Nicotine DependencePhase 4V-TMSNCT07145866
Varenicline and Accelerated Transcranial Magnetic Stimulation (TMS) for Quitting Nicotine Use (Pilot Study)
A Phase 4 study testing Varenicline, Transcranial Magnetic Stimulation and Nicotine Cessation Counseling in people with Nicotine Dependence and Transcranial Magnetic Stimulation, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Nicotine Dependence, Transcranial Magnetic Stimulation, Vaping
- What is being tested?
- Varenicline, Transcranial Magnetic Stimulation and Nicotine Cessation Counseling
- Type of treatment
- Medical device, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Jul 2026to Dec 2028
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
Who cannot join
- 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;
- Contraindication to D-Cycloserine (including allergy to D-Cycloserine, significant renal impairment or known kidney disease, pregnancy)
- Receiving or planning to receive other TMS treatments or investigational drugs during course of participation
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- 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.).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Massachusetts General Hospital
Boston, Massachusetts, 02114
Jodi M Gilman, PhD, 617-643-7293, jgilman1@mgh.harvard.edu
About this study
Official title: Evaluation of Varenicline and Accelerated TMS for Reduction of Nicotine Use
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:
- 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 one day of up to 20 TMS treatments
- Take a single dose of D-Cycloserine medication on the day of TMS treatment
- Complete 12 brief, weekly study visits
- Complete 6 brief, monthly follow up visits
- Complete a brief daily survey each day that they take the study drug
Read the detailed description
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.
- Conditions
- Nicotine Dependence, Transcranial Magnetic Stimulation, Vaping, Smoking Cessation, Smoking (Tobacco) Addiction
- Being tested
- Varenicline, Transcranial Magnetic Stimulation, Transcranial Magnetic Stimulation Sham, Nicotine Cessation Counseling, D-cycloserine
- Keywords
- Vaping, Smoking, Nicotine, Adults, Cessation, Varenicline, Transcranial Magnetic Stimulation, TMS, D-Cycloserine
- Medical subject headings
- Tobacco Use Disorder, Vaping, Smoking Cessation, Smoking, Behavior, Addictive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VareniclineDrug
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 StimulationDevice
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 ShamDevice
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.
Nicotine Cessation CounselingBehavioural
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.
D-cycloserineDrug
Eligible participants will receive a single dose of 125 mg D-Cycloserine shortly before the start of TMS treatment.
| Study group | Role | What they receive |
|---|---|---|
| Varenicline + Active Enhanced TMS | Active comparator | 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. Receives: Drug: Varenicline; Device: Transcranial Magnetic Stimulation; Behavioral: Nicotine Cessation Counseling; Drug: D-cycloserine |
| 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 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. Receives: Drug: Varenicline; Device: Transcranial Magnetic Stimulation Sham; Behavioral: Nicotine Cessation Counseling |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Baseline, Week 12
Secondary outcomes (6)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, Week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Aug 2025
- Study start2 Jul 2026
- Primary completionSep 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Nicotine DependenceStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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 enhanced TMS, or 2) varenicline + sham TMS.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Brigham and Women's Hospital
- Responsible party
- Principal investigator, Jodi Gilman, Massachusetts General Hospital
- Investigators
- Jodi M Gilman, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07145866
- Sponsor's protocol ID
- 2025P001964
- Acronym
- V-TMS
- Status last verified
- Sep 2026
- First submitted
- 12 Aug 2025
- Last updated
- 15 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
- Individual data sharing
- No