Psychiatry Research 326 (2023) 115340

Contents lists available at ScienceDirect

Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Review article

Repetitive transcranial magnetic stimulation for smoking cessation: Next

steps for translation and implementation into clinical practice
Victor M. Tang a, b, c, d, e, f, *, Rachel Goud a, c, Laurie Zawertailo a, d, e, g, Peter Selby a, b, c, d, e, h, i,
Adina Coroiu a, d, Matthew E. Sloan a, b, c, d, e, g, Meghan Jo-Ann Chenoweth c, d, g,
Daniel Buchman d, i, Christine Ibrahim a, b, j, Daniel M. Blumberger b, c, d, f, Bernard
Le Foll a, b, c, d, e, g, h, i, j, k
a
Addictions Division, Centre for Addiction and Mental Health, 100 Stokes St, Toronto, ON, Canada
b
Institute for Medical Science, Temerty Faculty of Medicine, University of Toronto, Canada
c
Department of Psychiatry, University of Toronto, Temerty Faculty of Medicine, Canada
d
Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Canada
e
Centre for Addiction and Mental Health, Institute of Mental Health Policy Research, Canada
f
Centre for Addiction and Mental Health, Temerty Centre for Therapeutic Brain Intervention, Canada
g
Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Canada
h
Department of Family and Community Medicine, Temerty Faculty of Medicine, University of Toronto, Canada
i
Dalla Lana School of Public Health, University of Toronto, Canada
j
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada
k
Waypoint Research Institute, Waypoint Centre for Mental Health Care, Penetanguishene, ON, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Tobacco smoking is a significant determinant of preventable morbidity and mortality worldwide. It is now
Brain stimulation possible to modulate the activity of the neurocircuitry associated with nicotine dependence using repetitive
Nicotine Transcranial Magnetic Stimulation (rTMS), a non-invasive neurostimulation approach, which has recently
Tobacco
demonstrated efficacy in clinical trials and received regulatory approval in the US and Canada. However there
Smoking
Repetitive transcranial magnetic stimulation
remains a paucity of replication studies and real-world patient effectiveness data as access to this intervention is
extremely limited. There are a number of unique challenges related to the delivery of rTMS that need to be
addressed prior to widespread adoption and implementation of this treatment modality for smoking cessation. In
this paper, we review the accessibility, scientific, technological, economical, and social challenges that remain
before this treatment can be translated into clinical practice. By addressing these remaining barriers and sci­
entific challenges with rTMS for smoking cessation and delineating implementation strategies, we can greatly
reduce the burden of tobacco-related disease worldwide.

1. Introduction increase (GBD 2019 Tobacco Collaborators, 2021). Despite decades of

1.1. Significant disease burden from smoking
Tobacco use is a leading cause of morbidity and mortality across the
world. Recent estimates of the global burden of disease from tobacco
report 1.14 billion current smokers, 7.69 million attributable deaths,
and 200 million disability adjusted years in the year 2019 (GBD 2019
Tobacco Collaborators, 2021; Le Foll et al., 2022). Given overall popu­
lation increases, the total number of current smokers continues to
tobacco control efforts, approximately 13% of adults currently smoke in
Canada and the US (Canada, 2020; Cornelius et al., 2022). In the US,
Individuals who continue to smoke into middle age die ~10 years earlier
than non-smokers3 from a variety of causes including lung and other
cancers (e.g., oral, laryngeal, esophageal, stomach, pancreatic, bladder,
cervical, colon, and rectal cancers), chronic obstructive pulmonary
disease, stroke, and heart disease (Gelband et al., 2015; Hecht, 2002).
The risk for tobacco-related illnesses and death typically increases with
increasing number of cigarettes and duration of smoking (Burns, 2003;

* Corresponding author at: Addictions Division, Centre for Addiction and Mental Health, 100 Stokes St, Toronto, ON, Canada.
E-mail address: victor.tang@camh.ca (V.M. Tang).

