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

Summary

Background

Post-traumatic stress disorder (PTSD) is a debilitating condition leading to significant personal and societal burden. Standard treatments frequently demonstrate limited efficacy, leading to persistent symptoms and high dropout rates. Psilocybin has shown promise in treating depression, a condition that is often comorbid with PTSD. We aimed to explore participant experiences of psilocybin treatment for PTSD, emphasising the role of monitoring and support for safety, direct and indirect engagement with trauma-related material during psilocybin treatment, and differences between psilocybin and standard treatments.

Methods

This qualitative study was nested within a quantitative, open-label phase 2 trial assessing the safety and tolerability of COMP360 psilocybin in adults with PTSD. Eligible participants were adults (18 years or older) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for PTSD secondary to a traumatic event experienced in adulthood. Recruitment was conducted at three sites across two countries: two in the United States and one in the United Kingdom. Enrolled participants underwent standardised preparation, a single psilocybin administration session, and follow-up integration sessions. Semi-structured interviews were conducted before, the day after, and 12 weeks post-treatment. Data were analysed using reflexive thematic analysis, which is a distinct and theoretically grounded approach to co-construction of recurring themes pertaining to participants' preparedness for treatment, how participants’ index trauma presented during treatment, and how psilocybin compared to standard treatments. The quantitative phase 2 trial, which the present qualitative study is nested within, is registered with ClinicalTrials.gov, NCT05312151.

Findings

Between June 10, 2022, and Feb 12, 2024, 21 participants were enrolled and participated in this qualitative sub-study and completed the in-person qualitative interviews. The analysis revealed four core themes: (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. Emphasising safety, treatment education, and informed consent, the treatment facilitated an experience of both direct and indirect engagement with trauma-related material during psilocybin treatment. Unlike standard treatments requiring direct confrontation with trauma memories, psilocybin appears to enable a broader, indirect engagement with traumatic material via a range of affective, somatic and self-transcendent experiences (e.g., moments of perceived unity, dissolution of self, or felt connection with a larger whole).

Interpretation

Our qualitative findings suggests that psilocybin treatment, when administered with standardised preparation and treatment support, may offer a meaningful therapeutic opportunity for Patients with PTSD. Future work should include larger controlled studies and use mixed methods to explore how symptom change, functional outcomes, and patient narratives interact.

Funding

Compass Pathways, plc.

Research in context.

Evidence before this study

Post-traumatic stress disorder (PTSD) is a prevalent psychiatric condition for which current treatments often offer limited relief. Trauma-focused psychological therapies are typically first-line, but many individuals experience persistent symptoms and high dropout rates. Pharmacological options such as Selective Serotonin Reuptake Inhibitors (SSRIs) are widely prescribed but show limited efficacy and are associated with adverse effects. Interest in psychedelic therapies is growing, with MDMA-assisted therapy showing promise in PTSD and psilocybin treatment in depression, a condition often comorbid with trauma. However, no published studies had qualitatively examined psilocybin treatment for PTSD in clinical settings. Before commencing this study on June 10, 2022, we searched PubMed, Embase, and ClinicalTrials.gov for human studies published in English using the terms “psilocybin,” “PTSD,” and “qualitative” (2000–2022), and found no relevant results.

Added value of this study

To our knowledge, this is the first qualitative study examining participant experiences of investigational psilocybin treatment for PTSD in a clinical trial, with this qualitative analysis nested within a phase 2 open-label trial assessing the safety and tolerability of COMP360 psilocybin in adults with PTSD. It offers insight into how individuals engaged with trauma-related material during psilocybin administration, what supported treatment engagement, and how the experience compared to standard therapies. This study provides a foundation for the considered development of psilocybin treatment as a potential option for individuals underserved by existing PTSD interventions and underscores the role of qualitative methods in shaping the clinical development of novel trauma treatments.

Implications of all the available evidence

The findings of this study provide insights for future investigations of psilocybin in PTSD and contribute to the wider development of psychedelic therapies for psychiatric conditions characterised by high rates of trauma exposure. These findings may also inform protocol design, participant preparation, and provider training in future studies. Results underscore the role of structured support throughout psilocybin treatment, including preparation and treatment education, in enhancing safety and engagement. While based on a small, open-label sample, these qualitative findings offer a foundation for future trials. Future work should include larger controlled studies and use mixed methods to explore how symptom change, functional outcomes, and patient narratives interact.

Introduction

Post-traumatic stress disorder (PTSD) presents a significant burden to patients, communities, and healthcare systems, with estimated lifetime prevalence ranging from 8% to 12%.¹ In 2018, the total excess economic burden of PTSD in the US was estimated at $232.2 billion.² PTSD significantly reduces quality of life, contributing to cognitive and psychosocial impairments, employment difficulties, and substance abuse, while also imposing a high societal and economic burden, including increased healthcare costs and heightened risk for depression and suicide.^1,3

Although first-line exposure-based and cognitive psychological treatments offer benefit, a substantial portion of patients experience persistent symptoms.⁴ Furthermore, some experience adverse reactions to exposure-based psychotherapies and high dropout rates have been recorded.⁵ Approved pharmacotherapies (e.g., sertraline and paroxetine) demonstrate limited efficacy, with only 20–30% of patients achieving full remission.^6,7 This may be due to the complexity of PTSD. It may be simply inadequate to target a single neurotransmitter mechanism, like stress reactivity with SSRIs or hyperarousal with beta-blockers.⁸ Accordingly, there is a significant and urgent demand for better ways to alleviate the personal, societal, and economic burdens of PTSD.

