Modifying Informed Consent to Help Address Functional Unmasking in Psychedelic Clinical Trials.

In psychedelic clinical trials, participants often cannot be masked to whether they received the active drug or placebo, because the drug's effects are so noticeable. This can bias outcomes because participants' expectations influence their responses. One proposed solution is to modify the informed consent process to obscure some details of the study design, which has been used in several recent trials. However, this approach raises serious ethical concerns. The authors review the use of such modifications in trials from 2000 to 2024, discuss the regulatory landscape, and suggest ways to reduce risks. They conclude that modified consent may improve trial interpretability but has not been explicitly tested and may not be appropriate in all cases.

Study at a glance

Abstract

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.