A Study of Psilocybin for Major Depressive Disorder (MDD)

NCT03866174 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: PSIL201
• Study Type: interventional
• Target: 347
• Locations: 1 country
• Sites: 11

Brief 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 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.

Conditions

Depressive Disorder, Major

Keywords

Psilocybin, Psychedelics, Depression, MDD

Outcome Measures

Primary Outcomes (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.

  Baseline; Day 43 post-dose

Secondary Outcomes (4)

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

  Baseline; Day 8 post-dose

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

  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

  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

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

Study Arms (2)

Psilocybin

EXPERIMENTAL

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; Other: Set and Setting (SaS) Protocol

Niacin

ACTIVE COMPARATOR

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; Other: Set and Setting (SaS) Protocol

Interventions

Psilocybin DRUG

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.

Also known as: Psilocybine, Psilocibin, Indocybin

Psilocybin

Niacin DRUG

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

Also known as: Vitamin B3

Niacin

Set and Setting (SaS) Protocol OTHER

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.

Niacin; Psilocybin

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Usona Institute: lead
• The Emmes Company, LLC: collaborator

Study Sites (11)

University of California, San Francisco

San Francisco, California, 94121, United States

Location

Pacific Neuroscience Institute

Santa Monica, California, 91404, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Segal Trials

Lauderhill, Florida, 33319, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Great Lakes Clinical Trials

Chicago, Illinois, 60640, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21229, United States

Location

Hassman Research Institute

Berlin, New Jersey, 08009, United States

Location

New York University School of Medicine

New York, New York, 10016, United States

Location

Cedar Clinical Research

Draper, Utah, 84020, United States

Location

University of Wisconsin - Madison

Madison, Wisconsin, 53706, United States

Location

Related Publications (26)

• 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.

  PMID: 24550805 BACKGROUND

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

  PMID: 14761703 BACKGROUND

• 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.

  PMID: 12813115 BACKGROUND

• 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.

  PMID: 26063472 BACKGROUND

• 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.

  PMID: 10024062 BACKGROUND

• 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.

  PMID: 12893101 BACKGROUND

• 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.

  PMID: 15023483 BACKGROUND

• 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.

  PMID: 10826464 BACKGROUND

• 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.

  PMID: 10772396 BACKGROUND

• 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.

  PMID: 8886555 BACKGROUND

• 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.

  PMID: 10388970 BACKGROUND

• 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.

  PMID: 9705031 BACKGROUND

• 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.

  PMID: 11331685 BACKGROUND

• 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.

  PMID: 12489070 BACKGROUND

• 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.

  PMID: 11990888 BACKGROUND

• Spiegel D, Giese-Davis J. Depression and cancer: mechanisms and disease progression. Biol Psychiatry. 2003 Aug 1;54(3):269-82. doi: 10.1016/s0006-3223(03)00566-3.

  PMID: 12893103 BACKGROUND

• Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:26-31.

  PMID: 11480881 BACKGROUND

• Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL, Leon AC, Mueller TI, Rice JA, Keller MB. A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry. 1998 Aug;55(8):694-700. doi: 10.1001/archpsyc.55.8.694.

  PMID: 9707379 BACKGROUND

• Miller IW, Keitner GI, Schatzberg AF, Klein DN, Thase ME, Rush AJ, Markowitz JC, Schlager DS, Kornstein SG, Davis SM, Harrison WM, Keller MB. The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry. 1998 Nov;59(11):608-19. doi: 10.4088/jcp.v59n1108.

  PMID: 9862607 BACKGROUND

• Simon GE. Long-term prognosis of depression in primary care. Bull World Health Organ. 2000;78(4):439-45.

  PMID: 10885162 BACKGROUND

• Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016 Jul;3(7):619-27. doi: 10.1016/S2215-0366(16)30065-7. Epub 2016 May 17.

  PMID: 27210031 BACKGROUND

• Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.

  PMID: 27909165 BACKGROUND

• Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016 Dec;30(12):1165-1180. doi: 10.1177/0269881116675512.

  PMID: 27909164 BACKGROUND

• Raison CL, Sanacora G, Woolley J, Heinzerling K, Dunlop BW, Brown RT, Kakar R, Hassman M, Trivedi RP, Robison R, Gukasyan N, Nayak SM, Hu X, O'Donnell KC, Kelmendi B, Sloshower J, Penn AD, Bradley E, Kelly DF, Mletzko T, Nicholas CR, Hutson PR, Tarpley G, Utzinger M, Lenoch K, Warchol K, Gapasin T, Davis MC, Nelson-Douthit C, Wilson S, Brown C, Linton W, Ross S, Griffiths RR. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023 Sep 5;330(9):843-853. doi: 10.1001/jama.2023.14530.

  PMID: 37651119 DERIVED

• Penn A, Dorsen CG, Hope S, Rosa WE. Psychedelic-Assisted Therapy: Emerging Treatments in Mental Health Disorders. Am J Nurs. 2021 Jun 1;121(6):34-40. doi: 10.1097/01.NAJ.0000753464.35523.29.

  PMID: 33993135 DERIVED

• Greenway KT, Garel N, Goyette N, Turecki G, Richard-Devantoy S. Adjunctive music improves the tolerability of intravenous ketamine for bipolar depression. Int Clin Psychopharmacol. 2021 Jul 1;36(4):218-220. doi: 10.1097/YIC.0000000000000363.

  PMID: 33902087 DERIVED

Related Links

• World Health Organization Overview of Depression

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Psilocybin; Niacin; Niacinamide; SET protein, human; Clinical Protocols

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Nicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Therapeutics; Epidemiologic Study Characteristics; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Sofiya Hupalo
• Organization: Usona Institute

sofiya.hupalo@usonainstitute.org

608-210-5955

Study Officials

• Charles Raison, MD

  Usona Institute

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2019
• First Posted: March 7, 2019
• Study Start: January 23, 2020
• Primary Completion: June 28, 2022
• Study Completion: June 28, 2022
• Last Updated: April 22, 2026
• Results First Posted: April 22, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)