Safety and Efficacy of Microdosing Psilocybin over 8 Weeks for Major Depressive Disorder: A Randomized Clinical Trial
Rotem Petranker, Norman A. S. Farb, Omer A. Syed, Erica J. Li, David Shore, Thomas Anderson, Adam Blackman
Research Square February 23, 2026 preprint DOI: 10.21203/rs.3.rs-8319478/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Open-label |
|---|---|
| Sample size | 39 |
| Population | Adults aged 27 to 65 with major depressive disorder and mild to moderate symptom severity |
| Intervention | Psilocybin |
| Dose | 2 mg |
| Duration | 4-week intervention, with 4-week open-label extension |
| Topics | Depression Psilocybin Microdosing |
| Keywords | Placebo Adverse effect Randomized controlled trial Clinical trial Depression economics Depressive symptoms Psychological intervention Antidepressant Physical therapy Rating scale Repeated measures design |
| Registration | NCT05259943 |
| Key findings | Repeated low doses of psilocybin did not demonstrate statistically greater efficacy than placebo for reducing depressive symptoms in adults with major depressive disorder. |
Abstract
Abstract 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
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Repeated low doses of psilocybin (2 mg) did not demonstrate statistically greater efficacy than placebo for reducing depressive symptoms over four weeks.
Synthesized
Comparable studies
Other randomized controlled trials on psilocybin and microdosing, most cited first.