Microdosing Psilocybin for Major Depressive Disorder: Study Protocol for a Phase II Double-Blind Placebo-Controlled Randomized Partial Crossover Trial

Abstract

Background: Major depressive disorder (MDD) is the leading cause of disability worldwide, affecting roughly 322 million people. Recently, doses of psilocybin have shown promise in treating mood disorders, sparking interest in other dosing practices. According to anecdotal reports and observational studies, microdosing psilocybin yields benefits to mental health; however, rigorously controlled trials have failed to produce compelling evidence for this.Aims: To conduct a phase II, double-blind, placebo-controlled, randomized partial crossover trial to compare microdosing psilocybin to placebo for MDD, evaluating its safety, tolerability, and preliminary antidepressant effects.Method: 40 adults with MDD will be randomized to four doses of psilocybin (2 mg) or placebo (maltodextrin) once weekly over four weeks, then four doses of psilocybin (2 mg) once weekly for an additional four weeks. The primary efficacy endpoint will be change in depression symptoms, as measured at baseline (0 weeks), after the experimental phase (4 weeks), and after the open-label phase (8 weeks). A battery of mood, well-being, attention, creativity, mindfulness, and pro-sociality measures will be administered at each time point. Follow ups will occur every six months for up to two years after the trial start date, as part of a long-term extension study.Conclusions: Findings will inform future research on microdosing psilocybin for MDD, regarding dose regimens, effect sizes, and expectancy bias. Findings will also facilitate discussions on the comparable benefits of sub- versus threshold doses of psilocybin, and the therapeutic value of radically altered perception.