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. Author manuscript; available in PMC: 2025 May 1.
Published in final edited form as: Drug Alcohol Depend. 2024 Mar 30;258:111278. doi: 10.1016/j.drugalcdep.2024.111278

A Randomized Controlled Trial of Intermittent Theta Burst Stimulation to the Medial Prefrontal Cortex for Tobacco Use Disorder: Clinical Efficacy and Safety

Merideth A Addicott 1, Kaitlin R Kinney 1, Santiago Saldana 2, Edward Hak-Sing Ip 2, Hannah DeMaioNewton 1, Warren K Bickel 3, Colleen A Hanlon 4,5
PMCID: PMC11088513  NIHMSID: NIHMS1986902  PMID: 38579605

Abstract

Objective:

This study aimed to evaluate the clinical efficacy and safety of administering intermittent theta burst stimulation (iTBS) to the medial prefrontal cortex for tobacco use disorder.

Methods:

A randomized sham-controlled trial was conducted, with 38 participants receiving 28 sessions of active (n=25) or sham (n=13) iTBS (2 sessions/day, 600 pulses/session, 110% resting motor threshold, AFz target) along with smoking cessation education (Forever Free © booklets) over 14 visits. Primary outcomes included self-reported cigarette consumption and abstinence, verified by urinary cotinine tests. Secondary outcomes included symptoms of tobacco use disorder, negative mood, and safety/tolerability.

Results:

Both active and sham groups reported reduced cigarette consumption (β = −0.12, p = 0.015), cigarette craving (β = −0.16, p = 0.002), and tobacco withdrawal symptoms (β = −0.05, p < 0.001). However, there were no significant time × group interaction effects for any measure. Similarly, the two groups had no significant differences in urinary cotinine-verified abstinence. Adverse events occurred with similar frequency in both groups.

Conclusion:

There were no differences in cigarette consumption between the active and sham iTBS groups, both groups decreased cigarette consumption similarly. Further research is needed to compare iTBS to standard high-frequency rTMS and explore the potential differences in efficacy. Despite limitations, this study contributes to experimental design considerations for TMS as a novel intervention for tobacco and other substance use disorders, emphasizing the need for a more comprehensive understanding of the stimulation parameters and target sites.

Keywords: intermittent theta burst stimulation, TMS, tobacco use disorder, medial prefrontal cortex, smoking cessation, randomized controlled trial

1. Introduction

An estimated 28.3 million U.S. adults aged 18 and older smoke cigarettes, which is about 11.5% of the U.S. adult population (CDCP, 2023). The majority of people who smoke cigarettes express interest in quitting, and approximately 40% make a quit attempt each year (DHHS, 2014). However, only about 7.5% of quitters successfully maintain abstinence for at least 6 months (Creamer et al., 2019). Indeed, most smoking relapse occur within 8 days of the quit attempt (Hughes et al., 2004). With the assistance of pharmacotherapies, such as nicotine replacement therapy, bupropion, and varenicline, abstinence rates increase to 17.3% compared with 10.5% of clinical trial participants receiving placebo (Eisenberg et al., 2008). Clearly, novel interventions are needed to improve cessation outcomes among tobacco and other substance use disorders. In the past decade, a method of non-invasive brain stimulation, known as repetitive transcranial magnetic stimulation (rTMS), has been increasingly investigated as a novel smoking cessation therapy (Hauer et al., 2019, Petit et al., 2022, Tang et al., 2023).

