Patient perspectives and experiences with psilocybin treatment for treatment-resistant depression: a qualitative study

Depression is a prevalent disorder with substantial unmet need: up to 30% of patients do not respond adequately to standard treatments. Classic psychedelics, and psilocybin in particular, have re-emerged as candidate therapeutics for major depressive disorder and treatment-resistant depression (TRD). Clinical trials to date have administered one or two doses (commonly 10–30 mg) and reported rapid, sometimes sustained, reductions in depressive symptoms, but qualitative research on patients' subjective experiences and on contextual factors (set and setting) remains limited. This study aimed to fill that gap by exploring expectations and lived experiences of TRD patients who participated in a double-blind, randomized, dose-finding Phase 2b trial of a single oral psilocybin session (1 mg active control, 10 mg, or 25 mg). Using in-depth interviews and an Interpretative Phenomenological Analysis framework, the investigators sought to identify themes about preparation, the dosing experience, and integration that could inform optimisation of psilocybin treatment for this vulnerable population.

The qualitative study used Interpretative Phenomenological Analysis (IPA) and purposive sampling to recruit participants from a Phase 2b double-blind randomised trial of psilocybin for TRD conducted at two university medical centres in the Netherlands. Eligible trial participants were adults with single or recurrent episode major depressive disorder without psychotic features who met TRD criteria (failure to respond to at least two antidepressant trials). Trial procedures required discontinuation of contraindicated medications at least 2 weeks before dosing and remaining off antidepressants through key study endpoints; full trial details are reported elsewhere. All trial participants received three 60–90 minute preparatory sessions with the lead therapist (the third session also including a co-therapist), an eight-hour psilocybin dosing day with two therapists present, a next-day integration session with both therapists, and a one-week integration session with the lead therapist only. Randomisation allocated participants to 1 mg, 10 mg, or 25 mg of a proprietary synthetic psilocybin formulation; participants, therapists, and investigators remained blinded throughout recruitment and qualitative data collection. Of 44 participants at the two sites, coordinators approached 22; 13 agreed and 11 (8 women, 3 men; age range 24–66, mean 45.5) completed interviews. After de-blinding, 4 interviewees had received 1 mg, 3 received 10 mg, and 4 received 25 mg. Interviews were conducted via videoconference between 3 and 15 months after dosing (mean 6.5 months) by the first author, who had not been involved in the trial. Semi-structured interviews averaged 75 minutes and followed a guide probing expectations, preparation, the psilocybin session, and integration. Transcripts were analysed in MAXQDA following IPA procedures; emergent themes were discussed within a multidisciplinary team. The Standards for Reporting Qualitative Research (SRQR) and COREQ checklist were used to support methodological rigour.

Three overarching themes emerged from interviews: (1) challenges with trust-building and expectation management; (2) navigating the experience; and (3) the need for a more comprehensive treatment. Each theme contained several subthemes that reflected diverse patient perspectives. Under the first theme, many participants reported longstanding distrust of mental healthcare stemming from repeated treatment failures and feeling dismissed by providers. Despite this, most interviewees described positive relationships with the study therapists, valuing calmness, warmth and attentiveness, which fostered safety. Several participants felt the three preparatory sessions were insufficient to build full trust, disclose complex biographical material, and prepare emotionally for the psilocybin session; the required tapering of antidepressants within the trial timeline also increased anxiety for some. Expectations were variable: some tried to minimise hope after repeated disappointments, while others held specific hopes for insights or emotional contact and felt disappointed when experiences differed from those expectations. A few participants proposed peer involvement in preparation to normalise reactions and reduce shame. The second theme addressed how participants navigated the dosing day. Ability to surrender varied considerably: some felt able to let go, supported by therapists, whereas others experienced difficulty relinquishing control, in part because co-therapists were sometimes newly introduced and because lying supine under observation felt awkward or invasive. Use of an eye mask and headphones aided introspection for some but induced claustrophobia or retraumatisation for others. Reports of the dosing experience ranged from deeply meaningful, emotional, and awe-filled episodes to overwhelming, distressing states of intense unhappiness that were hard to process. Music was frequently described as steering internal content—hopeful music tended to elicit more positive material, while melancholic or heavy tracks could evoke sadness or death-related imagery. Participants disagreed about the playlist; some found it guiding and beautiful, others found it clichéd or irritating. The third theme captured a widespread desire for more comprehensive care. Several participants wanted multiple or dose-escalated psilocybin sessions, arguing that lower or initial doses could familiarise them with the experiential terrain and enable building on prior sessions. Two participants attempted microdosing at home to recapture effects but reported no clear benefits and noted the lack of supervised guidance. Integration posed challenges: many found it difficult to put experiences into words or to make sense of intense or distressing episodes. Although the protocol included two post-dosing talks (day after and one week later), some felt these were either too soon or too limited; weekly study questionnaires were experienced as burdensome and insufficient for sense-making. In terms of clinical outcome data reported by participants, three of the 11 interviewees were responders in remission at week 12 (two had received 1 mg, one 25 mg), while the remaining eight had no statistically significant MADRS changes.

Breeksema and colleagues interpret these findings as illuminating how substance, set, and setting interact to shape patient experiences of psilocybin treatment for TRD. Trust and therapeutic alliance were highlighted as central: despite general scepticism toward mental healthcare, many participants were able to form trusting relationships with study therapists, but the limited preparatory contact and late introduction of co-therapists undermined surrender for some. The investigators note that the capacity to 'let go' is a known predictor of positive psychedelic outcomes and may be compromised in TRD patients by prior adversity and high neuroticism, suggesting the need for extra preparatory and supportive measures for this group. Preparation, education and expectation-management emerged as actionable targets for optimisation. The authors recommend more time for psychoeducation, explicit mitigation of unrealistic expectations, practical guidance for coping with loss of control and the physical context of an eight-hour, supine session, and consideration of peer-led preparation. They also flag the contentious requirement in many trials to discontinue antidepressants: post hoc signals and small studies suggest co-administration may not attenuate effects and might even be associated with better outcomes, implying this practice warrants re-evaluation. Regarding treatment customisation, the researchers caution that psychologically vulnerable patients may sometimes experience painful episodes that do not lead to therapeutic transformation; determining whether this reflects unsuitable candidacy or modifiable contextual factors is important. They advocate for gradual intensification across multiple sessions, integration within a therapeutic framework, involvement of patients' existing therapists, and more flexible, personalised approaches in naturalistic studies to enhance ecological validity. The discussion also notes instances of unsupervised microdosing outside the trial and emphasises the potential for harm when psychedelics are used without therapeutic support. The authors acknowledge several limitations: interviews were conducted while blinding remained in place, producing a heterogeneous sample; remote videoconference interviews during the COVID-19 pandemic may have constrained rapport and non-verbal data; interviews occurred 3–15 months post-dosing so recall and intervening experiences could have influenced accounts; recruitment by site coordinators and restriction to two Dutch centres may limit generalisability; and the findings reflect a regulated trial context that constrains therapeutic flexibility. These caveats temper conclusions and highlight areas for future research design and reporting improvements.

The authors conclude that implementing psilocybin treatment for TRD should balance patients' need for time, trust-building and tailored education with practical limits on therapist availability. To facilitate surrender and post-session sense-making, they recommend investing in rapport, personalised preparation, and staged increases in experiential intensity across multiple sessions. Integration within sustained psychotherapy—ideally involving patients' regular therapists—and inclusion of experienced patients in preparation and integration (peer support) may improve retention and outcomes. Finally, Breeksema and colleagues call for naturalistic and pragmatic studies that permit personalised therapeutic approaches alongside continued efficacy research to establish real-world potential.