A Study of Psilocybin for Major Depressive Disorder (MDD)

Depressive Disorder, Major Clinical Trial

Official title:

A Randomized, Double-Blind, Support-of-Concept Phase 2 Study of Single-Dose Psilocybin for Major Depressive Disorder (MDD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03866174
• Other study ID #: PSIL201
• Status: Completed
• Phase: Phase 2
• Start date: October 15, 2019
• Est. completion date: June 28, 2022

Study information

• Verified date: May 2023
• Source: Usona Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: June 28, 2022
• Est. primary completion date: June 28, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major

Intervention

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

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.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Hassman Research Institute	Berlin	New Jersey
United States	Great Lakes Clinical Trials	Chicago	Illinois
United States	Cedar Clinical Research	Draper	Utah
United States	Segal Trials	Lauderhill	Florida
United States	University of Wisconsin - Madison	Madison	Wisconsin
United States	Yale University	New Haven	Connecticut
United States	New York University School of Medicine	New York	New York
United States	University of California, San Francisco	San Francisco	California
United States	Pacific Neuroscience Institute	Santa Monica	California

Sponsors (2)

Lead Sponsor	Collaborator
Usona Institute	The Emmes Company, LLC

Country where clinical trial is conducted

United States, 

References & Publications (23)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 possible score of 60. Higher scores represent a more severe condition. The total (composite) MADRS score is used as the endpoint.	Baseline; Day 43 post-dose
Secondary	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.	Baseline, Day 8 post-dose
Secondary	Change in on-site rater administered Sheehan Disability Scale (SDS) score from Baseline to post-dose Day 43	The SDS is a composite of three self-rated items designed to measure the extent to which three major sectors in the patient's life are impaired by psychiatric symptoms, including depression.	Day 8, 15, 29, and 43 post-dose
Secondary	Sustained depressive symptom response defined as a = 50% reduction from Baseline central rater MADRS score at all post-dose assessments	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.	Day 8, 15, 29, and 43 post-dose
Secondary	Sustained depressive symptom remission defined as a central rater MADRS total score = 10 at all post-dose assessments	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.	Day 8, 15, 29, and 43 post-dose

External Links

•   World Health Organization Overview of Depression