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Prog Neuropsychopharmacol Biol Psychiatry. Author manuscript; available in PMC 2022
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July 13.
Published in final edited form as:
Prog Neuropsychopharmacol Biol Psychiatry. 2021 July 13; 109: 110290. doi:10.1016/
j.pnpbp.2021.110290.
Repetitive transcranial magnetic stimulation as a potential
treatment approach for cannabis use disorder
Tonisha Kearney-Ramos, Ph.D.1,2,*, Margaret Haney, Ph.D.1,2
1New York State Psychiatric Institute, New York, New York, USA
2Columbia University Irving Medical Center, New York, New York, USA
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Abstract
The expanding legalization of cannabis across the United States is associated with increases
in cannabis use, and accordingly, an increase in the number and severity of individuals with
cannabis use disorder (CUD). The lack of FDA-approved pharmacotherapies and modest efficacy
of psychotherapeutic interventions means that many of those who seek treatment for CUD relapse
within the first few months. Consequently, there is a pressing need for innovative, evidence-
based treatment development for CUD. Preliminary evidence suggests that repetitive transcranial
magnetic stimulation (rTMS) may be a novel, non-invasive therapeutic neuromodulation tool
for the treatment of a variety of substance use disorders (SUDs), including recently receiving
FDA clearance (August 2020) for use as a smoking cessation aid in tobacco cigarette smokers.
However, the potential of rTMS for CUD has not yet been reviewed. This paper provides a
primer on therapeutic neuromodulation techniques for SUDs, with a particular focus on reviewing
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the current status of rTMS research in people who use cannabis. Lastly, future directions are
proposed for rTMS treatment development in CUD, with suggestions for study design parameters
and clinical endpoints based on current gold-standard practices for therapeutic neuromodulation
research.
Keywords
Non-invasive brain stimulation; Substance use disorders; Brain networks; Functional
neuroimaging; Treatment development; Narrative review
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*
Corresponding author at: Columbia University Irving Medical Center, Substance Use Research Center, 1051 Riverside Drive, Unit
120, New York, NY 10032, Tonisha.kearney-ramos@nyspi.columbia.edu.
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Conflicts of Interest
The authors have no conflicts of interest to disclose.
Kearney-Ramos and Haney Page 2
I. INTRODUCTION
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Public Health Status of Cannabis Use and Cannabis Use Disorder.

Cannabis is one of the most widely used recreational drugs in the world, with over 188
million reported users worldwide in 2019 (World Drug Report, 2020). Although at present
cannabis remains illegal at the federal level in the United States (U.S.), in 2018, 43.5
million people endorsed using cannabis in the past year in the U.S. alone (>15% of U.S.
population), behind only alcohol (65%) and tobacco (25%) (SAMHSA, 2019). Rates of
cannabis use have increased in the past decade, paralleling changes in the social and political
climate favoring legalization (Cerda et al., 2020; Hasin et al., 2019; Kerridge et al., 2017).
Likewise, dramatic shifts in sociopolitical stances surrounding cannabis have coincided
with a general decrease in stigmatization of cannabis use across the population. Public
perception of the risks of regular cannabis use fell dramatically in the last 10-15 years, with
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a 50-80% decrease in perceived risk for U.S. adolescents (between 2004-2016; Hasin, 2018),
a decrease from 50% to 33% for U.S. adults (between 2002-2014; Hasin, 2018), and an 11%
jump in the number of adults perceiving there to be no risk at all (Compton et al., 2016).
As of December 2020, 15 states plus the District of Columbia have legalized medical and
recreational cannabis use; 35 states legalized medical use only; and 16 states decriminalized
non-medical use, with 67% of the general public now believing that cannabis should be legal
(Pew, 2019) compared to 35% in 2008 (Pew, 2010).
Contrary to these increasingly positive public views, research and clinical data have shown
that heavy cannabis use is often associated with cognitive impairment, increased risk
for psychotic disorders and other mental and medical comorbidities, lower educational
attainment, and unemployment (Colizzi & Bhattacharyya, 2018; Sherman & McRae-Clark,
2016; Volkow et al., 2014). Although the majority of people who use cannabis do not go
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on to develop any major complications associated with their cannabis exposure, as many
as 30% of people who use cannabis endorse experiencing sufficiently disruptive symptoms
and adverse life consequences attributed to their cannabis use so as to meet standard clinical
criteria for a DSM-5 Cannabis Use Disorder (CUD) diagnosis (Budney et al., 2019). Further,
the number of individuals with CUD has steadily increased with expanding legalization
(Hall & Lynskey, 2020; Hasin, 2018; Hasin et al., 2019), and the numbers and severity
are predicted to continue to increase as cannabis becomes even more widely accepted and
available and the perceived risk continues to decline (Budney et al., 2019; Hall & Lynskey,
2020; Hasin, 2018).
Need for More Effective Cannabis Use Disorder Treatment Options.

Currently, combined psychotherapeutic and pharmacological interventions are considered
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best practice for treatment of substance use disorders (SUDs) (Ray et al., 2020). Yet,
unlike many other common SUDs (such as, Alcohol Use Disorder, Opioid Use Disorder,
Tobacco Use Disorder), there are no pharmacotherapies which have reached FDA approval
for the treatment of CUD (Kondo et al., 2020). While several investigational pharmacologic
treatments have shown promise for CUD, none have attained sufficient support for
clinical translation, to date (Brezing & Levin, 2018; Kondo et al., 2020; Sherman &
McRae-Clark, 2016). Currently, the most widely implemented interventions for CUD
Prog Neuropsychopharmacol Biol Psychiatry. Author manuscript; available in PMC 2022 July 13.
remain psychotherapeutic approaches, including cognitive-behavioral therapy, psychosocial

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therapies such as family and community-based programs, and contingency management

(Gates et al., 2016; Sherman & McRae-Clark, 2016), all of which have demonstrated
efficacy in reducing frequency and quantity of cannabis use, but with only modest and
short-lived abstinence rates (Dutra et al., 2008; Sherman & McRae-Clark, 2016). Aggregate
public health reports on CUD treatment outcomes reveal that relapse rates across traditional
treatment modalities remain high within the first year after treatment completion (Budney
et al., 2008; Hasin, 2018). In fact, several studies have shown that most CUD patients
relapse within the first few months of treatment. Moreover, meta-analyses have found lower
post-treatment abstinence rates for people who use cannabis than for either cocaine, opioid,
or polysubstance users (Dutra et al., 2008). Thus, individuals contending with CUD have a
generally low probability of treatment success, leaving many without adequate support to
overcome their problematic use patterns.
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Given steadily increasing numbers of people who use cannabis, corresponding increases
in the incidence and severity of CUD diagnoses, and limited efficacy of current treatment
options, expanding and improving upon CUD treatment approaches represents a critical
public health need. Fundamentally, to achieve greater efficacy and durability, CUD
interventions should aim to mitigate the limitations or complement the strengths of current
treatment models, or both.
Identifying Novel Directions for Cannabis Use Disorder Treatment Development.

In terms of etiology, research spanning the last several decades and integrated across
multiple scientific disciplines has supported the understanding that substance use and
behavioral disorders are fundamentally diseases of the brain, involving aberrant functioning
in key areas responsible for regulating emotion, cognition, and behavior (Diehl et al.,
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2018; Koob & Volkow, 2016; Leshner, 1997; Verdejo-Garcia et al., 2019; Volkow et
al., 2016). In fact, the complex, multifaceted behavioral manifestations of SUDs are not
solely the result of dysfunction in isolated brain regions but emerge from alterations in
function and organization of large-scale, spatially distributed networks of brain regions
and their interconnections (Ekhtiari et al., 2016; Fatima et al., 2019; Koob & Volkow,
2016). Maladaptive changes in the structure, function, and neurochemistry within and
between these core neural circuits are associated with the emotional dysregulation, cognitive
impairments, and behavioral dysfunction that contribute to the development of drug-
dominated cognitive-behavioral schema and likely lead to the transition from occasional,
recreational use to problematic, unhealthy patterns of use characterizing SUDs (Fatima et
al., 2019; Koob & Volkow, 2016; Verdejo-Garcia et al., 2019; Volkow et al., 2014; Yanes et
al., 2018).
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Despite our increasingly enriched understanding of the brain mechanisms underlying many
key features of SUDs, the real-world implementation of this neuroscientific knowledge into
clinical practice, or even into clinical research, has been slow (Ekhtiari et al., 2019; Steele
et al., 2019; Verdejo-Garcia et al., 2019). High-quality brain data could potentially aid in
addressing limitations of current treatment models, thereby improving treatment approaches
and reducing the low treatment success rates (Ekhtiari et al., 2019; Singh & Rose, 2009;
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Steele, 2020; Steele et al., 2019; Verdejo-Garcia et al., 2019).
Exploring a Brain-based Treatment Approach for Cannabis Use Disorder.

Therapeutic neuromodulation approaches are an increasingly prevalent group of techniques
used in neurology and psychiatry to target the neural endophenotypes of neuropsychiatric
diseases in order to produce clinically relevant symptom improvement (Brunoni et
al., 2019; Diehl et al., 2018; Fox et al., 2014). The most common neuromodulation
approaches include neurostimulation techniques [which use external electronic tools to apply
electromagnetic fields that exogenously alter activity patterns of sensitive cells; principally,
neuronal cells (Chervyakov et al., 2015b)], and neurofeedback techniques [which are
a group of biofeedback methods that involve learning self-regulation of cognitive and
emotional states through volitional control of specific brain rhythms, typically facilitated by
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neurorecording tools that can instantaneously measure brain waves and neurophysiological
responses to produce a real-time signal, such as a visual or auditory cue, that conveys
time-locked feedback of the status and quality of attainment of a desired neurofunctional
state (Martz et al., 2020)]. In general, these neuromodulation techniques operate by
directly influencing neural functioning in brain regions and their associated functional
circuits that then produce measurable cognitive and behavioral outputs, thereby enabling
empirical demonstration of the causal links between neural manipulation and behavior
change (Bestmann et al., 2008; Pascual-Leone et al., 2000; Silvanto & Pascual-Leone,
2012; Sliwinska et al., 2014; Vosskuhl et al., 2018). This contrasts with neuroimaging
methods, such as functional magnetic resonance imaging (fMRI), positron emission
tomography (PET), or electroencephalography (EEG), which chiefly use observational
neurophysiological recording techniques during varying mental or behavioral states to infer
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brain-behavior associations (Sack & Linden, 2003; Silvanto & Pascual-Leone, 2012). As
such, neuromodulation can uniquely be used to directly target, selectively and directionally
manipulate, and, ideally, normalize aberrant neural processing circuits that contribute to
specific maladaptive behaviors (Diehl et al., 2018; Dunlop et al., 2017; Guse et al., 2010;
Hanlon et al., 2016; Sack & Linden, 2003; Yavari et al., 2016). Using these techniques alone
or in conjunction with other established treatment modalities can provide an alternative or
improvement upon SUD treatment approaches.
Among the most promising neuromodulation approaches for SUD treatment are the
non-invasive brain stimulation (NIBS) techniques. In particular, repetitive transcranial
magnetic stimulation (rTMS) has been the most widely investigated NIBS approach in
neurology and psychiatry, although other noteworthy modalities include the transcranial
electrical stimulation (tES) methods, which principally comprise transcranial direct current
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stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial

random noise stimulation (tRNS). While there are numerous literature reviews which have
comprehensively summarized the conceptual framework and current status of therapeutic
neuromodulation studies investigating NIBS across a range of SUD groups (Coles et al.,
2018; Diana et al., 2017; Dunlop et al., 2017; Ekhtiari et al., 2019; Hanlon et al., 2016;
Luigjes et al., 2019; Verdejo-Garcia et al., 2019; Yavari et al., 2016), the evidence presented
in support of rTMS has generally outpaced what is known about tES techniques, and as
such, rTMS treatment findings tend to occupy a large portion of these discussions, with
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tDCS research making up a close second (Ekhtiari et al., 2019). More importantly, however,
none of these comprehensive literature reviews summarize and discuss the current state of
NIBS research for CUD.
Thus, the objective of the present review is to discuss issues related to using NIBS to target
substance use-related neural circuitry for the treatment of CUD.
In general, there is a surprising paucity of therapeutic neuromodulation research in CUD,

with, to our knowledge, only three rTMS (Prashad et al., 2019; Sahlem et al., 2018; Sahlem
et al., 2020) and one tDCS (Boggio et al., 2010) interventional studies published, to date.
Here we will focus solely on reviewing the rTMS-based interventional studies since there
is greater clinical appraisal of rTMS for SUDs, and in psychiatry in general, enabling a
more informed discussion on the relative merits of rTMS for CUD. We will assimilate the
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contributions of the three rTMS studies into a discourse on the potential utility of these
approaches for CUD; highlight challenges unique to cannabis and CUD that might confound
the implementation of rTMS in this population; integrate recent discoveries in neuroscience
and technological or methodological advancements in neuromodulation techniques; and
finally, propose a framework or foundation for the future development of rTMS research in
CUD.
II. INVESTIGATING REPETITIVE TRANSCRANIAL MAGNETIC