https://doi.org/10.1016/j.psychres.2023.115340
Received 15 May 2023; Received in revised form 4 July 2023; Accepted 7 July 2023
Available online 11 July 2023
0165-1781/© 2023 Elsevier B.V. All rights reserved.
V.M. Tang et al.
Haiman et al., 2006).
1.2. Limitations of current smoking cessation treatments
Quitting smoking can reduce risk of dying from smoking-related
disease3 but continuous cessation is difficult to achieve (Chaiton et al.,
2016). Unaided quit success may be as low as 5% and existing
evidence-based pharmacotherapy cessation treatments (varenicline,
nicotine replacement therapy [NRT], bupropion, and cytisine) increase
long-term abstinence rates to 10–30% (Schlam and Baker, 2013).
Modelling of data from over 40 smoking cessation trials suggest that
12-month abstinence rates are 23% or less with these medications
(Jackson et al., 2019). Varenicline is the current ‘gold standard’ phar­
macotherapy since it has been shown to robustly increase the odds of
smoking cessation to a larger degree than bupropion and NRT (Eisen­
berg et al., 2010; Wu et al., 2006). However, varenicline is not effective
in a large portion of people who smoke (Agboola et al., 2015). At 2
weeks, abstinence rates are low at only 32% (Agboola et al., 2015),
which is important given that discontinuation rates are high early in the
treatment course (Catz et al., 2011) and abstinence during the first week
of a quit attempt is highly predictive of abstinence at follow up (Ashare
et al., 2013). Therefore, there is a strong need for novel and adjuvant
therapies to increase continued smoking cessation. There is also a need
to develop treatments when available pharmacotherapies are either
ineffective or intolerable. The use of varenicline is also limited by side
effects. For example, nearly 30% of smokers receiving varenicline
treatment report nausea (Cahill et al., 2016), and nausea is a commonly
cited reason for treatment discontinuation (Halperin et al., 2009; Peng
et al., 2020) which in turn reduces cessation rates (Peng et al., 2020).
Need for Treatments Targeting Novel Neurobiological Models of Tobacco
Addiction.
Nicotine, the major psychoactive compound in cigarette smoke, is
very addictive, and the reason why the vast majority of smokers are
dependent (Jha and Peto, 2014; West, 2017). Importantly, addictions
include involvement of neuronal circuits involved in reward, cognition,
and emotions that predispose to dependence and misuse, as well as
being maladaptively changed because of chronic and persistent use
(Koob and Volkow, 2016). A three stage process has been proposed to
include binge/intoxication stage (driven by incentive salience), negative
affect/withdrawal stage (driven by reward deficit and stress) and
craving stage (preoccupation/anticipation stage driven by executive
dysfunction; Koob and Volkow, 2016; Le Foll et al., 2022). Only in the
last decade has it become clear that the frontal cortical circuits under­
lying the craving stage could serve as a therapeutic target.
Outside of the frontal cortex, other regions of interest remain under-
explored in the rTMS literature. Particularly, the insula (also known as
the insular cortex) has been recently established as having a prominent
role in controlling craving and smoking behavior. This was first realized
in lesion studies, whereby people who smoke who suffered damage to
the insula were more likely to quit smoking easily and quickly (less than
1 day after the lesion) than those with damage elsewhere (Naqvi &
Bechara, 2009). Subsequent research has found damage to the insula
predicts smoking cessation and increases the probability of quitting by
five times (Suñer-Soler et al., 2012), and also was associated with full
abstinence from all nicotine products (e.g., other forms of tobacco,
nicotine replacement therapy; Abdolahi et al., 2015b) less frequent and
severe withdrawal symptoms (Abdolahi et al., 2015a), and less smoking
urges (Abdolahi et al., 2017). Furthermore, the insula has been found to
have a high density of α4β2 neuronal nicotinic acetylcholine receptors
relative to other areas of the brain (Picard et al., 2013). Evidence for the
involvement of the insula in nicotine addiction has been strengthened by
various preclinical studies; for example, the insula has been shown to
control nicotine taking and nicotine seeking in animal models of relapse
(Forget et al., 2010; Pushparaj et al., 2013; Pushparaj et al., 2015).
Together these findings suggest that modulating the functioning of the
insula could represent a novel smoking cessation intervention.
2
Psychiatry Research 326 (2023) 115340
Repetitive Transcranial Magnetic Stimulation (rTMS): Evidence for Ef­
ficacy and FDA Clearance
Research over the past three decades has supported the clinical
benefit of repetitive transcranial magnetic stimulation (rTMS) for an
array of neuropsychiatric disorders (Lefaucheur et al., 2020). Most
notably, it is a well-established intervention for the treatment of major
depressive disorder (McClintock et al., 2018). RTMS works through the
generation of a rapidly alternating electric current within a coil placed
over the scalp, thereby inducing a magnetic field and secondary electric
field in a localized region of the brain causing neuronal depolarization
(Tik et al., 2017). It is generally well tolerated, though discomfort at the
site of stimulation and headache are common (Rossi et al., 2009). Study
of its therapeutic potential in treating nicotine dependence has been
growing in recent decades. We conducted a literature search of all
clinical trials in this area (as of January 2023), with each study sum­
marized in Table 1. We included studies that were primarily on treating
nicotine dependence as well as studies of rTMS for other psychiatric
disorders but included data on smoking outcomes. Beginning with the
first in 2003 (Eichhammer et al., 2003), there are now over 30 published
reports of clinical trials for nicotine dependence. Almost all studies used
the figure-of-8 coil to target the dorsolateral prefrontal cortex (DLPFC),
which is a common target in other neuropsychiatric disorders studied
with rTMS. One trial investigated the effects of rTMS at the superior
medical frontal cortex (SMFC) (Chang et al., 2018), one investigated the
inferior frontal gyrus (IFG) (Newman-Norlund et al., 2020), and one
investigated the superior frontal gyrus (SFG) (Rose et al., 2011). Number
of treatment sessions ranged from 1 to 21 sessions. There were 2 studies
that used a deep TMS coil, and these trials to date have the largest
sample sizes (Dinur-Klein et al., 2014; Zangen et al., 2021). Many studies
used a cue-induced craving paradigm with the rTMS treatments. Most of
these studies showed positive effects on reducing craving or consump­
tion, although many of these also represent pilot studies that have small
sample sizes. Furthermore, there are several studies that only investigate
the effects of one treatment session, which is unlikely to be an adequate
course of treatment.
In the US, regulatory approval has been granted for rTMS use in a
wider scope of conditions such as obsessive compulsive disorder and
migraines (Cohen et al., 2021). Most recently, the Food and Drug
Administration (FDA) and Health Canada has cleared a deep TMS
(dTMS) coil developed by Brainsway as an effective intervention in
smoking cessation, which represented a pivotal advance in the use of
rTMS for tobacco addiction. This advancement was based on the work of
Zangen et. al (2021), leading the first large multicentre double-blinded
randomized controlled trial (RCT) in this domain, proposing a safe
treatment protocol stimulating relevant brain circuits with rTMS to aid
smoking cessation. In this landmark study, 262 participants who were
chronic smokers receiving a course of bilateral dTMS directed to the
insular and lateral prefrontal cortices had a significantly higher
four-week continuous quit rate at week 6 (25.3% in completers),
compared to sham (6.4%). The intent to treat sample had continuous
quit rates at long term follow up, week 18, of 19.4% from active dTMS
compared to 8.7% in the sham group. Patients in the active dTMS arm
further displayed a greater acute decrease in craving scores and the
magnitude of this change was shown to be predictive of an individual’s
likelihood of future quitting. The dTMS coil used in this pivotal trial is
mechanistically similar to conventional rTMS coils, however is designed
to deliver a much deeper and wider area of stimulation allowing greater
stimulation of the bilateral prefrontal cortices and deeper structures
including the insula (Dinur-Klein et al., 2014; Zangen et al., 2021). The
therapeutic benefits in smoking cessation is theorized to result from
stimulating critical neural regions in the preoccupation/anticipation
stage of addiction (Dinur-Klein et al., 2014; Zangen et al., 2021). Prior to
this trial, a separate independent pilot RCT had shown the efficacy of
dTMS for smoking cessation relative to sham (Dinur-Klein et al., 2014).
Overall, these recent advances represent an important paradigm shift
in the treatment of nicotine dependence. It represents a unique modality
V.M. Tang et al. Psychiatry Research 326 (2023) 115340

Table 1
Summary of clinical studies on rTMS and smoking cessation.
Reference N (Active, Sham) Comorbid Study Design Frequency, Pulses per Session, # Target Site; Clinical
Psychiatric of Sessions/Time Interval Coil Type Outcome
Conditions

