MAHVASH KHAN, MUHAMMAD OMAR MALIK, MUHAMMAD UZAIR, NIMRA FARID, AYYAZ AHMED, SHABIR KHAN, MUHAMMAD ISMAIL
DOI: https://doi.org/Background: Major depressive disorder (MDD) is a leading cause of disability worldwide. Conventional antidepressants often fail in treatment-resistant cases, and emerging evidence suggests psilocybin-assisted therapy may offer substantial antidepressant effects, possibly via immunomodulatory mechanisms.
Methods: This systematic review and meta-analysis followed PRISMA 2020 standards. Randomized controlled trials (RCTs), controlled clinical trials, and observational studies published between 2016 and 2024 were identified through searches in PubMed, Scopus, and Cochrane. Outcomes evaluated included validated depression scales (MADRS, QIDS, HDRS), response (≥50% symptom reduction), remission rates, and biomarkers related to inflammation and neuroplasticity. Risk of bias was assessed with RoB-2, ROBINS-I, and SYRCLE tools; GRADEpro was used to assess certainty of evidence. Meta-analysis pooled data from five RCTs with homogeneous outcomes.
Results: Psilocybin therapy was associated with a large reduction in continuous depression scores (SMD = −2.08; 95% CI −3.47 to −0.68) and roughly threefold higher odds of response compared with control (OR = 3.10; 95% CI 1.88 to 5.12; I² = 0% for response outcomes). Continuous outcome heterogeneity was high (I² = 95%), likely due to variations in depression scales, dosing protocols, and psychological support intensity. Biomarker data (e.g., reductions in IL-6, TNF-α, CRP; increases in BDNF) provided preliminary evidence of immunomodulation. Certainty of evidence was rated moderate for response outcomes and low for continuous change due to inconsistency and imprecision.
Conclusion: This review supports psilocybin-assisted therapy as a promising intervention for MDD, with both clinical and immunological effects, especially among treatment-resistant populations. Future large-scale, multisite RCTs with standardized protocols, active comparators, longer follow-ups, and greater biomarker sampling are needed to clarify mechanisms and long-term safety.
