The efficacy and safety of psilocybin-assisted therapy for major depressive disorder: a meta-analytic review of clinical outcomes
Mohsen Khosravi, Domenico de Berardis, Massimo Tusconi
Mental Wellness April 21, 2026 Peer reviewed DOI: 10.4081/mw.2026.40 via OpenAlex
Summary
The meta-analysis of 13 clinical trials with 606 participants found no statistically significant antidepressant effect of psilocybin-assisted psychotherapy for major depressive disorder and treatment-resistant depression, indicated by a pooled standardized mean difference of -0.79. There was significant variability among studies, primarily due to the type of control group used. The analysis suggests that psilocybin's effectiveness may depend on trial design and session frequency, highlighting the need for more controlled research.
Study at a glance
| Design | systematic review and meta-analysis |
|---|---|
| Sample size | 606 |
| Population | participants with major depressive disorder and treatment-resistant depression |
| Key finding | The pooled analysis revealed no statistically significant overall antidepressant effect of psilocybin-assisted psychotherapy. |
Abstract
This systematic review and meta-analysis synthesized data from 13 clinical trials (n=606) evaluating psilocybin-assisted psychotherapy for major depressive disorder and treatment-resistant depression. Despite early enthusiasm, the pooled standardized mean difference (-0.79, 95% confidence interval: -3.98 to 2.40, p=0.63) revealed no statistically significant overall antidepressant effect, with extreme heterogeneity (I2=96.9%) across studies. Notably, the type of control group (active comparator vs. placebo/waitlist) accounted for 98.7% of between-study variance, with waitlist and low-dose comparators producing exaggerated effect sizes. Session frequency was a significant moderator: 2 to 5 psilocybin sessions yielded larger effects, while more intensive protocols attenuated benefit. Neither participant age nor follow-up duration significantly influenced outcomes. Evidence of reporting bias and small-study effects was detected (Egger’s test p=0.012). Sensitivity analyses demonstrated that no single study accounted for the non-significant pooled result. Overall, psilocybin’s antidepressant efficacy appears highly context-dependent—shaped by trial design, comparator, and session structure—rather than universally robust. These findings underscore the need for larger, rigorously controlled trials to clarify psilocybin’s therapeutic role in depression.