Accelerated Deep Transcranial Magnetic Stimulation for Smoking Cessation
Phase: PHASE2
Conditions: Tobacco Use Disorder, Addiction Nicotine
Sponsor: Waypoint Centre for Mental Health Care

 
 
 
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Accelerated Deep Transcranial Magnetic 
Stimulation for Smoking Cessation 
 
Trial Principal Investigator: Bernard Le Foll 
Project ID: 5240 
Version Number: 1.1 
Version Date: 05-Nov-2025 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Sponsor: 
 
 
 
 
 
 
 
 
 
Lead Principal  
Investigator: 
 
 
Site-Principal  
Investigators: 
 
 
 
 
Co-Investigators: 
Bernard Le Foll, MD, PhD, MCFP(AM) 
500 Church Street, Penetanguishene, ON L9M 1G3  
705-549-3181 Ext 2142 
 
Waypoint Centre for Mental Health Care 
Waypoint Research Institute 
500 Church Street, Penetanguishene, ON L9M 1G3 
705-549-3181 Ext 2308 
 
 
Bernard Le Foll, MD, PhD, MCFP(AM) 
500 Church Street, Penetanguishene, ON L9M 1G3  
705-549-3181 Ext 2142 
 
Plabon Ismail, MD, FRCPC 
Waypoint Centre for Mental Health Care 
Peter Giacobbe, MD, FRCPC 
Sunnybrook Research Institute 
 
 
Nir Lipsman, MD, PhD, FRCSC 
Benjamin Davidson, MD, PhD 
Daniel Blumberger, MD, MSc, FRCPC 
Saulo Castel, MD, PhD, FRCPC 
Rahat Hossain, MD, FRCPC 
Sean Nestor, MD, PhD, FRCPC 
Enoch Ng, MD, PhD, FRCPC 
Vincent Xi-Yu Wang, MD 
Florence Tang, MA 
 
Funder: 
Waypoint Centre for Mental Health Care 
500 Church Street, Penetanguishene, ON L9M 1G3 
705-549-3181 Ext 2308 
 
Sunnybrook Research Institute 
2075 Bayview Ave, North York, ON M4N 3M5 
416-480-6100 
 

 
 
 
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Table of Contents 
 
STATEMENT OF COMPLIANCE ................................................................................................................. 6 
LIST OF ABBREVIATIONS.......................................................................................................................... 7 
CLINICAL TRIAL SUMMARY ...................................................................................................................... 9 
1.0 INTRODUCTION ................................................................................................................................ 10 
1.1 
BACKGROUND .............................................................................................................................. 10 
1.2 
STUDY INTERVENTION .................................................................................................................. 12 
1.3 
PRECLINICAL DATA TO DATE ......................................................................................................... 12 
1.4 
CLINICAL DATA TO DATE............................................................................................................... 13 
1.5 
RISKS/BENEFITS .......................................................................................................................... 14 
2.0 CLINICAL TRIAL OBJECTIVES ....................................................................................................... 15 
2.1 
PRIMARY OBJECTIVES .................................................................................................................. 15 
2.2 
SECONDARY OBJECTIVES ............................................................................................................. 16 
3.0 CLINICAL TRIAL DESIGN ................................................................................................................ 16 
3.1 
OVERALL DESIGN ......................................................................................................................... 16 
3.2 
PRIMARY ENDPOINTS ................................................................................................................... 17 
3.3 
SECONDARY ENDPOINTS .............................................................................................................. 17 
4.0 PARTICIPANT SELECTION, RECRUITMENT AND WITHDRAWAL .............................................. 17 
4.1 
TARGET POPULATION ................................................................................................................... 17 
4.2 
PARTICIPANT RECRUITMENT AND SCREENING................................................................................ 18 
4.3 
EQUITY, DIVERSITY AND INCLUSION CONSIDERATIONS ................................................................... 19 
4.4 
ELIGIBILITY CRITERIA ................................................................................................................... 19 
4.4.1 
Inclusion Criteria .................................................................................................................... 19 
4.4.2 
Exclusion Criteria................................................................................................................... 20 
4.5 
LIFESTYLE CONSIDERATIONS ........................................................................................................ 20 
4.6 
SCREEN FAILURES ....................................................................................................................... 21 
4.7 
PARTICIPANT WITHDRAWAL CRITERIA ........................................................................................... 21 
4.7.1 
When and How to Withdraw Participants .............................................................................. 21 
4.7.2 
Follow-up for Withdrawn Participants .................................................................................... 22 
5.0 STUDY INTERVENTION ................................................................................................................... 23 
5.1 
DESCRIPTION ............................................................................................................................... 23 
5.2 
TREATMENT REGIMEN .................................................................................................................. 24 
5.3 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ................................................. 24 
5.4 
ADMINISTRATION OF STUDY INTERVENTION ................................................................................... 24 
5.5 
PARTICIPANT COMPLIANCE MONITORING ....................................................................................... 24 
5.6 
CONCOMITANT THERAPY .............................................................................................................. 24 
5.7 
PACKAGING ................................................................................................................................. 25 
5.8 
BLINDING OF STUDY INTERVENTION .............................................................................................. 25 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 25 
5.9.1 
Receipt of Study Intervention Supplies ................................................................................. 25 
5.9.2 
Storage .................................................................................................................................. 25 
5.9.3 
Dispensing of Study Intervention........................................................................................... 25 
5.9.4 
Return or Destruction of Study Intervention .......................................................................... 26 
6.0 RESEARCH PROCEDURES ............................................................................................................. 26 
6.1 
RESEARCH VISITS ........................................................................................................................ 26 

 
 
 
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6.2 
SCHEDULE OF EVENTS ................................................................................................................. 32 
7.0 STATISTICAL PLAN ......................................................................................................................... 33 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 33 
7.2 
STATISTICAL METHODS ................................................................................................................ 33 
8.0 SAFETY AND ADVERSE EVENTS ................................................................................................... 34 
8.1 
DEFINITIONS ................................................................................................................................ 34 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 35 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS .................................................................................. 35 
8.3.1 
Investigator Reporting: Notifying the Sponsor ....................................................................... 35 
8.3.2 
Investigator Reporting: Notifying the REB ............................................................................. 35 
8.3.3 
Sponsor Reporting of Adverse Events: Notifying Health Canada ......................................... 36 
8.3.4 
Sponsor Reporting of Adverse Events: Notifying Sites ......................................................... 36 
8.4 
REPORTING OF DEVICE DEFICIENCIES ........................................................................................... 36 
8.5 
SAFETY MANAGEMENT PLAN ........................................................................................................ 36 
8.6 
UNBLINDING PROCEDURES ........................................................................................................... 38 
8.7 
DATA AND SAFETY MONITORING BOARD ....................................................................................... 38 
9.0 CLINICAL TRIAL DISCONTINUATION AND CLOSURE ................................................................. 38 
9.1 
CLINICAL TRIAL DISCONTINUATION ................................................................................................ 38 
10.0 DATA HANDLING AND RECORD KEEPING ................................................................................... 39 
10.1 
SOURCE DOCUMENTS & CASE REPORT FORMS ............................................................................. 39 
10.2 
PROTOCOL DEVIATIONS ............................................................................................................... 39 
10.3 
RECORD RETENTION .................................................................................................................... 39 
10.4 
CLINICAL TRIAL REGISTRATION ..................................................................................................... 39 
11.0 STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 39 
11.1 
STUDY MONITORING PLAN ............................................................................................................ 39 
11.2 
TRAINING AND QUALIFICATIONS OF STUDY PERSONNEL ................................................................. 40 
11.3 
AUDITING AND INSPECTING ........................................................................................................... 40 
12.0 ETHICAL CONSIDERATIONS .......................................................................................................... 40 
12.1 
RESEARCH ETHICS BOARD (REB) APPROVAL ............................................................................... 40 
12.2 
INFORMED CONSENT PROCESS & DOCUMENTATION ...................................................................... 41 
13.0 PRIVACY AND CONFIDENTIALITY ................................................................................................. 42 
14.0 CLINICAL TRIAL FINANCES ............................................................................................................ 43 
14.1 
FUNDING SOURCE ........................................................................................................................ 43 
14.2 
CONFLICT OF INTEREST ................................................................................................................ 43 
15.0 PUBLICATION POLICY/DATA SHARING ........................................................................................ 43 
15.1 
FUTURE SECONDARY USE OF DATA .............................................................................................. 43 
16.0 REFERENCES ................................................................................................................................... 44 

 
 
 
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STATEMENT OF COMPLIANCE 
 
This clinical trial will be carried out in accordance with the following:  
• International Council for Harmonisation Good Clinical Practice (ICH GCP) 
• Tri-Council Policy Statement 2022 (TCPS 2) 
• ISO 14155:2020 for Medical Device Clinical Trials 
• Personal Health Information Protection Act (PHIPA), 2004; Chapter 3 Schedule A 
(PHIPA) and applicable regulations 
• Institutional and REB policies and procedures 
 
 
 
 
 
________________________________  
_____________________________ 
Signature of PI 
 
 
 
 
Date 
 
 
 
________________________________  
_____________________________ 
Signature of Waypoint Site-PI 
 
 
Date 
 
 
 
________________________________  
_____________________________ 
Signature of Sunnybrook Site-PI  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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LIST OF ABBREVIATIONS 
 
aTMS  
Accelerated Transcranial Magnetic Stimulation 
AE  
 
Adverse Events 
ASRM  
Altman Self-Rating Mania Scale 
CAMH 
Centre for Addiction and Mental Health 
DLPFC  
Dorsolateral Prefrontal Cortex 
DSM-V  
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
FDA  
U.S. Food and Drug Administration 
FTND   
Fagerstrom Test of Nicotine Dependence 
GABA  
Gamma-Aminobutyric Acid 
GAD-7  
General Anxiety Disorder-7 
GBDP  
Global Burden of Disease Project 
HCG             Human Chorionic Gonadotropin 
ICF            
Informed Consent Form 
MAR  
Missing At Random 
MINI  
Mini International Neuropsychiatric Interview 
MNSW  
Minnesota Nicotine Withdrawal Scale 
NIBS  
Non-Invasive Brain Stimulation 
PHQ-9 
Patient Health Questionnaire-9 
REB  
Research Ethics Board 
REDCap       Research Electronic Data Capture 
RMT           Resting Motor Threshold 

 
 
 
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RPN           
Research Practice Nurse 
rTMS  
Repetitive Transcranial Magnetic Stimulation 
TASS  
TMS Adult Safety Screening Questionnaire 
TLFB   
Timeline Follow-Back 
TMS  
Transcranial Magnetic Stimulation 
TCQ-SF         Tobacco Craving Questionnaire-Short-Form 
TTC  
Toronto Transit Commission 
 
 
 
 
 
 
 
 

9 
 
 
CLINICAL TRIAL SUMMARY 
 
Title 
Accelerated deep transcranial magnetic stimulation for 
smoking cessation 
Short Title 
adTMS smoking 
Phase 
Phase II 
Methodology 
One-arm, open-label pilot study 
Clinical trial Duration 
24 months 
Participating site(s) 
2 sites: Waypoint Centre for Mental Health Care and 
Sunnybrook Research Institute 
Objectives 
To examine the efficacy of accelerated deep transcranial 
magnetic stimulation on smoking abstinence 
Number of 
Participants 
40, aiming 30 completers 
Duration of 
Intervention 
5 days  
Statistical 
Methodology 
Descriptive statistics, mixed effect logistic regression, and 
linear/generalized mixed models will analyze abstinence and 
secondary outcomes, adjusting for covariates and missing 
data under the MAR assumption 
 

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1.0 INTRODUCTION 
 
Tobacco use disorder is a serious and growing public health issue. The Global Burden 
of Disease Project (GBDP) estimated that 1.14 billion people smoked worldwide in 
2019[1]. Smoking tobacco accounts for 7.69 million deaths per year and is the leading 
risk factor for death among males[1]. Increasing therapeutic strategies effective for the 
treatment of tobacco use disorder is therefore of tremendous importance. While first-
line pharmacotherapies for tobacco use disorder demonstrate efficacy for short-term 
smoking cessation, relapse remains a challenge for smokers[2,3]; more modalities to 
address smoking cessation are needed. 
 
In recent years, non-invasive brain stimulation (NIBS) approaches, such as 
transcranial magnetic stimulation (TMS), have gained attention. In 2020, the U.S. Food 
and Drug Administration (FDA) approved a deep TMS system for use in smoking 
cessation in adults[4], which was also approved by Health Canada in 2022, marking 
the first approval in the addiction field. This system focuses on the insula, which has 
been recognized as being related to nicotine cues and the self-administration of 
nicotine[5,6] in our previous studies. Our group has also evaluated deep TMS's 
efficacy in smoking cessation as an add-on treatment strategy to varenicline[7]. 
Beyond addiction, TMS has been approved and utilized in many neuropsychiatric 
disorders, such as treatment-resistant depression and obsessive-compulsive disorder, 
and has gradually developed many different modalities within TMS. One of these 
promising modalities is the accelerated protocol for TMS (aTMS). 
 
aTMS could reduce depressive symptoms with a large effect size[8], which is 
comparable to or even superior to the standard TMS protocol in some settings[9,10]. 
For depression, deep aTMS could reach response and remission in less than one 
week, with such effects persisting for up to 6 months[11]. Given the great potential of 
this TMS protocol and the current need to expand and improve the modality for 
smoking cessation, we aim to examine deep aTMS's efficacy in smoking cessation and 
relapse prevention. To our knowledge, this will be the first trial testing deep aTMS for 
tobacco use disorder. 
 
