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Major Depressive DisorderPhase 2NCT06592833

Psilocybin With Pimavanserin Compared to Psilocybin Alone for the Treatment of Major Depressive Disorder

A Phase 2 study testing Psilocybin and Pimavanserin in people with Major Depressive Disorder, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

This is an interventional, parallel arm assignment treatment study in individuals with Major Depressive Disorder (MDD). Each individual will be treated with a single dose of pimavanserin or placebo plus a single dose of psilocybin. Read more about this study

Who is it for?
Ages 21 to 80 years
Conditions the study is for
Major Depressive Disorder
What is being tested?
Psilocybin and Pimavanserin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
60 participants
Where
1 siteUnited States
Study dates
25 Feb 2025to Apr 2029
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age 21-80 years, any gender
  • Current primary diagnosis of Unipolar Major Depressive Disorder (MDD) without psychotic features using DSM-5 criteria
  • 24-item Hamilton Rating Scale for Depression (HRSD) ≥16
  • Current diagnosis of Major Depressive Episode (MDE)
  • Capable of providing informed consent and complying with study procedures
  • Currently using or agreeing to use a highly effective contraception, if person of childbearing potential (such as condoms, IUD, or oral contraceptive), for duration of the study. Male participants agree to use highly effective contraception with partners of childbearing potential
  • Discontinuation of any serotonergic drug for at least 2 weeks or 5 half-lives (whichever of the two is longer) prior to psilocybin exposure

Who cannot join

  • Any severity of substance use disorder in the last 6 months (excluding tobacco use disorder) as determined by DSM-V criteria via the SCID
  • Current psychiatric hospitalization or psychiatric hospitalization within the last 6 months
  • Use of psychedelics in the last 12 months
  • Non-medical or illicit use of ketamine in the past 12 months
  • Negative reaction after prior use of psychedelics
  • Past or current psychotic disorder (including psychotic MDD), mania, or bipolar disorder
Show all 33Show fewer
  • Severe depression as indicated by Clinical Global Impressions (CGI)-Severity score ≥ 5 at baseline
  • Significant suicidal ideation as indicated by C-SSRS > 2 in the past 6 months at time of screening
  • Suicide attempt in the past 2 years, or clinician concern that the patient poses a risk to self or others
  • Acute, severe, or unstable medical illness
  • Weight > 300 lbs., or girth size incompatible with scanner bore
  • Any conditions/qualities that make participation in MRI imaging unsafe*
  • Any physical or intellectual disability adversely affecting ability to complete assessments.
  • Current pregnancy or currently breast feeding.
  • Any clinically significant abnormal lab test result, including clinically significant abnormal baseline liver and/or renal function tests
  • Currently being treated with a contraindicated medication. Contraindicated medications include antipsychotic medications, serotonergic antidepressant medications, and mood stabilizers that may attenuate the effects of psilocybin. Strong CYP3A4 inhibitors and inducers are also contraindicated. UGT1A9 and UGT1A10 inhibitors, monoamine oxidase, and aldehyde or alcohol dehydrogenase inhibitors are prohibited concomitant medications.
  • History of abnormal QT prolongation or QTc interval >450 ms on screening
  • Use of medications known to prolong the QT interval
  • Any congenital prolongation of the QT interval or a family history of long QT syndrome
  • A family history of sudden cardiac or unexplained death
  • A family history in a first-degree relative of psychosis/schizophrenia or related disorders
  • A first-degree family history of bipolar disorder
  • A history of cardiac arrhythmias or who require treatment with an antiarrhythmic medication
  • A history of any cardiovascular disorder/condition known to increase the possibility of QT prolongation, or any other risk factors for prolonged QT interval/torsades de pointes (including symptomatic bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, heart failure, or Brugada Syndrome)
  • Preexisting cardiovascular conditions, including cardiac valvulopathy, pulmonary hypertension, hypertension, tachycardia, and any cardiovascular conditions that may be worsened/exacerbated by elevated blood pressure or heart rate.
  • Baseline vital sign parameters at screening and on day of dosing prior to dose that exceed to the following values for systolic blood pressure (SBP), diastolic (DBP), and heart rate (HR): SBP > 139 mmHg, DBP 89 mmHg, and HR > 90 bpm
  • Hypersensitivity to either psilocybin or pimavanserin
  • Psychiatric or other condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin
  • Positive urine toxicology at screening
  • Any clinically significant abnormalities on 12-lead electrocardiogram (ECG)
  • Mini-Mental State Examination (MMSE) score < 25
  • Brief Psychiatric Rating Scale (BPRS-6) > 5
  • Potential fall risk

