Using Psilocybe Cubensis Mushrooms with or without Fluoxetine for Treatment-Resistant Depression

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

This clinical trial investigates the effects of Psilocybe cubensis mushrooms, a natural psychedelic, in combination with fluoxetine, a common antidepressant, for patients suffering from treatment-resistant Major Depressive Disorder. Participants will be randomly assigned to receive either the combination of mushrooms and fluoxetine or mushrooms with a placebo, while undergoing psychotherapy. The study aims to assess the differences in antidepressant effects and side effects between the two treatment groups. The trial will include both quantitative and qualitative analyses to evaluate the outcomes.

Why it matters

Who can join: the full rules

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.

Where it's running

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

Study contacts

• Study coordinator: Francisney P Nascimento, 1
• Email: ensaios.clinicos.lcp@unila.edu.br
• Phone: +55 45 99933-3479

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.