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T. Chen et al.
protocols refer to multiple iTBS interventions conducted within a single day, thereby
providing a higher quantity of pulse stimulation in a shorter period of time. One of
largest number of accelerated TBS intervention studies have been conducted in
populations with depression. Among them, the SAINT developed by the research
team at Stanford University provides ten interventions in 1day and 90,000 pulses
totally in 5days, targeting the left DLPFC, with a remission rate as high as 78.6–90%
after the SAINT protocol [66, 67]. Due to its outstanding intervention effect, in
2022, the FDA approved it for the treatment of treatment-resistant depression.
Compared to depression, there have been few accelerated iTBS protocols conducted
in addiction [104, 105]. In one study by Steele etal., 19 patients with cocaine use
disorder were recruited for a within-subjects controlled study. Patients received
three iTBS treatments per day for 10days (a total of 30 iTBS treatments). The
stimulation target of this protocol was the left dlPFC.Compared to the patients’
performance before treatment, after receiving iTBS intervention, the patients
reduced their weekly cocaine consumption by 78% and the number of usage days
by 70% within 4weeks [105]. This indicates that the accelerated iTBS protocol has
signicant utility in reducing cocaine use. Another randomized controlled clinical
study conducted in a population with nicotine use disorder suggested that four times
a day for a total of 20 iTBS treatments did not outperform the sham group in reducing psychological cravings and nicotine dependence levels [104]. Therefore, based
on current ndings, it is difcult to clearly determine the therapeutic effect and
value of accelerated iTBS protocols for addiction. When conducting accelerated
iTBS interventions, attention should be paid to the setting of certain parameters,
with studies suggesting that the setting of parameters such as time intervals, stimulation intensity, and brain region localization methods signicantly affect the nal
clinical efcacy [106]. For instance, intervals between treatments of 50–90min can
induce changes in neural plasticity, while less than 40min cannot [106].
A summary of studies in different diseases found that the most commonly
reported side effects of accelerated TBS protocols are headache, fatigue, and nausea, with a headache incidence rate of 31.3% [106]. No studies reported serious side
effects. Overall, there is no evidence to suggest that the adverse reactions of accelerated TBS protocols are higher than those of traditional rTMS intervention protocols.
6.2.5.3 Continuous TBS
cTBS is a pattern of rTMS that simulates the 4–7Hz burst discharges recorded in
the hippocampus, an electrophysiological activity closely related to synaptic plasticity. The basic characteristic of cTBS is the occurrence of three burst pulses every
200ms, with an intra-burst frequency typically set at 50Hz, although studies have
also used other frequencies such as 30 and 40Hz. In addiction research, cTBS interventions have primarily targeted brain regions such as the DLPFC, rIFG, mPFC,
and orbital frontal cortex (OFC). Among them, in populations with alcohol use disorder, cTBS interventions targeting the right DLPFC or the left DLPFC have both
been found to increase cravings/risk of relapse [107, 108]. Studies conducted in
populations with methamphetamine use disorder have shown that 10 sessions of
cTBS intervention targeting the right DLPFC effectively reduced psychological
6 Addictive Disorders
163
cravings, while cTBS stimulation of the left DLPFC did not signicantly improve
effects [95]. cTBS interventions in the OFC (mPFC) region have shown stronger
consistency in therapeutic effects. For instance, a study by Ankit etal. explored the
efcacy of cTBS as an adjunctive treatment to naltrexone for patients with opioid
use disorder, nding that targeting the right OFC signicantly reduced craving
scores [109]; another study conducted in populations with alcohol use disorder,
targeting the mPFC brain region, reduced alcohol consumption within 3months
after treatment initiation [110]; in methamphetamine populations, Chen etal. compared the efcacy of ventromedial prefrontal cortex (vmPFC) cTBS and DLPFC
iTBS, nding that both interventions had comparable effects on cravings [24];
Hanlon etal.’s work suggested that mPFC cTBS could downregulate the activation
of brain regions associated with drug cues, such as the striatum and mPFC cortex
[111], providing a mechanistic understanding of the value of mPFC interventions.
