Efficacy of Psilocybin and Trazodone Combination in Treatment-resistant Depression: a Randomized Controlled Proof-of-concept Study (PSILOTRAZ)

NCT07210112 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: D24-P003
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

Brief Summary

Psilocybin, a serotonin receptor agonist in the brain, significantly and quickly improves depressive symptoms while inducing profound acute subjective effects. The benefit-risk ratio of psilocybin in treatment-resistant depression seems favorable, but needs to be confirmed. Moreover, the role of 5-HT2A receptors, involved in the psychedelic experience, on the therapeutic efficacy of psilocybin is still poorly understood. For example, pre-administration of trazodone, a 5-HT2A antagonist antidepressant, could annihilate the acute subjective effects of psilocybin without altering its beneficial effects (Rosenblat et al., 2023). We intend to test this hypothesis by comparing, in a randomized, double-blind, placebo-controlled study, the effect of two possible doses of trazodone (total or partial occupancy of 5-HT2A receptors) on the benefit/risk ratio of psilocybin. We hypothesize that the therapeutic effects of psilocybin are partially independent of 5-HT2A receptor activation and thus persist even after total or partial neutralization of its acute subjective effects.

Conditions

Depression - Major Depressive Disorder; Treatment-resistant Depression (TRD)

Keywords

psilocybin; trazodone; TRD; RCT

Outcome Measures

Primary Outcomes (1)

• Change from Baseline in the mean score of Montgomery-Åsberg Depression Rating Scale (MADRS) at 1 month

  Mean difference of MADRS scores between one month and Baseline, between the following groups: psilocybin + trazodone 30 mg (Group 3) and placebo + trazodone (Group 4).

  Baseline, Month 1

Secondary Outcomes (16)

• Change from Baseline in the MADRS scores at Month1 in the Groups 1, 2 and 4

  Baseline and Month 1

• Change from Inclusion in the MADRS scores at Baseline, Day0 H7, Day 1, Day 7, Month 2 and Month 3 in each group

  Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 2 and Month 3

• Change from Inclusion in the Beck Depression Inventory (BDI-II) scores at Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3 in each group

  Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3

• Change from Inclusion in the Columbia-Suicide Severity Rating Scale (C-SSRS) scores at Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3 in each group

  Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3

• Response rate

  Baseline, Day 7, Month 1, Month 2 and Month 3

Study Arms (4)

Group 1

EXPERIMENTAL

Psilocybin PEX010 25 mg + trazodone placebo (pharmaceutical master preparation prepared according to GPP)

Drug: Psilocybin 25 mg per os; Drug: Placebo of trazodone

Group 2

EXPERIMENTAL

Psilocybin PEX010 (25 mg) + trazodone 5 mg

Drug: Psilocybin 25 mg per os; Drug: Trazodone 5mg

Group 3

EXPERIMENTAL

Psilocybin PEX010 (25 mg) + trazodone 30 mg

Drug: Psilocybin 25 mg per os; Drug: Trazodone 30 mg

Group 4

PLACEBO COMPARATOR

PCB2 (Placebo of PEX010 (25)) + trazodone 30 mg

Drug: Trazodone 30 mg; Drug: Placebo of psilocybin

Interventions

Psilocybin 25 mg per os DRUG

Caps of psilocybin administered orally once (V3) under medical and psychologist supervision in group 1, 2, and 3 and in an open-label setting for group 4

Group 1; Group 2; Group 3

Trazodone 5mg DRUG

Oral preparation of trazodone administered orally once (V3) with psilocybin in Group 2

Group 2

Trazodone 30 mg DRUG

Oral preparation of trazodone administered orally once (V3) with psilocybin in Groups 3 \& 4

Group 3; Group 4

Placebo of psilocybin DRUG

Caps of psilocybin placebo will be administered at V3 in group 4

Group 4

Placebo of trazodone DRUG

A placebo of trazodone will be administered orally at V3 in group 1

Group 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient with major depressive episode without psychotic features according to DSM-5 criteria;
• Treatment-resistant depressive episode, i.e. failure to respond to at least two lines of antidepressant medication at an adequate dose and for a sufficient period of time (6 weeks according to the MGH-ATRQ);
• MADRS ≥ 20;
• Written signed informed consent;
• Patient covered by the social security system.

You may not qualify if:

• Bipolar disorder;
• Schizophrenia and psychosis;
• Personal or family history of psychotic disorder;
• History of personality disorder;
• Post-traumatic stress disorder, obsessive-compulsive disorder, eating disorders;
• Alcohol or substance use disorder in past 12 months or positive urine toxins at time of assessment;
• Significant suicide risk, as defined by: (a) suicidal ideation as indicated by items 4 or 5 on the C-SSRS within the past six months, at Screening, during the Screening Period, or at Baseline (b) demonstrating suicidal behaviors in the past six months, or; (c). clinical assessment of significant suicidal risk or risk of self-injury during participant interview;
• Patient with a psychiatric decompensation following a previous use of psychedelic substance like LSD;
• Comorbidities or somatic specificities:
• Pregnancy and breastfeeding women;
• Cardiovascular history (myocardial infarction, stroke, heart rhythm disorder, uncontrolled hypertension, QT interval prolongation, tachycardia and poor cardiovascular health);
• Uncontrolled diabetes;
• Uncontrolled thyroid disorder;
• Epilepsy;
• Parkinson's disease treated by selegiline or levodopa;

Sponsors & Collaborators

• Centre Hospitalier St Anne: lead

Study Sites (1)

GHU Paris Psychiatrie and Neurosciences

Paris, 75014, France

Location

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Interventions

Psilocybin; Trazodone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Piperazines; Heterocyclic Compounds, 1-Ring; Pyridones; Pyridines

Study Officials

• Lucie BERKOVITCH, MD

  GHU Paris Psychiatrie and Neurosciences - Neuromodulation Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lucie BERKOVITCH, MD

CONTACT

+33 145657481; l.berkovitch@ghu-paris.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2025
• First Posted: October 7, 2025
• Study Start: October 8, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): June 30, 2030
• Last Updated: October 7, 2025

Record last verified: 2025-09

Locations

FR (1)