Objective To determine the efficacy of psilocybin as an antidepressant compared with placebo or non-psychoactive drugs. Design Systematic review and meta-analysis. Data sources Five electronic databases of published literature (Cochrane Central Register of Controlled Trials, Medline, Embase, Science Citation Index and Conference Proceedings Citation Index, and PsycInfo) and four databases of unpublished and international literature (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Theses Global, and PsycEXTRA), and handsearching of reference lists, conference proceedings, and abstracts. Data synthesis and study quality Information on potential treatment effect moderators was extracted, including depression type (primary or secondary), previous use of psychedelics, psilocybin dosage, type of outcome measure (clinician rated or self-reported), and personal characteristics (eg, age, sex). Data were synthesised using a random effects meta-analysis model, and observed heterogeneity and the effect of covariates were investigated with subgroup analyses and metaregression. Hedges’ g was used as a measure of treatment effect size, to account for small sample effects and substantial differences between the included studies’ sample sizes. Study quality was appraised using Cochrane’s Risk of Bias 2 tool, and the quality of the aggregated evidence was evaluated using GRADE guidelines. Eligibility criteria Randomised trials in which psilocybin was administered as a standalone treatment for adults with clinically significant symptoms of depression and change in symptoms was measured using a validated clinician rated or self-report scale. Studies with directive psychotherapy were included if the psychotherapeutic component was present in both experimental and control conditions. Participants with depression regardless of comorbidities (eg, cancer) were eligible. Results Meta-analysis on 436 participants (228 female participants), average age 36-60 years, from seven of the nine included studies showed a significant benefit of psilocybin (Hedges’ g=1.64, 95% confidence interval (CI) 0.55 to 2.73, P<0.001) on change in depression scores compared with comparator treatment. Subgroup analyses and metaregressions indicated that having secondary depression (Hedges’ g=3.25, 95% CI 0.97 to 5.53), being assessed with self-report depression scales such as the Beck depression inventory (3.25, 0.97 to 5.53), and older age and previous use of psychedelics (metaregression coefficient 0.16, 95% CI 0.08 to 0.24 and 4.2, 1.5 to 6.9, respectively) were correlated with greater improvements in symptoms. All studies had a low risk of bias, but the change from baseline metric was associated with high heterogeneity and a statistically significant risk of small study bias, resulting in a low certainty of evidence rating. Conclusion Treatment effects of psilocybin were significantly larger among patients with secondary depression, when self-report scales were used to measure symptoms of depression, and when participants had previously used psychedelics. Further research is thus required to delineate the influence of expectancy effects, moderating factors, and treatment delivery on the efficacy of psilocybin as an antidepressant. Systematic review registration PROSPERO CRD42023388065. The relevant aggregated data and statistical code will be made available on reasonable request to the corresponding author.

中文翻译：

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裸盖菇素治疗抑郁症状的功效：系统评价和荟萃分析


目的 确定裸盖菇素作为抗抑郁药与安慰剂或非精神活性药物相比的疗效。设计系统回顾和荟萃分析。数据来源 五个已发表文献电子数据库（Cochrane Central Register of Controlled Trials、Medline、Embase、Science Citation Index and Conference Proceedings Citation Index 和 PsycInfo）以及四个未发表文献和国际文献数据库（ClinicalTrials.gov、WHO 国际临床试验注册中心） Platform、ProQuest Dissertations andTheses Global 和 PsycEXTRA），以及参考文献列表、会议记录和摘要的手工检索。数据合成和研究质量 提取了有关潜在治疗效果调节因素的信息，包括抑郁类型（原发性或继发性）、既往使用迷幻药、裸盖菇素剂量、结果测量类型（临床医生评分或自我报告）和个人特征（例如，年龄、性别）。使用随机效应荟萃分析模型合成数据，并通过亚组分析和元回归研究观察到的异质性和协变量的影响。 Hedges g 被用作治疗效应大小的衡量标准，以解释小样本效应和纳入研究的样本量之间的实质性差异。使用 Cochrane 的偏倚风险 2 工具评估研究质量，并使用 GRADE 指南评估汇总证据的质量。资格标准随机试验，其中裸盖菇素作为独立治疗用于具有临床显着抑郁症状的成人，并使用经过验证的临床医生评级或自我报告量表来测量症状的变化。 如果实验和对照条件下都存在心理治疗成分，则纳入指导性心理治疗的研究。患有抑郁症的参与者，无论是否患有合并症（例如癌症），均符合资格。结果 对 436 名参与者（228 名女性参与者）、平均年龄 36-60 岁的 9 项纳入研究中的 7 项进行的荟萃分析显示，裸盖菇素具有显着益处（Hedges g=1.64，95% 置信区间 (CI) 0.55 至 2.73） ，P<0.001）与比较治疗相比抑郁评分的变化。亚组分析和元回归表明，患有继发性抑郁症（Hedges g=3.25，95% CI 0.97 至 5.53），使用自我报告抑郁量表（例如 Beck 抑郁量表（3.25，0.97 至 5.53））进行评估，并且年龄较大和先前使用致幻剂（元回归系数分别为 0.16、95% CI 0.08 至 0.24 和 4.2、1.5 至 6.9）与症状的更大改善相关。所有研究的偏倚风险都很低，但基线指标的变化与高异质性和小研究偏倚的统计显着风险相关，导致证据评级的确定性较低。结论 当使用自我报告量表测量抑郁症状且参与者之前使用过致幻剂时，裸盖菇素对继发性抑郁症患者的治疗效果显着更大。因此，需要进一步的研究来描述预期效应、调节因素和治疗实施对裸盖菇素作为抗抑郁药疗效的影响。系统审评注册PROSPERO CRD42023388065。相关汇总数据和统计代码将根据合理要求向通讯作者提供。