Matvey Michelle, Kelley D Parker, Bradley Ellen R, Chiong Winston, O'Donovan Aoife, Woolley Josh
Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California, San Francisco.
San Francisco Veterans Administration Medical Center, San Francisco, California.
JAMA Psychiatry. 2025 Mar 1;82(3):311-318. doi: 10.1001/jamapsychiatry.2024.4312.
There is unprecedented clinician, industry, and patient interest in the therapeutic development of psychedelic drugs. This is due to a combination of promising clinical trial results, positive media coverage, and the lack of novel pharmacologic treatments for psychiatric disorders in recent decades. However, the field faces a key methodological challenge: masking participants to treatment conditions in psychedelic clinical trials has been largely unsuccessful.
When participants can tell whether they received active drug or placebo, their responses to clinical assessments, questionnaires, and even their functional imaging and biological data can be influenced by preconceptions about treatment effects. Positive patient expectancies combined with ineffective masking may skew outcomes and inflate effect sizes. This complicates efforts to determine the safety and efficacy of psychedelic drugs. Here, we explore a method to help address this problem: modifying informed consent to obscure information about the study design.
We reviewed all contemporary (2000-2024) clinical trials of psychedelic or methylenedioxymethamphetamine (MDMA) therapy and corresponded with the investigators to compile information on the use of modifications to informed consent in these studies.
Modifying informed consent to obscure details of the study design has been implemented in several psychedelic clinical trials and may offer a way to strengthen masking. However, this approach poses significant ethical risks. We examine examples of modifications used in the psychedelic literature, discuss the current regulatory landscape, and suggest strategies to mitigate risks associated with modified informed consent.
Incorporating modified informed consent in future psychedelic clinical trials may improve interpretability and impact, but this has not been explicitly tested. Modifications to informed consent may not be appropriate in all cases, and risks to participants should be minimized by implementing appropriate guardrails.
临床医生、制药行业和患者对迷幻药物的治疗开发有着前所未有的兴趣。这是由一系列因素共同导致的，包括临床试验结果令人鼓舞、媒体的正面报道以及近几十年来精神疾病缺乏新型药物治疗方法。然而，该领域面临一个关键的方法学挑战：在迷幻药物临床试验中，使参与者对治疗条件保持盲态在很大程度上并不成功。
当参与者能够判断自己接受的是活性药物还是安慰剂时，他们对临床评估、问卷的回答，甚至他们的功能成像和生物学数据都可能受到对治疗效果的先入之见的影响。患者的积极预期加上无效的盲法可能会使结果产生偏差并夸大效应量。这使得确定迷幻药物的安全性和有效性变得更加复杂。在此，我们探索一种有助于解决这一问题的方法：修改知情同意书以模糊有关研究设计的信息。
我们回顾了所有当代（2000 - 2024年）迷幻药物或亚甲基二氧甲基苯丙胺（摇头丸）治疗的临床试验，并与研究人员进行了沟通，以汇总这些研究中对知情同意书进行修改的使用情况信息。
在一些迷幻药物临床试验中已经采用了修改知情同意书以模糊研究设计细节的做法，这可能为加强盲法提供一种途径。然而，这种方法带来了重大的伦理风险。我们研究了迷幻药物文献中使用的修改示例，讨论了当前的监管环境，并提出了减轻与修改后的知情同意书相关风险的策略。
在未来的迷幻药物临床试验中纳入修改后的知情同意书可能会提高可解释性和影响力，但这尚未经过明确测试。对知情同意书的修改在所有情况下可能都不合适，应通过实施适当的保障措施将对参与者的风险降至最低。
