Commentary on methods for addressing functional unblinding and mechanistic uncertainty in clinical trials of psychedelic-assisted treatments

Purpose of Review: This commentary summarizes how the intense and distinctive subjective effects of psychedelics complicate tests of the efficacy and mechanisms of action (MOAs) of psychedelic-assisted treatments (PATs) for mental-health conditions. Specifically, we discuss a) how estimates of PAT efficacy are confounded under functional unblinding and b) uncertainty surrounding whether subjective or neurobiological effects are causal therapeutic MOAs of PATs. We then review methodological solutions to address these challenges.Recent Findings: Several novel methodologies have been discussed in the literature. For testing PAT efficacy under functional unblinding, potential solutions include improved active placebo conditions, expectancy-focused recruitment and consent procedures, better measurement of expectancies and blinding, and more rigorous statistical modeling. For testing whether subjective effects are causal MOAs in PATs, strategies that disentangle the subjective and neurobiological effects of psychedelics are needed. Potential methods include administering psychedelics under general anesthesia, developing non-psychoactive psychedelic analogues, leveraging Mendelian randomization, and studying psychedelic microdosing. Participant safety and ethical considerations are critical for many of these strategies. Ultimately, combining multiple innovative methods may offer the most robust insights. Summary: Future empirical efforts to develop these strategies will be crucial for advancing our limited understanding of whether and how PATs achieve clinical benefits in psychiatry.