1.1 
Background 
 
Disease burden of smoking: The Global Burden of Disease Project (GBDP) estimated 
that the number of smokers worldwide increased from under 1 billion in 1990 to 1.14 
billion in 2019[1,12]. Smoking is more prevalent among individuals with mental health 
disorders and co-addictions, such as substance use disorder, anxiety, depression, 
phobias, psychosis, and antisocial personality or conduct disorders[13–16]. Smoking 
that begins in adolescence or young adulthood and continues throughout life has a 
more severe impact on health than smoking that starts later or is not persistent[17,18]. 
If current trends continue, at least 320 million smoking-related deaths will occur among 
those under 30 unless they quit[19]. The mortality rate among long-term smokers could 

11
 
 
be greater than one in two, potentially reaching as high as two in three[17,18,20,21], 
with half of these deaths likely occurring in middle age (30-69 years), leading to a loss 
of two or more decades of life[17,18]. Smoking remains the leading cause of premature 
death before age 70 in much of Europe and North America[17,18]. However, smoking 
cessation significantly reduces the risks associated with smoking. Smokers who quit 
before age 40 can avoid nearly all the increased mortality risks[19,21], and those who 
quit by age 50 reduce their risk of death from lung cancer by about two-thirds[22]. 
Given the significant health risks and high mortality associated with smoking, 
particularly among vulnerable populations, investigating new modalities for smoking 
cessation is crucial to reducing these risks and improving public health outcomes. 
 
Repeated Transcranial Magnetic Stimulation (rTMS) as an innovative approach: rTMS 
is a technique that has been found to be useful as a potential treatment for 
neuropsychiatric diseases. rTMS is non-invasive, does not require anesthesia, and is 
not associated with significant side effects. There is compelling evidence that rTMS 
works by affecting the function of neuronal circuits and inducing local changes in 
neural excitability. Transient inactivation of a specific brain structure can also be 
induced in humans through rTMS, through mechanisms that are likely associated with 
potentiation of GABAB receptor mediated inhibitory neurotransmission[23]. However, 
rTMS effects are complex and likely involve local modifications in the dynamic release 
patterns of various neurotransmitters, including dopamine[24–28]. The fact that there is 
in vivo evidence that rTMS of frontal brain regions has a modulatory effect on 
dopaminergic system, suggest that rTMS may be particularly useful in neuropsychiatric 
disorders associated with dopamine dysfunction, such as addiction[25,29].  Moreover, 
with the recent development of Deep rTMS H-coils, it has become feasible to perform 
rTMS on deeper brain structures such as the insula[30–32]. 
 
Insula as a target structure: Several lines of research implicate the insula as a critical 
substrate in nicotine dependence following evidence that insular lesions produce a loss 
of self-reported cravings for cigarettes and immediate cessation of smoking without 
relapse[33,34]. As observed and examined by Naqvi et al., smokers with brain damage 
involving the insula are more likely to experience a disruption in their smoking 
addiction, often resulting in the ability to quit smoking without relapse and persistent 
urges, compared to smokers with brain damage that does not involve the insula[34]. 
They further proposed that the insula plays a role in the recall of the interoceptive 
effects of drug taking, and through interactions with other brain regions, mediates 
conscious urges and decision-making precipitating relapse[35]. This hypothesis is 
supported by preclinical studies[5,6,36–38] conducted at our translational addiction 
research laboratory, where we demonstrated that electrical stimulation at insular cortex 
significantly reduced nicotine-taking and nicotine-seeking behaviors triggered by cues 
and priming. These effects appear to be specific to nicotine-related behaviors, as 
stimulation did not affect food-taking behavior[6]. Additionally, GABA agonist-induced 
inactivation of both the granular and agranular insular cortex reduced nicotine self-
administration[5,36]. Our previous preclinical studies have also shown that the insula 
plays a pivotal role in other addictions, including alcohol intake behavior[37] and rodent 
gambling task[38]. Neuroimaging studies further evidence significant associations 

12
 
 
between cue-induced activation of the insula and self-reported craving for a 
cigarette[39], with greater bilateral insular pre-quit activity also predicting relapse in 
smokers[40]. Alongside the approval of deep TMS for clinical use in smoking[41], our 
laboratory has also tested the utility of insula-targeting deep TMS as an adjunctive 
treatment to varenicline, a psychopharmacological agent used for smoking 
cessation[7]. 
 
1.2 
Study Intervention 
 
Accelerated Transcranial Magnetic Stimulation (aTMS) protocols are increasingly being 
explored to address the practical challenges of conventional repetitive TMS (rTMS) and 
to enhance overall efficacy. Conventional rTMS typically involves one session daily over 
several weeks. In contrast, aTMS intensifies this approach by delivering multiple 
sessions per day, ranging from 2 to 10 sessions. In this study, we will implement the H4 
deep aTMS protocol, administering 20 sessions over one week—four sessions daily for 
five consecutive days—targeting the bilateral insular cortex and prefrontal cortex using 
the Health Canada-approved H4 coil. The parameters used in each session will adhere 
to those approved by Health Canada, and will be described later (see Section 5.1). This 
method aims to improve efficacy and accessibility for smoking cessation, building on a 
more condensed and intensive schedule. 
 
1.3 
Preclinical Data to Date 
 
Our Translational Addiction Research Laboratory has collected significant pre-clinical 
evidence supporting this trial. Preclinical results from our studies reveal that temporary 
insular inactivation in rats leads to reduced nicotine self-administration and seeking 
after exposure to nicotine-associated cues or a priming dose (Figure 1)[5,6]. These 
findings have been replicated under several conditions in rodent models, 
demonstrating that silencing the granular or agranular subregions of the insular cortex 
via local infusions of GABA receptor agonists (baclofen and muscimol) decreases both 
the motivation to self-administer nicotine and the likelihood of relapse when nicotine 
cues or priming doses are reintroduced [5,6,37]. 
 
Mechanistically, these results suggest that the insula integrates the interoceptive and 
affective states that drive nicotine use—disrupting insular activity weakens the craving 
and “urge” signals that typically reinforce smoking behavior [5,37]. Notably, such 
insular manipulations have been shown to have minimal effects on other reinforcers, 
such as food, indicating a degree of specificity for nicotine dependence[5]. Overall, 
these insights underscore the critical role of the insula in the neurocircuitry of tobacco 
addiction and support targeting insular function as a promising approach for reducing 
nicotine use and preventing relapse in smokers. 
 

13
 
 
 
 
 
1.4 
Clinical Data to Date 
 
In a clinical trial, our group has suggested the efficacy of deep TMS in smoking 
cessation as an add-on treatment strategy to varenicline (Figure 2)[7]. 
 
 
 
In previous aTMS depression studies, the effect of aTMS may be attributed to several 
factors, including optimized neurocircuit-based targeting, an accelerated treatment 
schedule, and a higher total pulse count[42–46]. Optimized neurocircuit-based 
targeting can be achieved through e-field modeling or personalized, connectivity-based 
biomarkers, such as DLPFC-subgenual anterior cingulate cortex connectivity[42]. The 
higher total pulse count may also contribute to positive treatment outcomes. For 
example[47], 90,000 pulses delivered with accelerated protocol (1,800 pulses per 
session, 10 sessions per day, 5 days per week, over one week) demonstrated better 
efficacy in treating depression compared to 18,000 pulses administered through a 
standard protocol (600 pulses per session, 1 session per day, 5 days per week, over 6 
weeks). However, the individual components of aTMS still need to be isolated. Many 
Figure 1. Effect of insula inactivation on 
(A) nicotine- (.15 mg/kg SC, 10 min 
before the session) or (B) cue-induced 
reinstatement of nicotine seeking tests 
after extinction (n = 8 and n = 6, 
respectively).; **p<0.01; 
***p<0.001. Extracted from [5]. 
Figure 2. Abstinence rates at Week 4, 12, and 26. 
Abstinence was measured by 7- day point-
prevalence abstinence. All measures were 
confirmed with plasma cotinine. Bars represent 
(±) standard error. Group sample sizes: Week 4 
(n =18 active, n =16 sham), Week 12 (n =17 
active, n =15 sham), and Week 26 (n = 16 active, 
n =15 sham).; *p<0.05. 
 

14
 
 
previous aTMS depression studies combine more than one of these factors. Therefore, 
even when considering aTMS beyond smoking cessation, isolating the effect of the 
accelerated treatment schedule is crucial to understand this technique. 
 
1.5 
Risks/Benefits 
 
 
Risk: Several recent investigations have demonstrated that aTMS maintains a 
favorable safety profile similar to conventional once-daily protocols[47–49]. In a real-
world study of accelerated deep TMS for major depression, no serious adverse events 
were observed among 111 patients receiving two to ten sessions per day[11]. Parallel 
evidence from a transdiagnostic review of 63 aTMS studies likewise concluded that 
aTMS appears to be safe and well-tolerated, with adverse event rates comparable to 
once-daily TMS[50]. 
 
The most serious potential adverse event with TMS is seizure. Among 1543 
participants undergoing 43,873 aTMS sessions, only one seizure (0.0023%) was 
reported—a rate similar to or lower than that of conventional rTMS delivered once per 
day[50]. Notably, the patient who experienced this single event later resumed standard 
once-daily TMS safely and achieved remission. 
 
Headaches are the most frequently reported side effect, and aTMS is no exception, 
though rates appear comparable to those in conventional once-daily rTMS. In the 
aTMS review, 28.4% of participants reported headaches, followed by mild, transient 
scalp pain or discomfort (8.3%)[50]. Similar to once-daily TMS, these effects often 
diminish over the first few sessions. Apart from headache and scalp discomfort, side 
effects such as fatigue and other adverse events remained below 10%, and dropout 
rates attributable to side effects were approximately 2%[50].  
 
This underscores that intensifying the treatment schedule with multiple daily sessions 
does not substantially amplify risk. Overall, the safety and tolerability of aTMS are 
consistent with the well-established profiles observed in standard TMS protocols. 
 
 
Benefit: The advantage of an accelerated approach is based on three theoretical 
reasons[9,51]. First, it presumes that equal or greater effects can be achieved by 
repeatedly applying stimulation within a short time interval. Second, it suggests that the 
effects induced within densely scheduled sessions have durable efficacy. Third, aTMS 
has the theoretical advantage of an accelerated response to treatment, given that it 
clusters the stimulation intervention within days. Regarding the theoretical equal or 
greater effect of aTMS, neurophysiologic evidence supports this by showing that a 
greater effect on cortical excitability is observed if a second rTMS session is 
administered within 24 hours of the first session[52]. Such equal or greater effects are 
also observed clinically in patients with depression treated with aTMS[9]. The durability 

15
 
 
and rapid onset of the proposed effects have also been demonstrated in naturalistic 
studies applying aTMS for depression[11]. Supporting a more densely clustered 
protocol, other research has proposed a dose-response relationship for rTMS, 
indicating that the number of stimuli and total session number correlate with the 
response[53]. 
 
In addition to the possible benefits already mentioned, examining the efficacy of aTMS 
for smokers has practical significance. The daily administration of rTMS over several 
weeks can limit its accessibility, particularly for patients who are working or must travel 
long distances to reach a treatment site[54]. Furthermore, individuals with tobacco use 
disorder often struggle with treatment adherence, even with psychopharmacological 
approaches[55], while longer treatment courses are more difficult to adhere to. About 
98% of adults with tobacco use disorder complete psychopharmacological treatment in 
randomized controlled trial[56], but only 25~30% of adults with tobacco use disorder 
complete nicotine replacement therapy or psychopharmacological treatment in real life 
settings[57,58]. By consolidating the full course of TMS treatments from weeks into 
days, aTMS offers advantages in addressing these challenges, making it particularly 
relevant for patients with addictive disorders. For example, in a conventional once-daily 
20-session treatment course, patients need to visit the TMS clinic over 20 days. In 
contrast, this proposed accelerated protocol allows 20 sessions to be administered 
within 5 days, meaning patients only need to visit the clinic for 5 days. By further 
confirming the comparable effectiveness of accelerated TMS to the standard protocol, 
we expect this approach to greatly enhance the feasibility and acceptability of the 
treatment for patients. 
 
