Research Associate The Hastings Center New York, New York
Abstract: In clinical research, placebo-controlled, double-blind randomized trials (RCTs) are considered the gold standard for isolating the efficacy of novel interventions. This design is based on comparing the effects of the experimental drug with a placebo, with blinding used to distribute nonspecific effects and participant expectancy equally across both groups. However, in psychedelic clinical trials, compounds like psilocybin, LSD, DMT, and MDMA-AT pose challenges due to their psychoactive properties, raising concerns about “functional unblinding.” Some studies report high accuracy in participants guessing their assigned treatment group, leading critics to question whether symptom improvements in psychedelic trials are due to expectancy effects rather than the pharmacologic effects of the drugs themselves.
Various approaches have been proposed to address this issue, such as better expectancy measurement, statistical adjustments, and using “active placebos” as comparators. While isolating the pharmacologic effects of psychedelics is imperative for clinical trials, I argue that psychiatry should forgo the insistence on a non-expectancy drug recipient control and instead focus on comparing the expectancy effects in drug recipients with those in whom expectancy is induced or suppressed without psychedelics. Accordingly, I propose a novel design for psychedelic clinical trials that adapts the “balanced placebo design” originally developed for controlling expectancy effects in research related to alcohol use. This modified three-arm trial incorporates “active placebos” that mimic the interoceptive events that drive expectancy while also allowing for the exploration of whether expectancy-induced effects are unique to psychedelics in their therapeutic potential.
After participating in this conference, attendees should be able to:
articulate the problems of "functional unblinding" in clinical trials and its perceived relevance to psychedelic research.
appreciate the barriers to separating expectancy from pharmacology in psychedelic research, and the rationale for preserving expectancy effects as clinically significant variables that should not be eliminated in clinical trials.
understand the historical significance of the 2x2 balanced trial design and the ethical and clinical arguments for applying a modified version within psychedelic research.
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