Recently, trials with 3,4-Methylenedioxymethamphetamine (MDMA) have demonstrated significant reductions in PTSD symptoms over 18 weeks of treatment.⁹ MDMA is a markedly psychoactive drug, which increases prosocial feelings.¹⁰ When combined with psychotherapy, it is believed to enhance therapeutic outcomes without inducing the profoundly altered states of consciousness typically associated with psychedelic experiences. It appears more promising than the only approved drug therapies, sertraline and paroxetine.¹¹

MDMA is often compared with the serotonergic agonists, lysergic acid diethylamide (LSD) and psilocybin. However, the psychedelic effects of both the latter drugs are much more intense at clinically effective doses,¹² drawing participants into a highly immersive, inwardly focused psychological state, which is characterised by vivid introspection and an engagement with shifting internal thoughts and emotions. This contrasts with the dialogical interactions typically associated with traditional psychotherapy conducted with a therapist. For this reason–although this perspective is contested,¹³ it has been argued that to be effective in treatment-resistant depression,¹⁴ the psychedelic experience does not require psychotherapy in the conventional sense.¹⁵ Therefore, the support provider role can be viewed as distinct. It may not necessarily require formal psychotherapy training but should be undertaken by individuals with protocol-specific training and the requisite experience and competencies to promote participant safety and appropriate care. Stand-alone psychotherapy, by contrast, remains a specialist clinical intervention delivered only by appropriately qualified clinicians when treating mental-health patients. Nevertheless, preparation before, support during and follow-up after drug administration appear to be important in psilocybin treatment. Therefore, the current support approach, designed specifically for clinical trials,¹⁶ was employed in the present study investigating the safety and tolerability of psilocybin as treatment for PTSD and its unblinded effects on PTSD symptoms.

Psychedelic treatment for PTSD is novel, and standard quantitative measures of psychotropic drug outcomes lack detailed descriptions of patient experience and meaning making. Qualitative research methodologies are highly suitable for providing deeper insight into the process of treatment, suggesting potential change mechanisms, enhancing methodological rigor, and ultimately improving therapeutic practices and procedures.¹⁷ The present phase 2 clinical trial of psilocybin in patients with adult trauma meeting the criteria for PTSD provided the first opportunity to conduct a thematic analysis on interviews with participants with PTSD designed to capture their experience in COMP360 psilocybin treatment.¹⁸ Themes were developed that reflected recurring patterns across the data and were interpreted in relation to three key questions: (1) whether participants felt they were prepared to engage in the treatment; (2) how participants' index-trauma presented during the psychedelic experience and whether it appeared to be the focus for symptom resolution; and (3) how psilocybin treatment compared to participants’ experiences with other first-line, evidence-based PTSD treatments.

Methods

Study design and ethics

The present qualitative study was nested within a quantitative open-label, phase 2 trial designed to evaluate the safety and tolerability of COMP360 psilocybin in PTSD following a traumatic event experienced during adulthood (NCT05312151). The qualitative study outlined here was prespecified, within exploratory endpoints, within the protocol of the phase 2 trial. The protocol is available at: https://cdn.clinicaltrials.gov/large-docs/51/NCT05312151/Prot_000.pdf. Recruitment was conducted between June 10, 2022, and Feb 12, 2024 at three clinical sites across two countries: two in the United States and one in the United Kingdom. Participants’ perceptions of and attitudes toward the investigational COMP360 psilocybin treatment for PTSD were assessed by conducting a qualitative interview-based sub-study, the focus of this report. The quantitative measures of adverse effects and PTSD symptoms were analysed and will be published separately.¹⁸

This study received ethical approval from Advarra Institutional Review Board (Reference number: Pro00055122) in the United States and Brent Research Ethics Committee (Reference number: 21/LO/0507) in the United Kingdom. Written informed consent was obtained from all participants prior to enrolment in the study.

Participants

Eligible participants were adults (18 years of age or older) who met DSM-5 diagnostic criteria for PTSD secondary to a traumatic event experienced in adulthood (Table 1). 21 participants provided informed consent to participate in the qualitative sub-study and were interviewed in person.

Table 1.

Participant characteristics.

Parameter	Statistic	COMP360 25 mg (N = 21)
Age at screening (years)	n	21
	Mean (SD)	38.4 (7.70)
Sex
Male	n (%)	8 (38.1)
Female	n (%)	13 (61.9)
Ethnicity
White	n (%)	17 (81.0)
Black or African American	n (%)	0
Asian	n (%)	4 (19.0)
Hispanic or Latino	n (%)	0
Middle Eastern or North African	n (%)	0
Other	n (%)	0
Country
United Kingdom	n (%)	13 (61.9)
United States	n (%)	8 (38.1)
Index trauma event
Physical or sexual assault	n (%)	7 (33.3)
Combat or war-zone exposure	n (%)	6 (28.6)
Serious accident	n (%)	1 (4.8)
Other traumatic event	n (%)	7 (33.3)
Duration of PTSD (Months)	n	21
	Mean (SD)	90.1 (69.77)

Values are presented as mean ± SD for continuous variables and n (%) for categorical variables. PTSD = post-traumatic stress disorder. Data shown are for participants receiving COMP360 25 mg (N = 21).

Procedures

The trial was conducted at three sites in the United Kingdom (King's College London) and the United States (Sunstone Therapies and Icahn School of Medicine at Mount Sinai). Eligible participants underwent a 3–6-week run-in period to taper off antidepressants/antipsychotics. Seven participants continued pre-existing talking therapies during the study to mitigate risk of destabilisation. During the course of the trial, participants met with the study support providers three times for pre-administration preparation before receiving a single 25 mg dose of COMP360 psilocybin during a 6–8-h administration session. Follow-up included risk assessment and integration sessions one day, 1 week, and 2 weeks post-administration. Participants were monitored for 12 weeks post-treatment and were asked to stay off PTSD medications for at least 4 weeks post-administration (Fig. 1).

Fig. 1.

Study process overview. Timeline illustrates relevant sub-study procedures across visits (V1–V10). The screening period included two preparation visits (V1a–V1b) with a variable duration of 2–6 weeks. The baseline assessment and preparation session (V2) occurred on Day −1, followed by the COMP360 administration session (V3) on Day 1. Integration sessions were conducted at V4 (Day 2), V5 (Week 1), and V6 (Week 2). The final follow-up visit (V10) took place at Week 12 (end of study, EOS). Qualitative interviews were conducted at V2, V4, and V10. V, visit; EOS, end of study.