rTMS has the potential to selectively target specific brain regions and influence extended brain networks that are thought to underlie substance use and other psychiatric disorders (bibr">Hanlon et al., 2018). The most common rTMS target site in tobacco cessation research has been the dorsolateral prefrontal cortex (DLPFC) (Hauer et al., 2019, Petit et al., 2022), similar to prior rTMS research in depression (Schutter, 2009). While depression and tobacco use disorder share some deficits, such as impaired executive control, the optimal rTMS target site for tobacco use disorder may be unique. A different rTMS target site that may be better suited for tobacco and other substance use disorders is the medial prefrontal cortex (MPFC). The MPFC, extending down into the ventromedial PFC, is involved in reward signaling, assigning value, arousal, emotional processing, and other processes disrupted in addiction (Goldstein et al., 2002). Importantly, converging evidence exists that smoking and other drug cues elicit brain activation in a network engaging the MPFC, anterior cingulate cortex, and the anterior insula cortices (Hanlon et al., 2018). A spatial topography analysis of these cue-reactivity hotspots indicated the MPFC (Brodmann area 10) may be a fruitful rTMS target site (Hanlon et al., 2018). Indeed, the largest clinical trial of rTMS for smoking cessation to date, which supported the use of rTMS in reducing cigarette smoking and craving, targeted the medial and lateral PFC and the insula (Zangen et al., 2021). While the results of this study are promising, the smoking cessation rates were modest (19% in the intent-to-treat sample) (Zangen et al., 2021). The H4 coil used by Zangen et al. has a broad electrical field, and it may be possible to improve efficacy by employing a more targeted approach (e.g., focusing on a single target site such as the MPFC).

In addition to determining the best spatial target for smoking cessation, it is also critical to determine the best frequency of stimulation. Nearly all rTMS studies on tobacco and other substance use disorders have used high- (e.g., 10 or 20 Hz) or low- (e.g., 1 Hz) frequency standard pulse sequences (Ekhtiari et al., 2019, Hauer et al., 2019, Antonelli et al., 2021, Petit et al., 2022). A drawback of the standard sequence is that a typical therapeutic session of rTMS administers 1000 to 3000 stimulation pulses, which lasts between 10 to 40 minutes. The therapeutic session’s length can increase the patient’s time burden and potential discomfort. Alternatively, an accelerated pulse sequence thought to mimic the natural rhythms of neuronal firing, known as intermittent theta burst stimulation (iTBS), delivers high-frequency pulses (e.g., 50 Hz) within lower frequency rhythms (e.g., 5 Hz), which reduces the length of a session to 2–3 minutes (Huang et al., 2005, Suppa et al., 2016). iTBS has been shown to produce comparable efficacy on alleviating depression compared to standard 10 Hz pulse sequence, with similar safety and tolerability profiles (Bakker et al., 2015). Also similar to 10 Hz pulse sequences, iTBS has been shown to facilitate motor evoked potentials (MEPs), suggesting enhanced cortical excitability (Maeda et al., 2000, Huang et al., 2005, Suppa et al., 2016). A previous study that administered iTBS for smoking cessation reported four sessions of iTBS to the right DLPFC, along with cognitive behavioral therapy, increased smoking abstinence rates at 3 months compared to sham iTBS (Dieler et al., 2014).

Altogether, accumulating evidence suggests that administering iTBS to the MPFC may have the potential to target a brain network that underlies tobacco addiction-related craving, while reducing the overall session length. Here, we report the results of a randomized, sham-controlled trial (RCT) of iTBS to the MPFC in participants with tobacco use disorder. We administered rTMS in 28 sessions (2 sessions/visit) during a 10 visit acute phase (3–5 visits/week) and a 4 visit follow-up phase (1 visit/week), along with guided reading of smoking cessation education booklets. We assessed the clinical efficacy of rTMS using self-report and biochemically verified measures of cigarette smoking. Also, we assessed other symptoms of tobacco use disorder and mood as secondary outcomes.

2. Materials and Methods

2.1. Participants

This sham-controlled RCT was conducted at Wake Forest University School of Medicine from August 2020 through September 2022. The Institutional Review Board approved the protocol and registered at clinicaltrials.gov (NCT04159571). Participants were blinded to the treatment condition.

Adults aged 18–75 years who smoked at least 10 cigarettes per day and wanted to quit smoking were recruited. Advertisements for the study were posted using flyers, newspaper ads, and social media. Participants provided written informed consent and passed the TMS adult safety screen. Exclusion criteria included the use of noncombustible tobacco/nicotine products, the use of pharmacotherapies for smoking cessation, any non-prescription substance use (except marijuana, alcohol, and tobacco) within the past 30 days by self-report and by urine drug screen (McKesson, Irving TX), the presence of any severe axis I psychiatric disorder according to DSM-5 criteria (APA, 2013), any history of traumatic brain injury, neurological condition, or seizure disorder, the presence of metal in the head, chronic migraines, or pregnancy.