2.0 CLINICAL TRIAL OBJECTIVES  
 
We will test, for the first time, the overall feasibility of bilateral accelerated deep 
transcranial magnetic stimulation (deep aTMS) for smoking abstinence, including 
measures of tolerability, acceptability, retention, and adherence. Our secondary 
objectives are to assess the effects of deep aTMS on short-term point prevalence 
abstinence—measured by self-reported abstinence over the past 7 days and confirmed 
with urine cotinine—at the end of treatment (Week 1), and at Weeks 3, 5, 9, 13, and 26, 
as well as prolonged and continuous abstinence rates at Weeks 13 and 26. We also 
aim to explore the potential for rapid onset of effect, along with its impact on attenuating 
craving, reducing cigarette consumption, and decreasing dependence severity 
throughout the study. 
 
 
2.1 
Primary Objectives 
 

16
 
 
To assess the overall feasibility of bilateral accelerated deep TMS (aTMS) for smoking 
abstinence, including measures of tolerability, acceptability, retention, and adherence. 
 
2.2 
Secondary Objectives 
 
Secondary Aim 1: To examine the effect of bilateral deep aTMS on short-term 
abstinence at the end of TMS treatment, at post-treatment follow-ups (point prevalence 
abstinence at Week 3, Week 5, Week 9, Week 13, Week 26), 
 
Secondary Aim 2: To examine the effect of bilateral deep aTMS on prolonged and 
continuous abstinence at 3-month and 6-month follow-up (Week 13 and Week 26). 
 
Secondary Aim 3: To examine the effect of bilateral deep aTMS on other smoking 
outcomes throughout study duration including self-reported craving, cigarette smoking 
and dependence severity. 
 
 
3.0 CLINICAL TRIAL DESIGN 
3.1 
Overall Design 
 
This clinical trial is designed as a one-arm, open-label study to evaluate the efficacy and 
feasibility of the H4 deep accelerated transcranial magnetic stimulation (aTMS) protocol 
for smoking cessation. The absence of a control group is intentional, as this pilot study 
focuses on assessing the intervention’s preliminary efficacy in a single arm of 40 
participants with tobacco use disorder who are motivated to quit, aiming for 30 completers 
to guide a future controlled trial. Each participant’s involvement will last 26 weeks, starting 
with a screening phase at Week 0, followed by a one-week treatment period in Week 1, 
and concluding with follow-up visits at Weeks 3, 5, 9, 13, and 26. The entire trial is 
expected to span approximately 2 years, covering recruitment, treatment, and follow-up 
for all participants. 
 
During Week 1, participants will receive 20 rTMS sessions using the Health Canada-
approved H4 deep TMS coil, administered at four sessions per day over five consecutive 
days, targeting the insular cortex, alongside brief counseling adapted from the Mayo 
Clinic’s ‘Smoke Free and Living It’ manual. Daily assessments will monitor safety, 
Timeline Followback (TLFB), and nicotine craving and withdrawal symptoms. The primary 
outcome is overall feasibility, including measures of tolerability, acceptability, retention, 
and adherence. Secondary outcomes include 7-day point prevalence abstinence—
verified by self-report and urine cotinine levels (<200 ng/mL)—at the end of treatment and 
at Weeks 3, 5, 9, 13, and 26. We will also assess 3-month abstinence at Week 13 and 6-
month abstinence at Week 26, both verified by continuous self-reported abstinence during 

17
 
 
the respective periods and corresponding urine cotinine levels. Factors such as 
comorbidities, pre-existing tobacco use disorder severity, or motivation level for 
abstinence may influence results; these are addressed through eligibility criteria and 
statistical adjustments. 
 
It is anticipated that a proportion of enrolled participants may not proceed to the treatment 
phase (Week 1) due to scheduling, logistical, or personal factors. These individuals will 
be classified as early dropouts and excluded from the intent-to-treat analysis, which will 
include only participants who initiate at least one TMS session.  
 
3.2 
Primary Endpoints 
 
The overall feasibility of accelerated deep TMS (aTMS) for smoking abstinence: assessed 
through tolerability (frequency of side effects reported at each visit during Week 1), 
acceptability (self-reported ratings collected at the end of treatment), retention rate (the 
proportion of participants who completed the full study), and adherence rate (the 
proportion of completed sessions among participants who initiated treatment). 
3.3 
Secondary Endpoints 
 
1. Proportion of participants achieving 7-day point prevalence abstinence at end of 
treatment, Week 3, Week 5, Week 9, Week 13, and Week 26.  
 
2. Proportion of participants achieving prolonged and continuous abstinence at Week 13 
and Week 26. 
 
3. Change in self-reported craving, average cigarettes smoked per day, and 
dependence severity (e.g., using standardized questionnaires) from baseline through 
study completion. 
 
4.0 PARTICIPANT SELECTION, RECRUITMENT AND 
WITHDRAWAL 
4.1 
Target Population 
 
This trial targets 40 adults (aged 18-65) with tobacco use disorder who smoke ≥10 
cigarettes daily, have an FTND score ≥4, and a Contemplation Ladder score ≥7, aiming 
for 30 completers. Pregnant people, children, cognitively impaired individuals (MMSE 
<24), and those with rTMS safety concerns, such as underlying neurological diseases or 
a history of seizures or suicidal behavior, are excluded.  

18
 
 
4.2 
Participant Recruitment and Screening 
 
Recruitment: Participants in the proposed study will be individuals with tobacco use 
disorder (n=40). The anticipated accrual rate is approximately 20 participants per year. 
With a target sample size of 40, we expect to complete enrollment over a period of 2 
years. We will recruit through various sources: local newspaper ads, the community, 
Waypoint Centre for Mental Health Care, and Sunnybrook Health Sciences Centre 
clinics, word of mouth, and/or through posters/flyers distributed in and around the 
research sites. Approved study recruitment ads will be placed primarily around, but not 
limited to, the Midland-Penetanguishene and  downtown Toronto areas to target 
participants who can feasibly travel to either study site. In Toronto, ads may also be 
placed in TTC streetcars, buses and subways. Ads and flyers will be approved by the 
REB. Participants may also be recruited from similar protocols approved at each 
research center provided they have agreed to being contacted about future studies. 
   
Eligibility Screening: Potential participants will undergo Waypoint or Sunnybrook REDCap 
pre-screening to determine initial eligibility. They will subsequently be invited to an in-
person or remote Screening Assessment to confirm final eligibility to participate. Following 
the review and signing of the Informed Consent Form, the following measures and 
assessments will be administered at the screening visit:  
 
1)  Fagerstrom Test of Nicotine Dependence (FTND). The FTND is a measure of physical 
dependence severity.  
 
2) Mini International Neuropsychiatric Interview (MINI). MINI will be used to diagnose 
tobacco use disorder in participants and/or any other psychiatric issues.  
 
3) Smoking Contemplation Ladder. This questionnaire allows for the measure of 
readiness to quit smoking in individuals. A cutoff score of 7 is commonly used to 
determine individuals who are motivated to quit.  
 
4) Medical and/or psychiatric assessment by study physician (or delegate).  
 
5) Demographic and contact forms.  
 
6) TASS form (TMS Adult Safety Screening Questionnaire).  
 
7) Concomitant medication log. 
 
 
Compensation: Participants who complete the full study will receive a total compensation 
of $550, provided either in cash (in CAD) or as an electronic gift card (e.g., 
EverythingCard). This amount comprises $25 for the screening and baseline visit each, 
$250 for the series of accelerated rTMS visits ($50 per visit for five visits), and $50 for 
each of the five follow-up visits. 

19
 
 
 
 
4.3 
Equity, Diversity and Inclusion Considerations 
 
This study aims to recruit a diverse sample that reflects Ontario’s population, ensuring 
the inclusion of historically underserved groups from various socioeconomic backgrounds. 
Given that we will also be recruiting participants at Sunnybrook Health Sciences Centre 
in Toronto, the most multicultural city in Canada, we anticipate strong minority group 
inclusion and will implement recruitment strategies that promote participation without 
restrictions based on race or ethnicity. Additionally, in alignment with Waypoint Centre for 
Mental Health Care’s Equity, Diversity, and Inclusion strategy, we will integrate training 
on Indigenous Cultural Safety, Anti-Black Racism, and EDI principles to foster an 
inclusive research environment. Recruitment and retention strategies will also be 
designed to ensure that our research team and staffing reflect the diverse patient 
populations we serve. 
 
Recognizing that sex and gender differences influence addiction and treatment outcomes, 
our study will integrate sex- and gender-based analysis to ensure a comprehensive 
approach to data interpretation. We will collect and analyze self-reported biological sex 
and gender identity to assess potential differences in treatment efficacy and interpret 
findings through a sex- and gender-based lens, ensuring that our recommendations 
remain relevant across diverse populations. Given established sex-related differences in 
smoking behaviors and nicotine metabolism, we will make every effort to recruit an equal 
number of male and female participants for robust sex-based analyses. Additionally, 
studies have shown that hormonal fluctuations can influence rTMS effects, with women 
exhibiting greater sensitivity to stimulation during periods of high estrogen. To ensure 
safety, pregnant or breastfeeding individuals will be excluded, as the safety of deep TMS 
in these populations has not been established. 
4.4 
Eligibility Criteria 
4.4.1 
Inclusion Criteria 
 
The participant must meet all of the inclusion criteria to be eligible for this clinical trial: 
1. Aged 18 years or older; 
2. Tobacco use disorder as assessed by DSM-5; 
3. Fagerstrom Test of Nicotine Dependence (FTND) ≥ 4; 
4. Reported motivation to quit within 30 days as assessed using the Contemplation 
Ladder score of ≥ 7; 
5. Must sign and date the informed consent form; 
6. Stated willingness to comply with all study procedures. 
7. Able to communicate in English. 

20
 
 
4.4.2 
Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in 
this clinical trial: 
1. Reported smoking abstinence in the 3 months preceding screening visit; 
2. Current use of other smoking cessation aids;  
3. Contraindication to rTMS;  
4. Pregnancy, trying to become pregnant or breastfeeding;  
5. Current or recent history of cerebrovascular disease;  
6. Unstable major psychiatric disorder(s) (i.e. Axis I Disorders) that would prevent 
participation in the study at PI (or its delegate) discretion;  
7. Serious current or personal history of medical condition/disease (neurological 
disorders, brain lesions, multiple sclerosis, head trauma, loss of consciousness, 
hearing loss, etc.) preventing same inclusion as per PI (or its delegate) discretion;  
8. Current, personal history or family history of seizures;  
9. Concomitant use of medication that lowers seizure threshold, such as clozapine;  
10. Concomitant use of more than 2 mg lorazepam (or an equivalent) or any 
anticonvulsants. 
4.5 
Lifestyle Considerations 
 
• Refrain from use of unregulated or illicit substance use during the rTMS treatment 
course. If there is use of any of these substances they will be assessed by a study 
physician to ensure that they are safe to continue with treatment. 
• Refrain from problematic alcohol use that includes frequent and recent binge drinking 
(5 or more drinks on an occasion for men or 4 or more drinks on an occasion for 
women), the presence of significant alcohol withdrawal symptoms, unpredictable 
pattern of use with varying amounts of drinking, and in the high-risk category according 
to low-risk drinking guidelines. Any of these signs will require assessment by a study 
physician.  
• Cannabis use will be assessed prior to treatment start. In general, they will be advised 
not to make any abrupt changes to their cannabis use without informing the study team. 
Those that show up visibly intoxicated or in withdrawal from any substance, including 
cannabis, will need to be seen by a study physician to ensure safety and whether they 
are appropriate to continue in the trial. Recreational cannabis use is not prohibited as 
long as they are not exhibiting signs of problematic cannabis use that would destabilize 
them medically or psychiatrically.  
• If problematic substance use as above should arise during the trial, to notify the 
principal investigator to manage with any other clinical care providers connected to the 
participant. Emergency medical services will be accessed as needed. Withdrawal from 
the trial will be determined based on inclusion/exclusion/withdrawal criteria and safety 
considerations at the discretion of the PI and study team.  
• Cigarette smoking induces the liver enzyme CYP1A2, and thus increases metabolism 
by certain medications that are metabolized by CYP1A2[59]. Participants that are on 

21
 
 
these medications will be reviewed to determine whether dose reductions may be 
needed if patients reduce their cigarette smoking during the treatment course.  
• As well, patients with diabetes will also be instructed to monitor their blood sugars more 
regularly due to the variable effects of smoking cessation on blood sugar control and 
insulin sensitivity[60].  
 
4.6 
Screen Failures  
For all screen failures, information including demography, screen failure details, and 
eligibility criteria will be collected. Re-screening generally will be considered after ≥1 
month and/or at the discretion of the Lead PI, Site-PI, and study team depending on 
reason for screen failure.  
 
4.7 
Participant Withdrawal Criteria 
4.7.1 
When and How to Withdraw Participants 
Patient participants are free to withdraw from participation in the clinical trial at any time. 
Completion of the study visits involving doing self-report surveys or semi-structured 
interviews do not have any withdrawal criteria except clinical instability precluding them 
from safely engaging in the assessment, as determined by the Lead PI/Site-PI.  
 