The clinical-trial support model utilised in this trial was delivered over the three main treatment phases: pre-administration preparation, administration, and follow-up integration¹⁶ (Table 2). In clinical trials, the support is delivered by specially trained health care professionals who possess an active license in good professional standing and have the relevant education, training and/or experience in mental health, counselling or psychological therapies. In preparation, support providers provide treatment education and prepare the participant to navigate their experience in administration safely and autonomously. During administration, support providers allow the participant's experience to unfold naturally, providing minimal and non-directive intervention and acting as a safeguard. In integration, support providers support the participant's reflection on their experience without offering interpretations or solutions, while remaining vigilant to any persistent unusual beliefs or ideations of harm to self or others.

Table 2.

Overview of the support structure.

Study phase	Core activities
Preparation	•Discussing treatment educational material and participant expectations •Discussing participants' life events pertinent to safety during psilocybin administration •Participant setting an intention for the administration session •Establishing support strategies and boundaries around physical touch for the administration session •Practicing experiential exercises (e.g., basic breath and body awareness exercises).
Administration	•Confirming participant's intention for the administration session •Confirming support strategies and implementing as needed and agreed •Assessing safety at the end of the administration session
Integration	•Inviting participant to select salient themes from their experience •Exploring salient themes and making meaning with non-directive support from the support provider •Identifying activities for ongoing integration outside of sessions (e.g., journaling) •Assessing safety and monitoring unusual beliefs or psychiatric destabilizsation

Preparation: discussing treatment educational material and participant expectations; discussing participants' life events pertinent to safety during psilocybin administration; participant setting an intention for the administration session; establishing support strategies and boundaries around physical touch for the administration session; practicing experiential exercises (e.g., basic breath and body awareness exercises). Administration: confirming participant's intention for the administration session; confirming support strategies and implementing as needed and agreed; assessing safety at the end of the administration session. Integration: inviting participant to select salient themes from their experience; exploring salient themes and making meaning with non-directive support from the support provider; identifying activities for ongoing integration outside of sessions (e.g. journaling); assessing safety and monitoring unusual beliefs or psychiatric destabilisation.

Qualitative interview procedures

One-to-one, in-person, semi-structured qualitative interviews were conducted at three time points: the day before, the day after, and 12 weeks following the psilocybin administration session. However, this manuscript reports exclusively on the interviews conducted on the day after the psilocybin treatment session and followed one integration session. These interviews were selected for analysis because they captured participants’ immediate reflections on the treatment experience and its perceived relevance to their trauma histories and recovery processes.

Participants were informed about the purpose of the qualitative study and provided written informed consent. Interviews explored participants' experience of standard treatments, subjective experience of psilocybin's effects, perceptions of psilocybin treatment in the context of traumatic-stress, and ways to optimise the treatment protocol. A semi-structured, open-ended interview guide was used across all sites to ensure consistency, while allowing interviewers to use prompts to support elaboration and facilitate participants' own meaning–making processes.

Each interview lasted approximately 60–90 min, was conducted in person in a private clinical setting, audio recorded using encrypted devices, and transcribed verbatim. Interview transcripts were uploaded to NVivo (version 14) to support data organisation and analysis.

Data analysis

Data were analysed using reflexive thematic analysis (RTA) as outlined by Braun and Clarke.¹⁹ This approach aligns with an interpretivist epistemology, recognising that meaning is actively constructed through the researcher's reflexive engagement with the data, and that themes represent patterns of shared meaning rather than objective truths.

We adopted a primarily inductive and experiential orientation, staying close to participants' accounts while attending to the meaning–making processes they articulated. The number of interviews analysed (n = 21) was deemed sufficient based on the concept of information power²⁰ given the specificity of the sample, the focused aim of the study, the depth of the interviews, and the richness of the resulting data corpus.

All transcripts were derived from interviews conducted the day after psilocybin treatment sessions. NLM read and re-read these transcripts as part of the data familiarisation process, making detailed notes and generating preliminary codes. This coding process was iterative and interpretative, rather than seeking consensus or verification. Codes were developed, refined, and interpreted through critical reflection, aligning with the principles of RTA. To mitigate potential bias arising from the involvement of a single primary coder, NLM and VW met regularly to reflect on the meanings they were inferring, interrogate assumptions, and consider multiple readings of the data.

Draft themes were constructed to capture central organising concepts and were reviewed by the broader author group (MA, ZE, AG, GMG, DK, NK, NLM, VW), enabling peer debriefing and enhancing interpretative depth. Illustrative quotations were initially selected by NLM and VW and presented to MA, ZE, AG, GMG, DK, and NK as part of the peer review process. These were finalised following further consultation with JR. This process supported analytic rigour and ensured that selected excerpts effectively illustrated the interpreted patterns of meaning developed through the analytic process.

In line with Braun and Clarke's¹⁹ guidance, quotations serve not as empirical validation but rather as evocative illustrations of the analytic narrative. They support transparency, allow engagement with participants' voices, and provide insight into the interpretative story constructed through analysis.^19,21,22

We avoided use of terms such as “saturation,” recognising that in reflexive approaches, analytic insight is not assumed to be exhausted. Instead, the analytical process continued until the research team felt the interpretative account offered coherence and depth in relation to the research questions.

Qualitative research methodologies, such as RTA, aim to understand the complexity of human experiences and social phenomena. Unlike quantitative approaches, which seek generalisable patterns through statistical inference, RTA explores meaning and context from participants’ situated perspectives.^23,24 Therefore, we use terms like “some,” “about half,” and “several” to convey analytic interpretations, rather than quantify phenomena. This approach captures the richness of lived experience and honours the reflexive role of the researcher in meaning-making.

Reflexivity and researcher positioning

In keeping with the principles of reflexive thematic analysis, the lead author (NLM) maintained a reflexive journal throughout the analytic process to document reflections, emotional responses, and evolving interpretations. The research team brought a diverse range of professional backgrounds to the study, including psychiatry, psychology, neuroscience, clinical trial operations and trauma-focused qualitative and quantitative research. Several members had prior experience working with trauma-affected populations and hold roles across both academic and industry settings relevant to psychedelic therapy.

