The Evaluation of the Efficacy and Safety of the Use of Psilocybin in the Treatment of Adults with Treatment-Resistant Depression

Treatment-resistant depression (TRD) has been well-researched within scientific literature, although the therapeutic value of psilocybin is not fully understood. The aim of this systematic review is to determine a stable and effective dosage unit to inform health professionals of the benefits of psilocybin, using peer-reviewed literature and meta-analysis. The review will also compare selective serotonin reuptake inhibitors (SSRIs) with psychotherapy to draw conclusions and recommendations of psilocybin therapy to improve day-to-day living for affected patients. PubMed and the University of Portsmouth Discovery online database (EBSCOhost) were individually utilised from December 2024 to March 2025. Five open-label studies and 2 randomised controlled trials (RCTs) were selected to assess psilocybin efficacy and safety. Appraisal checklists along with search criteria were used to determine eligibility and reliability of these data. The random-effects meta-analyses demonstrated that psilocybin at 25 mg within specific integrated sessions was effective at treating TRD compared to 10 mg and 1 mg by comparing clinical trials between two doses and single doses. Psilocybin at 25 mg was found to significantly reduce patients’ depressive severity compared to the baseline, which was prevalent in the two-dose studies (n = 5) compared to the single-dose studies (n = 2), due to the number of studies produced. The overall evidence suggests that psilocybin is an effective therapeutic for treatment-resistant depression, with a dosage unit of 25 mg administered as a single capsule per dosing session, with one dose per clinical session. Limitations to the evidence and this review have affected the overall results; therefore, more relevant studies are needed.