Therapeutic effects of psilocybin in major depressive disorder: a systematic review and meta-analysis exploring dose effects.

Background: Several recent trials indicate positive effects of psilocybin in patients with major depressive disorder. However, questions need to be addressed regarding the relationship between dosage and therapeutic outcomes, such as the recommended dose range and frequency for optimal practice as well as the dose-dependent adverse effects.

Objective: (1) to assess the effectiveness and tolerability of psilocybin on major depression; (2) to explore a suitable dosing regimen for psilocybin treatment concerning both dose and frequency.

Methods: Four databases (Cochrane Library, EMBASE, Pubmed, Web of Science) were searched up to February 23, 2024, to include primary studies evaluating the use of psilocybin in adults presenting major depressive disorder. All primary studies evaluating psilocybin in adults diagnosed with MDD were included. Case series, animal research, meta-analyses, and systematic reviews were excluded. The primary outcomes assessed were changes in depression scores, response rates, remission rates, and safety and tolerability profiles. Two reviewers performed study selection and data extraction independently based on the prepared criteria. The quality and potential risk of bias in each trial were evaluated using criteria outlined in the Cochrane Handbook. The review was registered in the PROSPERO (CRD420251115865).

Results: Seven trials including 464 participants were identified (one meeting abstract included). The overall quality of included trials is moderate, as assessed with Cochrane Handbook. Psilocybin presented significant effects in treating major depression with safety and tolerability. In a certain range, the higher dose and frequency resulted in a better effect. Our findings indicate the dose regimen of 35-50 mg/70kg and double-dosing may be a promising dosing strategy.

Conclusion: The results support the potential application of psilocybin for treating major depressive disorder. Given that the included trials are limited by small sample sizes and short follow-up periods, further clinical studies with longer follow-up periods are needed to fully assess the efficacy and safety of high-dose psilocybin.