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).

Assessments and instruments. Depressive symptoms are measured primarily with MADRS (Baseline, Week 1, Pre-dose/Week 2, Week 4, Week 6). For characterization/triage, HAM-D-21 may be used at baseline. The psychedelic experience is measured with 5D-ASC (6-24 h post-dose) and SOCQ (~24 h post-dose). Psychological flexibility is assessed with AAQ-10 (Baseline, Week 4, Week 6). Safety is captured with the UKU Side Effect Rating Scale at Baseline, Week 1, Pre-dose/Week 2, 24-48 h post-dose, Week 4, Week 5 and Week 6; adverse events and serious adverse events are recorded throughout.

Outcome measures. Primary outcome: Change in MADRS total score from Baseline to Week 4. Key secondary outcomes: Response (≥50% MADRS reduction) at Week 4; Remission (MADRS ≤10) at Week 4; durability (Baseline→Week 6 change); UKU totals/subscales and incidence of adverse events (any, moderate-severe) and serious adverse events.

Exploratory outcomes: 5D-ASC total/domains and proportion meeting "complete mystical experience"; SOCQ selected domains; AAQ-10 changes (Baseline→Week 4/6); correlations between psychedelic-experience metrics and antidepressant outcomes; comparative profiles of adverse effects between arms.

Statistical approach. The primary analysis compares arms using ANCOVA for Week-4 MADRS, adjusting for baseline MADRS (continuous). Results are presented as adjusted mean difference, 95% confidence interval, and standardized effect size (e.g., Hedges g). Given the pilot nature (N=24), inference is estimative rather than confirmatory; findings are interpreted with reference to a clinically meaningful margin for exploratory non-inferiority (e.g., -4 MADRS points). Secondary and exploratory outcomes are summarized with effect estimates and 95% CIs; p-values, if reported, are descriptive. A linear mixed model using all time points may be used as a sensitivity analysis for missing data assumed missing-at-random.

Safety and oversight. Safety monitoring includes systematic UKU assessments and continuous adverse-event surveillance from consent through Week 6, with prespecified criteria for temporary interruption or discontinuation. Concomitant medications that could compromise masking or interact serotonergically are restricted per protocol; permitted rescue options and timing windows are specified to protect outcome integrity.

This Phase 2a pilot aims to inform feasibility, mechanism, and effect size by directly testing whether concurrent fluoxetine meaningfully alters the acute psychedelic experience, antidepressant response, or tolerability/safety of psychedelic-assisted therapy in TRD.