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 with 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.
