Commentary on Methods for Addressing Functional Unblinding and Mechanistic Uncertainty in Clinical Trials of Psychedelic-Assisted Treatments
Current Treatment Options in Psychiatry November 11, 2025 Dan Petrovitch, Sarah E. Victor, A. Schmidt et al. 2 citations
The intense and distinctive subjective effects of psychedelics complicate tests of the efficacy and mechanisms of action of psychedelic-assisted treatments for mental-health conditions. Estimates of treatment efficacy are confounded under functional unblinding, and uncertainty surrounds whether subjective or neurobiological effects are causal mechanisms. Methodological solutions include improved active placebo conditions, expectancy-focused recruitment and consent procedures, better measurement of expectancies and blinding, and rigorous statistical modeling. Strategies to disentangle subjective and neurobiological effects include administering psychedelics under general anesthesia, developing non-psychoactive analogues, leveraging Mendelian randomization, and studying microdosing. Combining multiple innovative methods may offer the most robust insights.