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Depressive Disorder, MajorPhase 2NCT03866174

A Study of Psilocybin for Major Depressive Disorder (MDD)

A Phase 2 study testing Psilocybin, Niacin and Set and Setting (SaS) Protocol in people with Depressive Disorder, Major, run by Usona Institute at 11 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 21 to 65 years
Conditions the study is for
Depressive Disorder, Major
What is being tested?
Psilocybin, Niacin and Set and Setting (SaS) Protocol
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
347 participants
Where
11 sitesUnited States
Study dates
23 Jan 2020to 28 Jun 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

United States11 sites

  • Emory University

    Atlanta, Georgia, 30322

  • Johns Hopkins University

    Baltimore, Maryland, 21229

  • Hassman Research Institute

    Berlin, New Jersey, 08009

  • Great Lakes Clinical Trials

    Chicago, Illinois, 60640

  • Cedar Clinical Research

    Draper, Utah, 84020

  • Segal Trials

    Lauderhill, Florida, 33319

  • University of Wisconsin - Madison

    Madison, Wisconsin, 53706

  • Yale University

    New Haven, Connecticut, 06520

  • New York University School of Medicine

    New York, New York, 10016

  • University of California, San Francisco

    San Francisco, California, 94121

  • Pacific Neuroscience Institute

    Santa Monica, California, 91404

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
Psilocybin, Niacin, Set and Setting (SaS) Protocol
Keywords
Psilocybin, Psychedelics, Depression, MDD
Medical subject headings
Depressive Disorder, Major, Depression

What participants receive

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

  • PsilocybinDrug

    Also called Psilocybine, Psilocibin, Indocybin

    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.

  • NiacinDrug

    Also called Vitamin B3

    The active placebo is encapsulated using a HPMC capsule and contains 100 mg of pharmaceutical grade niacin.

  • Set and Setting (SaS) ProtocolOther

    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.

Study groups in NCT03866174
Study groupRoleWhat they receive
PsilocybinExperimentalParticipants 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.
Receives: Drug: Psilocybin; Other: Set and Setting (SaS) Protocol
NiacinActive comparatorParticipants 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.
Receives: Drug: Niacin; Other: Set and Setting (SaS) Protocol

What is being measured

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

  1. Change in Central Rater Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Baseline to Post-dose Day 43

    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.

    Measured: Baseline; Day 43 post-dose

Secondary outcomes (4)

  1. Change in Central Rater MADRS Score From Baseline to Post-dose Day 8

    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.

    Measured: Baseline; Day 8 post-dose

  2. Change in On-site Rater Administered Sheehan Disability Scale (SDS) Score From Baseline to Post-dose Day 43

    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.

    Measured: Baseline; Day 43 post-dose

  3. Sustained Depressive Symptom Response Defined as a ≥ 50% Reduction From Baseline Central Rater MADRS Score at All Post-dose Assessments

    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.

    Measured: Day 8, 15, 29, and 43 post-dose

  4. Sustained Depressive Symptom Remission Defined as a Central Rater Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score ≤ 10 at All Post-dose Assessments

    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.

    Measured: Day 8, 15, 29, and 43 post-dose

Timeline

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

  1. First posted7 Mar 2019
  2. Study start23 Jan 2020
  3. Primary completion28 Jun 2022
  4. Study completion28 Jun 2022

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
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
347 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03866174
Sponsor's protocol ID
PSIL201
Status last verified
Mar 2026
First submitted
5 Mar 2019
Last updated
22 Apr 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Carhart-Harris RL, Leech R, Hellyer PJ, Shanahan M, Feilding A, Tagliazucchi E, Chialvo DR, Nutt D. The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci. 2014 Feb 3;8:20. doi: 10.3389/fnhum.2014.00020. eCollection 2014.

    PubMed 24550805

  • Nichols DE. Hallucinogens. Pharmacol Ther. 2004 Feb;101(2):131-81. doi: 10.1016/j.pharmthera.2003.11.002.

    PubMed 14761703

  • Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS; National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003 Jun 18;289(23):3095-105. doi: 10.1001/jama.289.23.3095.

    PubMed 12813115

  • Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Aug 22;386(9995):743-800. doi: 10.1016/S0140-6736(15)60692-4. Epub 2015 Jun 7.

    PubMed 26063472

  • Wulsin LR, Vaillant GE, Wells VE. A systematic review of the mortality of depression. Psychosom Med. 1999 Jan-Feb;61(1):6-17. doi: 10.1097/00006842-199901000-00003.

    PubMed 10024062

  • Joynt KE, Whellan DJ, O'Connor CM. Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiatry. 2003 Aug 1;54(3):248-61. doi: 10.1016/s0006-3223(03)00568-7.

    PubMed 12893101

  • Thomas AJ, Kalaria RN, O'Brien JT. Depression and vascular disease: what is the relationship? J Affect Disord. 2004 Apr;79(1-3):81-95. doi: 10.1016/S0165-0327(02)00349-X.

    PubMed 15023483

  • Davidson K, Jonas BS, Dixon KE, Markovitz JH. Do depression symptoms predict early hypertension incidence in young adults in the CARDIA study? Coronary Artery Risk Development in Young Adults. Arch Intern Med. 2000 May 22;160(10):1495-500. doi: 10.1001/archinte.160.10.1495.

    PubMed 10826464

  • Jonas BS, Lando JF. Negative affect as a prospective risk factor for hypertension. Psychosom Med. 2000 Mar-Apr;62(2):188-96. doi: 10.1097/00006842-200003000-00006.

    PubMed 10772396

  • Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE. Depression and risk for onset of type II diabetes. A prospective population-based study. Diabetes Care. 1996 Oct;19(10):1097-102. doi: 10.2337/diacare.19.10.1097.

    PubMed 8886555

  • Kawakami N, Takatsuka N, Shimizu H, Ishibashi H. Depressive symptoms and occurrence of type 2 diabetes among Japanese men. Diabetes Care. 1999 Jul;22(7):1071-6. doi: 10.2337/diacare.22.7.1071.

    PubMed 10388970

  • Barefoot JC, Heitmann BL, Helms MJ, Williams RB, Surwit RS, Siegler IC. Symptoms of depression and changes in body weight from adolescence to mid-life. Int J Obes Relat Metab Disord. 1998 Jul;22(7):688-94. doi: 10.1038/sj.ijo.0800647.

    PubMed 9705031

  • Pine DS, Goldstein RB, Wolk S, Weissman MM. The association between childhood depression and adulthood body mass index. Pediatrics. 2001 May;107(5):1049-56. doi: 10.1542/peds.107.5.1049.

    PubMed 11331685

  • Raikkonen K, Matthews KA, Kuller LH. The relationship between psychological risk attributes and the metabolic syndrome in healthy women: antecedent or consequence? Metabolism. 2002 Dec;51(12):1573-7. doi: 10.1053/meta.2002.36301.

    PubMed 12489070

  • Jorm AF. History of depression as a risk factor for dementia: an updated review. Aust N Z J Psychiatry. 2001 Dec;35(6):776-81. doi: 10.1046/j.1440-1614.2001.00967.x.

    PubMed 11990888

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Psilocybin, Niacin and Set and Setting (SaS) Protocol in people with Depressive Disorder, Major, run by Usona Institute at 11 sites 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 6 inclusion and 11 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: finished, as of the sponsor's last update on 22 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites 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. 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?

Yes. Results are posted in the registry (first posted 22 Apr 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). 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 NCT03866174, which also lists 26 linked publications.

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 22 Apr 2026.

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