2.2. Procedures

2.2.1. Overview.

The estimated electrical field for the MPFC, the activity flow, and timeline for events are shown in Figure 1. Following consent and screening, eligible participants were randomized to receive active or sham iTBS (2:1 ratio) using a predetermined randomization list. The rTMS was administered in an acute phase (20 sessions) and a follow-up phase (8 sessions). Two iTBS sessions were given per visit (600 pulses per session, with a 20–30 minute inter-session interval; 1200 pulses of iTBS per visit). The acute phase included 10 visits (3–5 per week). The follow-up phase included 4 visits (1 per week).

Figure 1.

Figure 1.

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A) TMS electric field at the AFz location (V/m), B) Flow of study activities at each rTMS visit, and C) Study timeline and events schedule. rTMS visits consisted of 2 intermittent theta-burst (iTBS) sessions, each consisting of 600 pulses at 110% resting motor threshold, separated by a 20–30 minute inter-session interval. rTMS was administered in an acute treatment phase (20 sessions, 3–5 visits per week) and a follow-up phase (8 sessions, 1 visit per week). Ŝmoking assessments included a timeline follow-back of cigarette consumption, urinary cotinine, cigarette craving using the Brief Questionnaire of Smoking Urges (QSU), and tobacco withdrawal symptoms using the Minnesota Withdrawal Scale (MNWS). *Other assessments included the Fagerstrom Test of Nicotine Dependence, Profile of Mood States, Beck Depression Inventory, and State Anxiety Inventory. rTMS: repetitive transcranial magnetic stimulation.

Participants were asked to make a quit attempt on approximately the 6th rTMS visit day or approximately one week after their first rTMS visit. The cessation attempt was supported by an educational booklet, “Forever Free: A Guide to Remaining Smoke Free” (University of South Florida, 2000). The study coordinator guided participants one-on-one though each booklet on rTMS study visits 2–9, during the inter-session interval.

The primary outcome measure was cigarette consumption. Abstinence was defined as a self-report of no cigarettes smoked verified with urine cotinine levels < 200 ng/ml (DRI Cotinine Assay, Thermo Fisher Scientific, High Point, NC). Secondary outcomes included changes in craving, dependence severity, withdrawal symptoms and negative mood.

2.2.2. Behavioral Assessments.

At each visit, participants completed a timeline follow-back of cigarette consumption (i.e., cigarettes smoked each day since the last study visit) (Sobell et al., 1992). Measures of cigarette craving (Brief Questionnaire of Smoking Urges; QSU) (Cox et al., 2001), and tobacco withdrawal symptoms (Minnesota Nicotine Withdrawal Scale; MNWS) (Hughes et al., 1986) were also collected at the start of every rTMS visit. Measures of tobacco dependence severity (Fagerstom Test of Nicotine Dependence; FTND) (Heatherton et al., 1991), negative mood (Profile of Mood States; POMS, mood disturbance score) (McNair et al., 1992), state anxiety (State-trait Anxiety Inventory; STAI) (Spielberger et al., 1970), depression (Beck Depression Inventory; BDI) (Beck et al., 1996), and urine samples for cotinine assay were collected at the start of rTMS visits 1, 6, 10 and follow-up visits 1, 2, 3, and 4. Behavioral economic measures were collected on rTMS visits 1, 6, 10 and follow-up visits 1, 2, 3, and 4; results of these measures will be published elsewhere.

2.2.3. TMS parameters.

Treatment was delivered using a Cool B-65 A/P coil on a MagPro R30 (Magventure, Denmark). The resting motor threshold for each individual was determined using Parameter Estimation by Sequential Training, an automated algorithm designed to establish TMS thresholds (Mishory et al., 2004, Borckardt et al., 2006). The Cartesian position of the coil (X,Y,Z) was determined by standardized posts from the EEG 10–20 system; the AFz position was used for the MPFC stimulation (Beam et al., 2009). The locations and coil orientation were indicated on a nylon cap worn during the rTMS sessions. Each participant had their own unique cap, marked with their coil target location and the outline of the coil over this target. The distance between the nasion and the brim of the cap was measured for each participant and kept consistent across visits.

