Clinical TrialTreatment-Resistant Depression (TRD)PsilocybinPsilocybinPlaceboRecruiting

Administration of Psilocybe Cubensis Mushrooms with or Without Fluoxetine with or Without Fluoxetine for Refractory Depression: a Randomized Double-blind Controlled Trial Controlled Clinical Trial – COGUNILA (COGUNILA)

This randomised, quadruple-blind, placebo-controlled Phase I/II trial (n=50) will investigate the antidepressant, psychedelic, and adverse effects of Psilocybe cubensis mushrooms (equivalent to 30 mg of psilocybin) with or without daily fluoxetine (20mg) in adults with treatment-resistant depression.

Target Enrollment
50 participants
Study Type
Phase I/II interventional
Design
Randomized, quadruple Blind

Detailed Description

Randomized, quadruple-blind, parallel-group Phase 2a pilot in adults with treatment-resistant major depressive disorder comparing concurrent fluoxetine 20 mg/day versus matching placebo around a single 3 g Psilocybe mushroom dosing session with manualized psychotherapeutic support.

Primary outcome is change in MADRS from baseline to Week 4; secondary outcomes include response and remission rates at Week 4 and durability to Week 6, plus measures of the acute psychedelic experience (5D-ASC, SOCQ), psychological flexibility (AAQ-10), and safety/tolerability (UKU, adverse events).

Study Protocol

Preparation

2 sessions

Dosing

1 sessions

Integration

2 sessions

Therapeutic Protocol

Manualized psychotherapy included

Study Arms & Interventions

Psilocybin + Fluoxetine

experimental

Single 3 g psilocybin-containing mushroom dose with concurrent fluoxetine 20 mg/day (started 14 days before dosing, continued 14 days after) plus manualized psychotherapy.

Interventions

  • Psilocybin3 g
    via Oral• single dose• 1 doses total

    3 g standardized Psilocybe mushrooms; batch-assayed for psilocybin/psilocin.

  • Compound20 mg
    via Oral• daily for 4 weeks

    Fluoxetine 20 mg/day started 14 days before dosing and continued 14 days after.

  • Compound
    via Other• manualized psychotherapy (2 prep + dosing-day support + 2 integration)

    Therapeutic support paired with dosing.

Psilocybin + Placebo

inactive

Single 3 g psilocybin-containing mushroom dose with matching placebo capsules daily plus manualized psychotherapy.

Interventions

  • Psilocybin3 g
    via Oral• single dose• 1 doses total

    3 g standardized Psilocybe mushrooms; batch-assayed for psilocybin/psilocin.

  • Placebo
    via Oral• daily for 4 weeks

    Matching placebo capsules started 14 days before dosing and continued 14 days after.

  • Compound
    via Other• manualized psychotherapy (2 prep + dosing-day support + 2 integration)

    Therapeutic support paired with dosing.

Participants

Ages
25 – 65
Sexes
Male & Female

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: 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.

Study Details

Locations

Federal University of Latin American Integration — Foz do Iguaçu, Paraná, Brazil

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