STIMULATION TECHNIQUES AS NOVEL, EMPIRICALLY DERIVED,
NEUROBIOLOGICALLY TARGETED TREATMENT APPROACHES FOR
CANNABIS USE DISORDER
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Principles of Repetitive Transcranial Magnetic Stimulation (rTMS) for Therapeutic

Applications.
General TMS Physiology.—TMS involves the use of electromagnetic induction to
generate an electrical current in the brain that leads to the depolarization of neurons (Barker
et al., 1985). In humans, TMS is delivered non-invasively in conscious and alert individuals
by placing a small to moderate-sized electromagnetic coil, typically encased in plastic
housing, gently against the scalp. An electric pulse generator, or stimulator, generates a
rapidly oscillating electric current within the coil which results in a perpendicular magnetic
field directly beneath it. This magnetic field readily penetrates the skull to reach the cerebral
cortex, thus enabling the mostly painless delivery of discrete magnetic pulses to particular
cortical locations with reliably high spatial specificity (Deng et al., 2013; Hanlon et al.,
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2013). These rapidly oscillating magnetic pulse fields then induce a secondary, electric
(eddy) current in the underlying cortical tissue which, owing to the electrochemical nature
of neuronal cells, is capable of modulating the excitability and activity patterns in those
neurons in accordance with Faraday’s Law of electromagnetic induction (Barker, 1991;
Chervyakov et al., 2015b; Lefaucheur et al., 2014; Pascual-Leone et al., 2000).
Although the most widely used TMS coils, e.g., figure-8 coils, tend to have relatively
shallow stimulation depths, with induced fields typically reaching superficial cortical tissue
of only ~1-4 cm2 (Deng et al., 2013; 2014; Stokes et al., 2013), TMS techniques have the
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ability to manipulate large-scale, spatially distributed networks of brain regions by not only
generating changes in activity at the direct stimulation target beneath the coil, but also by
evoking reciprocal changes in activity in downstream functionally and structurally connected
cortical and subcortical regions via transsynaptic modulation (Bestmann et al., 2008; Hanlon
et al., 2013; 2017; Opitz et al., 2016; Pascual-Leone et al., 1998; Strafella et al., 2001;
To et al., 2018; Vink et al., 2018). Specifically, when the TMS-induced electrical current
in the targeted cortex is sufficiently strong, it is capable of depolarizing those underlying
neurons, as well as promoting a cascade of neurotransmitter release, excitatory postsynaptic
potentials, and eventually action potentials in downstream neurons receiving mono- and
poly-synaptic inputs from the stimulated neurons (Chervyakov et al., 2015b). This is why
direct TMS effects at relatively superficial cortical targets are so useful for non-invasively
producing widespread neural effects that impact multiple interrelated circuits, including
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those encompassing deeper subcortical regions, which ultimately influence the complex,
multifaceted psychophysiological processes regulated by these brain networks (Bestmann et
al., 2008; Opitz et al., 2016; To et al., 2018).
Conventional (Fixed-Frequency) rTMS.—When TMS pulses are delivered repeatedly

in rapid succession, known as repetitive TMS (rTMS), durable alterations in neuronal firing
patterns along the corticospinal tract can occur through promotion of neural plasticity—an
intricate set of processes resulting in sustained changes in neural activity patterns and
functional and structural circuit organization, as well as the corresponding neurobehavioral
consequences of these changes, which endure beyond stimulation cessation (Chen et al.,
1997; Hoogendam et al., 2010; Maeda et al., 2000; Siebner et al., 2000). While the precise
mechanisms governing rTMS-induced neural plasticity remain elusive and a fervent topic of
investigation (Hoogendam et al., 2010; Rossi et al., 2009; 2021), extensive preclinical and
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clinical research point to a role of synaptic coupling efficiency, with either strengthening
or weakening of neural communication pathways corresponding to the induction of either
long-term potentiation (LTP) or long-term depression (LTD), respectively (see reviews by
Chervyakov et al., 2015b; Platz & Rothwell, 2010; Stagg & Nitsche, 2011). Furthermore,
the magnitude, direction, and duration of neuroplasticity induction are governed by
intensity- and timing-specific parameters, such as the rTMS stimulation intensity (set as
a given percentage of an individual’s motor threshold; described below), stimulation pulse
rate, total pulse number, inter-pulse interval, duration of pulse trains, inter-train interval, etc.
(Hoogendam et al., 2010; Maeda et al., 2000; Pell et al., 2011).
In general, high-frequency rTMS (HF-rTMS; ≥5 Hz pulse rate) typically produces an

excitatory (LTP-like) effect, which leads to an enduring increase in cortical excitability
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and is employed when up-regulating activity within a targeted region or circuit is desired
(Chervyakov et al., 2015b; Hoogendam et al., 2010; Pascual-Leone et al., 1994; Siebner et
al., 2000). Whereas, low-frequency rTMS (LF-rTMS; ≤1 Hz pulse rate) typically produces
an inhibitory (LTD-like) effect, which leads to an enduring decrease in cortical excitability
and is employed when down-regulating activity within a targeted region or circuit is desired
(Chen et al., 1997; Chervyakov et al., 2015b; Hoogendam et al., 2010).
Measuring Cortical Excitability.: Historically, the modulating effects of rTMS on cortical

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excitability have been directly evaluated on the basis of measurable shifts in the peak-to-
peak amplitude of motor evoked potentials (MEPs) (Barker et al., 1986; Hallett, 1996;
Rossini et al., 1994). MEPs are the physiological responses elicited in peripheral muscles
when TMS is delivered over corresponding regions of the primary motor cortex (M1).
Namely, when a single TMS pulse is applied to the M1 hand or leg region, a reliable
contraction is induced in the contralateral hand or leg muscle (respectively), which is
often visually observable and the amplitude of which can be detected using peripheral
physiological recording, such as surface electromyography (EMG) (Barker et al., 1985;
Bestmann & Krakauer, 2015; Rothwell et al., 1987; Day et al., 1989). The magnitude
of the MEP amplitude represents the number of neurons successfully depolarized by
the TMS pulse (Groppa et al., 2012), with larger MEP amplitudes indicating a greater
number of neurons sensitive and responsive to stimulation and is thus a reflection of higher
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corticospinal excitability (Nitsche & Paulus, 2000; Ridding & Rothwell, 1997). In this
way, measurement of MEPs constitutes one of the hallmark biomarkers for non-invasive
quantification of corticospinal excitability levels (Bestmann & Krakauer, 2015; Chipchase et
al., 2012).
Patterned rTMS.—Beyond the conventional fixed frequency rTMS varieties, there are
also patterned variants of rTMS which are becoming increasingly popular. Patterned rTMS
refers to protocols involving short, repeated bursts of rTMS pulses, known as pulse trains,
accompanied by brief pauses between these pulse trains, which are referred to as intertrain
intervals (ITIs) (Rossi et al., 2009; 2021; Suppa et al., 2016). The specific pattern of
pulse burst delivery within a pulse train can alter the consequent rTMS-induced effects.
For instance, thetaburst stimulation (TBS), which is the most commonly explored group
of patterned rTMS variants, involves theta frequency (5 Hz) pulse rates which mimic
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endogenous neuronal firing patterns employed by the brain during natural learning and
memory processes (Di Lazzaro et al., 2005; 2008; Huang et al., 2005; 2009). TBS follows
a rhythmic bursting pattern consisting of three-pulse bursts delivered at 50 Hz every 200
ms (aka at 5 Hz) (Huang et al., 2005; Suppa et al., 2016). Depending on the precise
temporal pattern of TBS pulse delivery, either excitatory, LTP-like neural after-effects (i.e.,
intermittent TBS, or iTBS: 2-sec train of TBS with 10-sec ITI for a total of 190 sec and 600
total pulses; Huang et al., 2005) or inhibitory, LTD-like neural after-effects (i.e., continuous
TBS, or cTBS: 40-sec train of uninterrupted TBS and 600 total pulses; Huang et al., 2005)
can be induced in a circuit-specific way (Dunlop et al., 2017; Hanlon et al., 2013; 2017).
Further, TBS-induced changes in cortical excitability have been shown to be more robust
and enduring, and with session lengths only a fraction of those required for conventional
rTMS (i.e., ~15-40 min vs. ~2-5 min for conventional rTMS and TBS, respectively) (Huang
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et al., 2007; 2008; 2009; Ishikawa et al., 2007; Katayama & Rothwell, 2007).
Standard rTMS Session Procedures.—There is a multitude of approaches to

conducting an rTMS treatment session, with the number and variety of ways increasing
exponentially over time as new data and technologies emerge that further refine various
aspects of the treatment process. However, at the least, a standard rTMS treatment procedure
will generally involve several fundamental steps which are described below.
Motor Threshold Determination.: During a standard rTMS procedure, the first step is
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to determine an individual’s motor threshold (MT), which is the lowest TMS stimulation
intensity required to apply over the M1 region for that individual to exhibit a reliable
corticospinal response (Rossini et al., 1994), and is based on MEP measurements. MTs are
known to show considerable intra- and inter-individual variability, even in healthy people
(Groppa et al., 2012; Kloppel et al., 2008; Lopez-Alonso et al., 2014; Tranulis et al., 2006).
Because intrinsic levels of cortical excitability vary across individuals, these differences can
directly impact the intensity of stimulation a given individual needs to achieve neuronal
depolarization in response to TMS, which is reflected by the magnitude of their estimated
MT (Pellegrini et al., 2018; Rossi et al., 2009).
Treatment Stimulation Dose.: Consequently, the rTMS treatment stimulation “dose”

(Peterchev et al., 2012), which is the therapeutic dose of rTMS applied to the clinical brain
target of interest, is a personalized treatment parameter which is adjusted by MT to account
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for individual differences in cortical excitability. Customarily, the treatment dose is derived
from the MT value estimated while at rest, known as the resting MT (rMT). The rMT is the
minimum stimulation intensity of single-pulse TMS needed to be applied to M1 to produce a
reliable MEP response (e.g., MEP amplitude of at least 50μV-1mV in at least 50% of a series
of single-pulse TMS trials; Rossini et al., 1994) in the contralateral abductor pollicis brevis
(APB) muscle in the hand (for shallow coil designs) or contralateral tibialis anterior muscle
in the leg (for deeper coil designs) while these muscles are relaxed and neutral (Priori et
al., 1993; Roth et al., 2014; Schecklmann et al., 2020). As such, personalized dosing of
therapeutic rTMS is calibrated for each patient by constituting a relative percentage of their
estimated rMT (Hanajima et al., 2007; Peterchev et al., 2012; Pridmore et al., 1998).
Scalp-to-cortex Distance.: In addition to adjusting for individual differences in rMT, it is