Based on existing cTBS intervention studies, it seems that mPFC cTBS intervention has potential for reducing psychological cravings. However, it is not yet sufcient to form recommendation suggestions. On the other hand, compared to iTBS
interventions, cTBS protocols are generally considered to reduce the activation
level of the stimulated target area and related circuits. Therefore, for addiction disorders with complex circuit abnormalities, if combined intervention strategies are
carried out, they may bring stronger effects. For example, a randomized controlled
clinical study found that mPFC cTBS combined with DLPFC iTBS intervention
was superior to single DLPFC iTBS intervention in reducing cravings [24].
6.2.5.4 Bilateral TBS
There are at least two approaches to stimulate bilateral brain region. One is sequential stimulation, where one brain region is stimulated followed by another; the other
involves using dTMS coils to simultaneously intervene in large areas of both brain
hemispheres. For instance, in the treatment of treatment-resistant depression, bilateral DLPFC rTMS intervention has been found to signicantly reduce the degree of
depression. Blumberger et al. conducted a randomized controlled clinical study
comparing the efcacy of bilateral DLPFC rTMS intervention with bilateral DLPFC
iTBS interventions and found that they had equivalent effects in reducing depression levels [112]. Since rTMS takes up to 48min, while iTBS protocols last for
4 min, this to some extent increases the opportunity and cost-effectiveness for
patients with treatment-resistant depression to access treatment equitably. On the
other hand, bilateral TBS interventions seem to have superior clinical outcomes
compared to unilateral ones. A naturalistic observation study found that patients
receiving bilateral DLPFC stimulation required fewer treatment sessions and had
lower posttreatment anxiety symptoms compared to those receiving unilateral stimulation, suggesting that bilateral TBS may have superior antianxiety effects and a
slightly faster response time [113]. In the eld of addictive disorders, there is currently a lack of large-scale comparative studies on bilateral interventions. A study in
a cocaine population used H4 deep coils to explore the efcacy differences between
15Hz intervention and iTBS intervention targeting the frontal and insular cortices.
The study found that both protocols had equivalent effects on craving intervention
164
[99]. In comparison, bilateral PFC iTBS intervention takes only 3min, which is just
20% of the time for 15Hz intervention. This result enhances the clinical appeal of
TBS intervention strategies. As current research is scarce, further exploration and
study of bilateral TBS protocols will help promote the more diverse clinical application of rTMS intervention strategies.
T. Chen et al.
6.2.6 MST
Since Lisanby etal. rst reported on the successful and intentional induction of
seizures using rTMS in 2001 [114], many researchers have explored the appropriate
parameters and intervention effects of magnetic seizure therapy (MST). As a novel
intervention protocol, MST is based on the ability of high frequency rTMS to induce
therapeutic seizures and exert therapeutic effects on severe psychiatric disorders
[115, 116]. Compared to traditional electroconvulsive therapy (ECT), MST typically has fewer neurocognitive adverse reactions [117]. This may be related to the
fact that seizures induced by MST originate from the supercial cortical areas,
whereas during ECT the current passes through deep brain areas [114].
To date, there have been few studies reporting the application of MST technology in populations with addictive disorder. In fact, the application of ECT has historically been used to address psychosis, catatonia, and other conditions resulting
from drug use [118, 119], rather than treating addiction itself. Some researchers
even argue that the use of ECT technology to intervene in the treatment of methamphetamine use disorder is ethically controversial [120]. Whether MST technology
should be conducted in addicted populations, what parameters should be set, and
what clinical indicators should be focused on, are issues that the further researchers
should give considerable consideration.
6.3 tDCS
6.3.1 Conventional tDCS
6.3.1.1 Efficacy
Transcranial direct current stimulation (tDCS) is an innovative neuromodulation
technique that targets specic brain regions by applying a steady current between
two or more electrodes. The currents induced by tDCS increase the likelihood of
neuronal activation through depolarizing or hyperpolarizing neurons without
directly eliciting action potentials [121]. In recent years, the role of tDCS in interventions for substance dependence and addiction has been extensively examined [10].
