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

Tobacco Use Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05452772
• Other study ID #: IRB00326148
• Secondary ID: U01DA052174
• Status: Recruiting
• Phase: Phase 2
• Start date: November 1, 2023
• Est. completion date: December 2025

Study information

• Verified date: March 2024
• Source: Johns Hopkins University
• Contact: Matthew Johnson, Ph.D
• Phone: 410-550-0056
• Email: mwj[@]jhu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multi-site, double-blind, randomized clinical trial of the 5-HT2A receptor agonist psilocybin for smoking cessation. Three 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.

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 three 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. completion date: December 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years and older

Eligibility

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

• Be healthy as determined by screening for medical problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis lab tests. See Exclusion Criteria below for specific ECG and specific blood test criteria

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

Related Conditions & MeSH terms

• Tobacco Use Disorder

Intervention

Drug:
• Psilocybin
Participants will received two psilocybin sessions, 1 week apart
• Niacin
Participants will received two niacin sessions, 1 week apart

Locations

Country	Name	City	State
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	New York University	New York	New York

Sponsors (4)

Lead Sponsor	Collaborator
Johns Hopkins University	National Institute on Drug Abuse (NIDA), New York University, University of Alabama at Birmingham

Country where clinical trial is conducted

United States, 

References & 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. — View Citation

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. — View Citation

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. Erratum In: Am J Drug Alcohol Abuse. 2017 Jan;43(1):127. — 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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Prolonged Abstinence	A secondary measure of abstinence will be prolonged abstinence, defined as no smoking at all after the target quit date, with the exception that smoking lapses during an initial 2-week grace period after the target quit date are not counted.	12 months
Secondary	Cognitive control (Multi-Source Interference Task) at Screening (Visit 0)	The Multi-Source Interference Task is a measure of cognitive control that requires participants to inhibit a prepotent response when engaged in a voluntary task-based action. The Multi-Source Interference Task will be administered at screening - approximately 4 weeks prior to the first psilocybin / niacin session (i.e., 4 weeks prior to the target quit date), and again at Visits 5 and 6.	Approximately 4 weeks prior to the target quit date
Secondary	Cognitive control (Multi-Source Interference Task) at Visit 5	The Multi-Source Interference Task is a measure of cognitive control that requires participants to inhibit a prepotent response when engaged in a voluntary task-based action. The Multi-Source Interference Task will be administered at Visit 5 - 1 day after the first psilocybin / niacin session (i.e., 1 day after the target quit date), and again at Visit 6.	Approximately 1 day after the target quit date
Secondary	Cognitive control (Multi-Source Interference Task) at Visit 6	The Multi-Source Interference Task is a measure of cognitive control that requires participants to inhibit a prepotent response when engaged in a voluntary task-based action. The Multi-Source Interference Task will be administered at Visit 6, the day of the second psilocybin / niacin session (i.e., 2 days after the target quit date).	Approximately 2 days after the target quit date
Secondary	Smoking Urges (Questionnaire on Smoking Urges; Factor 2) at Screening	The Questionnaire on Smoking Urges is a multidimensional assessment of smoking craving with demonstrated sensitivity to smoking cessation. Participants will respond using a 7-point scale, where 1 = "Strongly Disagree", 4 = "Neither Agree nor Disagree", and 7 = "Strongly Agree". The scale consists of 10 items and scores can range from 10 - 70, with higher scores reflecting stronger urges to smoke.The Questionnaire on Smoking Urges will be administered at screening - approximately 4 weeks prior to the first psilocybin / niacin session (i.e., 4 weeks prior to the target quit date), and again at Visits 5 and 6.	Approximately 4 weeks prior to the target quit date
Secondary	Smoking Urges (Questionnaire on Smoking Urges; Factor 2) at Visit 5	The Questionnaire on Smoking Urges is a multidimensional assessment of smoking craving with demonstrated sensitivity to smoking cessation. Participants will respond using a 7-point scale, where 1 = "Strongly Disagree", 4 = "Neither Agree nor Disagree", and 7 = "Strongly Agree". The scale consists of 10 items and scores can range from 10 - 70, with higher scores reflecting stronger urges to smoke. The Questionnaire on Smoking Urges will be administered at Visit 5 - 1 day after the first psilocybin / niacin session (i.e., 1 day after the target quit date), and again at Visit 6.	Approximately 1 day after the target quit date
Secondary	Smoking Urges (Questionnaire on Smoking Urges; Factor 2) at Visit 6	The Questionnaire on Smoking Urges is a multidimensional assessment of smoking craving with demonstrated sensitivity to smoking cessation. Participants will respond using a 7-point scale, where 1 = "Strongly Disagree", 4 = "Neither Agree nor Disagree", and 7 = "Strongly Agree". The scale consists of 10 items and scores can range from 10 - 70, with higher scores reflecting stronger urges to smoke. The Questionnaire on Smoking Urges will be administered at Visit 6, the day of the second psilocybin / niacin session (i.e., 2 days after the target quit date).	Approximately 2 days after the target quit date