Investigational psilocybin treatment for post-traumatic stress disorder: a qualitative study of participant experience, trauma engagement, and differences from standard treatment

The paper situates post-traumatic stress disorder (PTSD) as a common, disabling condition for which existing first-line psychological therapies and approved pharmacotherapies often produce incomplete benefit, high dropout, or limited remission. The authors note growing interest in psychedelic-assisted approaches—MDMA has shown promise in PTSD and psilocybin has demonstrated efficacy in depression, which is frequently comorbid with PTSD—but indicate that no prior qualitative studies had examined how people with PTSD experience psilocybin treatment in clinical settings. The study aimed to explore participants' subjective experiences of investigational psilocybin treatment for PTSD, with particular emphasis on non‑pharmacological safety and support factors, how index-trauma material presented during psilocybin administration (directly or indirectly), and how participants compared psilocybin with standard PTSD treatments. The qualitative analysis was nested within an open‑label Phase II trial of COMP360 psilocybin and intended to inform protocol design, provider training, and hypotheses about process-level change in future investigations.

This qualitative sub-study was pre-specified within an open‑label Phase II trial (NCT05312151) assessing the safety and tolerability of COMP360 psilocybin in adults whose PTSD stemmed from a traumatic event experienced in adulthood. Recruitment occurred at three sites across two countries (two sites in the United States and one in the United Kingdom) between June 10, 2022 and Feb 12, 2024. Twenty‑one participants provided informed consent to the qualitative sub-study and completed in‑person interviews. Ethical approvals were obtained from Advarra (US) and Brent Research Ethics Committee (UK). The funder, Compass Pathfinder Limited, participated in design, data collection, analysis, interpretation and manuscript preparation. Trial procedures relevant to the qualitative study: participants completed a 3–6‑week run‑in to taper antidepressants/antipsychotics when required; seven participants continued pre‑existing talking therapies. Participants met support providers for preparation (three pre‑administration meetings), received a single 25 mg dose of COMP360 during a 6–8 hour administration session, and attended integration and safety assessments on Day 2, Week 1 and Week 2, with monitoring up to 12 weeks post‑treatment. Participants were asked to avoid PTSD medications for at least 4 weeks after dosing. Qualitative data collection focused on semi‑structured, one‑to‑one interviews conducted in person at three time points (day before, day after, and 12 weeks post‑dosing); this manuscript reports only the interviews conducted the day after dosing (each ~60–90 minutes). Interviews explored prior treatment experiences, subjective effects of psilocybin, encounters with trauma‑related material, and ideas for protocol optimisation. Audio recordings were transcribed verbatim and managed in NVivo 14. Data analysis used reflexive thematic analysis (RTA) following Braun and Clarke. The analytic orientation was primarily inductive and experiential; NLM led coding and developed themes iteratively, with regular reflection and peer debriefing with VW and broader author group to interrogate interpretations and enhance analytic depth. The authors used the concept of information power to justify the sample size rather than saturation. Reflexivity practices (a reflexive journal and team discussion) were reported. The analysis examined patterns about preparedness for treatment, how index trauma presented during psilocybin sessions, and comparative reflections versus standard PTSD treatments.