For instance, NLM and JR had prior clinical and research experience in psychedelic treatment studies for depression and PTSD, which informed their sensitivity to participants’ accounts of altered states and treatment engagement. VW, an experienced qualitative trauma researcher new to psychedelic studies, contributed a fresh perspective that encouraged grounding interpretations in the language and framing used by participants.

Regular peer debriefing sessions were used to critically reflect on how personal and disciplinary perspectives may have influenced the analytic process. These reflexive practices were not intended to eliminate subjectivity but to make its influence visible and analytically useful, consistent with Braun and Clarke's recommendations for high-quality RTA.²⁴

Role of the funding source

This study was sponsored by Compass Pathfinder Limited, who participated in study design; data collection, analyses, and interpretation; and manuscript preparation. The authors and sponsor collaborated on the final report and approved the submitted version.

Results

Between June 10, 2022, and Feb 12, 2024, 21 participants were recruited and interviewed for the qualitative sub-study. The study was completed as defined by the protocol without serious adverse events or patient dropouts. The qualitative interviews and analysis were conducted blind to the analysis of quantitative outcomes. Four themes and related sub-themes emerged from the RTA and are shown in Fig. 2.

Fig. 2.

Core themes and sub-themes. The figure illustrates the four core themes and associated sub-themes identified from qualitative interviews exploring participants' experiences of COMP360 psilocybin treatment for post-traumatic stress disorder (PTSD). Core Theme 1 (Non-pharmacological factors for psychological safety and trust) includes sub-themes related to preparation, treatment education, and trust. Core Theme 2 (Experiential nature of investigational psilocybin treatment) captures expanded access to self and non-verbal or somatic responses during psilocybin administration. Core Theme 3 (Engagement with trauma-related material during investigational psilocybin treatment) includes direct and indirect trauma engagement. Core Theme 4 (Comparative reflections on prior therapies and investigational psilocybin treatment) reflects participants' perspectives on symptom management and the self-directed, whole-person nature of psilocybin treatment. PTSD = post-traumatic stress disorder.

The main themes were ‘Non-Pharmacological Factors for Psychological Safety and Trust’, ‘Experiential Nature of Psilocybin Treatment’, ‘Engagement with Trauma-Related Material During Psilocybin Treatment’ and ‘Comparative Reflections on Prior Therapies and Psilocybin Treatment’. Each contributed to addressing our key questions of (1) whether participants felt they were adequately prepared to engage in treatment; (2) how participants' index-trauma presented during the psychedelic experience and whether it appeared to be the focus for symptom resolution; and (3) how psilocybin treatment compared to participants' experiences with other first-line, evidence-based PTSD treatments.

Core theme 1: non-pharmacological factors for psychological safety and trust

This key theme identified the positive impact of the treatment's non-pharmacological factors on participants' sense of psychological safety and trust. The following sub-themes were identified: (1) preparation; (2) treatment education; (3) setting intentions; (4) trust and rapport with study team; (5) utility of the nondirective approach; and (6) self-directed integration. The findings within each sub-theme are explored below, with participant quotes for illustration.

Preparation

The majority of participants affirmed the utility of the preparation sessions, providing participants with an opportunity to familiarise with the investigational psilocybin treatment process and practice support strategies to face the wide-ranging experiences catalysed by psilocybin. This, in turn, enhanced feelings of safety and trust in the treatment process, whilst encouraging self-agency and openness to novel and potentially challenging experiences.

“They [preparation sessions] gave me a really good idea of what I actually wanted to accomplish out of it myself. I didn't really know exactly prior to all of that, but giving the providers all of the information, like answering all their questions, it built up a bit of a roadmap that I think was incredibly useful”

(R34)

Treatment education

Participants highlighted the significance of education around the wide-ranging effects of psilocybin, and particularly in correcting any misconceptions that participants might have had about investigational psilocybin treatment. This appeared to increase participants' capacity to engage in the treatment process, mitigating concerns about psilocybin's effects and creating a clinically meaningful distinction between standard and psilocybin treatment.

“In hindsight, [the preparation sessions were] incredibly helpful ….before joining the study, my thought was that … you ingest the substance and then you’re basically just talking for eight hours, like a normal therapeutic session … what was great about the preparation ones was it very gently … nudged me away from that preconception and said, just let go and be open”

(C6)

Setting intentions

A significant number of participants described how ‘setting intentions’ prior to investigational psilocybin treatment provided a sense of purpose to their treatment session. Participants highlighted consequent enhanced feelings of autonomy and preparedness ahead of the treatment session, encouraging engagement with potentially challenging but meaningful material.

“We had … thought about my intentions beforehand, and it was very much about … not running away from things … going deeper with things … because we'd worked through that quite a bit beforehand, I was in the sort of mentally, I was in the right place to be able to do that in the session.”

(D8)

Trust and rapport with study team

Participants also reported that consistent, positive interactions with the study team promoted feelings of safety and trust, especially in the context of known PTSD symptoms (e.g., avoidance, shame, and fear). Participants described how these interactions encouraged them to fully commit to and embrace all aspects of their psilocybin treatment session.

“it … felt quite transparent and just human. I felt that there were a lot of procedures behind it, which felt good, but then didn't take away from the fact that it was a very … human experience … knowing that there was a lot of integrity in the processes and ideas behind the study, but then also … human … interfaces with the whole team, which … contributed a lot to … that feeling of safety.”

(G14)

Utility of the nondirective approach

Participants highlighted the clinical utility of the self-directed and intrapersonal nature of psilocybin treatment, wherein participants are encouraged to explore their immediate experience and responses to psilocybin's effects. During the treatment session, participants described the utility of support providers encouraging inner-exploration, curiosity and autonomy as opposed to providing suggestions, interpretations or solutions to participants.

