2023 Article 1776

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A systematic review and meta-analysis of neuromodulation

therapies for substance use disorders
✉
Dhvani D. Mehta1,2 , Angela Praecht1,2, Heather B. Ward 3, Marcos Sanches1, Maryam Sorkhou 1,2
, Victor M. Tang 1,2
,
✉
Vaughn R. Steele 4, Colleen A. Hanlon 5 and Tony P. George 1,2
© The Author(s) 2023
While pharmacological, behavioral and psychosocial treatments are available for substance use disorders (SUDs), they are not
always effective or well-tolerated. Neuromodulation (NM) methods, including repetitive transcranial magnetic stimulation (rTMS),
transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) may address SUDs by targeting addiction
neurocircuitry. We evaluated the efficacy of NM to improve behavioral outcomes in SUDs. A systematic literature search was
performed on MEDLINE, PsychINFO, and PubMed databases and a list of search terms for four key concepts (SUD, rTMS, tDCS, DBS)
was applied. Ninety-four studies were identified that examined the effects of rTMS, tDCS, and DBS on substance use outcomes (e.g.,
craving, consumption, and relapse) amongst individuals with SUDs including alcohol, tobacco, cannabis, stimulants, and opioids.
Meta-analyses were performed for alcohol and tobacco studies using rTMS and tDCS. We found that rTMS reduced substance use
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and craving, as indicated by medium to large effect sizes (Hedge’s g > 0.5). Results were most encouraging when multiple
stimulation sessions were applied, and the left dorsolateral prefrontal cortex (DLPFC) was targeted. tDCS also produced medium
effect sizes for drug use and craving, though they were highly variable and less robust than rTMS; right anodal DLPFC stimulation
appeared to be most efficacious. DBS studies were typically small, uncontrolled studies, but showed promise in reducing misuse of
multiple substances. NM may be promising for the treatment of SUDs. Future studies should determine underlying neural
mechanisms of NM, and further evaluate extended treatment durations, accelerated administration protocols and long-term
outcomes with biochemical verification of substance use.
Neuropsychopharmacology (2024) 49:649–680; https://doi.org/10.1038/s41386-023-01776-0
INTRODUCTION behaviors and inhibition [15]. Thus, use of NM to stimulate right

Substance use disorders (SUDs) account for 500,000 deaths DLPFC may strengthen executive functions by inhibiting the left
annually in the U.S alone [1, 2]. Moreover, SUDs frequently co- DLPFC to counterbalance hemispheric imbalance, which may
occur with psychiatric disorders, including schizophrenia and contribute to reduction of substance consumption and craving
mood disorders [3–5]. Although there are validated pharmacolo- [16, 17]. Invasive and/or non-invasive NM may be promising brain-
gic and psychotherapeutic treatments available for SUDs, relapse based approaches since they modulate SUD-related mesolimbo-
rates are high [6, 7]. Thus, development of neuroscience-informed cortical circuitry [8, 9, 18]. Such interventions include repetitive
therapeutics for SUDs is critical. Neuromodulation (NM) may offer transcranial magnetic stimulation (rTMS), transcranial direct
such opportunities [8, 9]. current stimulation (tDCS), and deep brain stimulation (DBS).
Reinforcing effects of substances are primarily mediated by
mesocorticolimbic systems, which include midbrain dopamine Repetitive transcranial magnetic stimulation (rTMS)
(DA) projections to prefrontal cortex (PFC) and ventral striatum rTMS is a non-invasive NM technique that has shown utility for
[nucleus accumbens (NAc)] [10, 11]. Substance misuse is neurological and psychiatric disorders [19]. Application of alter-
associated with mesolimbic hypodopaminergia [12], and dysfunc- nating magnetic fields to the scalp through a copper wire induces
tion of dorsolateral prefrontal cortex (DLPFC) and dorsal anterior temporary electrical currents and modulates cortical excitability in
cingulate cortex (dACC), which are involved in decision-making localized brain tissue [20] (Fig. 1a). Numerous studies have
and self-control. Moreover, the ventral PFC, including the demonstrated enduring functional and structural neuroplastic
orbitofrontal cortex (OFC) and ventral anterior cingulate cortex changes in target regions [21, 22], and increased DA release in the
(vACC), is involved in limbic arousal and emotional processing mesolimbic system [23–26].
[13]. Hence, dysfunction in these systems has been associated Stimulation parameters vary significantly with respect to
with SUDs [14]. Furthermore, left DLPFC mediates reward-based stimulus intensity, frequency and total number of pulses, which
motivation, while right DLPFC is involved in withdrawal-related can produce differential effects [27]. Typically, low frequency (LF;
1
Addictions Division, CAMH, Toronto, ON, Canada. 2Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. 3Department of
Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. 4Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
5
Brainsway, Inc., Winston-Salem, NC, USA. ✉email: dhvani.mehta@mail.utoronto.ca; tony.george@camh.ca
Received: 20 July 2023 Revised: 6 November 2023 Accepted: 20 November 2023

Published online: 12 December 2023
D.D. Mehta et al.
650
Fig. 1 Neuromodulation techniques. Diagrams to illustrate the three neuromodulation techniques investigated: (a) rTMS (Deep TMS image
acquired from Brainsway, Inc.), (b) tDCS, (c) DBS.
≤1 Hz) stimulation produces local inhibitory effects while high Deep brain stimulation (DBS)
frequency (HF; ≥5 Hz) stimulation produces local excitatory effects DBS is an invasive NM technique used to treat Alzheimer’s disease,
on motor cortex [28, 29]. rTMS primarily alters motor cortical Parkinson’s disease, and obsessive compulsive disorder [44]. It
excitability and inhibition, with indirect effects on craving or involves a neurosurgical procedure wherein implanted electrodes
motivation. Frequency-dependent rTMS effects on regional brain deliver electrical pulses directly to targeted brain regions, which
activity may have implications for clinical therapeutics in modulates neural circuitry and subsequently alters neuroplasticity
neuropsychiatric disorders [30, 31]. Coil type can also modulate (Fig. 1c). While rTMS and tDCS use lower frequencies to induce
effects; while traditional TMS employs a figure-8 coil design and excitation or inhibition of neurons, DBS blocks neural transmission
can only reach depths of 0.7 cm, deep TMS, wherein a three- with high-frequency stimulation [45]. Implanted electrodes are
dimensional H-coil helmet design is used, can stimulate a deeper connected to an implantable pulse generator placed under the
and broader brain area, reaching a depth of 3.2 cm [32]. skin of the chest wall, allowing for continuous stimulation at a pre-
Two robust rTMS adaptations have emerged wherein bursts of set frequency [46]. Thus, stimulation parameters can be modu-
magnetic pulses, referred to as theta burst stimulation (TBS), are lated as a patient’s condition changes.
applied. In intermittent theta burst stimulation (iTBS), a two Unlike other surgical interventions, DBS does not damage brain
second train of TBS bursts is repeated every ten seconds, inducing tissue [47], but given its invasive nature, is associated with
long-term potentiation and cortical excitability [33, 34]. Contrast- infection, seizures or stroke. DBS is well-tolerated once the patient
ingly, continuous theta-burst stimulation (cTBS) applies trains of has recovered from the primary surgical procedure [48]. Focal
uninterrupted TBS bursts and induces long-term depression and stimulation of deep brain regions involved in addiction neuro-
inhibitory effects [34]. circuitry (e.g. NAc) may facilitate SUD treatment.
rTMS appears safe when administered according to recom- We conducted a systematic review and meta-analysis to
mended guidelines [35]. There is little risk beyond local discomfort determine the efficacy of NM for improving addiction outcomes
at the site of stimulation and other minor side effects (e.g. mild (e.g., drug craving, consumption, and relapse). As significant
headache, dizziness) [36]. Importantly, a deep-TMS system was progress has been made in this area, a systematic review and
recently cleared by the Food and Drug Administration (FDA) for meta-analysis building on previous narrative reviews [8, 9] with
smoking cessation [37]. However, long-term effects of repeated quantification of NM effects in SUDs is warranted.
rTMS sessions are unknown [38].
Transcranial direct current stimulation (tDCS) METHODS

Using two or more electrodes (i.e., anodal, cathodal), tDCS delivers Search strategy
a low intensity current (0.5–2.0 milliamps [mA]) to a targeted brain A comprehensive literature search by two authors (D.M. and A.P., trained
region for several minutes (Fig. 1b). This allows for polarity- on Covidence) was conducted using Medline, PubMed and PsycINFO
dependent modulation of the neuronal resting membrane databases, in accordance with Preferred Reporting Items for Systematic
potential and cortical excitability. Cathodal current decreases Reviews and Meta-Analyses (PRISMA) guidelines [49] (Supplementary
Fig. 1), through October, 2023. Articles published after 2000 in peer-
while anodal current increases cortical excitability [39, 40]. Similar reviewed journals were considered. A list of keywords and search terms for
to rTMS, tDCS protocols can vary with respect to numerous four key concepts (SUD, rTMS, tDCS, DBS) was applied (See Supplementary
parameters such as current strength, electrode size and place- Table 1 for Search Strategy). Reference lists of relevant reviews were also
ment, stimulation duration and frequency [41]. screened for applicable articles. The review was registered at PROSPERO
tDCS is an accessible, low-cost stimulation method that is well- (CRD42023475165).
tolerated, though minor side effects such as scalp irritation are
reported [42]. Similar to rTMS, tDCS has been used to effectively treat Eligibility criteria
neuropsychiatric conditions such as Parkinson’s disease, chronic pain, Using PICOS [50], studies were included if they satisfied the following
and major depression [43]. Although underlying mechanisms for criteria – Population (P): Studies recruiting participants (18+ years of age)
tDCS are not fully understood, induction of neurochemical changes in diagnosed with SUD/dependence of alcohol, tobacco, cocaine, metham-
targeted brain tissue is being investigated for SUD treatment. phetamine, opioids, or cannabis, according to standardized criteria (e.g.,
Neuropsychopharmacology (2024) 49:649 – 680

Table 1. Repetitive Transcranial Magnetic Stimulation (rTMS) [Total N = 2406; Total Studies = 51].
Citation Sample Study Design # of Sessions & Stimulation Stimulation Coil Type Craving Consumption Other Results
Size Targeted Intensity Frequency Effect Size Effect Size Outcome(s)
Region (Hedge’s g) (Hedge’s g) Effect Size
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
Alcohol: Single Active Stimulation Session
Total N = 149; 5 Studies
Herremans et N = 31 A randomized, 1 Active 110% 20 Hz Figure-8 Craving NA NA No significant effect on alcohol
al. [56] prospective, single- OR Coil Active vs. craving was observed following
blind, sham-controlled 1 Sham Session Sham: active rTMS compared to sham
study with recently Right DLPFC −0.18 stimulation.
detoxified alcohol- (w/ MRI- [−0.93–0.56]
dependent participants neuronavigation)
Herremans et N = 29 A randomized, single- 1 Active 110% 20 Hz Figure-8 Craving NA Executive No significant post-treatment
al. [57] blind, sham-controlled, AND Coil Active vs. Functioning effects of active or sham rTMS
crossover study with 1 Sham Session Sham: NA were observed on alcohol craving,

recently detoxified, Right DLPFC −0.33 compared to baseline.
alcohol-dependent (w/ MRI- [−0.85–0.19] No significant difference in
participants neuronavigation) executive functioning or alcohol
craving was observed following
one active rTMS session
compared to sham.
Herremans et N = 26 An open label, sham- 1 Active 110% 20 Hz Figure-8 Craving NA NA No significant difference in
al. [58] controlled, crossover AND Coil Active vs. alcohol craving was observed
study with recently 1 Sham Session Sham: following 1 active rTMS session
detoxified alcohol- Right DLPFC 0 compared to sham.
dependent participants (w/ MRI- [−0.77–0.77]
neuronavigation)
Hanlon et al. N = 24 A single-blind, sham- 1 Active 110% 3-pulse Figure-8 Craving NA BOLD Signal No significant difference in
[59] controlled, crossover AND bursts Coil Active vs. NA alcohol craving was observed
study with alcohol- 1 Sham Session presented at Sham: following 1 active cTBS session
dependent participants of 5 Hz 0.17 compared to sham.
cTBS [−0.39–0.72] cTBS significantly ↓ evoked BOLD
Left Frontal signal in left OFC, insula, and
Pole lateral sensorimotor cortex.
Jansen et al. N = 39 A randomized, single- 1 Active 110% 10 Hz Figure-8 Craving NA Emotion No significant post-treatment
[60] blind, sham-controlled OR Coil Active vs. Regulation effect of active or sham rTMS was
D.D. Mehta et al.
study with recently 1 Sham Session Sham: NA observed on alcohol craving,

