Psilocybe Cubensis Mushrooms With or Without Fluoxetine for Refractory Depression: a Phase 2a Pilot Randomized Clinical Trial (COGUNILA)

This is a Phase 2a pilot, exploratory, randomized, double-blind, placebo-controlled, parallel-group clinical trial designed to estimate the effect of concurrent fluoxetine on the efficacy, acute psychedelic experience, and safety of a psychedelic-assisted psychotherapy session in adults with treatment-resistant major depressive disorder (TRD).

Rationale. Selective serotonin reuptake inhibitors (SSRIs) rapidly increase synaptic 5-HT via SERT blockade (days), whereas receptor-level adaptations (e.g., 5-HT2A down-regulation/desensitization) typically require weeks. By administering the psychedelic session after 2 weeks of fluoxetine (and continuing fluoxetine for 2 additional weeks), the study primarily probes the impact of SERT blockade per se on the psychedelic experience and antidepressant outcomes, while minimizing later, slower receptor adaptations. The design-psychedelic for both arms with blinding of fluoxetine vs matching placebo-also improves masking compared with classic "psychedelic vs placebo" trials and directly addresses the practical question of whether SSRI co-administration attenuates, has no meaningful impact, or improves tolerability.

Participants and eligibility. Adults ≥25 and <65 years with current DSM-5-TR MDD, moderate to severe, confirmed by SCID-5, and MADRS ≥20 at baseline. TRD is defined here as Partial Response in the current episode: ≥1 adequate antidepressant trial (therapeutic dose for ≥6-12 weeks, adherence ≥80%) with <50% symptom reduction or clinically significant residual symptoms. Key exclusions include bipolar/psychotic disorders (personal) or first-degree family history, acute suicide risk, contraindications to study medications, unstable medical illness, and current use of serotonergic agents that cannot meet protocol-defined washout. (Full Inclusion/Exclusion lists appear in the Eligibility section.)

Interventions. All participants receive a single psychedelic-assisted session with manualized preparation (2 sessions), dosing-day support, and integration (2 sessions). Administration will be carried out with 3g of standardized Psilocybe mushrooms for all participants, with batch assay (e.g., LC-MS) to determine the amount of psilocybin and psilocin present in the sample. Participants are randomized 1:1 to:

Fluoxetine 20 mg/day for 4 weeks (started 2 weeks before the psychedelic session and continued 2 weeks after), or Matching placebo for 4 weeks on the same schedule. Randomization and masking. Allocation is randomized 1:1, stratified by baseline severity (MADRS 20-29 vs ≥30) using permuted blocks of variable size. Masking is quadruple (participants, care providers, investigators, and outcome assessors). Fluoxetine and placebo are provided in identical capsules; blinding integrity is assessed post-dose and at Week 4 (guess + confidence).