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Study on Psilocybin and Trazodone for Adults with Treatment-Resistant Depression

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is focused on studying the effects of a new treatment for treatment-resistant depression. This condition occurs when a person with depression does not respond to at least two different types of antidepressant medications. The study will explore the use of a combination of two substances: psilocybin, which is a compound found in certain types of mushrooms, and trazodone, a medication commonly used to treat depression. The psilocybin will be given in the form of 25 mg capsules, and trazodone will be administered as oral drops with a concentration of 60 mg/ml. The study will also include a placebo group for comparison.

The purpose of the study is to evaluate whether a single administration of the psilocybin and trazodone combination, along with psychotherapeutic support, can improve symptoms of depression in adults with treatment-resistant depression over a period of one month. Participants will receive either the combination treatment or a placebo, and their progress will be monitored through various assessments. These assessments will include questionnaires and scales that measure the severity of depression symptoms, such as the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI).

Throughout the study, participants will be observed for any changes in their condition, including potential side effects. The study aims to provide insights into the effectiveness of this new treatment approach and its impact on the quality of life for individuals with treatment-resistant depression. The trial will last for several months, with regular check-ins to assess the participants' mental health and overall well-being.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Inclusion visit

    During the inclusion visit, eligibility for the study is confirmed. This involves checking if the criteria are met, such as being 18 years or older, having a major depressive episode without psychotic features, and having a specific score on the depression rating scale. Consent to participate is also obtained.

  2. Step 2

    Baseline assessment

    At the baseline assessment, initial measurements are taken. This includes completing questionnaires to assess depression levels and other related factors. These measurements serve as a starting point for evaluating changes over time.

  3. Step 3

    Treatment administration

    The treatment administration involves receiving a single dose of the study medication. This could be a combination of psilocybin 25 mg and trazodone 30 mg, or a placebo. The medication is taken orally, and support is provided during this process.

  4. Step 4

    Follow-up assessments

    Several follow-up assessments are conducted to monitor progress. These occur at different intervals: 7 days, 1 month, 2 months, and 3 months after the treatment. During these visits, questionnaires are completed to evaluate changes in depression symptoms and any side effects experienced.

  5. Step 5

    Final evaluation

    The final evaluation takes place at the end of the study period. This involves a comprehensive assessment of the treatment's impact on depression symptoms and overall well-being. The results are compared to the baseline measurements to determine the effectiveness of the treatment.

Who can join the trial?

6 criteria

  • Age must be 18 years or older.
  • Must have a major depressive episode without psychotic features, as defined by the DSM-5 criteria (a standard classification of mental disorders).
  • Must have a MADRS score of 20 or higher. (MADRS is a scale used to measure the severity of depression symptoms.)
  • Must have a treatment-resistant depressive episode, meaning there was no improvement after trying at least two different antidepressant medications at the right dose for at least six weeks.
  • Must provide free, informed, and written consent to participate in the study.
  • Must be covered by the social security system.

Who cannot join the trial?

9 criteria

  • Patients who are not diagnosed with treatment-resistant depression cannot participate. Treatment-resistant depression means that the depression has not improved after trying at least two different treatments.
  • Patients who are under 18 years old or over 65 years old cannot participate.
  • Patients who are pregnant or breastfeeding cannot participate.
  • Patients with a history of severe heart problems cannot participate.
  • Patients with a history of severe liver or kidney disease cannot participate.
  • Patients with a history of severe mental health disorders, other than depression, cannot participate.
  • Patients who have used illegal drugs or abused alcohol in the past 6 months cannot participate.
  • Patients who are currently participating in another clinical trial cannot participate.
  • Patients who have allergies to psilocybin or trazodone cannot participate. Psilocybin is a compound found in certain mushrooms, and trazodone is a medication used to treat depression.
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Investigated drugs

  • Psilocybin

    is a substance that comes from certain types of mushrooms, often called "magic mushrooms." In this study, it is used to help treat depression that hasn't improved with other treatments. Psilocybin can cause changes in mood, perception, and thought, which might help people see their depression in a new way. It is given with support from a therapist to help guide the experience and make it as beneficial as possible.

  • Trazodone

    is a medication commonly used to treat depression. It works by helping to balance certain chemicals in the brain that affect mood. In this study, trazodone is used alongside psilocybin to see if the combination can better help people who have not responded to other depression treatments. Trazodone can also help with sleep, which is often a problem for people with depression.

What is already known about the treatment

  • Psilocybin

    Psilocybin is administered orally, typically in the form of capsules or tablets, and is used in combination with psychotherapeutic support. It is currently being studied for its potential benefits in treating treatment-resistant depression. The main therapeutic indication is to help improve symptoms of depression in patients who have not responded to other treatments. At the molecular level, psilocybin works by affecting serotonin receptors in the brain, which can alter mood and perception. It is classified as a psychedelic compound.

  • Trazodone

    Trazodone is also administered orally, usually in tablet form, and is used alongside psilocybin and psychotherapeutic support in clinical trials. It is a well-established medication in the treatment of depression and is being explored for its effectiveness in treatment-resistant cases. The primary therapeutic use is to alleviate symptoms of depression. Trazodone works by influencing serotonin levels in the brain, helping to improve mood and emotional balance. It is classified as an antidepressant.

Investigated diseases

Treatment-resistant depression – Treatment-resistant depression is a form of major depressive disorder that does not respond to standard treatments, such as antidepressant medications and psychotherapy. It is characterized by persistent depressive symptoms despite trying multiple treatment strategies. The progression of this condition involves ongoing feelings of sadness, hopelessness, and a lack of interest or pleasure in most activities. Patients may also experience changes in sleep, appetite, and energy levels. Over time, the lack of response to treatment can lead to increased frustration and distress. The condition requires ongoing management and evaluation to explore alternative therapeutic options.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2024-512911-34-00Protocol codeD24-P003Estimated enrolment112 patientsSponsorGroupe Hospitalier Universitaire Paris Psychiatrie Et Neuroscience

sourced from the EU Clinical Trials Register and site verification

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