Psilocybe Cubensis Mushrooms With or Without Fluoxetine for Refractory Depression

NCT06898606 | Recruiting Phase 1 DMC

• 2 other identifiers: COGUNILACAAE: 77979424.0.0000.0107
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Depressive Disorder

Keywords

Psilocybin; Depression; Fluoxetine; Treatment; Psychedelics

Outcome Measures

Primary Outcomes (1)

• Montgomery-Åsberg Depression Rating Scale (MADRS)

  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.

  4 weeks

Secondary Outcomes (4)

• Montgomery-Åsberg Depression Rating Scale (MADRS)

  4 week

• MADRS Remission

  4 week

• Durability of Antidepressant Effect

  6 week

• Side Effect Rating Scale UKU

  Baseline; Week 1; Pre-dose (Week 2); 24-48 h post-dose; Week 4; Week 6

Other Outcomes (3)

• Quality of Psychedelic Experience (SOCQ)

  ~24 h after the dosing session

• Acceptance and Action Questionnaire - AAQ-10

  Baseline to Week 4; Baseline to Week 6

• 5-Dimensions Altered States of Consciousness (5D-ASC)

  24 hours after the dosing session

Study Arms (2)

Psilocybin + Fluoxetine

EXPERIMENTAL

2 preparation sessions for the psychedelic experience 1. dosing session with 3g Psilocybe mushrooms (single oral dose), with psychotherapy assistance 2. integration sessions Fluoxetine 20 mg/day for 4 weeks (started 2 weeks before dosing and continued 2 weeks after)

Drug: Psilocybin and Psilocyn; Behavioral: Psychotherapy-assisted session; Drug: Fluoxetine

Psilocybin + Placebo

PLACEBO COMPARATOR

2 preparation sessions for the psychedelic experience 1. dosing session with 3g Psilocybe mushrooms (single oral dose), with psychotherapy assistance 2. integration sessions Pharmaceutical grade talc, matching placebo (identical capsules), daily for 4 weeks (started 2 weeks before dosing and continued 2 weeks after).

Drug: Psilocybin and Psilocyn; Drug: Placebo; Behavioral: Psychotherapy-assisted session

Interventions

Psilocybin and Psilocyn DRUG

Oral dose administered via Psilocybe mushrooms material batch-assayed by LC-MS to standardize psilocybin and psilocyn content.

Psilocybin + Fluoxetine; Psilocybin + Placebo

Placebo DRUG

Matching capsules, once daily for 4 weeks (-14 to +14 days).

Psilocybin + Placebo

Psychotherapy-assisted session BEHAVIORAL

Same manualized procedures as Arm 1.

Psilocybin + Fluoxetine; Psilocybin + Placebo

Fluoxetine DRUG

20 mg/day for 4 weeks (-14 to +14 days relative to dosing day).

Psilocybin + Fluoxetine

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Federal University of Latin American Integration: lead

Study Sites (1)

Federal University of Latin American Integration

Foz do Iguaçu, Paraná, 85870-650, Brazil

RECRUITING

MeSH Terms

Conditions

Depressive Disorder; Depression

Interventions

Psilocybin; Fluoxetine

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Propylamines; Amines; Organic Chemicals

Study Officials

• Francisney P Nascimento, 1

  Federal University of Latin American Integration

  STUDY DIRECTOR

Central Study Contacts

Francisney P Nascimento, 1

CONTACT

+55 45 99933-3479; ensaios.clinicos.lcp@unila.edu.br

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo-controlled, parallel-group trial in adults with treatment-resistant major depressive disorder. All participants receive one psychedelic-assisted session with 3g of Psilocybin musshoroms and psychotherapy; they are randomized to concurrent daily fluoxetine 20 mg or matching placebo for 4 weeks (started 2 weeks before dosing and continued 2 weeks after). The study compares psychedelic experience, antidepressant effects, and adverse events between arms.

Study Record Dates

• First Submitted: November 30, 2024
• First Posted: March 27, 2025
• Study Start: September 5, 2024
• Primary Completion (Estimated): August 20, 2026
• Study Completion (Estimated): November 20, 2026
• Last Updated: March 27, 2026

Record last verified: 2026-03

Locations

BR (1)