Addressing blinding in classic psychedelic studies with innovative active placebos.

Rationale: Classic psychedelics show promise as a treatment for various neuropsychiatric disorders. However, weak blinding integrity in trials has been argued to limit the capacity to definitively attribute therapeutic effects to the classic psychedelic and dose under investigation. This highlights the need to explore alternative active placebos.

Objectives: We aimed to describe the drawbacks of current placebo conditions used in classic psychedelic studies, propose criteria for suitable active placebos, and review interventions that may fit these criteria.

Results: The active placebos that have typically been used in modern-day trials of classic psychedelics may not adequately blind participants, investigators, or raters. Considerations for the characteristics of ideal active placebos in classic psychedelic studies include 1) acute psychoactive effects, 2) acute physiological effects, 3) onset and duration of acute effects, 4) safety, and 5) lack of therapeutic effects in the target disease. Here, we identified several pharmacological agents that may have potential as active placebos in trials involving moderate-to-high doses of certain short-acting and long-acting classic psychedelics, as well as low-dose administration and microdosing regimes.

Conclusion: To accurately assess safety and efficacy of classic psychedelics as therapeutic drugs, future research should apply a thoughtful process for selecting active placebos and consider ancillary strategies to improve blinding in trials involving these drugs.