ImportanceA clear and comprehensive understanding of risks associated with psychedelic-assisted therapy is necessary as investigators extend its application to new populations and indications.ObjectiveTo assess adverse events (AEs) associated with classic psychedelics, particularly serious AEs (SAEs) and nonserious AEs (NSAEs) requiring medical or psychiatric evaluation.Data SourcesThe search for potentially eligible studies was conducted in the Scopus, MEDLINE, PsycINFO, and Web of Science databases from inception through February 8, 2024.Study SelectionTwo independent reviewers screened articles of classic psychedelics (lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT], and 5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) involving administration in clinical or research contexts.Data Extraction and SynthesisAE data were extracted and synthesized by 2 reviewers and were used for random-effects meta-analysis of AE frequency and heterogeneity. Risk of bias assessment focused on AE ascertainment (eg, systematic assessment and quality of follow-up).Main Outcomes and MeasuresA hybrid approach was used for capture of all reported AEs following high-dose classic psychedelic exposure and confirmatory capture of AEs of special interest, including suicidality, psychotic disorder, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder. AEs were stratified by timescale and study population type. Forest plots of common AEs were generated, and the proportions of participants affected by SAEs or NSAEs requiring medical intervention were summarized descriptively.ResultsA total of 214 unique studies were included, of which 114 (53.3%) reported analyzable AE data for 3504 total participants. SAEs were reported for no healthy participants and for approximately 4% of participants with preexisting neuropsychiatric disorders; among these SAEs were worsening depression, suicidal behavior, psychosis, and convulsive episodes. NSAEs requiring medical intervention (eg, paranoia, headache) were similarly rare. In contemporary research settings, there were no reports of deaths by suicide, persistent psychotic disorders, or hallucinogen persisting perception disorders following administration of high-dose classic psychedelics. However, there was significant heterogeneity in the quality of AE monitoring and reporting. Of 68 analyzed studies published since 2005, only 16 (23.5%) described systematic approaches to AE assessment, and 20 studies (29.4%) reported all AEs, as opposed to only adverse drug reactions. Meta-analyses of prevalence for common AEs (eg, headache, anxiety, nausea, fatigue, and dizziness) yielded comparable results for psilocybin and LSD.Conclusions and RelevanceIn this systematic review and meta-analysis, classic psychedelics were generally well tolerated in clinical or research settings according to the existing literature, although SAEs did occur. These results provide estimates of common AE frequencies and indicate that certain catastrophic events reported in recreational or nonclinical contexts have yet to be reported in contemporary trial participants. Careful, ongoing, and improved pharmacovigilance is required to understand the risk and benefit profiles of these substances and to communicate such risks to prospective study participants and the public.

中文翻译：

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经典迷幻药研究中的不良事件


重要性随着研究人员将其应用扩展到新的人群和适应症，有必要清楚、全面地了解与致幻剂辅助治疗相关的风险。 目的评估与经典致幻剂相关的不良事件 (AE)，特别是严重 AE (SAE) 和非严重 AE (NSAE)需要医学或精神病学评估。数据来源从开始到2024年2月8日，在Scopus、MEDLINE、PsycINFO和Web of Science数据库中对潜在合格研究进行了搜索。研究选择两位独立审稿人筛选了经典迷幻药（麦角酸二乙酰胺[ LSD]、裸盖菇素、二甲基色胺 [DMT] 和 5-甲氧基-N,N-二甲基色胺 [5-MeO-DMT]）涉及临床或研究环境中的给药。数据提取和合成 AE 数据由 2 位评价者提取和合成，并用于 AE 频率和异质性的随机效应荟萃分析。偏倚风险评估侧重于 AE 确定（例如，系统评估和随访质量）。主要结果和措施采用混合方法捕获高剂量经典致幻剂暴露后所有报告的 AE，并确认捕获特别感兴趣的 AE ，包括自杀、精神障碍、躁狂症状、心血管事件和致幻剂持续性知觉障碍。 AE 按时间尺度和研究人群类型进行分层。生成了常见 AE 的森林图，并对受 SAE 或需要医疗干预的 NSAE 影响的参与者比例进行了描述性总结。 结果 总共纳入 214 项独特研究，其中 114 项 (53.3%) 报告了总共 3504 名参与者的可分析 AE 数据。 健康参与者中没有报告出现严重不良事件，而患有先前存在神经精神疾病的参与者中约有 4% 报告了严重不良事件；这些严重不良事件包括恶化的抑郁症、自杀行为、精神病和惊厥发作。需要医疗干预的非不良事件（例如偏执、头痛）同样罕见。在当代研究环境中，没有关于服用高剂量经典致幻剂后因自杀、持续性精神障碍或致幻剂持续性知觉障碍而死亡的报告。然而，AE 监测和报告的质量存在显着的异质性。自 2005 年以来发表的 68 项分析研究中，只有 16 项 (23.5%) 描述了 AE 评估的系统方法，20 项研究 (29.4%) 报告了所有 AE，而不仅仅是药物不良反应。对常见不良事件（例如头痛、焦虑、恶心、疲劳和头晕）患病率的荟萃分析得出了裸盖菇素和 LSD 的可比较结果。结论和相关性在这项系统评价和荟萃分析中，经典致幻剂在临床或临床中普遍具有良好的耐受性。尽管 SAE 确实发生过，但根据现有文献的研究设置。这些结果提供了常见 AE 频率的估计，并表明在娱乐或非临床背景下报告的某些灾难性事件尚未在当代试验参与者中报告。需要仔细、持续和改进的药物警戒，以了解这些物质的风险和益处，并将这些风险传达给潜在的研究参与者和公众。