Recruiting
Phase 1/2
Psilocybe Cubensis Mushrooms With or Without Fluoxetine for Refractory Depression
Condition(s) studied
Depressive Disorder
Investigational drug(s) / intervention(s)
Psilocybin and PsilocynPlaceboPsychotherapy-assisted sessionFluoxetine →
Psilocybin and Psilocyn: Oral dose administered via Psilocybe mushrooms material batch-assayed by LC-MS to standardize psilocybin and psilocyn content.
Placebo: Matching capsules, once daily for 4 weeks (-14 to +14 days).
Psychotherapy-assisted session: Same manualized procedures as Arm 1.
Fluoxetine: 20 mg/day for 4 weeks (-14 to +14 days relative to dosing day).
Study summary
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.
Eligibility
Inclusion Criteria Age: ≥25 and \<65 years. Diagnosis: Current Major Depressive Disorder (MDD), moderate to severe, per DSM-5-TR, confirmed with SCID-5.
Baseline severity: MADRS ≥20 at baseline (reassessed at the pre-dose visit to confirm ongoing eligibility).
Partial Response in the current episode (PRD): ≥1 adequate antidepressant trial in this episode (therapeutic dose for ≥6-12 weeks, adherence ≥80%) with \<50% symptom reduction or clinically significant residual symptoms.
Clinical stability and ability to provide informed consent; willingness to comply with all study procedures (preparation, dosing session, integration, and follow-ups).
Contraception: For participants with reproductive potential, negative pregnancy test and agreement to use effective contraception during the study.
Exclusion Criteria Psychiatric disorders: Bipolar I/II disorder, any psychotic disorder, or current MDD with psychotic features; first-degree family history of psychotic or bipolar disorder.
Suicide risk: Acute suicidal risk, e.g., active suicidal ideation with intent or plan, recent attempt, or clinical judgment requiring urgent intervention.
Interacting medications: Current use of serotonergic antidepressants (SSRI/SNRI/MAOI, clomipramine) or other pro-serotonergic agents (e.g., triptans, linezolid, lithium, tramadol, dextromethorphan) that cannot be discontinued per protocol-defined washout.
Other psychotropics: Unstable doses of antipsychotics, mood stabilizers, or long-acting benzodiazepines within the last 2 weeks; need for medications that would compromise blinding on the dosing day.
Psychotherapy changes: Initiation or major change in psychotherapy within 2 weeks prior to baseline (to preserve clinical stability).
Medical conditions: Clinically significant or unstable medical illness (cardiovascular, neurological, hepatic, renal), prolonged QTc, known hypersensitivity/contraindication to fluoxetine or study materials.
Pregnancy or breastfeeding. Substance use: Current substance use disorder (excluding nicotine/caffeine) within the past 3 months; non-medical cannabis use that cannot meet the pre-dose abstinence window (e.g., ≥72 h).
Any condition that, in the investigator's opinion, would make participation unsafe or interfere with the assessments.
Washout note (to include in Procedures/Eligibility):
SSRIs/SNRIs: 7 days or ≥5 half-lives; prior fluoxetine: ≥6 weeks; MAOIs: ≥14 days before randomization/dosing. Participants must be willing and able to follow the washout schedule.
Primary outcome measure(s)
- Montgomery-Åsberg Depression Rating Scale (MADRS) — 4 weeks
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.
Trial sites (1)
| Facility | City | Region | Status |
|---|
| Federal University of Latin American Integration |
Foz do Iguaçu |
Paraná |
Recruiting |
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