This Phase 2a pilot, exploratory, randomized, double-blind, placebo-controlled, parallel-group trial will estimate whether concurrent fluoxetine alters the antidepressant effect, acute psychedelic experience, or safety of a psychedelic-assisted psychotherapy session in adults with treatment-resistant major depressive disorder (TRD). Eligible participants (ages 25-64) have DSM-5-TR MDD, moderate-severe, MADRS ≥20, and partial response in the current episode (≥1 adequate antidepressant trial of 6-12 weeks with \<50% symptom reduction). All participants receive one dosing session with 3g of standardized Psilocybe mushrooms - with batch assay (e.g., LC-MS) to determine the amount of psilocybin and psilocin present in the sample - with manualized preparation and integration. Participants are randomized 1:1 to fluoxetine 20 mg/day or matching placebo for 4 weeks, started 2 weeks before the psychedelic session and continued 2 weeks after. Masking is quadruple (participant, care provider, investigator, outcomes assessor). The primary outcome is change in MADRS from Baseline to Week 4, assessed by a remote, blinded rater. Key secondary outcomes include response (≥50% MADRS reduction) and remission (MADRS ≤10) at Week 4, and durability at Week 6. Exploratory outcomes assess the psychedelic experience (5D-ASC, SOCQ), psychological flexibility (AAQ-10), and safety/tolerability (UKU and adverse events). Findings will be interpreted as estimates with 95% confidence intervals to inform the design of a subsequent confirmatory trial.
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Parallel
Psilocybin and Psilocyn
DrugOral dose administered via Psilocybe mushrooms material batch-assayed by LC-MS to standardize psilocybin and psilocyn content.
Placebo
DrugMatching capsules, once daily for 4 weeks (-14 to +14 days).
Psychotherapy-assisted session
BehavioralSame manualized procedures as Arm 1.
Fluoxetine
Drug20 mg/day for 4 weeks (-14 to +14 days relative to dosing day).
Montgomery-Åsberg Depression Rating Scale (MADRS)
The primary antidepressant outcome is the change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline (Day 0) to Week 4. MADRS ranges 0-60 (higher = more severe). Interviews will be conducted by a remote, blinded, independent assessor using the structured interview guide at Baseline, Week 1, Pre-dose (Week 2), Week 4 and Week 6. The primary contrast will be the adjusted difference between arms at Week 4 (ANCOVA controlling for baseline MADRS); effect size and 95% CI will be reported.
Montgomery-Åsberg Depression Rating Scale (MADRS)
Proportion of participants achieving ≥50% reduction in MADRS total score from baseline to Week 4.
MADRS Remission
Proportion of participants with MADRS total score ≤10 at Week 4.
Durability of Antidepressant Effect
Change in MADRS total score from baseline to Week 6.
Side Effect Rating Scale UKU
UKU Side Effect Rating Scale total and subscales (psychic, neurologic, autonomic, sexual); incidence of adverse events (any; moderate-severe) and serious adverse events.
Quality of Psychedelic Experience (SOCQ)
States of Consciousness Questionnaire (SOCQ) selected domains (pre-specified) to characterize phenomenology beyond MEQ-30 and explore correlations with antidepressant outcomes.
Acceptance and Action Questionnaire - AAQ-10
Change in Acceptance and Action Questionnaire (10- item) score from baseline to Week 4 and Week 6; exploratory correlations with ΔMADRS and 5D-ASC/SOCQ.
5-Dimensions Altered States of Consciousness (5D-ASC)
Change in 5-Dimensions Altered States of Consciousness (5D-ASC) total and domain scores to assess the global and detailed phenomenology of the psychedelic experience and to explore correlations with antidepressant outcomes.
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