“And at different times (support providers) were just very … acknowledging. I really don’t remember them saying anything during my dosing session or anything they said to me of any substance. I more remember just feeling supported …”

(O28)

Self-directed integration

A large portion of participants also described the value of integration sessions in promoting psychological safety by validating participants’ perceptions, encouraging continued inner-exploration and offering an opportunity to reflect on shifts in relation to trauma-related perspectives concerning self, others and the world.

“just talking about it out loud with someone that you know is not going to be judgmental about it, I think really helps just making meaning out of the experience. You would not want to go out into the world and talk to somebody that thinks it's bad, or that would bring any shame or anything into the story”

(V27)

Core theme 2: experiential nature of psilocybin treatment

The second key theme addresses the experiential nature of the investigational psilocybin treatment session. This theme encompasses the following sub-themes: (1) expanded access to self and (2) non-verbal and somatic responses. These two sub-themes are outlined below, with illustrative quotes from participants.

Expanded access to self

Participants described perceiving a range of expanded sense of self, gaining access to different, deeper, or previously unknown self-states during the investigational psilocybin treatment session. Often accompanied by strong affect and physical sensations, participants reported perceiving an internal sense of distance from their everyday self-concept and identity. This appeared to increase the sense of connection to, as opposed to separation from, self.

“the whole approach of leaning in and … the way in which psychedelics seem to work in opening up, almost giving you … a direct door to that really, really deep part of yourself … I think psychedelics … goes … to the deepest realm within us and is just so open to anything happening and then the integration afterwards is also done in that same way … open way, that’s self-led”

(F12)

Of note, several participants also highlighted the difficulty associated with increased access to previously avoided cognitions and affects, including substantial emotional pain during the investigational psilocybin treatment session. These participants acknowledged the challenging nature of these transient experiences while simultaneously asserting that confronting, rather than avoiding, such material appeared to present a valuable therapeutic opportunity.

“In a way, it [psilocybin treatment session] can be interpreted both positively and negatively … I just feel completely … opened up and just feel very raw and vulnerable. I think there are parts of me that has resisted that since then and … the fear of just feeling this way forever … just continuing to be deep in that suffering and sadness. Then on the other hand … that experience of just feeling so strongly was really positive, I would say. And that is really stuck with me.”

(G14)

Non-verbal and somatic responses

Some participants described meaningful somatic and non-verbal experiences (e.g., muscle relaxation, increased bodily awareness) during the investigational psilocybin treatment session. This enhanced state of introspection and immersion appeared to promote reflection on trauma-related material.

“It is repairing the connections, and it's also repairing the nerves in the body. So the feeling of jitteriness or shaking or whatever those different feelings all surrounding PTSD that are frequent in the body, it's diminishing it. It's like going into those tissues or those blood vessels … So I remember, and especially right after the treatment, it was really vivid, how good my whole body felt, my joints, my muscles

(O28)

In contrast, several participants also noted the potential for challenging, transient somatic reactions that seemed to lack any immediate, personal or reparative psychological significance.

“It felt like just everything hurt … like physically, except for my head … like my muscles, I guess. And, you know … it was just really bad. And I thought it would never end, but it did”

(S36)

Core theme 3: engagement with trauma-related material during psilocybin treatment

All participants reported encountering trauma-related content, with distinct direct and indirect engagement with trauma-related material taking place during the investigational psilocybin treatment session. Several participants reported both forms of trauma engagement, interchangeably occurring during different phases of the session.

Direct trauma engagement

Some participants reported vividly imagining, remembering, and/or exploring salient moments and themes associated with their index trauma. This imaginal directness appeared short-lived, often accompanied by trauma-related affect (e.g., grief, fear, guilt), physical sensations and a visceral sense of recall associated with their index trauma.

“Very difficult at the time, but it was difficult to deal with the emotion … I relived the experience. Lack of a better way to describe it, the blood and gore, but I relived the experience. So that was difficult, but very important.”

(T38)

Albeit challenging and intense, participants discussed how the treatment session appeared to enable a more complete access to aspects associated with their index trauma. Subsequently, these participants reported an overarching sense that the direct encounter with their trauma via psilocybin treatment was meaningful or necessary.

“It was around, you know, the atrocities in REDACTED, around like the suicide of REDACTED. And it was … intense, but it felt … productive … it felt like, it was necessary somehow … that kind of … physical … element … releasing a lot of emotion … Especially as someone where that’s … harder for me to do without … some kind of tool … I think that was good”

(A2)

Indirect trauma engagement

Some participants reported encountering during their psilocybin treatment session a range of affects, cognitions and somatic states linked to their index trauma, without the direct recall, imaginal exposure or sense of reliving the traumatic event. Participants possessed an awareness of their index trauma during the psilocybin treatment session, often characterised by an expectation or concern about directly confronting trauma-related imagery.

“There was a point during the session where I started to feel fear, and felt as though something might have come up, I was thinking it could be a memory, a flashback or something. That then didn’t happen, but a lot of the emotions that I feel around the trauma … surfaced along with that, that fear.”

(F12)

Further, these participants discussed the utility of confronting traumatic-stress symptoms, such as avoidance and fear, as opposed to directly encountering the event itself.

“You don’t need to revisit trauma in order to work through that trauma in this session in this way, so afterwards in the integration … I could see I need to make that connection, the connection is powerful and you need to do that … but I do know you don’t need to speak about all the events that happened … the symptoms I feel is much more debilitating for me than the actual events that happened”

(B4)

Core theme 4: comparative reflections on prior therapies and psilocybin treatment

This theme highlights participants’ reports of perceived differences between investigational psilocybin treatment and standard treatments (e.g., approved pharmacotherapies and psychological therapies) for PTSD.

Five sub-themes were identified: (1) symptom management versus addressing the perceived root issue; (2) from avoidance to openness: experiencing previously avoided material; (3) non-directive focus of psilocybin treatment; (4) self-directed nature of psilocybin treatment; and (5) whole person approach versus symptomatic focus. The findings within each sub-theme are explored below, with participant quotes for illustration.