Participants received up to 28 sessions of intermittent theta burst stimulation (iTBS) (2 sessions/visit, 600 pulses/session, 110% of the resting motor threshold, 20–30 minute inter-session interval, daily total of 1200 pulses). Standard parameters were used for iTBS: 20 trains of stimulation wherein each train contains 30 pulses of TMS (15 pulses/second delivered in 3 pulse bursts (50 Hz) for 2 seconds followed by an 8-second inter-train interval) (Huang et al., 2005). During each active and sham rTMS session, the amplifier output was escalated from 20% machine amplitude to 110% RMT in 3% increments over approximately 30–120 seconds (per patient tolerability) as in previous studies (Kearney-Ramos et al., 2018, McCalley et al., 2022). See Supplementary Information for estimated electrical field maps induced by rTMS.

2.2.4. Integrated sham system.

The MagVenture MagPro system has an integrated active sham that uses two surface electrodes placed on the forehead to mimic the sensation of active rTMS. The coil is visually identical on both sides, but only one side directs an electric field on the participants’ heads. The capacitor can sense whether the TMS coil is positioned in a direction wherein the active or the sham side is facing the participant’s head. The capacitor instructs the coordinator that it is either “Coil Ready” or to “Flip Coil” based upon the participant’s unique randomization code. Electrodes (Natus Inc.) were placed on the forehead beneath the coil, over the frontalis muscle. During stimulation, electrical current was applied through the surface electrodes at an intensity adjusted to their individual motor threshold. The current intensity was turned to ‘9’ on the sham unit based on in-laboratory quality assurance indicating the sensation at ‘9’ from the electrodes was comparable to the intensity in active mode without electrodes. At the last follow-up visit, participants were asked to record whether they received real or sham stimulation and indicate their level of confidence on a Likert scale ranging from 1 to 10.

2.2.5. Behavioral priming before and during rTMS.

Exposure to drug cues before undergoing rTMS can enhance the effectiveness of the treatment (Isserles et al., 2013, Dinur-Klein et al., 2014, Carmi et al., 2018). Prior to administering rTMS, participants were directed to recollect their most recent smoking experience. The staff member instructed the participant to “think about smoking, the negative aspects. Think about how it makes you feel and why you want to quit. You can take back control. Smoking shouldn’t control you.”

2.3. Data Analysis

Power analysis assuming medium to large effect size (d = 0.8) indicated a sample size of 28 individuals in the active treatment group was necessary to detect a within-subject effect with 80% statistical power. We intended to recruit 69 participants, with an anticipated attrition rate of 22%. Recruitment was terminated after 57 participants due to time limitations.

The primary outcome measure was cigarette consumption, with self-reported abstinence verified by urinary cotinine tests. Secondary outcome measures included changes in symptoms of tobacco use disorder (cigarette craving, tobacco dependence severity, and withdrawal symptoms), and negative mood. Group differences in baseline measures were compared using independent samples t-tests, or Mann-Whitney U tests, depending on the normality of the data, and Chi-square tests or ANOVAs. One participant was removed from the years of education comparison for having an outlying value (>2.5 standard deviations from the group mean). Generalized estimating equations analyzed the effects of time (rTMS visit number), TMS group (active and sham), and the time × group interaction. Behavioral measures were analyzed using SAS.

3. Results

3.1. Characteristics of the sample

A total of 57 participants were consented and assessed for eligibility. Three eligible participants were lost to contact prior to the first treatment visit and were not randomized. Forty participants were randomized with 26 to receive active rTMS and 14 sham rTMS. Four participants were lost to contact during treatment, 4 were withdrawn by the investigator for having positive urine drug screens (exclusionary for safety reasons), and 6 were withdrawn for adverse events/personal reasons including 2 participants removed from the dataset due to potential unblinding of their randomization to study staff. One participant was lost to contact during the follow-up period. The modified intent-to-treat efficacy sample included 38 participants including 25 active rTMS and 13 sham rTMS. See Figure 2 for CONSORT diagram of participant flow. One participant received active rTMS with a reduced number of pulses (400 pulses/session). This participant was retained in the analysis because excluding them was found to have minimal effects on the statistical outcomes. See Supplementary Information for details.