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also recommended that intra- and inter-individual differences in the scalp-to-cortex (STC)
distance for the therapeutic brain target be taken into consideration when establishing
the treatment threshold (Kahkonen et al., 2004; Kozel et al., 2000). This is because
rTMS-induced effects on cortical depolarization are directly impacted by the electrical field
potential actually reaching the brain tissue, which is known to decay rapidly in proportion
to the distance between the coil and cortex, a function of the physical laws governing
the influence of distance on electromagnetic induction as defined by Maxwell’s equations
(Kozel et al., 2000; Stokes et al., 2007). In particular, since the rMT is measured at the
motor cortex, areas of the brain with cortical tissue further away from the scalp than the
motor cortex will typically require stronger TMS intensities in order to achieve comparable
electrical field potentials to achieve neuronal depolarization (Janssen et al., 2014; Kahkonen
et al., 2004; Knecht et al., 2005). Thus, therapeutic targets within the PFC, for example,
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might require stimulation thresholds of 110%-130% the rMT (or 10-30% higher stimulation
intensities than the motor cortex) in order to attain expected neural effects given the greater
STC distances for most prefrontal regions relative to M1 (Kähkönen et al., 2004; Kozel et
al., 2000; Milev et al., 2016; Stokes et al., 2007; 2013).
Moreover, there is considerable variability in the precise STC distances measured for
the same brain region across different individuals (Kozel et al., 2000; Stokes et al.,
2007; 2013). In fact, beyond normative inter-individual variability, many neurologic and
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psychiatric populations, including those with SUDs, are known to exhibit disease-related
cortical atrophy which can further increase STC distance and alter MEP and MT estimates
in patients relative to healthy controls (Chervyakov et al., 2015a; Groppa et al., 2012;
Hanlon et al., 2019a; Iriarte & George, 2018; Klöppel et al., 2008). Thus, several tools
have been developed to allow researchers and clinicians to directly measure STC distances
from neuroanatomical MRI images acquired for individual patients or participants (MANGO
software, http://ric.uthscsa.edu/mango/; BrainRuler software, Summers & Hanlon, 2017),
which can be used to make additional personalized adjustments to rTMS treatment dose
thresholds based on their unique STC distance anatomy (Kozel et al., 2000).
Individually titrated stimulation dosing not only provides a systematic and personalized way
of quantifying stimulation doses for maximal efficacy, but also for staying within established
safety guidelines (Rossi et al., 2009; 2021; Westin et al., 2014) since, for some individuals,
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stimulation intensities in excess of the doses required to effectively reach and modulate the
cortex may lead to excitotoxicity or seizure induction, at worst, or unnecessary side effects,
such as headaches and scalp pain, at best (Westin et al., 2014). Effectually, adherence to
these procedures helps to ensure that each recipient has the best chance of achieving the
desired therapeutic response while minimizing the incidence of adverse events (McClintock
et al., 2018; Rossi et al., 2009; 2021; Wasserman, 1998).
Cortical Targeting & TMS Coil Positioning.: The next step after the rMT has been
identified and used to establish the rTMS treatment dose, is to position the TMS coil
over the therapeutic brain target for the duration of the treatment session. Coil positioning
is typically determined using a standard procedure, such as a distance-based method
(e.g., 5 cm rule; Pascual-Leone et al., 1996) or anatomical landmark-based method
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(e.g., International EEG 10-20 system; Herwig et al., 2003) which relies on previously
established standardized coordinates for the expected locations and relative distances of
key neuroanatomical structures. More recently, though, more advanced cortical targeting
procedures which account for individual differences in brain anatomy and function
have become widely available and are preferred for their accuracy and precision; e.g.,
methods involving personalized anatomical or functional MRI-based frameless stereotactic
neuronavigation systems (Rusjan et al., 2010; Sack et al., 2009; Sparing et al., 2008). Then,
to ensure consistency in positioning across repeat rTMS treatment sessions, the precise
location and orientation of coil placement for each individual is documented during their
first session. Depending on the particular method of cortical targeting that is implemented,
these parameters are either documented through inscription on a nylon head cap which
is worn at the first and each consequent session or saved and later uploaded within the
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neuronavigation system software.
Sham Condition & Blinding Integrity.—As with any well-designed research study or
randomized clinical trial, it is expected that a blinded parallel or crossover placebo condition
(for medical devices, typically referred to as a “sham”) will be included to control for any
non-specific effects (Broadbent et al., 2011; Conde et al., 2019; Duecker & Sack, 2015;
Flanagan et al., 2019; Loo et al., 2000; Zis et al., 2020). This is especially the case when
study outcomes are based largely or in part on subjective measurements, such as the self-
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report endpoints common in SUD clinical trials (e.g., drug craving, withdrawal symptoms,
mood, sleep quality, timeline follow-back, etc.), as these outcomes make it more difficult
to disentangle placebo effects than quantifiable, objective outcome measures (Fregni et al.,
2006ab; Rossi et al., 2009; Wasserman & Lisanby, 2001).
Although there are a number of different sham methods which have been developed for
rTMS research, the overall goal of an effective sham is to simulate the multisensory
experience of active rTMS by including the sound, pressure, and scalp sensations produced
by real rTMS, but without any physiological effects on the CNS (Broadbent et al., 2011;
Conde et al., 2019; Lisanby et al., 2001; Loo et al., 2000; Rossi et al., 2009). Previous
studies have demonstrated that when these criteria are met, participants are generally unable
to differentiate real from sham stimulation, with most people guessing at no better than
chance when reporting whether they received real or sham stimulation in a given session
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(Borckardt et al., 2008; Broadbent et al., 2011; Flanagan et al., 2019; Hanlon et al.,
2015). However, to monitor and maintain continued assurance of effective blinding, current
guidelines recommend that participants should be surveyed after each session or study
period to routinely assess blinding integrity (Berlim et al., 2013; Broadbent et al., 2011;
Flanagan et al., 2019; Lefaucheur et al., 2014; Rossi et al., 2021) in order to maintain rigor
and reproducibility.
rTMS Parameter Space.—There are a number of key factors which determine whether
an individual will respond or not respond to rTMS treatment, as well as those influencing
the magnitude, direction, timing, and durability of any rTMS-induced clinical effects that do
emerge (Lefaucheur et al., 2014).
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Number of Treatment Sessions.: Typically, a single session of rTMS (e.g., ranging from
~600-3600 pulses delivered in anywhere from 3-40 min) will produce acutely observable
neurophysiological effects [such as, MEPs in the hand or leg muscles, changes in heart
rate or blood pressure, changes in brain activity as measured by altered blood flow
and oxygenation, glucose metabolism, dopamine signaling, etc.] starting immediately, and
lasting anywhere from ~30 min (i.e., for HF-rTMS or iTBS) to several hours (i.e., for
LF-rTMS or cTBS) post-stimulation (Hoogendam et al., 2010; Suppa et al., 2016; Ziemann
et al., 2008). However, longer-term effects which endure for weeks, months, or years,
and/or measurable alterations in more complex psychophysiological processes, such as
cognitive, emotional, and behavioral correlates, typically emerge only after several rTMS
sessions are delivered successively in a fairly systematic manner (i.e., repeated over several
days per week for multiple weeks, or several times per day over several days, such as in
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accelerated protocols) (Madeo et al., 2020; Rossi et al., 2009; 2021; Song et al., 2019;
Teng et al., 2017). This is because the neurobiological mechanisms purportedly underlying
rTMS-induced LTP- and LTD-like plasticity are cumulative processes evoked by repeated
synaptic perturbation which ultimately activate neurochemical and neurophysiological
pathways that take time to manifest (e.g., changes in gene expression which facilitate the
altered production of neurotransmitters, receptor proteins, and signaling molecules necessary
for long-term modulation of synapse strength, neuronal architecture, and functional and
structural connectivity, etc.) (Hoogendam et al., 2010; Platz & Rothwell, 2010; Rossi et al.,
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2009; 2021).
In fact, based on the principal study backing the 2008 FDA clearance of rTMS for treatment-
resistant major depressive disorder (TRD) (O’Reardon et al., 2007), and similar studies
which followed (Fitzgerald et al., 2006), rTMS treatment response was shown to accumulate
over time to reach a clinically meaningful level. According to the pioneering TRD rTMS
treatment protocol, daily rTMS sessions were required for at least 4-6 weeks before clinical
success could be achieved, with larger consequent studies showing significant suppression
of depressive relapse with the addition of a number of intermittent maintenance sessions in
the weeks to months following initial treatment completion (Berlim et al., 2014; Janicak et
al., 2010; Manzardo et al., 2019; Richieri et al., 2013). Similarly, a meta-analysis of NIBS
studies across SUD groups showed that multi-session treatment protocols reliably show
larger effect sizes for reducing drug craving and consumption than single-session protocols,
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with the number of sessions and total number of pulses administered proportional to the
extent of drug craving reduction achieved, indicating a clear dose-response effect (Song et
al., 2019).
Diverse rTMS Treatment Parameters.: That said, the precise number, duration, and
spacing of rTMS treatment sessions required to achieve clinically meaningful outcomes
is not always immediately apparent, nor is it uniform across rTMS applications in either
research or clinical practice (Lefaucheur et al., 2014; 2020; Rossi et al., 2009; 2021; Teng
et al., 2017). This is because such factors are often conditioned on the specific clinical
population being addressed, rTMS modality and parameters being implemented, and any
clinical and demographic variance present at the individual level (Davila et al., 2019;
Lefaucheur et al., 2014; Manzardo et al., 2019; Ridding & Ziemann, 2010; Xie et al., 2013).
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Given the multiplicity of design decisions arising from the vast and varied rTMS parameter
space, understanding the consequences of making certain parameter choices over others
continues to be a rich, ongoing area of investigation in the field, with research expressly
dedicated to the development, appraisal, and optimization of rTMS procedures with the
ultimate goal of generating best practices for achieving and maximizing therapeutic success
across various clinical groups (Ekhtiari et al., 2019; Lefaucheur et al., 2014; 2020; Rossi et
al., 2021; Verdejo-Garcia et al., 2019).
Safety & Tolerability.—As a non-invasive form of neuromodulation, interventions based

on rTMS are generally well tolerated and involve minimal risk of serious side effects.
Headaches, Scalp Pain & Neck Discomfort.: The most commonly reported side effects
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include mild, transient headaches, neck pain, or scalp tenderness at the site of stimulation
(see Machii et al., 2006 for review of rTMS side effects). The headaches and scalp
discomfort are thought to be a consequence of coincidental excitation of muscle and sensory
nerves overlying the skull at the site of stimulation which result in muscle tension, twitching,
and prickly tingling sensations (Lefaucheur et al., 2014; Machii et al., 2006). For susceptible
individuals who do experience unpleasant local pain or muscle tension-type headaches, the
discomfort is usually temporary and diminishes shortly after stimulation cessation. However,
if headaches and pain persist, most patients will respond well to over-the-counter analgesics,
which is the clinical recommendation as published in current rTMS safety guidelines

