Effectiveness of Noninvasive Brain Stimulation Protocols on Drug Craving and Consumption/Relapse in Substance Use Disorders: A Systematic Review and Meta-analysis of 208 Clinical Trials and 36 Protocols

Effectiveness of Noninvasive Brain Stimulation Protocols on Drug Craving and Consumption/Relapse in Substance Use Disorders: A Systematic Review and Meta-analysis of 208 Clinical Trials and 36 Protocols | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var 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Baker , Andre R Brunoni , Mohsen Ebrahimi , Eduardo A Garza-Villarreal , Tony P George , Rita Z Goldstein , Manish Kumar Jha , Tonisha Kearney-Ramos , Rayus Kuplicki , Bernard Le Foll , Kelvin O Lim , Martin P Paulus , Arash Rahmani , Gregory Sahlem , Victor M Tang , Hosna Tavakoli , Alireza Valyan , Ti-Fei Yuan , Mehran Zare-Bidoky , Marom Bikson , Colleen A Hanlon , Michael Nitsche , Hamed Ekhtiari doi: https://doi.org/10.1101/2025.09.21.25335559 Ghazaleh Soleimani 1 Department of Psychiatry and Behavioral Sciences, University of Minnesota , MN, USA 2 Department of Biomedical Engineering, University of Minnesota , MN, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Afra Souki 3 Department of Psychology, University of Tehran , Tehran, Iran MSc Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Afra Souki Sara Honari 4 Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences , Mashhad, Iran MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Travis E Baker 5 Center for Molecular and Behavioral Neuroscience, Rutgers University , Newark, New Jersey 07102 PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andre R Brunoni 6 University of São Paulo Medical School , Psychiatry, São Paulo, Brazil MD-PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mohsen Ebrahimi 7 Iranian National Center for Addiction Studies (INCAS) , Tehran, Iran MSc Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eduardo A Garza-Villarreal 8 Institute of Neurobiology, Universidad Nacional de México campus Juriquilla , Queretaro, Mexico MD-PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tony P George 9 Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto , Toronto, ON, Canada 10 Addictions Division, Centre for Addiction and Mental Health (CAMH) , Toronto, ON, Canada MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rita Z Goldstein 11 Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai , New York City, New York PhD Roles: Professor Find this author on Google Scholar Find this author on PubMed Search for this author on this site Manish Kumar Jha 12 Department of Psychiatry, University of Texas Southwestern Medical Center , Dallas, TX, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tonisha Kearney-Ramos 13 Department of Psychiatry & Behavioral Sciences, Duke University Medical Center , Durham, NC 27710 PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rayus Kuplicki 14 Laureate Institute for Brain Research (LIBR) , OK, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bernard Le Foll 15 Department of Psychiatry, University of Toronto , Toronto, ON, Canada MD-PhD Roles: Professor Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kelvin O Lim 1 Department of Psychiatry and Behavioral Sciences, University of Minnesota , MN, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Martin P Paulus 14 Laureate Institute for Brain Research (LIBR) , OK, USA MD Roles: Professor Find this author on Google Scholar Find this author on PubMed Search for this author on this site Arash Rahmani 1 Department of Psychiatry and Behavioral Sciences, University of Minnesota , MN, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gregory Sahlem 16 Brain Stimulation Lab, Department of Psychiatry & Behavioral Sciences, Stanford School of Medicine , Stanford, CA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Victor M Tang 17 Addictions Division, Centre for Addiction and Mental Health , Toronto, ON, Canada MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hosna Tavakoli 18 Institute for Cognitive Sciences Studies (ICSS) , Tehran, Iran PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alireza Valyan 19 Allameh Tabataba’i University , Tehran, Iran PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ti-Fei Yuan 20 Shanghai Key laboratory of Psychotic disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine , Shanghai, China PhD Roles: Professor Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mehran Zare-Bidoky 21 Iranian National Center for Addiction Studies, Tehran University of Medical Sciences , Tehran, Iran MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marom Bikson 22 Department of Biomedical Engineering, The City College of New York , New York, NY, USA PhD Roles: Professor Find this author on Google Scholar Find this author on PubMed Search for this author on this site Colleen A Hanlon 23 Department of Cancer Biology, Wake Forest University School of Medicine , NC, USA 24 BrainsWay , Burlington, MA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Nitsche 25 Department of Psychology and Neurosciences, Leibniz Research Center for Working Environment and Human Factors , Dortmund, Germany 26 University Clinic of Psychiatry and Psychotherapy, Protestant Hospital of Bethel Foundation, University Hospital OWL, Bielefeld University , Bielefeld, Germany 27 German Center for Mental Health (DZPG) , Bochum, Germany MD Roles: Professor Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hamed Ekhtiari 1 Department of Psychiatry and Behavioral Sciences, University of Minnesota , MN, USA 14 Laureate Institute for Brain Research (LIBR) , OK, USA MD-PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: ekhti001{at}umn.edu hekhtiari{at}laureateinstitute.org Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Background Transcranial Magnetic, Electrical, and Focused-Ultrasound Stimulation (TMS/tES/tFUS) are major noninvasive brain stimulation (NIBS) techniques used to treat various psychiatric disorders, including substance use disorders (SUDs). Although NIBS with varying stimulation parameters shows promising effects on drug-related