This Phase 2b open-label, single-arm pilot mechanistic trial (n=50) evaluates psilocybin-assisted therapy (PAT) for adults with mild-to-moderate depression at Washington University in St. Louis. Each participant receives the Usona Institute PAT protocol: 2 preparation sessions (~8 hours total), one Dosing Day with a single 25 mg oral psilocybin capsule, and 3 integration sessions at Trial Days 2, 8 and 15 (~80 min each) with two trained facilitators. Participants on a stable antidepressant monotherapy may continue their medication, and those with a MADRS score ≥7 at Trial Day 30 are eligible for one optional re-administration. Primary endpoints are change in depression severity (MADRS) and psychological flexibility (MPFI) at ~1 week (Trial Day 8) and ~30 days after dosing. Exploratory aims characterise neural mechanisms via up to 10 fMRI sessions per participant (including imaging during dosing using precision functional brain mapping), proteomic blood biomarkers (the senescence-associated secretory phenotype, SASP), and cognitive functioning via the NIH Toolbox. The study is designed to estimate feasibility, effect sizes and operational parameters — it is not powered for confirmatory hypothesis testing — to inform a subsequent adequately-powered trial.
Depression is the leading cause of disability worldwide, affecting an estimated 300 million people. Despite available treatments, response rates remain modest, and treatment resistance is common. Novel treatments are needed that act rapidly, produce lasting effects and work differently than existing antidepressants.
In clinical trials, psilocybin has shown promise as a treatment for depression due to its rapid onset of antidepressant effects and sustained benefits.
This study will use MRI scanning of the brain and other biological measures (biomarkers) to investigate how psilocybin affects brain activity and psychological flexibility before, during, and after receiving psilocybin in participants with depressive symptoms.
Open-label psilocybin-assisted therapy (PAT) delivered per the Usona Institute Phase III (PSIL301 / UAspire) protocol. Each participant receives ~20 hours of psychological support from two trained Facilitators (Lead + Assistant), comprising: 2 preparation sessions (~8 hours total) up to two weeks before dosing; one Dosing Day with a single 25 mg oral psilocybin capsule taken with ~8 oz of water, supported by two Facilitators in a dedicated room (eye shades, headphones, pre-selected music); and 3 integration sessions on approximately Trial Days 2, 8, and 15 (~80 minutes each). When feasible, fMRI scanning is performed during the dosing session. Participants on a stable antidepressant monotherapy may continue their medication. Participants with a MADRS score ≥7 at the Trial Day 30 Visit are eligible for one optional open-label re-administration of 25 mg psilocybin, preceded by one ~90-minute preparation session and followed by 3 further integration sessions.