Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin
This open-label waitlist trial (n=30) assessed the feasibility of psilocybin-assisted psychotherapy (PAP/PAT) in a complex population with treatment-resistant depression (TRD), including major depressive and bipolar II disorders, baseline suicidality, and significant comorbidity. Participants received one, two, or three sessions of PAP with psilocybin (25mg), accompanied by preparation and integration psychotherapy sessions. Immediate treatment showed greater reductions in depression severity (MADRS) compared to the waitlist period, with a large effect size (g = 1.07, p < 0.01). Repeated doses were associated with further reductions in depression severity. Adverse events were transient, and the study demonstrated feasibility, preliminary antidepressant efficacy, safety, and tolerability in this population.
Authors
- Roger McIntyre
- Shokouh Meshkat
- Rodrigo Mansur
Published
Abstract
Background
Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period.
Methods
Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466).
Findings
Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge’s g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline.
Conclusions
PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity.Funding: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.
Research Summary of 'Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin'
Introduction
Over the past two decades, interest in serotonergic psychedelics has resurged, with psilocybin showing promise for rapid and robust antidepressant effects. Previous clinical trials of psilocybin-assisted psychotherapy (PAP) have reported preliminary efficacy in major depressive disorder (MDD), treatment-resistant depression (TRD) and in patients with life-limiting illness, but have commonly used small samples, intensive psychotherapy protocols, and strict eligibility criteria that exclude many real-world, complex patients. These design features raise concerns about generalisability, potential expectancy effects and functional unblinding, and leave open questions about the durability of benefit and whether repeated dosing is helpful when relapse occurs. This randomised trial set out to address those gaps by evaluating feasibility, preliminary efficacy and safety of a briefer PAP model in a more clinically complex TRD sample. Specifically, Rosenblat and colleagues conducted a waiting-list randomised clinical trial that broadened eligibility (including both MDD and bipolar II disorder, comorbid personality disorders, baseline suicidality and no upper limit on prior failed treatments) and permitted repeat psilocybin doses for participants showing signs of relapse. The study therefore aimed to test whether a condensed psychotherapy “dose” and flexible repeat psilocybin administration could be delivered safely and produce antidepressant effects in a real-world refractory population.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Rosenblat, J. D., Meshkat, S., Doyle, Z., Kaczmarek, E., Brudner, R. M., Kratiuk, K., Mansur, R. B., Schulz-Quach, C., Sethi, R., Abate, A., Ali, S., Bawks, J., Blainey, M. G., Brietzke, E., Cronin, V., Danilewitz, J., Dhawan, S., Di Fonzo, A., Di Fonzo, M., . . . McIntyre, R. S. (2024). Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin. Med, 5(3), 190-200.e5. https://doi.org/10.1016/j.medj.2024.01.005
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Jacobs, E., Zahid, Z., Hinkle, J. et al. · BMJ (2026)
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