detoxified alcohol- Right DLPFC −0.31 compared to baseline.
dependent participants (w/ MRI- [−0.78–0.15] One active rTMS session reduced
neuronavigation) self-reported experienced
emotions in response to positive
and negative images.
Alcohol: Multiple Active Stimulation Sessions
Mishra et al. N = 45 A prospective, single- 10 Active 110% 10 Hz Figure-8 Craving NA NA Active rTMS significantly ↓ alcohol
[61] blind, sham-controlled OR Coil Active vs. craving compared to sham.
study with alcohol- 10 Sham Sham:
dependent participants Sessions −2.64
Right DLPFC [−3.46 –
−1.81]
Hoppner et al. N = 19 A randomized, sham- 10 Active 90% 20 Hz Figure-8 Craving NA Depressive No significant difference in
[62] controlled study with OR Coil Active vs. Symptoms alcohol craving or mood was
alcohol-dependent 10 Sham Sham: Active vs. observed following active rTMS,
female participants (14 Sessions 1.12 Sham: compared to sham and baseline.
days after Left DLPFC [0.15–2.09] −0.15
detoxification) [−1.06–0.75]
651
652
Table 1. continued
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
Ceccanti et al. N = 18 A randomized, double- 10 Active 120% 20 Hz H-coil (H- Craving Consumption Dopamine Active dTMS significantly ↓
[63] blind, sham-controlled OR 1) Active vs. Active vs. Pathway alcohol craving compared to
study with alcohol- 10 Sham Sham: Sham: Modulation sham.
dependent male Sessions of −1.64 [−2.71 −2.07 NA Significant ↓ in cortisolemia and
participants deep TMS – −0.57] [−3.21– −0.92] prolactinemia was observed
(dTMS) following active dTMS compared
mPFC to sham, suggesting dopamine
increase.
Girardi et al. N = 20 An open-label, double- 20 Active 120% 20 Hz H-coil (H- Craving NA Depressive Combined pharmacotherapy and
[64] blind, sham-controlled Sessions of 1) Active vs. Symptoms dTMS resulted in a significant ↓ in
study with alcohol- dTMS with SDT Sham: Active vs. alcohol craving and depressive
dependent participants OR −1.49 [−2.48 Sham: symptoms
with dysthymia SDT alone – −0.50] −1.26
receiving concurrent Bilateral DLPFC [−2.22 –
standard detoxification −0.30]
treatment
Addolorato et N = 11 A randomized, sham- 12 Active 100% 10 Hz Figure-8 NA Consumption DAT Active rTMS significantly ↓ striatal
al. [65] controlled study with OR Coil Active vs. Availability DAT availability and alcohol
alcohol-dependent 12 Sham Sham: NA consumption compared to
participants Sessions 0.16 baseline.
Bilateral DLPFC [−1.03–1.35]
Perini et al. N = 56 A randomized, double- 15 Active 120% 10 Hz H-coil (H- Craving Consumption NA No significant difference in
[66] blind, sham-controlled OR 8) Active vs. Active vs. alcohol craving or consumption
D.D. Mehta et al.
study with alcohol- 15 Sham Sham: Sham: was observed following active
dependent participants Sessions of 1.28 −0.52 dTMS compared to sham
dTMS [0.71–1.86] [−1.05–0.01] stimulation.
Insula
Raikwar et al. N = 60 A randomized, single- 10 Active 120% 10 Hz Figure-8 Craving NA NA No significant difference in
[67] blind, sham-controlled OR Coil Active vs. alcohol craving was observed
study with alcohol- 10 Sham Sham: following active rTMS compared
dependent male Sessions −0.19 to sham stimulation.
participants Left DLPFC [−0.70–0.31]
Harel et al. N = 51 A randomized, double- 15 Active 100% 10 Hz H-coil (H- Craving Consumption NA Active dTMS significantly ↓ pHDD
[68] blind, sham-controlled +5 7) Active vs. Active vs. and alcohol craving compared to
study with recently Maintenance Sham: Sham: sham.
abstinent, alcohol- OR −2.39 [−3.15 −2.61
dependent participants. 15 Sham – −1.63] [−3.39 –
+5 −1.82]
Maintenance
Sessions of
dTMS
mPFC and ACC
Zhang et al. N = 48 A randomized, double- 10 Active 110% 20 Hz Figure-8 Craving Consumption NA Active rTMS significantly ↓ days of
[69] blind, sham-controlled OR Coil Active vs. Active vs. heavy drinking and alcohol
study with alcohol- 10 Sham Sham: Sham: craving compared to sham.
dependent participants. Sessions −2.22 [−2.99 −1.84
Left DLPFC – −1.45] [−2.57 –
−1.12]
Hoven et al. N = 80 A randomized, dingle- 10 Active 110% 10 Hz Figure-8 Craving NA Abstinent No significant difference in
[70] blind, sham-controlled OR Coil Active vs. Days Over number of abstinent days over
study with recently 10 Sham Sham: 6-months 6-months or alcohol craving was
abstinent, alcohol- Sessions −0.16 Active vs. observed following active rTMS
dependent participants. Right DLPFC [−0.59–0.28] Sham: compared to sham stimulation.
−0.13
[−0.56–0.30]

Table 1. continued
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
McCalley et al. N = 50 A randomized, double- 10 Active 110% 3-pulse Figure-8 Craving NA Alcohol Cue Active cTBS significantly ↓ brain
[71] blind, sham-controlled OR 50 Hz bursts Coil Active vs. Reactivity reactivity to alcohol cues and
study with alcohol- 10 Sham given every Sham: NA alcohol craving compared to sham.
dependent participants. Sessions of 200 ms (at −4.36 [−5.38 Sobriety No significant difference in
cTBS 5 Hz) – −3.34] NA sobriety was observed, though
mPFC active cTBS participants were three
times as likely to remain sober at
the 3-month follow-up.
Tobacco: Single Active Stimulation Session
Rose N = 15 A repeated measure, 1 Active (1 Hz) 90% LF: 1 Hz Figure-8 Cue-induced NA NA 10-Hz SFG rTMS significantly ↓

et al. [83] counterbalanced design AND and Coil Craving cigarette craving following
with tobacco- 1 Active (10 Hz) HF: 10 Hz (Neutral neutral cue presentation, relative
dependent participants AND Cue) to 1-Hz SFG and MOC.
( > 15 CPD) 1 Control (MOC) 10 Hz vs. Conversely, 10-Hz rTMS
Session Sham: significantly ↑ cigarette craving
SFG −6.13 [−7.84 after presentation of smoking
– −4.42] cues.
Cue-induced
Craving
(Smoking
Cue)
10 Hz vs.
Sham:
−2.37 [−3.31
– −1.44]
Li N = 14 A randomized, double- 1 Active 100% 10 Hz Figure-8 Subjective NA NA Active rTMS, but not sham,
et al. [74] blind, sham-controlled AND Coil Craving significantly ↓ subjective craving
crossover study with 1 Sham Session Active vs. and cue-induced tobacco craving
tobacco-dependent Left DLPFC Sham: compared to baseline.
participants −1.02 [−1.81
– −0.24]
Cue-induced
D.D. Mehta et al.
Craving
Active vs.
Sham:
−0.27
[−1.01–0.48]
Pripfl et al. N = 11 A sham-controlled, 1 Active 90% 10 Hz Figure-8- Cue-induced NA EEG Delta Active rTMS significantly ↓ EEG
[75] crossover study with AND Coil Craving Power delta power and tobacco craving
tobacco-dependent 1 Sham Session Active vs. Active vs. compared to sham.
participants Left DLPFC Sham: Sham:
(w/ MRI- −0.26 −0.23
neuronavigation) [−1.10–0.58] [−1.06–0.61]
Li N = 10 A sham-controlled, 1 Active 100% 10 Hz Figure-8 Craving NA mOFC and Active rTMS significantly ↓ activity
et al. [72] counterbalanced, AND Coil Active vs. NAc Activity in mOFC and NAc.
crossover study with 1 Sham Session Sham: NA No significant difference in
tobacco-dependent Left DLPFC −0.04 tobacco craving was observed.
participants [−0.92–0.83]
Tobacco: Multiple Active Stimulation Sessions
Eichhammer N = 14 A double-blind, sham 2 Active 90% 20 Hz Figure-8 Craving Consumption NA Active rTMS significantly ↓
et al. [76] controlled, crossover AND Coil NA Active vs. cigarette consumption compared
study with tobacco- 2 Sham Sessions Sham: to sham.
dependent participants (on a single day) −0.38 No significant difference in
Left DLPFC [−1.13–0.37] tobacco craving was observed.
653
654
Table 1. continued
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
Amiaz et al. N = 48 A randomized, double- 10 Active + 6 100% 10 Hz Figure-8 Craving Consumption Dependence Active rTMS significantly ↓
[77] blind, sham-controlled Maintenance Coil Active Active (Neutral Active cigarette consumption and
study with tobacco- OR (Neutral Cue Cue (Neutral Cue nicotine dependence compared
dependent participants 10 Sham + 6 Provocation) Provocation) Provocation) to sham. However, this was not
Maintenance vs. Sham: vs. Sham: vs. Sham: maintained 6-months post-
Sessions −0.12 −1.01 −1.93 treatment.
Left DLPFC [−0.86–0.63] [−1.80 – [−2.83 – Craving was decreased only in the
(with neutral or Active −0.23] −1.03] group that received active rTMS
smoking cue- (Smoking Active Active following smoking cue
provocation) Cue (Smoking Cue (Smoking provocation.
Provocation) Provocation) Cue
vs. Sham: vs. Sham: Provocation)
−3.26 [−4.48 −2.99 vs. Sham:
– −2.03] [−4.16 – −2.45
−1.82] [−3.51 –
−1.39]
Wing et al. N = 15 A randomized, double- 20 Active 90% 20 Hz Figure-8 Craving NA NA Active rTMS significantly ↓
[78] blind, sham-controlled OR Coil Active vs. tobacco craving compared to
study with tobacco- 20 Sham Sham: sham and baseline.
dependent participants Sessions −0.43
with comorbid Bilateral DLPFC [−1.47–0.62]
schizophrenia (SCZ)
Dieler et al. N = 74 A randomized, sham 4 Active 80% 50 Hz Figure-8 Craving NA Abstinence iTBS with adjunct CBT produced ↑
D.D. Mehta et al.
[79] controlled study with OR Coil Active vs. NA abstinence rates at 3 months
tobacco-dependent 4 Sham Sham: compared to sham.
participants Sessions of iTBS 0.32 No significant effect on craving
with concurrent [−0.13–0.78] was observed
CBT
Right DLPFC
Dinur-Klein et N = 115 A prospective, 13 Active 120% LF: 1 Hz H-coil NA Consumption Abstinence 10-Hz dTMS significantly ↓
al. [84] randomized, sham- OR or (H-ADD) 10 Hz vs. Sham: NA cigarette consumption and
controlled study with 13 Sham HF: 10 Hz −5.25 nicotine dependence compared
tobacco-dependent Sessions of [−6.29 – to low frequency dTMS and sham.
participants dTMS −4.21] The combination of dTMS with
( > 20 CPD) Lateral PFC and smoking cue provocation
Insula enhanced this reduction in
(with or without consumption.
smoking cue- No significant difference in
provocation) abstinence rates was observed
between groups.
Prikryl et al. N = 35 A randomized, 15 Active 110% 10 Hz Figure-8 NA Consumption NA Active rTMS significantly ↓
[80] double-blind, sham- OR Coil Active vs. cigarette consumption compared
controlled study with 15 Sham Sham: to sham.
tobacco-dependent Sessions −0.44
male participants with Left DLPFC [−1.11–0.24]
comorbid SCZ
Trojak et al. N = 37 A prospective, 10 Active 120% 1 Hz Figure-8 Craving NA Abstinence Active rTMS combined with NRT
[81] randomized, sham- OR Coil Active vs. NA produced significantly ↑ abstinent
controlled study with 10 Sham Sham: participants. However, this was not
tobacco-dependent Sessions with 0.11 maintained at follow-up (12 weeks).
participants receiving concurrent NRT [−0.53–0.76] No lasting effects on tobacco
concurrent nicotine Right DLPFC craving was observed.
replacement therapy (w/ MRI-
(NRT) neuronavigation)

Table 1. continued
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
Kozak et al. N = 27 A double-blind, sham- 6 Active 90% 20 Hz Figure-8 Craving NA Cognition Active rTMS had no significant
[73] controlled, crossover AND Coil Active vs. NA effects on tobacco craving,
study with tobacco- 6 Sham Sham: tobacco withdrawal, or cognitive
dependent participants Sessions 0.18 outcomes, when compared to
with & without Bilateral DLPFC [−0.59–0.95] sham.
comorbid SCZ
Abdelrahman N = 40 A randomized, double- 10 Active 80% 20 Hz Figure-8 Craving Consumption Depressive Active rTMS significantly ↓
et al. [82] blind, sham-controlled OR Coil Active vs. Active vs. Symptoms cigarette consumption and
study with tobacco- 10 Sham Sham: Sham: Active vs. tobacco craving compared to
dependent participants Sessions −0.96 [−1.62 −1.62 Sham: sham.
Left DLPFC – −0.31] [−2.33 – −1.26 Significant improvement in
−0.91] [−1.93 – depressive symptoms was