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(Lefaucheur et al., 2014; Rossi et al., 2009).
Importantly, rTMS-related pain and discomfort has been shown to decline fairly rapidly
over the first few daily treatment sessions, with or without analgesic intervention (Janicak et
al., 2008; Anderson et al., 2009). This is thought to be related to desensitization processes
of the sensory nerves as predicted by the gate control theory of pain (Melzack & Wall,
1965). Thus, to facilitate desensitization and enhance tolerability, newer treatment protocols
generally incorporate a “ramping” procedure which involves intentionally initiating below
the target stimulation dose and gradually increasing stimulation intensity over the first few
days (Rossi et al., 2009) or seconds (Hanlon et al., 2017) of treatment.
Hearing Impairment.: Further, the TMS pulse causes mechanical vibrations in the coil
which produce a brief, intense sound impulse, which is often referred to as a TMS coil
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“click” (Counter & Borg, 1992; Counter et al., 1991; Goetz et al., 2015; Koponen et
al., 2020). Exposure to this click during rTMS sessions has even been shown to produce
mild hearing loss as reflected by transient increases in auditory threshold (Loo et al.,
2001; Pascual-Leone et al., 1992). However, these hearing disturbances are largely or
completely avoided by requiring participants and operators to wear hearing protection,
such as adjustable foam earplugs, throughout the duration of rTMS sessions (Levkovitz et
al., 2007; Rossi et al., 2007; Janicak et al., 2008; Schraven et al., 2013). Thus, hearing
protection earplugs are the current safety recommendation to prevent TMS-induced acoustic
trauma, in addition to performing auditory threshold testing before and after rTMS sessions
to routinely monitor safety and health (Counter et al., 1991; Rossi et al., 2009; 2021).
Seizure Induction.: Broadly-speaking, however, the most serious potential side effect of
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rTMS involves the risk of seizure induction (Rossi et al., 2009). While the risk of provoking
a seizure is the most concerning of the acute adverse events associated with rTMS, it
remains an extremely rare occurrence, under research and clinical circumstances alike,
particularly since the development, dissemination, and broad adherence to consensus clinical
safety guidelines (Rossi et al., 2009; 2021). In fact, in its entire clinical and research history
up to 2020, the overall risk of TMS-related seizures in humans remains <1% (Lerner et al.,
2019; Stultz et al., 2020), with most reported seizures involving patients with pre-existing
neurological conditions or treatment parameters outside the recommended guidelines (Chen
et al., 1997; McClintock et al., 2018; Rossi et al., 2009; 2021; Wasserman, 1998). Risk
factors which have been shown or are purported to increase the likelihood of seizure
induction include history of traumatic brain injury/concussion, stroke, or neurologic disease
with altered seizure threshold, sleep deprivation, heavy alcohol or benzodiazepine use or
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withdrawal, personal or family history of epilepsy or seizures, and the use of psychotropic
medications which lower the seizure threshold (Lerner et al., 2019; Stultz et al., 2020).
However, even under circumstances with elevated patient-risk, the relative risk of seizure is
still lower than for most common psychotropic medications (Shafi, 2019), making TMS a
fundamentally minimal-risk intervention.
Comparison to tES NIBS Approaches.—As with rTMS, tES techniques, such as tDCS
and tACS, are also considered non-invasive, albeit they involve the principal use of electrical
rather than magnetic stimulation (Bikson et al., 2016). Specifically, tES involves delivering
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either direct (tDCS) or alternating (tACS) low-intensity electric currents through cortical
tissue via strategic placement of surface electrodes on the scalp and/or upper body (Ekhtiari
et al., 2019; Woods et al., 2016). In contrast to TMS, tDCS is not believed to influence
neuronal firing patterns directly, but instead, is purported to involve the subthreshold
modulation of cortical excitability through the induction of a polarity-dependent shift in
neuronal membrane potential which is what leads to an increased or decreased likelihood
of consequent depolarization (Bindman et al., 1964; Nitsche & Paulus, 2000; 2001; Woods
et al., 2016). Further, the tDCS-induced direction of membrane polarization is defined by
the relative placement of the anodal and cathodal electrodes over the stimulation target of
interest (Kabakov et al., 2012; Rawji et al., 2018; Woods et al., 2016). Importantly, the
electrical current density in the scalp via the mechanisms involved in tES techniques is much
lower than the secondary (eddy) electrical currents induced by TMS-based techniques; thus,
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TMS is capable of stimulating cortical tissue with a fraction of the cutaneous pain associated
with tES (Rossi et al., 2009).
Potential for Effective rTMS Interventions in SUDs/CUD.—The potential for NIBS

to represent a paradigm shift in psychiatry by achieving robust clinical outcomes as a
targeted, non-pharmacologic, brain-centric treatment approach, while largely avoiding the
drawbacks of the more invasive neuromodulation methods is a major justification for the
expansion of NIBS research, particularly in complex patient populations (Chen et al., 2017;
Grunhaus et al., 2000; 2003; Ren et al., 2014). Considering the often-intransigent chronic
relapse cycles characterizing SUDs, individuals contending with substance use problems
are, perhaps, an archetype of the complex and treatment-resistant clinical populations that
might benefit most from the relatively low risk but potentially high reward NIBS-based
treatment approaches (Bulteau et al., 2020). Thus far, rTMS-based protocols have been the
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most widely studied, effective, and well-tolerated neuromodulation-based treatment options

for SUDs, making them a practical choice for rapid translation from clinical research to the
clinic.
The following sections provide a preliminary exploration of the current literature assessing
whether the promise of rTMS-based interventions emerging for other SUD groups might
extend to individuals with CUD.
Studies Investigating rTMS Treatment Potential for Cannabis Use Disorder.

1. Sahlem et al., 2018. Feasibility and Proof-of-Principle Study of Single-
session Left DLPFC HF-rTMS.—Although NIBS studies for various SUDs have
consistently demonstrated the ability of DLPFC-targeted rTMS to reduce drug cue-elicited
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craving and/or drug consumption after multiple sessions, and sometimes even after a single
session (Coles et al., 2018; Song et al., 2019; Zhang et al., 2019), Sahlem & colleagues
(2018) were the first to conduct a study investigating rTMS targeted to the DLPFC in
people who smoke cannabis. This double-blinded, sham-controlled, within-subject crossover
design study was conducted to determine if a single session of HF (excitatory)-rTMS could
be feasibly (i.e., safely, tolerably) delivered to the L DLPFC in a group of non-treatment-
seeking cannabis smokers with CUD, and whether single-session active HF-rTMS could
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produce anti-craving effects relative to sham stimulation in this population.
Non-treatment seeking cannabis smokers meeting DSM-5 criteria for CUD (n=18) were
randomized to receive a single session of either active or sham HF-rTMS (10 Hz, 110%
rMT, 4000 pulses; Magventure figure-8 design coil) to the L DLPFC (F3 International
10-20 EEG system coordinate) while completing a cannabis cue exposure paradigm; one
week later they received a single session of the other stimulation condition. Feasibility
and tolerability were measured by the rate of retention in the study and the percentage
of participants able to tolerate full-dose active rTMS, respectively. Self-reported cannabis
craving was assessed before and after both stimulation sessions using the standardized
Marijuana Craving Questionnaire (MCQ).
The authors reported that HF-rTMS to the L DLPFC was both safely and tolerably delivered
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to cannabis smokers with CUD, as 16 of the 18 participants completed the trial (i.e., 89% of
participants were retained across all 3 study visits), and all 16 of the treatment completers
tolerated the active rTMS at full dose without any adverse experiences. However, there
was no impact of stimulation on cannabis craving, as MCQ scores following HF-rTMS
did not significantly differ from baseline, relative to sham, indicating that a single session
of L DLPFC-targeted HF-rTMS was not sufficient to reduce cue-elicited craving in heavy
cannabis smokers.
Discussion of Limitations and Contributions.: While Sahlem et al. (2018) did not reveal
an effect of rTMS on cannabis craving, it was a single session, which has only rarely
been shown to affect drug craving (Ekhtiari et al., 2019; Kearney-Ramos et al., 2019; Song
et al., 2019), and was thus, not a surprising finding. In fact, as mentioned previously,
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this is consistent with most of the FDA-cleared rTMS protocols in psychiatry which
require frequent (typically daily) stimulation sessions over multiple weeks to months before
clinically significant symptom improvements are anticipated (O’Reardon et al., 2007; Politi
et al., 2008; Rapinesi et al., 2016; Senova et al., 2019).
2. Sahlem et al., 2020. Case Report on Feasibility and Clinical Effects of

Accelerated Multi-session L DLPFC HF-rTMS Intervention.—As a letter to the
Editor, Sahlem & colleagues (2020) followed up with a case series extending their single-
session proof-of-principle study to a multi-session interventional study. In this open-label
safety and tolerability pilot study, 20 sessions of L DLPFC HF-rTMS were administered in
an accelerated format over a 2-week period (i.e., 2 sessions daily over 10 business days)
to participants with CUD who reported a desire to reduce their cannabis use. Following
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the 2-week treatment course, participants were followed for an additional four weeks to
determine whether potential treatment effects on cannabis craving and use were enduring.
For each daily visit, the two rTMS treatment sessions were delivered with a 30-min break
between them. Cannabis craving was assessed at the beginning of each visit using the MCQ
short form (MCQ-SF). All other stimulation protocols and parameters were identical to
those reported in their previous study [see above; or (Sahlem et al., 2018)]. Participants
also received one session of motivational enhancement therapy per treatment week, and
follow-up assessments at weeks 2 and 4 post-treatment completion.
Of 9 enrolled participants, 6 dropped out prior to treatment completion. Aside from

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1 participant dropping out due to treatment-related headaches, no adverse events were

reported. For the 3 study completers, the 2-week course of accelerated HF-rTMS treatment
to the L DLPFC decreased both cannabis craving (mean MCQ-SF score decrease of ~16
points; from 50.3 ± 7.1 pre-treatment to 34.0 ± 26.2 post-treatment), and cannabis use (mean
weekly use measured via the TimeLine Follow-Back decreased by roughly half immediately
following treatment and was sustained for all subsequent follow-up weeks).
Discussion of Limitations and Contributions.: Sahlem & colleagues (2020) acknowledge

that there were several critical limitations of their case report study, including the open-label
design, small sample size, and low retention rate. They pointed out that their retention rate
compared poorly to rTMS treatment studies in other SUD populations, which usually range
from 56% to 100%, or even in comparison to other CUD treatment trials, which typically
range from 36% to 71% (Sherman & McRae-Clark, 2016). The authors propose that their
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low retention may reflect the accelerated treatment schedule (two treatment sessions per day,
each day per study week), rather than the rTMS, per se. Notably, 75% of the non-completers
acknowledged that scheduling issues were the main barrier to their study completion.
Furthermore, the researchers initiated a new study investigating rTMS treatment in a nearly
identical study population, but with only two treatment visits per week (Clinicaltrials.gov:
NCT03144232). While still ongoing, the authors report that the less time-intensive trial, so
far, has a better retention rate (63%). They postulate that individuals with CUD may have
particular difficulty with time-intensive interventions, often being more high-functioning
than individuals from other SUD groups, which tends to correspond to a higher likelihood of
being employed (which can drastically decrease scheduling availability), and to being more
ambivalent about engaging in treatment, overall.
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In all, while no firm conclusions can be drawn due to the aforementioned limitations, their
study provides the first possible evidence that L DLPFC HF-rTMS may have a beneficial
impact on cannabis craving and use in individuals with CUD, making it worthy of continued
examination as a novel brain-based treatment approach.
3. Prashad et al., 2019. Mitigating Aberrant Exteroceptive Processing in CUD

thru Posterior Cingulate cortex/Precuneus HF-Deep rTMS.—Prashad & colleagues
(Prashad et al., 2019) were the first to investigate modulating the posterior cingulate cortex
(PCC) and precuneus as a potential NIBS target for treatment of CUD. The PCC, which
is the posterior-most region of the cingulate gyrus, is a medial limbic structure that is
surrounded by and contiguous with the precuneus, which is the medial portion of the
superior parietal lobule (SPL) (Fox et al., 2005; Gusnard et al., 2001). The PCC/precuneus
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together serve as the functional hub of the default mode network (DMN) (Fox et al., 2005;
Gusnard et al., 2001), a large-scale network of brain regions comprising the PCC/precuneus,
dorsomedial prefrontal cortex (DMPFC), and bilateral inferior parietal lobule (IPL) (Fox
et al., 2005; Gusnard et al., 2001; Raichle et al., 2001; Utevsky et al., 2014). In healthy
individuals, the DMN is reliably more active during resting wakefulness, such as when
conscious but not engaged in any specific mental task, e.g., daydreaming; self-referential
rumination, envisioning the future, thinking about one’s own traits, emotional states or those
of others—all thought processes occurring without an explicitly established goal in mind.