Abdelrahman et al. 20, 20 Anxiety and RCT 20 Hz (rTMS), 2000 pulses, 10 L-DLPFC; No difference in nicotine
(2021) depressive sessions/1 per day Figure-of-8 consumption, dependence or craving;
disorder anxiety and depressive symptoms
reduced compared to sham.
Amiaz et al. (2009) Sham-neutral N/A RCT 10 Hz (rTMS), 1000 pulses, 10 L-DLPFC; Reduction in nicotine consumption,
(n=13), sessions/1 per day followed by 6 Figure-of-8 dependence and craving.
Sham-cue (n=11), maintenance sessions (3 sessions
Active-neutral in 1 week then once per week for 3
(n=15), weeks)
Active-cue (n=13)
Cailhol et al. (2014) 5, 4 BPD RCT 10 Hz (rTMS), 2000 pulses, 10 R-DLPFC; Two patients reported spontaneous
sessions/1 per day Unknown smoking cessation. Improvements in
anger and affective instability at 3
months, improvements in Tower of
London planning task, non-significant
differences in response rate.
Chang et al. (2018) 14 N/A Open label 20 Hz (rTMS), 1000 pulses per L-DLPFC Increased smoking cessation and
clinical trial site, 10 sessions/NR L-SMFC; reductions in cravings.
Figure-of-8
Dieler et al. (2014) 38, 36 N/A RCT 50 Hz (iTBS), 600 pulses (3 pulses R-DLPFC; No reported differences in cravings
with 200 ms intervals for 2 s Figure-of-8 between groups, higher abstinence
repeated every 10 s), 4 sessions rates in active arm at 3 but not 6 or 12
total/semi-weekly months.
Dinur-Klein et al. Sham-cue(n=15), N/A RCT 10 Hz or 1 Hz (dTMS), 990 (HF) or BL-PFC and Significant reduction in cigarette
(2014) Sham no-cue 600 (LF) pulses, 10 sessions/1 per BL-Insula; consumption and nicotine dependence
(n=16), LF cue day H-coil in HF (but not LF) dTMS, enhanced
(n=7), reduction with exposure to smoking
LF no-cue (n=7), cues with 44% were abstinent at end of
HF cue (n=16), treatment and 33% at 6-month follow-
LF no-cue (n=16) up (in HF group).
Eichhammer et al. 14 N/A Cross-over RCT 20 Hz (rTMS), 1000 pulses, 2 L-DPLFC; Reduction in cigarette use reported, no
(2003) active and 2 sham sessions/1 per Unknown effect on craving.
day for four consecutive days in
randomized order
Friedrich et al. 2, 3 N/A RCT 10 Hz (rTMS), 3000 pulses, 5 L-DLPFC; Feasibility study (no measure of
(2019) sessions/in 1 day (30 min Figure-of-8 clinical effectiveness)
intervals in between)
Hayashi et al. 10 N/A Cross-over RCT 1 Hz (rTMS), 1800 pulses, 1 L-DLPFC; Transient inactivation of the DPLFC
(2013) session Figure-of-8 eliminated effects of immediate
cigarette availability on craving.
Huang et al. (2016) 21, 20 SCZ RCT 10 Hz (rTMS), 2000 pulses, 21 L-DLPFC; Reduction in cigarette consumption;
sessions/1 per day Figure-of-8 no changes in PANSS, general
psychopathology, or WCST.
Kamp et al. (2018) 32, 35 SCZ Secondary 10 Hz (rTMS), 1000 pulses, 15 L-DLPFC; No change in cigarette use, no change
analysis RCT sessions/1 per day Figure-of-8 in negative symptoms.
Kozak et al. (2018) 27 SCZ (n=13 Cross-over RCT 20 Hz (rTMS), 750 pulses per BL-DLPFC; No change in craving, no effect on
only) hemisphere, 6 sessions/2 per day Figure-of-8 cognition.
Lechner et al. rTMS+aWMT N/A RCT 10 Hz (rTMS), 2000 pulses, 10 L-DLPFC; Combining rTMS+aWMT led to
(2022) (n=12), sessions Figure-of-8 decreased performance on a smoking
rTMS+sWMT (n=9), analog task and worsened the effect of
Sham+aWMT either intervention on a back-digit
(n=11), task. Active rTMS (vs. sham) resulted
Sham+sWMT in improved performance on letter-
(n=11) sequency task, and aWMT (vs. sWMT)
improved performance on a back-digit
task. No significant differences in
delay discounting.
Li et al. (2013) 14 N/A Cross-over 10 Hz (rTMS), 3000 pulses, 1 L -DLPFC; Active arm reported reductions in
RCT session Figure-of-8 craving compared to sham, with
greater reductions seen in patients
with higher baseline levels of
dependence.
Li et al. (2017) 10 N/A Cross-over RCT 10 Hz (rTMS), 3000 pulses, 1 L -DLPFC; Active arm exhibited non-significant
session Figure-of-8 reduction in craving.
Li et al. (2020) 21, 17 N/A RCT 10 Hz (rTMS), 3000 pulses, 10 L-DLPFC; Reduction in cigarette use continuing
sessions/1 per day Figure-of-8 across all sessions and lower in active
Coil group at 1-month follow-up (no
influence seen by number of years
smoking or number of quit attempts).
No significant effect on Negative Effect
Factor (depressed mood, irritability,
frustration or anger, and anxiety).
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Table 1 (continued )
Reference N (Active, Sham) Comorbid Study Design Frequency, Pulses per Session, # Target Site; Clinical
Psychiatric of Sessions/Time Interval Coil Type Outcome
Conditions