For alcohol use disorders, Klauss etal. demonstrated that ve sessions of tDCS
signicantly reduced the relapse rate 6months poststimulation (50% vs. 88.2%),
although no signicant reduction in craving was observed [122]. In a subsequent
study with a larger sample size and ten sessions of tDCS, Klauss etal. reported
6 Addictive Disorders
165
signicant decreases in both alcohol craving and the 3-month relapse rate in the
active treatment group [123]. Similarly, Dubuson etal. found that active tDCS signicantly increased abstinence rates at a 2-week follow-up compared to sham stimulation [124]. In another study, den Uyl etal. showed that three sessions of tDCS
signicantly reduced cue-induced craving in individuals with alcohol use disorders
[125]. However, several studies have reported no efcacy of tDCS on craving or
relapse rates in patients with alcohol use disorders. For instance, Witkiewitz etal.
incorporated tDCS into a treatment regimen with mindfulness-based relapse prevention but found no signicant differences in posttreatment alcohol consumption
or craving between active and sham tDCS groups [126]. Similarly, den Uyl etal.
reported no signicant effects on craving or relapse rates following four sessions of
tDCS [127], with a subsequent study yielding similar negative results [128]. In conclusion, tDCS is a promising intervention method for patients with alcohol use disorders, although the optimal parameter sets for craving and relapse rate remains
unclear.
tDCS has shown relatively consistent effects on nicotine dependence, as indicated by a meta-analysis by Kang and colleagues [129]. Boggio etal. found that ve
sessions of tDCS signicantly decreased nicotine craving, cue-induced craving, and
nicotine consumption compared to sham stimulation [130]. Mondino etal. conducted an intervention using ten sessions of tDCS in individuals with nicotine
dependence and observed a signicant reduction in cigarette craving [131]. Ghorbani
etal. examined the relationship between the duration of tDCS (administering the
same dose) and its efcacy on relapse rates, nding that extended tDCS sessions
resulted in the highest abstinence rate at 6months [132].
For cocaine use disorder, the results of tDCS interventions have been inconsistent. Batista etal. reported a signicant reduction in craving for crack-cocaine following ve sessions of tDCS [133]. However, two other studies, conducted by
Verveer etal. and Gaudreault, found no effect of tDCS on cocaine craving [134,
135]. tDCS has shown promising effects on methamphetamine use disorder. Three
studies, employing ve, ten, and twenty sessions respectively, reported signicant
reductions in methamphetamine craving [136–138]. However, additional high-quality randomized controlled trials (RCTs) are needed to conrm these positive effects.
For opioid use disorder, tDCS has shown preliminary effects on reducing craving.
Taremian etal. and Eskandari etal. found that ten sessions of tDCS signicantly
decreased opioid craving [139, 140].
The application of tDCS in behavioral addictions remains in its early stages. Two
studies have investigated the effects of tDCS on internet gaming disorder (IGD)
[141, 142]. Lee etal. found that ten sessions of tDCS did not reduce cravings for
internet gaming [142]. Similarly, Jeong etal. used ten sessions of tDCS for IGD and
found no signicant difference in effect compared to sham stimulation [141].
Martinotti etal. employed ve sessions of tDCS on a mixed sample including individuals with both substance (cocaine, opioids, alcohol, cannabis) and behavioral
(gambling) addictions, reporting a signicant decrease in craving [143]. However, it
remains unclear whether this reduction was specically inuenced by the gambling
disorder subgroup. Therefore, more randomized controlled trials focused on IGD
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T. Chen et al.
and gambling disorders are necessary to conrm the efcacy of tDCS in treating
behavioral addictions.
Although the effects of tDCS vary across different types of addiction, it remains
a promising intervention overall, particularly due to its portability, simplicity, and
adaptability.
6.3.1.2 Safety
The tDCS treatment is widely regarded as a safe intervention method [144]. The
most commonly reported side effects are a mild tingling sensation and a brief perception of light ashes at the beginning and end of stimulation [145]. Another frequent side effect is erythema on the skin beneath the electrodes [146]. Additional
side effects include temporary headaches and dizziness. Severe side effects, such as
seizures, have been rarely reported in tDCS studies. Studies indicate that a current
density of 52mA is required to induce brain tissue lesions—signicantly higher
than the standard protocol of 1–2mA.Thus, tDCS is considered a safe, noninvasive
neuromodulation method for applications in addiction treatment.