Figure 2.

Figure 2.

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Consort diagram of study participants.

Participants withdrawn/lost to contact were classified as non-abstinent. No differences in baseline demographics or clinical characteristics were observed, other than the active rTMS group had higher smoking craving at baseline (t(38) = 2.2, p = 0.033). The groups did not differ in TMS resting motor threshold or accurately guessing the active/sham conditions. See Table 1 for baseline characteristics.

Table 1.

Demographic Characteristics of Enrolled Participants at Baseline

Active TMS (n = 25) Sham TMS (n = 13) p valuea
Demographics
 Sex (M/F) 10/15 6/7 .72b
 Age (years) 56 (12) 54 (15) .71
 Education (years) 15 (3) 17 (4) .05c
 Race (White/Black/Other) 17/7/1 11/1/1 .22b
Smoking Characteristics
 Cigarettes per Day 18 (9) 19 (7) .72c
 Smoking Duration (years) 32 (11) 29 (14) .39
 Age Began Smoking (years) 20 (7) 19 (5) .76c
 Tobacco Dependence (FTND) 5 (2) 4 (2) .50
 Smoking Craving (QSU) 34 (15) 24 (11) .034
Mood Scales
 Depression (BDI) 6 (4) 6 (7) .50c
 State Anxiety (STAI) 47 (4) 46 (5) .90c
 Negative Mood (POMS) 19 (17) 21 (21) .98c
TMS characteristics
 Initial RMT (% stimulator power) 50 (7) 55 (7) .08
 Blinding assessment at Follow-up 10/5 3/5 .84b
 4 (correct/incorrect) 7.6(1.6)/8.0(1.9) 7.7(3.2)/7.4(2.5) .95d
 Confidence Ratings
 Adverse Events (n) 1 2 --
 Number of completed TMS visits 12(5) 11 (6) .63
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Results are reported as mean (standard deviation), unless otherwise noted.

a

Independent samples t-test, unless otherwise noted

b

Chi-square test

c

Mann-Whitney U test

d

ANOVA

3.2. Primary outcomes

Cigarette consumption and abstinence verified by urinary cotinine:

During the rTMS treatment period, cigarette consumption (cigarettes per day) decreased over time (β = −0.12, p = 0.015) in both the active and sham rTMS groups, but there were no significant group or time × group interaction effect (p’s > 0.3). Self-reported abstinence (7-day point prevalence by the end of their participation period) was achieved by 5 of the 25 participants in the active group, 4 of these were confirmed by urinary cotinine concentrations < 200 ng/ml (16%), and by 2 of the 13 participants in the sham group, both cases were confirmed by urinary cotinine (15%) (p > 0.6). There were no significant effects of group, time, or their interaction on urinary cotinine concentrations (p’s > 0.09). See Figure 3 for study outcomes.

Figure 3.

Figure 3.

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Cigarette consumption, craving, withdrawal and negative mood symptoms in Active (n = 25) and Sham (n = 13) rTMS groups at baseline (BL), rTMS treatment visits 1, 6, and 10, and follow-up (FU) visits 1 through 4. Separate generalized estimating equations were performed for each measure to investigate the effects of rTMS group, time, and the group × time interaction. Cigarette consumption (timeline follow-back; TLFB), craving (Questionnaire of Smoking Urges; QSU) and tobacco withdrawal (Minnesota Withdrawal Scale; MNWS) decreased over time (p’s < 0.05). There was a trend towards more craving in the Active group (p = 0.058). There were no significant effects on negative mood. Error bars show the standard error of the mean.

