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

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)

Interventions

DRUG

Psilocybin 25 mg per os

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

DRUG

Trazodone 5mg

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

DRUG

Trazodone 30 mg

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

DRUG

Placebo of psilocybin

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

DRUG

Placebo of trazodone

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

Sponsors & Collaborators

• Centre Hospitalier St Anne

  lead OTHER

Principal Investigators

• Lucie BERKOVITCH, MD · GHU Paris Psychiatrie and Neurosciences - Neuromodulation Institute

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-10-08

Primary Completion

2029-12-31

Completion

2030-06-30

Countries

• France

Study Locations