A Phase 4 interventional study of Varenicline and Transcranial Magnetic Stimulation in Nicotine Dependence, Transcranial Magnetic Stimulation and Vaping, sponsored by Massachusetts General Hospital. Recruiting at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-09-15.
Sponsored by Massachusetts General Hospital · Phase 4, Interventional, and Treatment
The goal of this clinical trial is to learn if a combination of varenicline and enhanced accelerated Transcranial Magnetic Stimulation (aTMS) works to help adults quit using nicotine products. Researchers will compare varenicline + active aTMS with a single dose of D-Clycloserine to varenicline + sham (inactive) aTMS with a placebo pill to see the effect of enhanced aTMS on reaching abstinence. The main question it aims to answer is: Does receiving active enhanced aTMS + varenicline lead to higher abstinence rates and lower nicotine craving?
Participants will be asked to:
This is a 9-month randomized parallel design, double-blind, 2-arm clinical trial consisting of a combination of circuit-targeted TMS and varenicline in 30 adults aged 18-65 with nicotine use disorder who would like to reduce or stop nicotine use.
Eligible participants will complete a baseline assessment of questionnaires and laboratory assessments. They will be randomized to receive varenicline and either active enhanced or sham TMS. Participants will be randomized at their baseline scan visit, during which they will undergo urinalysis, an fMRI scan, and a task and questionnaire battery.
Shortly after, participants will complete a TMS treatment preparation visit during which the treatment target is located and stimulation intensity of the TMS is determined. This target is used in the subsequent TMS Treatment visit of up to 20 TMS treatments. Participants' quit date will be set following their TMS treatment day.
Participants will receive varenicline medication the week of the TMS treatment preparation visit and will be instructed to take it for 12 weeks titrated to 1mg twice daily over seven days.
At the TMS treatment visit, those assigned to active enhanced aTMS will receive a single dose of D-Cycloserine medication while those assigned to sham TMS will receive placebo.
The week after completing their TMS treatments, they will return for a second imaging visit identical to the baseline scan.
Each week of the varenicline treatment period, participants will complete weekly study visits with study staff, either virtually or in-person, to determine nicotine use and complete questionnaires regarding their substance use in the past week, depression, and anxiety. These visits will include brief sessions of nicotine use cessation counseling with a trained study staff member.
After 12 weeks of varenicline treatment, participants will attend monthly follow-up visits with study staff over six months, either virtually or in-person, to assess long-term nicotine cessation outcomes.
1,027 studies on the registry are indexed under Tobacco Use Disorder; 128 are open to participants now.
This study's planned enrollment of 30 is below the median of 90 across 892 interventional studies indexed under Tobacco Use Disorder.
Browse Tobacco Use Disorder studies →Massachusetts General Hospital is the lead sponsor of 2,586 studies on the registry; 447 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
In this arm, participants will take 12 weeks of varenicline. They will also receive a single dose of 125 mg D-Cycloserine and one day of up to 20 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 12 brief nicotine cessation counseling sessions.
Drug: Varenicline · Device: Transcranial Magnetic Stimulation · Behavioral: Nicotine Cessation Counseling · Drug: D-cycloserine
In this arm, participants will receive 12 weeks of varenicline and instructions on how to take it. They will also receive one day of up to 20 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 12 brief nicotine cessation counseling sessions.
Drug: Varenicline · Device: Transcranial Magnetic Stimulation Sham · Behavioral: Nicotine Cessation Counseling
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
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 up to 20 treatments in one day.
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 up to 20 treatments in one day. 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.
Each participant will receive 12 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.
Eligible participants will receive a single dose of 125 mg D-Cycloserine shortly before the start of TMS treatment.
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 enhanced aTMS + 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline, Week 12
7-day point prevalence abstinence at Week 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.
Time frame: Week 12
Nicotine withdrawal symptoms
Minnesota Nicotine Withdrawal Scale (MNWS) total scores over study weeks 1 to 12. The MNWS is an 8-item measure assessing the severity of nicotine withdrawal symptoms. Items are scored on an ordinal scale from 0 ("not at all") to 4 ("extreme") with total scores ranging from 0 to 32. Higher scores indicate greater severity of nicotine withdrawal symptoms.
Time frame: Baseline, Week 12
Nicotine Craving (vaping)
Summed scores from the Questionnaire of Vaping Craving (QVC) over Study Weeks 1 to 12. The QVC is a 10-item self-rated validated measure (ranging from 10 to 70) of vaping craving that examines desire and intent to vape and anticipation of positive outcomes related to e-cigarette use, with higher scores indicating greater cravings to vape. This is applicable to those who report using e-cigarettes.
Time frame: Baseline, Week 12
Nicotine Craving (smoking)
Summed scores from the Questionnaire on Smoking Urges-Brief (QSU-Brief) over Study Weeks 1 to 12. This is a 10-item self-report measure of smoking urges and cravings with scores ranging from 10-70; higher scores indicate greater cravings to smoke. This is applicable to those who report smoking cigarettes.
Time frame: Baseline, Week 12
Change in Depressive Symptoms
The Beck Depression Inventory-II (BDI-II) will be used to assess symptoms of depression. The scale ranges from 0 - 63, with a higher score indicating greater depression.
Time frame: Baseline, Week 12
Change in Anxiety Symptoms
The Beck Anxiety Inventory (BAI) will be used to assess the frequency of anxiety symptoms, including cognitive and somatic symptoms. Higher scores indicate greater anxiety severity, with scores ranging from 0-63.
Time frame: Baseline, Week 12
Incidence of treatment-emergent adverse events during the treatment period [Safety]
Open-ended questioning will be used to assess adverse events throughout the trial. This outcome reports on the number of participants who reported at least one adverse event between the first imaging visit (Week 0) to the end of treatment (Week 12).
Time frame: Week 0-Week 12
Plan to share: No
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Studies of the drug tested here: Cycloserine
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