For the Week1, accelerated deep TMS treatment period: An investigator will discontinue 
or withdraw a participant for the following reasons: 
• Requires in-patient psychiatric hospitalization. 
• Develops clinically significant hypomanic or manic symptoms. Possible hypomanic or 
manic syndromes may be identified by study staff and a study physician will be 
immediately notified to conduct an assessment.  
• Cannot tolerate stimulation at 90% RMT on ≥5 treatment sessions overall.  
• Develops any medical illness that may be unstable or experience a seizure.  
• If a participant must miss rTMS treatments because of COVID-19 symptom 
screening/exposure restrictions and are not allowed to be on-site, those sessions will 
not count towards having to discontinue from study treatment per withdrawal criteria. 
It will be at the discretion of the investigators on a case-by-case basis if a participant 
needs to discontinue treatment during the trial should the absence secondary to 
COVID-19 symptom restrictions be prolonged. 
For the entire study period: An investigator may discontinue or withdraw a participant for 
the following reasons: 
• Pregnancy 
• Withdraws consent. 

22
 
 
• Meets an exclusion criterion (either newly developed or not previously recognized) 
related to safety that precludes further treatment. 
• Demonstrates clinical instability to the point where further participation in the study 
would not be in the best interests of the participant, at the discretion of the PI and the 
study investigator team. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded      
within the participant’s research record, and/or legal health record. Data up to the point 
of their last visit may be included in the analysis. 
 
 
4.7.2 
Follow-up for Withdrawn Participants 
If a participant withdraws consent, they can also request the withdrawal of their data 
subject to any research-specific restrictions, unless the data has already been de-
identified and shared. Once withdrawn from the clinical trial, no further research 
procedures or evaluations will be performed, or additional research-specific data 
collected on the participant. Reasonable effort will be made to obtain permission to 
document the reason for withdrawal.  
 
4.7.3 
Early Termination Visit 
If a patient participant withdraws from the clinical trial, they will be asked to attend an 
Early Termination Visit. This includes all assessments included in the post rTMS 
treatment visit as well as: 
• Assessment of new and ongoing AEs. 
• Assessment of any complications following the study intervention. 
• Documentation of all concomitant medications. 
 
The PI will ensure the participant is appropriately followed for any additional care as 
required. Data collected until the time of withdrawal may be used in analyses.    
 
4.7.4 
Participants who are Lost to Follow-up 
A patient participant will be considered lost to follow-up if they fail to return for >3 
scheduled visits that cannot be rescheduled and are unable to be contacted by the 
research team.  
 
The following actions will be taken if a participant fails to attend a required study visit: 
• The research team will attempt to contact the participant and reschedule the missed 
visit within the next 4 weeks and reconfirm whether the participant wishes to and/or 
should continue in the study.  

23
 
 
• Before a participant is deemed lost to follow-up, the research team will make every 
effort to regain contact with the participant (where possible, at least five contact 
attempts including both telephone calls and emails, unless specific contact 
preferences were specified by the participant). These contact attempts will be 
documented in the participant’s research record and/or legal health record.   
• Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the clinical trial with a primary reason of lost to follow-up. Data up to 
the point of their last visit will be included in the analysis.  
 
 
5.0 STUDY INTERVENTION  
5.1 
Description 
Treatment will be delivered through the H4 coil (Brainsway, Israel) and Brainsway 
stimulator system, generally following previously established reports[41]. Week 1, the 
treatment period, will begin on the participant's Target Quit Date (TQD), which will be 
standardized to coincide with the first day of TMS, as smokers are believed to be most 
susceptible to relapse during the early abstinence phase[61]. However, this may vary 
due to scheduling constraints. Resting motor threshold (RMT) will be established to 
determine stimulation intensity at the beginning of the treatment course. This is obtained 
by finding the optimal position of the helmet that elicits reliable activation of the right 
abductor pollicis brevis muscle, before then aligning the helmet symmetrically and 
moving it 6 cm anteriorly. Titration of stimulus intensity may occur to enhance 
tolerability. Stimulation intensity will be set at 120% RMT, with a minimum of 90% RMT 
if there are issues with tolerability. Initial sessions may start at a lower intensity 
(approximately 70% RMT) and increase accordingly. Sixty trains of 30 pulses each 
(total 1,800 pulses) will be applied at 10 Hz, for 3 second trains, with a 15 second inter-
train interval, for approximately 18 minutes of treatment time. For each day within Week 
1, four sessions will be administered, with an intersession interval of 30 minutes. TMS 
could be reschedule the next week in case of holidays, hospital closure or other factors 
that prevent booking the subjects. 
 
Participants will be asked to abstain from smoking for ≥2 hours before each visit in 
Week 1. Before the first session of each day in Week 1, it will be preceded by a brief 
provocation procedure that involves participants being asked to imagine one of their 
biggest triggers for smoking cravings, viewing pictures of smoking and handling a 
cigarette and lighter (with no lighter fluid) guided by a scripted recorded voice. In their 
baseline clinical assessment, participants will identify a list of their top 5 triggers for 
smoking. For the first session of each day in Week 1, prior to stimulation, first the 
participant will be asked to close their eyes and imagine one of the identified triggers for 
30 seconds. Next they will be presented with real cigarettes and a lighter, and then  be 
asked to listen to a recording for how to handle a cigarette and a lighter for 2 minutes. 
The recording will tell the participant to hold both items; they will not be asked to light 
the cigarette or smoke the cigarette. The cigarette and lighter will be as similar as 

24
 
 
possible to what each individual participant usually uses. If possible, the lighter fluid will 
be removed from the lighter to reduce fire risk. Following this, they will watch a 
PowerPoint presentation of smoking pictures for 2 minutes and 30 seconds. Thus, the 
entire procedure will be 4 minutes prior to stimulation start administered by trained 
research staff. 
 
5.2 
Treatment Regimen 
The treatment course consists of daily treatment with four sessions per day, over five 
days in Week 1 (one week), for a total of 20 treatment sessions. 
 
5.3 
Method for Assigning Participants to Treatment Groups 
Since this is a one-arm trial, all participants will receive accelerated deep TMS, with no 
randomization or allocation to different groups. 
 
5.4 
Administration of Study Intervention 
Deep TMS with accelerated protocol: Each treatment will be administered by an 
rTMS technician, RPN, or other trained individual. The individual responsible for 
administering all treatments will be adequately trained through the Sunnybrook 
Research Institute and Waypoint Centre for Mental Health Care, in collaboration with 
the University of Toronto, which offers a successful rTMS technician course covering all 
the technical and hands-on training required for the safe and effective delivery of rTMS. 
 
Each day in Week 1 will last approximately 3 hours including 4 minutes for general setup, 
3 minutes for the cue-induced craving protocol, and four 18-minute rTMS sessions 
interleaved with three 30-minute intervals approximately (4-3-18-30-18-30-18-30-18). 
Scheduling may vary slightly based on equipment availability. 
 
5.5 
Participant Compliance Monitoring 
Attendance to rTMS treatment sessions will be tracked and missed sessions will be 
counted. Any withdrawal from the study due to non-compliance will be addressed as per 
section 4.7.  
 
5.6 
Concomitant Therapy 
All prescribed medications, over-the-counter medications, and supplements will be 
recorded and reviewed by the Lead PI/Site-PI at screening/baseline. Concomitant 

25
 
 
medications and therapies will be verified with research participants at each study visit. 
All participants will have the opportunity to discuss their concomitant medications, and 
the risks and benefits of the study intervention will be reviewed with the study doctor 
(see Section 4.4.2: Patient Participant Exclusion Criteria). 
Currently, no pharmacological agents have been shown to have any clear interactions 
(whether beneficial or harmful) with rTMS. Participants will be informed that the pilot and 
pivotal RCTs supporting the use of deep TMS for smoking cessation also excluded 
individuals already using other smoking cessation treatments. Therefore, participants 
will be asked not to initiate any new medications intended to aid smoking cessation 
during the 13-week study course, as outlined in Section 4.4.2. 
As mentioned in Section 4.5: Lifestyle Considerations, reducing cigarette smoking may 
alter the levels of certain medications due to its effects on CYP1A2 metabolism. 
Additionally, smoking reduction may impact insulin resistance and glycemic control in 
individuals with diabetes. In such cases, medications metabolized by CYP1A2 or those 
used for diabetes management may require dose adjustments at the discretion of the 
study physician and the prescribing physician. 
 
5.7 
Packaging 
N/A 
5.8 
Blinding of Study Intervention 
This is an open-label trial, so there will be no blinding for participants and study 
assessors.  
  
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 
Receipt of Study Intervention Supplies 
N/A 
 
5.9.2 
Storage 
Details of rTMS device storage will be maintained and overseen by the Harquail Centre 
for Neuromodulation at Sunnybrook Research Institute and Neuromodulation Program at 
Waypoint Centre for Mental Health. Existing devices are stored at the two sites. 
Maintenance and calibration will be according to manufacturer guidance from Brainsway 
and will be performed according to their standards.  
5.9.3 
Dispensing of Study Intervention 
N/A 
 

26
 
 
5.9.4 
Return or Destruction of Study Intervention 
N/A 
 
6.0 RESEARCH PROCEDURES 
6.1 
Research Visits 
 
Prescreening during initial contact through phone, email or REDcap: A delegated 
research staff will conduct prescreening with the participants during their initial contact 
call to determine their initial eligibility to be screened in the study. This consists of a set 
of questions regarding inclusion and exclusion criteria. During pre-screening, we will ask 
participants to indicate their preferred site (Waypoint or Sunnybrook). 
 
Screening visit (SC): A delegated research staff will conduct the informed consent 
discussion with the patients at the beginning of the screening visit before the 
assessments to determine their eligibility to participate in the study (Section 6.2. Table). 
The informed consent process will include a short quiz of five questions to ensure that 
the participant understands the key information provided. This quiz will be completed 
after the ICF is explained and before the participant signs it. The screening visit will 
confirm eligibility through the eligibility checklist that also relies on administration of the 
TASS and FTND, and the Mini International Neuropsychiatric Interview (MINI) to screen 
for psychiatric diagnoses according to the DSM-5. We will also collect demographic 
information, medical history and current medications. The informed consent and 
assessments may be performed virtually, depending on the scheduling availability of 
study staff and the participant (refer to Sections 8.5 and 12.2).  
 
 
o Informed consent (including informed consent quiz) 
o Medical history for underlying diseases 
o Basic demographics, such as age, sex at birth 
o Mini International Neuropsychiatric Interview (MINI) 
o TMS Adult Safety Screening Questionnaire (TASS) 
o Smoking Contemplation Ladder 
o Target Quit Day, for scheduling the week for TMS treatment[61] 
o Concomitant medication log, recorded by its generic name, dosage, and dosing 
frequency  
o Fagerstrom Test of Nicotine Dependence (FTND). The FTND is a measure of 
physical dependence severity.  
 
 
 
Baseline visit (BL):  
 

27
 
 
The baseline visit will consist of urine testing using point-of-care dip testing, a 
concomitant medication survey, and self-report questionnaires. All components of the 
baseline visit must be completed within 30 days prior to W1D1; otherwise, they should 
be reassessed. 
 
For the urine drug panel test at the baseline visit (BL) and at the fifth day of Week1 
(W1D5), which includes opioids, stimulants, and alcohol, the rationale is that intoxication 
or withdrawal from stimulants or alcohol may affect the safety of receiving TMS. While the 
use of non-nicotine substances does not determine eligibility, participants will be advised 
to refrain from using these substances during treatment in Week 1. However, if the use 
of a non-nicotine substance demonstrates clinical instability to the extent that continued 
participation would not be in the best interest of the participant, PI and the study 
investigator team may decide to discontinue their involvement at PI and Site-PI's 
discretion (refer to Section 4.7.1). The final eligibility will be determined by the site PIs 
based on information collected at the screening and baseline visits. 
 
The screening and baseline visits may be completed on site in a single day, depending 
on research staff availability and participant preference. 
 
Urine testing: 
o Urine drug panel, to test recent substance use, including opioids, stimulants, and 
alcohol, as intoxication or withdrawal from stimulants or alcohol may affect the 
safety of receiving TMS 
o Urine pregnancy test, if required. To confirm pregnancy status, as pregnancy is an 
exclusion criterion. 
o Urine cotinine test (threshold: 200 ng/ml) to confirm recent cotinine use. 
 
Self-report questionnaires: 
o Timeline Follow-Back (TLFB) – Amount of cigarette used every day since the last 
follow-up 
o Fagerstrom Test of Nicotine Dependence (FTND). The FTND is a measure of 
physical dependence severity.  
o Tobacco Craving Questionnaire-Short-Form (TCQ-SF), to measure smoking 
craving. 
o Minnesota Nicotine Withdrawal Scale (MNWS), to measure the nicotine withdrawal 
symptoms. 
o Patient Health Questionnaire (PHQ-9), to track the possible effects of TMS on 
depression symptoms. 
o General Anxiety Disorder-7 (GAD-7), to track the possible effects of TMS on 
anxiety symptoms.  
o Altman Self-Rating Mania Scale (ASRM), to track the possible effects of TMS on 
developing manic/hypomanic symptoms. 
 