Twenty‑one participants were interviewed for the qualitative sub‑study; the trial completed without serious adverse events or participant dropouts. The reflexive thematic analysis identified four core themes with related subthemes: (1) non‑pharmacological factors for psychological safety and trust; (2) the experiential nature of psilocybin treatment; (3) engagement with trauma‑related material during psilocybin treatment; and (4) comparative reflections on prior therapies and psilocybin treatment. The qualitative analysis was conducted blind to the quantitative outcomes. Theme 1 — Non‑pharmacological factors for psychological safety and trust: most participants endorsed the value of preparation sessions, treatment education, intention setting, and rapport with the study team in fostering psychological safety and agency. Participants described the non‑directive posture of support providers as helpful for encouraging inner exploration rather than offering interpretations or solutions. Integration sessions were reported to validate experiences, aid meaning‑making, and support continued self‑directed processing. Theme 2 — Experiential nature of psilocybin treatment: participants described an "expanded access to self," reporting transient distance from their usual self‑concept and access to deeper or previously inaccessible self‑states, often accompanied by strong affect and bodily sensations. Somatic and non‑verbal responses (e.g. muscle relaxation, increased bodily awareness) were reported as meaningful by some and challenging or transient by others. Several participants emphasised that intense emotional pain could occur during the session but was experienced as therapeutically significant. Theme 3 — Engagement with trauma‑related material: all participants reported encountering trauma‑related content during the session, with two distinct modes. Direct engagement involved vivid imaginal recall or reliving of salient trauma moments accompanied by strong affect and bodily reactions; some participants described this as difficult but important for therapy. Indirect engagement involved trauma‑linked affects, cognitions or somatic states without explicit re‑experiencing of the event; several participants felt that addressing trauma‑adjacent symptoms (e.g. avoidance, fear) could be therapeutic even without direct memory recall. A participant described feeling fear and expecting a memory or flashback that did not materialise, yet trauma‑related emotions surfaced. Theme 4 — Comparative reflections on prior therapies: participants contrasted psilocybin treatment with conventional pharmacotherapies and psychological therapies. Several reported that standard medications were primarily symptom‑management (e.g. numbing), whereas psilocybin appeared to facilitate encountering root difficulties, greater emotional openness, and a whole‑person focus. The non‑directive and self‑directed character of psilocybin support was experienced as less rigid and more personal than manualised psychotherapies, although participants acknowledged the intensity and demand of the experience. Representative participant reflections included comparisons of psilocybin as a single, non‑dependent dose that opened emotional access, contrasted with daily pharmacotherapies.

L. and colleagues interpret the findings as reflecting the central role of non‑pharmacological elements—preparation, treatment education, intention setting, rapport and a non‑directive support stance—in promoting psychological safety and enabling participants to engage with the psilocybin experience. Participants reported feeling prepared to face a range of potential phenomena, despite acknowledging the inherent ineffability of peak psychedelic experiences. Regarding trauma engagement, the authors highlight that about half the sample did not directly re‑visit traumatic memories during dosing; instead, many experienced indirect intrapersonal processes (expanded self‑perspective, affective and somatic changes) that appeared to facilitate re‑evaluation of maladaptive trauma‑related narratives and reduce experiential avoidance. Where direct re‑experiencing occurred, it was often intense and somatically anchored; some participants construed such encounters as emotionally releasing or therapeutically meaningful. The authors note that these processes might align with constructs from existing trauma theories (for example, emotional processing, dual representation, or memory reconsolidation), but they emphasise such links as speculative because the qualitative design did not test mechanisms. The authors position psilocybin as offering a different pathway from conventional treatments: participants described a shift from avoidance to openness and a perceived move from symptomatic management toward engagement with broader personal and interpersonal patterns. They argue this may explain why some participants found psilocybin experiences more personally meaningful than prior interventions. At the same time, authors stress the necessity of safeguards, careful screening, and skilled support because the experiential states can be distressing. The study's limitations are acknowledged: a small, purposive sample drawn from adults with single‑incident or adult‑onset trauma (excluding complex, childhood‑onset PTSD), interpretative findings inherent to reflexive thematic analysis, potential influence of researchers' perspectives, and specialist treatment sites and support providers that limit generalisability. The authors do not claim causal mechanisms or clinical efficacy; rather they present participants' meaning‑making as one interpretative account. They recommend future longitudinal, mixed‑methods and controlled trials to link subjective experience with symptom trajectories, neurobiological markers and outcomes, and to evaluate the addition or necessity of manualised psychotherapies alongside psilocybin. The authors also note plans to cross‑reference these qualitative data with the trial's quantitative outcomes as part of broader research.