5-HT2A Agonist Psilocybin in the Treatment of Tobacco Use Disorder

NCT ID: NCT05452772

Last Updated: 2025-07-29

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-11-01
• Study Completion Date: 2027-05-31

Brief Summary

This is a multi-site, double-blind, randomized clinical trial of the 5-HT2A receptor agonist psilocybin for smoking cessation. Four sites with experience in conducting psilocybin research will be involved in this trial: Johns Hopkins University (JHU), the University of Alabama at Birmingham (UAB), and New York University (NYU). The proposed study will treat 66 participants (22 at each site), randomized to receive either: 1) oral psilocybin (30 mg in session 1 and either 30 mg or 40 mg in session 2); or 2) oral niacin (150 mg in session 1 and either 150 mg or 200 mg in session 2), with sessions 1 week apart.

Detailed Description

This is a multi-site, double-blind, randomized clinical trial of the 5-HT2A receptor agonist psilocybin for smoking cessation. The investigators previously conducted an open-label pilot trial (N = 15) of psilocybin paired with cognitive behavior therapy (CBT). Data showed a biologically-verified 7-day point-prevalence abstinence rate of 67% at 12 months and 60% at 2.5 years (continuous abstinence rates: 53% and 47%, respectively). The investigators are now conducting an open-label randomized comparative efficacy trial of psilocybin vs. nicotine patch, both in combination with CBT. Interim results (N = 44; 22 per group) show greater biologically-verified abstinence rates at 12 months for psilocybin: 7-day point-prevalence: 59% vs. 27%; continuous abstinence: 36% vs. 9%. Despite these promising findings, the investigators have yet to conduct a double-blind study of psilocybin for smoking cessation. Furthermore, previous psilocybin study samples have been largely White with higher socioeconomic status (SES). The current trial will address these issues across four sites with experience in conducting psilocybin research: Johns Hopkins, the University of Alabama at Birmingham (UAB), and New York University (NYU). A diverse sample with regard to ethno-racial identity and SES will be recruited at each site. The proposed double-blind study will treat 66 participants (22 at each site), randomized to receive either: 1) psilocybin; 30 mg in session 1 and either 30 or 40 mg in session 2, with sessions 1 week apart; or 2) niacin; 150 mg in session 1 and either 150 mg or 200 mg in session 2, with sessions 1 week apart. Niacin was selected because it has been used as an active placebo in two previous randomized therapeutic trials of psilocybin, and the FDA has informed the investigators that niacin is the FDA's preferred active placebo for psilocybin. CBT will be administered to both groups and will allow the investigators to test psilocybin's efficacy above and beyond an established treatment approach. Biochemically-confirmed 7-day point-prevalence abstinence will be assessed throughout for up to 12 months. The investigators hypothesize that psilocybin (compared to niacin) will cause increased biologically-confirmed 7-day point-prevalence abstinence at 12-month follow-up. Based on pilot data, the investigators will test cognitive/psychological mediators of treatment response. The investigators hypothesize that psilocybin will be associated with improved cognitive control and decreased anticipation of withdrawal relief (from smoking) 1 day after the target quit date, which will be associated with greater 7-day point-prevalence abstinence at 12- month follow-up. This trial will provide a rigorous test of efficacy in a diverse study sample, and test relevant mechanisms, for an innovative smoking cessation treatment showing potential for substantial efficacy.

Conditions

Tobacco Use Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Psilocybin

30 mg in session 1 and either 30 mg or 40 mg in session 2, with sessions 1 week apart. Dosing will be based on participants' responses to the Mystical Experiences Questionnaire (MEQ30), taken at the end of their first session. Participants with a score ≥60% of the maximum on the MEQ30 will remain at a dose of 30 mg of psilocybin for the second session. Participants with an MEQ30 score below 60% will receive a dose of 40 mg for the second session.

Group Type: ACTIVE_COMPARATOR

Psilocybin

Intervention Type: DRUG

Participants will received two psilocybin sessions, 1 week apart

Niacin

150 mg in session 1 and either 150 mg or 200 mg in session 2, with sessions 1 week apart. Dosing will be based on participants' responses to the Mystical Experiences Questionnaire (MEQ30), taken at the end of their first session. Participants with a score ≥60% of the maximum on the MEQ30 will remain at a dose of 150 mg niacin for the second session. Participants with an MEQ30 score below 60% will receive a dose of 200 mg niacin for the second session.