 
 
Treatment period (Week 1) 

28
 
 
 
Accelerated deep TMS will be administered daily, with four sessions per day, lasting 
approximately 3 hours (refer to Section 5.4), along with assessments for safety/adverse 
effects and scales for nicotine dependence, craving, and withdrawal symptoms. 
Participants’ activities were not systematically controlled during treatment sessions or 
during the intersession intervals; participants were allowed to do light cognitive activities 
such as reading or using their computer or smartphone. 
 
On each day of Week 1, the TCQ-SF will be administered twice to measure nicotine 
craving—once before and once after the aTMS treatment. 
 
Brief counseling for smoking cessation, adapted from the Mayo Clinic’s ‘Smoke Free 
and Living It’ manual, will be administered at W1D1 and W1D5. The brief counseling 
sessions may also be offered remotely, based on participant preference and logistical 
feasibility. 
 
 
The first day of Week 1 (W1D1) 
 
o Concomitant medication log, recorded by its generic name, dosage, and dosing 
frequency  
o Timeline Follow-Back (TLFB) – Amount of cigarette used every day since the last 
follow-up 
o Tobacco Craving Questionnaire-Short-Form (TCQ-SF), to measure smoking 
craving. TCQ-SF will be administered twice—once before and once after the 
aTMS treatment. 
o Minnesota Nicotine Withdrawal Scale (MNWS), to measure the nicotine withdrawal 
symptoms. 
o Urine drug panel 
o Urine pregnancy test, if required 
o Brief counseling for smoking cessation, adapted from the Mayo Clinic’s ‘Smoke 
Free and Living It’ manual. 
o Resting motor threshold measurement 
o Accelerated deep TMS treatment 
o Adverse event log 
 
The second, third, and fourth days of Week 1 (W1D2, W1D3, W1D4) 
o Concomitant medication log, recorded by its generic name, dosage, and dosing 
frequency  
o Timeline Follow-Back (TLFB) – Amount of cigarette used every day since the last 
follow-up 
o Tobacco Craving Questionnaire-Short-Form (TCQ-SF), to measure smoking 
craving. TCQ-SF will be administered twice—once before and once after the 
aTMS treatment. 
o Minnesota Nicotine Withdrawal Scale (MNWS), to measure the nicotine withdrawal 
symptoms. 

29
 
 
o Accelerated deep TMS treatment 
o Adverse event log 
 
The fifth day of Week 1 (W1D5) 
 
At the end of Week 1 (W1D5), a urine cotinine test will be performed, alongside TLFB to 
determine 7-day point-prevalence abstinence.  
 
At W1D5, for acceptability assessment, a TMS Experience Questionnaire will be 
administered. Participants will be asked to retrospectively rate (from 1=not at all to 
5=very much so) 15 items querying their perceptions of the treatment, its side effects, 
and its benefits as well as their preferences regarding treatment format and logistics. 
 
o Concomitant medication log, recorded by its generic name, dosage, and dosing 
frequency  
o Timeline Follow-Back (TLFB) – Amount of cigarette used every day since the last 
follow-up 
o Fagerstrom Test of Nicotine Dependence (FTND). The FTND is a measure of 
physical dependence severity.  
o Tobacco Craving Questionnaire-Short-Form (TCQ-SF), to measure smoking 
craving. TCQ-SF will be administered twice—once before and once after the 
aTMS treatment. 
o Minnesota Nicotine Withdrawal Scale (MNWS), to measure the nicotine withdrawal 
symptoms. 
o Patient Health Questionnaire (PHQ-9), to track the possible effects of TMS on 
depression symptoms. 
o General Anxiety Disorder-7 (GAD-7), to track the possible effects of TMS on 
anxiety symptoms.  
o Altman Self-Rating Mania Scale (ASRM), to track the possible effects of TMS on 
developing manic/hypomanic symptoms 
o Accelerated deep TMS treatment 
o Adverse event log 
o Urine drug panel 
o Urine pregnancy test, if required 
o Urine cotinine test (threshold: 200 ng/ml) 
o TMS Experience Questionnaire 
o Brief counseling for smoking cessation, adapted from the Mayo Clinic’s ‘Smoke 
Free and Living It’ manual. 
 
 
 
Follow-up period (Week 3, 5, 9) 
 
During the Week 3, Week 5, and Week 9 visits, a urine cotinine test and TLFB will be 
administered to determine 7-day point-prevalence abstinence. Side effect evaluation 
and brief smoking counseling will also be provided at these three visits, along with 

30
 
 
assessments for nicotine dependence, withdrawal, craving, and symptoms of 
depression, anxiety, and mania. 
 
o Concomitant medication log, recorded by its generic name, dosage, and dosing 
frequency  
o Timeline Follow-Back (TLFB) – Amount of cigarette used every day since the last 
follow-up 
o Fagerstrom Test of Nicotine Dependence (FTND). The FTND is a measure of 
physical dependence severity.  
o Tobacco Craving Questionnaire-Short-Form (TCQ-SF), to measure smoking 
craving. 
o Minnesota Nicotine Withdrawal Scale (MNWS), to measure the nicotine withdrawal 
symptoms. 
o Patient Health Questionnaire (PHQ-9), to track the possible effects of TMS on 
depression symptoms. 
o General Anxiety Disorder-7 (GAD-7), to track the possible effects of TMS on 
anxiety symptoms.  
o Altman Self-Rating Mania Scale (ASRM), to track the possible effects of TMS on 
developing manic/hypomanic symptoms 
o Adverse event log 
o Urine cotinine test (threshold: 200 ng/ml) 
o Brief counseling for smoking cessation, adapted from the Mayo Clinic’s ‘Smoke 
Free and Living It’ manual. 
 
 
Follow-up period (Week 13 and 26) 
 
During the Week 13 and 26 visit, a urine cotinine test and TLFB will be administered to 
determine prolonged abstinence and continuous abstinence. Three-month or six-month 
prolonged abstinence is defined as abstinence from the end of treatment (W1D5) to 
the end of follow-up (Week 13 or 26), while three-month or six-month continuous 
abstinence is defined as abstinence from the target quit day (in Week 1) to the end of 
follow-up (Week 13 or 26). Assessments for nicotine dependence, withdrawal, craving, 
and symptoms of depression, anxiety, and mania will also be performed. 
o Concomitant medication log, recorded by its generic name, dosage, and dosing 
frequency  
o Timeline Follow-Back (TLFB) – Amount of cigarette used every day since the last 
follow-up 
o Fagerstrom Test of Nicotine Dependence (FTND). The FTND is a measure of 
physical dependence severity.  
o Tobacco Craving Questionnaire-Short-Form (TCQ-SF), to measure smoking 
craving. 
o Minnesota Nicotine Withdrawal Scale (MNWS), to measure the nicotine withdrawal 
symptoms. 
o Patient Health Questionnaire (PHQ-9), to track the possible effects of TMS on 
depression symptoms. 

31
 
 
o General Anxiety Disorder-7 (GAD-7), to track the possible effects of TMS on 
anxiety symptoms.  
o Altman Self-Rating Mania Scale (ASRM), to track the possible effects of TMS on 
developing manic/hypomanic symptoms 
o Adverse event log 
o Urine cotinine test (threshold: 200 ng/ml) 
o Brief counseling for smoking cessation, adapted from the Mayo Clinic’s ‘Smoke 
Free and Living It’ manual. 
 
 
All assessments and surveys during research visits can be completed in one of two 
ways, based on participant preferences or each site’s standard data collection 
practices: 
1. Paper option: Assessments and surveys printed from REDCap will be 
completed by hand. A study delegate will review the paper source for 
completeness and accuracy and enter the data into REDCap. 
2. Electronic: A study delegate will log into REDCap and will remain present 
while the participant enters their responses to assessments on an electronic 
device (e.g., computer, iPad). The study delegate will review the assessment 
for completeness before saving and help the participant navigate to the next 
assessment or survey, as necessary. 
 
 
Procedures for addressing active suicidal ideation during research visits can be found 
in Section 8.5 (Safety Management Plan).

32
 
 
6.2 
Schedule of Events 
Below is the table outlining the assessments, measures, and treatments done at each visit. 
 
 
 
Screening 
Baseline 
Treatment 
Follow-ups 
 
Week 
 
 
W1 
W3 
W5 
W9 
W13 
W26 
 
Visit 
Code/Number 
SC 
BL 
W1D
1 
W1D
2  
W1D
3 
W1D
4 
W1D
5 
W3 
W5 
W9 
W13 
W26 
Assessments & Measures 
In-person visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
Contact & 
Demographic 
Form 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
TASS 
X 
 
 
 
 
 
 
 
 
 
 
 
Smoking 
Contemplation 
Ladder 
X 
 
 
 
 
 
 
 
 
 
 
 
Quit day plan 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication Log 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Urine Drug Panel 
 
X 
X 
 
 
 
X 
 
 
 
 
 
Urine Pregnancy 
Test (if required) 
 
X 
X 
 
 
 
X 
 
 
 
 
 
TLFB(Cigarettes) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FTND 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
TCQ-SF (regular 
or pre-TMS) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TCQ-SF (post-
TMS) 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
MNSW 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
GAD-7 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
ASRM 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
AE Log 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Counseling 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Urine cotinine test 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Confirm 
eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
TMS Experience 
Questionnaire 
 
 
 
 
 
 
X 
 
 
 
 
 
Point Prevalence 
Abstinence 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Prolonged 
Abstinence 
 
 
 
 
 
 
 
 
 
 
X 
X 
Continuous 
Abstinence  
 
 
 
 
 
 
 
 
 
 
X 
X 
RMT for TMS 
 
 
X 
 
 
 
 
 
 
 
 
 
Treat
TMS 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 

33
 
 
7.0 STATISTICAL PLAN 
7.1 
Sample Size Determination 
 
We aim to assess the abstinence rate at different time points and the feasibility of the 
accelerated deep TMS protocol for smoking cessation. Based on our previous trial[7], 
which tested the efficacy of deep TMS as an add-on to varenicline treatment, the point 
prevalence abstinence rate at Week 12 (8 weeks after the treatment ends) was 82.4% in 
the varenicline + deep TMS group and 30.7% in the varenicline + sham stimulation group. 
For this feasibility study, we plan to recruit 30 completers, targeting a sufficient number 
of completers to allow for meaningful estimates of the abstinence rate across multiple 
time points. This sample size is consistent with the exploratory nature of a pilot study and 
will provide valuable preliminary data for planning a larger, fully powered clinical trial in 
the future. 
 
7.2 
Statistical Methods 
 
Descriptive statistics will be used to summarize the baseline clinical and demographic 
variables for the study population. Subjects with missing values will be compared with 
completers on baseline characteristics, to help in the understanding of the reasons for 
missing values, if at least 10 subjects (25%) are found to be missing.  
 
For the abstinence measure, an intent-to-treat (ITT) approach will be used, including all 
participants who received at least one TMS session, regardless of treatment completion.  
 
Mixed effect logistic regression, using abstinence at the end of treatment, Week 3, Week 
5, Week 9, Week 13, and Week 26 as dependent variables will be adjusted to the data. 
Categorical time points (end of treatment and Week 3, Week 5, Week 9, Week 13 and 
Week 26) will be specified as fixed effect, and subject intercepts as random effects. 
Baseline variables correlated with missingness and/or known to be associated with the 
outcome will be added as covariates, with focus on model parsimony (not to include many 
covariates) due to small sample size. Abstinence will  be analyzed at the end of treatment, 
Week 3, Week 5, Week 13, and Week 26 as part of our secondary objectives.  
 
Mixed effect models using maximum likelihood estimation accounts for missingness in 
the dependent variable by using all available information in the estimation, under the MAR 
assumption (Missing At Random – the values of a data points are not associated with the 
missing status of the data point after accounting for relevant covariates)[1]. Other 
measures related to our secondary objectives (e.g., FTND, TLFB, etc.)  will also be 
analyzed using linear mixed or generalized mixed models, depending on the nature of the 
outcome of interest. Graphs will be used to explore the data, the models assumptions (for 
example, residual plots), as well as model results (for example, estimated means plot). 

34
 
 
Due to small sample, effect sizes with 95% confidence intervals as well as standardized 
effect sizes will be reported. 
 
8.0 SAFETY AND ADVERSE EVENTS 
8.1 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the investigational product.   
 
In this trial, symptoms commonly associated with smoking withdrawal (e.g., irritability, 
anxiety, increased appetite, restlessness, and difficulty concentrating) will not be 
classified as adverse events unless they exceed the expected severity or duration. These 
withdrawal-related symptoms will still be systematically documented and monitored using 
standardized measures, such as the Minnesota Nicotine Withdrawal Scale (MNWS), and 
assessed during study visits for safety monitoring purposes. 
 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that is:  
• Fatal. 
• Life-threatening. 
• Requires or prolongs hospital stay. 
• Results in persistent or significant disability or incapacity. 
• A congenital anomaly or birth defect; or 
• An important medical event (events that may not be life threatening but are of major 
clinical significance, such as a drug overdose or seizure that did not result in in-patient 
hospitalization).  
 