6.3.1.3 Treatment Regimen
The parameter set for tDCS includes electrode positioning, current intensity, stimulation duration per session, and the total number of sessions within an intervention
course. In addiction intervention, the most commonly targeted stimulation area is
the left or right DLPFC, with either an anode or cathode placed accordingly. For
current intensity, most studies use 1–2mA to ensure an adequate stimulation dose.
Typically, the duration of stimulation per session ranges from 10 to 20min, with the
number of sessions varying from a single session to a maximum of 20 sessions [10].
Evidence suggests that certain stimulation site congurations may have a higher
probability of impacting craving and relapse. For alcohol use disorders, positioning
the anode on the right DLPFC and the cathode on the left DLPFC has shown
improved efcacy in reducing craving and relapse rates [122–124, 127, 128]. This
conguration has also been observed to be effective in nicotine addiction [130, 132,
147]. For methamphetamine and opioid use disorder, most studies have employed
the same anode–cathode arrangement, with positive outcomes on craving reduction
[136, 138–140]. Nonetheless, additional high-quality studies are needed to conrm
the optimal stimulation sites for these types of addiction.
For behavioral addiction, both Lee etal. and Jeong used a montage with the
anode placed on the left DLPFC and the cathode on the right DLPFC, with a current
intensity of 2mA over a total of ten stimulation sessions, but no effect on craving
was observed [141, 142]. It remains unclear whether alternative electrode montages
could produce different effects. Martinotti etal. employed a montage with the anode
on the right DLPFC and the cathode on the left DLPFC, using a current intensity of
1.5mA, which resulted in a signicant reduction in craving [143]. Further exploration of tDCS parameter sets is needed for applications in behavioral addictions.
There is currently no evidence that variations in current intensity systematically
inuence the effectiveness of tDCS in addiction treatment. Generally, multi-session
interventions are more effective than single-session stimulations [148]. However, it
6 Addictive Disorders
Table 6.2 TDCS in addictive disorder
Levels +
Clinical recommendations
Anode
tDCS
Conventional
tDCS
HD-tDCS Unclear Unclear Unclear Unclear Unclear NA
Abbreviations: HD-tDCS high-denition transcranial direct current stimulation, NA not applicable, DCS transcranial direct current stimulation
position
Unclear Unclear Unclear Unclear Unclear NA
Cathode
position
Intensity
(mA)
Length
(min)
Duration
(sessions)
references
167
remains unclear whether increasing the number of stimulation sessions can produce
long-lasting effects.
6.3.1.4 Clinical Recommendations
For SUDs, Fregni etal. recommend using combined right DLPFC anodal and left
DLPFC cathodal tDCS for at least 13min per session, which is considered probably
effective in reducing cravings for alcohol use disorders [121]. In the 2022 version of
expert consensus on clinical applications of tDCS in China, it is suggested that for
methamphetamine addiction, positioning the anode on the right DLPFC and the
cathode on the left DLPFC for 20min per session may improve symptoms. For
nicotine dependence, tDCS with the anode on the left DLPFC and the cathode on
the right DLPFC for 20min per session (in more than ve sessions) is rated as effective. However, no specic recommendations have been established for all types of
addiction (Table6.2), and further randomized controlled trials are needed to conrm the effects of tDCS on SUDs.
