A Study of Psilocybin for Major Depressive Disorder (MDD)

March 31, 2026 updated by: Usona Institute

A Randomized, Double-Blind Study of Single-Dose Psilocybin for Major Depressive Disorder (MDD)

One hundred participants, ages 21 to 65, who meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for major depressive disorder (MDD) will be stratified by study site and randomized with a 1-to-1 allocation under double-blind conditions to receive a single 25 mg oral dose of psilocybin or a single 100 mg oral dose of niacin. Niacin will serve as an active placebo.

The purpose of this study is to evaluate the potential efficacy of a single 25 mg oral dose of psilocybin for MDD compared to the active placebo in otherwise medically-healthy participants, assessed as the difference between groups in changes in depressive symptoms from Baseline to Day 43 post-dose.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Major depressive disorder (MDD) has become a health crisis of epidemic proportions in the modern world. One in six individuals in the United States will experience an episode of major depression in his or her lifetime, and it is estimated that major depression will rank second after cardiac disease as a cause of international medical morbidity by the year 2020. Depression is associated with greater disability than are most other chronic illnesses and is a risk factor for mortality. Additionally, depression predicts the later development of a number of medical conditions, including cardiac and cerebrovascular disease, hypertension, diabetes, obesity, metabolic syndrome, dementia, and cancer. Unfortunately, most patients with depression do not experience a complete resolution of symptoms with antidepressant treatment. Partial-but incomplete-response to antidepressants is associated with an increased risk of full symptomatic relapse (even when on therapy) and a worse long-term disease course. Combined with the high prevalence and significant disability associated with MDD, the fact that currently available treatments are not fully adequate highlights the tremendous need to identify novel treatment strategies.

Data suggest that psilocybin may have behavioral effects relevant to the treatment of depression and recent studies also suggest that psilocybin may possess antidepressant properties. To further assess the effects of psilocybin on MDD signs and symptoms, this trial will enroll 100 participants, ages 21 to 65, who meet criteria for MDD. Participants will be stratified by study site and randomized with a 1-to-1 allocation under double-blind conditions to receive a single 25 mg oral dose of psilocybin or a single 100 mg oral dose of niacin. Niacin will serve as an active placebo.

To enhance participant safety, a Set and Setting (SaS) protocol will be utilized similar to the protocol that has been used in all modern studies of psilocybin. The SaS protocol for this study includes: 1) a period of preparation with session Facilitators prior to dosing; 2) administration of study medications in an aesthetically pleasing room under the supervision of two Facilitators who are present throughout the session; and 3) three post-dose integration sessions during which participants are encouraged to discuss their intervention experience with the Facilitators. The SaS protocol will be identical for those randomized to psilocybin or active placebo.

The primary objective of this study is to evaluate the potential efficacy of a single 25 mg oral dose of psilocybin for MDD compared to the active placebo (niacin), assessed as the difference between groups in changes in depressive symptoms from Baseline to Day 43 post-dose.

Study Type

Interventional

Enrollment (Actual)

347

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94121
        • University of California, San Francisco
      • Santa Monica, California, United States, 91404
        • Pacific Neuroscience Institute
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Yale University
    • Florida
      • Lauderhill, Florida, United States, 33319
        • Segal Trials
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University
    • Illinois
      • Chicago, Illinois, United States, 60640
        • Great Lakes Clinical Trials
    • Maryland
      • Baltimore, Maryland, United States, 21229
        • Johns Hopkins University
    • New Jersey
      • Berlin, New Jersey, United States, 08009
        • Hassman Research Institute
    • New York
      • New York, New York, United States, 10016
        • New York University School of Medicine
    • Utah
      • Draper, Utah, United States, 84020
        • Cedar Clinical Research
    • Wisconsin
      • Madison, Wisconsin, United States, 53706
        • University of Wisconsin - Madison

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 21 to 65 years old
  • Able to swallow capsules
  • If of childbearing potential, agree to practice an effective means of birth control throughout the duration of the study
  • Have an identified support person and agree to be accompanied home by that person following dosing
  • Have sustained moderate-severe depression symptoms at Screening and Baseline
  • Meet DSM-5 criteria for a diagnosis of major depressive disorder and are currently experiencing a major depressive episode of at least a 60-day duration at the time of screening

Exclusion Criteria:

  • Women who are pregnant or who intend to become pregnant during the study or who are currently nursing
  • Have any of the following cardiovascular conditions: uncontrolled hypertension, coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction, tachycardia, artificial heart valve, a clinically significant screening ECG abnormality, or any other significant cardiovascular condition
  • Have a history of stroke or Transient Ischemic Attack (TIA)
  • Have moderate to severe hepatic impairment
  • Have epilepsy
  • Have insulin-dependent diabetes
  • Have a positive urine drug test
  • Nicotine dependence that would disallow an individual to be nicotine free for the 7-10 hours during the dosing period
  • Meet DSM-5 criteria for schizophrenia spectrum or other psychotic disorders, including major depressive disorder with psychotic features, or Bipolar I or Bipolar II Disorder
  • Meet DSM-5 criteria for antisocial personality disorder
  • Meet DSM-5 criteria for a moderate or severe alcohol or drug use disorder

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Psilocybin
Participants will receive a single 25 mg dose of psilocybin along with the Set and Setting (SaS) protocol. Psilocybin is administered orally as a capsule and taken with water.
Drug: Psilocybin
The psilocybin used in this study is synthetically manufactured in a laboratory and meets quality specifications suitable for human research use. The active drug is encapsulated using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of psilocybin.
Other Names:
  • Psilocybine, Psilocibin, Indocybin
Other: Set and Setting (SaS) Protocol
The SaS Protocol prescribes 6-8 hours of preparatory meetings with two facilitators prior to dosing, a 7-10 hour dosing session in a comfortable room under the supervision of the same two facilitators, and 4 hours of post-dose integration sessions with facilitators. During the dosing session participants are encouraged to wear eyeshades and listen to a curated playlist on headphones.
Active Comparator: Niacin
Participants will receive a single 100 mg dose of niacin along with the Set and Setting (SaS) protocol. Niacin is administered orally as a capsule and taken with water.
Drug: Niacin
The active placebo is encapsulated using a HPMC capsule and contains 100 mg of pharmaceutical grade niacin.
Other Names:
  • Vitamin B3
Other: Set and Setting (SaS) Protocol
The SaS Protocol prescribes 6-8 hours of preparatory meetings with two facilitators prior to dosing, a 7-10 hour dosing session in a comfortable room under the supervision of the same two facilitators, and 4 hours of post-dose integration sessions with facilitators. During the dosing session participants are encouraged to wear eyeshades and listen to a curated playlist on headphones.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Central Rater Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Post-dose Day 43
Time Frame: Baseline; Day 43 post-dose
The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total score range of 0-60. Higher scores represent a more severe condition. The total (composite) MADRS score is used as the endpoint.
Baseline; Day 43 post-dose

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Central Rater MADRS Score From Baseline to Post-dose Day 8
Time Frame: Baseline; Day 8 post-dose
The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The total (composite) MADRS score is used as the endpoint.
Baseline; Day 8 post-dose
Change in On-site Rater Administered Sheehan Disability Scale (SDS) Score From Baseline to Post-dose Day 43
Time Frame: Baseline; Day 43 post-dose
The SDS consists of three self-rated items designed to measure the extent to which three major domains in the patient's life are impaired by psychiatric symptoms, including depression. The SDS Mean score is calculated as the mean of three items (work/school, social life, family life/home responsibilities), each scored 0 to 10. Mean score range: 0 to 10. Higher scores indicate greater functional impairment.
Baseline; Day 43 post-dose
Sustained Depressive Symptom Response Defined as a ≥ 50% Reduction From Baseline Central Rater MADRS Score at All Post-dose Assessments
Time Frame: Day 8, 15, 29, and 43 post-dose
Sustained depressive symptom response defined as ≥50% reduction from Baseline central-rater MADRS total score at all of the following post-dose assessments: Day 8, Day 15, Day 29, and Day 43. Participants who did not meet the criterion at all four timepoints were classified as non-responders. MADRS total score range: 0 to 60; higher scores indicate more severe depression.
Day 8, 15, 29, and 43 post-dose
Sustained Depressive Symptom Remission Defined as a Central Rater Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score ≤ 10 at All Post-dose Assessments
Time Frame: Day 8, 15, 29, and 43 post-dose
Sustained depressive symptom remission defined as a central-rater MADRS total score ≤ 10 at all of the following post-dose assessments: Day 8, Day 15, Day 29, and Day 43. Participants missing a MADRS assessment at any post-dose timepoint were excluded from this analysis. MADRS total score range: 0 to 60; higher scores indicate more severe depression.
Day 8, 15, 29, and 43 post-dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Usona Institute

Collaborators

The Emmes Company, LLC

Investigators

  • Study Director: Charles Raison, MD, Usona Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 23, 2020

Primary Completion (Actual)

June 28, 2022

Study Completion (Actual)

June 28, 2022

Study Registration Dates

First Submitted

March 5, 2019

First Submitted That Met QC Criteria

March 5, 2019

First Posted (Actual)

March 7, 2019

Study Record Updates

Last Update Posted (Actual)

April 22, 2026

Last Update Submitted That Met QC Criteria

March 31, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PSIL201

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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