Adverse Event Collection Period 
The period during which adverse events must be collected is normally defined as the 
period from the initiation of any research procedures to the end of the study treatment 
follow-up.  For this clinical trial, the study treatment follow-up is defined as 30 days 
following the last administration of the study intervention.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the clinical trial.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. At screening, any clinically 
significant abnormality should be recorded as a preexisting condition.  Throughout the 
clinical trial, any new clinically significant findings/abnormalities that meet the definition of 
an adverse event must also be recorded and documented as an adverse event.  

35
 
 
 
Post-study Adverse Event 
At the last scheduled visit, each participant will be asked of any subsequent event(s) that 
the participant believes might reasonably be related to participation in this clinical trial. 
The Sponsor should be notified of any death or reportable adverse event occurring at any 
time after a participant has discontinued or terminated participation that may reasonably 
be related to this clinical trial. The Ssponsor should also be notified if the study team 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a participant that was involved in this clinical trial.  
 
8.2 
Recording of Adverse Events 
Safety monitoring will be implemented through the documentation and monitoring of AEs 
and SAEs through the use of incidence tables by severity, relationship to treatment and 
baseline parameters. Thorough causality analyses will be undertaken, and the necessary 
corrective and preventive actions will be implemented as applicable. All clearly related 
signs, symptoms, and abnormal diagnostic procedure results will be recorded in the 
research record and clinical chart and assessed by the Site-PI or other study physician in 
a timely manner allowing sufficient time to meet required reporting timelines for SAEs if 
needed. 
 
In the event of a disagreement between the Lead PI and the site-PI over the assessment 
of a serious adverse event, the Lead PI will defer to the judgement of the Site-PI. If there 
is direct documented evidence that contradicts the Site-PI, the Lead PI will ask the Site-
PI to provide the details of the event for sponsor assessment within 24 hours of the 
request, as per CAMH institutional procedures. 
 
8.3 
Reporting of Serious Adverse Events 
8.3.1 
Investigator Reporting: Notifying the Sponsor 
This is an investigator-initiated study; the Lead PI is the Sponsor (Dr. Le Foll, Waypoint). 
Delegated study personnel will report SAEs to the Lead PI as soon as possible (within 24 
hours of becoming aware of the event). 
 
8.3.2 
Investigator Reporting: Notifying the REB 
The process for notification to the REB, designated by Clinical Trial Ontario, for 
applicable serious adverse events (SAEs) must be completed as per REB reporting 
requirements. SAEs and unanticipated events must be recorded and reported to the 
REB in accordance with the REB’s reporting requirements and timelines. Copies of 
each report and documentation of REB notification and REB receipt/acknowledgement 
must be kept in the Investigator Study Binder. 

36
 
 
8.3.3 
Sponsor Reporting of Adverse Events: Notifying Health Canada 
In accordance to Health Canada incident reporting for medical devices guidance, all 
reportable incidents are completed by the manufacturer and importer. Thus, as the study 
team, we will report all reportable incidences to the manufacturer and importer 
(Brainsway). This includes incidences where we become aware of an event that occurred 
with the device that is assessed to be linked to the device based on all available 
information and medical assessment, and it leads to death, serious deterioration in the 
state of health of the person, or potential for death or serious deterioration in health of the 
person.  
  
8.3.4 
Sponsor Reporting of Adverse Events: Notifying Sites 
Adverse events that meet Health Canada reporting criteria must be submitted to Health 
Canada by the Sponsor within the required timelines. Serious adverse events that occur 
at external sites must be reported to the Sponsor within 24 hours of the site’s awareness 
of the SAE. Updates to SAEs must be provided to the Sponsor as soon as possible and 
within 24 hours of site awareness of the update.  
 
Adverse events which have been assessed and determined to meet the criteria for a 
serious unexpected adverse event will be reported on a monthly basis to all participating 
study sites via a monthly line listing. The line listing will include all serious unexpected 
adverse events that have occurred at all participating study sites. The line listing will be 
sent by the Sponsor to the participating study site(s) no later than 10 business days after 
the end of the month for which the serious unexpected adverse events are being reported. 
The site-PI must review and document their acknowledgement of the serious unexpected 
adverse events via their dated signature within a review timeline of 10 business days. The 
signed line listings must be filed in the site’s records, and copies of signed line listings 
received from the participating study site(s) must be retained in the Trial Master File of 
the Sponsor. 
8.4 
Reporting of Device Deficiencies 
Device deficiencies and malfunctions will be reported directly to the Manufacturer within 
48 business hours. Device deficiencies will also be recorded in the Device Recall and 
Deficiencies Log maintained in the Investigator Binder. No information about participants 
will be included.  
8.5 
Safety Management Plan 
Participant safety will be monitored as outlined in section 1.5 Risks/Benefits. Patient 
participants will receive full information regarding the treatment that includes known side 
effects of rTMS. Best practice guidelines for rTMS are now available and will be 
followed accordingly during this trial[62].  
 
Criteria by which participants will be removed for safety reasons is outlined in 4.7 
Participant Withdrawal Criteria. 
 

37
 
 
The reporting procedure to ensure any information relevant to participant welfare is 
detailed in 8.2 Reporting of Adverse Events and 8.3 Reporting of Serious Adverse Events. 
Adverse events are monitored according to TCPS2 and Sunnybrook Health Science 
Centre’s “Guidelines for Reporting an Internal Serious Adverse Event”. Adverse events 
will be assessed for at each study visit after treatment start.  
 
In the event of a suspected or confirmed breach of privacy, we will follow protocols 
according to the TCPS2, Ontario's Personal Health Information Protection Act (PHIPA), 
and Sunnybrook Health Science Centre’s guideline “Privacy and security of personal 
health information”.   
 
In the event that the participant presents for an rTMS treatment visit and is visibly 
intoxicated or in withdrawal from substance use, the rTMS technician/RPN or other study 
staff will notify the study physician or delegate, and treatment will not be delivered on that 
day. Resuming treatment or withdrawal from rTMS will be at the discretion of the Lead PI 
and study team based on clinical assessment of risks. 
 
In the event that the participant expresses active suicidal ideation during a study visit, 
such as indicated by the PHQ-9, the trained study personnel will follow existing safety 
escalation policies by contacting the Site-PI or delegate immediately. The Site-PI or 
delegate will then contact the participant for follow-up. If a participant reports feeling 
unsafe due to suicidal thoughts or requires medical attention, study personnel will advise 
to contact 911 or go to the nearest Emergency Room. All adverse events will be assessed 
and reported accordingly. 
 
Depending on the current situation of the COVID-19 pandemic, or participant preference, 
some study procedures might  be conducted virtually. Virtual assessments will include 
clinical rating scale assessments and self-report questionnaires and will be done via a 
secure video conferencing platform (Webex or Zoom)with a physician backup.  
 
For virtual assessments, videoconferencing (e.g. Webex, Zoom) is preferred, as some of 
our assessments require scoring based on behavioral observation. If the participant has 
no access to videoconferencing, the procedures will be completed via telephone. Both 
videoconferencing and telephone calls will not be recorded.  
 
Virtual Assessment Safety Plan:  
Some participants may report worsening of symptoms or suicidal ideation that may pose 
a safety risk during virtual assessments. In addition, some participants may report 
adverse events that may require further investigation due to safety reasons. In such cases, 
the trained study personnel will follow existing safety escalation policies by contacting the 
Site-PI or delegate immediately. The Site-PI or delegate will then contact the participant 
for follow-up. If a participant reports feeling unsafe due to suicidal thoughts or requires 
medical attention, study personnel will advise to contact 911 or go to the nearest 
Emergency Room. All adverse events will be assessed and reported accordingly. 
 

38
 
 
The following safety measures will be implemented for all virtual assessments over 
Webex or phone: 
• Confirmation of an emergency contact number for the participant, and an alternate 
phone number to contact them if there is an emergency, or if the call/virtual session 
ends inadvertently 
• Confirm the participant’s address, and that they are in a fixed location for the 
duration of the call 
• Confirm there is immediate access to necessary communications technology (i.e., 
landline or mobile device) in order to communicate with relevant research supports 
or emergency services in case of an emergent research situation 
• Check in on participants who leave/drop off a virtual session (i.e., if there is a safety 
concern) by phone or separate videoconference. 
• A physician backup to the study staff is available at all times 
  
8.6 
Unblinding Procedures 
This is an open-label study and there will be no blinding procedures. 
8.7 
Data and Safety Monitoring Board 
A Data and Safety Monitoring Board is not needed as this is not a regulated trial. Deep 
TMS (H4 coil) is already authorized for clinical use in smoking cessation, and its risk 
profile—primarily transient headaches or mild scalp discomfort, with rare seizures—is well 
characterized. Participants will undergo daily monitoring for adverse effects during Week 
1, and repeated assessments at follow‐up visits (Weeks 3, 5, 9, 13, and 26). The Lead PI 
will assume the overall responsibility for the management of the data and ensure proper 
protections against risk are in place with all study staff handling the data. The Lead PI will 
meet regularly with study staff to review collected data, confidentiality of data, and 
adherence to the study protocol and all relevant SOPs and research standards.   
 
9.0 CLINICAL TRIAL DISCONTINUATION AND 
CLOSURE 
9.1 
Clinical Trial Discontinuation 
This clinical trial may be temporarily suspended or prematurely terminated if there is 
sufficient reasonable cause (i.e. closure based on Lead PI decision, sponsor/funder 
decision, REB or other oversight bodies’ decision; review of serious, unexpected and 
related AEs; noncompliance; futility). Notification, which includes the reason for study 
suspension or termination, will be provided by the suspending or terminating party to 
research participants, the Site-PI, funding agency, Waypoint, and Sunnybrook.  If the 
clinical trial is prematurely terminated or suspended, the Site-PI will promptly inform 
research participants, the REB, and the sponsor, and will provide the reason(s) for the 
termination or suspension. All communication with participants for this purpose will go 

39
 
 
through REB review and approval.  Research participants will then be contacted, as 
applicable, and be informed of changes to the study visit schedule. 
10.0 DATA HANDLING AND RECORD KEEPING 
10.1 
Source Documents & Case Report Forms 
Data for this clinical trial will be managed using REDCap electronic case report forms. 
This system is maintained on Waypoint and Sunnybrook servers, with data backed up 
periodically. Please reference this study’s Data Management Plan (DMP). 
10.2 
Protocol Deviations 
No deviations from or changes to the protocol will be implemented without prior approval 
from the REB, unless to eliminate an immediate hazard to a participant. Any recorded 
protocol deviations will be reviewed by the PI in a timely manner. Any protocol deviations 
meeting the criteria of an Unanticipated Problem will be reported to REB. 
10.3 
Record Retention 
In accordance to policy Health Canada’s notice “Period reduced for keeping clinical trial 
records for drugs and natural health products” and Sunnybrook Research Institute’s 
guideline “Guidance for Participants, Sponsors, and Researchers: Information about the 
changes to Clinical Trial Record Retention Periods”, the research records of this clinical 
trial will be retained for 10 years after trial completion.  
10.4 
Clinical Trial Registration 
In accordance with TCPS 2, a description of the clinical trial will be registered in a publicly 
accessible database, such as www.clinicaltrials.gov or equivalent, before the start of 
recruitment activities. The content will be updated throughout the duration of the clinical 
trial. All results, including negative results must be entered at the completion of the clinical 
trial. 
11.0 STUDY MONITORING, AUDITING, AND 
INSPECTING 
11.1 
Study Monitoring Plan 
Quality assurance and quality control will be provided by the study Sponsor (Dr. Le Foll, 
Waypoint). The Sponsor will have primary responsibility for ensuring the well-being of 
research participants during their enrollment in the study, and that the conduct of the trial 
follows the currently approved protocol, ICH GCP and other applicable requirements. 
There will be meetings weekly with study personnel to review collected data, data 
confidentiality, and adherence to protocol design, recruitment, and participant complaints. 
During meetings the study Sponsor will also review the enrollment data, the collection 
and integrity of survey, qualitative, and clinical data, and any adverse event associated 
with the various components of the study, in collaboration with study co-investigators. 

40
 
 
Data will be verified in a targeted review during weekly meetings depending on data 
collected. The Sponsor will ensure there are periodic, focused reviews of specific key 
indices of data (such as endpoint outcomes, safety data, recruitment/screening data, etc.) 
within the study team throughout the duration of the trial. Lastly, all REDCap data values 
undergo automated consistency and validity checks as detailed in the Data Management 
Plan. A CAMH-appointed monitor will conduct centralized (remote) monitoring in 
accordance with the Sponsor’s study monitoring plan. This will involve reviewing consent 
and protocol adherence, source data verification, AE/SAE capture and reporting, and 
assessing participant safety and protection of rights. Centralized monitoring visits will be 
scheduled in coordination with each participating site, with findings reported to both the 
Sponsor and the site PIs.  
 
