COMP360 psilocybin has potential as a future treatment for PTSD. Over 75% of participants were classified as responders, and over half were remitters at the end of the 12-week trial. These results are promising when contrasted against SSRI clinical trials in which treatment response rates scarcely exceed 60%. Meaningful comparison with older PTSD trials is challenging, however, chiefly because those studies investigated drugs that have chronic dosing regimens and employed randomized-controlled designs. In addition, the transition to DSM-5 has since restructured how PTSD is diagnosed and assessed, introducing further divergence. Our protocol definitions for response and remission were derived from a systematic review that highlighted the inconsistency of the criteria employed and recommended response and remission thresholds of ⩾15-point change from baseline and a total score ⩽20, respectively. Recent studies for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in PTSD defined clinical response as a decrease of ⩾10 points on the CAPS-5 and remission as a loss of diagnosis and a CAPS-5 total score ⩽11, which if applied instead, would yield a higher response rate, but lower remission rate (Supplemental Table). The MDMA-assisted psychotherapy studies consisted of three treatment sessions across an 18-week period and assessed symptoms at different timepoints compared with the current trial. Applying identical CAPS-5 definitions, response and remission rates at Week 4 and Week 12 were greater following single-dose COMP360 psilocybin, followed up over 12 weeks, than those achieved after two treatment sessions of MDMA-assisted psychotherapy. While the Baseline mean CAPS-5 total score in the current study indicated a similar level of severity of PTSD symptoms as was reported at baseline in the MAPP1 trial (enrolling severe PTSD)and was even greater than in the MAPP2 trial (enrolling at least moderate PTSD), the latter two trials did not exclude participants with childhood trauma or complex PTSD, complicating direct comparisons. Treatment was also associated with sustained improvements in functional impairment and quality of life. This is important because the burden of PTSD on psychosocial function and quality of life is so substantial, and can linger even after remission of symptoms. Addressing such outcomes, therefore, assumes importance for comprehensively treating PTSD. As in other psilocybin studies, 5D-ASC OB, a dimension associated with desynchronization of brain networksand positive, more connected emotional states, was correlated with better therapeutic outcomes. Assessed after administration, this dimension was robustly associated with CAPS-5 change from Baseline until the end of the study. Psychedelic experience intensity is correlated with plasma psilocin and fMRI-assessed cortical network connectivityand may therefore represent a proximal pharmacodynamic predictor of later clinical response. Such a correlation may predict a dose-effect relationship as seen for psilocybin in treatment-resistant depression. This OB effect was well differentiated from the correlations of response with other dimensions of the 5D-ASC, which were all of opposite direction or negligible strength. That greater AED and RV were negatively correlated with efficacy is dissimilar to the patterns seen in treatment-resistant depression, in which no such associations were observed. In PTSD, a condition with marked somatic and emotional reactivity, it may be intuitive to suspect that negative experiences, such as those captured by the AED, undermine the likelihood of therapeutic response. The link between efficacy and RV is less straightforward. This dimension captures diminished awareness of the external environment and altered attention. While these qualities are not necessarily indicative of treatmentemergent dissociation, they may resemble cognitive and perceptual shifts familiar to those with PTSD (particularly those with dissociative symptomatology) and could be perceived as disorienting, potentially moderating the therapeutic impact of the psychedelic experience. Further exploration of how the quality of psychedelic experience shapes treatment response in PTSD may be informative for next-generation psychedelic treatment for this patient group. This was a feasibility study with significant limitations. First, it was a small, open-label trial without a comparator arm; larger, controlled studies are required to understand fully the safety and efficacy of COMP360 psilocybin for PTSD. Second, participants with complex PTSD or at clinically significant risk of suicide were excluded from the study. Finally, there were limited vital sign data available during the administration session: more frequent on-treatment assessment is needed to characterize the acute effects of psilocybin on pulse and blood pressure. The landscape of PTSD pharmacotherapy and drug development has been described previously as in crisis, requiring urgent redress. In this trial, COMP360 psilocybin administered in a single session with psychological support was found to be generally well-tolerated and without serious risk to safety. Trial secondary endpoints indicated that treatment was associated with a rapid and sustained reduction in PTSD symptoms and improved functioning and quality of life over a 12-week follow-up period. Future studies are needed to ascertain the safety and efficacy of psilocybin as a novel treatment for this regrettably underserved patient group.