Marques et al. 23 N/A RCT 1 Hz (rTMS), 1200 pulses, 1 L-FP (n=12) L FP stimulation (but not MC)
(2022) session or MC decreased cigarette cue reactivity. A
(n=11); significant correlation was observed
Figure-of-8 between score in verbal memory recall
and reduction of neutral cue-
reactivity.
Mikellides et al. Active-neutral N/A RCT 5 Hz and 20 trains with 8 s inter- L-DLPFC; No differences in nicotine
(2022) (n=29) Active-cue train interval (10 pulses/train at Figure-of-8 consumption, craving, or on a
(n=30), Sham-cue 50 Hz) (iTBS), 600 pulses, 20 perceived stress scale.
(n=30) sessions/5 per day with 30-min in
between
Moeller et al. (2022) 10,10 SCZ RCT 10 Hz (dTMS), 1800 pulses, 15 BL-PFC and No differences in cigarette
sessions/one per day BL-Insula; consumption, however active dTMS
H4 coil group observed to be slower in
initiating smoking. Active group had a
reduction in positive SCZ symptoms
(not general or negative subscales).
Nawara et al. (2021) 27, 27 N/A RCT 10 Hz (rTMS), 1000 pulses, 6 L-DLPFC; No difference in cigarette
sessions/3 per week with one Figure-of-8 consumption or craving.
session per day
Newman-Norlund 12 N/A Cross-over RCT 3-burst pulses at 5 Hz for 10 R-IFG; iTBS improved, while cTBS impaired,
et al. (2020) pulses/s, 10 pulses/train, 20 Figure-of-8 inhibitory control; stimulation did not
trains, 10 s inter-train interval affect performance in control
(iTBS) or 3-burst pulses presented conditions (such as novelty detection
at 6 Hz for 18 pulses/s, 600 and response execution).
pulses/train, 0.1 inter-train
interval (cTBS), NR pulses, 1
session
Ponciano-Rodrıguez 10 N/A Retrospective 575 Hz (HFLI TMS), NR pulses, 24 L-DLPFC; Smoking cessation achieved in all
et al. (2021) cohort session/1 every 3 days for 8 weeks Circular coil patients after all session, 80%
continued abstinence at 3-month
follow-up. No significant median
decrease in anxiety or depression
scores however 60% and 70% showed
decrease in symptoms respectively.
Poulet et al. (2016) 54 MDD Secondary 1 Hz (rTMS), 360 pulses, 5 R-DLPFC; Significantly higher number of ex-
analysis RCT sessions per week/1 per day for Figure-of-8 smokers in responder groups, while
minimum 2 (max 6) weeks none found in non-responders.
Prikryl et al. (2014) 20, 20 SCZ RCT 10 Hz (rTMS), 2000 pulses, 21 L-DLPFC; Reduction in consumption. No
sessions/1 per day Figure-of-8 correlation found between changes in
negative or depressive SCZ symptoms
and cigarette usage.
Rose et al. (2011) 15 N/A Cross-over RCT 1 Hz or 10 Hz (rTMS), NR pulses, 3 L-SFG (10 Hz Craving after cues increased in 10-Hz
sessions/1 per day or 1 Hz) or condition but reduced with neutral
LF MC (1 cues. Upon smoking in 10-Hz
Hz); condition, immediate reduction in
Figure-of-8 cravings and attenuation of airway
sensation intensity.
Sheffer et al. (2013) 66 (including n=19 N/A RCT 10 Hz or 20 Hz (rTMS), 900 L-DLPFC; No effect on consumption among
non-smokers) pulses, 1 session per each Unknown smokers with no intention to quit.
condition (10 Hz, 20 Hz, sham)/1 Reduction in delay discounting of
per day monetary gains in both smokers and
non-smokers but increased
discounting of monetary losses.
Sheffer et al. (2018) 16, 13 N/A RCT 20 Hz (rTMS), L-DLPFC; Reduced delay discounting, increased
900 pulses, 8 sessions/1 per day Figure-of-8 latency to relapse, abstinence rates
and intervention uptake. No
differences found in treatment
acceptability, comparability of
treatment, motivations, self-efficacy,
MNWS, craving or PSS-4.
Shevorykin et al. 23 N/A RCT 20 Hz (rTMS), 900 pulses (n-16) L-DLPFC; Increasing treatment duration and
(2022) or 1800 pulses (n=7), 8 (n=9) or Figure-of-8 intensity increased probability of
12 (n=6) or 16 (n=8) sessions/1 abstinence,
per day
Trojak et al. (2015) 18, 19 N/A RCT 1 Hz (rTMS), R-DLPFC; No difference in discontinuation
360 pulses, 10 sessions/1 per day Figure-of-8 between groups at all time points (2, 6,
12 weeks). Higher abstinence rates in
active after 1st phase, no difference in
2nd and 3rd. Reduced compulsivity in
craving in active.
Wing et al. (2012) 6, 9 SCZ RCT 20 Hz (rTMS), 750 pulses per BL-DLPFC; Reduction in craving by in 1-week, no
hemisphere, 20 sessions/1 per day Figure-of-8 change following or in abstinence
rates.
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V.M. Tang et al. Psychiatry Research 326 (2023) 115340

Table 1 (continued )
Reference N (Active, Sham) Comorbid Study Design Frequency, Pulses per Session, # Target Site; Clinical
Psychiatric of Sessions/Time Interval Coil Type Outcome
Conditions

Zangen et al. (2021) 123, 139 N/A RCT 10 Hz (dTMS), 1800 pulses, 18 BL-LPFC and Greater cigarette quit rate,
sessions/1 per day BL-Insula; consumption and craving among
H4 coil active group.

Abbreviations: N = sample size; # = number; RCT = randomized control trial; rTMS = repetitive transcranial magnetic stimulation; L = left; DLPFC = dorsolateral
prefrontal cortex; N/A = not applicable; BPD = borderline personality disorder; R = right; NR = not recorded; SMFC = superior medial frontal cortex; iTBS =
intermittent theta burst stimulation; LF = low frequency; HF = high frequency; dTMS = deep transcranial magnetic stimulation; BL = bilateral; PFC = prefrontal
cortex; SCZ = schizophrenia; PANSS = positive and negative syndrome scale; WCST = Wisconsin card sorting test; aWMT = active working memory training; sWMT =
sham working memory training; FP = frontal pole; MC = motor cortex; IFG = inferior frontal gyrus; HFLI = high frequency low intensity; MDD = major depressive
disorder; SFG = superior frontal gyrus; MNWS = Minnesota Nicotine Withdrawal Scale; PSS-4 = Perceived Stress Score; LPFC = lateral prefrontal cortex.

of treatment that can directly and non-invasively modulate the neuro­
circuitry implicated in nicotine dependence. The level of evidence is
now very promising for the efficacy of dTMS in smoking cessation after a
pivotal RCT demonstrating clinical effectiveness (Zangen et al., 2021),
and the seminal pilot RCT preceding it (Dinur-Klein et al., 2014).
Finally, regulatory approval in both the US and recently Canada paves
the way for this treatment to be delivered in clinical practice to
treatment-seeking patients in a safe and regulated manner. Despite the
achievement of these milestones, the path for how this novel technology
could be further optimized and effectively implemented in an accessible,
practical, and effective for patients in real-world clinical settings is not
clear. This paper aims to address these remaining challenges and discuss
innovative approaches and future research avenues that will reduce
barriers and increase the reach of this potentially life-saving interven­
tion to smokers (Fig. 1).
2. rTMS technical considerations and optimizing treatment
parameters
Particularly challenging for the development of rTMS is the large
parameter space with which to explore and refine. Important clinical
and neurobiological implications are possible for factors including, but
not limited to, coil type, target site, laterality, stimulation frequency,
pulse number and patterns. Interestingly, while the Brainsway H4 dTMS
coil for smoking cessation is supported by the 2 highest quality RCTs and
regulatory approval, to our knowledge, all other studies of rTMS for
nicotine dependence have used a figure-of-8 coil. Although the studies
using figure-of-8 coils had smaller sample sizes than the dTMS studies,
the former are more numerous suggesting that there is substantial in­
terest and potential in further developing these types of coils as a
treatment for nicotine dependence (Table 1). The theoretical advantage
of these coils is the ability to be more focal and targeted with the site of
stimulation, thus allowing for greater precision in modulating neuro­
circuits of interest. Almost all trials using the figure-of-8 coil target the
DLPFC of one hemisphere; however, the dTMS coils target most of the
entire PFC region (and thus the DLPFC) bilaterally. There is a large body
of research investigating spatial specificity of rTMS stimulation. MRI-
guided neuronavigation enables the positioning of a coil over a spe­
cific anatomical site (e.g., the DLPFC) (Blumberger et al., 2016). This has
been motivated by studies that show the difficulty of finding the DLPFC
based on scalp-based measurements alone (Herwig et al., 2001), which
do not account for the individual heterogeneity in cortical anatomy.