Group Type: ACTIVE_COMPARATOR

Niacin

Intervention Type: DRUG

Participants will received two niacin sessions, 1 week apart

Interventions

Psilocybin

Participants will received two psilocybin sessions, 1 week apart

Intervention Type: DRUG

Niacin

Participants will received two niacin sessions, 1 week apart

Intervention Type: DRUG

Other Intervention Names

Active Experimental Group; Active Comparator Group

Eligibility Criteria

Inclusion Criteria

• 21 years old or older
• Be a daily smoker (minimum of 5 cigarettes/day on a typical day and breath CO of 6 or greater at screening) with multiple unsuccessful previous quit attempts, and report a continued desire to quit smoking
• Read, write, and speak English
• Agree to abstain from smoking for the psilocybin/niacin session from 1 hour before psilocybin/niacin administration until at least 8 hours afterward
• Agree to refrain from using any psychoactive drugs, including alcoholic beverages, within 24 hours of psilocybin/niacin administration

Exclusion Criteria

• The use of e-cigarettes or tobacco products other than machine-manufactured combustible cigarettes (e.g., cigarillos) on more than 5 of the previous 30 days
• Women who are pregnant (positive pregnancy test) or nursing, or are not practicing an effective means of birth control
• Positive urine drug screen for illicit drugs (excluding cannabis)
• Positive urine breath test for alcohol. Participants with positive tests will be rescheduled
• For blood samples, the following lab values will be exclusionary: transaminases greater than x2 the upper limit of normal lab reference range, hemoglobin less than 11 g/d, and creatinine clearance < 40 ml/min using the Cockroft-Gault equation.
• For ECG screening: The ECG will be read by a cardiologist. Corrected heart rate (QTc) greater than 450 msec will be excluded.
• Patients who have baseline vital signs that exceed the following measurements will be excluded from participation: Systolic blood pressure (SBP) > 139 mmHG, diastolic blood pressure (DBP)> 89 mmHG, and heart rate of <=95 beats per minute (BPM). The investigators will perform serial heart rate monitoring with 3 total attempts. That is, heart rate must be <=95 bpm on one of these attempts to be included in the study.
• Currently taking on a regular basis (e.g., daily) antidepressants of any drug class, antipsychotics, or monoamine oxidase inhibitors (MAOIs), or serotonin-acting dietary supplements (e.g., 5-hydroxy- tryptophan, St. John's wort). Currently taking efavirenz, Acetaldehyde dehydrogenase inhibitors such as disulfiram (Antabuse), Alcohol dehydrogenase inhibitors, or uridine diphosphate glucuronosyltransferase 1-9 (UGT1A9) inhibitors or uridine diphosphate glucuronosyltransferase 1-10 (UGT1A10) inhibitors such as phenytoin, regorafenib, eltrombopag. For individuals who have intermittent or "as needed" use of such medications, psilocybin sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose
• Current use of medications for smoking cessation (i.e., varenicline, nicotine replacement products, bupropion)
• Current neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of significant head trauma (loss of consciousness > 24 hours), or central nervous system (CNS) tumor
• Recent (within the past 12 months) or an extensive history of psychedelic use (>20 lifetime uses)
• Current or past history of meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), or Bipolar I or II Disorder. Current or past history within the last 5 years of meeting DSM-5 criteria for alcohol or drug use disorder (excluding caffeine and nicotine) or severe major depression
• Recent (past year) history of suicidal behavior or attempt or high-level current suicidal ideation assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)
• Have a first- or second-degree relative with schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), or bipolar I or II disorder
• Currently meets DSM-5 criteria for Dissociative Disorder, Anorexia Nervosa, Bulimia Nervosa, Major Depression, or Post-traumatic Stress Disorder

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Alabama at Birmingham

OTHER

Sponsor Role: collaborator

New York University

OTHER

Sponsor Role: collaborator

National Institute on Drug Abuse (NIDA)

NIH

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Matthew Johnson, Ph.D

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status: RECRUITING

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

Site Status: RECRUITING

New York University

New York, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Matthew Johnson, Ph.D

Role: CONTACT

mwj@jhu.edu

410-550-0056

Gideon Naudé, Ph.D.

Role: CONTACT

gnaude1@jhmi.edu

410-550-2774

Facility Contacts

Seher Premani, M.P.H.

Role: primary

spremani@uab.edu

205-975-7721

Lindsey Owens, M.A.

Role: backup

ltowens@uab.edu

205-975-7721

Hadi Zaki, B.S.

Role: primary

hzaki1@jhmi.edu

443-291-9154

Samantha Khan, M.P.H

Role: primary

Samantha.Khan2@nyulangone.org

646-501-4199

Denise Balili, M.S.

Role: backup

denise.balili@nyulangone.org

646-501-2623

References

Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011 Jan;68(1):71-8. doi: 10.1001/archgenpsychiatry.2010.116. Epub 2010 Sep 6.

Reference Type: BACKGROUND

PMID: 20819978 (View on PubMed)

Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014 Nov;28(11):983-92. doi: 10.1177/0269881114548296. Epub 2014 Sep 11.

Reference Type: BACKGROUND

PMID: 25213996 (View on PubMed)

Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse. 2017 Jan;43(1):55-60. doi: 10.3109/00952990.2016.1170135. Epub 2016 Jul 21.

Reference Type: BACKGROUND

PMID: 27441452 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27909164 (View on PubMed)

Other Identifiers

U01DA052174

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB00326148

Identifier Type: -

Identifier Source: org_study_id