−0.58] observed following active rTMS
treatment compared to sham and
baseline.
Zangen et al. N = 262 A multicenter, 15 Active 120% 10 Hz H-coil (H- Craving NA Continuous Active dTMS produced a ↑ CQR
[37] randomized, double- +3 4) Active vs. Quit Rate compared to sham.
blind, sham-controlled Maintenance Sham: (CQR) Active dTMS significantly ↓
study with tobacco- OR −3.42 [−3.80 Active vs. tobacco craving compared to
dependent participants 15 Sham – −3.04] Sham: sham.
+3 2.12
Maintenance [1.82–2.42]
Sessions of
dTMS
Bilateral PFC
and Insula
Ibrahim et al. N = 42 A randomized, double- 20 Active 120% 10 Hz H-coil (H- Craving Consumption Abstinence Active dTMS had no significant
[86] blind, sham-controlled OR 11) Active vs. Active vs. NA effect on craving or consumption
study with tobacco- 20 Sham Sham: Sham: at the end of stimulation
dependent participants Sessions of −0.35 −0.12 treatment (Week 4). However, at
receiving concurrent dTMS [−1.03–0.33] [−0.79–0.56] the end of varenicline treatment
varenicline treatment Insular Cortex (Week 12), smokers in the active
group had significantly higher
D.D. Mehta et al.
abstinence rates than those who

received sham (82.4% vs. 30.7%).
Moeller et al. N = 20 A randomized, double- 15 Active 120% 10 Hz H-coil (H- NA Self- Psychiatric Active dTMS significantly ↑ the
[85] blind, sham-controlled OR 4) administration Symptoms latency for patients to smoke their
study with tobacco- 15 Sham NA NA first cigarette, compared to sham.
dependent participants Sessions of Active dTMS produced a stepwise
with comorbid SCZ dTMS reduction in psychotic symptoms
Bilateral PFC overtime.
and Insula
Cannabis: Single Active Stimulation Session
Total N = 14; 1 Study
Sahlem et al. N = 14 A randomized, double- 1 Active 110% 10 Hz Figure-8 Craving NA Retention rTMS can be safely administered
[87] blind, sham-controlled, AND Coil Active vs. NA to cannabis-dependent patients
crossover study with 1 Sham Session Sham: and is well tolerated.
cannabis-dependent Left DLPFC 0.42 No significant reduction in
participants [−0.33–1.17] craving was observed following
active rTMS compared to sham.
655
656
Table 1. continued
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
Cannabis: Multiple Active Stimulation Sessions
Bidzinski et al. N = 19 A randomized, double- 20 Active 90% 20 Hz Figure 8 NA Consumption Psychiatric Non-significant reduction in
[88] blind, sham-controlled OR Coil Active vs. Symptoms cannabis consumption and an
parallel groups study 20 Sham Sham: NA improvement in positive
with cannabis- Sessions −0.34 symptoms of psychosis were
dependent participants Bilateral DLPFC [−1.30–0.62] observed following active rTMS
with comorbid SCZ compared to sham.
A trend towards a greater
reduction in craving was
observed following active rTMS.
Cocaine: Single Active Stimulation Sessions
Hanlon et al. N = 24 A single-blind, sham- 1 Active 110% 3-pulse Figure-8 Craving NA BOLD Signal No significant difference in
[59] controlled, crossover AND bursts Coil Active vs. NA cocaine craving was observed
study with cocaine- 1 Sham Session presented at Sham: following 1 active cTBS session
dependent participants of 5 Hz 0.01 compared to sham.
cTBS [−0.55–0.58] cTBS significantly ↓ evoked BOLD
Left Frontal signal in the caudate, accumbens,
Pole anterior cingulate, orbitofrontal
(OFC) and parietal cortex.
Cocaine: Multiple Active Stimulation Sessions
D.D. Mehta et al.

Bolloni et al. N = 10 A randomized, double- 12 Active 100% 10 Hz H-coil (H- NA Consumption NA Active dTMS did not significantly
[89] blind, sham-controlled OR 1) Active vs. affect cocaine consumption
study with cocaine- 12 Sham Sham: compared to sham.
dependent participants Sessions of −1.46 [−2.50 – However, a decreasing trend in
dTMS −0.41] consumption between baseline and
Bilateral PFC 6-months post-dTMS was observed
in the active group.
Terraneo et al. N = 32 A randomized, open- 8 Active 100% 15 Hz Figure-8 Craving NA Relapse Active rTMS significantly ↑ clean
[90] label study with Sessions Coil Active vs. NA urine screens and ↓ cocaine
cocaine-dependent OR Sham: craving compared to sham.
participants. SDT only −2.24 [−3.17
Left DLPFC – −1.30]
(w/ MRI-
neuronavigation)
Martinez et al. N = 18 A randomized, sham- 13 Active 90% − 110% LF:1 Hz H-coil (H- Craving Self- NA 10-Hz dTMS significantly ↓
[91] controlled study with OR or 7) NA administration cocaine self-administration,
cocaine-dependent 13 Sham HF:10 Hz NA relative to 1-Hz dTMS and sham.
participants. Sessions of No significant effect on craving
dTMS was observed.
mPFC and
dACC
Lolli N = 62 A randomized, blinded, 15 Active 100% 15 Hz Figure-8 Cue-induced NA Time to No significant difference between
et al. [92] sham-controlled study OR Coil Craving Urine the active and sham rTMS groups
with cocaine- 15 Sham Active vs. Negativation in the time to urine
dependent participants. Sessions Sham: NA negativization.
Left DLPFC 0.24 However, cue-induced cocaine
[−0.43–0.92] craving significantly ↓ in the
active rTMS group only.

Table 1. continued
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
Martinotti et N = 80 A randomized, blinded, 20 Active 100% 15 Hz Figure-8 Craving NA % of There were no significant
al. [93] sham-controlled, + 24 Coil Active vs. Negative differences in cocaine craving and
multicentre study with Maintenance Sham: Urine Tests consumption between active and
cocaine-dependent OR −0.21 NA sham rTMS groups.
participants. 20 Sham [−0.68–0.27]
+ 24
Maintenance
Sessions of
accelerated
(twice daily)
rTMS
Left DLPFC

Methamphetamine: Single Active Stimulation Session
Li N = 18 A single-blind, sham- 1 Active 100% 1 Hz Figure-8 Cue-induced NA NA Active rTMS significantly ↑ cue-
et al. [94] controlled, crossover AND Coil Craving induced craving for
study with 1 Sham Session Active vs. methamphetamine in MUD
methamphetamine- Left DLPFC Sham: participants compared to sham.
dependent participants 4.42 This effect was not observed in
and matched healthy [2.79–6.04] healthy controls.
controls.
Methamphetamine: Multiple Active Stimulation Sessions
Su N = 30 A randomized, double- 5 Active 100% 10 Hz Figure-8 Cue-induced NA Cognition Active rTMS significantly ↓ cue-
et al. [95] blind, sham-controlled OR Coil Craving NA induced craving for
study with 5 Sham Active vs. methamphetamine compared to
methamphetamine- Sessions Sham: sham.
dependent participants. Left DLPFC −0.65 Significant improvement in
[−1.39–0.08] cognition post-rTMS.
Liang et al. N = 48 A double-blind, 10 Active 100% 10 Hz Not Cue-induced NA Depressive Active rTMS significantly ↓ cue-
[96] randomized, sham- OR Mentioned Craving Symptoms induced craving for
controlled study with 10 Sham Active vs. NA methamphetamine, as well as
D.D. Mehta et al.
methamphetamine- Sessions Sham: improved depressive symptoms

dependent male Left DLPFC −6.84 [−8.36 and sleep quality, compared to
participants. – −5.33] sham.
Liu N = 90 A randomized, 20 Active 100% 10 Hz Figure-8 Craving NA NA rTMS treatment significantly ↓
et al. [97] between-subjects study Sessions Coil Active vs. No methamphetamine craving, with
with OR Treatment: the effect lasting 30 days post-
methamphetamine- No Treatment −5.34 [−6.23 treatment.
dependent female Left DLPFC – −4.46]
participants.
Chen et al. N = 74 A between groups, 10 Active 100% (iTBS) 3-pulse Figure-8 Cue-induced NA Depressive Cue-induced craving for
[98] randomized, sham- Left DLPFC or 50 Hz bursts Coil Craving Symptoms methamphetamine was
controlled study with iTBS (A) 110% (cTBS) given every A vs. Sham: NA significantly ↓ in all three active
methamphetamine- OR 200 ms (at −0.88 [−1.55 TBS groups compared to sham.
dependent participants. 10 Active 5 Hz) – −0.20] Combined iTBS and cTBS
Left vmPFC B vs. Sham: treatment significantly improved
cTBS (B) −1.31 [−2.02 depressive and withdrawal
OR – −0.60] symptoms compared to sham and
10 Active C vs. Sham: baseline.
Left DLPFC −1.53 [−2.25
iTBS and Left – −0.81]
vmPFC cTBS (C)
OR
10 Sham
Sessions
657
658
Table 1. continued
[95% CI] [95% CI] (Hedge’s g)
[95% CI]
Su N = 126 A randomized, double- 20 Active 100% 3-pulse Figure-8 Craving NA Cognition Active iTBS significantly ↓
et al. [99] blind, sham-controlled OR 50 Hz bursts Coil Active vs. NA methamphetamine craving
study with 20 Sham given every Sham: and improved cognition and
methamphetamine- Sessions of iTBS 200 ms (at −1.14 [−1.52 sleep quality, compared to
dependent participants. Left DLPFC 5 Hz) – −0.76] sham.
Su N = 60 A randomized, double- 20 Active 100% 3-pulse Figure-8 Cue-induced NA Functional Active iTBS significantly ↓
et al. [100] blind, sham-controlled OR 50 Hz bursts Coil Craving Connectivity methamphetamine craving
study with 20 Sham given every Active vs. NA compared to sham.
methamphetamine- Sessions of iTBS 200 ms (at Sham: A significant ↑ in functional
dependent patients Left DLPFC 5 Hz) −1.01 [−1.55 connectivity between left
– −0.47] DLPFC and inferior parietal
lobule was observed following
iTBS, which correlated with
craving reduction.
Yuan et al. N = 73 A randomized, double- 10 Active 100% 1 Hz Figure-8 Cue-induced NA Impulse Significant ↓ in cue-induced
[101] blind, sham-controlled OR Coil Craving Inhibition craving following active
study with 10 Sham Active vs. NA rTMS compared to sham and
methamphetamine- Sessions Sham: baseline.
dependent male Left PFC −0.21 Significant improvement in
participants [−0.67–0.25] accuracy and reaction time
following single session of
rTMS, maintained after 10
sessions and at 3 weeks
D.D. Mehta et al.
post-treatment.
Opioid: Multiple Active Stimulation Sessions
Shen et al. N = 20 A randomized, sham- 5 Active 100% 10 Hz Figure-8 Cue-induced NA NA Active rTMS caused a
[103] controlled, study with OR Coil Craving significant ↓ in craving scores
heroin-dependent male 5 Sham Active vs. after presentation of heroin-
participants Sessions Sham: related cues, compared to
Left DLPFC −3.12 [−4.43 sham.
– −1.82]
Liu N = 99 A randomized, double- 20 Active (1 Hz) 100% LF: 1 Hz Figure-8 Cue-induced NA NA Both of the active rTMS groups
et al. [104] blind, sham-controlled OR or Coil Craving had a significant ↓ in cue-induced
study with heroin- 20 Active HF: 10 Hz 1 Hz vs. No heroin craving compared to no
dependent male (10 Hz) Sessions Treatment: treatment.
participants OR −0.57 [−1.04 The effects were consistent 60
No Treatment – −0.09] days following treatment
Left DLPFC 10 Hz vs. No cessation.
Treatment:
−0.71 [−1.18
– −0.25]
Li N = 100 A retrospective, sham- 40 Active 100% 20 Hz Figure-8 Craving NA Depressive Active rTMS significantly ↓ in
et al. [105] controlled study with OR Coil Active vs. Symptoms morphine craving and
morphine-dependent 40 Sham Sham: NA improved depressive
participants receiving Sessions with −1.79 [−2.25 symptoms, compared to
concurrent occupational concurrent OT – −1.32] baseline and sham.
therapy (OT) Left DLPFC