Fig. 1. Summary of challenges and future directions of implementing rTMS for smoking cessation.

5
V.M. Tang et al.
However, these tools are not typically used with the dTMS coils given
the spread of stimulation is so diffuse (Deng et al., 2013). For dTMS,
changing the target of stimulation requires changing from one H-coil to
another. Although these different coils provide diffuse stimulation in the
brain generally over the frontal cortex and its underlying structures,
certain brain regions receive relatively greater intensity of stimulation
than others depending on the design and winding of these coils (Tendler
et al., 2016), as postulated by computational electric field modeling.
Understanding the relationship between coil design and area of the brain
stimulated will be crucial to further advancing our understanding of
how rTMS works to treat nicotine dependence.
Selecting the optimal site of stimulation will require a better un­
derstanding of how rTMS can engage a neurocircuit model of nicotine
dependence. Broadly speaking, the PFC has a key role in executive
function and cognitive control of drug seeking behaviours. Moreover,
differing connections between the various PFC subregions and cortico-
subcortical networks may be clinically relevant. For example, Hanlon
and colleagues used functional neuroimaging to demonstrate that
stimulating the DLPFC compared to the ventromedial PFC (VMPFC)
activated downstream areas such as the hippocampus and caudate to
differing degrees on functional neuroimaging (Hanlon et al., 2013), and
that this VMPFC (vs. DLPFC) functioning in cocaine users showed
greater relative differences to controls (Hanlon et al., 2016), suggesting
that the VMPFC may be a more clinically relevant target in cocaine use
disorder. A similar translational approach examining the activation
patterns of different brain regions in nicotine dependence, and their
ability to be modified by rTMS, would advance this treatment as a
neurobiologically guided intervention. With respect to the dTMS coil,
including the approved H4 coil for smoking cessation, it remains un­
known whether this can be further refined depending on whether the
stimulation is specific to the insula (Tendler et al., 2016) or requires the
stimulation of distributed sites as well (as seen in the H4 coil where the
bilateral PFC is also involved). In the study of dTMS for alcohol use
disorder, it was found that in the insula specific H8 coil was not found to
be effective compared to sham (Perini et al., 2020). In contrast, a follow
up study showed that the H7 coil which targets the medial prefrontal
cortex and anterior cingulate cortex was effective for alcohol use dis­
order compared to sham (Harel et al., 2022). rTMS is typically delivered
in low frequency or high frequency stimulation. It is believed that low
frequency produces an inhibition of the brain area that is stimulated,
while high frequency produces an excitation (McClintock et al., 2018).
To date there has been limited work comparing low and high frequency
of dTMS. In a study of healthy human subjects, we showed that using a
dTMS coil targeting the insula, low frequency inhibitory stimulation, but
not high frequency excitatory stimulation, attenuated dopamine levels
as measured through Positron Emission Tomography in the substantia
nigra, sensorimotor striatum and associative striatum (Malik et al.,
2018). These findings suggest the potential of low frequency rTMS to
modulate dopamine release in the reward-processing regions of the
brain of smokers. We also have shown that inhibitory stimulation of the
insula also reduced nicotine-taking and nicotine seeking in a preclinical
animal model (Forget et al., 2010). It is therefore plausible that inhibi­
tion of the insula through low frequency stimulation may produce
therapeutic effects in human subjects. On the other hand, the clinical
trials showing benefit of dTMS for smoking cessation have used an
excitatory, high frequency paradigm (Zangen et al., 2021), including the
dTMS pilot trial showing that HF was superior to LF (Dinur-Klein et al.,
2014). It should be noted that in depression, meta-analyses have shown
equivalence of efficacy between low and high frequency rTMS (Berlow
et al., 2020). Thus, more research is required to understand the effects of
high vs. low frequency stimulation on the insula and the consequent
effects on smoking cessation. How and under what conditions that HF
and LF modifies relevant functional connectivity in the brain requires
further exploration. Furthermore, basic assumptions regarding LF being
inhibitory on cortical activity and HF being excitatory may not neces­
sarily hold true depending on other factors such as stimulation intensity,
6
Psychiatry Research 326 (2023) 115340
context-dependent brain activity, and the time course that cortical
excitability is being measured (Klomjai et al., 2015). Importantly, low
frequency treatment parameters have also been shown to be less painful
and thus more tolerable (Kaur et al., 2019; Rossi et al., 2009), with a
lower risk of seizures compared to high frequency rTMS, and thus it is
also important to factor in the risk-benefit ratio of HF vs. LF protocols
(Lefaucheur et al., 2020).
3. Costs, equipment, and infrastructure
3.1. Cost
The high operating costs for rTMS provides an economic challenge to
successful implementation. For example, current cost analyses for usage
in treatment-resistant depression estimates $6146 USD per individual
remission, largely due to the need for specialized equipment, space
within hospital facilities, and staff support encompassing trained tech­
nicians administering the intervention with on-site physician coverage
(Mendlowitz et al., 2019). In the Canadian context, even though Health
Canada granted approval for rTMS for depression since 2002, less than
half of Canadian provinces and territories provide public funding for
rTMS in depression, and some provinces limit funding to only few cen­
tres (Health Quality Ontario, 2021). In the Unites States, insurance
coverage is essential to accessing rTMS, and is currently extremely
limited for the indication of smoking cessation treatment. It is impera­
tive that insurance coverage matches with the current scientific evi­
dence of rTMS for smoking cessation, as overly restrictive policies will
lead to many people potentially not receiving a treatment that can
substantially reduce morbidity and mortality. It has been established
that those who smoke accrue greater indirect costs in lost work pro­
ductivity (Baker et al., 2018a), and cost benefit analyses of providing
coverage for other smoking cessation therapies find that there is a
favourable return of investment due to the mitigation of costs attribut­
able to smoking-related disease (Baker et al., 2018b). We recommend
that similar analyses be conducted in rTMS for smoking cessation in
future research. Tobacco use is deadly, and itself a costly social and
public health problem. While there is evidence of clinical effectiveness,
the cost-effectiveness of dTMS for smoking cessation still needs to be
established. In the literature supporting rTMS for depression,
cost-benefit effectiveness studies have been informative in demon­
strating that the costs of treatment are justified and may be superior to
repeated medication trials (Voigt et al., 2017). We suggest that similar
analyses of rTMS for smoking cessation will be crucial to ensuring that
this intervention can be implemented in healthcare settings. Another
obvious barrier is the availability and accessibility of the appropriate
infrastructure and trained professionals required to deliver such in­
terventions. Relative to the population need, rTMS is unavailable in
most clinical settings; of the limited number of brain stimulation centers,