6.3.2 HD-tDCS
Compared to conventional tDCS interventions, high-denition tDCS (HD-tDCS)
more focally delivers a weak current to specic brain areas through multiple small
electrodes placed on the scalp, thereby precisely modulating subcortical neural
activity and reducing the impact on nontarget areas. In HD-tDCS research, the 4×1
ring montage is the most commonly used montage, endowing HD-tDCS with the
ability to have a single required activity without being affected by cortical stimulation of the opposite polarity. HD-tDCS has been studied in some psychiatric diseases. For example, in schizophrenia research, central cathodal stimulation to CP5
(temporoparietal junction) using the 10/10 EEG system with four return electrodes
at FT7, FC3, PO7, P1 has been shown to signicantly reduce the occurrence of
persistent auditory hallucinations [149]. Studies conducted in elderly patients with
depression also suggest that central anodal stimulation of 2mA to F3 using the
10/10 EEG system with four return electrodes FC1, AF3, F7, FC5 each carrying
0.5mA can reduce depression levels [150]. Another point of interest is whether
HD-tDCS differs from or is superior to conventional tDCS in terms of intervention
168
effects. To answer this question, some researchers have explored the differences in
the impact on neural activity between the two and found that traditional tDCS leads
to a reduction in theta power [151]. However, another study denied the existence of
such effect differences [152]. From the limited literature search, no studies have
reported the application of HD-tDCS technology in the eld of addiction.
Conventional tDCS technology has already shown clinical application value, and
future exploration of the intervention effects and mechanisms of HD-tDCS technology in addiction will also broaden the application direction of tDCS technology.
T. Chen et al.
6.4 TMS vs. tDCS
6.4.1 Efficacy
According to previous meta-analyses, there are considerable differences in the
effects of rTMS and tDCS in treating addictive disorders. High-frequency TMS
targeting the DLPFC has demonstrated medium to large effect sizes in alcohol,
nicotine, and cocaine dependence [10, 20]. In contrast, the effects of tDCS are less
consistent, tend to vary with individual differences, and generally show lower effect
sizes than those of repetitive TMS (rTMS) [20]. This discrepancy may stem from
the distinct neural mechanisms of TMS and tDCS. TMS directly evokes action
potentials, which are more likely to induce LTP, whereas tDCS primarily modulates
neuronal membrane potentials, affecting the likelihood of activation without directly
inducing action potentials [153, 154]. Future research could focus on optimizing the
parameters of both TMS and tDCS to improve therapeutic outcomes and further
elucidate how individual differences inuence efcacy.
6.4.2 Safety
TMS and tDCS are both considered safe intervention methods. However, it is worth
noting that in rare cases, particularly during high-frequency stimulation, TMS may
induce seizures, a risk that is minimal with tDCS.In clinical practice, precautions
should be taken to address the potential for TMS-induced seizures, including having
protocols in place. Additionally, mild and possible side effects, such as dizziness,
discomfort at the stimulation site, and minor skin irritation, should be discussed
with patients beforehand to alleviate concerns and enhance treatment compliance.
6.5 Conclusion
As emerging interventions for addiction, both TMS and tDCS have shown promising potential. However, current studies suggest that the consistency and reliability
of these physical interventions still require enhancement. Further research is needed
to conrm the clinical efcacy of TMS and tDCS in treating addictive disorders.
6 Addictive Disorders
169
Future studies could focus on several key areas. First, optimal stimulation parameters and intervention protocols for different addiction types should be determined,
given the varying effects of the same protocol across different types of addiction.
Second, the underlying neural mechanisms of these interventions should be
explored, potentially through a combination of animal and human studies or by
synchronizing neural signal acquisition during stimulation [155, 156]. Such
approaches could provide insights into the neural mechanisms, clinical effects, and
their causal relationships. Third, the long-term effects and safety of these interventions should be assessed through extended follow-up measurements, which would
guide future treatment protocols. Finally, given individual variations in brain anatomy, state, and development, precision strategies such as neural circuit-targeted
interventions and closed-loop approaches merit exploration [157, 158]. These strategies may improve intervention consistency and enhance understanding of the neural mechanisms underlying TMS and tDCS in addictive disorders.
Acknowledgments None.
Disclosure/Conicts of Interest The authors declare no conicts of interest in conducting this
study or preparing the manuscript.
Financial Support This work was supported by National Nature Science Foundation (82,130,041,
82,201,650), Clinical Research Project of Shanghai Municipal Health Commission (20244Y0201),
and Shanghai Rising-star Cultivation Program (22YF1439200).
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