Symptom management versus addressing the perceived root issue

After their investigational psilocybin treatment session, some participants reported having greater access to the fundamental crux of their trauma-related difficulties, linking their immediate subjective responses with psilocybin to their index-trauma and symptoms. This contrasted with their experience with standard PTSD pharmacotherapies, where the perceived primary aim and benefit appeared to relate to reduction and management of PTSD symptoms, promoting a sense of stability and allowing a degree of psychosocial functioning.

“I know that they [pharmacotherapies] can be quite numbing … And with trauma, I think that’s the last thing you want. I think you want to be in touch with your emotions and you don’t want to be closed down. You want to be kind of opened up because trauma really boxes you up and shuts everything down. And the thing I really liked with psilocybin therapy, it was a single dose. It’s not something I had to think about to take every day. It’s not something I had to worry coming off of. Like it was a single dose and I wasn’t dependent on it”

(K20)

From avoidance to openness: experiencing previously avoided material

Participants described becoming more emotionally in touch with material that had previously been managed, suppressed, or kept at a distance. While some found the administration session intense and emotionally demanding, they also described being able to connect more fully with their experience and to recognise personally meaningful material that had remained out of reach in earlier therapies. Several also noted that strong bodily tension or physiological stress reactions in prior trauma work had made it difficult to stay with distressing material, whereas investigational psilocybin treatment sessions were described as allowing a fuller, more direct engagement with experiences that had long been inaccessible and avoided.

“With EMDR, there was part of me that was very much still suppressing it. So although I was letting a little bit of emotion out and … processing that, there was still so much more that I wasn't dealing with. And that for me wasn't very helpful … And so when I had the psilocybin experience, it made me realise how much pain I had gone through and how much pain I was suppressing”

(E10)

Non-directive focus of investigational psilocybin treatment

Some participants reported that the non-directive support in investigational psilocybin treatment prepared them for a broader exploration of self and external factors contributing to the participants' index trauma and symptoms. This appeared welcomed by participants, who reported being surprised and relieved by the non-directive nature of the treatment as opposed to active confrontation and reprocessing of traumatic memories often employed in standard PTSD treatments.²⁵

“It [psilocybin treatment] allowed me to come to terms with my experience that caused the PTSD, but it also allowed me to come to terms with things I didn't even realise were bothering me. It also allowed me to come to terms with and think differently about all the positive stuff in my life. Things I knew but I wasn't able to focus on.”

(U40)

Self-directed nature of investigational psilocybin treatment

Instead of developing an over reliance on support providers’ knowledge and skills, being guided to follow exposure-based protocols or complete series of cognitive-behavioural tasks, a significant number of participants reported adopting a more self-led approach in psilocybin treatment.

“the support providers very much felt like they were … there to … guide me … they were never pushing or telling me what to do … telling me that it should be like this … and that was, initially … a bit … it was different … because all my previous therapies had been very rigid and you’re being essentially told what to think and not think almost, it was actually really … beautiful and was consistent in that whole openness of both how the drug works and the style of therapy as well … this was more of a giving you the tools to heal rather than conventional CBT and stuff, it’s trying to heal.”

(F12)

Whole person approach versus symptomatic focus

In psilocybin treatment, some participants described perceiving an approach to care that was less symptom-focused, appeared less preoccupied with conceptualisations of pathology driven approaches to recovery, and more focused on promoting participants’ capacity for inner exploration.

“Other [PTSD] treatments can be very rigid and … clinical and less personal. I think a lot of treatments are conceptualised in terms of getting rid of the symptoms … instead of … trying to understand [them] and come from a place of compassion. Like I’ve had with the psilocybin”

(K20)

Discussion

Given the reflexive thematic analysis framework employed in collecting the data, we will offer interpretations that are reflections on meaning, rather than empirically verified claims about mechanisms. Nevertheless, this process is important in generating explanations which may enhance understanding of how patients derive benefit from, and make sense of, their experiences with high dose investigational psilocybin.

Regarding whether participants were adequately prepared to engaged in treatment, the goal of preparation in COMP360 psilocybin treatment is to provide the participant with necessary treatment education and prepare them to navigate the administration experience safely and autonomously.¹⁶ Participants suggested that providing education on psilocybin's potential effects and the rationale for the support sufficiently established a sense of psychological safety and trust, and in turn enhanced their capacity to engage in the treatment process. Participants emphasised the utility of setting an intention or sense of purpose prior to their investigational psilocybin treatment session, as well as practising support strategies to sustain attention on the present-moment experience. In this context, intention or purpose did not necessarily entail directing the experience towards a specific outcome; rather, participants described it as a means of preparing themselves mentally and emotionally, for example by approaching the session with openness, curiosity, or courage, and orienting towards fuller engagement with the experience. Finally, participants recognised their support providers' non-directive stance, characterised by refraining from providing advice, solutions, and interpretations.

The adequacy of informed consent processes in psychedelic trials is an important issue.²⁶ The ineffability of the peak experience is, by definition, difficult to communicate to the naïve participant. It was supposed that Patients with PTSD may display vulnerability during psychedelic treatment because PTSD is associated with dysregulated fear responses,²⁷ re-experiencing symptoms,²⁸ dissociation,²⁹ impairments in relationships due to distrust³⁰ and avoidance.³¹ Owing to the preparation process, participants' experiences in the present study suggested an overarching sense of informed readiness to engage in treatment. Participants appeared to feel prepared to face a broad spectrum of potential phenomena, while recognising retrospectively that anticipating the specific subjective aspects of their experience would have been impossible. Transparency about this inability to predict precisely the individual experience, consistency in messaging concerning psilocybin's potential effects, shared decision-making, intention setting, and correction of misconceptions associated with psilocybin treatment could have all promoted feelings of agency and autonomy. Moreover, the preparation process also seemed to foster rapport and trust between participants and support providers, subsequently enhancing confidence in the treatment process. Given the potential for re-traumatisation in Patients with PTSD when accessing healthcare,³² this underscores the need for training to ensure a safe and supportive treatment environment and experience.

