Safety and Efficacy of Psilocybin in the Management of Treatment-Resistant Depression: A Systematic Review

Abstract Background: Conventional pharmacotherapy for treatment-resistant depression (TRD) has been found to provide limited benefit in a subset of patients. Psilocybin-assisted therapy has emerged as a promising modality due to its rapid-acting antidepressant effects and favourable tolerability profile shown in early trials. Despite growing research interest in psilocybin-assisted therapy the evidence for its use remains fragmented. Aim: To systematically review the evidence on the safety and efficacy of psilocybin in adults with TRD. Methods: This review follows the Preferred Reporting Items for Systematic Reviews (PRISMA) and JBI Manual for Systematic Reviews of Effectiveness. PubMed ®, MEDLINE ®, the Cochrane Collaboration's CENTRAL ® trials registry, PsycINFO ® and EMBASE ® were searched between 2014 and 2025 for clinical trials and observational studies that met the inclusion criteria for psilocybin versus other antidepressants for TRD. The JBI Critical Appraisal Checklists were used to assess the quality of the clinical trials. The review protocol was registered on PROSPERO (CRD420251063913) Results: Six trials met the inclusion criteria. Psilocybin showed promising results in lowering depressive scores in participants with TRD. Common adverse events included anxiety, nausea, headache, fatigue and suicidal ideation. No serious safety concerns or cases of physiological toxicity were identified. Study limitations included small sample sizes, open-label designs, and heterogeneous psychotherapy protocols. Conclusions: Psilocybin as a novel therapy for TRD demonstrates promising efficacy and tolerability safety profile. Nonetheless, current evidence remains preliminary, and larger, methodologically robust randomized trials are needed to confirm efficacy, optimize dosing, and standardize psychological support frameworks.