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DMN function typically involves “deactivation” or comparatively less activity when engaged
in externally directed, goal-based task performance (Fox et al., 2005; Gusnard et al., 2001)
which is believed to allow for re-allocation of neural processing resources to task-active
functional networks engaged in service of goal attainment (Fox et al., 2005; Gusnard et al.,
2001).
The PCC/precuneus is implicated in stimulus-driven (automatic) exteroceptive processing,

which is the continuous, implicit or passive monitoring (i.e., outside of conscious awareness)
of salient external stimuli (Fransson, 2005; Littel et al., 2012; Lou et al., 2010; Luber et al.,
2012). Its role within the DMN involves passively monitoring the surrounding environment
for salient stimuli, with particular emphasis on surveilling stimuli with potential self-
relevance (Davey et al., 2016; Schilbach et al., 2008; Utevsky et al., 2014). When salient
external stimuli (or cues conditioned to be motivationally relevant to the individual) enter
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into sensory perception, the PCC/precuneus reflexively augments arousal levels, and re-
orients attention to bring those stimuli from passive to conscious awareness for additional
processing (Corbetta et al., 2008; Davey et al., 2016; Schilbach et al., 2008; Utevsky et al.,
2014). Through this function, the PCC/precuneus, and the DMN as a whole, serve as an
attentional resource dedicated to the self-referential processing needed to dynamically direct
and maintain self-motivated behavior (Corbetta et al., 2008; Gusnard et al., 2001; Raichle et
al., 2001; Uddin, 2015).
In people who use substances chronically, however, exteroceptive processing can be

disproportionately heightened (i.e., excessive attentional resources are both implicitly and
explicitly allocated to the continuous monitoring and reflexive orientation to potentially
self-relevant external stimuli, such as drug cues) (Harris et al., 2018; Littel et al., 2012;
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Littel & Franken, 2011). Ample research has illustrated the contribution of drug cue-
dominated attention in the increased vigilance, stronger attentional capture, and heightened
motivational relevance of conditioned drug stimuli in long-term, heavy substance users,
processes often referred to as a drug cue attentional bias and/or drug cue reactivity
(Harris et al., 2018; Harris et al., 2016; Waters et al., 2003). These processes exhibit
bidirectional moderating relationships with drug cue-evoked craving, both of which can
trigger drug-seeking and -use behaviors and precipitate relapse in abstinent individuals
(Cadet et al., 2014; Littel et al., 2012; Paulus et al., 2013; Siegel, 2005; Waters et al., 2003).
Neuroimaging studies have revealed increased activity in the PCC/precuneus during drug
cue exposure across a range of SUD groups (Brody et al., 2007; Claus et al., 2013; Grant et
al., 1996; McBride et al., 2006; McClernon et al., 2009; Tapert et al., 2003), including heavy
cannabis users (Feldstein Ewing et al., 2012; Filbey & Dunlop, 2014; Filbey et al., 2016),
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with elevated PCC/precuneus activation in response to cannabis cue exposure as evidence

of enhanced drug cue reactivity and reward-motivated attentional bias to cannabis stimuli
(Filbey et al., 2016).
In this study, Prashad & colleagues used rTMS to modulate PCC/precuneus activity in 10
people who smoke cannabis and 10 non-using healthy controls, with the goal of normalizing
PCC/precuneus function in the heavy cannabis users, i.e., by reducing heightened salience
and reactivity to external self-relevant and cannabis-related cues. The authors assessed
rTMS-induced changes in neural response to personalized self-relevant and cannabis-related

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visual stimuli using event-related potential (ERP) recording, an EEG-based neuroimaging

approach. Given that their aim was to stimulate the PCC/precuneus, which is a relatively
deep, medial brain structure, they indicated that use of a traditional figure-8 TMS coil
design, which has a distinctly more focal and shallow cortical stimulation field and depth
(~2 cm), was ill-suited (Deng et al., 2013; Deng et al., 2014). Thus, the authors used the
double-cone style coil, a more advanced TMS coil design enabling deeper, albeit broader,
stimulation than the figure-8 coil (Hayward et al., 2007; Vanneste et al., 2012). Before
and after rTMS, participants underwent a modified oddball paradigm which evoked neural
response to external stimuli, and included personalized self-relevant and cannabis-related
stimuli that occurred infrequently and were expected to elicit the P3, as well as the preceding
P2 and N2 ERP responses, which are indices of attention to novel, self-relevant stimuli
(Gray et al., 2004). The authors hypothesized that they would find a greater P2, N2,
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and P3 response to self-relevant stimuli during baseline compared to after HF-rTMS in

both cannabis users and non-using controls, with no change following LF-rTMS (as this
condition served as a negative control). Additionally, they predicted greater response to
cannabis-related stimuli during baseline compared to after HF-rTMS in the cannabis group,
due to the high salience of these cues in people who use cannabis, but not for controls who
do not use cannabis.
The ERP results showed that, at baseline, the cannabis group exhibited greater PCC/
precuneus reactivity to self-relevant cues than controls, consistent with a heightened
exteroceptive processing. This elevated reactivity to external, self-relevant stimuli in the
cannabis group was normalized to control levels following HF-rTMS to the PCC/precuneus.
The authors interpreted these findings as: (1) support for aberrant activity in the PCC/
precuneus in people who use cannabis; (2) demonstration that aberrant PCC/precuneus
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activity in cannabis users underlies their excessive salience attribution and reactivity to
external self-relevant cues; and (3) demonstration that directly manipulating dysfunctional
PCC activity, such as through neuromodulation, may provide a viable new option for
mitigating exteroceptive processing abnormalities that contribute to the heightened self-
relevant and drug cue-induced attentional bias, and corresponding drug cue-induced craving
and seeking behaviors.
Discussion of Limitations and Contributions.: While the authors predicted a greater

response to cannabis-related stimuli in people who use cannabis, their ERP results showed
a lack of differences between the groups or across rTMS conditions, which was inconsistent
with prior literature. The authors attributed this to the drug use history characteristics of
their sample; while those in the cannabis group were near-daily cannabis users, most did not
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meet diagnostic criteria for CUD. They point out that most prior studies revealing significant
differences in cannabis cue-related salience reactivity involved samples of daily heavy
cannabis users, whereas lighter users have often been more similar to non-using controls
(such as in Pope et al., 2001; Bolla et al., 2002). It is important to note, however, that results
of the present study were limited by the small sample sizes in both groups (n=10 each). In
addition, several demographic differences were found between the groups at baseline (such
as, education, age, alcohol use), which may confound study outcomes. Nonetheless, these
data provide the first investigation of a novel rTMS stimulation target, the PCC/precuneus,
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for the potential treatment of CUD, making the replication and extension of these findings in
a larger, well-matched sample potentially worthwhile.
III. FUTURE DIRECTIONS OF REPETITIVE TRANSCRANIAL MAGNETIC

STIMULATION RESEARCH FOR TREATMENT OF CANNABIS USE
DISORDER.
Given the substantial heterogeneity (i.e., study design, participant characteristics, study
objectives, outcome measures, etc.) across the rather small number of reports (n=3 studies),
the data from the present literature on rTMS for people who use cannabis are too dissimilar
to synthesize, and thus it is not yet possible to draw firm conclusions about the clinical
validity of rTMS for CUD. However, the present studies reveal the general feasibility and
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tolerability of several rTMS-based procedures in people who use cannabis and reinforce the
worth of pursuing NIBS-based approaches as novel forms of treatment for CUD in future
investigations.
Below is a brief breakdown of some of the potential challenges to developing rTMS-

based interventions for CUD, as well as some of the critical design decisions (i.e., study
parameters and outcome measures) derived from pre-existing literature on NIBS for SUDs
which should be considered when developing future rTMS treatment studies in cannabis
users.
Limitations & Challenges Specific to Cannabis Use and Cannabis Use Disorder.
There are a number of factors associated with the neuropathophysiological correlates of
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chronic cannabis use which may confound the success of rTMS-based treatments for CUD.
Functional & Structural Neural Deficits.—For instance, ample prior research has
demonstrated the considerable influence of state-dependent neural effects on rTMS
outcomes, wherein the magnitude and direction of treatment response often vary as a
function of the initial functional state and structural integrity of the intended brain targets
(Dunlop et al., 2015; James et al., 2017; Kearney-Ramos et al., 2018b; 2019; Nicolo et al.,
2015; Salomons et al., 2014; Silvanto & Pascual-Leone, 2012; Weigand et al., 2018). The
precise impact that neuropathophysiological sequelae of any primary and/or co-occurring
disease conditions may have on intrinsic brain states or on the brain’s capacity for rTMS-
induced plasticity, is of unknown, or at best, poorly understood, consequence and should
thus be a critical consideration for future therapeutic neuromodulation research in SUDs,
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and psychiatry in general (Iqbal et al., 2019; Lefaucheur et al., 2014; Rossi et al., 2009).
For instance, interactions between disease states and stimulation may lead to illness-specific
side effects, such as the increased risk of mania induction in patients with bipolar disorder,
the increased risk of seizure induction in patients with cortical lesions, or the influence
of brain atrophy on electrical current distribution in patients with prior traumatic brain
injuries or co-morbid neurodegenerative conditions (Iriarte & George, 2018; Rossi et al.,
2009). Relatedly, frequent, heavy cannabis use is known to exacerbate the risk of psychosis
or schizophrenia in individuals with predispositions to these conditions (Bossong et al.,
2014; Di Forti et al., 2015; 2019), though the psychotomimetic effects of cannabis exposure
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have also been shown in otherwise healthy individuals with no pre-existing risk factors
(Bhattacharyya et al., 2012; Marconi et al. 2016). As such, the potential for mania-related
side effects of rTMS represents an important potential contraindication to rTMS therapy for
individuals with CUD, which should be studied further in future research, and ultimately,
weighed carefully against the potential benefits of this treatment option relative to other
modalities.
With regard to cannabis use and its role in functional and structural brain alterations, it is
important to note that while the data are largely conflicting and many confounds remain
to be addressed in the literature (opposing findings reviewed or highlighted recently in
Chye et al., 2020; Colizzi et al., 2020; Ferland & Hurd, 2020; Figueiredo et al., 2020), it
has generally been recognized that long-term heavy cannabis exposure is associated with
functional and structural deficits across several critical brain regions (Ferland & Hurd, 2020;
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Zehra et al., 2018), particularly those enriched with cannabinoid type 1 receptors (CB1Rs),
such as the hippocampus, amygdala, striatum, PFC, insula, cingulate gyrus, and cerebellum
(Battistella et al., 2014; Blest-Hopley et al., 2020; Bloomfield et al., 2019; Lorenzetti et
al., 2016; 2019; Zehra et al., 2018). In fact, some of the hallmark cognitive-behavioral
symptoms of CUD involve memory, attention, and executive function impairments (Blest-
Hopley et al., 2020; Ganzer et al., 2016; Zehra et al., 2018) which have been linked to
varying levels of gray matter volume and density reductions and thinning cortical thickness
(Battistella et al., 2014; Chye et al., 2020; Cousijn et al., 2012; Yucel et al., 2008), as well as
changes in brain activity (Batalla et al., 2013; Blest-Hopley et al., 2020; Ganzer et al., 2016;
Martin-Santos et al., 2010) across these areas.
Furthermore, functional and structural connectivity data acquired from a wide range of
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neuroimaging modalities have shown that chronic cannabis use is associated with patterns
of local and global dysconnectivity in key cognitive-behavioral networks encompassing
many of these cannabinoid-rich regions (Cheng et al., 2014; Filbey & Dunlop, 2014;
Manza et al., 2018; Pujol et al., 2014). These neural deficits have direct implications for
the potential efficacy of therapeutic neuromodulation in patients with CUD, given that
aberrant functional and structural integrity and connectivity within and between key neural
circuit nodes is a known barrier to adequate modulation of large-scale brain networks via
rTMS-based techniques (Diekhoff-Krebs et al., 2017; Groppa et al., 2012; Klöppel et al.,
2008). This is because from a network-based perspective, coordinated neural activity (i.e.,
resting state activity or task-related network engagement) must rely upon intact structural
connections (Philip et al., 2014). Thus, pre-existing disease-related network dysconnectivity
can greatly impact the transsynaptic signal propagation mechanisms by which rTMS-based
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techniques are purported to influence distal cortical and subcortical nodes downstream from
the immediate stimulation targets, and substantially limit or preclude the clinical benefits of
rTMS on large-scale cognitive-behavioral networks in that group (Opitz et al., 2016; Rossi et
al., 2009).
Recently, the impact of structural integrity on rTMS-induced circuit modulation was directly
illustrated in a SUD population in a study by Kearney-Ramos et al. (2018b). Using
interleaved TMS/fMRI (Bestmann et al., 2008; Paus, 2005), the authors examined the
TMS-evoked responses in the frontal-striatal reward-motivation circuit in chronic cocaine

