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

NCT05452772 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: IRB00326148U01DA052174
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 3

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.

Conditions

Tobacco Use Disorder

Keywords

Smoking Cessation; Smoking; Cigarettes; Cigarette Smoking

Outcome Measures

Primary Outcomes (1)

• Potential Efficacy (Smoking Cessation)

  Smoking cessation will be dichotomously coded 7-day point prevalence abstinence at 12-month follow-up. This binary outcome (abstinent versus non-abstinent) will be verified via three measures of recent smoking-(1) timeline follow-back (TLFB), a self-report calendar completed retrospectively by participants indicating the number of cigarettes smoked each day; (2) exhaled carbon monoxide (CO), an objective and biological measure of smoking over approximately the past 24 hours; and (3) urinary cotinine level, an additional biological and objective measure of nicotine exposure and allows for detection of smoking or other nicotine product use over the previous six days. Though these measures are not study outcomes individually, they will verify 7-day point prevalence abstinence at 12-month follow-up - the primary outcome. Specifically, 0 cigarettes reported on the TLFB, breath CO of ≤6 ppm, and urine cotinine levels of \<200ng/mL will be considered smoking abstinence.

  12 months

Secondary Outcomes (7)

• Prolonged Abstinence

  12 months

• Cognitive control (Multi-Source Interference Task) at Screening (Visit 0)

  Approximately 4 weeks prior to the target quit date

• Cognitive control (Multi-Source Interference Task) at Visit 5

  Approximately 1 day after the target quit date

• Cognitive control (Multi-Source Interference Task) at Visit 6

  Approximately 2 days after the target quit date

• Smoking Urges (Questionnaire on Smoking Urges; Factor 2) at Screening

  Approximately 4 weeks prior to the target quit date

Study Arms (2)

Psilocybin

ACTIVE COMPARATOR

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.

Drug: Psilocybin

Niacin

ACTIVE COMPARATOR

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.

Drug: Niacin

Interventions

Psilocybin DRUG

Participants will received two psilocybin sessions, 1 week apart

Also known as: Active Experimental Group

Psilocybin

Niacin DRUG

Participants will received two niacin sessions, 1 week apart

Also known as: Active Comparator Group

Niacin

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• University of Alabama at Birmingham: collaborator
• New York University: collaborator
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (3)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

RECRUITING

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21224, United States

RECRUITING

New York University

New York, New York, 10016, United States

RECRUITING

Related Publications (4)

• 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.

  PMID: 20819978 BACKGROUND

• 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.

  PMID: 25213996 BACKGROUND

• 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.

  PMID: 27441452 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

MeSH Terms

Conditions

Tobacco Use Disorder; Smoking Cessation; Smoking; Cigarette Smoking

Interventions

Psilocybin; Niacin

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Health Behavior; Behavior; Tobacco Smoking; Tobacco Use

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

Study Officials

• Matthew Johnson, Ph.D

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Matthew Johnson, Ph.D

CONTACT

410-550-0056; mwj@jhu.edu

Gideon Naudé, Ph.D.

CONTACT

410-550-2774; gnaude1@jhmi.edu

Study Design

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

Study Record Dates

• First Submitted: June 30, 2022
• First Posted: July 11, 2022
• Study Start: November 1, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): May 1, 2027
• Last Updated: July 29, 2025

Record last verified: 2025-07

Locations

US (3)