behaviors such as craving and consumption/relapse, the question of which protocol is most effective remains unresolved. Method To address this gap, we conducted a living systematic review and meta-analysis to quantify the effects of TMS/tES/tFUS on SUD. Controlled trials of TMS/tES/tFUS for all types of SUD were selected up to January 1, 2024. Findings The final systematic review included 208 trials (121 TMS, 86 tES, 1 tFUS), with 116 randomized sham-controlled trials (59 TMS, 57 tES) eligible for meta-analysis due to a low risk of bias. Data from 5,106 participants in active and 4,914 in sham groups were analyzed. TMS showed medium effects on craving (g = 0.52, 95% CI: 0.29-0.75, p < 0.001, I^2 = 89.36) and consumption (g = 0.41, CI: 0.26-0.56, p < 0.001, I^2 = 61.56). tES showed a medium effect on craving (g = 0.40, CI: 0.25-0.55, p < 0.001, I^2 = 60.69) and a small effect on consumption (g = 0.27, CI: 0.15-0.38, p = 0.013, I^2 = 22.67). Among the 36 different protocols examined, subgroup analyses identified the strongest effect for reducing both craving and consumption with high-frequency deep TMS using the H4 coil (single study) (g = 3.92 and 1.12, respectively, p < 0.001), with a maximum electric field over the frontopolar cortex. This effect was followed by high-frequency rTMS over the left DLPFC (g = 0.66 and 0.52, respectively, p < 0.05), as well as bilateral anodal-right cathodal-left (g = 0.49 and 0.42, respectively, p < 0.0001) and anodal-left cathodal-right (g = 0.38 and 0.31, respectively, p < 0.05) tES with direct current (tDCS) over the DLPFC, with maximum electric field on the frontopolar cortex. Interpretation Our results provide evidence that TMS and tES stimulation over frontopolar and DLPFC regions produce medium to large effect sizes in reducing drug craving and consumption/relapse in SUD. While requiring further replication in future studies, these findings highlight the promise of these interventions. 1. Introduction Substance use disorders (SUDs) are major global health challenges, affecting millions of individuals worldwide and contributing significantly to morbidity and mortality. Alcohol use disorder affects approximately 5% of the global population (∼400 million people), 1 and other SUDs impact about 0.7% of the population (∼36 million worldwide). 2 These conditions impose a substantial burden on individuals, families, societies, and healthcare systems, highlighting the urgent need for effective global prevention and treatment strategies. Numerous compounds have undergone scrutiny as potential pharmacotherapies for SUDs. However, as of early 2025, only a limited number of medications have demonstrated robust efficacy (consistent, reproducible, and clinically durable) and gained approval from the United States Food and Drug Administration (FDA). 3 However, for some SUDs, such as methamphetamine use disorder (MUD) and cannabis use disorder (CUD), there are currently no FDA-approved pharmacological treatments, leaving clinicians with limited options beyond behavioraltherapies. The significant global burden of SUDs, combined with their neurotoxic and neuroadaptive effects on the brain, underscores a critical treatment gap due to the lack of effective pharmacotherapies. The high rates of relapse and ongoing health consequences in individuals with SUDs emphasize the pressing need for novel therapeutic approaches. Neuromodulation, particularly non-invasive brain stimulation (NIBS), has emerged as a promising alternative intervention, targeting the pathophysiological mechanisms underlying SUD. 4 In this regard, transcranial electrical (tES), magnetic (TMS), and focused ultrasound (tFUS) stimulation have shown promise as potential treatments for SUDs. 5 , 6 NIBS techniques employ varied stimulation protocols, including different frequencies, intensities, and target areas, to modulate brain activity and support therapeutic outcomes. Treatment outcomes in NIBS studies commonly include reduced drug craving, enhanced self-regulation, with key measures often assessing both short-term drug consumption and longer-term relapse prevention. A major focus of recent NIBS research has been the application of anodal tES or high-frequency TMS to the dorsolateral prefrontal cortex (DLPFC), a region commonly targeted in depression protocols to enhance cortical excitability. This interest is driven by overlapping DLPFC-mediated executive function deficits observed in both depression and SUDs. 7 However, there are multiple trials targeting other sites, and the optimal site(s) and protocols for effective addiction treatment remain unclear. 8 To address this gap, we conducted a living systematic review and meta-analysis with three primary aims: (1) to characterize the heterogeneity of NIBS parameter spaces used in SUD research; (2) to quantify the overall effect size of NIBS on drug craving and consumption/relapse, and evaluate how stimulation parameters influence outcomes; and (3) to identify the most effective stimulation protocols. These findings aim to inform the development of more effective interventions and support policy and regulatory decisions in global addiction treatment efforts. Regarding a recently published review of review papers on (non)invasive methods in the field of SUD, by the end of 2024, there are at least five systematic review papers (with or without meta-analysis) in this area. 9 , 10 One of the most recent and comprehensive ones was published in 2023 by Mehta et al., which covered studies up to the end of October 2023 and only reported the meta-analysis for alcohol and nicotine use disorders. 6 Here, (1) in the systematic review part, we reported results up to the end of 2023, which will be updated annually through the International network of tES and TMS for Addiction Medicine (INTAM) infrastructure, 5 (2) in the meta-analysis part, we conducted a comprehensive subgroup analysis covering all types of SUDs (rather than focusing on two samples as Mehta et al. did), and (3) we performed subgroup analyses of stimulation protocols specifically to identify the most effective protocol for each stimulation type, including deep and figure-of-eight coil TMS as well as tES studies. 