the majority are not equipped with dTMS devices or the expertise to
treat nicotine dependence given that the most treated conditions are
mood disorders. There is a clear need to examine the cost-effectiveness
of this intervention and whether increasing funding for this intervention
is warranted.
3.2. Geography and equitable access
Currently, rTMS is largely inaccessible for most patients residing
outside of large, urban academic centres, where these brain stimulation
centres are more often located (Goldbloom & Gratzer, 2020). As rTMS
treatment typically involves multiple sessions extended over weeks with
follow-up “booster” sessions, additional costs for housing and other
accommodations should be factored in when considering treatment of
individuals residing outside such areas. Exploring implementation in
community clinics can reduce these geographical barriers and excess
cost burdens. Considering the pervasiveness of tobacco addiction in the
general population and that smokers are often from disadvantaged
V.M. Tang et al.
sociodemographic groups (Garrett et al., 2019), there is an immense
need to overcome such barriers to improve availability. This can be
achieved by reducing the costs of the device, promotion within hospital
infrastructure and community settings, and increasing the number of
highly trained support staff. As we endeavor to provide dTMS as a
smoking cessation treatment for all patients, policy should follow a
bioethical lens to ensure equity in treatment access.
3.3. Home-based neuromodulation
In light of the on-going COVID-19 pandemic, hospital-based treat­
ments have become more complicated as in-person visits have been
discouraged to limit strain on our healthcare system. Moreover, this
global disruption of healthcare has increased the burden of illness from
addiction (Imtiaz et al., 2021). During this pandemic period, there has
emerged a set of international guidelines for the conduct of clinical
services and research of non-invasive brain stimulation approaches, and
within it, the promotion of developing at home neuromodulation
treatments (Bikson et al., 2020).
Availability of a simple and affordable alternative coil and stimulator
could pave the way for development of at-home rTMS. Several proof-of-
concept studies of at-home rTMS devices have been published. One pilot
RCT reported on the use of a miniature rTMS machine with TMS coils
worn on the head using subthreshold stimulation (Lee et al., 2019) that
was able to provide high-frequency (10 Hz) stimulation. Another study
involved a custom-built helmet that can hold existing currently available
rTMS coils over a desired stimulation target, suggesting the potential for
use in situations where trained rTMS technicians are not available for
coil positioning (Badran et al., 2020). Lastly, single-pulse at-home TMS
devices have received FDA clearance for migraine with aura and are
supported by high quality RCT evidence (Lipton et al., 2010); however,
these devices are not currently able to provide repetitive pulses that are
needed for smoking cessation efficacy. Ideally, the development of an
rTMS device effective for smoking cessation would overcome many of
these accessibility barriers and increase the availability of this clinically
effective treatment. We suggest that these reports describing the
development of home-based neuromodulation for other neuropsychi­
atric conditions can help us generate ideas for how this could also be
done for smoking cessation treatment.
4. Education and acceptability
4.1. Education among clinicians
As the clinical effectiveness of rTMS continues to be realized, this
must be matched with appropriate training and exposure among
healthcare professionals. Treatments that should be considered standard
of care are not available to patients if physicians and other healthcare
workers are not adequately trained to provide the treatment. For
example, electroconvulsive therapy, which has long been considered an
effective brain stimulation treatment in psychiatry, has found to be
inadequately taught in psychiatric resident programs according to sur­
vey studies (Yuzda et al., 2002), and consistent clinical exposure and
training of residents is rare (Goldbloom & Gratzer, 2020). In the US,
there is reported inconsistency in training experiences for rTMS for
psychiatric conditions (Trapp & Williams, 2021) and a lack of knowl­
edge in prescribing practices among psychiatrists (Stern et al., 2016). In
one US survey, among psychiatrists who did not receive formal educa­
tion in TMS, only one in four knew how to refer (Stern et al., 2016).
Inadequate training will bias perspectives and attitudes of physician
‘gatekeepers’ to this treatment, making it less widely available than it
can be. As documented in the ECT literature, clinician perspectives can
perpetuate stigma against these treatments, negatively bias patient
preferences, and limit referrals to interventional brain stimulation ser­
vices (Griffiths & O’Neill-Kerr, 2019). Furthermore, it is largely un­
known the awareness and education efforts required for physicians in
7
Psychiatry Research 326 (2023) 115340
primary care or family medicine who are more commonly treating
people with nicotine dependence. Therefore, knowledge translation
strategies for newly approved therapies such as rTMS for smoking
cessation are needed, and barriers in medical education and awareness
among practicing clinicians need to be addressed before we can expect
widespread impact from this treatment.
4.2. Patient attitudes and tobacco-related stigma
There is also limited understanding as to how such interventions will
be viewed and accepted among potential patients with tobacco addic­
tion. A cross-sectional study in the US and Canada found rTMS was
perceived more negatively than pharmacotherapy and talk therapy for
depression, however a second survey delivered with a detailed
description of the background and treatment procedures associated with
showed more favorable perceptions from the respondents (Morrison
et al., 2022). RTMS has not gained such widespread awareness in the
general population. Providing an informed, accurate overview of this
technology to patients will be important as rTMS grows as a treatment
option in the social conscious. It is pertinent to explore stigma and
vulnerability related to smoking addiction in relation to emerging
neurotechnology such as rTMS. Various levels of stigma—self, inter­
personal, structural— plays a strong role in societal acceptance and
patient treatment decisions. It is also recognized that rates of smoking
tend to be higher amongst those who are more marginalized in society,
such as those with lower income and levels of education (Palipudi et al.,
2012), making these people disproportionately more stigmatized for
their smoking. Brain-based explanations of substance use disorders (e.g.
“addiction is a brain disease”) aid in reducing addiction-related stigma
as it emphasizes a person should not be blamed for a biological condition
as it is beyond their control (Buchman et al., 2010). However, there may
be unintended consequences framing addiction, and specifically nico­
tine addiction, in this regard if it causes patients and clinicians to neglect
the socio-environmental influences. Moreover, a recent meta-analysis by
Loughman and Haslam (Loughman & Haslam, 2018) suggests neurobi­
ological explanations for mental disorders may in fact share similar
stigma as biogenetic explanations. However, it is still unknown how
neurobiological explanations of smoking, and associated treatment with
neurotechnology such as rTMS, may influence an individual’s experi­
ence of stigma. Future research should include qualitative studies into
patient perspectives of using non-invasive brain stimulation to treat
conditions like nicotine dependence. Given the uniqueness of this type of