Taken together, adequate preparation, characterised by thorough treatment education, a sense of psychological safety, present-moment focus practice, and autonomy may promote a safe and manageable engagement with novel content catalysed by psilocybin, thereby allowing participants to leverage psilocybin's effects for positive change.

Regarding how participants' index-trauma presented during the psychedelic experience, prior to consenting to taking part in the trial, most participants presumed that it would be necessary to confront trauma-related material directly during treatment, including the memories and images that were most painful. This was accompanied by significant anticipatory anxiety. However, for about half of the sample, directly re-visiting or recalling traumatic memories did not occur during psilocybin administration. Although this initially resulted in surprise and even confusion, it did not appear to prevent clinically meaningful experience. Rather, participants’ accounts suggested that psilocybin-induced intrapersonal processes, characterised by expanded or altered sense of self, and by extension, others and the world, indirectly facilitated a re-evaluation of maladaptive trauma, and self-related narratives. Participants also appeared to endorse the value of exploring a range of phenomena during psilocybin administration, including trauma-adjacent self-narratives, affect, values, and beliefs, rather than focusing solely on the traumatic event itself.

Emerging evidence suggests that psilocybin may attenuate experiential avoidance in depression, a process linked to improvements in mental health outcomes and predicted by experiences of ego dissolution and psychological insight.³³ While experiential avoidance in depression often involves disengagement from distressing thoughts, emotions, or self-relevant narratives, in PTSD it more specifically includes the avoidance of trauma-related cues, memories, or somatic sensations. In this study, psilocybin enabled some participants to directly confront traumatic content. This was at times accompanied by challenging somatic and affective states, potentially suggesting a more visceral and complete access to trauma material. This may have disrupted maladaptive avoidance behaviours that have been found to maintain PTSD symptoms.³⁴

These unfiltered encounters with trauma-related content, which some participants interpreted as emotionally releasing, could have helped participants to expand their capacity to connect with a broader emotional range during and after the session. The intense emotional and somatic experiences during psilocybin sessions also appeared to allow some participants to leverage and reinforce pre-existing resources such as insightfulness, motivation, resilience, and learning capacities for therapeutic benefit. Further, some participants described an increased capacity to stay emotionally engaged and reflect meaningfully on their experiences following psilocybin treatment. However, these same experiential states and psychological processes could also present challenges. Several participants described moments of distress or discomfort, underscoring the need for appropriate safeguards. Risks were mitigated through careful participant screening, comprehensive preparation, and informed consent procedures. Importance of safety and trust were actively discussed with participants, and study teams sought to establish and maintain these throughout the treatment process.

Regarding how psilocybin treatment compared to patients' experiences with other first-line, evidence-based PTSD treatments, overall participants tended to describe prior interventions as offering symptom management or short-term stabilisation, rather than meaningful or lasting change. Many felt that conventional pharmacotherapies did not address the full complexity of their PTSD experiences or support deeper self-understanding. In this study, participants' narratives suggest that psilocybin-catalysed experiences enabled them to confront, rather than avoid challenging material, potentially allowing them to address the perceived root causes of their struggles more effectively. Cognitive and exposure-based psychotherapies aim to facilitate emotional processing and extinction of fear responses by supporting patients to confront traumatic memories, restructure maladaptive beliefs, and reduce avoidance symptoms.⁴ Study participants reported indirect and direct forms of engagement with trauma-related sequelae, highlighting the importance of adequate preparation aimed at increasing participants’ willingness to adopt an active stance towards treatment. Participants are required not only to understand the potential for encountering trauma-related material on a deeper, more visceral level but also to demonstrate a readiness to engage with potentially challenging therapeutic processes. Further, some future study participants will have likely tried other evidence-based treatments, creating a range of implicit and explicit expectations surrounding the role and nature of engagement with trauma-related sequelae, largely associated with exposure or cognitive treatments. Our findings underscore the importance of encouraging participants to adopt an open and curious stance towards potential novel pathways for change and their present-moment experiences. Patients accustomed to direct forms of trauma processing as treatment may benefit from being told that this need not necessarily occur with psilocybin.

Current evidence-based psychotherapies are largely manualised, so that support providers follow a range of pre-set, specific procedures and techniques.³⁵ Manualised interventions standardise care and can enhance the quality, fidelity, and replicability of effective treatments across settings. However, in this study, participants discussed their experiences of standard psychotherapies in negative terms when compared with the self-directedness of psychedelic experience. They preferred the non-specific focus and self-directed nature of psilocybin treatment to a rigid clinical focus on the processing of traumatic memories. Correspondingly, conventional trauma-focused psychotherapy being viewed as restrictive and impersonal, could in part contribute to high dropout rates and limited efficacy.³⁶ Further, several participants reflected on intrapersonal, interpersonal, and sociocultural dynamics they perceived as contributing to their ongoing difficulties, often extending beyond the focal traumatic event. When participants reflected on these broader patterns, such as relationships or identity, they often spoke of developing greater self-understanding or self-compassion in relation to their difficulties, potentially experiencing therapeutic opportunities not typically available in treatments focused primarily on direct exposure to trauma-related stimuli.

This study has some limitations. This was a small sample, and participants were selected based on trauma encountered in adulthood, in line with a focus on PTSD as defined by single-incident or adult-onset exposure. In contrast, complex PTSD is typically associated with prolonged, repeated, and often early-life, developmental trauma, and is marked by additional disturbances in affect regulation, self-concept, and social functioning. Therefore, treatment of complex PTSD requires further study. In addition, as is characteristic of RTA, the findings presented here are interpretative and contextualised within the perspectives of both participants and researchers. The themes were not discovered as objective facts but co-constructed through the researchers' engagement with participants’ narratives. Researcher subjectivity, disciplinary backgrounds, and experiential knowledge inevitably shaped the analytic process. While we aimed for transparency and reflexivity throughout, the meanings identified should be understood as one possible interpretation rather than the definitive account.

