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Psilocybin and pimavanserin for adults with major depressive disorder

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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 studying Major depressive disorder, a common form of depression that can cause low mood, loss of interest, and other ongoing emotional symptoms. The trial uses psilocybine, taken by mouth as a capsule, and pimavanserin, taken by mouth as a tablet. Some participants receive psilocybine with pimavanserin, while others receive psilocybine with placebo. The purpose of the study is to understand how psilocybine may affect brain activity in relation to its psychedelic effects, and how this may relate to depression.

The study lasts for several scans over a short period, with brain MRI tests done before and after treatment. MRI is a scan that uses magnetic fields to take pictures of the brain. During the study, changes in brain connections are compared across the different treatment groups. No other study procedures are described here.

The research process

The trial runs in 4 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Study start and first treatment period

    After joining the study, you enter the treatment period for major depressive disorder. You take either psilocybine or pimavanserin tartrate by mouth, depending on the study group assigned to you.

    The psilocybine group receives 25 mg in capsule form, taken orally.

    The pimavanserin tartrate group receives 34 mg in tablet form, taken orally.

    A placebo capsule is also used in the study. A placebo looks like a study medicine but does not contain an active medicine.

  2. Step 2

    Brain scans during the study

    During the trial, you undergo magnetic resonance imaging (MRI), which is a brain scan that uses magnetic fields and radio waves to create images of the brain.

    The scan includes a resting-state functional sequence, which looks at how different parts of the brain are connected when you are resting.

    The scan also includes a T1-weighted anatomical sequence, which gives detailed pictures of the structure of the brain.

    These scans are used across scan 1, scan 2, and scan 3 to measure changes in brain connectivity.

  3. Step 3

    Measurement of brain connectivity changes

    From the MRI images, the study measures resting-state network functional connectivity, which means how strongly different brain areas communicate with each other while the brain is at rest.

    The study uses a brain model to calculate beta values from the images. A beta value is a number used to describe the size of a measured change.

    Changes in these beta values that are statistically significant are considered relevant to the study results.

  4. Step 4

    Study completion

    The trial ends after the planned imaging assessments and treatment comparisons are completed during the study period.

    The study compares the results from patients who received psilocybine + pimavanserin with those from patients who received psilocybine + placebo.

Who can join the trial?

7 criteria

  • Be an adult between 18 and 65 years old.
  • Have a diagnosis of major depressive disorder that is non-psychotic, meaning there are no psychotic symptoms such as losing touch with reality or having hallucinations.
  • Be experiencing a current major depressive episode, meaning a current period of depression that meets the study’s clinical definition.
  • Have depression that has been resistant to at least one previous adequate antidepressant treatment, meaning at least one antidepressant medicine was tried at a proper dose and for a proper length of time, but did not work well enough.
  • Have a score of 14 or higher on the 24-HDRS, which is a doctor-rated depression scale used to measure how severe the depression is.
  • Have the legal capacity to give informed consent, meaning the person can understand the study information and is legally able to agree to take part.
  • Personally sign consent to take part in the study.

Who cannot join the trial?

15 criteria

  • Having a current or past severe mental disorder other than the study condition, or a substance use disorder (a pattern of drug or alcohol use that causes problems), except for nicotine dependence.
  • Having any medical reason that makes psilocybin or pimavanserin unsafe to use.
  • Having any medical reason that makes MRI unsafe, such as metal implants or other MRI restrictions.
  • Being pregnant or breastfeeding.
  • Having a history of heart rhythm problems or other heart conditions, or having a QTc value above 450 ms in men or 470 ms in women. QTc is a measure on the heart tracing that shows how the heart resets between beats.
  • Having electrolyte abnormalities, meaning abnormal levels of important minerals in the blood such as sodium, potassium, or magnesium.
  • Taking other medicines during the study that can raise the risk of QTc prolongation (a longer-than-normal heart reset time), such as certain antibiotics, antipsychotics, anti-nausea medicines, or heart rhythm medicines.
  • Having poor kidney function or poor liver function that is clinically important.
  • For people who can become pregnant: having a negative pregnancy test before joining and on the day of joining is required, and using two highly effective forms of birth control, including one barrier method such as a condom, is required throughout the study. If these conditions are not met, the person cannot participate.
  • Not being able to attend all study visits and procedures as planned.
  • Having active suicidal thoughts.
  • Having a first-degree relative (parent, sibling, or child) with a history of any psychotic disorder, which is a mental illness that can affect a person's sense of reality.
  • Having any serious medical condition now or in the past that could create a health risk or make study results harder to interpret.
  • Having had electroconvulsive therapy (a treatment that uses brief electrical stimulation of the brain), esketamine, or any experimental medicine or intervention in the last month, or ever having used serotonergic psychedelic drugs (psychedelic drugs that act on serotonin, a brain chemical).
  • Currently using other medicines or substances that could interfere with the study drugs.
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Investigated drugs

  • Psilocybin

    is the main study drug being tested in this trial. It is taken by mouth as a capsule and is being studied for its possible antidepressant effects in people with major depressive disorder. In this trial, psilocybin is given together with either pimavanserin or a placebo so researchers can see how much of its brain effect is linked to the usual psychedelic experience.

  • Pimavanserin

    is an oral medicine being tested alongside psilocybin. It is used to reduce or block serotonin-related psychedelic effects, so researchers can study whether psilocybin may still have antidepressant effects even when the typical psychedelic experience is lessened. This helps the team compare brain activity and mood changes with and without those psychedelic effects.

What is already known about the treatment

  • Psilocybine

    Psilocybine is taken by mouth as a capsule, and in this trial it is given as a 25 mg dose. It is a hallucinogenic compound that is being studied in medical research for depression and other mental health conditions, although it is not a standard routine medicine for these uses. It is classified as a psychedelic agent, and it works mainly by activating serotonin receptors in the brain, especially the 5-HT2A receptor, which can change brain signaling and mood-related networks.

  • Pimavanserin tartrate

    Pimavanserin tartrate is taken by mouth as a tablet, usually at a 34 mg dose in clinical use and in this study. It is an approved medicine and is mainly used to treat hallucinations and delusions linked to Parkinson’s disease psychosis, and it has also been studied for other mental health conditions. It is classified as an atypical antipsychotic, and it works by blocking the 5-HT2A serotonin receptor in the brain, which can reduce certain unusual thoughts or perceptions without strongly affecting dopamine receptors.

Investigated diseases

Major depressive disorder - Major depressive disorder is a mood disorder marked by persistent sadness or low mood, loss of interest or pleasure, and changes in sleep, appetite, energy, and thinking. It often develops in episodes, with symptoms lasting for weeks or longer. The condition can vary in intensity over time, and some people have repeated episodes separated by periods of improvement.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-521690-14-00Protocol codeIRSP-PSI-2024-171Estimated enrolment60 patientsSponsorFundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

sourced from the EU Clinical Trials Register and site verification

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