A Systematic Review of Study Design and Placebo Controls in Psychedelic Research

Introduction: Effective blinding is especially challenging in randomized controlled trials (RCTs) involving psychedelics due to the inherent alterations in consciousness that these compounds induce. In this systematic review and exploratory analysis, we aim at synthesizing the methodologies used in RCTs involving classic psychedelics and identify procedures that can help minimize unblinding and bias. Methods: We completed a literature search that included prospective RCTs published between 1963 and January 2023, in which participants were randomized to receive either a classic psychedelic or placebo. Results: A total of 1402 papers were included in the initial search. After eligibility criteria were applied, 50 papers from 48 clinical trials were included. Most studies were double blinded (n = 34), used a within-subjects design (n = 32 studies), and included inert placebos (n = 35). The majority of studies did not report on the integrity of blinding procedures (n = 34 studies); however, in studies that did, blinding was unsuccessful. Conclusion: To improve blinding and lower expectancy effects, we suggest incorporating active placebos and utilizing dose response or active comparator study designs.