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

Summary

This study explored how patients with severe depression that didn’t respond to typical treatments experienced psilocybin therapy. Researchers interviewed 11 patients about their experiences and found that building trust with therapists, managing expectations, and having multiple treatment sessions were crucial. Many patients found the experience intense and overwhelming, and most wanted ongoing support to understand what they experienced and how it affected their recovery.

Background

Depression affects over 300 million people worldwide, with up to 30% of patients failing to respond to current treatment options including psychotherapy and antidepressant medication. Psilocybin is the most researched classic psychedelic for treatment-resistant depression and has received FDA breakthrough therapy status. While set and setting are considered essential for treatment efficacy and safety, patient perspectives on these aspects have rarely been investigated.

Objective

To explore the expectations and lived experiences of treatment-resistant depression patients who participated in a double-blind randomized controlled trial with a single dose of oral psilocybin (1, 10, or 25 mg), with particular attention to how contextual factors such as set and setting influence treatment experience and outcomes.

Results

Three major themes emerged: challenges with trust-building and expectation management, navigating intense experiences (including the role of music), and the need for more comprehensive treatment. Participants reported general distrust in mental healthcare but developed trust in study therapists. Key findings included the difficulty of surrendering to experiences, varying responses to music, and the importance of multiple sessions, sustained therapeutic support, and adequate time for integration and sensemaking.

Conclusion

Future psilocybin treatment approaches should invest in building therapeutic trust, customize education and expectation management, gradually increase dose intensity over multiple sessions, provide sustained psychotherapy support, and involve experienced patients in trial and treatment design. Naturalistic studies allowing more flexible, personalized approaches are needed to establish the real-world potential of psilocybin treatment for mental disorders.
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