3.3. Secondary outcomes

Symptoms of tobacco use disorder:

Cigarette craving decreased over time (β = −0.16, p = 0.002), and the active rTMS group trended towards higher craving than the sham group (β = 5.81, p = 0.058), but time × group was not significant (p = 0.52). Tobacco withdrawal symptoms decreased over time (β = −0.05, p < 0.001), but group and time × group was not significant (p’s > 0.1). There were no significant effects of group, time or their interaction on tobacco dependence severity. See Figure 3 for study outcomes.

Negative Mood:

There were no significant effects of group, time, or their interaction on symptoms of depression, state anxiety, or negative mood (p’s > 0.09). See Figure 3 for study outcomes.

3.4. Efficacy of the blind

At the fourth follow-up visit, 67% of participants (10 out of 15) in the active rTMS group accurately guessed whether they received active or sham rTMS, as well as 37.5% of participants (3 out of 8) in the sham group, differences were not significant (p > 0.8). The average confidence rating was 7.7 ± 2.0, on a scale from 1 to 10. There was no significant difference in confidence ratings (interaction effect, p > 0.9). See Table 1.

3.5. Safety and tolerability

No serious adverse events occurred. The only adverse events reported were prolonged headache, drooping eyelid, and memory problems. Adverse events occurred with similar frequency in both groups. See Table 1.

4. Discussion

To our knowledge, this is the first randomized, sham-controlled trial (RCT) to administer intermittent theta burst stimulation (iTBS) to the medial prefrontal cortex (MPFC) of treatment-seeking individuals with tobacco use disorder. Treatment consisted of 28 sessions of iTBS completed over a 3–5 week acute phase and a 4 week follow-up phase. All participants reported steep reductions in cigarette consumption and craving, but no significant differences were found between the active and sham rTMS groups. Similar rates of urinary cotinine-verified abstinence (7-day point prevalence) were observed between the two groups (16% abstinent in active group vs 15% abstinent in sham group). Secondary measures of symptoms of tobacco use disorder, depression, anxiety, and negative mood were similar between active and sham groups. Together, these data suggest that the reduction of cigarette smoking observed in this trial may have been due to the smoking cessation education, ancillary environmental variables, and participant characteristics associated with the study.

rTMS has been investigated as a treatment for tobacco and other substance use disorders for over a decade. In general, studies support the efficacy of multi-session, high-frequency rTMS in reducing drug craving and consumption (Ekhtiari et al., 2019, Hauer et al., 2019, Antonelli et al., 2021, Petit et al., 2022, Tang et al., 2023). In particular, other RCTs for tobacco use disorder, which used sample sizes and a number of treatment sessions similar to the present study, have reported that standard, high-frequency rTMS to the left DLPFC reduces self-reported cigarette use compared to sham (Amiaz et al., 2009, Sheffer et al., 2018, Li et al., 2020, Abdelrahman et al., 2021). The FDA-cleared indication for TMS was done with a coil that stimulates the MPFC (as in this trial) and the insula bilaterally (Zangen et al., 2021). In this study, we administered an accelerated pulse sequence (i.e., iTBS) to the MPFC, based on evidence that iTBS is effective in reducing symptoms of depression similar to standard high-frequency rTMS (Blumberger et al., 2018, Li et al., 2020, Chu et al., 2021). To our knowledge, only two previous studies have administered iTBS for smoking cessation. An early RCT that administered 4 sessions of iTBS to the right DLPFC reported higher rates of abstinence after active TMS compared to sham (Dieler et al., 2014). However, a recent RCT administered 20 sessions of iTBS to the left DLPFC reported no difference in cigarette use between active and sham conditions (Mikellides et al., 2022). Similar research among individuals with cocaine use disorder reported that iTBS administered to the medial and lateral PFC and insula (using an H4 coil) had similar effects on reducing cocaine use and craving as standard 15 Hz rTMS stimulation (Sanna et al., 2019). In addition, research among individuals with methamphetamine use disorder reported that iTBS administered to the left DLPFC had similar effects on reducing craving and withdrawal symptoms as standard 10 Hz rTMS (Liu et al., 2022). However, no sham control was used in either of these studies and therefore potential placebo effects cannot be ruled out. This raises the question of whether iTBS has the same therapeutic efficacy as standard high-frequency rTMS pulses in substance use disorders. An RCT comparing iTBS to high-frequency rTMS, with a sham control condition, in individuals with a substance use disorder is necessary to address this question.

