Methodological moderators of psilocybin-assisted therapy in depression: A systematic review and meta-analysis
Longer preparation and integration sessions linked to larger antidepressant effects.
The study specifically explored how different methodological factors across trials influenced the magnitude of antidepressant effects. It focused on whether variations in study design and therapeutic delivery practices moderated outcomes.
Studies that included longer and more intensive preparation, dosing support, and post-session integration tended to show stronger antidepressant responses, suggesting that the context and therapeutic support surrounding psilocybin administration matter.
“Psilocybin-assisted therapy (PAT) is an emerging intervention for depression. Though several clinical trials report promising results for PAT in treating depression, there remains a need for consensus on optimal methodologies and standardization of PAT protocols. The objective of this review was to assess the efficacy of PAT in treating depressive symptoms and to systematically examine the influence of methodological moderators underlying antidepressant responses.
We searched the electronic databases of PubMed, MEDLINE, PsychInfo and Embase for randomized-controlled trials (RCTs) using PAT as a treatment intervention for major depressive disorder. The primary outcomes were standardized mean difference (SMD) of change in depressive symptoms pre- versus post-treatment sessions, and the difference in antidepressant treatment effects among various PAT methodologies in a subgroup analysis. Seven RCTs involving 522 participants were analyzed. The overall random effects model found PAT to have a large and significant antidepressant effect.
The subgroup analyses found larger effects, albeit non-significant differences in subgroup heterogeneity, associated with studies that administered psilocybin in bodyweight-adjusted doses and provided longer preparation, dosing, and integration sessions and provided non-manualized psychotherapy.
This study presents the first systematic examination of PAT methodologies influencing antidepressant effects and provides preliminary insights for clinicians in designing future PAT protocols for depression.”
Note
This is the first systematic meta-analytic examination focused on how methodological differences across trials might moderate antidepressant outcomes of psilocybin therapy.
The results provide early guidance for clinicians and researchers on optimising therapeutic protocols, particularly emphasising the potential value of:
Individualised dosing regimens
Extended and supportive preparatory and integration sessions
Therapeutic flexibility rather than rigid protocol manuals
Syed OA, Tsang B, Nestor SM, Lipsman N, Husain MI, Alam F, Giacobbe P. Methodological moderators of psilocybin-assisted therapy in depression: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2026 Jan 24;183:106573. doi: 10.1016/j.neubiorev.2026.106573. Epub ahead of print. PMID: 41587629. Read Paper
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