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users. Interleaved TMS/fMRI is a multimodal imaging technique that involves the successive
delivery of single-pulse TMS during the brief intervals between fMRI acquisition of
individual functional brain volumes, thus enabling measurement of the real-time causal
effects of TMS on functional activity in brain networks at both the direct stimulation target
and indirect downstream subcortical network nodes (Bestmann et al., 2008; 2000ab; Sack
et al., 2002). In this study, 49 individuals with cocaine use disorder underwent interleaved
TMS/fMRI imaging using an MRI-compatible TMS coil positioned over the ventromedial
prefrontal cortex (VMPFC), or standard frontal pole EEG 10-20 coordinate, FP1 (Jasper,
1958). Blood oxygen level-dependent (BOLD) fMRI signal changes following active vs.
sham single-pulse TMS were calculated and compared for the area directly beneath the coil
(i.e., VMPFC) and several subcortical regions exhibiting afferent and efferent connectivity
with the VMPFC (i.e., bilateral limbic and striatal regions). Diffusion tensor imaging (DTI)
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and voxel-based morphometry (VBM) were used to quantify white matter integrity and gray
matter volume (GMV) within and between the functional nodes, respectively, followed by
calculating the relationships between these neural architecture measures and TMS-evoked
BOLD response.
The authors found that the size of the TMS-evoked BOLD response in the VMPFC
stimulation target and downstream subcortical nodes was significantly positively correlated
with GMV in the VMPFC, as well as white matter integrity (given by fractional anisotropy)
in the structural tracts connecting the VMPFC to the downstream limbic and striatal regions,
such that cocaine users with greater gray matter and white matter atrophy showed poorer
TMS responses. This provided the first clear demonstration, in a relatively large sample of
individuals with SUD, that the ability of the TMS-evoked functional effects to propagate
from the superficial cortical target to distal, downstream subcortical network nodes is
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significantly dependent upon intact structural integrity in the circuit of interest.
Hanlon et al. (2019a) later corroborated these findings by demonstrating that, similarly,
in people with alcohol use disorder, over half of the individual differences in response to
active rTMS could be attributed to inherent variability in several neural architecture features,
including STC distance, GMV in the cortical stimulation target, and white matter tract
integrity connecting the stimulated cortical target and its downstream nodes.
Consequently, when considering the findings of these former studies, they suggest that
disruptions in structural integrity within and along tracts connecting critical nodes of
large-scale functional networks have an impact on functional connectivity—both of which
are dysconnectivity features inherent to many neuropsychiatric disorders (Menon, 2011;
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Sutherland et al., 2012; Zhang & Volkow, 2019)—and are likely to reduce the ability of
rTMS-induced effects to propagate to downstream targets, which may ultimately hinder how
effectively rTMS is able to produce modulatory effects on plasticity and activity in the
networks as a whole (Groppa et al., 2012; Klöppel et al., 2008; Nahas et al., 2004; Philip et
al., 2020). These data are consistent with the impact of functional and structural integrity on
rTMS outcomes in clinical populations with neurodegenerative disorders (Anderkova et al.,
2015; Chervyakov et al., 2015a), traumatic brain injuries (Diekhoff-Krebs et al., 2017; Nouri
& Cramer, 2011; Riley et al., 2011), and aging-related neural atrophy (Iriarte & George,
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2018; Nahas et al., 2004).
Therefore, while disagreement persists in the cannabis field with regard to the existence
and/or direction of causality of structural and functional brain impairments in CUD (an
obvious topic independently warranting further examination; Ferland & Hurd, 2020), the
potential limiting impact any such pre-existing deficits might have on the clinical benefits
of rTMS as a therapy for CUD should, at the very least, elevate the clinical significance of
further evaluating these factors in the design and interpretation of outcomes in future rTMS
treatment studies in this population. One avenue for future work would be to incorporate
measures of structural architecture, such as white matter integrity, GMV, and STC distance,
into research and clinical protocols, such as for optimization of patient-specific cortical
targeting and stimulation dosing, in order to personalize and maximize the clinical utility of
rTMS-based treatment models in people who use cannabis.
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Altered Synaptic Plasticity Induction.—A related correlate of long-term exposure to

cannabis that might impact rTMS treatment response involves the sustained disruption of
synaptic plasticity, as has been demonstrated preclinically (Fratta & Fattore, 2013; Hoffman
& Lupica, 2013), and in humans (Fitzgerald et al., 2009). A recent study by Martin-
Rodriguez et al. (2020) extended upon this by showing that long-term cannabis exposure
has deleterious effects on the capacity for rTMS-induced cortical plasticity induction. In this
study, 45 young adult men underwent two sessions of TBS in which either cTBS (inhibitory)
or iTBS (excitatory) was applied over the primary motor cortex, followed by measurement
of resulting changes in contralateral MEPs relative to baseline. Of the 45 young men, 30
had used cannabis daily over the previous 6 months (n=15 of whom met DSM-5 criteria
for CUD; n=15 of whom did not have CUD diagnosis) and 15 were demographically
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matched non-using controls. Results showed that the non-CUD men who used cannabis and
the non-using controls exhibited significant MEP inhibition following cTBS, as expected,
while inhibition was not seen in the cannabis users with CUD. Furthermore, when MEP
outcomes were correlated with self-reported measures of problematic cannabis use, the
greatest reductions in motor cortical plasticity (aka reduced capacity for plasticity induction)
were seen in participants with the most severe cannabis use problems. Conversely, no group
differences were identified for iTBS-induced (excitatory) cortical plasticity outcomes. While
further research involving larger sample sizes will be needed to corroborate these findings,
this study provides the first evidence that CUD, and more specifically, heavy cannabis use
associated with severe cannabis use-related problems, may contribute to impairments in
inhibitory cortical plasticity. These data are consistent with previous work revealing cortical
inhibition deficits (Goodman et al., 2017) and reductions in GABAA-mediated inhibition for
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subjects with daily chronic cannabis use that also corresponded with plasma THC levels
(Fitzgerald et al., 2009).
That said, the Martin-Rodriguez (2020) data also seem to indicate that plasticity deficits
associated with chronic heavy cannabis use are limited to LTD-like (or inhibitory) plasticity.
If that holds up in future larger studies replicating and expanding upon these findings, then
when considering the potential efficacy of rTMS-based interventions, these results may be
rather encouraging for people who use cannabis but do not meet criteria for CUD, as those
individuals may respond well to therapeutic approaches involving inhibitory rTMS (such
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as, protocols explored in Hanlon et al., 2015; 2017; Kearney-Ramos et al., 2018a; 2019).
Conversely, for people with more severe cannabis use, such as those with CUD who endorse
cannabis-related problems, deficits in cortical inhibition induction may preclude adequate
response to inhibitory stimulation protocols, perhaps making alternative treatment strategies
more suitable for this group. An obvious alternative would be to focus on excitatory
stimulation models (such as the majority of rTMS-based protocols tested for treatment
across SUD groups; see Ekhtiari et al., 2019 for recent comprehensive review).
Additionally, methods which alter the threshold for plasticity induction through
manipulation of physiology or various design parameters could be incorporated to enhance
outcomes; for instance, inclusion of pharmacologic agents which favor cortical inhibition
mechanisms (Schwenkreis et al., 1999; 2000; Ziemann, 2004; 2013; Ziemann et al., 1998),
or via priming protocols which promote state-dependent manipulation of baseline cortical
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excitability to facilitate induction of cortical plasticity of a desired magnitude and direction

(Rossi et al., 2009; 2021; also see Hoogendam et al., 2010; Karabanov et al., 2015; Suppa et
al., 2016 reviews which discuss several of these approaches).
Notably, a recent review by Hanlon et al. (2018) summarized existing evidence of

disruptions in cortical excitability and other neurophysiological properties in several SUD
groups, including cocaine, alcohol, and nicotine users, and highlighted the impact these
neural alterations had on their responses to rTMS. Specifically, several reports have revealed
heightened MTs (Hanlon et al., 2015) and reduced MEPs in people who use cocaine
chronically relative to non-using controls (Boutros et al., 2001, 2005; Sundaresan et al.,
2007; Gjini et al., 2012). These lower MEP values in the cocaine group were interpreted
as a reflection of lower cortical excitability (Ziemann et al., 1998; Di Lazzaro et al., 2008),
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which, along with higher MT levels, is a neurophysiological property known to negatively

correlate with rTMS plasticity induction and corresponding clinical outcomes (Pellegrini
et al., 2018). Furthermore, a TMS/fMRI study from the Hanlon Lab demonstrated that
people who use cocaine heavily exhibit frontral-striatal dysconnectivity, as the application
of single-pulse TMS to the VMPFC elicited markedly lower reciprocal BOLD responses
in downstream ventral striatal afferents in the cocaine group compared to healthy controls
(Hanlon et al., 2016).
Impairments in SUD-related functional network connectivity and integrity is known

to negatively impact rTMS-induced neuromodulation of clinical brain targets, thus
compromising the attainment of clinical benefit from rTMS-based interventions in
associated groups. Thus, while relative cortical excitability, MT values, and TMS-evoked
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BOLD response, and circuit connectivity or integrity have not been comprehensively
evaluated within the context of potential efficacy of rTMS-based interventions in people
with CUD, the extant evidence in the literature regarding neurobiological correlates of
chronic cannabis use and their likely impact on synaptic plasticity induction, provides a
foundation for considering the factors that may play a role in the clinical success of NIBS
treatments for CUD, and thus highlights the many potential avenues for future research to
begin filling these knowledge gaps.
Role of Brain-derived Neurotrophic Factor (BDNF) Deficits in Plasticity

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Potential.—Long-term cannabis use has also frequently been associated with reductions
in neural compounds involved in nerve health, including nerve growth factor (NGF) and
brain-derived neurotrophic factor (BDNF) (Jockers-Scherübl et al., 2004). BDNF is a
neurotrophin that is involved in the genesis, differentiation, survival, and repair of neuronal
cells (Binder & Scharfman, 2004; Chao et al., 2006; Cheeran et al., 2008), and is thus a
key modulator of neuroplasticity and adaptive processes underlying experience-dependent
learning and memory (Egan et al., 2003; Hariri et al., 2003; Ninan et al., 2010; Pezawas
et al., 2004; Yamada et al., 2002). Numerous studies have found reduced levels of BDNF
in people who regularly use cannabis (D’Souza et al., 2009; Lisano et al., 2019; Miguez
et al., 2019), with some indication that reduced BDNF levels may play a role in the
learning and memory deficits and general cognitive impairments characteristic of long-term
cannabis exposure (D’Souza et al., 2009; Miguez et al., 2019; Yucel et al., 2016). BDNF
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expression is, in part, regulated by CB1R-mediated activation of signaling pathways which

result in the transcription of BDNF mRNA (Berghuis et al., 2005; Derkinderen et al.,
2003). Thus, cannabinoid receptors play a regulatory role in modulating the levels of BDNF
molecules circulating in the brain and periphery. Animal and PET studies in people who use
cannabis heavily have consistently revealed substantial downregulation and desensitization
of CB1Rs after long-term cannabis use (Colizzi et al., 2016; Gonzalez et al., 2005; Hirvonen
et al., 2012; Lichtman & Martin, 2005; Weinstein et al., 2016). Consequently, reduced
CB1R function and corresponding dysregulation of CB1R-mediated BDNF signaling, may
represent one of the potential mechanisms by which BDNF expression is blunted in this
population (D’Souza et al., 2009).
Relatedly, with regard to the potential success of rTMS-based techniques for the treatment
of CUD, it is critical to note that BDNF levels have a direct impact on the potential for
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rTMS-induced plasticity induction processes (Cheeran et al., 2008; Figurov et al., 1996).
Even in healthy individuals, there exists a single nucleotide polymorphism (SNP) producing
a valine-to-methionine substitution at codon 66 (Val66Met) in the human BDNF gene which
influences human cortical plasticity induction (Egan et al., 2003; Kleim et al., 2006; Ninan
et al., 2010; Soliman et al., 2010) and, consequently, neural response to rTMS (Cheeran et
al., 2008) and other brain stimulation techniques (Antal et al., 2010; Riddle et al., 2020).
In fact, this SNP is relatively common in the general population (65% Val66Val vs. 35%
Val66Met in Caucasians), making any of its functional consequences potentially significant
to the ultimate efficacy of rTMS treatment in the population at large. Current research has
been demonstrated that Met allele carriers have impaired LTP and LTD plasticity potential,
as they exhibit markedly blunted, or even absent, responses to both excitatory and inhibitory
rTMS, as opposed to their homozygous Val counterparts who exhibit expected plasticity
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responses (Cheeran et al., 2008; Cirillo et al., 2012; Hwang et al., 2015).
Thus, while not yet directly evaluated in people with CUD, chronic cannabis use-related
suppression of BDNF levels may present similar challenges to rTMS-induced plasticity
as those caused by general variability in BDNF genotype, thereby further contributing
to uncertainty with regard to the potential clinical efficacy of rTMS-based interventions
in CUD. In general, illnesses or mitigating conditions which alter the neurochemistry
and neurophysiology underlying plasticity induction are likely to block or substantially