D.D. Mehta et al.
659
effect on heroin craving or heroin

consumption, compared to sham.
DSM-IV or DSM-5); Intervention (I): Intervention employing either rTMS,
Active rTMS had no significant
symptoms was observed post-

tDCS, or DBS; Comparison (C): Studies including either sham stimulation, a
control group receiving no intervention or an active control arm were
improvement in depressive
included. DBS studies were exempted considering the ethical constraints
However, a significant
on the use of control groups with invasive brain surgery/stimulation;
Outcomes (O): Studies investigating substance-related outcomes (con-
sumption, craving, cue-induced craving, abstinence, relapse) as primary or
secondary outcomes of interest using a validated measurement tool (e.g.
treatment.
Obsessive Compulsive Drinking Scale [OCDS]); Study Design (S): Studies
Results
employing either a parallel (between-subject) or cross-over (within-subject)

randomized controlled trial (RCT). For DBS, case series (N ≥ 2) were
permitted.
Bold values have been used to highlight the outcome of interest and the brain region targeted, to improve clarity. Substance use disorder investigated is also shown in bold. Studies were excluded if: (1) recruited participants without a SUD and/or
a standardized criteria for diagnosis (e.g., “heavy drinkers”); (2) lacked a
(Hedge’s g)
Outcome(s)
Depressive
Symptoms
Effect Size
well-defined control group (rTMS and tDCS studies); (3) literature review,
[95% CI]
meta-analysis, dissertation, abstract, conference presentation or case

Other
report.
NA
Study selection
Consumption
Consumption
Two authors (D.M. and A.P.) independently screened titles and abstracts
(Hedge’s g)
Effect Size
obtained on Covidence to determine eligibility for full-text review, and

[95% CI]
subsequently reviewed the full text of the screened studies. Disagreements

were resolved by consensus, and review with the senior author (T.P.G.).
NA
Data extraction and risk of bias

(Hedge’s g)
For included studies, two authors (D.M. and A.P.) extracted author
Effect Size
[0.27–2.19]
Active vs.
[95% CI]
information, sample size, study design, stimulation parameters, primary

Craving
Craving
Sham:
substance use outcomes (craving and consumption), and any secondary

1.23
outcomes. Effect sizes (Hedge’s g) of substance use and other outcomes

were calculated for each study using post-treatment data of active and
control (sham and/or no treatment) groups, respectively (see Tables 1–4).
Coil Type
Due to the heterogeneity in follow-up periods across studies, treatment

Figure-8
effects were determined using end-of-treatment data, unless otherwise

Coil
stated. For DBS studies with no control conditions, within-subject (pre-post

treatment) effect sizes were calculated.
The Cochrane Risk-of-Bias Tool (RoB-2) [51] assessed quality of included
RCTs. Studies with a high risk of bias were subsequently excluded if at least
Stimulation
Frequency
four domains were considered of moderate risk, or if two or more domains

were flagged as high risk. The Risk Of Bias In Non-randomized Studies of
15 Hz
Interventions (ROBINS-I) [52] tool assessed risk of bias in non-randomized

studies (DBS Studies); all extracted DBS studies were included in this
review.
Stimulation
Intensity
Meta-analysis
100%
To quantify NM effects, we performed meta-analyses on rTMS and tDCS

studies investigating alcohol and tobacco use disorders. Acute versus
repeated stimulation were independently evaluated. Meta-analyses were
# of Sessions &
conducted when three or more studies evaluated a synonymous outcome

Sessions with
(craving, cue-induced craving, and/or consumption).

Left DLPFC
concurrent
We utilized standardized mean difference (SMD; Hedge’s g) with 95%

11 Active
Targeted
11 Sham
Region
confidence intervals (CI’s) in each selected meta-analysis to calculate the

MMT
effect size of NM-related changes in alcohol and tobacco craving, cue-

OR
induced craving, and/or consumption (p ≤ 0.05, two-tailed). Random-

effects models pooled individual SMDs, and used data from studies that
reported end-of-treatment substance use data from active and control
concurrent methadone
A randomized, double-
blind, sham-controlled
participants, receiving
maintenance therapy
treatment arms. Negative values indicated that active stimulation

study with heroin-
produced greater reductions in craving, cue-induced craving, and/or

dependent male
consumption compared to sham treatment. The I2 statistic estimated

Study Design
between-trial heterogeneity; I2 of ≤40% was considered low heterogeneity,

40–60% moderate heterogeneity, and >60% high heterogeneity [53].
(MMT)
Meta-analyses were performed using R version 4.3.1 [54] with package

metafor [55].
Sample
N = 20
RESULTS
Size
We identified a total of 94 studies that met our inclusion criteria,

continued
with a total of 4306 participants.
Repetitive transcranial magnetic stimulation (rTMS)

et al. [102]
Fifty-one studies investigating rTMS as treatment for SUDs were

Citation
Table 1.
identified, with 2406 participants receiving either active or control

Tsai
treatment (sham stimulation or no treatment; Table 1).

D.D. Mehta et al.
660
Alcohol. Sixteen studies [56–71] investigated the effects of rTMS smoking cues reduced cigarette consumption and cue-induced
for alcohol use disorder (AUD). Eleven studies used multiple active craving, respectively.
sessions (10–20 sessions) with HF stimulation (10–20 Hz) targeting Meta-analyses were performed on acute and repeated rTMS for
right, left, or bilateral dorsolateral prefrontal cortex (DLPFC), TUD. Of four single-session rTMS studies, three reported cue-
medial prefrontal cortex (mPFC) or insula [61–71]. Findings were induced craving (n = 40) and were subsequently evaluated,
mixed, with seven studies [61, 63–65, 68, 71] demonstrating indicating no significant effect of a single active versus sham
significant post-TMS reductions in alcohol craving and/or con- stimulation session (SMD = −0.95, 95% CI: −2.30 to 0.41, p = 0.17,
sumption compared to sham stimulation. Notably, 3/7 positive I2 = 87.4%; Fig. 3A). Of twelve multi-session studies, six reported
studies applied deep TMS using various H-coils as opposed to the tobacco consumption (n = 342) and eight reported subjective
traditional Figure-8 coil, suggesting that this technology may be craving (n = 593). While repeated rTMS significantly reduced
particularly efficacious in treating AUD. Two studies employed the cigarette use (SMD = −1.65, 95% CI: −3.00 to −0.30, p = 0.01,
H-1 coil to target the mPFC and bilateral DLPFC, respectively, I2 = 95.1%; Fig. 3C), there was no significant effect of active versus
whilst one opted for the H-7 coil to target both the mPFC and sham stimulation on craving (SMD = −0.86, 95% CI: −1.80 to 0.08,
anterior cingulate cortex (ACC) concurrently. One study [71] p = 0.07, I2 = 94.8%; Fig. 3B).
applied a 10 session cTBS stimulation protocol to the mPFC, with
significant reductions in alcohol craving. Cannabis. Only two RCTs [87, 88] examined the use of rTMS for
Of these eleven studies, ten were combined in a meta-analysis to cannabis use disorder (CUD). Sahlem et al. [87] used a
determine the effects of repeated rTMS stimulation on alcohol randomized, sham-controlled, crossover design to investigate
craving (n = 447). Active rTMS significantly reduced craving scores in therapeutic effects of a single 10 Hz stimulation session applied
AUD compared to sham (SMD = −1.25, 95% CI: −2.34 to −0.15, to left DLPFC, finding no significant differences in cannabis
p = 0.02, I2 = 95.8%; Fig. 2B). Similarly, meta-analysis of five repeated craving compared to sham. Kozak-Bidzinski et al. [88] applied
rTMS trials (n = 184) demonstrated that multiple rTMS sessions 20 sessions of 20 Hz rTMS to bilateral DLPFC using a parallel
produced greater reductions in alcohol consumption than sham groups design in participants with CUD and schizophrenia. Non-
(SMD = −1.39, 95% CI: −2.37 to −0.41, p < 0.01, I2 = 86.2%; Fig. 2C). significant reductions in cannabis consumption were noted
Five studies [56–60] evaluated the effects of a single active post-TMS versus sham (60 versus 5%), and trends towards
(10–20 Hz) stimulation session and found no significant improve- reductions in urine toxicology (carboxy-tetrahydrocannabinol)
ments in alcohol craving or consumption post-TMS when compared and craving were observed.
to sham. Four studies [56–58, 60] targeted the right DLPFC, while one
[59] targeted the left frontal pole with cTBS. Accordingly, meta- Cocaine. Six studies [59, 89–93] investigated rTMS for cocaine
analysis of craving outcomes in these five trials (n = 149) revealed use disorder. Two studies demonstrated a significant decrease in
that acute active versus sham rTMS did not significantly decrease cocaine craving following multiple sessions of 15 Hz rTMS to the
craving (SMD = −0.16, 95% CI: −0.42 to 0.09, p = 0.21, I2 = 0%; left DLPFC. Martinez et al. [91] applied both 1 Hz and 10 Hz
Fig. 2A). stimulation to mPFC and ACC using the H-7 coil, finding no
significant effect on cocaine craving, though a reduction in
Tobacco. Sixteen studies [37, 72–86] examined efficacy of rTMS cocaine self-administration was present in the 10 Hz condition
for tobacco use disorder (TUD). All studies demonstrated versus 1 Hz rTMS and sham. Conversely, Bolloni et al. [89] found no
reductions in tobacco craving/cue-induced craving and/or cigar- significant effects of deep TMS on cocaine consumption when
ette consumption following active versus sham rTMS, with the targeting the PFC with H-1 coil, though there was a trend for
exception of Li et al. [72] and Kozak et al. [73]. While Li et al. decreased consumption between baseline and 6-months post-
applied a single 10 Hz stimulation session targeting the left DLPFC, TMS in the active group. Hanlon et al. [59] applied a single
Kozak et al. [73] tested multiple HF sessions (20 Hz) targeting the stimulation session, finding no treatment-related effects on
bilateral DLPFC in individuals with comorbid schizophrenia (SCZ). craving following cTBS to the left frontal pole.
However, Moeller et al. [85] applied deep-TMS to the PFC and
insula using the H-4 coil in nicotine-dependent SCZ patients and Methamphetamine. Eight studies [94–101] investigated the use
found that active stimulation increased the latency to smoke, of rTMS for methamphetamine (MA) use disorder. Seven studies
suggesting reduced motivation. Similarly, Ibrahim and colleagues [95–101] exhibited significant improvements in MA unconditioned
[86] applied multiple sessions of active versus sham deep TMS to and cue-induced craving and/or consumption following multiple
insular cortex in smokers receiving concurrent varenicline treat- active rTMS sessions (5–20) targeting the left DLPFC or left PFC
ment, and found significant rTMS-related effects in smoking (1–10 Hz), compared to sham treatment. Interestingly, Li et al. [94]
abstinence at Week 12. found that a single 1 Hz stimulation session applied to the left
Dinur-Klein et al. [84] and Zangen et al. [37] also applied deep- DLPFC increased cue-induced MA craving compared to sham.
TMS to the lateral PFC and insula using the H-ADD and H-4 coils Notably, three studies [98–100] adopted iTBS and/or cTBS
respectively, and found significant reductions in tobacco con- stimulation parameters and reported positive results consistent
sumption and craving [37, 84]. Importantly, Dinur-Klein et al. [84] with standard rTMS.
applied both 1 Hz (LF) and 10 Hz (HF) stimulation to the lateral
prefrontal cortex (PFC) and insula, finding that cigarette con- Opioids. Four studies [102–105] evaluated outcomes in opioid
sumption decreased significantly only in the 10 Hz condition. use disorder (OUD) patients following multiple HF rTMS sessions
These studies were amongst the largest studies of NM for SUDs, (5–40) targeting the left DLPFC. Three studies [103–105] reported
with sample sizes of 115 and 262 respectively. The study by significant improvements in opioid craving and/or cue-induced
Zangen et al. [37] is the only multisite clinical trial in the addiction craving, with the exception of Tsai et al. [102] who evaluated
NM field, and led to FDA clearance of the H-4 coil for smoking treatment effects in participants receiving concurrent methadone
cessation. maintenance therapy. Although there was no significant impact
Notably, while Trojak et al. [81] reported positive results, on opioid craving or consumption, an improvement in depressive
findings were not maintained at follow-up (12 weeks), signifying a symptoms was present post-treatment. Li et al. [105] also
lack of durability in long-term outcomes, though this was the only observed improvements in depressive symptoms, in conjunction
study to apply LF stimulation (1 Hz) exclusively. with reduced opioid craving, though their participants received
Additionally, two studies [77, 84] investigated cue-induced concurrent occupational therapy. Liu et al. [104] applied both 1 Hz
provocation prior to stimulation, and found that presentation of and 10 Hz stimulation to the left DLPFC, finding that both