treatment modality, qualitative research methods can provide needed
information on patient beliefs and attitudes that will affect the reach and
adoption of rTMS.
5. Placement within current treatment algorithms
The implementation of rTMS into routine clinical practice will
require consideration of the other currently available evidence-based
treatments for smoking cessation. Broadly speaking, these in­
terventions include psychosocial treatments (such as counseling or
behavioral approaches) and pharmacotherapy (Le Foll et al., 2022). For
the latter, these include several evidenced based treatments that have
regulatory approval for this indication. These treatments may also be
underrecognized and underused in clinical practice, but efforts to
advance screening and brief interventions have improved access to
treatment and increased smoking cessation rates (Selby & Zawertailo,
2022). Head-to-head trials and meta-analyses have demonstrated the
superiority of varenicline and combination NRT (long-acting and
short-acting agents used together) (Thomas et al., 2022), and thus a
stepwise approach recommends these agents as first-line options, and
others such as bupropion as second line options (Selby & Zawertailo,
2022). Thus, given the challenges of feasibility, acceptability, and
implementation barriers as described in this paper, when is the optimal
time for rTMS to be offered to patients?
V.M. Tang et al.
In the pivotal trial with which the FDA protocol for rTMS was
cleared, virtually all participants enrolled had tried other forms of
smoking cessation treatment. Although this was not pre-defined in the
inclusion criteria, the authors report that all participants did not stop
smoking after one quit attempt using other treatment methods, with
68% having made at least 3 attempts where they were unable to quit.
However, the nature of these previous treatment attempts were not
described in detail. It is known that the challenge with nicotine cessation
is sustained abstinence. Indeed, relatively recent modeling of data from
over 40 smoking cessation trials suggest that 12-month abstinence rates
are 23% or less with these medications (Jackson et al., 2019). Thus while
pharmacotherapy can assist smokers in reaching short-term abstinence,
there are diminishing benefits of cessation medication for sustained
abstinence (Rosen et al., 2018). Thus, it is possible that patients can
receive short term benefit from standard treatments but relapse (and
continue to relapse) shortly after. The relative benefit of combination
rTMS and pharmacotherapy vs. each treatment alone is unknown. Tro­
jak and colleagues (Trojak et al., 2015) compared active vs. sham rTMS
as an adjunct to NRT and observed higher quit rates with the combi­
nation of active rTMS and NRT, however their protocol was different to
the FDA approved treatment using the dTMS coil, as this trial used a
figure of 8 coil to deliver low frequency (1 Hz) stimulation to the right
DLPFC.
Furthermore, most clinical trials offer rTMS in combination with
some form of psychosocial support which can comprise of supportive
talk (Zangen et al., 2021), brief counselling sessions (Nawara et al.,
2021), manualized cognitive behavioural therapy (Dieler et al., 2014),
and/or group therapy.(Wing et al., 2012) More research is required to
investigate whether combining rTMS with psychosocial treatment ap­
proaches enhances smoking cessation rates. Such treatment combina­
tions may be particularly effective, given that rTMS can theoretically
activate or enhance learning effects through neuroplasticity (Tik et al.,
2017), which has direct relevance to cognitive-based therapies. Studies
of rTMS typically target the frontal cortex, which has primary functions
in cognitive control and executive function. It has been postulated that
neurocircuits that are targeted by neurostimulation interventions may
be more amenable to modulation if activated in tandem with the rTMS
treatment (Deng et al., 2020). Many studies, including the FDA cleared
protocol, have designed the treatment protocol to include cue-induced
craving activation prior to stimulation for this reason. Thus far, only
scarce, secondary data is available to support the added benefit of
adding craving activation, compared to no craving activation. The pilot
dTMS trial by Dinur-Klein and colleagues did not show a significant
difference in their primary outcomes of abstinence in those who
received a smoking cue with treatment compared to those who did not
(Dinur-Klein et al., 2014). However, based the secondary outcome of
changes on the Fagerström Test for Nicotine Dependence for cue vs. no
cue, the authors proceeded with assuming the benefit of having this for
the pivotal trial protocol. The importance of investigating the benefit of
multiple interventions at once is clinically relevant, since this increases
the complexity, cost, training, and even risk of adverse effects of treat­
ment. In order to best clarify the placement of rTMS within current
treatment standards, research needs to be done to further characterize
(1) the number and type of previous treatment trials, (2) the definition of
an unsuccessful treatment trial, and (3) head-to-head comparisons of
different treatments, including combination treatments.
6. Real-world patient populations and comorbidities
6.1. Consideration of patient characteristics and common comorbidities
Clinical trials for smoking cessation often do not represent typical
smokers found in the community. From an implementation science
perspective, the necessary steps after initial demonstration of efficacy is
clarifying how a novel intervention can be adapted to patient-level
characteristics, in the context of unique provider and organization
8
Psychiatry Research 326 (2023) 115340
level factors. Most often, studies assessing rTMS in smoking cessation
excluded patients with an active psychiatric illness and/or other sub­
stance use disorder (Table 1); however, it is important to recognize the
large proportion of individuals with a mental disorder that use ciga­
rettes. Surveys based in the US have estimated up to 50–70% of in­
dividuals with bipolar disorder (Heffner et al., 2011) and 70–85% of
individuals with schizophrenia smoke (Ziedonis et al., 2008), and
smoking rates are higher in individuals with self-reported anxiety,
depression and substance use disorder than in the general population
(Smith et al., 2014). Some studies have theorized that this is due to
nicotine’s ability to alleviate some negative symptoms such as stress,
low mood and lack of concentration (Aubin et al., 2012; Minichino et al.,
2013). Alternatively, having a psychiatric disorder is a risk factor for
smoking relapse (Álvarez Gutiérrez et al., 2016). Nevertheless, the
prevalence of psychiatric comorbidities in the real-world population of
those with tobacco addiction impose important considerations in
determining clinical guidelines and suggest the need to conduct studies
of rTMS in those with psychiatric comorbidities. Furthermore, common
psychiatric medications either increase or decrease cortical excitability,
and have implications on the efficacy and safety of rTMS delivery (Rossi
et al., 2009). Responses to rTMS show broad intra- and inter-variability
and can be influenced by patient substance use as well. For example,
comorbid substance use may alter the excitability of the sensorimotor
system. Notably, alcohol use at the time of testing is important to
consider. Individuals experiencing alcohol withdrawal may exhibit
increased hyperexcitability in cortical regions (Turco et al., 2020).
Some studies on nicotine-dependent individuals with comorbid
anxiety and depressive symptoms have demonstrated clinical effec­
tiveness in reducing psychiatric symptoms (Table 1) (Abdelrahman
et al., 2021; Ponciano-Rodríguez et al., 2021). As there are higher