2. Method 2.1. Search Strategy in the Systematic Review Phase A comprehensive literature search was conducted in PubMed for studies published up to January 1, 2024, involving tES, TMS, and tFUS as interventions for SUDs. Search terms are detailed in Table S1 . The review follows the latest Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). 11 The initial search identified 508 TMS, 663 tES, and 156 tFUS articles. Two independent investigators (AS, HT) screened and extracted data, with a 3 rd reviewer (GS) resolving discrepancies by consulting with the senior author (HE) (see supplementary materials). Extracted data and key figures are available on the INTAM OSF page ( https://osf.io/sv8ky ) and will be updated annually, with comprehensive results published every five years. 2.2. Study Inclusion for the Meta-Analysis Phase For the meta-analysis, a refined subset of studies was selected from the systematic review dataset. Studies included if they: (1) were randomized controlled trials reporting craving and/or consumption/relapse as outcome measures, and (2) provided sufficient statistical data—such as means and standard deviations (SDs) for pre- and post-intervention, mean change scores, F-values, or relapse rates—to enable effect size estimation for active versus sham stimulation. Studies were excluded if they: (1) lacked a sham-controlled condition, or (2) did not report sufficient data for effect size calculation and failed to provide these data upon request from the first or last author. 2.3. Assessment of the Risk of Bias of the Included Studies Cochrane’s risk-of-bias tool (RoB 2) was used to rate the methodological quality of the included studies. 12 The five main domains covered by this tool are (1) bias due to the randomization process and timing of identification or recruitment of participants, (2) deviation from intended intervention, (3) missing outcome data, (4) measurement of outcomes, and (5) selection of the reported result. Two authors (AS, SH) independently assessed each item for each study. If there were any unresolved disagreements, these were discussed with a third person (MZB), and the final decision was then made. 2.4. Hedges’ g Calculations Meta-analytic models were implemented using the “metafor” package in R. Effect sizes were calculated by comparing changes in drug craving/consumption/relapses between active stimulation and sham control groups. Hedges’ g was used as the effect size metric, accompanied by 95% confidence intervals (CIs). All analyses were conducted using random-effect models to account for between-study heterogeneity. Positive effect sizes indicated greater reductions in craving, consumption, or relapse following active stimulation compared to sham. 2.5. Publication Bias Assessment To assess the potential impact of publication bias, which could either inflate or deflate effect sizes in meta-analyses, 13 , 14 two distinct evaluations were conducted. (1) The original funnel plot was compared with a modified version generated through the application of the trim and fill technique. 15 (2) Egger’s regression test was implemented, which gauges the degree of funnel plot asymmetry by assessing the intercept resulting from a regression of standard normal deviation against precision. 16 A P-value for the intercept falling below 0.05 indicated the presence of substantial publication bias across the array of comparisons. 2.6. Subgroup Analysis Pooled effect sizes (small (≈0.2), medium (≈0.5), and large (≈0.8)) were calculated to clarify the effects of different parameters, including substance types, number of sessions, study design (parallel vs crossover), target laterality, stimulation target, stimulation intensity, and stimulation duration. To provide insights about different stimulation protocols, pooled effect sizes were also calculated based on stimulation type (excitatoryvs inhibitory) and stimulation target. 3. Results 3.1. Systematic Review Phase Results 121 TMS, 86 tES, and 1 tFUS studies met our inclusion criteria (see PRISMA flowchart in Figure 1 ). Notably, individual studies often included multiple experiments (e.g., targeting different brain regions), resulting in a greater number of experiments than the total number of studies. Download figure Open in new tab Figure 1. PRISMA Flowcharts for tES, TMS, and tFUS Studies in Substance Use Disorders. This PRISMA flow diagram represents published trials of tES, TMS, and tFUS for individuals with substance use disorders from inception up to 1 January 2024. The last two sections of the PRISMA flow diagram indicate the total number of studies included in the systematic review and meta-analysis (studies that reported craving or consumption/relapse as outcome measures were included in the meta-analysis). Some studies reported both craving and consumption/relapse as outcomes, while others included multiple comparisons (e.g., varying stimulation intensities or control conditions). Consequently, a single publication could contribute multiple assessments/experiments to the analysis. In the systematic review part, “n” refers to the number of publications included, whereas in the meta-analysis part, "n" refers to the total number of assessments (e.g., craving or consumption/relapse assessments). Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation, tFUS: transcranial focused ultrasound stimulation. n=13 studies only defined the protocol, and n=3 studies used results from substance use disorders solely for electric field simulations without pre-post measures. Additionally, we were unable to retrieve the full text for one older study. The included studies were conducted across 21 countries, with the highest contributions from the United States (n=49, 23.7%) and China (n=50, 24.2%). Studies were conducted on different substances, including nicotine (n=62, 28.2%), alcohol (n=60, 27.3%), amphetamines (n=40, 18.2%), cocaine (n=25, 11.4%), opioids (n=25, 11.4%), and cannabis (n=8, 3.6%). The time trend indicates that 60% of the studies were published in the last five years, with a publication peak in 2022 ( Figure 2 ). Download figure Open in new tab Figure 2. Global Distribution and Trends in tES/TMS Studies for Substance Use Disorders. The figure illustrates the global trends in tES/TMS research on substance use disorders. Colors range from light yellow to purple, with darker shades indicating a higher number of publications. Only papers with full text available in English were included, which may lead to a relative over-representation of English-speaking countries. In the lower panels, studies are color-coded by the type of intervention: tES in red and TMS in blue. (a) Global Map of Study Distribution: A heatmap displays the number of published tES/TMS studies in each country, with darker shades representing higher publication densities. (b) Annual Trends in Publications by Country: This panel presents the number of tES/TMS studies categorized by year of publication, grouped by addictive substance and country. (c) Study Distribution by Substance of Use and Country: This panel categorizes the number of tES/TMS studies in each country based on the type of addictive substance studied. Studies are color-coded by intervention type: tES in red and TMS in blue. Note that some studies included multiple types of addictive substances, resulting in a total count of 220 items, which exceeds the actual number of studies included. Abbreviations : tES: transcranial electrical stimulation; TMS: transcranial magnetic stimulation. A total of 5,843 individuals received active stimulation ( Figure 3 ), including 4,303 males, 1,200 females, and 340 participants with unspecified sex. Participants represented various substance use conditions: active users/non-treatment-seekers (44%), treatment-seekers/pre-treatment (23%), detoxification (20%), and recovery (14%) phases. All individuals received one or more sessions of active TMS (n=3,740) or tES (n=2,103). Download figure Open in new tab Figure 3: Participant Demographics in tES/TMS Trials for Substance Use Disorders (Total number of subjects in the active stimulation arm = 5843). This Sankey diagram illustrates the distribution of participants in the active arm, divided by gender, treatment status of their addiction, types of substances used, and types of intervention. The width of the boxes in each column indicates the relative prevalence of each category, while the width of the connecting ribbons represents the proportion of participants shared between categories. Note: ’Multiple’ denotes studies that included participants with various substance use disorders or those that did not specify the dominant substance used by the patients. Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation. Both tES and TMS studies targeted a range of brain regions, categorized into 10 main subregions (See supplementary materials Figure S.1 ). The majority of experiments focused on the dorsolateral prefrontal cortex (DLPFC, 81.5%; left DLPFC: 52.39%, right DLPFC: 29.11%). Other targets included frontopolar cortex (6.5%), insular cortex (4.4%), inferior frontal gyrus (IFG, 2.9%), frontal-parietal-temporal junction (FPT, 2.2%), anterior cingulate cortex (ACC, 0.7%), cerebellar cortex (0.7%), superior frontal gyrus (SFG, 0.4%), posterior cingulate cortex (PCC, 0.4%), and precuneus (0.4%). Figure 4 visualizes the distribution of TMS and tES experiments by stimulation type—excitatory (anodal tDCS, high-frequency TMS), inhibitory (cathodal tDCS, low-frequency TMS), and tACS—and by target region. Download figure Open in new tab Figure 4: Stimulation targets for tES/TMS trials for substance use disorders. Stimulation targets based on the type of stimulation are shown for the cortical surface, Excitatory : HF TMS and anodal tDCS, tACS, Inhibitory : LF TMS, and cathodal tDCS. The depicted number of cortical locations is equal to 299 and exceeds 207 (the total number of tES/TMS studies in this systematic review) due to the application of multiple stimulation protocols in some studies. Notably, in one tDCS study, an HD electrode with anode and cathode placement over the left DLPFC was employed. In studies investigating bilateral and deep TMS stimulation protocols, as well as in one temporoparietal stimulation study, each reported target was considered as two targets: one in each hemisphere. The term "Frontopolar" collectively refers to the medial prefrontal cortex (mPFC), ventromedial prefrontal cortex (vmPFC), and superior medial frontal cortex (sMFC) regions across the studies. Abbreviations : tES: transcranial electrical stimulation, tDCS: transcranial direct current stimulation, tACS: transcranial alternating stimulation, TMS: transcranial magnetic stimulation, HF TMS: high-frequency TMS (≥ 5 Hz), LF TMS: low-frequency TMS (≤ 1 Hz), SFG: superior frontal gyrus, DLPFC: dorsolateral prefrontal cortex, IFG: inferior frontal gyrus, ACC: anterior cingulate cortex, PCC: posterior cingulate cortex. Among the 121 TMS studies reviewed, most employed conventional (fixed/not-patterned frequency) repetitive TMS (rTMS, n=75) followed by intermittent theta burst stimulation (iTBS, n=16), continuous theta burst stimulation (cTBS, n=8), deep transcranial magnetic stimulation (dTMS, n=13), or combinations of different TMS types, such as cTBS and iTBS (n=9). Among the 86 tES studies, the vast majority used transcranial direct current stimulation (tDCS, n=83), with only three studies applying transcranial alternating current stimulation (tACS, n=3). Within the tDCS studies, only one study used 4x1 high-definition (HD) electrodes (n=1), while most employed large conventional electrode pads (n=78); electrode type was not reported for seven tDCS studies (supplementary materials Figure S.2 ). Additional methodological details are presented in supplementary Figures S2–S6, highlighting variability in electrode/coil positioning (most commonly: EEG 10–20 system; n = 112), primary outcome measures (craving: n = 159; consumption/relapse/abstinence: n = 111), and control conditions (most commonly sham-controlled; n = 110). The most frequently used stimulation parameters were 2 mA intensity for tES (n = 65) and 10 Hz frequency for TMS (n = 57). Notably, significant improvements were most often reported following high-frequency TMS over the left DLPFC (n = 153) and anodal tDCS over the right DLPFC (n = 61). 