D.D. Mehta et al.
661
Fig. 2 Meta-analyses of AUD studies using rTMS. Forest plots of studies evaluating (A) alcohol craving following a single-session of rTMS (B)
alcohol craving following multi-session rTMS (C) alcohol consumption following multi-session rTMS.
conditions produced similar reductions in cue-induced opioid Alcohol. Fourteen studies [106–119] examined the effects of
craving compared to no treatment. tDCS for AUD. Nine [106, 108–110, 113, 114, 116, 117, 119] demon-
strated positive effects on alcohol craving and/or consumption
Transcranial direct current stimulation (tDCS) following right or left anodal tDCS to DLPFC. While single
Thirty-six studies investigating tDCS as treatment for SUDs, with stimulation sessions of right anodal and left anodal tDCS to the
1582 participants receiving either active or control treatment DLPFC demonstrated comparable effects, multi-session studies
(sham stimulation or no treatment; Table 2). showed that right anodal DLPFC stimulation was consistently

D.D. Mehta et al.
662
Fig. 3 Meta-analyses of TUD studies using rTMS. Forest plots of studies evaluating (A) tobacco cue-induced craving following a single-
session of rTMS (B) tobacco craving following multi-session rTMS (C) tobacco consumption following multi-session rTMS.
effective [113, 114, 119] but left anodal DLPFC stimulation was While nine studies reported positive effects on alcohol use
inconsistent [108, 110–112]. Variations of stimulation intensity outcomes following active tDCS, meta-analyses of craving and
(1–2 mA) and duration (10–30 min) were explored, though these consumption outcomes in single- and multi-session studies did not
differences did not produce consistent outcomes. reveal significant SMDs for active versus sham stimulation. Analysis

Table 2. Transcranial Direct Current Stimulation (tDCS) [Total N = 1582; Total Studies = 36].
Author Sample Study Design # of Sessions & Active Craving Consumption Other Results
Size Targeted Region Stimulation Effect Size Effect Size Outcome(s)
Intensity & (Hedge’s g) (Hedge’s g) Effect Size
Duration [95% CI] [95% CI] (Hedge’s g)
[95% CI]
Alcohol: Single Active Stimulation Session
Boggio N = 13 A randomized, sham-controlled, 1 Session of An+ 2 mA for Craving NA NA Both An+ right and An+ left tDCS
et al. [106] crossover study with alcohol- Right, Ca- Left 20 min An+ Right vs. significantly ↓ alcohol craving,
dependent participants. DLPFC Sham: compared to sham and baseline.
AND −1.96 These results were maintained when
1 Session of An+ [−2.83 – −0.98] presented with alcohol cues.
Left, Ca- Right An+ Left vs.
DLPFC Sham:
AND −1.05
1 Session of Sham [−1.83 – −0.20]

Nakamura- N = 49 A randomized, sham-controlled, 1 Session of An+ 1 mA for Craving NA P3 ERPs indicated an ↑ in P3 amplitude to
Palacios crossover study with alcohol- Left DLPFC, Ca- 10 min Active vs. Amplitude alcohol related sounds in the active
et al. [115] dependent participants. CSDA Sham: NA tDCS group compared to sham.
OR −0.16 No significant effect of treatment on
1 Sham Session [−1.29–0.98] alcohol craving was observed.
den Uyl N = 41 A randomized, sham-controlled 1 Session of An+ 1 mA for Craving NA Response Active tDCS over the left DLPFC
et al. [109] study with alcohol-dependent Left DLPFC, Ca- 10 min DLPFC vs. Bias significantly ↓ alcohol craving,
participants. CSOA Sham: NA compared to sham and IFG
OR −0.15 stimulation.
l Session of An+ [−0.92–0.62] No significant effect of tDCS on
IFG (F7xCz), Ca-- IFG vs. Sham: response bias was observed.
IFG (FzxT3) 0.19
OR [−0.57–0.95]
1 Sham Session
Wietschorke N = 30 A randomized, double-blind, 1 Session of An+ 1 mA for Craving NA Alcohol Cue Active tDCS significantly ↓ alcohol cue
et al. [117] sham-controlled study with Right, Ca- Left 20 min Active vs. Reactivity reactivity and alcohol craving,
alcohol-dependent participants. DLPFC Sham: NA compared to sham.
OR −0.55
1 Sham Session [−1.26–0.20]
D.D. Mehta et al.
Vanderhasselt N = 45 A randomized, double-blind, 1 Session of An+ 2 mA for NA Consumption Reward- Active tDCS significantly ↓ reward-
et al. [116] sham-controlled study with Right, Ca- Left 20 min NA triggered triggered approach bias and alcohol
alcohol-dependent participants. DLPFC Approach consumption, compared to sham.
AND Bias
1 Sham Session NA
Alcohol: Multiple Active Stimulation Sessions
da Silva N = 13 A randomized, sham-controlled 5 Sessions of An+ 2 mA for Craving NA Relapse A significant ↑ in relapse rates was
et al. [108] study with alcohol-dependent Left, Ca- Right 20 min Active vs. NA observed following active tDCS
male participants. DLPFC Sham: (66.7%) compared to sham (14.3%).
OR −1.87 However, active tDCS significantly ↓
5 Sessions of [−3.17 – −0.56] alcohol craving.
Sham
Klauss N = 33 A randomized, sham-controlled 5 Sessions An+ 2 mA for Craving NA Relapse A significant ↓ in relapse rates was
et al. [113] study with alcohol dependent Right, Ca- Left 13 min Active vs. NA observed 6-months following active
participants. DLPFC Sham: tDCS (50%) compared to sham
OR −0.16 (88.2%).
5 Sessions of [−0.84–0.53] No significant effect on alcohol
Sham craving was observed.
den Uyl N = 78 A randomized, double-blind, 3 Sessions An+ 1 mA for Cue-induced NA A significant ↓ in cue-induced alcohol
et al. [110] sham-controlled, 2-by-2 factorial Left DLPFC, Ca- 15 min Craving craving, but not overall craving, was
663
664
Table 2. continued
[95% CI]
design study with alcohol CSOA with active Active vs. Approach observed in the active tDCS groups
dependent participants receiving CBM (A) Sham: Bias compared to sham.
concurrent cognitive bias OR 0 [−0.44–0.44] NA There were no enhancement effects
modification (CBM). 3 Sessions An+ of tDCS on CBM.
Left DLPFC, Ca-
CSOA with control
CBM (B)
OR
3 Sessions of Sham
with active CBM (C)
OR
3 Sessions of Sham
with control CBM
(D)
den Uyl N = 91 A randomized, double-blind, 4 Sessions An+ 2 mA for Craving NA Abstinence Active tDCS had no significant effect
et al. [111] sham-controlled study with Left DLPFC, Ca- 20 min Active/CBM+ Active/CBM on abstinence duration at 3- or
alcohol-dependent participants CSOA with active vs. Sham: 1.18 + vs. Sham: 6-months post-treatment. Alcohol
receiving concurrent CBM. CBM [0.63–1.73] 0.26 craving ↓ overtime in all conditions.
OR Active/CBM- vs. [−0.25–0.77] There were no enhancement effects
4 Sessions An+ Sham: −0.30 Active/CBM- of tDCS on CBM.
Left DLPFC, Ca- [−0.80–0.21] vs. Sham:
CSOA without 0.24
D.D. Mehta et al.
CBM [−0.27–0.74]
OR
4 Sessions of
Sham with active
CBM
den Uyl N = 83 A randomized, double-blind, 4 Sessions An+ 2 mA for Craving NA Attentional Active tDCS had no significant effect
et al. [112] sham-controlled, 2-by-2 factorial Left, Ca- Right 20 min A vs. C: Bias on attentional bias, alcohol craving, or
design study with alcohol DLPFC with active −0.49 NA relapse.
dependent participants receiving ABM (A) [−1.11–0.13] There was no evidence of a beneficial
concurrent attentional bias OR B vs. D: effect of active tDCS, ABM, or the
modification (ABM). 4 Sessions An+ −0.74 combination.
Left, Ca- Right [−1.36 – −0.11]
DLPFC with
control ABM (B)
OR
4 Sessions of
Sham with active
ABM (C)
OR
4 Sessions of
Sham with control
ABM (D)
Klauss N = 49 A randomized, double-blind, 10 Sessions of An 2 mA for Craving NA Relapse A ↓ in alcohol craving was observed
et al. [114] sham-controlled study with + Right, Ca- Left 20 min Active vs. NA following active tDCS and sham.
alcohol-dependent participants. DLPFC Sham: However, the change in craving was
OR −0.58 significant only in the active tDCS
10 Sessions of [−1.17–0.02] group.
Sham Active tDCS significantly ↓ relapse
rates at 3-months post-treatment.

Table 2. continued
[95% CI]
Claus N = 79 A randomized, double-blind, 4 Sessions An+ 2 mA for NA Consumption Approach There was no significant effect of
et al. [107] sham-controlled, 2-by-2 factorial Right IFG, Ca- 20 min A vs. C: Bias active tDCS, CBM, or CBM-tDCS
design study with alcohol Contralateral −0.25 NA interaction on alcohol approach bias.
dependent participants receiving Upper Arm with [−0.89–0.39] While active tDCS displayed a trend
concurrent CBM. active CBM (A) B vs. D: towards a reduction in alcohol
OR 0.22 consumption, the difference was not
4 Sessions An+ [−0.40–0.84] significant.
Right IFG, Ca-
Contralateral
Upper Arm with
control CBM (B)

OR
4 Sessions of
Sham with active
CBM (C)
OR
4 Sessions of
Sham with control
CBM (D)
Witkiewitz N = 84 A randomized, double-blind, 8 Sessions of An+ 2 mA for Craving Consumption NA There was no significant difference in
et al. [118] sham-controlled study with Right IFG, Ca- Left 30 min Active vs. Active vs. post-treatment alcohol consumption
alcohol-dependent participants Upper Arm Sham: Sham: and craving between active and sham
receiving concurrent with active MBRP 0.07 −0.14 tDCS.
mindfulness-based relapse OR [−0.36–0.50] [−0.57–0.29]
prevention (MBRP). 8 Sessions of
Sham with active
MBRP
Dubuson N = 125 A randomized, double-blind, 5 Session of An+ 2 mA for Craving NA Abstinence Active tDCS (A, B) significantly ↑
et al. [119] sham-controlled, 2-by-2 factorial Right, Ca- Left 20 min A vs. C: NA abstinence rates at 2-week follow up
design study with alcohol DLPFC with active 0.48 compared to sham (C, D),
dependent participants receiving ICT (A) [−0.09–1.04] independent of ICT. Active tDCS with
D.D. Mehta et al.
concurrent inhibitory control OR B vs. D: concurrent ICT (A) produced the

training (ICT). 5 Session of An+ 0.12 highest abstinence rates.
Right, Ca- Left [−0.43–0.67] No treatment effects on craving were
DLPFC with observed.
control ICT (B)
OR
5 Sessions of
Sham with active
ICT (C)
OR
5 Sessions of
Sham with control
ICT (D)
665
666
Table 2. continued
[95% CI]
Tobacco: Single Active Stimulation Session
Fregni N = 24 A randomized, double-blind, 1 Session of An+ 2 mA for Craving NA NA Active tDCS of both the right and left
et al. [125] sham-controlled crossover study Right, Ca- Left 20 min An+ Right vs. DLPFC significantly ↓ tobacco craving
with tobacco-dependent DLPFC Sham: compared to sham.
participants. AND −0.47
1 Session of An+ [−1.04–0.10]
Left, Ca- Right An+ Left vs.
DLPFC Sham:
AND −0.38
1 Session of Sham [−0.95–0.19]
Xu N = 24 A single-blind, counterbalanced, 1 Session of An+ 2 mA for Craving NA Negative Compared to sham, active tDCS
et al. [120] sham-controlled study with Left DLPFC, Ca- 20 min Active vs. Affect significantly ↓ negative affect, which is
tobacco-dependent participants. CSOA Sham: NA positively correlated with
AND 0.05 dependence level, but had no effect
1 Session of Sham [−0.52–0.61] on tobacco craving.
Meng N = 27 A randomized, counterbalanced, 1 Session of An+ 1 mA for NA Consumption Attention A significant ↓ in cigarette
et al. [121] sham-controlled study with Left, Ca- Right FPT 20 min Single Cathodal Bias consumption was observed following
tobacco-dependent participants OR vs. Sham: NA double cathodal tDCS, compared to
1 Session of −0.16 sham and single cathodal tDCS.
Double An+ [−1.08–0.77] Attention bias showed a declining
D.D. Mehta et al.
Bilateral Occipital Double trend after bilateral cathodal tDCS,

