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Safety and dose‑finding study of trazodone hydrochloride and psilocybin in patients 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 study focuses on people who have Treatment-Resistant Depression, a form of depression that does not improve with usual medicines. Researchers are testing whether taking the sleep‑helping drug Trazodone before a single dose of the psychedelic compound psilocybin can make the experience safer and easier to handle.

The purpose of the study is to see if the combination is safe, well‑tolerated, and practical to use. Participants will start with a low amount of Trazodone that is gradually increased over several visits. After the selected dose is reached, a fixed amount of psilocybin will be taken, and the person will be monitored for about a month. During this time, doctors will check vital signs such as heart rate and blood pressure, perform simple heart tests, and run laboratory checks. They will also ask participants about any changes in mood, thoughts of self‑harm, and how they feel during the psilocybin experience. The study will also look at pharmacokinetics, which means how the body absorbs, distributes, and clears both medicines.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Lead‑in phase begins

    After enrollment, you start a short lead‑in period during which no study medication is taken. this time allows the study team to confirm eligibility and collect initial health information.

  2. Step 2

    Baseline assessments

    Before any medication, you complete questionnaires about your depression, undergo basic measurements such as blood pressure and heart rhythm (electrocardiogram, or ECG), and provide blood samples for laboratory tests. these results serve as a reference for later safety checks.

  3. Step 3

    First trazodone dose

    You receive trazodone oral drops at a dose of 75 mg. the drops are taken by mouth according to the study schedule, typically a short time before the next medication.

    The purpose of this dose is to evaluate how trazodone may change the effects of the following psilocybin dose.

  4. Step 4

    Psilocybin administration

    After the trazodone dose, you take one capsule containing 25 mg of psilocybin. the capsule is swallowed with water under supervision.

  5. Step 5

    Immediate safety monitoring

    For at least 24 hours after the combined trazodone‑psilocybin session, you are observed for any side effects. staff check vital signs, repeat the ECG, and ask about any new or worsening thoughts of self‑harm using the Columbia‑Suicide Severity Rating Scale (C‑SSRS).

  6. Step 6

    Dose‑escalation sessions (if applicable)

    The study may repeat steps 3 to 5 with higher doses of trazodone in later sessions, while the psilocybin dose remains the same (25 mg). each new trazodone dose follows the same safety checks before and after administration.

  7. Step 7

    Follow‑up assessments through day 30

    Over the next 30 days after the final combined dose, you attend scheduled visits or calls. during these follow‑ups the study team repeats vital sign measurements, ECGs, laboratory tests, and the C‑SSRS questionnaire to monitor any delayed effects.

    You also complete questionnaires that explore your experience of the psilocybin session and any changes in depressive symptoms.

  8. Step 8

    Study completion

    Once all assessments up to day 30 are finished, the trial participation ends. you receive a summary of the study findings that relate to safety and tolerability.

Who can join the trial?

11 criteria

  • Age: You must be between 18 and 65 years old.
  • Language: You need to speak and understand Italian well enough to complete the study questionnaires and interviews.
  • Study participation: You must be willing and able to attend five study visits, give blood and urine samples, undergo pregnancy and drug‑screening tests, and complete questionnaire assessments.
  • Depression diagnosis: You must have been diagnosed with Major Depressive Disorder (MDD) using the standard criteria called DSM‑5. In addition, you must not have improved after trying at least two different antidepressant medicines (such as SSRIs or SNRIs) at proper doses for 4–6 weeks.
  • Hospital or outpatient status: Whether you are staying in the hospital or receiving care as an outpatient, you can join if you meet all other requirements.
  • Informed consent: You must be able to read, understand, and sign a written document that explains the study and confirms that you agree to take part.
  • Birth‑control requirement: If you could become pregnant, you must agree to use a highly effective method of contraception during the study and for a set time after it ends.
  • No recent serious substance abuse: You should not have had a severe problem with alcohol or illegal drugs in the past year that could affect the study.
  • Stopping other antidepressants: You must have stopped any antidepressant medicines that affect serotonin or norepinephrine (called monoaminergic drugs, such as SSRIs or SNRIs) at least 2 weeks before the first study dose (for fluoxetine, at least 5 weeks). If you are still on these medicines, you must agree to slowly reduce (or “taper”) them under close supervision by your psychiatrist and the study team.
  • Stopping MAOIs: If you are taking a type of antidepressant called a monoamine oxidase inhibitor (MAOI), you must completely stop it after a gradual taper and be off the medication for at least 2 weeks before the baseline visit.
  • Body size: Your body mass index (BMI) must be between 18.0 and 30.0, and you must weigh at least 45 kilograms at the screening visit.