3.2. Risk of Bias of the Included Studies None of the included studies had a high risk of bias. Forty-eight percent (n=56) of the studies had some concerns. The main reason for the studies’ risk of biases being rated as some concerns was related to the “selection of the reported result domain” (n=53), followed by the “randomization process” (n=3). The thorough rating for each study can be found in Supplementary Figure S.7 . 3.3. Meta-Analysis Phase Results From a total of 208 studies, 1 was related to tFUS. Out of 207 tES/TMS studies in our systematic review, our meta-analysis included 50 TMS studies for craving (69 total assessments) and 29 TMS studies for consumption/relapse (64 total assessments). In tES studies, 45 studies for craving (55 total assessments) and 31 studies (total 55 assessments) for consumption/relapses were included. All other reported outcome measures are categorized in supplementary materials Table S.4 . For TMS, we included 1,661 participants in the active group, and 1,610 participants in the sham group for craving, and 711 active and 695 sham participants for consumption. In total, our meta-analysis evaluated data from 5,106 participants in the active groups and 4,914 participants in the sham groups. Our results showed a significant medium effect of TMS on craving (Hedges’ g = 0.52, CI = [0.29, 0.75], p < 0.001, I² = 89.36) and a medium effect on consumption/relapse (Hedges’ g = 0.41, CI = [0.26, 0.56], p < 0.001, I² = 61.56). tES demonstrated a similar medium effect on craving (Hedges’ g = 0.40, CI = [0.25, 0.55], p < 0.001, I² = 60.69) and a small effect on consumption/relapse (Hedges’ g = 0.27, CI = [0.15, 0.38], p = 0.013, I² = 22.67). Associatedforest and funnel plots are available in the supplementary materials, Figures S8, and the specific questionnaires used in the different studies to quantify craving and consumption/relapse are detailed in Figure S.10 . 3.4. Subgroup Analysis In our subgroup analysis, we examined the effects of different stimulation protocols on craving and consumption/relapse outcomes. The analysis identified high-frequency deep TMS with the H4 coil as having the strongest effect on both craving (Hedges’ g = 3.92) and consumption (Hedges’ g = 1.12), with a highly significant p-value of <0.0001 (single study). The H4 coil is designed to target the anterior cingulate cortex (ACC) and the bilateral insula, which are key regions involved in the salience network (this coil induces the maximum electric field strength over the frontopolar area). This effect was followed by high-frequency repetitive TMS (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC), which also showed significant (p < 0.05) reductions in craving (Hedges’ g = 0.65, in a total 21 studies) and consumption (Hedges’ g = 0.52, in a total 14 studies). Among the tES protocols, anodal tDCS over the left DLPFC with return electrode over the right DLPFC showed significant (p < 0.05) effects in reducing both craving (Hedges’ g = 0.38, 14 studies) and consumption (Hedges’ g = 0.3, 10 studies). Similarly, cathodal tDCS over the left DLPFC with the return electrode over the right DLPFC showed strong evidence (p < 0.0001) for reducing craving (Hedges’ g = 0.49, 23 studies) and consumption (Hedges’ g = 0.42, 15 studies). To show the primary target region in each protocol, we created computational head models to visualize the electric field distribution over the cortex. Based on the results, the frontopolar area in the H4 coil trials, DLPFC stimulation in tES trials, with the stimulating electrode positioned over the left or right DLPFC and the return electrode placed on the contralateral DLPFC, and the left DLPFC in rTMS trials (which demonstrated the largest Hedges’ g values) received the maximum electric field strength ( Figure 5 ). Further subgroup analyses to show the effects of different parameters such as substance type, session type, randomization, hemisphere targeted, stimulation target, stimulation polarity or frequency, symmetry of stimulation or type of the coil, intensity, and duration of treatment can be found in supplementary materials Figure S.9 . (e.g., for substance type, significant effects of tES on craving were found for opioids (Hedges’ g ≈ 1.26, p = 0.000), multiple substances (Hedges’ g ≈ 0.85, p = 0.022), nicotine (Hedges’ g ≈ 0.45, p = 0.011), and amphetamines (Hedges’ g ≈ 0.44, p = 0.000). For tES consumption, a significant effect was observed for multiple substances (Hedges’ g ≈ 0.98, p = 0.000). TMS significantly reduced craving for opioids (Hedges’ g ≈ 1.15, p = 0.006) and amphetamines (Hedges’ g ≈ 0.93, p = 0.000), and significantly reduced consumption for cocaine (Hedges’ g ≈ 1.25, p = 0.022) and nicotine (Hedges’ g ≈ 0.47, p = 0.000). All other subgroup effects were not statistically significant). Download figure Open in new tab Figure 5: Exploring Overall Effects of 36 Protocols in tES/TMS Studies on Craving and Consumption. This figure illustrates the impact of tES/TMS on craving and consumption/relapse by examining different types of stimulation protocols. The total number of experiments is color-coded, with tES studies in red and TMS studies in blue. Additionally, the total number of participants in the active and sham arms is indicated in parentheses. Each horizontal line within the plots represents a distinct stimulation protocol, with dots for effect sizes and horizontal lines for confidence intervals. Computational head models show the protocols with the largest significant Hedges’ g values in rTMS, dTMS, and tES trials, highlighted in green. In the tES section, the first position indicates anode placement, and the second indicates cathode placement. Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation, dTMS: deep transcranial magnetic stimulation. The figure includes three color codes: red, blue, and green. tES protocols are coded in red, while TMS protocols are coded in blue. The heatmap represents the number of studies, with darker tones indicating a higher number of assessments that utilized the corresponding protocol. On the right panel, rTMS, dTMS, and tES protocols are sorted based on the number of assessments that are used in each protocol. Protocols with significant Hedge’s g values in both craving and consumption outcomes are highlighted in green, and their computational head models are presented. 4. Discussion This systematic review and meta-analysis evaluated the parameter space of NIBS techniques — TMS, tES, and tFUS — for SUDs and quantified their effects on drug craving and consumption/relapse. A total of 208 studies published through early 2024 (TMS=121, tES=86, tFUS=1) were included, revealing substantial heterogeneity in experimental design, stimulation protocols, target regions, and outcome measures. The meta-analysis incorporated 50 TMS studies (69 assessments), 45 tES studies (55 assessments) examining craving, and 29 TMS studies (64 assessments) and 31 tES studies (55 assessments) examining consumption/relapse, constituting the largest analysis to date in this field. The results showed that TMS had significant medium effects on both craving and consumption/relapse reduction ( g = 0.52 and g = 0.41, respectively), while tES had a medium effect on craving ( g = 0.40) and a small effect on consumption/relapse ( g = 0.27). Subgroup analyses revealed notable variability in participant characteristics, study designs, stimulation parameters, and treatment efficacy. Among 34 evaluated protocols, the most effective approaches included: (1) tES targeting the DLPFC with a bilateral montage (stimulating electrode over the left or right DLPFC and return electrode on the contralateral side with maximal electric field over the frontopolar cortex), (2) high-frequency deep TMS using an H4 coil targeting the ACC and bilateral insula (regions within the salience network, with maximal electric field over the frontopolar cortex), and (3) high-frequency rTMS over the left DLPFC. Additional subgroup findings indicated that tES was most effective in opioid, nicotine, and polysubstance use disorders, while TMS showed significant effects in nicotine, cocaine, amphetamine, and opioid use disorders. Both single- and multi-session tES trials significantly reduced craving, whereas only multi-session TMS trials were effective in reducing consumption. Other stimulation parameters did not show consistent effects across craving and consumption/relapse outcomes. The largest prior meta-analysis by Song et al. (2019) included 1,095 participants with conditions including alcohol, nicotine, illicit drug, and food-related disorders. 17 While their results indicated that active stimulation (tDCS and TMS) outperformed sham, the final meta-analysis results differed in some aspects from our findings. The divergence of findings could be related to differences in the included trials. Nevertheless, similar to our findings, their TMS results showed a medium effect on craving (g=0.52, CI=[0.29, 0.75], p<0.001, I²=89.36) and consumption (g=0.45, CI=[0.25, 0.65], p<0.001, I²=67.7). tES showed a medium effect on craving (g=0.40, CI=[0.25, 0.55], p<0.001) and a small effect on consumption (g=0.19, CI=[0.06, 0.32], p=0.015) (12). These results contrast with Mostafavi et al. (2020), which reported no significant effects of tDCS/rTMS in 617 participants with alcohol use disorders, 18 but align with many other meta-analyses in the field. 6 , 17 , 19 – 22 Comparing multi-session and single-session protocols, we found that increasing the number of TMS sessions was linked to larger reductions in craving and consumption, consistent with the meta-analysis by Song et al. (2019), 17 who reported a larger impact from multi-session protocols. Within the same meta-analysis, a focused analysis of rTMS over the DLPFC also found a significant positive correlation between the total number of stimulation pulses and craving reduction effect size in studies employing excitatory stimulation over the left DLPFC (P = 0.01). 17 However, our results for tES were more heterogeneous: while both single (n=24) and multi-session (n=31) tES protocols significantly reduced craving, only single-session (n=7), not multi-session (n=25), protocols showed a significant effect on consumption. This may be potentially due to the early assessment conducted shortly after the single stimulation, the high dropout rate in follow-ups for multi-session trials, which is a common challenge in SUD studies, or the low number of single-session studies of consumption. In this vein, it is important to note that while sufficient multi-session TMS trials (n=50 for craving and n=43 for consumption) were available, the number of trials for single-session TMS was limited (n=19 for craving and n=2 for consumption), potentially similarly affecting the robustness of these findings. Additionally, the effectiveness of rTMS in reducing craving was protocol-dependent, with variability observed across studies. The differences in outcomes may also reflect the heterogeneity in protocols, including variations in stimulation intensity, duration, frequency, and electrode/coil positioning. For example, while some protocols demonstrated strong positive effects, others yielded unclear or even negative outcomes. This variability underscores the need to interpret aggregated results cautiously, as averaging across diverse protocols may obscure the positive effects of specific approaches. Interestingly, no significant effects were observed for alcohol use disorder in the studies included in the meta-analysis, which may be due to insufficiently tailored protocols or the limited number of high-quality trials focusing on this substance. Despite the promising results, only one protocol has received FDA clearance to date. Our meta-analysis identified this FDA-cleared protocol—dTMS with the H4 coil—as having the largest effect size compared to the other included 34 protocols (including rTMS, dTMS with different coils, and tES). However, more studies are needed with this coil with craving and consumption as outcome measures. 