Previously, we administered 10 sessions of cTBS to the MPFC among individuals with alcohol use disorder (McCalley et al., 2022). Despite not achieving statistical significance in the abstinence rates between the groups, individuals who received active TMS were slightly more likely to remain sober 3 months after treatment initiation (McCalley et al., 2022). However, in the present study, we chose to administer iTBS. In the TMS literature, there is a commonly reported heuristic based on tests of proximal stimulation. iTBS and standard high-frequency rTMS (e.g., > 5 Hz) are reported to have excitatory effects, while cTBS and low-frequency rTMS (e.g., 1 Hz) have inhibitory effects on the underlying cortex (Ekhtiari et al., 2019). Indeed, an initial test of iTBS and cTBS indicated post-stimulation excitatory and inhibitory effects, respectively, on motor evoked potentials (MEPs) after 600 pulses (Huang et al., 2005). However, we recently tested the number of iTBS and cTBS pulses on MEPs. We found no orderly effects or the hypothesized excitatory/inhibitory relationship on MEPs, especially at the most common number of pulses (i.e., 600) (McCalley et al., 2021). This adds to a larger literature in which iTBS and cTBS did not reliably increase or decrease MEP amplitude; and test-retest reliability tends to be small (McCalley et al., 2021, Kanig et al., 2023). Here, we chose to administer iTBS because of the lack of consistent iTBS/cTBS effects on MEPs and because the iTBS sequence used here is FDA-cleared for depression. Furthermore, the 8 second inter-train interval in this iTBS sequence enables a smoother escalation from 20% machine amplitude to 110% RMT, and this escalation helps with patient comfort.

A unique feature of our protocol was the use of a flexible rTMS schedule. While acute rTMS treatments are typically administered 5 days per week (Monday-Friday), we allowed participants to attend 3–5 visits/week across 2–4 weeks until they reached the acute phase dose (i.e., 20 sessions of iTBS). This flexible scheduling in the acute phase was followed by the follow-up phase where participants attended 1 visit/week for 4 weeks, similar to the protocol used by Zangen et al., 2021. A lower treatment density of 3 rTMS sessions per week has been shown to be noninferior to 5 rTMS sessions per week among patients with depression (Galletly et al., 2012). The advantage of the flexible schedule is to better accommodate participant’s work schedules and reduce attrition. However, the extent to which delivering 1 or 2 sessions/day on 3 or 5 visits/week influences the efficacy and durability of rTMS is unknown.

A challenge of interpreting substance use data from RCT rTMS studies with sham control conditions is that a notable placebo effect occurs in the sham condition (Amiaz et al., 2009, Dinur-Klein et al., 2014, Mikellides et al., 2022). Placebo effects of sham rTMS have been reported in the context of depression as well (Razza et al., 2018), and are perhaps more powerful during the use of a medical device, rather than an oral placebo (Kaptchuk et al., 2000). Unfortunately, this leads to a decreased likelihood of separating the therapeutic effects of the active versus the sham intervention. The placebo effect may also be attributed to numerous face-to-face visits with the study team, which is a relatively unique feature of rTMS treatment. The attention and informal motivation from the staff may lead to a positivity bias in the participants’ perception of the intervention. A positivity bias may be the reason why slightly more than half of the participants guessed they had received active rTMS. The decreased cigarette consumption in both active and sham groups may have been due to the smoking cessation educational booklets, and this intervention has been reported by other rTMS studies (Carl et al., 2020). Lastly, the present study, which required 15 in-person visits, was open to enrollment in July 2020 when COVID transmission rates were high, and vaccines were unavailable. The participants who enrolled in the study were potentially highly motivated to quit smoking and were willing to risk COVID exposure to receive treatment. Altogether, these various factors could have contributed to a placebo effect in the sham group, and significant reductions of cigarette consumption in both groups.

