A systematic review and meta-analysis of randomized trials evaluated the efficacy of psilocybin as an antidepressant compared with placebo or non-psychoactive drugs. The review included 436 participants from seven studies, showing a significant benefit of psilocybin (Hedges' g=1.64, 95% CI 0.55 to 2.73, P<0.001) on depression scores. Subgroup analyses indicated that secondary depression, self-report measures, older age, and previous psychedelic use were associated with greater improvements. However, the evidence was of low certainty due to heterogeneity and small study bias. The study found that psilocybin was more effective in patients with secondary depression, those using self-report scales, and those with prior psychedelic use. The results suggest that factors such as depression type, outcome measures, and personal characteristics influence psilocybin's efficacy. The review highlights the need for further research to clarify these factors and optimize treatment delivery. Limitations include a lack of racial and ethnic diversity and potential expectancy effects. The findings suggest that psilocybin may be a promising treatment for depression, but its implementation in clinical practice requires careful consideration of setting, training, and cost. Future research should focus on large-scale trials, diverse populations, and methods to minimize expectancy effects.A systematic review and meta-analysis of randomized trials evaluated the efficacy of psilocybin as an antidepressant compared with placebo or non-psychoactive drugs. The review included 436 participants from seven studies, showing a significant benefit of psilocybin (Hedges' g=1.64, 95% CI 0.55 to 2.73, P<0.001) on depression scores. Subgroup analyses indicated that secondary depression, self-report measures, older age, and previous psychedelic use were associated with greater improvements. However, the evidence was of low certainty due to heterogeneity and small study bias. The study found that psilocybin was more effective in patients with secondary depression, those using self-report scales, and those with prior psychedelic use. The results suggest that factors such as depression type, outcome measures, and personal characteristics influence psilocybin's efficacy. The review highlights the need for further research to clarify these factors and optimize treatment delivery. Limitations include a lack of racial and ethnic diversity and potential expectancy effects. The findings suggest that psilocybin may be a promising treatment for depression, but its implementation in clinical practice requires careful consideration of setting, training, and cost. Future research should focus on large-scale trials, diverse populations, and methods to minimize expectancy effects.