A team of researchers has identified a potential solution to a key challenge in psychedelic drug trials: participants' ability to tell whether they received the active drug or placebo.

In a special communication, published in JAMA Psychiatry, the researchers from the University of California, San Francisco, and the San Francisco Veterans Administration Medical Center examined how modifying informed consent procedures could improve scientific validity while maintaining ethical standards.

The analysis found that between 94% and 100% of participants in psychedelic trials correctly identified when they received the active treatment vs placebo. This "functional unmasking" potentially affected results through expectancy effects and placebo responses, raising concerns about skewed outcomes and inflated effect sizes. Expectancy effects—when participants' beliefs about treatment influence their outcomes—were particularly problematic, as highlighted in the study.

The researchers identified three primary ways in which psychedelic trials had modified informed consent:

• Obscuring information about study arms and treatment chances
• Withholding specific details about drugs and dosages
• Masking information about placebo features or comparator drugs.

For instance, a 2006 study told participants they could receive one of 11 different interventions, even though only two—psilocybin and methylphenidate—were possible. Similarly, a 2018 study obscured details about methylenedioxymethamphetamine dosages and the identity of the comparator drug. Such strategies sought to reduce unmasking without increasing risks to participants.

While 10 psychedelic studies implemented modified consent procedures, only five evaluated whether these changes improved masking effectiveness. Moreover, no study was specifically designed to test the impact of consent modifications on masking efficacy. This highlighted a critical gap in the field, underscoring the need for further research to establish standardized best practices for measuring masking success.

Pharmacological randomized controlled trials (RCT) are generally not considered minimal risk under APA guidelines, which restrict the use of modified informed consent. However, the Belmont Report permits modifications if all significant risks are disclosed and adequately managed. The study authors emphasized that ethical compliance requires adherence to core principles, including participant debriefing and transparency about risks.

"Each psychedelic RCT involves unique considerations, including the safety and efficacy of the specific intervention, clinical population, risk of masking failure, and strength of participants' expectations," the study authors indicated, underscoring the complexity of balancing scientific rigor with ethical obligations.

To mitigate ethical risks, the researchers proposed several guardrails:

• Mandatory debriefing: Participants should be informed about withheld details after the study concludes.
• Participatory research: Engaging stakeholders, such as patients and community representatives, can help assess the acceptability of modifications.
• Participant-authorized modifications: Explicitly informing participants that some study details are intentionally omitted allows for informed decision-making.
• Access to active treatment: Open-label extension arms can ensure participants receive the active intervention, addressing concerns about fairness.

The researchers also stressed the importance of measuring expectancy effects and masking success in future trials. Developing standardized methods for these assessments will be critical to improving the rigor and interpretability of psychedelic research.

This analysis came as the U.S. Food and Drug Administration has granted breakthrough therapy designations to at least five psychedelic treatments, fueling optimism about their therapeutic potential. The study was supported by the Veterans Administration Mental Illness Research, Education, and Clinical Center, and the NIH National Institute on Aging. Conflict of interest disclosures are available in the study.