Lobe, Double Ca- Cathodal vs. but the results were not significantly
Bilateral FPT Sham: different from sham.
OR −2.24
1 Session of Sham [−3.42 – −1.07]
Kroczek N = 25 A randomized, double-blind, 1 Session of An+ 2 mA for Cue-induced NA Functional There was no significant difference in
et al. [122] sham-controlled study with Left DLPFC, Ca- 15 min Craving Connectivity cue-induced tobacco craving
tobacco-dependent participants. OFC Active vs. NA between active and sham tDCS.
OR Sham: Active tDCS significantly ↑ functional
1 Session of Sham 0.54 connectivity between DLPFC and
[−0.26–1.34] OFC, compared to sham.
Falcone N = 25 A randomized, double blind, 1 Session of An+ 1 mA for NA Consumption None Active tDCS significantly ↑ latency to
et al. [123] within-subject, counterbalanced, Left DLPFC, Ca- 20 min During Session smoke and ↓ cigarette consumption
sham-controlled smoking-lapse Right SOA Active vs. during the ad libitum smoking
study with tobacco-dependent AND Sham: session, compared to sham.
participants 1 Session of Sham −0.19
[−0.74–0.37]
Yang N = 32 A single-blind, within-subject, 1 Session of An+ 1 mA for Cue-induced NA Functional Active tDCS significantly ↓ tobacco
et al. [124] sham-controlled study with Right, Ca- Left 30 min Craving Connectivity craving compared to sham, which
tobacco-dependent male DLPFC Active vs. NA correlated with DLPFC-
participants. AND Sham: parahippocampal gyrus (PHG)
1 Session of Sham −0.22 coupling.
[−0.71–0.28]

Table 2. continued
[95% CI]
Tobacco: Multiple Active Stimulation Sessions
Boggio N = 27 A randomized, sham-controlled 5 Sessions of An+ 2 mA for Subjective Consumption NA A significant ↓ in subjective tobacco
et al. [126] study with tobacco-dependent Right, Ca- Left 20 mins Craving NA craving, cue-induced tobacco craving,
participants. DLPFC Active vs. and cigarette consumption was
OR Sham: observed following active tDCS
5 Sessions of −0.85 [−1.64 – compared to sham.
Sham −0.06]
Cue-induced
Craving
Active vs.

Sham:
−1.09
[−1.90 – −0.28]
Fecteau N = 12 A randomized, blinded, sham- 5 Sessions of An+ 2 mA for NA Consumption: Risk Taking Active tDCS significantly ↓ cigarette
et al. [127] controlled, crossover study with Right, Ca- Left 30 min Active vs. NA consumption compared to sham, up
tobacco-dependent participants. DLPFC Sham: to four days after the end of the
AND −1.83 stimulation regiment.
5 Sessions of [−3.18 – −0.48] No differences in risk taking behavior
Sham were observed between treatment
conditions.
Smith N = 37 A randomized, double-blind, 5 Sessions of An+ 2 mA for Craving Consumption: Cognition Active tDCS significantly ↑ cognitive
et al. [128] sham-controlled study with Left DLPFC, Ca- 20 min Active vs. Active vs. Active vs. performance, compared to sham.
tobacco-dependent participants CSOA Sham: Sham: Sham: There was no significant effect of
with comorbid SCZ OR 0.25 0.13 0.15 active tDCS on tobacco craving or
5 Sessions of [−0.45–0.93] [−0.56–0.81] [−0.54–0.83] consumption.
Sham
Ghorbani N = 170 A randomized, sham-controlled Bupropion for 8 2 mA for NA NA Abstinence Longer duration tDCS (D) resulted in
Behnam et al. study with tobacco-dependent weeks (A) 20 min NA the highest abstinence rate at 6
[129] male participants. OR Dependence months (25.7%) and was significantly
D.D. Mehta et al.
20 Sessions (over 4 NA more effective than the shorter

weeks) of An+ duration tDCS (B) and both sham
Right, Ca- Left protocols (C, E).
DLPFC (B) Longer duration tDCS (D) significantly
OR ↓ nicotine dependence compared to
20 Sessions of pharmacotherapy alone (A).
Sham (over 4
weeks) (C)
OR
20 Sessions (over
12 weeks) of An+
Right, Ca- Left
DLPFC (D)
OR
20 Sessions of
Sham (over 12
weeks) (E)
667
668
Table 2. continued
[95% CI]
Müller N = 45 A randomized, sham-controlled 5 Sessions of An+ 2 mA for Craving Consumption NA There were no significant differences
et al. [130] study with tobacco-dependent Left, Ca- Right 20 min Active vs. Active vs. in cigarette craving and consumption
participants DLPFC Sham: Sham: between active and sham tDCS
OR −0.90 [−1.52 – −0.15 groups.
5 Sessions of −0.27] [−0.74–0.45]
Sham
Cocaine: Multiple Active Stimulation Sessions
Batista N = 36 A randomized, double-blind, 5 Sessions of An+ 2 mA for Craving NA NA Significant ↓ in craving for crack-
et al. [131] sham-controlled study with Right, Ca- Left 20 min Active vs. cocaine in active tCDS group
cocaine-dependent male DLPFC Sham: compared to baseline and sham.
participants. OR −0.29
5 Sessions of [−0.95–0.37]
Sham
Verveer N = 41 A randomized, sham-controlled 10 Sessions of An 2 mA for Craving NA Relapse No significant effect of active tDCS on
et al. [132] study with cocaine-dependent + Right, Ca-- Left 13 min Active vs. NA relapse rates or cocaine craving
participants. DLPFC Sham: compared to sham.
OR −0.13 Exploratory analysis indicated a
10 Sessions of [−0.73–0.46] significant ↓ in relapse rates after
Sham active tDCS compared to sham in
individuals using crack cocaine only.
D.D. Mehta et al.
Gaudreault N = 17 A randomized, double-blind, 15 Sessions of An 2 mA for Craving NA Sleepiness No significant difference in cocaine
et al. [133] sham-controlled study with + Right, Ca-- Left 20 min Active vs. Active vs. craving was present between
cocaine-dependent participants. DLPFC Sham: Sham: treatment groups, though a
OR −0.14 −1.53 decreasing trend in craving was more
15 Sessions of [−1.20–0.92] prominent in the active tDCS group.
Sham Active tDCS significantly improved
daytime sleepiness compared to
sham.
Methamphetamine: Single Active Stimulation Session
Shahbabaie N = 30 A randomized, double-blind, 1 Session of An+ 2 mA for Subjective NA NA Active tDCS significantly ↓ self-
et al. [134] sham-controlled, crossover study Right DLPFC, Ca- 20 min Craving reported craving at rest but ↑
with methamphetamine- CSOA Active vs. methamphetamine craving during
dependent male participants AND Sham: cue-exposure, compared to sham.
1 Session of Sham −0.57 [−1.08 –
−0.05]
Cue-induced
Craving
Active vs.
Sham:
1.12 [0.58–1.67]
Shahbabaie N = 15 A, randomized, double-blind, 1 Session of An+ 2 mA for Craving NA Resting Active tDCS significantly ↓
et al. [135] sham-controlled, crossover study Right, Ca- Left 20 min Active vs. State methamphetamine craving compared
with methamphetamine- DLPFC Sham: Network to sham.
dependent male participants AND −0.85 Activity Active tDCS significantly modulated
1 Session of Sham [−1.60 – −0.26] NA default mode network (DMN),
executive control network (ECN), and
salience network (SN).

Table 2. continued
[95% CI]
Methamphetamine: Multiple Active Stimulation Sessions
Rohani Anaraki N = 36 A randomized, double-blind, 5 Sessions of An+ 2 mA for Subjective NA NA Active tDCS significantly ↓ cue-
et al. [136] sham-controlled study with Right, Ca- Left 20 min Craving induced methamphetamine craving,
methamphetamine- dependent DLPFC Active vs. but not self-reported instant craving,
male participants OR Sham: compared to sham.
5 Sessions of −0.12
Sham [−0.83–0.60]
Cue-induced
Craving
NA

Alizadehgoradel N = 39 A randomized, double-blind, 10 Sessions of An 2 mA for Craving NA Executive Active tDCS significantly ↓
et al. [137] sham-controlled study with + Right, Ca- Left 20 min Active vs. Function methamphetamine craving and
methamphetamine- dependent DLPFC Sham: NA improved cognitive executive control
male participants OR −0.92 functions involved in addictive
10 Sessions of [−1.59 – −0.26] behavior, compared to sham.
Sham
Xu N = 75 A randomized, double-blind, 20 Sessions of An 1.5 mA for Cue-induced NA Cognitive Active tDCS with concurrent CCAT
et al. [138] sham-controlled study with + Right, Ca- Left 20 min Craving Function significantly ↓ cue-induced
methamphetamine- dependent DLPFC with Active vs. NA methamphetamine craving compared
female participants computerized Sham: to sham + CCAT and treatment as
cognitive −0.65 usual.
addiction therapy [−1.22 – −0.08] No significant improvement in
(CCAT) (A) attention bias, verbal learning and
OR memory, impulse control, and social
20 Sessions of cognition was observed.
Sham with CCAT
(B)
OR
No Treatment (C)
D.D. Mehta et al.
Opioid: Single Active Stimulation Session

Wang N = 20 A randomized, single-blind, 1 Session of 1.5 mA for Cue-induced NA None Active tDCS significantly ↓ cue-
et al. [141] sham-controlled study with Bilateral Ca- FPT, 20 min Craving induced craving of heroin, compared
heroin-dependent male An+ OL Active vs. to sham and baseline.
participants OR Sham:
1 Session of Sham −2.74
[−3.96 – −1.52]
Opioid: Multiple Active Stimulation Sessions
Taremian N = 60 A randomized, sham-controlled 10 Sessions of An 2 mA for Craving NA Depressive Active tDCS with concurrent MMT
et al. [140] study with opioid-dependent + Right, Ca- Left 20 min Active vs. Symptoms significantly ↓ opium craving, and
participants receiving concurrent DLPFC with MMT Sham: Active vs. depressive symptoms compared to
methadone maintenance OR −1.13 Sham: sham+MMT and MMT alone.
treatment (MMT) 10 Sessions of [−1.80 – −0.46] −0.65
Sham [−1.27–0.00]
with MMT
OR
only MMT
669
D.D. Mehta et al.
670
of subjective craving from four single-session trials (n = 187) were
Though lower expression levels were
tDCS group compared to sham, the
Both active tDCS groups and sham

non-significant (SMD = −0.60, 95% CI: −1.22 to 0.01, p = 0.06,
greater effect. Active right anodal

present in the active right anodal
significantly ↓ in opium craving,

I2 = 69.0%; Fig. 4A), as were sub-group analyses of craving (n = 777,
though active tDCS exhibited a
tDCS significantly ↓ impulsivity

difference was not statistically
SMD = −0.14, 95% CI: −0.57 to 0.28, p = 0.51, I2 = 80.6%; Fig. 4B)
and consumption (n = 242, SMD = −0.08, 95% CI: −0.39 to 0.23,
p = 0.62, I2 = 0%; Fig. 4C) from eight multi-session trials.
compared to sham.
Tobacco. Eleven studies [120–130] were conducted on tDCS in
TUD. All studies applied 2.0 mA stimulation for 15–30 min, except
significant.
for Falcone et al. [123] and Meng et al. [121] both of whom applied
Results
1.0 mA stimulation for 20 min. Seven studies, including Falcone
Bold values have been used to highlight the outcome of interest and the brain region targeted, to improve clarity. Substance use disorder investigated is also shown in bold.
et al. and Meng et al. reported positive effects on tobacco craving
and/or cigarette consumption [121, 123–127, 129], with right
anodal DLPFC stimulation being most effective, particularly with
An+ Left vs.
An+ Left vs.

[−1.13–0.63]
[−1.60–0.17]
[−1.23–0.54]
[−1.65–0.13]
multi-session protocols [125–129]. Notably, Ghorbani-Behnam
(Hedge’s g)
Outcome(s)
Expression
Effect Size
An+ Right
An+ Right
Cytokines
vs. Sham:
vs. Sham:
Levels of
[95% CI]
TNF-ɑ et al. [129] compared extended tDCS treatment (20 sessions over
Sham:
Sham:
Other
−0.26
−0.75
−0.36
−0.79
12 weeks) with a shorter treatment duration (20 sessions over
IL-6
4 weeks), with 8 weeks of bupropion and sham stimulation.