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suppress the neural response to rTMS-based techniques, and thus should be considered
when designing future studies evaluating the clinical merits of rTMS for CUD (Rossi et al.,
2009). That said, it is also encouraging to note that preclinical (Muller et al., 2000) and
human studies (Zanardini et al., 2006; Yukimasa et al., 2006) have shown that rTMS is also
capable of enhancing BDNF expression, particularly following longer treatment protocols.
Thus, it may be that for long-term cannabis users with BDNF-related plasticity impairments
to exhibit successful clinical responses to rTMS, the number of treatment sessions must
be extended beyond the standard 4-6 weeks of daily sessions recommended under current
clinical guidelines. Perhaps this added time and exposure to rTMS will serve to facilitate the
intended neuromodulatory outcomes by providing sufficient opportunity for the underlying
mechanisms leading to BDNF normalization to be activated, thereby surmounting key
barriers to plasticity. However, data also exists calling into question whether rTMS produces
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its clinical effects through alterations in BDNF, although such reports have so far been for
other patient populations (Brunoni et al. 2015; Jiang & He, 2019), and not yet assessed in
individuals with CUD or other SUDs.
As such, while it is helpful to consider the unanswered questions and ways to alter the
design of rTMS protocols to meet the potential needs of individuals with CUD, until future
research is conducted to provide further and stronger preliminary evidence of rTMS efficacy
in people who use cannabis, it is difficult to definitively predict whether and which factors
will limit rTMS outcomes in this population, which also precludes the value of developing
concrete courses of action for maximizing as of yet indeterminate treatment success. Put
more succinctly, there are a lot of unknowns, which is all the more reason continued
high-quality research is critically needed in this area.
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Future Design Considerations for rTMS Studies in Cannabis Use Disorder.

A. rTMS Brain Targets.
Dorsolateral Prefrontal Cortex (DLPFC).: The majority of investigations into NIBS for
SUDs, including those focused on either rTMS or tDCS designs, have focused on targeting
the DLPFC (either the L or R DLPFC, or both simultaneously) making it the most widely
studied NIBS target for SUDs, to date (Ekhtiari et al., 2019; Jansen et al., 2013; Song et
al., 2019). First, as the central hub of the executive control network which functions in
a regulatory role across a majority of cognitive, behavioral, and emotional processes, the
DLPFC is an obvious neurocognitive target for NIBS-based treatment approaches as it has
the greatest potential for far-reaching therapeutic impact (Diehl et al., 2018; Ekhtiari et al.,
2019; Goldstein & Volkow, 2011). Second, the DLPFC was the first neural treatment target
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to amass sufficiently compelling evidence to achieve the world’s first FDA clearance for a
neuromodulation-based treatment approach in psychiatry (i.e., rTMS for TRD which was
FDA cleared in 2008; O’Reardon et al., 2007; Berlim et al., 2014). Since then, the DLPFC
has been one of the most common preliminary targets investigated as a proof-of-principle
and feasibility litmus test for neuromodulation treatment in a wide variety of neurological
and psychiatric disease populations (Berlim et al., 2014; Dunlop et al., 2017; Fox et al.,
2014; Hanlon et al., 2017). In addition, given its relatively superficial cortical location,
it is one of the few core SUD-related brain regions with easy accessibility to the widest
assortment of NIBS stimulation devices, including those limited by shallow stimulation

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depths.
It is noteworthy to also highlight the recent ground-breaking first FDA clearance of a

NIBS-based treatment approach for application in a SUD group (BrainsWay Press Release,
August 24, 2020); namely, involving HF-rTMS for treatment in tobacco cigarette smokers.
In the principal study leading to this FDA clearance (Dinur-Klein et al., in press), delivery
of 18 near-daily sessions of HF deep rTMS to the bilateral lateral PFC and insula via the
BrainsWay H4-coil was shown to aid in tobacco cigarette smoking cessation by improving
the continuous quit rate, reducing cigarette craving, and decreasing the average number of
cigarettes smoked per week. While the broad swath of cortex stimulated by the H4-coil
is not limited solely to the DLPFC, instead also involving stimulation of the bilateral
insula and other contiguous parts of the lateral PFC, the L and R DLPFC comprise
a substantial proportion of the targeted brain tissue, and thus contribute greatly to the
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purported neurobehavioral success of this technique. Thus, this newly approved approach
contributes further to the existing literature supporting the value of the DLPFC as a
viable treatment target, while it also highlights the potential merits of using a NIBS-based
treatment protocol which broadly modulates multiple SUD-related neural circuit nodes in
order to produce or enhance clinically meaningful outcomes.
Given the growing body of high-quality evidence supporting the success of DLPFC-targeted
NIBS interventions across SUD groups (Dinur-Klein et al., in press; Ekhtiari et al., 2019;
Jansen et al., 2013; Song et al., 2019), the DLPFC remains a compelling treatment target
for CUD that deserves continued investigation in future research studies focused on the
development of novel, brain-based therapeutic tools for problematic cannabis use.
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Other Brain Regions.: There are, however, a number of other logical NIBS brain targets
(Ekhtiari et al., 2019), some of which have shown substantial promise across a growing
number of SUD groups [e.g., the medial prefrontal cortex/frontal pole (Hanlon, 2019;
Kearney-Ramos et al., 2019), anterior cingulate cortex (Martinez et al., 2018), insula
(Ibrahim et al., 2019), etc.], as well as some which have newly emerged as potentially
of interest [e.g., PCC/precuneus, as investigated for the first time by Prashad et al. (2019);
discussed in the present review]. However, evidence for these other novel targets has not
yet reached the level of support in SUD groups as has been demonstrated for the DLPFC;
thus, additional research is critical to ascertaining the potential clinical relevance of these
alternative targets for treatment in people who use cannabis.
B. rTMS Clinical Specificity.

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Biomarker-based Validation of rTMS Clinical Endpoints.: An increasingly important

proof-of-principle feature of many NIBS treatment development studies is the use of
fMRI or other neurorecording tools (such as, EEG, PET, TMS/fMRI, etc.) to demonstrate
treatment target engagement by characterizing the ability of NIBS to strategically
manipulate the intended neural biomarkers (Caulfield & George, 2018; Dunlop et al., 2017;
Fox et al., 2012; 2013; Hanlon et al., 2013; 2016; James et al., 2017; Siebner et al.,
2009; Weigand et al., 2018). Furthermore, these neural biomarkers can facilitate a clearer
understanding of the neurobiological mechanisms underlying NIBS treatment effects on

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CUD-related clinical endpoints (e.g., by correlating brain changes to changes in biologically

determined drug use, self-reported drug use, craving, cue reactivity, cognitive and behavioral
markers of SUD-related problems, etc.).
For instance, despite there being a lack of anti-craving effect after single-session active
rTMS for both Sahlem et al. (2018) and Prashad et al. (2019), it could still be of added
value to know whether Sahlem et al.’s HF-rTMS protocol was capable of engaging and
modulating activity in the stimulation target (L DLPFC) and its associated circuitry in
their group of cannabis smokers by demonstrating rTMS-specific changes in either fMRI
or EEG-based recordings as evidence of successful neural outcomes. The inclusion of
biomarker-based outcome measures for the validation of clinical target engagement and
elucidation of the neurobiological mechanisms underlying NIBS treatment efficacy are
increasingly being recognized as best practice for well-designed NIBS-based clinical trials
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(Dunlop et al., 2017; Ekhtiari et al., 2016; 2019; Fox et al., 2012; Hanlon et al., 2016; James
et al., 2017; Kearney-Ramos et al., 2019; Liston et al., 2014; Medaglia et al., 2020; Siebner
et al., 2009).
The pursuit of clinical neurobiomarker characterization in NIBS research will serve as

a critical step toward developing and incorporating personalized medicine frameworks
into NIBS intervention models (Cocchi & Zalesky, 2018; Ekhtiari et al., 2016; Verdejo-
Garcia et al., 2019). Ideally, such innovations would facilitate the integration of clinical,
demographic, and brain-based tools for “deep phenotyping” of individual patients, enabling
advancements in disease classification, treatment selection, and outcome prediction (e.g.,
informed diagnosis, treatment prognostication, monitoring, and adjustment) (Gordon et
al., 2017; Medaglia et al., 2020; Philip et al., 2014; Poldrack et al., 2015; Singh &
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Rose, 2009). However, for these data rich approaches to work, they must be informed
by empirically validated biomarkers reflecting the fundamental mechanisms contributing to
and/or predicting individual differences in treatment success or failure (Cocchi & Zalesky,
2018; Dunlop et al., 2017; Hanlon et al., 2016; Hawco et al., 2017; James et al., 2017; Liston
et al., 2014; Medaglia et al., 2020; Nicolo et al., 2015; Philip et al., 2014; 2018; Rossi et al.,
2021).
Precision-oriented Cortical Targeting.: The clinical purpose of NIBS in psychiatry is to

normalize aberrant brain function corresponding to psychopathology. Thus, NIBS-based
clinical outcomes fundamentally depend on accurate and reliable coil placement during
stimulation at the intended neurocognitive targets, and even minor deviations in coil
positioning can lead to large variations in the underlying brain regions that are stimulated
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(Brasil-Neto et al., 1992; Fuhr et al., 1991; Herbsman et al., 2009; Kraus et al., 1993).
Mounting evidence has established the advantages of incorporating personalized cortical
targeting and coil positioning techniques during rTMS administration using state-of-the-art
(f)MRI-guided neuronavigation procedures (Bashir et al., 2011; Ekhtiari et al., 2019; Kim
et al., 2014; Medaglia et al., 2020; Rossi et al., 2021; Rusjan et al., 2010; Sack et
al., 2009; Sparing et al., 2008). Neuronavigation systems are auxiliary devices that are
used in conjunction with pre-existing rTMS setups to facilitate high-precision stereotactic
positioning and orientation of TMS coils during stimulation sessions, using targets tailored
to an individual’s own anatomical or functional neuroanatomy (i.e., as derived from their

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baseline functional and/or structural MRI images). Personalized positioning using their own
brain anatomy can then be established, monitored, and adjusted in real-time to maintain
target accuracy and maximize full dose delivery of stimulation to intended neural treatment
foci, in addition to allowing for reproducible targeting over separate visits across multi-
session courses of treatment (Bashir et al., 2011; Medaglia et al., 2020; Schönfeldt-Lecuona
et al., 2005).
Further, MRI-guided cortical targeting should be considered in individuals with known or

potential structural abnormalities (such as, those with past traumatic brain injuries, stroke
histories, aging-related atrophy, or other diseases known to impact structural integrity,
including SUDs), as using their unique neuroanatomy to guide coil placement can help
to identify optimal hot spots (Ahdab et al., 2010; Ameli et al., 2009; Bradfield et al., 2012;
Taylor et al., 2018), while circumventing lesion locations (Gugino et al., 2001; Julkunen
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et al., 2009). This is because accidental stimulation of brain lesions may induce electrical
currents that follow unpredictable paths through damaged cortical tissue and cerebrospinal
fluid, running the risk of producing undesirable or even unsafe psychological (e.g.,
confusion or memory deficits) or behavioral (e.g., motor impairment) side effects, including
seizures (Sack et al., 2009). Thus, neuronavigation provides a personalized approach to
cortical targeting which improves safety without sacrificing clinical benefit (Caulfield et al.,
2017; Nahas et al., 2004; Rossi et al., 2021; Wagner et al., 2008). The safety advantages are
also apparent in the use of personalized positioning for adjustment of stimulation intensity
as a function of differences in STC distance, since the increased accuracy of personalized
targets usually results in better stimulus response and, consequently, estimate significantly
lower stimulation doses (Gugino et al., 2001; Schmidt et al., 2009). Lower stimulation doses
have the obvious advantage of reducing the potential for seizure induction or other adverse
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events (Deng et al., 2014; Rossi et al., 2021). From a research design perspective, it has also
been suggested that enhanced precision of coil placement can improve the effect sizes of
rTMS treatment outcomes, thereby decreasing the number of participants needed for a given
study or clinical trial (Sack et al., 2009).
That said, while there are many critical advantages to MRI-guided techniques, particularly
for ensuring rigor and reproducibility in highly controlled research study designs or adding
clinical precautions in complex patient populations, much evidence supports the suitability
of the more traditional cortical targeting methods (such as BeamF3; clinicalresearcher.org/
software.htm; Beam et al., 2009), as they are generally able to provide reasonable
approximations to the advanced techniques in a majority of participants (Moghtadaei et
al., 2015; Nikolin et al., 2019). This is significant because it supports the continued merits of
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conventional techniques, particularly under broader circumstances, such as if/when rTMS