smoking rates in individuals with major depressive disorder (Wein­
berger et al., 2018), rTMS treatment may provide therapeutic benefit in
targeting both mood symptoms and smoking cessation. However, three
studies examining smokers with a diagnosis of schizophrenia did not
show clinical benefit in positive symptoms (Huang et al., 2016), nega­
tive symptoms (Huang et al., 2016; Kamp et al., 2018), or cognition
(Kozak et al., 2018). As rTMS gains more attraction as a psychiatric
treatment option, it will be pertinent to explore its duality in effective­
ness for patients with multiple disorders.
In addition, it is known that vulnerability to develop tobacco
addiction, to respond to treatment or to quit smoking are influenced by
sex (Verplaetse et al., 2018) and gender (Smith et al., 2016). Although
smoking is more common in males (Le Foll et al., 2022), females tend to
show different response rates to nicotine replacement therapy and
smoking cessation medications (Perkins & Scott, 2008; Smith et al.,
2017), suggesting differences in neurocircuitry than biological males,
yet there is limited knowledge on how this may translate to respon­
siveness in rTMS therapy. One study found neuroplastic responses to
high-frequency stimulation in the prefrontal cortices are greater with
higher endogenous estrogen levels in women (Chung et al., 2019);
however, the role of sex hormones in modulating treatment outcomes is
still under investigation. Importantly, sexual minorities and gender
minorities have higher rates of smoking relative to the general popula­
tion (Evans-Polce et al., 2020).
6.2. Considerations with electronic cigarette use
Rates of current smoking have decreased over the past two decades,
from 20.9% of U.S. adults in 2005 to 12.9% in 2020 (Cornelius et al.,
2022). However, this decline has coincided with a rise in electronic
cigarette (e-cigarette) use (Obisesan et al., 2020), with many adults
using these devices to quit smoking (Hajek et al., 2022), despite long
term health risks still being unclear. The high rates of ‘dual use’ in adult
smokers, and growing increase of new e-cigarette users (particularly
among younger populations) impose important considerations as Can­
ada moves towards gaining regulatory approval for rTMS for smoking
V.M. Tang et al.
cessation. Most clinical studies assessing rTMS effectiveness exclude
patients who use nicotine through other products besides cigarettes
(Zangen et al., 2021) and the real-world effectiveness for vaping prod­
ucts yet to be clinically known. Nicotine-containing e-cigarettes likely
produces overlapping addictive processes within the brain as cigarette
smoking. Whether rTMS shows similar therapeutic benefits for e-ciga­
rette cessation as smoking cessation is particularly clinically relevant as
e-cigarette usage continues to increase.
7. Conclusions
The evidence base supporting the efficacy and safety of rTMS for
smoking cessation is rapidly increasing, recently reaching a critical mass
and paving the way for FDA and Health Canada approval of the dTMS
coil for this indication. These advances signal the potential for rTMS to
be translated and implemented into mainstream clinical practice
(Fig. 1). Before this can happen, remaining clinical, social, economic,
and technological barriers need to be recognized and addressed for this
progress to continue. Relative lack of effectiveness data and comparative
effectiveness to other currently available treatments are also crucial
gaps that future research must address. Many of these barriers require
thinking clearly about real-world feasibility and practicality that may
not be addressed in the RCT and clinical trial literature. These broader
questions may be guided by frameworks for developing and evaluating
complex interventions, such as the UK’s Medical Research Council
guidelines (Skivington et al., 2021). Furthermore, rTMS presents an
exciting new frontier for brain-based treatments for nicotine depen­
dence, and the field is primed for further exploration and targeting of
neurobiological mechanisms. Finding solutions for these challenges will
allow rTMS to be an important breakthrough in reducing the enormous
burden of smoking related morbidity and mortality that continues
worldwide.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Data availability
No primary data was used in this manuscript.
CRediT authorship contribution statement
Victor M. Tang: Conceptualization, Methodology, Project adminis­
tration, Supervision, Visualization, Writing – original draft. Rachel
Goud: Writing – original draft, Writing – review & editing. Laurie
Zawertailo: Writing – review & editing. Peter Selby: Writing – review
& editing. Adina Coroiu: Writing – review & editing. Matthew E.
Sloan: Writing – review & editing. Meghan Jo-Ann Chenoweth:
Writing – original draft, Writing – review & editing, Writing – original
draft. Daniel Buchman: Writing – review & editing. Christine Ibra­
him: Writing – review & editing. Daniel M. Blumberger: Writing –
review & editing. Bernard Le Foll: Conceptualization, Methodology,
Project administration, Supervision, Visualization, Writing – original
draft.
Declaration of Competing Interest
Dr. Tang receives research support through the Brain & Behavior
Research Foundation, the Physician Services Incorporated Foundation,
Research in Addiction Medicine Scholars (RAMS) Program
(R25DA033211) from the National Institute on Drug Abuse, and the
Labatt Family Network for Research on the Biology of Depression. Dr.
Blumberger receives research support from CIHR, NIH, Brain Canada
and the Temerty Family through the CAMH Foundation. He received
9
Psychiatry Research 326 (2023) 115340
research support and in-kind equipment support for an investigator-
initiated study from Brainsway Ltd. and has been the site principal
investigator for three sponsor-initiated studies for Brainsway Ltd. He
also received in-kind equipment support from Magventure for 3
investigator-initiated studies. He received medication supplies for an
investigator-initiated trial from Indivior. He has participated in one
Scientific Advisory Board Meeting for Janssen and one meeting for
Welcony Inc. Dr. Bernard Le Foll has obtained funding from Pfizer Inc.
(GRAND Awards, including salary support) for investigator-initiated
projects. Dr Le Foll has obtained funding from Indivior for a clinical
trial sponsored by Indivior. Dr. Le Foll has in-kind donations of cannabis
products from Aurora Cannabis Enterprises Inc. and study medication
donations from Pfizer Inc. (varenicline for smoking cessation) and Bio­
projet Pharma. He was also provided a coil for a Transcranial magnetic
stimulation (TMS) study from Brainsway. Dr. Selby reports receiving
funding support for research from Pfizer Inc., Ontario Brain Institute,
Canadian Cancer Society Research Institute, and Canadian Institutes of
Health Research. Dr. Le Foll has obtained industry funding from Canopy
Growth Corporation (through research grants handled by the centre for
Addiction and Mental Health and the University of Toronto), Bioprojet
Pharma, Alcohol Countermeasure Systems (ACS), Alkermes and Uni­
versal Ibogaine. Lastly, Dr. Le Foll has received in kind donations of
nabiximols from GW Pharmaceuticals for past studies funded by CIHR
and NIH. He has participated in a session of a National Advisory Board
Meeting (Emerging Trends BUP-XR) for Indivior Canada and is part of
Steering Board for a clinical trial for Indivior. He has been consultant for
Shinogi. He is supported by CAMH, Waypoint centre for Mental Health
Care, a clinician-scientist award from the department of Family and
Community Medicine of the University of Toronto and a Chair in
Addiction Psychiatry from the department of Psychiatry of University of
Toronto.
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