Silva Francisca, Butlen-Ducuing Florence, Guizzaro Lorenzo, Balabanov Pavel
Office for Neurological and Psychiatric Disorders, European Medicines Agency, Amsterdam, the Netherlands.
Institut Gustave Roussy, Psycho-Oncology Unit, Interdisciplinary Department for the Organisation of Patient Pathways, Cancer Campus, Grand Paris, France.
Neurosci Appl. 2025 Feb 26;4:105516. doi: 10.1016/j.nsa.2025.105516. eCollection 2025.
There is a growing body of clinical research on the therapeutic potential of psychedelics for the treatment of mental health disorders, notably depression. Accordingly, the new revision of the European Medicines Agency guideline on the clinical investigation of products for depression will incorporate a section covering specific regulatory recommendations for the design of studies with psychedelics. The present review investigated the methodological approaches adopted in completed controlled trials of psychedelics for depression in light of initial considerations included in the draft guideline revision. A systematic search conducted on scientific databases (Embase and Medline) and clinical trial registries (clinicaltrials.gov and WHO ICTPR) identified 8 completed trials as of February 2024. The trials tested psilocybin, LSD, Ayahuasca, and DMT, for major depressive disorder or treatment-resistant depression, and were all pahse 2 or 1/2. Patterns in pre-defined methodological variables pertaining to trial design, population, interventions, outcome measures and safety assessments were analysed and collated against considerations on unblinding and expectancy, choice of comparator, the definition of treatment frameworks, the characterisation of the subjective psychedelic experience and the specification of adverse events in relation to subjective psychedelic effects. Areas for future research, including long-term efficacy and safety and the influence of inter-individual differences, can be investigated in larger studies, necessary for marketing authorisation applications. Ultimately, balancing the intricacies of conducting trials with psychedelics with ensuring adherence to regulatory requirements can be facilitated by early dialogue with medicines regulators, and will be essential for the medical development of psychedelics to address unmet patient needs.
关于迷幻药治疗精神健康障碍尤其是抑郁症的治疗潜力，临床研究越来越多。因此，欧洲药品管理局关于抑郁症治疗产品临床研究的指南新修订版将纳入一部分内容，涵盖针对迷幻药研究设计的具体监管建议。本综述根据指南修订草案中的初步考虑因素，调查了已完成的迷幻药治疗抑郁症对照试验所采用的方法学途径。截至2024年2月，在科学数据库（Embase和Medline）和临床试验注册库（clinicaltrials.gov和世界卫生组织国际临床试验平台注册库）上进行的系统检索确定了8项已完成的试验。这些试验测试了裸盖菇素、麦角酸二乙酰胺、死藤水和N,N-二甲基色胺用于治疗重度抑郁症或难治性抑郁症，且均为2期或1/2期试验。分析并整理了与试验设计、人群、干预措施、结局指标和安全性评估相关的预定义方法学变量模式，并对照关于揭盲和预期、对照物选择、治疗框架定义、主观迷幻体验特征以及与主观迷幻效应相关不良事件的具体说明等方面的考虑因素。未来研究领域，包括长期疗效和安全性以及个体差异的影响，可以在规模更大的研究中进行调查，这对于上市许可申请是必要的。最终，与药品监管机构的早期对话有助于平衡开展迷幻药试验的复杂性与确保遵守监管要求之间的关系，这对于迷幻药的医学开发以满足未满足的患者需求至关重要。