While most rTMS studies for substance use disorder have targeted the DLPFC, two other RCTs for smoking cessation applied rTMS to the medial and lateral PFC and insula (using an H4 coil) across 13–18 daily sessions of 10 Hz stimulation. Both studies reported decreased cigarette use (Dinur-Klein et al., 2014, Zangen et al., 2021). The H4 coil (BrainsWay, Israel) was designed to stimulate the MPFC and the inferior lateral PFC extending to the insula, although the peak electric field intensity is in the MPFC (Fiocchi et al., 2018). Thus, these prior studies support the targeting of the MPFC. Furthermore, Joutsa et al. mapped focal brain lesions among individuals who smoked cigarettes at the time of the brain damage and who either did or did not quit smoking abruptly (i.e., addiction remission) (Joutsa et al., 2022). Lesions were mapped to brain networks, revealing positive and negative functional connectivity among brain regions associated with addiction remission. Specifically, lesions related to addiction remission were positively connected to the mid-cingulate and insula and negatively connected to the MPFC (Joutsa et al., 2022). This also suggests stimulation to the MPFC (approximately BA 10) could be a fruitful TMS target. This is a similar location to the H4 coil as well as our target site at AFz. However, it is unknown whether the relatively focal targeting of the MPFC with a figure-8 coil is as effective as the broader cortical targeting produced by the H4 coil. Altogether, this literature illustrates the potential value of continuing TMS research targeting the MPFC for tobacco as well as other substance use disorders. A barrier to targeting the MPFC are researchers’ concerns that stimulating the MPFC would be more uncomfortable for the participants than stimulating the DLPFC. However, we have shown that our incremental ramping approach produces similar pain ratings between MPFC and DLPFC target sites across several pulse sequences (cTBS, iTBS, and 10 Hz) (Smith et al., 2021).

Recruitment for this study was negatively impacted by COVID shutdowns, which also interfered with the ability to collect neuroimaging data on all participants. Another limitation included a high rate of attrition. In all, 60% attrition was observed from randomization to last follow-up, although only 5 participants were lost to contact. This resulted in a smaller sample size than intended and thus this study is underpowered for a behavioral effect of TMS, although our sample size in the active rTMS group was similar to previous studies.

In summary, this study did not find a significant therapeutic effect of rTMS for tobacco use disorder; cigarette use, craving, and tobacco withdrawal symptoms all decreased across time similarly in the active and sham rTMS groups. Compared to other published studies, this study was unique due to the use of iTBS, the targeting of the MPFC, the flexible scheduling, and the use of a smoking cessation educational intervention. Future studies may consider combining rTMS with pharmacotherapies, e.g., (Ibrahim et al., 2023). While accumulating evidence supports the MPFC as a TMS target in substance use disorders, future research should address the question of whether iTBS is similar to standard high-frequency rTMS, compared to low-frequency rTMS or cTBS, in treating substance use disorders.

Supplementary Material

1

Highlights.

  • Intermittent theta burst stimulation (iTBS) was tested for tobacco use disorder

  • iTBS was administered on the medial prefrontal cortex for 14 visits

  • Both active and sham iTBS reduced the number of cigarettes per day

Role of funding source:

NIH NIDA R01DA044471.

Footnotes

Author disclosures

Declaration of Competing Interest:

This NIH project was originally awarded to Drs. Colleen Hanlon and Warren Bickel (Multiple Principal Investigator). After the completion of data collection, Dr. Hanlon’s role as Principal Investigator was transferred to Dr. Merideth Addicott. Colleen Hanlon is employed by BrainsWay and has financial interest in the company. The remaining authors declare no competing interests.

Declaration of Competing Interest: Colleen Hanlon is employed by BrainsWay and has financial interest in the company. The remaining authors declare no competing interests.

Authorship contribution statement:

Colleen Hanlon and Warren Bickel contributed to the study’s conception and design. Data collection was conducted by Colleen Hanlon, Kaitlin Kinney, and Hannah DeMaioNewton. Santiago Saldana and Edward Ip conducted data analysis. Merideth Addicott wrote the first draft of the manuscript and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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