Additionally, the treatment sites and support providers were already specialised in the use of psilocybin and in the treatment of PTSD. Rather than seeking generalisability in the statistical sense, the value of these findings lies in their potential transferability to similar clinical contexts. We also acknowledge that participants’ meaning-making often drew on therapeutic language, which may resemble, but does not equate to, causal mechanisms of change. Our study does not claim to establish mechanisms or outcomes but instead offers insight into how participants made sense of their experiences in context.

Future research may build on these findings through longitudinal, mixed-methods approaches that further explore the relationship between subjective experience, therapeutic processes, and clinical outcomes, while remaining attentive to the epistemological assumptions underlying each method.

In conclusion, preparation sessions encompassing treatment education, intention setting and establishing psychological safety and trust with the study team were highlighted as significant factors influencing treatment experience. The unique features of psilocybin treatment required participants to recalibrate their expectations for PTSD care, particularly in relation to interactions with trauma during the treatment session. Throughout the preparation period, participants learned to navigate this new treatment paradigm, adopting an open and curious stance toward their present moment experience, believed to be crucial in reducing the risk of counterproductive experiential avoidance during the psilocybin experience. Together, these aspects of participant support underscore the importance of effective preparation and informed consent for promoting patient safety and treatment engagement toward meaningful therapeutic gains. Conducting robust qualitative analyses of participants' perceptions may aid in generating a more comprehensive understanding of the treatment's therapeutic effects, promote safety and help optimise future research protocols and models of monitoring and support in psilocybin for PTSD. Further, understanding the differences between standard and psilocybin treatment may help empower future, prospective PTSD trial participants to make better informed decisions that align with their goals, preferences, and values. Further, while the primary aim of this analysis was to explore how participants made sense of their treatment experiences, several themes such as reductions in experiential avoidance, emergence of somatic awareness, and moments of emotional release may align with constructs found in established trauma theories, including Emotional Processing Theory,³⁷ Dual Representation Theory³⁸ and memory reconsolidation frameworks.³⁹ However, these associations remain speculative within the context of a reflexive thematic analysis and were not tested empirically. Future research may benefit from examining how such theoretical models could inform the design of psychedelic treatment protocols or serve as frameworks for understanding therapeutic outcomes. Mixed-methods approaches that integrate qualitative insights with symptom trajectories, neurobiological markers, and psychological mechanisms may be especially valuable in this regard. While the present study does not include such integration, cross-referencing these qualitative data with quantitative outcomes is planned as part of our wider programme of research. Should psilocybin continue to demonstrate safety and feasibility in the absence of established or manualised evidence-based psychotherapies, there may be justification for comparative trials that test the impact of such adjunctive therapies on outcome and process.

Contributors

NLM contributed to conceptualization, methodology, data curation, formal analysis, investigation, writing—original draft, writing—review and editing, supervision, and project administration. VW contributed to conceptualization, methodology, data curation, investigation, writing—original draft, writing—review and editing, and supervision. JR contributed to conceptualization, data curation, data verification, investigation, and writing—review and editing. NK was involved in conceptualization, methodology, data curation, data verification, investigation, and writing—review and editing. MA contributed to data curation, investigation, methodology, and writing—review and editing. ZE and AG contributed to data curation, investigation, and methodology. DK contributed to data curation, data verification, methodology, and investigation. GMG contributed to conceptualization, supervision, data verification, and writing—review and editing. AC contributed to conceptualization, supervision, writing—review and editing, and data verification. RY and EM contributed to conceptualization, methodology, supervision, and writing—review and editing. NLM, VW, AC, and JR accessed and verified the underlying data. All authors reviewed and approved the final manuscript.

Data sharing statement

This clinical trial produced qualitative and clinical data containing sensitive personal information. Data collected will not be made available.

Declaration of interests

NLM, AG, EM, GMG, DK, MA, NK, and ZE are current or past employees of subsidiaries of Compass Pathways plc through its subsidiary Compass Pathfinder Ltd and own shares, share options, and/or restricted share units in Compass Pathways plc. EM is a former officer and director of Compass Pathways plc. NLM became an employee of Compass Pathways during manuscript development but was not employed by the funder during data collection or analysis. GMG has consulted for Sun pharma, Signant health and Takeda in the last 3 years. NLM has received consulting fees from Sunstone Therapies, Compass Pathfinder Ltd (study support provider), Beckley PsyTech (manual review), Small Pharma (weekend seminar). NLM reports no shareholdings in pharmaceutical companies and no shareholdings in companies developing psychedelics. NK has received grant funding from the National Institute for General Medical Sciences and the William K. Warren Foundation and has consulted for BehaVR. JR reports providing services for the Psychoactive Trials Group at King's College London, which has received grant funding from Supporting Wounded Veterans, the Multidisciplinary Association for Psychedelic Studies, Beckley PsyTech, the UK National Institute for Health Research, and Compass Pathways (funding received and managed by King's College London); attending trial-related meetings paid for by Compass Pathways; and consulting for Beckley PsyTech and Clerkenwell Health. AC reports research funding from the UK Medical Research Council, ADM Protexin, the National Institute for Health and Care Research, the European Union Horizon Europe/Innovate UK, Beckley Psytech, and the Wellcome Trust; consultancy or advisory work for Otsuka, Compass Pathways, Janssen, Viatris, and Medscape; and serves as President (unpaid) of the International Society for Affective Disorders. RY received funding from the DOD, The Bob and Renee Parsons Foundation, the Steven & Alexandra Cohen Foundation, the Applebaum Foundation, and Compass Pathways LTD. Dr. Yehuda also received non-financial support from MAPS PBC (Multidisciplinary Association for Psychedelic Studies Public Benefit); and honoraria for talks at the Boston Trauma Conference, UPenn Nursing School, Action Trauma Summit, Annual Psychiatric Times™ World CME Conference, ADAA, META, Blue Spirit Costa Rica: Wisdom and Well Being, ISCR, SELF, Danish Psychiatric Society, NICABM, Dialogues in Mental Health 2nd edition, Pioneer Works, APA Annual Meeting 2024, and UCSF Grand Rounds outside the submitted work. MA is a co-founder of Sunstone Therapies and holds equity in the company.