Addressing blinding in classic psychedelic studies with innovative active placebos.

Classic psychedelics show promise for treating neuropsychiatric disorders, but weak blinding integrity in clinical trials limits the interpretability of therapeutic effects, making alternative active placebos necessary. This review describes drawbacks of current placebos, proposes criteria for suitable active placebos—including acute psychoactive and physiological effects, matched onset and duration, safety, and lack of therapeutic effects for the target disease—and identifies several pharmacological agents that may serve as active placebos for moderate-to-high doses of short- and long-acting psychedelics, as well as low-dose and microdosing regimens. Future research should apply a thoughtful selection process and ancillary strategies to improve blinding.

Study at a glance

Abstract

Classic psychedelics have shown promise in the treatment of various neuropsychiatric disorders. However, weak blinding integrity has been argued to limit the interpretability of therapeutic effects observed in psychedelic clinical trials, highlighting the need to explore alternative active placebos. Here, 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 putatively fit these criteria. 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. 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. To accurately assess the safety and efficacy of classic psychedelics as therapeutics, future research should apply a thoughtful process for selecting active placebos and consider ancillary strategies to improve blinding in trials involving these substances.