Who cannot join the trial?

15 criteria

  • If you have a current or past diagnosis of serious mental health conditions such as depression with psychotic features, schizophrenia or related psychotic disorders, bipolar disorder, certain personality disorders (including paranoid, schizoid, schizotypal, or borderline), or post‑traumatic stress disorder (PTSD), you cannot join the study.
  • If you are unable to build a good working relationship with the study therapists during the first two preparatory sessions, you will be excluded.
  • If you are pregnant, breastfeeding, or plan to become pregnant within the next three months, you are not eligible.
  • If you are allergic to any ingredient in the study medications, you cannot participate.
  • If you have uncontrolled hormone or metabolism problems (for example, untreated overactive thyroid called hyperthyroidism), severe breathing problems (such as respiratory failure or acute respiratory depression), or a diagnosis of epilepsy or a known family history of seizures, you are excluded.
  • If you have a serious physical illness that the investigator believes would increase risk or interfere with the study procedures, you cannot take part.
  • If you have a known allergy or hypersensitivity specifically to psilocybin, trazodone, or any inactive ingredients in the study drugs, you are excluded.
  • If you are currently taking medications or substances that are not allowed for the study and have not stopped them for at least 7–14 days (a “washout” period), you cannot join.
  • If a first‑degree relative (parent, sibling, or child) has a history of psychosis or bipolar disorder, you are excluded.
  • If you have had strong suicidal thoughts (active thoughts with intent) within the past six months, or a suicide attempt or serious suicidal behavior within the past year, you cannot participate.
  • If you have a current substance use disorder (such as alcohol or drug dependence) within the past 12 months, excluding only tobacco or caffeine use, you are not eligible.
  • If you have used classic psychedelics (like LSD, psilocybin, mescaline, or DMT) in the past year, or have used them more than five times in your lifetime, you cannot join the study.
  • If you have a high heart or blood‑vessel risk (as measured by SCORE2), uncontrolled high blood pressure (greater than 150/100 mm Hg), pressure problems in the brain (intracranial hypertension) or lungs (pulmonary hypertension), a recent stroke or heart attack within the last six months, or heart failure, you are excluded.
  • If you have any other serious physical condition that could cause a dangerous rise in blood pressure, the investigator may deem you ineligible.
  • If you have an established diagnosis of epilepsy or a family history of epileptic disorders, you cannot participate.
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Investigated drugs

  • Trazodone

    is a medication that is usually used to help with sleep and mood problems. In this study, participants take trazodone before receiving psilocybin. The researchers want to see if trazodone can make the mind‑changing effects of psilocybin milder, while still allowing the possible antidepressant benefits. They are checking how safe it is, how well people tolerate it, and whether it can be given at higher amounts safely.

  • Psilocybin

    is a naturally occurring substance found in certain mushrooms that can change perception, mood, and thinking. In this trial, a fixed dose of psilocybin is given to people with treatment‑resistant depression to explore its potential antidepressant effects. The study looks at how the drug behaves in the body, how safe it is, and whether taking it after trazodone changes its impact on consciousness.

What is already known about the treatment

  • TRITTICO (Trazodone Hydrochloride)

    This medication is given as oral drops, placed under the tongue or swallowed. It is an approved antidepressant that has been used for many years and is well described in medical books. It is mainly used to treat depression and sometimes trouble sleeping. It works by increasing the amount of serotonin, a brain chemical, by blocking its re‑uptake and also by blocking certain serotonin receptors, and it belongs to the class of serotonin modulators and antidepressants.

  • PEX010 Psilocybin Capsules

    The drug comes in a capsule that is taken by mouth. Psilocybin is still an investigational substance and is being studied in research trials for mental health conditions. It is being tested mainly for depression that does not improve with other treatments. After the capsule is swallowed, psilocybin is turned into psilocin, which activates serotonin receptors in the brain, especially the 5‑HT2A type, and it is classified as a psychedelic serotonergic agent.

Investigated diseases

Treatment‑resistant depression - It is a type of major depressive disorder that persists despite at least two adequate trials of different antidepressant medications. People with this condition experience ongoing low mood, loss of interest, and other depressive symptoms that do not substantially improve. The symptoms may fluctuate in intensity but often become chronic, affecting daily functioning and relationships. The condition can also contribute to persistent fatigue, sleep problems, and cognitive difficulties.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-523346-27-00Estimated enrolment30 patientsSponsorUniversita' Degli Studi G. D'Annunzio Di Chieti

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