Varenicline and Accelerated Transcranial Magnetic Stimulation (TMS) for Quitting Nicotine Use (Pilot Study)

NCT07145866 | Not Yet Recruiting Phase 4 FDA Drug FDA Device

• 1 other identifier: 2025P001964
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn if a combination of varenicline and accelerated Transcranial Magnetic Stimulation (aTMS) works to help adults quit using nicotine products. Researchers will compare varenicline + active aTMS to varenicline + sham (inactive) aTMS to see the effect of aTMS on reaching abstinence. The main question it aims to answer is: Does receiving active aTMS + varenicline lead to higher abstinence rates and lower nicotine craving? Participants will be asked to:

• Complete 2 brain MRI scans
• Take varenicline every day for 12 weeks
• Quit using nicotine products at the end of the second week of varenicline
• Complete 5 consecutive days (Monday-Friday, uninterrupted) of TMS treatments
• Complete 12 brief, weekly follow-up visits
• Complete a brief daily survey each day that they take the study drug

Conditions

Nicotine Dependence; Transcranial Magnetic Stimulation; Vaping; Smoking Cessation; Smoking (Tobacco) Addiction

Keywords

Vaping; Smoking; Nicotine; Adults; Cessation; Varenicline; Transcranial Magnetic Stimulation; TMS

Outcome Measures

Primary Outcomes (3)

• Biochemically-confirmed continuous nicotine abstinence across study weeks 9-12

  Point-prevalence abstinence from e-cigarette use was defined as self-report of no e-cigarette use since the last visit, bioverified by saliva cotinine \<30 ng/ml. Continuous abstinence is defined as observed point-prevalence abstinence over specified study visits at weeks 9, 10, 11 and 12. The primary analysis will compare the proportion of participants achieving continuous abstinence in the TMS + varenicline group versus the Sham + varenicline group using a chi-square test. If expected cell counts are low (\<5 in any cell), Fisher's exact test will be used instead.

  Week 9-Week 12

• Resting State Functional Connectivity (rsFC)

  Within-network resting state Functional Connectivity (rsFC) will be computed by extracting the mean BOLD time series from each region of interest comprising the addiction circuit and calculating pairwise Pearson correlations, which will then be Fisher z-transformed and averaged across all ROI pairs to derive a single within-network rsFC metric per participant at each time point. To isolate effects at the circuit level rather than changes induced by stimulation of the medial prefrontal cortex (mPFC) target site itself, the mPFC stimulation region will be excluded from the connectivity analyses. The primary analytic approach will use a linear mixed-effects model with fixed effects for time (baseline vs. post-treatment), treatment group (TMS vs. sham TMS), and their interaction, as well as a random intercept for each participant.

  Baseline, Week 12

• Change in Insula Activation to Nicotine Cues During a Cue Reactivity Task Measured by fMRI

  Neural responses to nicotine and neutral cues will be modeled, convolved with the canonical hemodynamic response function, and contrast images for nicotine \> neutral cues will be generated for each participant at each time point. These contrast images will be entered into second-level analyses to test group-level effects. The primary region of interest (ROI) will be the bilateral anterior insula, defined using an anatomical mask from the Harvard-Oxford atlas. The main analytic model will be a mixed-effects repeated-measures ANOVA or linear mixed-effects model with fixed effects of time (pre vs. post), treatment group (TMS + varenicline vs. sham TMS + varenicline), and their interaction, with subject-level random intercepts. The key test of our hypothesis is the time × treatment interaction within the anterior insula ROI, which reflects whether treatment modulates cue-elicited insula activity.

  Baseline, Week 12

Secondary Outcomes (6)

• 7-day point prevalence abstinence at Week 12

  Week 12

• Nicotine withdrawal symptoms

  Baseline, Week 12

• Nicotine Craving (vaping)

  Baseline, Week 12

• Nicotine Craving (smoking)

  Baseline, Week 12

• Change in Depressive Symptoms

  Baseline, Week 12

Other Outcomes (1)

• Incidence of treatment-emergent adverse events during the treatment period [Safety]

  Week 0-Week 12

Study Arms (2)

Varenicline + Active TMS

ACTIVE COMPARATOR

In this arm, participants will take 12 weeks of varenicline. They will also receive 5 consecutive days of 5 hourly TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. Participants will also receive 6 brief nicotine cessation counseling sessions.

Drug: varenicline; Device: Transcranial Magnetic Stimulation; Behavioral: Nicotine Cessation Counseling

Varenicine + Sham TMS

SHAM COMPARATOR

In this arm, participants will receive 12 weeks of varenicline and instructions on how to take it. They will also receive 5 consecutive days of 5 hourly TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. However, the sham setting will deliver no magnetic field to the brain; instead, it will deliver electrical current to the scalp to mimic the feel of active treatment. Participants will also receive 6 brief nicotine cessation counseling sessions.