Results showed that longer durations of tDCS resulted in the
highest abstinence rate at 6 months post-treatment (25.7%).
Consumption
While seven studies reported independent improvements in

(Hedge’s g)
Effect Size
tobacco-related outcomes, meta-analysis did not reflect similar

[95% CI]
effects. From four single-session studies, sub-group analyses of

craving (n = 72, SMD = −0.27, 95% CI: −0.60 to 0.06, p = 0.11,
NA
I2 = 0%; Fig. 5A) and consumption (n = 79, SMD = −0.79, 95% CI:
−2.07 to 0.49, p = 0.22, I2 = 84.7%; Fig. 5B) did not produce
−2.13 [−3.23 –
−1.39 [−2.34 –
significant effects with active versus sham stimulation. Similarly, in

An+ Right vs.
four multi-session trials, subgroup analyses of craving (n = 101,

An+ Left vs.
(Hedge’s g)
Effect Size
SMD = −0.50, 95% CI: −1.24 to 0.24, p = 0.19, I2 = 70.5%; Fig. 5C)
[95% CI]
Craving
Craving
−1.04]
−0.43]
and consumption (n = 86, SMD = −0.47, 95% CI: −1.49 to 0.56,

Sham:
Sham:
p = 0.37, I2 = 79.2%; Fig. 5D) were non-significant.
Cocaine. Three studies [131–133] examined tDCS on cocaine

Stimulation
Intensity &
craving using right anodal DLPFC stimulation, reporting conflict-

Duration
2 mA for
ing results. While Batista et al. [131]. observed a reduction in

20 min
Active
cocaine craving after 5 sessions of 2 mA/20 min tDCS, Verveer

et al. [132]. and Gaudreault et al. [133]. found no significant effects
on craving following 10 active 2 mA/13 min or 15 active 2 mA/
20 min sessions, respectively.
10 Sessions of An
10 Sessions of An
Targeted Region
+ Left, Ca- Right
+ Right, Ca- Left

# of Sessions &
10 Sessions of
Methamphetamine. Five studies [134–138] investigated the

DLPFC (A)
DLPFC (B)
effects of tDCS on MA use disorder, all of which reported a

significant reduction in MA unconditioned or cue-induced craving
Sham
OR
OR
compared to sham following right anodal DLPFC tDCS. Four

studies [134–137] applied 2.0 mA stimulation for 20 min, whereas
Xu et al. [138] combined 1.5 mA tDCS with computerized cognitive
addiction therapy (CCAT). While both studies by Shahbabaie et al.
A randomized, double-blind,
[134, 135] examined effects of a single stimulation session, the

sham-controlled study with
remaining three studies [136–138] opted for a multi-session

opioid-dependent male
protocol (5–20 sessions). Notably, 4/5 [134–137] of these studies

evaluated males only, while the remaining study examined only
female participants [138].
Study Design
participants.
Opioids. Three studies [139–141] were conducted on tDCS

treatment efficacy for OUD. Two studies [139, 140] applied ten
sessions of 2.0 mA tDCS to the DLPFC for 20 min. Taremian et al.
[140] evaluated opioid craving and depressive symptoms in
participants receiving methadone, and compared right anodal
Sample
DLPFC stimulation with sham. Active tDCS significantly reduced

N = 31
Size
opioid craving and depressive symptoms, compared to sham, and

methadone alone. Eskandari et al. [139] compared left anodal
continued
DLPFC stimulation with right anodal DLPFC stimulation and sham,

observing a significant reduction in craving in all groups; active
groups exhibited greater effects. Wang et al. [141] applied a single
et al. [139]
Eskandari
stimulation session targeting the fronto-parietal-temporal area at

Author
Table 2.
1.5 mA for 20 min. Despite these differences, a significant decline

in heroin craving was observed, which persisted with the
presentation of opioid-related cues.

D.D. Mehta et al.
671
Fig. 4 Meta-analyses of AUD studies using tDCS. Forest plots of studies evaluating (A) alcohol craving following a single-session of tDCS (B)
alcohol craving following multi-session tDCS (C) alcohol consumption following multi-session tDCS.
Deep brain stimulation (DBS) Alcohol. Four studies [142–145] investigated effects of DBS
Seven studies investigated DBS as SUD treatment, with 48 on AUD by targeting the NAc. All studies observed significant
participants receiving active or sham stimulation (Table 3). decreases in alcohol consumption and/or craving post-treatment.

D.D. Mehta et al.
672
Fig. 5 Meta-analyses of TUD studies using tDCS. Forest plots of studies evaluating (A) tobacco craving following a single-session of tDCS (B)
tobacco consumption following a single-session of tDCS (C) tobacco craving following multi-session tDCS (D) tobacco consumption following
multi-session tDCS.

Table 3. Deep Brain Stimulation (DBS) [Total N = 48; Total Studies = 7].
Author Sample Study Design Targeted # of Craving, Consumption, Secondary Results
Region Treatments and/or Abstinence Outcome(s)
Effect Size (Hedge’s g) Effect Size
[95% CI] (Hedge’s g) [95%
CI]
Alcohol: Continuous Active Stimulation
Voges et al. N=5 Case reports of alcohol-dependent NAc Continuous Craving None A significant ↓ in alcohol craving was
[142] male participants. Post vs. Pre: observed in all participants. 2/5 patients
−3.96 [−6.71 – −1.21] remained completely abstinent for > 4
Abstinence years.
NA
Muller et al. N=5 Case reports of alcohol-dependent NAc Continuous Craving None All participants reported a persistent
[143] male participants. Post vs. Pre: disappearance of alcohol craving. 2/5
−2.11 [−3.66 – −0.57] participants remained abstinent post-

Abstinence treatment, and the remaining 3 showed a
NA marked reduction of alcohol
consumption.
Davidson et al. N=6 A phase 1 pilot study with alcohol- NAc Continuous Consumption Molecular & DBS led to a significant ↓ in alcohol
[144] dependent female participants. Post vs. Pre: Functional consumption 1-year post-treatment in all
−2.01 [−3.40 – −0.62] Imaging participants, as well as a ↓ in alcohol-
NA related compulsivity.
Clinical improvements were correlated
with a reduction in NAc metabolism and
disrupted functional connectivity
between the NAc and visual association
cortex.
Bach et al. N = 12 A double-blind, randomized, sham- NAc Continuous Craving None While there was no difference in
[145] controlled multi-center study with Post vs. Pre: continuous abstinence between
treatment-resistant alcohol- −1.36 [−2.62 – −0.11] treatment groups at 6-months, active DBS
dependent participants. Active vs. Sham: led to a significantly higher proportion of
−0.61 [−1.77–0.55] abstinent days over the 6-month period
Abstinent Days and lower craving scores, compared to
Post vs. Pre: sham.
1.12 [−0.10–2.33]
D.D. Mehta et al.
Active vs. Sham:

0.93 [−0.26–2.12]
Tobacco: Continuous Active Stimulation
Kuhn et al. N = 10 A retrospective, self-report, NAc Continuous Dependence None 3/10 participants quit smoking post-
[146] longitudinal study with tobacco- Post vs. Pre: treatment.
dependent participants −0.40 [−1.28–0.49]
Opioid: Continuous Active Stimulation
Kuhn et al. N=2 Case reports of heroin-dependent NAc Continuous Craving Depressive A significant ↓ in craving and depressive
[147] participants NA Symptoms symptoms was observed 1-year post-DBS
NA in both participants.
Chen et al. N=8 An open-label study with heroin- NAc/ALIC Continuous Craving None Simultaneous and continuous DBS to the
[148] dependent participants Post vs. Pre: NAc and ALIC led to high abstinence
−5.75 [−7.97 – −3.53] rates (62.5%) and a ↓ in opioid craving, 2
Abstinence years post-treatment. 5/8 participants
NA remained abstinent for more than 3 years.
Moreover, improved quality of life and
alleviated mental disorders were
observed.
Bold values have been used to highlight the outcome of interest and the brain region targeted, to improve clarity. Substance use disorder investigated is also shown in bold.
673
D.D. Mehta et al.
674
Notably, Bach et al. [145] (N = 12) was the first to compare active
4/4 (100%) Hedge’s g = −2.36,
1/1 (100%) Hedge’s g = −0.40,
2/2 (100%) Hedge’s g = −5.75,

Outcome (Effect Size – Post
and sham DBS and found significant improvements in substance
Deep Brain Stimulation (DBS) [Total N = 48; 7
95% CI [−7.97 to −3.53]

use and craving following 6-months of active stimulation.
Studies with Positive
95% CI [−3.31, −1.41]
95% CI [−1.28–0.49]
Tobacco. One study examined the use of DBS on TUD by
targeting the NAc. Kuhn et al. [146] found that 3/10 TUD
vs. Pre.)
participants in their study quit smoking post-treatment, while
the remaining seven participants showed a significant decline in
tobacco craving and cigarette consumption.
NA
NA
NA
Opioids. Two studies [147, 148] examined effects of DBS
treatment in heroin-dependent participants and reported sig-
Bold values have been used to highlight the percentage of studies with positive outcomes, as well as the substance use disorder investigated, for improved clarity as well.
n = 28 (4 Studies)
n = 10 (2 Studies)
A Summary of End-of-Treatment Substance-use Outcomes in Neuromodulation for Substance Use Disorder Studies. [N = 4036, Participants; 94 Studies].
n = 0 (0 Studies)
n = 0 (0 Studies)
n = 0 (0 Studies)
n = 10 (1 Study)
nificant reductions in opioid craving and an increase in opioid

abstinence. While Kuhn et al. [147] targeted the NAc exclusively,
Population
Chen et al. [148] applied simultaneous stimulation to anterior limb

Studies]
of the internal capsule (ALIC) and NAc.
DISCUSSION
Outcomes (Effect Size – Active
5/5 (100%) Hedge’s g = −0.33,
3/3 (100%) Hedge’s g = −1.85,

9/14 (64%) Hedge’s g = −0.31,
7/11 (64%) Hedge’s g = −0.50,
1/3 (33%) Hedge’s g = −0.19,
We systematically reviewed the cumulative literature on the

efficacy of NM (rTMS, tDCS, DBS) for SUD treatment (Table 4).
Transcranial Direct Current Stimulation (tDCS)
Findings were inconsistent across each stimulation methodology,

95% CI [−0.87, −0.13]
95% CI [−0.27, −0.11]
95% CI [−2.47, −1.23]

95% CI [−0.62, 0.002]
95% CI [−0.89, 0.23]
and varied significantly with respect to SUD. This may be

attributed to variations in treatment parameters, symptom
severity across SUD participants, use of adjunctive treatment
vs. Control)
interventions and population heterogeneity, including the pre-

sence of comorbid psychiatric disorders, age, sex, and treatment
[Total N = 1582; 36 Studies]
history.
NA
Nonetheless, findings from rTMS and tDCS studies demon-

strated several commonalities. For rTMS, positive outcomes when
n = 94 (3 Studies)
treating tobacco, stimulant and opioid use disorders were

n = 0 (0 Studies)
observed, as indicated by post-treatment reductions in subjective

n = 734 (14
n = 448 (11
Population
and cue-induced substance craving and/or consumption when

n = 195 (5
n = 111 (3
compared to sham treatment. Accordingly, effect sizes were

Studies)
Studies)
Studies)
Studies)
clinically relevant (Hedge’s g > 0.5) but highly variable, consistent

with heterogeneity of the published literature [9]. Furthermore,
meta-analyses found that multi-session active versus sham rTMS
was particularly effective in reducing tobacco consumption, but
Outcomes (Effect Size – Active
7/16 (44%) Hedge’s g = −1.01,
3/6 (50%) Hedge’s g = −0.73,
7/8 (88%) Hedge’s g = −1.45,
3/4 (75%) Hedge’s g = −0.99,
effects on tobacco craving were non-significant. Interestingly,

1/2 (50%) Hedge’s g = 0.04,
g = −1.36, 95% CI [−2.09,
effects of rTMS on AUD were less consistent, with 7/16 studies

Repetitive Transcranial Magnetic Stimulation
demonstrating significant improvements. Subsequent meta-

95% CI [−1.62, −0.40]
14/16 (88%) Hedge’s
95% CI [−0.49, 0.57]
95% CI [−1.57, 0.11]
95% CI [−3.22, 0.32]
95% CI [−2.25, 0.27]
analyses found that multi-session rTMS produced significantly

greater reductions in alcohol craving and consumption. tDCS
(rTMS) [Total N = 2406; 51 Studies]
studies were promising in the treatment of tobacco, alcohol,

vs. Control)
stimulant, and opioid use disorders, as suggested by medium

effect sizes (Table 2). However, meta-analyses of tDCS trials for
−0.63]
Neuromodulation Method
AUD and TUD found that both single- and multi-session

stimulation were not superior to sham stimulation in reducing
craving or consumption, suggesting that rTMS may be superior to
n = 33 (2 Studies)
tDCS for these SUDs.