23 The next most efficacious protocol, high-frequency rTMS over the left DLPFC, showed a medium but significant effect on both outcomes, supported by 21 published papers. This protocol has received CE approval in Europe for psychoactive substance use disorder (PSUD) based on the results of only two SUD trials in cocaine addiction. 24 – 26 This efficacy is in line with the meta-analysis by Zhang et al. (2019), 27 who reported that excitatory rTMS of the left DLPFC was effective in reducing substance craving and consumption (Hedge’s g = -0.62), with a significant positive association between the total number of stimulation pulses and effect size (P = 0.01). Tseng et al. (2022) 28 also found that 10-Hz rTMS over the left DLPFC was associated with the largest decrease in smoking frequency (standardized mean difference = -1.22). Additionally, Petit et al. (2022) 29 reported that the participants who received tES/TMS were 2.39 times more likely to achieve sustained abstinence compared to those receiving sham stimulation, with an even greater likelihood observed for rTMS over the left DLPFC (risk ratio = 4.34) and for deep rTMS targeting the lateral prefrontal cortex and insula bilaterally (risk ratio = 4.64). However, TMS applied to the right DLPFC showed mixed effects. For tES, placing the anode over either the left or right hemisphere significantly affected craving reduction. However, laterality had no significant impact on reducing consumption or relapse. The most effective tES protocols involved bilateral DLPFC stimulation with the anode placed over either the left or right DLPFC, which induced the maximum electric fields over the frontopolar area. 30 5. Limitations This meta-analysis has several limitations that should be considered when interpreting the findings. Our literature search was restricted to English-language databases, potentially missing relevant studies published in other languages. There was substantial clinical heterogeneity (e.g., participant characteristics, substances used) and methodological variability (e.g., study design and outcome assessments) among the included studies. Despite these differences, the data from these studies were aggregated and analyzed as if they represented a single, uniform sample and intervention, which may have influenced the findings. Additionally, our meta-analysis included a variety of tools for measuring craving and consumption, with 17 different questionnaires for craving, 12 for objective, and 4 for subjective measures of consumption ( Figure S.10 ). This diversity in measurement tools may introduce inconsistencies and limit the comparability of results across studies. Differences in study designs, such as variations in session duration, frequency, and intervention intensity, may also have influenced the overall effect sizes, contributing to the observed heterogeneity. These factors emphasize the need for identifying the optimal features (for enhancing select outcomes) that could then be used to develop more standardized protocols in future research to enable more precise comparisons. 6. Conclusion This systematic review and meta-analysis, the largest to date, provided a comprehensive overview of the parameter space and therapeutic effects of NIBS technologies for SUDs. Analyzing 207 TMS and tES studies across 21 countries, along with one tFUS study, the findings underscore both the promise and complexity of NIBS interventions in this field. These findings suggest that: (1) both TMS and tES show significant therapeutic effects for SUDs, with varying levels of effectiveness, (2) both conventional and deep TMS, as well as bilateral DLPFC-targeted tES, demonstrate clinical utility, with the strongest evidence observed for deep TMS (dTMS)—though this is currently based on a single published study and requires replication, (3) the frontopolar cortex—receiving the highest electric field from the FDA-approved H4 dTMS coil and bilateral DLPFC tES montages—emerges as a promising target, supported by converging neuroimaging and lesion-mapping evidence, 31 , 32 (4) while dTMS shows a larger effect size, the left DLPFC remains a validated and widely studied target. Together, these findings highlight the potential of targeting both frontopolar-limbic and DLPFC-executive control circuits as dual intervention pathways in SUD treatment. 33 The global contribution to these studies suggests strong scalability of NIBS technologies, although cost-effectiveness and accessibility remain important areas for future investigation. Data Availability All data produced in the present study are available upon reasonable request to the authors. Funding Research reported in this publication was supported by the University of Minnesota MnDRIVE (Minnesota’s Discovery, Research and Innovation Economy) initiative awarded to G.S. and University of Minnesota’s Medical Discovery Team on Addiction (MDTA) support for International Network of tES/TMS Trials for Addiction Medicine (INTAM) ( https://med.umn.edu/addiction/network/intam ) awarded to H.E. COI: M.A.N. is a member of the scientific advisory boards of Neuroelectrics and Precisis. C.H. is a member of BrainsWay’s senior leadership (since November 2022) and has a financial interest in BrainsWay. She has also served on an advisory board for Welcony-Magstim and as a consultant for BrainsWay and Roswell Park Cancer Center. M.B. is an inventor on patents held by The City University of New York related to brain stimulation and holds equity in Soterix Medical Inc. He has served as a consultant, expert witness, grantee, or scientific advisor for multiple entities, including SafeToddles, Zabara Family Foundation, Boston Scientific, GlaxoSmithKline, Biovisics, Axonics, Mecta, SigmaStim, Lumenis, Halo Neuroscience, Wave Neuroscience, Google-X, i-Lumen, Humm, Neurolief, Allergan (AbbVie), Apple, Ybrain, Ceragem, Ceragem Clinical, and Remz. M.K.J. has received contract research grants from Neurocrine Bioscience, Navitor/Supernus, and Janssen Research & Development; honoraria for editorial roles with Psychiatry & Behavioral Health Learning Network and Psychiatric Clinics of North America (Elsevier); consulting fees from Janssen Scientific Affairs and Boehringer Ingelheim; DSMB service fees for