This systematic review and meta-analysis aimed to evaluate the efficacy of psilocybin as an antidepressant compared to placebo or non-psychoactive drugs. The study included nine randomized trials with a total of 436 participants, aged 36-60 years, who had clinically significant symptoms of depression. The meta-analysis found a significant benefit of psilocybin on reducing depression scores (Hedges’ g=1.64, 95% CI 0.55 to 2.73, P<0.001) compared to placebo. Subgroup analyses revealed that psilocybin was more effective for secondary depression, self-report measures, older patients, and those with a history of psychedelic use. The study also noted high heterogeneity and small study bias, leading to a low certainty of evidence. The findings suggest that psilocybin may be particularly beneficial for specific patient subgroups and when used in conjunction with psychological support. However, the high cost and standardized treatment setting pose challenges for its clinical implementation. Future research should focus on large-scale trials with long follow-up, diverse populations, and methods to minimize expectancy effects.This systematic review and meta-analysis aimed to evaluate the efficacy of psilocybin as an antidepressant compared to placebo or non-psychoactive drugs. The study included nine randomized trials with a total of 436 participants, aged 36-60 years, who had clinically significant symptoms of depression. The meta-analysis found a significant benefit of psilocybin on reducing depression scores (Hedges’ g=1.64, 95% CI 0.55 to 2.73, P<0.001) compared to placebo. Subgroup analyses revealed that psilocybin was more effective for secondary depression, self-report measures, older patients, and those with a history of psychedelic use. The study also noted high heterogeneity and small study bias, leading to a low certainty of evidence. The findings suggest that psilocybin may be particularly beneficial for specific patient subgroups and when used in conjunction with psychological support. However, the high cost and standardized treatment setting pose challenges for its clinical implementation. Future research should focus on large-scale trials with long follow-up, diverse populations, and methods to minimize expectancy effects.