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，有必要对迷幻药辅助治疗相关的风险进行清晰和全面的了解。目的评估与经典迷幻药相关的不良事件 （AEs），特别是需要医学或精神病学评估的严重 AEs （SAE） 和非严重 AEs （NSAEs）。数据来源从建库到 2024 年 2 月 8 日，在 Scopus、MEDLINE、PsycINFO 和 Web of Science 数据库中对可能符合条件的研究进行了检索。研究选择两位独立评价员筛选了涉及临床或研究环境中给药的经典迷幻药（麦角酸二乙胺 [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]）的文章。资料提取和综合AE 数据由 2 名评价员提取和综合，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 的确定（例如，系统评估和随访质量）。主要结局和措施采用混合方法捕获高剂量经典迷幻药暴露后所有报告的 AE，并确认捕获特别感兴趣的 AE，包括自杀倾向、精神障碍、躁狂症状、心血管事件和致幻剂持续性感知障碍。AE 按时间尺度和研究人群类型分层。生成常见 AE 的森林图，并描述性地总结了受 SAE 或 NSAE 影响需要医疗干预的参与者的比例。结果共纳入 214 项独特研究，其中 114 项 （53.3%） 报告了 3504 名参与者的可分析的 AE 数据。 没有健康参与者和大约 4% 的先前存在神经精神疾病的参与者报告了 SAE;这些 SAE 包括抑郁恶化、自杀行为、精神病和惊厥发作。需要医疗干预的 NSAE （例如，偏执狂、头痛） 同样罕见。在当代研究环境中，没有关于服用大剂量经典迷幻药后自杀、持续性精神障碍或致幻剂持续性感知障碍死亡的报告。然而，AE 监测和报告的质量存在显著异质性。在自 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 AE （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 的相似结果。结论和相关性在本系统评价和荟萃分析中，根据现有文献，经典迷幻药在临床或研究环境中通常耐受性良好，尽管确实发生了 SAE。这些结果提供了常见 AE 频率的估计值，并表明在娱乐或非临床环境中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惕性，以了解这些物质的风险和益处概况，并将这些风险传达给潜在的研究参与者和公众。