11.2 
Training and Qualifications of Study Personnel 
All study personnel will complete Good Clinical Practice (GCP), protocol, and REDCap 
training. The following study-specific trainings (e.g., Standard Operating Procedures) 
(SOPs) will be completed according to role and assigned tasks: Brief Counselling SOP, 
Urine Collection SOP, Smoking Craving Provocation Procedure SOP, and course on 
Good Data Collection Practices. Personnel who interact directly with participants must 
also complete TCPS-2 training. All required training will be completed prior to the Site 
Initiation Visit and updated as required (e.g., protocol amendments, newly-appointed 
staff). Completion will be documented via training logs and/or certificates. The Sponsor 
(or designated study coordinator) will maintain a master training log across sites. Each 
site will maintain their training log and delegation of duties log in the site’s Study Master 
File binder. 
11.3 
Auditing and Inspecting  
The Lead PI, Site-PI and site will permit study-related audits, and inspections by the REB, 
Waypoint, Sunnybrook, and applicable granting agencies or regulatory bodies, including 
access to all study-related documents (e.g., source documents, regulatory documents, 
data collection instruments, study data, etc.). The Lead PI will ensure the capability for 
audits/inspections of applicable study-related facilities (e.g., research pharmacy, clinical 
laboratory, imaging facility, etc.).  
12.0 ETHICAL CONSIDERATIONS  
12.1 
Research Ethics Board (REB) Approval 
Research Ethics Board (REB) approval will be obtained prior to beginning any research-
specific procedures. Following initial ethics approval, ongoing ethical approval will be 
maintained and the clinical trial will undergo REB review at least annually, in accordance 
with regulatory and REB requirements. The clinical trial will be conducted in accordance 
with the REB-approved study documents and the determinations (including any 
limitations) of the REB, and in compliance with REB requirements.  
 

41
 
 
Whenever new information becomes available that may be relevant to participant consent, 
a consent form and/or consent for addendum will be presented to the REB for review and 
approval prior to its use. Any revised written information will receive REB approval prior 
to use. 
12.2 
Informed Consent Process & Documentation 
The informed consent process will be obtained either remotely or in-person. 
 
In-person consent 
Informed consent is a process that is initiated prior to the individual agreeing to take part 
in the clinical trial and continues throughout their participation. 
 
Informed consent will be obtained from each participant prior to their participation in the 
clinical trial. Informed consent will be obtained by appropriately trained and qualified 
CAMH research personnel who do not have an existing clinical relationship with the 
participant.  The Lead PI and Site-PI will not obtain participant consent.   
 
Each participant will be provided with a current copy of the REB approved ICF prior to the 
consent discussion. Research personnel will explain the clinical trial to the participant and 
answer any questions that may arise. This discussion will include an explanation of the 
clinical trial purpose, procedures, potential risks and benefits, confidentiality 
considerations and participant rights (e.g., participants will not be penalized or lose any 
benefits regardless of what they decide, and they have the right to withdraw from the 
clinical trial at any time). Participants may take as much time as they need to make their 
decision, and may consult with others (e.g. family members, other health care providers, 
etc.) if they like. Following the consent discussion, and once the participant has decided 
to take part, the participant and the person conducting the consent discussion will 
personally sign and date the ICF. Each participant will be provided with a complete (fully 
signed) copy of the ICF. The original ICF(s) and the informed consent process will be 
documented in the source documents. 
 
Remote Consent Procedures 
Prior to the consent discussion, research personnel will contact participants using a verbal 
consent script. Research personnel will obtain consent to send a copy of the ICF to the 
participant prior to the consent discussion, which may occur via REDCap, email, mail, or 
secure file transfer according to participant preference.  
 
The consent discussion will occur by telephone or a secure video conferencing platform, 
at the participant’s preference. The consent discussion will be conducted by research 
personnel who are not the PI and do not have a clinical relationship with participants. 
 
Participants will be provided with a read-only copy of the ICF via REDCAP prior to 
conducting the consent discussion. The link may be used by participants as many times 
as they wish (it is not single use). Upon clicking the link, participants will review the landing 
page, and continue on to the ICF text.  The entire contents of the ICF will be displayed 

42
 
 
according to the current REB approved consent form, minus the signature/attestation 
page(s). 
 
Informed consent will be documented using the REDCap e-Consent Framework. 
Following the consent discussion, the prospective participant will be sent a link to the e-
consent via email, text, or chat feature in the secure video conferencing platformThe 
participant will complete the e-consent and be provided with the option to download 
and/or email themselves the signed ICF.  If email is chosen, the email will only be used 
for this purpose (it is not retained by REDCap).   
 
Following the participant signature, the person conducting the consent discussion will 
complete the Person Conducting Consent Discussion Attestation Page. PDF copies of 
the signed ICFs and Attestation pages will be retained in the REDCap File Repository.  
The research team will provide the participant with a copy of the fully signed ICF via mail 
and/or email, in accordance with the participant’s wishes.  
13.0 PRIVACY AND CONFIDENTIALITY 
All clinical trial-related documents and data will be held in strict confidence and stored at 
Waypoint or on Waypoint servers and will follow institutional policies and procedures to 
ensure participant privacy and confidentiality.  
 
REDCap software will be used for data collection and overall study data management 
over the course of this project. REDCap is an open-source, web-based clinical data 
management and electronic data capture system and database. The system is 
developed and managed in compliance with HIPAA, PIPEDA, and FDA 21 CFR Part 11 
regulations, providing functions such as defined user roles and privileges, user 
authentication and encryption, electronic signatures, de-identification of protected health 
information, comprehensive auditing features to record and monitor access and 
changes to data, and a validated software development lifecycle. This system will be 
used to design electronic case report forms (eCRFs), data entry, data monitoring and 
cleaning, and for the query and export of datasets for statistical analysis. 
 
Data is accessible by the research team only. No information concerning the clinical trial 
or the data will be released to any unauthorized third party without prior written approval 
of the sponsor, and the consent of the participant (where applicable).  
 
All research activities will be conducted in as private a setting as possible. The 
authorized representatives of the sponsor, representatives of the REB, regulatory 
agencies may inspect all documents and records required to be maintained by the PI, 
including but not limited to, medical records and pharmacy records for the participants in 
this clinical trial. The participant’s contact information will be securely stored at 
Waypoint for internal use during the clinical trial. At the end of the clinical trial, all 
records will continue to be kept in a secure location in accordance to applicable 
institutional and regulatory requirements. 
 

43
 
 
14.0 CLINICAL TRIAL FINANCES 
14.1 
Funding Source 
This trial has been submitted for funding consideration through the PSI Foundation 
(Application ID 2025-3725). However, recognizing the importance of this research, we 
will proceed with the REB submission concurrently, regardless of the outcome of the 
funding application. In the event that the initial funding application is unsuccessful or 
does not fully cover the trial’s financial needs, alternative funding sources will be 
pursued. These may include internal funding or in-kind support from Waypoint, 
Sunnybrook, and other potential internal and external funding opportunities. The Lead 
PI and research team remain committed to securing the necessary resources to ensure 
the successful execution of the trial without compromising its scientific integrity or 
ethical standards. 
14.2 
Conflict of Interest 
The investigators declare that no conflict of interest (COI) with this clinical trial (patent 
ownership, royalties, or financial gain greater than the minimum allowable by their 
institution, etc.) exist. 
  
15.0 PUBLICATION POLICY/DATA SHARING 
Publication 
The Lead PI will be responsible for publication of the results of the clinical trial in a peer-
reviewed journal publication. There are no publication policies for the participating 
funding agencies.  
 
15.1 Future Secondary Use of Data 
De-identified data from this trial may be used for future research by internal and/or 
external project collaborators. This data, having been stripped of direct identifiers, may 
be shared with researchers within the institution or external collaborators for secondary 
analyses, meta-analyses, or validation of findings. Any secondary use of the data will 
align with the original scope of research and comply with data sharing agreements, 
Waypoint and Sunnybrook policies, and relevant regulations, such as the Tri-Council 
Policy Statement (TCPS 2) and PHIPA. Data will be stored securely for 15 years. 
Researchers seeking access to the data for secondary analysis will be required to 
obtain appropriate approvals and adhere to applicable data use agreements. 
.   
  
 

44
 
 
16.0 REFERENCES 
 
[1] 
Reitsma MB, Kendrick PJ, Ababneh E, Abbafati C, Abbasi-Kangevari M, Abdoli A, et al. 
Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and 
attributable disease burden in 204 countries and territories, 1990-2019: a systematic 
analysis from the Global Burden of Disease Study 2019. Lancet 2021;397:2337–60. 
https://doi.org/10.1016/S0140-6736(21)01169-7. 
[2] 
Livingstone-Banks J, Norris E, Hartmann-Boyce J, West R, Jarvis M, Hajek P. Relapse 
prevention interventions for smoking cessation. Cochrane Database Syst Rev 2019;2. 
https://doi.org/10.1002/14651858.CD003999.PUB5. 
[3] 
Hajek P, Tønnesen P, Arteaga C, Russ C, Tonstad S. Varenicline in prevention of relapse 
to smoking: effect of quit pattern on response to extended treatment. Addiction 
(Abingdon, England) 2009;104:1597–602. https://doi.org/10.1111/J.1360-
0443.2009.02646.X. 
[4] 
Zangen A, Moshe H, Martinez D, Barnea-Ygael N, Vapnik T, Bystritsky A, et al. 
Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter 
double-blind randomized controlled trial. World Psychiatry 2021;20:397–404. 
https://doi.org/10.1002/WPS.20905. 
[5] 
Forget B, Pushparaj A, Le Foll B. Granular insular cortex inactivation as a novel 
therapeutic strategy for nicotine addiction. Biol Psychiatry 2010;68:265–71. 
https://doi.org/10.1016/J.BIOPSYCH.2010.01.029. 
[6] 
Pushparaj A, Hamani C, Yu W, Shin DS, Kang B, Nobrega JN, et al. Electrical 
Stimulation of the Insular Region Attenuates Nicotine-Taking and Nicotine-Seeking 
Behaviors. Neuropsychopharmacology 2013;38:690. 
https://doi.org/10.1038/NPP.2012.235. 
[7] 
Ibrahim C, Tang VM, Blumberger DM, Malik S, Tyndale RF, Trevizol AP, et al. Efficacy 
of insula deep repetitive transcranial magnetic stimulation combined with varenicline for 
smoking cessation: A randomized, double-blind, sham controlled trial. Brain Stimul 
2023;16:1501–9. https://doi.org/10.1016/J.BRS.2023.10.002. 
[8] 
Sonmez AI, Camsari DD, Nandakumar AL, Voort JLV, Kung S, Lewis CP, et al. 
Accelerated TMS for Depression: A systematic review and meta-analysis. Psychiatry Res 
2019;273:770–81. https://doi.org/10.1016/J.PSYCHRES.2018.12.041. 
[9] 
Shi R, Wang Z, Yang D, Hu Y, Zhang Z, Lan D, et al. Short-term and long-term efficacy 
of accelerated transcranial magnetic stimulation for depression: a systematic review and 
meta-analysis. BMC Psychiatry 2024;24:1–13. https://doi.org/10.1186/S12888-024-
05545-1/FIGURES/7. 
[10] Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, et al. Stanford 
accelerated intelligent neuromodulation therapy for treatment-resistant depression. 
American Journal of Psychiatry 2020;177:716–26. 
https://doi.org/10.1176/APPI.AJP.2019.19070720/ASSET/IMAGES/LARGE/APPI.AJP.2
019.19070720F3.JPEG. 
[11] Roth Y, Hanlon CA, Pell G, Zibman S, Harmelech T, Muir OS, et al. Real world efficacy 
and safety of various accelerated deep TMS protocols for major depression. Psychiatry 
Res 2023;328. https://doi.org/10.1016/J.PSYCHRES.2023.115482. 