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Depression and Anxiety Center Icahn School of Medicine at Mount Sinai contact

(212) 241-6539

dac@mssm.edu

United States1 site, 1 recruiting

  • Icahn School of Medicine at Mount Sinai, Center for Psychedelic Therapy Research

    New York, New York, 10025

    Depression and Anxiety Center, (212) 241-6539, dac@mssm.edu

    James Murrough

    Recruiting

Other trials in United States

About this study

Official title: Investigating the Role of Serotonin in the Mechanism of Action of Psilocybin in Patients With Major Depressive Disorder

This is an interventional, parallel arm assignment treatment study in individuals with Major Depressive Disorder (MDD). Each individual will be treated with a single dose of pimavanserin or placebo plus a single dose of psilocybin. Evaluations will be taken before dosing and following dosing at several timepoints up to 5 weeks post-dosing.

Read the detailed description

In this study, the researchers want to probe the role of the 5-HT2A receptor in mediating the subjective effects of psilocybin. While previous studies have shown that blockage of the 5-HT2A receptor reduces the psychedelic experience in humans, an animal study revealed that blockage of the 5- HT2A receptor abolished the psychedelic effects without affecting the antidepressant response. This suggests that the pathway responsible for the antidepressant response is dissociated from the psychedelic experience pathway, which is mediated by 5-HT2A signaling.

Being tested
Psilocybin, Pimavanserin, Placebo
Medical subject headings
Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PsilocybinDrug

    Psilocybin, 25mg, given once orally.

  • PimavanserinDrug

    Also called Nuplazid

    Pimavanserin, 34mg, given once orally

  • PlaceboDrug

    Matching placebo.

Study groups in NCT06592833
Study groupRoleWhat they receive
Psilocybin + PimavanserinActive comparatorsingle dose Psilocybin and single dose Pimavanserin
Receives: Drug: Psilocybin; Drug: Pimavanserin
Psilocybin + PlaceboPlacebo comparatorsingle dose Psilocybin and single dose Placebo
Receives: Drug: Psilocybin; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Mystical Experience Questionnaire (MEQ-30) Score

    Acute subjective effects of psilocybin measured by the Mystical Experience Questionnaire (MEQ-30). Full Scale ranges from 0 to 150, with higher scores indicating more mystical experience.

    Measured: 6 hours post-treatment

Secondary outcomes (1)

  1. Montgomery-Åsberg Depression Rating Scale (MADRS) Score

    The Montgomery-Åsberg Depression Rating Scale (MADRS) will be used to measure improvement in depressive symptoms 7 days after dosing. This 10-item clinician-rated scale measures the severity of depressive symptoms. Full scale ranges from 0 to 60, with higher scores indicating more depressive symptoms.

    Measured: 7 days after dosing

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Sep 2024
  2. Study start25 Feb 2025
  3. Primary completionMar 2029 (estimated)
  4. Study completionApr 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06592833
Sponsor's protocol ID
STUDY-23-00855
Status last verified
Nov 2026
First submitted
9 Sep 2024
Last updated
6 Nov 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: Because this study is privately funded, the research team is not required to share IPD.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Psilocybin and Pimavanserin in people with Major Depressive Disorder, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 6 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Depression and Anxiety Center Icahn School of Medicine at Mount Sinai ((212) 241-6539, dac@mssm.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mystical Experience Questionnaire (MEQ-30) Score (time frame: 6 hours post-treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06592833.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2026.

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