interventions expand beyond academic and specialized medical research environments
and into SUD treatment facilities in community clinics or rehab centers, which often do
not readily have access to the expensive, complex neuroimaging technology or expertise
necessary for (f)MRI-guided approaches (Brunoni et al., 2019; Nikolin et al., 2019).
Cue Exposure/Induction for Neurocognitive Specificity.: Another gold-standard brain

stimulation practice derived from prior NIBS research, involves the inclusion of an
active priming procedure (such as a cue induction/cue exposure paradigm) which has
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consistently been shown to substantially enhance the neurobehavioral outcomes of NIBS-

based interventions. This process works by enhancing the specificity of the induced
neuroplastic changes, primarily through activating and behaviorally engaging the precise
target circuit proximal to the time of modulation (Dinur-Klein et al., 2014; Hanlon et al.,
2017; Hoogendam et al., 2010; Kearney-Ramos et al., 2018a).
Specifically, during rTMS in cannabis users, specificity of neural circuit engagement

and maximal manipulation of target circuit activity can be facilitated through exposure
to multisensory cannabis cues which involve visual, tactile, and/or olfactory sensory
stimulation [such as those incorporated by (Sahlem et al., 2018; 2020)], and/or narrative
cue exposure [such as those involving personalized narratives recounted by each individual
regarding their own drug use contexts, co-users, and sensory memories which elicit craving
and drug-seeking and, thereby, actively engage relevant drug use circuitry].
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IV. CONCLUSIONS
The present review provides very early encouraging but not conclusive evidence that rTMS-
based therapies are feasible and tolerable treatment avenues for individuals with CUD. The
public health need for novel CUD interventions has increased in parallel with shifting social,
political, and legal circumstances surrounding cannabis use. The consequences of these
converging factors are evident in the ongoing global increases in cannabis use problems
and use disorders, thus elevating the importance of conducting high-quality, empirically
supported CUD treatment development trials for rapid clinical translation. While the limited
number and heterogeneity of reports examining rTMS for CUD, to date, clearly highlight
the need for robust expansion of research investigating the efficacy and optimization of
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NIBS-based strategies for treating cannabis use behaviors, the growing interest in this area
is encouraging and illustrates a clear impetus for establishing clinically meaningful studies,
with design parameters and endpoints most relevant to generating valid clinical evidence to
move rTMS treatment forward for those with CUD.
FUNDING AND DISCLOSURES

The authors declare no conflicts of interest.
TKR received research support from the National Institute on Drug Abuse (R01DA044339-02S1&03S1) and New
York State Psychiatric Institute Hadar Foundation fellowship.
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Highlights
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• Rise in cannabis use and CUD elevate public health need for effective CUD
treatment
• Very early preliminary evidence of feasibility and tolerability of rTMS in

CUD
• rTMS clinical efficacy in CUD unclear due to disparate study designs and
outcomes
• While evidence promising, limitations highlight need for more high-quality

research
• Implementation of gold-standard rTMS research designs may enhance future

outcomes
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TABLE 1.
MS studies for treatment of Cannabis use disorder
uthor N Sample Characteristics Study Sham Coil Brain Target # of Stimulation Stimulation Total Primary Secondary Results
s) Design Method Type Target Localization Sessions Intensity Frequency Pulses Outcome Outcome Summary
Participants Sex Age Average Method (in (in Hz) per Measure Measure(s)
Baseline %rMT) Session
Cann
use
ahlem 18 Non- 13 M 26.0 1.3 (± Randomized, Integrated Figure L DLPFC F3 EEG 2 (1 active; 110 10 Hz 4000 Feasibility Craving 16 (three
Kearney-Ramos and Haney
t al., treatment (81.3%) (± 1.3) double- sham with 8 Coordinate 1 sham) (retention (via MCQ) women)
018 seeking 17.9) grams/ blind, sham- scalp using Beam rate); completed
participants day; 23.5 controlled, a F3 Method b the trial
with CUD (± 4.3) within- electrodes Tolerability (89%
(via MINI) Cann use subject (% able to retained for
days/ crossover tolerate full the three
month design, dose rTMS) study visits;
single- 2 rTMS
session sessions).
study All of the
treatment
completers
tolerated
rTMS at full
dose without
adverse
effects.
There was
not a
significant
reduction in
the total
MCQ when
participants
received
active rTMS
as compared
to sham
rTMS.
ahlem 3 Participants 2M 38.3 31.7 (± Open-label Integrated Figure L DLPFC F3 EEG 20 over 10 120 10 Hz 4000 Feasibility Craving 3 out of 9
t al., meeting (67%) (± 15.1) pilot safety sham with 8 Coordinate days (2 per (retention (via enrolled
020 DSM-5 11.2) Cannabis and scalp using Beam day) rate); MCQSF) participants
criteria for ≥ use- tolerability a F3 Method Tolerability completed
electrodes
moderate sessions/ trial (% able to the full
CUD who week tolerate full study. No
were dose rTMS) adverse
interested in events were
reducing reported,
their except for 1
Cannabis participant
use dropping out
due to
treatment-
Page 52
Cann
use
related
headaches.
For the 3
study
completers
who
received the
full 2-week
course of
treatment,
Cannabis
craving and
Cannabis use
was reduced
(respectively,
mean MCQ-
SF score
decrease of
~16 points
and mean
weekly
Cannabis use
measured via
TLFB
decreased by
half)
rashad 20 10 5M 27.1 76.7 (± Randomized, 1 Hz Double- PCC/ 4-cm 2 (1-10 Hz 80 10 Hz vs. 1 2000 ERP ERP At baseline,
t al., participants (50%); (± 18.1) double- comparison cone precuneus posterior to experimental Hz response to response to Cannabis
019 who 5M 4.5); Cann use blind, active condition motor strip condition; self-relevant Cannabis group
regularly use (50%); 33.9 days in placebo- as negative in parietal 1-1 Hz cues before cues before exhibited
Cannabis; (± previous controlled, control cortex negative and after and after heightened
10 age- and 14.1) 90 days; crossover control) rTMS rTMS PCC/
sex-matched 0 Cann design, precuneus
non-using use days single- salience
controls in session reactivity to
previous study external self-
90 days relevant
stimuli (as
reflected by
increased
ERP
amplitude in
P3, and
faster
latencies in
the P3, N2,
and P2 ERP
components
in response
to self-
Page 53
Cann
use
relevant cues
during the
Modified
Oddball
Task,
relative to
non-using
controls),
which
normalized
to control
levels
following
HF-rTMS.
ham treatments were delivered using an established electronic sham system (Borckardt et al., 2008). The sham system consists of a coil that mimics the appearance and sound of rTMS, combined with
ranscutaneous electrical nerve stimulator (TENS) device which produces a small electrical stimulus delivered to the scalp just below the hairline, mimicking the feeling of active rTMS (Borckardt et al.,
08). Both the participant and the administrator remain blind to stimulation condition.
or tolerability, intensity was ramped up 10% of rMT every train from 60% rMT (200 pulses delivered sub 100%).
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Public Health Status of Cannabis Use and Cannabis Use Disorder.

Need for More Effective Cannabis Use Disorder Treatment Options.

remain psychotherapeutic approaches, including cognitive-behavioral therapy, psychosocial

therapies such as family and community-based programs, and contingency management

Identifying Novel Directions for Cannabis Use Disorder Treatment Development.

Steele, 2020; Steele et al., 2019; Verdejo-Garcia et al., 2019).

Exploring a Brain-based Treatment Approach for Cannabis Use Disorder.

stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial

In general, there is a surprising paucity of therapeutic neuromodulation research in CUD,

II. INVESTIGATING REPETITIVE TRANSCRANIAL MAGNETIC

Principles of Repetitive Transcranial Magnetic Stimulation (rTMS) for Therapeutic

Conventional (Fixed-Frequency) rTMS.—When TMS pulses are delivered repeatedly

In general, high-frequency rTMS (HF-rTMS; ≥5 Hz pulse rate) typically produces an

Measuring Cortical Excitability.: Historically, the modulating effects of rTMS on cortical

Standard rTMS Session Procedures.—There is a multitude of approaches to

Treatment Stimulation Dose.: Consequently, the rTMS treatment stimulation “dose”

Scalp-to-cortex Distance.: In addition to adjusting for individual differences in rMT, it is

neuronavigation system software.

Safety & Tolerability.—As a non-invasive form of neuromodulation, interventions based

which is the clinical recommendation as published in current rTMS safety guidelines

(Lefaucheur et al., 2014; Rossi et al., 2009).

Potential for Effective rTMS Interventions in SUDs/CUD.—The potential for NIBS

most widely studied, effective, and well-tolerated neuromodulation-based treatment options

Studies Investigating rTMS Treatment Potential for Cannabis Use Disorder.

produce anti-craving effects relative to sham stimulation in this population.

2. Sahlem et al., 2020. Case Report on Feasibility and Clinical Effects of

Of 9 enrolled participants, 6 dropped out prior to treatment completion. Aside from

1 participant dropping out due to treatment-related headaches, no adverse events were

Discussion of Limitations and Contributions.: Sahlem & colleagues (2020) acknowledge

3. Prashad et al., 2019. Mitigating Aberrant Exteroceptive Processing in CUD

of others—all thought processes occurring without an explicitly established goal in mind.

The PCC/precuneus is implicated in stimulus-driven (automatic) exteroceptive processing,

In people who use substances chronically, however, exteroceptive processing can be

with elevated PCC/precuneus activation in response to cannabis cue exposure as evidence

rTMS-induced changes in neural response to personalized self-relevant and cannabis-related

visual stimuli using event-related potential (ERP) recording, an EEG-based neuroimaging

and P3 response to self-relevant stimuli during baseline compared to after HF-rTMS in

Discussion of Limitations and Contributions.: While the authors predicted a greater

III. FUTURE DIRECTIONS OF REPETITIVE TRANSCRANIAL MAGNETIC

Below is a brief breakdown of some of the potential challenges to developing rTMS-

TMS-evoked responses in the frontal-striatal reward-motivation circuit in chronic cocaine

significantly dependent upon intact structural integrity in the circuit of interest.

2018; Nahas et al., 2004).

Altered Synaptic Plasticity Induction.—A related correlate of long-term exposure to

excitability to facilitate induction of cortical plasticity of a desired magnitude and direction

Notably, a recent review by Hanlon et al. (2018) summarized existing evidence of

which, along with higher MT levels, is a neurophysiological property known to negatively

Impairments in SUD-related functional network connectivity and integrity is known

Role of Brain-derived Neurotrophic Factor (BDNF) Deficits in Plasticity

expression is, in part, regulated by CB1R-mediated activation of signaling pathways which

and neurophysiology underlying plasticity induction are likely to block or substantially

Future Design Considerations for rTMS Studies in Cannabis Use Disorder.

assortment of NIBS stimulation devices, including those limited by shallow stimulation

It is noteworthy to also highlight the recent ground-breaking first FDA clearance of a

B. rTMS Clinical Specificity.

Biomarker-based Validation of rTMS Clinical Endpoints.: An increasingly important

understanding of the neurobiological mechanisms underlying NIBS treatment effects on

CUD-related clinical endpoints (e.g., by correlating brain changes to changes in biologically

The pursuit of clinical neurobiomarker characterization in NIBS research will serve as

Precision-oriented Cortical Targeting.: The clinical purpose of NIBS in psychiatry is to

to an individual’s own anatomical or functional neuroanatomy (i.e., as derived from their

Further, MRI-guided cortical targeting should be considered in individuals with known or