45
 
 
[12] Le Foll B, Piper ME, Fowler CD, Tonstad S, Bierut L, Lu L, et al. Tobacco and nicotine 
use. Nature Reviews Disease Primers 2022 8:1 2022;8:1–16. 
https://doi.org/10.1038/s41572-022-00346-w. 
[13] Goodwin RD, Pagura J, Spiwak R, Lemeshow AR, Sareen J. Predictors of persistent 
nicotine dependence among adults in the United States. Drug Alcohol Depend 
2011;118:127. https://doi.org/10.1016/J.DRUGALCDEP.2011.03.010. 
[14] Weinberger AH, Gbedemah M, Wall MM, Hasin DS, Zvolensky MJ, Goodwin RD. 
Cigarette use is increasing among people with illicit substance use disorders in the United 
States, 2002-14: emerging disparities in vulnerable populations. Addiction (Abingdon, 
England) 2018;113:719–28. https://doi.org/10.1111/ADD.14082. 
[15] Hassan AN, Le Foll B. Survival Probabilities and Predictors of Major Depressive Episode 
Incidence Among Individuals With Various Types of Substance Use Disorders. J Clin 
Psychiatry 2021;82. https://doi.org/10.4088/JCP.20M13637. 
[16] Smith PH, Mazure CM, McKee SA. Smoking and mental illness in the U.S. population. 
Tob Control 2014;23:e147–53. https://doi.org/10.1136/TOBACCOCONTROL-2013-
051466. 
[17] Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. N Engl J Med 
2014;370:60–8. https://doi.org/10.1056/NEJMRA1308383. 
[18] Jha P. The hazards of smoking and the benefits of cessation: a critical summation of the 
epidemiological evidence in high-income countries. Elife 2020;9. 
https://doi.org/10.7554/ELIFE.49979. 
[19] Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, et al. 
21st-century hazards of smoking and benefits of cessation in the United States. N Engl J 
Med 2013;368:341–50. https://doi.org/10.1056/NEJMSA1211128. 
[20] Banks E, Joshy G, Weber MF, Liu B, Grenfell R, Egger S, et al. Tobacco smoking and all-
cause mortality in a large Australian cohort study: Findings from a mature epidemic with 
current low smoking prevalence. BMC Med 2015;13:1–10. 
https://doi.org/10.1186/S12916-015-0281-Z/FIGURES/5. 
[21] Pirie K, Peto R, Reeves GK, Green J, Beral V. The 21st century hazards of smoking and 
benefits of stopping: a prospective study of one million women in the UK. Lancet 
2013;381:133. https://doi.org/10.1016/S0140-6736(12)61720-6. 
[22] Jha P. Avoidable global cancer deaths and total deaths from smoking. Nat Rev Cancer 
2009;9:655–64. https://doi.org/10.1038/NRC2703. 
[23] Daskalakis ZJ, Möller B, Christensen BK, Fitzgerald PB, Gunraj C, Chen R. The effects 
of repetitive transcranial magnetic stimulation on cortical inhibition in healthy human 
subjects. Exp Brain Res 2006;174:403–12. https://doi.org/10.1007/S00221-006-0472-0. 
[24] Strafella AP, Paus T, Fraraccio M, Dagher A. Striatal dopamine release induced by 
repetitive transcranial magnetic stimulation of the human motor cortex. Brain 
2003;126:2609–15. https://doi.org/10.1093/BRAIN/AWG268. 
[25] Strafella AP, Paus T, Barrett J, Dagher A. Repetitive transcranial magnetic stimulation of 
the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci 
2001;21. https://doi.org/10.1523/JNEUROSCI.21-15-J0003.2001. 
[26] Keck ME, Welt T, Post A, Müller MB, Toschi N, Wigger A, et al. Neuroendocrine and 
behavioral effects of repetitive transcranial magnetic stimulation in a psychopathological 
animal model are suggestive of antidepressant-like effects. Neuropsychopharmacology 
2001;24:337–49. https://doi.org/10.1016/S0893-133X(00)00191-3. 

46
 
 
[27] Keck ME, Welt T, Müller MB, Erhardt A, Ohl F, Toschi N, et al. Repetitive transcranial 
magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal 
system. Neuropharmacology 2002;43:101–9. https://doi.org/10.1016/S0028-
3908(02)00069-2. 
[28] Keck ME, Sillaber I, Ebner K, Welt T, Toschi N, Kaehler ST, et al. Acute transcranial 
magnetic stimulation of frontal brain regions selectively modulates the release of 
vasopressin, biogenic amines and amino acids in the rat brain. Eur J Neurosci 
2000;12:3713–20. https://doi.org/10.1046/J.1460-9568.2000.00243.X. 
[29] Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F. Imaging dopamine’s role in drug 
abuse and addiction. Neuropharmacology 2009;56 Suppl 1:3–8. 
https://doi.org/10.1016/J.NEUROPHARM.2008.05.022. 
[30] Zangen A, Roth Y, Voller B, Hallett M. Transcranial magnetic stimulation of deep brain 
regions: evidence for efficacy of the H-coil. Clin Neurophysiol 2005;116:775–9. 
https://doi.org/10.1016/J.CLINPH.2004.11.008. 
[31] Roth Y, Amir A, Levkovitz Y, Zangen A. Three-dimensional distribution of the electric 
field induced in the brain by transcranial magnetic stimulation using figure-8 and deep H-
coils. J Clin Neurophysiol 2007;24:31–8. 
https://doi.org/10.1097/WNP.0B013E31802FA393. 
[32] Roth Y, Zangen A, Hallett M. A coil design for transcranial magnetic stimulation of deep 
brain regions. J Clin Neurophysiol 2002;19:361–70. https://doi.org/10.1097/00004691-
200208000-00008. 
[33] Le Foll B, Pushparaj A, Pryslawsky Y, Forget B, Vemuri K, Makriyannis A, et al. 
Translational strategies for therapeutic development in nicotine addiction: rethinking the 
conventional bench to bedside approach. Prog Neuropsychopharmacol Biol Psychiatry 
2014;52:86–93. https://doi.org/10.1016/J.PNPBP.2013.10.009. 
[34] Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to 
cigarette smoking. Science 2007;315:531–4. https://doi.org/10.1126/SCIENCE.1135926. 
[35] Naqvi NH, Bechara A. The insula and drug addiction: an interoceptive view of pleasure, 
urges, and decision-making. Brain Struct Funct 2010;214:435–50. 
https://doi.org/10.1007/S00429-010-0268-7. 
[36] Pushparaj A, Kim AS, Musiol M, Trigo JM, Le Foll B. Involvement of the rostral 
agranular insular cortex in nicotine self-administration in rats. Behavioural Brain Research 
2015;290:77–83. https://doi.org/10.1016/J.BBR.2015.04.039. 
[37] Pushparaj A, Le Foll B. Involvement of the caudal granular insular cortex in alcohol self-
administration in rats. Behavioural Brain Research 2015;293:203–7. 
https://doi.org/10.1016/J.BBR.2015.07.044. 
[38] Pushparaj A, Kim AS, Musiol M, Zangen A, Daskalakis ZJ, Zack M, et al. Differential 
Involvement of the Agranular vs Granular Insular Cortex in the Acquisition and 
Performance of Choice Behavior in a Rodent Gambling Task. Neuropsychopharmacology 
2015;40:2832–42. https://doi.org/10.1038/NPP.2015.133. 
[39] Brody AL, Mandelkern MA, London ED, Childress AR, Lee GS, Bota RG, et al. Brain 
metabolic changes during cigarette craving. Arch Gen Psychiatry 2002;59:1162–72. 
https://doi.org/10.1001/ARCHPSYC.59.12.1162. 
[40] Jasinska AJ, Stein EA, Kaiser J, Naumer MJ, Yalachkov Y. Factors modulating neural 
reactivity to drug cues in addiction: a survey of human neuroimaging studies. Neurosci 
Biobehav Rev 2014;38:1–16. https://doi.org/10.1016/J.NEUBIOREV.2013.10.013. 

47
 
 
[41] Zangen A, Moshe H, Martinez D, Barnea-Ygael N, Vapnik T, Bystritsky A, et al. 
Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter 
double‐blind randomized controlled trial. World Psychiatry 2021;20:397. 
https://doi.org/10.1002/WPS.20905. 
[42] Weigand A, Horn A, Caballero R, Cooke D, Stern AP, Taylor SF, et al. Prospective 
Validation That Subgenual Connectivity Predicts Antidepressant Efficacy of Transcranial 
Magnetic Stimulation Sites. Biol Psychiatry 2018;84:28–37. 
https://doi.org/10.1016/J.BIOPSYCH.2017.10.028. 
[43] Nettekoven C, Volz LJ, Kutscha M, Pool EM, Rehme AK, Eickhoff SB, et al. Dose-
dependent effects of theta burst rTMS on cortical excitability and resting-state 
connectivity of the human motor system. J Neurosci 2014;34:6849–59. 
https://doi.org/10.1523/JNEUROSCI.4993-13.2014. 
[44] Fitzgerald PB, Hoy KE, Anderson RJ, Daskalakis ZJ. A STUDY OF THE PATTERN OF 
RESPONSE TO rTMS TREATMENT IN DEPRESSION. Depress Anxiety 2016;33:746–
53. https://doi.org/10.1002/DA.22503. 
[45] Cash RFH, Cocchi L, Lv J, Wu Y, Fitzgerald PB, Zalesky A. Personalized connectivity-
guided DLPFC-TMS for depression: Advancing computational feasibility, precision and 
reproducibility. Hum Brain Mapp 2021;42:4155–72. https://doi.org/10.1002/HBM.25330. 
[46] Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad BSR, Barmak F, et al. Stanford 
Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J 
Psychiatry 2022;179:132–41. https://doi.org/10.1176/APPI.AJP.2021.20101429. 
[47] Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, et al. Stanford 
accelerated intelligent neuromodulation therapy for treatment-resistant depression. 
American Journal of Psychiatry 2020;177:716–26. 
https://doi.org/10.1176/APPI.AJP.2019.19070720/SUPPL_FILE/APPI.AJP.2019.1907072
0.DS001.PDF. 
[48] Cole E, O’Sullivan SJ, Tik M, Williams NR. Accelerated theta burst stimulation: safety, 
efficacy, and future advancements. Biol Psychiatry 2024;95:523–35. 
https://doi.org/10.1016/j.biopsych.2023.12.004. 
[49] Fitzgerald PB, Hoy KE, Elliot D, Susan McQueen RN, Wambeek LE, Daskalakis ZJ. 
Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. 
Neuropsychopharmacology 2018;43:1565–72. https://doi.org/10.1038/s41386-018-0009-
9. 
[50] Caulfield KA, Fleischmann HH, George MS, McTeague LM. A transdiagnostic review of 
safety, efficacy, and parameter space in accelerated transcranial magnetic stimulation. J 
Psychiatr Res 2022;152:384–96. https://doi.org/10.1016/j.jpsychires.2022.06.038. 
[51] Fitzgerald PB. An update on the clinical use of repetitive transcranial magnetic 
stimulation in the treatment of depression. J Affect Disord 2020;276:90–103. 
https://doi.org/10.1016/J.JAD.2020.06.067. 
[52] Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A. Modulation of 
corticospinal excitability by repetitive transcranial magnetic stimulation. Clin 
Neurophysiol 2000;111:800–5. https://doi.org/10.1016/S1388-2457(99)00323-5. 
[53] George MS. Transcranial magnetic stimulation for the treatment of depression. Expert 
Rev Neurother 2010;10:1761–72. https://doi.org/10.1586/ERN.10.95. 

48
 
 
[54] Holtzheimer PE, McDonald WM, Mufti M, Kelley ME, Quinn S, Corso G, et al. 
Accelerated repetitive transcranial magnetic stimulation (aTMS) for treatment-resistant 
depression. Depress Anxiety 2010;27:960. https://doi.org/10.1002/DA.20731. 
[55] Karadoğan D, Önal Ö, Şahin DS, Kanbay Y, Alp S, Şahin Ü. Treatment adherence and 
short-term outcomes of smoking cessation outpatient clinic patients. Tob Induc Dis 
2018;16. https://doi.org/10.18332/TID/94212. 
[56] Hays JT, Leischow SJ, Lawrence D, Lee TC. Adherence to treatment for tobacco 
dependence: Association with smoking abstinence and predictors of adherence. Nicotine 
and Tobacco Research 2010;12:574–81. https://doi.org/10.1093/ntr/ntq047. 
[57] Liberman JN, Lichtenfeld MJ, Galaznik A, Mastey V, Harnett J, Zou KH, et al. 
Adherence to Varenicline and Associated Smoking Cessation in a Community-Based 
Patient Setting. vol. 19. 2013. 
[58] Balmford J, Borland R, Hammond D, Cummings KM. Adherence to and reasons for 
premature discontinuation from stop-smoking medications: Data from the ITC four-
country survey. Nicotine and Tobacco Research 2011;13:94–102. 
https://doi.org/10.1093/ntr/ntq215. 
[59] Conney AH, Reidenberg MM. Cigarette smoking, coffee drinking, and ingestion of 
charcoal-broiled beef as potential modifiers of drug therapy and confounders of clinical 
trials. Journal of Pharmacology and Experimental Therapeutics 2012;342:9–14. 
https://doi.org/10.1124/jpet.112.193193. 
[60] I ARA, Beigel Y, Schre R, Bman !, Shafer Z. Weight Gain and Insulin Resistance during 
Nicotine Replacement Therapy. vol. 22. n.d. 
[61] Cobb CO, Niaura RS, Donaldson EA, Graham AL. Quit now? Quit soon? Quit when 
you’re ready? Insights about target quit dates for smoking cessation from an online quit 
date tool. J Med Internet Res 2014;16. https://doi.org/10.2196/jmir.3086. 
[62] McClintock SM, Reti IM, Carpenter LL, McDonald WM, Dubin M, Taylor SF, et al. 
Consensus recommendations for the clinical application of repetitive transcranial 
magnetic stimulation (rTMS) in the treatment of depression. Journal of Clinical Psychiatry 
2018;79:35–48. https://doi.org/10.4088/JCP.16cs10905.