Drug: varenicline; Device: Transcranial Magnetic Stimulation Sham; Behavioral: Nicotine Cessation Counseling

Interventions

varenicline DRUG

Dosing of this FDA-approved medication will follow the below schedule, which follows the clinical standard: 0.5 mg once daily or 3 days, 0.5 mg twice daily for 4 days 1.0 mg twice daily for 11 weeks

Varenicine + Sham TMS; Varenicline + Active TMS

Transcranial Magnetic Stimulation DEVICE

Transcranial magnetic stimulation (TMS) is a noninvasive FDA-approved technique that is commonly used as a treatment for depression and has been approved for use in smoking cessation. In this study, TMS will be administered within FDA-approved guidelines under the supervision of a physician with experience in administering the treatment and monitoring for complications. Following an accelerated model, it will consist of 5 hourly treatments for 5 consecutive days.

Varenicline + Active TMS

Transcranial Magnetic Stimulation Sham DEVICE

Transcranial magnetic stimulation (TMS) is a noninvasive FDA-approved technique that is commonly used as a treatment for depression and has been approved for use in smoking cessation. In this study, TMS will be administered within FDA-approved guidelines under the supervision of a physician with experience in administering the treatment and monitoring for complications. Following an accelerated model, it will consist of 5 hourly treatments for 5 consecutive days. The sham setting will deliver no magnetic field to the brain but will deliver electrical current to the scalp to mimic the feel of active treatment.

Varenicine + Sham TMS

Nicotine Cessation Counseling BEHAVIORAL

Each participant will receive 6 sessions of brief nicotine cessation counseling by a trained study staff member. This will be provided at the weekly follow-up visits, spread out throughout the study. This counseling, while not the main aim of the study, should help participants manage their expectations of quitting and provide support and quitting strategies throughout the process.

Varenicine + Sham TMS; Varenicline + Active TMS

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 and ≤65;
• The ability to give written, informed consent;
• Fluency in English;
• Reported interest in quitting nicotine vaping or smoking within the next month;
• Nicotine dependence, as defined by a score of ≥4 on the 10-question E-cigarette Dependence Inventory (ECDI) or Fagerström Test for Nicotine Dependence (FTND);
• Smoke or vape nicotine daily for at least the past 90 days, as confirmed by self-report and timeline follow-back methods;
• Saliva cotinine \>30ng/mL;

You may not qualify if:

• Pregnancy or breastfeeding;
• Use of smoking cessation pharmacotherapy in the past month;
• Unwilling to abstain during the study from using smoking cessation aids other than those provided by the study;
• Prior adverse drug reaction to varenicline;
• Receiving or planning to receive other TMS treatments or investigational drugs during course of participation
• Contraindications to TMS (including seizures, metallic implants, severe existing tinnitus, etc.);
• Contraindications to MRI (including presence of a cardiac pacemaker or pacemaker wires, metallic particles in the body, vascular clips in the head or previous neurosurgery, prosthetic heart valves, claustrophobia);
• Inpatient psychiatric hospitalization or suicide attempts in the past six months, or recent active suicidal ideation or suicidal behavior identified at enrollment or baseline visits;
• History of seizures and/or history of TBI subtypes associated with elevated seizure risk (e.g. penetrating injury and intraparenchymal hemorrhage)
• History of unstable neurological illness or major medical illness, such as epilepsy or renal impairment, in the past six months, unless clearly resolved;
• In the opinion of the investigators, evidence of active problem substance use severe enough to compromise ability to safely participate;
• In the opinion of the investigators, unable to safely participate in this study and/or provide reliable data (e.g., claustrophobia, unable to tolerate TMS or MRI procedures, etc.).

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Brigham and Women's Hospital: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Tobacco Use Disorder; Vaping; Smoking Cessation; Smoking; Behavior, Addictive

Interventions

Varenicline; Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Behavior; Health Behavior; Compulsive Behavior; Impulsive Behavior

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinoxalines; Magnetic Field Therapy; Therapeutics

Study Officials

• Jodi M Gilman, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jodi M Gilman, PhD

CONTACT

617-643-7293; jgilman1@mgh.harvard.edu

Julia Jashinski, MSW

CONTACT

617-643-1984; jjashinski@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Harvard Medical School; Director of Neuroscience, Center for Addiction Medicine, Massachusetts General Hospital

Model Details: Up to 90 participants will be consented, and approximately 30 participants will be randomized in a double-blind, 2-arm parallel design clinical trial comparing nicotine use abstinence rates in participants randomly assigned to: 1) varenicline + active TMS, or 2) varenicline + sham TMS.

Study Record Dates

• First Submitted: August 12, 2025
• First Posted: August 28, 2025
• Study Start: March 15, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: January 16, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)