Safety and Efficacy of Microdosing Psilocybin over 8 Weeks for Major Depressive Disorder: A Randomized Clinical Trial

IMPORTANCE Microdosing psilocybin may be a novel treatment for major depressive disorder (MDD). OBJECTIVE Assessing the antidepressant effects and safety of repeated low doses of psilocybin in participants diagnosed with MDD. DESIGN This was a Phase II, randomized, double-blind, placebo-controlled clinical trial. SETTING The trial was conducted from July 2022 to December 2024 at two centers: a pediatric clinic and a dedicated psychedelic therapy clinic. PARTICIPANTS were 39 adults aged 27 to 65 years with a diagnosis of MDD and mild to moderate symptom severity. INTERVENTIONS Participants received four weekly doses of placebo or 2 mg psilocybin, followed by four weekly open-label psilocybin doses. MAIN OUTCOMES AND MEASURES Primary outcome: Patient Health Questionnaire with Self-Directed Assessment Scales (PHQ-9) score from baseline week four. Secondary outcome measures were symptom counts measured by the Structured Clinical Interview for DSM-5 (SCID-5) symptom count, Quick Inventory of Depressive Symptomatology (QIDS), and the Dysfunctional Attitudes Scale (DAS-A-17) from baseline to week four. RESULTS 39 participants (mean age 44.4; 56.4% female) reported similar reductions in PHQ-scores regardless of group assignment after four weeks (psilocybin: mean difference -5.4; placebo: -6.0). Similar trends were observed in the QIDS and SCID-5, but participants in the microdose-first group showed more symptoms reduction than those in the placebo-first group (psilocybin: mean difference -1.2; placebo: -0.1) for the DAS-A-17. Symptom reductions persisted through open-label phase, with no serious treatment-emergent adverse events. CONCLUSIONS AND RELEVANCE Repeated low doses of psilocybin were safe and well tolerated but did not demonstrate statistically greater efficacy than placebo. Trial participation itself contributed to clinically significant symptom improvement. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05259943