DBS produced reductions in craving, consumption and/or
n = 607 (16
n = 781 (16
Population
abstinence in alcohol, tobacco, and opioid use disorders. Available

n = 227 (6
n = 519 (8
n = 239 (4
Studies)
Studies)
Studies)
Studies)
Studies)
data is limited to case-series making it difficult to calculate effect

sizes (Table 3), with the exception of one randomized sham-
controlled study in AUD [145]. Sample sizes in DBS studies were
low (ranging 2–12, averaging 6.9 ± 3.1 participants), suggesting
the need for larger samples and randomized controlled trials.
Methamphetamine [N = 714; 13
Tobacco [N = 1239; 28 Studies]
Alcohol [N = 1369; 34 Studies]
Cannabis [N = 33; 2 Studies]
Cocaine [N = 321; 9 Studies]
Treatment parameters
Opioid [N = 360; 9 Studies]
Substance Use Disorder
Variability in treatment efficacy across NM studies may be

attributed to differences in stimulation parameters (e.g.,
stimulation target, frequency, intensity, treatment duration and
sample size/demographics). For both rTMS and tDCS studies,
multi-session protocols are more effective than single-sessions
protocols, as indicated by larger effect sizes and the number of
Studies]
Table 4.
positive outcome studies (see Tables 1–4). This is consistent with

previous reports in the addictions neuromodulation literature
[149]. However, total number of sessions needed to produce

D.D. Mehta et al.
675
long-lasting effects is unclear and requires further investigation. AUD due to targeting of deep brain structures (e.g., insula, nucleus
For rTMS, the most commonly used paradigm across substances accumbens). Subsequent meta-analyses did find positive effects of
was 10–20 sessions once daily. In contrast, studies investigating multi-session rTMS on alcohol craving and consumption. However,
TMS in depression suggest ≥30 sessions are needed for given that there are several evidence-based treatments available
treatment durability [150]. While studies demonstrated persis- for AUD [159], we suggest that neuromodulation treatment
tent effects, including post-TMS reductions in 3-month alcohol development should be focused on SUDs with a lack of
[71] and cigarette consumption [82] after only 10 sessions of evidence-based biological treatments, such as cannabis and
rTMS, durability of these effects remains uncertain as there is stimulants.
lack of long-term follow-up and biochemical verification beyond
1-month. Amiaz et al. [77] found that reductions in cigarette Target brain region
consumption after 10 sessions of rTMS were not maintained at Substance use outcomes with NM are influenced by targeted
6-months. Similarly, number of tDCS sessions needed remains brain region, as well as the subsequent bilateral or unilateral
unclear due to lack of long-term follow-up. tDCS protocols were stimulation of regions of interest. Most rTMS studies for SUDs have
also considerably shorter, with all but two studies [129, 138] targeted the DLPFC (38/50 studies). rTMS targeting the left DLPFC
applying ≤10 sessions overall. Interestingly, Ghorbani Behnam produced predominantly positive effects and clinically relevant
et al. [129] applied 20 total sessions and found that when these effect sizes when treating tobacco, stimulant and opioid use
sessions were distributed over a longer period of time (12 versus disorders, while those stimulating the right or bilateral DLPFC
4 weeks), tobacco abstinence was considerably higher at were less effective (Table 1). In contrast, studies in AUD were not
6-month follow-up. Accordingly, session frequency may also responsive to left DLPFC rTMS, though right and bilateral DLPFC
play an important role. Moreover, potential effects of an stimulation was effective when multiple sessions were conducted.
accelerated stimulation paradigm (e.g. more than one session Alternative regions were less commonly studied. Notably, the
daily) should also be further investigated. Studies in depression mPFC/frontal pole (with or without concurrent stimulation of ACC)
have found that accelerated protocols are safe and well- emerged as a novel therapeutic target, particularly with a deep
tolerated, and perform comparably to standard once-daily rTMS TMS protocol with H-coil technology, as indicated by studies with
[151–153]. Martinotti et al. [93] conducted the only randomized alcohol [63, 68] and cocaine [91]. Targeting bilateral PFC and
sham-controlled addictions study to adopt such an accelerated insular cortex with deep TMS may also be effective in alcohol and
stimulation approach, but reported unfavourable cocaine use tobacco treatment [37, 66, 84, 86].
outcomes following twice daily stimulation. Nonetheless, Steele Both DLPFC and mPFC have emerged as leading rTMS targets;
and colleagues [154] have found that three iTBS sessions/day for much remains unknown about the mechanism by which rTMS
10 days was tolerable and reduced cocaine consumption. induces its therapeutic effects in SUDs. An understanding of rTMS-
The need for maintenance sessions following initial stimula- induced alterations in SUD-related brain circuitry is limited as very
tion treatment should be further evaluated to increase durability few studies have incorporated neuroimaging. Furthermore, there
[155]. Two studies incorporated weekly reminder sessions is much uncertainty surrounding optimal target locations, both for
following 15 daily HF deep-TMS sessions, and found that specific SUDs and individual patients, as there have been no direct
reductions in alcohol consumption [68] and tobacco craving head-to-head comparisons of different active rTMS targets.
[37] persisted 3-months post-treatment. However, Amiaz et al. Consequently, it is possible that alternate targets may be required
[77] found that improvements in tobacco use outcomes for distinct SUDs. Interestingly, there is evidence that the Default
following 10 HF rTMS sessions and 8 maintenance sessions did Mode Network may be a SCZ-specific network of tobacco
not persist at 6-months; this may reflect the effects of the coil dependence [160]. It is critical that rTMS clinical trials include
(Figure-8 vs. H-coil) or the number of initial sessions (10 brain-based measures (e.g., MRI, EEG) in order to elucidate
versus 15). mechanisms of action and identify optimal treatment targets.
Four rTMS studies [83, 84, 91, 104] compared the effects of LF With respect to tDCS, right anodal DLPFC stimulation appears to
(1 Hz) and HF (10 Hz) stimulation and found that 10 Hz rTMS be most efficacious across all substances. However, right anodal
significantly reduced substance craving and/or consumption, DLPFC studies had considerably more stimulation sessions
suggesting that HF rTMS stimulation parameters have greater (≥5 sessions) than those applying left anodal DLPFC (≤5 sessions)
therapeutic potential in comparison to LF stimulation. Accord- stimulation. Thus, observed differences may be related to
ingly, most rTMS studies used HF stimulation (e.g., ≥5 Hz) treatment duration, and future studies should explore longer
regardless of SUD. For tDCS studies, the effects of stimulation durations of left anodal DLPFC tDCS.
intensity (1 mA vs. 2 mA) were less clear. However, tDCS outcomes Importantly, stimulation sites for rTMS and tDCS are con-
were more promising when stimulation sessions were of longer ventionally identified using the 10–20 EEG system or by
duration (>15 min). measuring distances from predefined external landmarks. While
Cue-exposure prior to rTMS may activate craving-related this one-size-fits-all approach produces approximate targeting of
neurocircuitry, and subsequent stimulation could then disrupt specified regions, it does not consider inter-individual differences
drug-related memory consolidation [156]. Accordingly, Dinur-Klein in brain morphology and network architecture. Neuronavigation-
et al. [84] incorporated smoking cue exposure prior to HF deep guided NM with magnetic resonance imaging (MRI) may achieve
TMS and found that it reduced cigarette consumption. Amiaz et al. greater precision with personalized targets. rTMS studies in
[77] evaluated differential effects of both neutral and smoking depression have demonstrated the benefits of such an approach
cues prior to HF rTMS, finding that smoking cues reduced cue- and found that clinical outcomes were significantly improved
induced tobacco craving. This expands on previous findings in when patients were stimulated closer to fMRI-personalized targets
both PTSD [157] and OCD [158], wherein provocation using brief [161]. Selected rTMS studies integrated MRI-neuronavigation
cue exposure prior to treatment alleviated symptoms compared to [56–58, 60, 75, 81, 90], though the number of studies was
no cue provocation. Future studies should determine whether cue insufficient to distinguish its effectiveness in comparison to non-
exposure should be utilized in all rTMS and tDCS protocols. personalized targeting. No tDCS studies were present. Conse-
There were inconsistencies for rTMS in AUD treatment, with quently, future randomized control trials are warranted to assess
positive outcomes reported in 44% of studies. Nonetheless, deep the clinical potential of neuronavigation-guided personalized
TMS was effective when compared to rTMS using a Figure-8 coil, rTMS and tDCS. Most DBS studies targeted the NAc, and were
suggesting that the H-coil may be advantageous when treating consistently positive.

D.D. Mehta et al.
676
Alternate neuromodulation modalities optimize clinical outcomes should be emphasized. Neuroimaging
Other NM methods that are less frequently used and excluded data (fMRI) should be acquired prior to, during, and following
from this review include Electroconvulsive Therapy (ECT) [162], treatment to elucidate the underlying neural mechanisms
Magnetic Seizure Therapy (MST) and Transcranial Alternating mediating treatment effects. Moreover, MRI-neuronavigation
Current Stimulation (tACS) [163]. Studies examining their effects may address potential discordance between coil/electrode place-
on SUDs are limited. We also excluded invasive ACC stimulation; ment and region of interest, potentially improving treatment
ACC implants have shown positive effects, particularly for AUD, efficacy.
although adverse events have been reported [164]. Finally, greater emphasis on co-occurring psychiatric disorders
is needed. rTMS may be a promising intervention for patients with
Psychiatric comorbidities SCZ and concurrent SUDs, warranting larger randomized sham-
Only a few studies have tested neuromodulation interventions in controlled trials. Finally, the potential of adjunctive psychother-
populations with comorbid psychiatric disorders. Notably, 3/4 of apeutic and/or pharmacological intervention should be deter-
rTMS studies that examined TUD participants with co-occurring mined, which may improve substance use outcomes [81]. While
SCZ observed significant reductions in tobacco craving and some studies have implemented concurrent pharmacological
consumption [78, 80, 85] (Table 1). Prevalence of tobacco use in interventions [78], few have parsed the clinical impact of each
SCZ is 60–80% and contributes to a 25-year decreased life therapy for augmentation of NM outcomes.
expectancy in SCZ [165], emphasizing the therapeutic potential of
rTMS for this comorbidity. Moreover, SCZ patients have high rates
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A systematic review and meta-analysis of neuromodulation

© The Author(s) 2023

Neuropsychopharmacology (2024) 49:649–680; https://doi.org/10.1038/s41386-023-01776-0

INTRODUCTION behaviors and inhibition [15]. Thus, use of NM to stimulate right

Received: 20 July 2023 Revised: 6 November 2023 Accepted: 20 November 2023

Transcranial direct current stimulation (tDCS) METHODS

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

study with recently 1 Sham Session Sham: NA observed on alcohol craving,

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

abstinence rates than those who

Total N = 202; 5 Studies

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

methamphetamine- Sessions Sham: improved depressive symptoms

Neuropsychopharmacology (2024) 49:649 – 680

effect on heroin craving or heroin

Active rTMS had no signiﬁcant

symptoms was observed post-

employing either a parallel (between-subject) or cross-over (within-subject)

meta-analysis, dissertation, abstract, conference presentation or case

obtained on Covidence to determine eligibility for full-text review, and

subsequently reviewed the full text of the screened studies. Disagreements

Data extraction and risk of bias

information, sample size, study design, stimulation parameters, primary

substance use outcomes (craving and consumption), and any secondary

outcomes. Effect sizes (Hedge’s g) of substance use and other outcomes

Due to the heterogeneity in follow-up periods across studies, treatment

effects were determined using end-of-treatment data, unless otherwise

stated. For DBS studies with no control conditions, within-subject (pre-post

four domains were considered of moderate risk, or if two or more domains

Interventions (ROBINS-I) [52] tool assessed risk of bias in non-randomized

To quantify NM effects, we performed meta-analyses on rTMS and tDCS

conducted when three or more studies evaluated a synonymous outcome

(craving, cue-induced craving, and/or consumption).

We utilized standardized mean difference (SMD; Hedge’s g) with 95%

conﬁdence intervals (CI’s) in each selected meta-analysis to calculate the

effect size of NM-related changes in alcohol and tobacco craving, cue-

induced craving, and/or consumption (p ≤ 0.05, two-tailed). Random-

treatment arms. Negative values indicated that active stimulation

produced greater reductions in craving, cue-induced craving, and/or

consumption compared to sham treatment. The I2 statistic estimated

between-trial heterogeneity; I2 of ≤40% was considered low heterogeneity,

Meta-analyses were performed using R version 4.3.1 [54] with package

We identiﬁed a total of 94 studies that met our inclusion criteria,

with a total of 4306 participants.

Repetitive transcranial magnetic stimulation (rTMS)

Fifty-one studies investigating rTMS as treatment for SUDs were

identiﬁed, with 2406 participants receiving either active or control

treatment (sham stimulation or no treatment; Table 1).

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680

Neuropsychopharmacology (2024) 49:649 – 680