studies funded by Eliem, Skye, Inversago, Vicore Pharma, and IQVIA; and speaker honoraria from multiple CME organizations. B.L.F. has received funding and in-kind donations from Indivior and Canopy Growth Corporation through CAMH and the University of Toronto. He has served on advisory boards or as a consultant for Indivior, Shinogi, and ThirdBridge, and has received travel support from Bioprojet. He is supported by CAMH, Waypoint Centre for Mental Health Care, and holds academic awards and a Chair in Addiction Psychiatry at the University of Toronto. V.M.T. has received research support from the Brain & Behavior Research Foundation, Canadian Institutes of Health Research, Physician Services Incorporated Foundation, NIDA, CAMH Discovery Fund, and several other institutional and philanthropic sources. The remaining authors have nothing to disclose. Supplementary materials Search terms View this table: View inline View popup Download powerpoint Table S.1. key terms used to search in the PubMed database Data extraction process After finalizing the inclusion process, literature search results were imported into three separate sheets for TMS, tES, and tFUS studies. Data extracted from the literature were filled into a spreadsheet by AS and HT. Consistency between the authors was honed through a calibration exercise in which all authors evaluated and discussed their ratings for 20 randomly chosen studies. 1 GS further refined the data extraction form to reduce inconsistency and ambiguity after the exercise. Data on study design features and basic methodological parameters were extracted first, and each article was reviewed independently by two investigators (AS and HT) in two separate spreadsheets, with inconsistencies resolved in discussions with GS and HE. Despite following a similar data extraction policy to the previously published INTAM systematic review, 2 a comprehensive screening of the literature by 2018 was conducted once again to ensure the absence of any inconsistencies. This step was taken to guarantee the accuracy and reliability of the extracted data. By re-screening the entire range of publications within the specified timeframe, potential discrepancies or errors in the data extraction process were identified and rectified. This approach aimed to maintain the integrity and consistency of the review, providing a robust foundation for the analysis and conclusions drawn from the included studies. Inclusion/Exclusion criteria and data extraction The initial search yielded a total of 508 articles on TMS, 663 articles on tES, and 156 articles on tFUS. Two independent investigators (AS, HT) reviewed the list of included studies and collected the coded data, and the 3 rd investigator (GS) reviewed the collected databases and solved eventual conflicts. During the initial screening, based on titles and abstracts, 179 TMS records, 418 tES records, and 151 tFUS records were excluded. The reasons for exclusion encompassed articles that were book chapters, commentaries, author corrections, editorials, and studies focused on disorders other than substance use disorders (SUDs). One TMS study was identified as a duplicate under a different title. Subsequently, 327 TMS articles, 242 tES, and 5 tFUS articles progressed to the next stage, which involved full-text screening to identify eligible articles. A precise full-text review was conducted, resulting in the inclusion of 121 TMS, 86 tES, and 1 tFUS articles. Exclusion criteria at this stage included review articles, studies with only healthy subjects, case reports and case series, studies involving subjects other than humans, study protocols, electric field modeling, and studies published in languages other than English. Single or paired-pulse TMS studies were excluded, while studies including repetitive transcranial magnetic stimulation (rTMS) and deep transcranial magnetic stimulation (dTMS) (a type of rTMS) were included. Notably, no published study utilizing transcranial random noise stimulation (tRNS) in the field of tES was identified. The PRISMA flowchart illustrating the inclusion/exclusion procedure for TMS, tES, and tFUS studies are presented in Figure 1 , respectively. Publication details, including the country of publication (defined as the first affiliation of the first author, or the affiliation of the majority of the authors if the country of the first author was unclear), the publication year (based on PubMed’s indexing), the main substance(s) of interest in the study, the main site of stimulation (were the stimulation electrode or coil is placed), the number of active stimulation sessions (participants received active tES or TMS), the number of subjects in the active arms, and the number of female subjects in the active arm were extracted. We categorized the current state of participants to four distinct time intervals at which the interventions were administered: (1) before the participant sought standard treatment (2) while the subject was treatment seeking but before undergoing standard treatment, (3) within the first month of standard treatment (mainly detoxification and stabilization) and (4) after the initial recovery period (more than one month). Additionally, the duration of the follow-up period, the control condition (active, sham, another therapy, another clinical population, or no-control conditions), the randomization method, the coil/electrode positioning system, the stimulation dose (for TMS: site of pulses, stimulation type, frequency, intensity, and the number of pulses; for tES: anode/cathode size and location, stimulation intensity, and duration), and the primary/secondary outcome measures were extracted. Additionally, a binary rating system (Yes/No) was used to indicate whether a study observed any significant effects on a specific outcome measure in response to the stimulation. We also checked if computational head models were generated for electric field distribution pattern assessment. View this table: View inline View popup Table S.2. Data Extraction for tES Studies. View this table: View inline View popup Table S.3. Data Extraction for TMS Studies. Stimulation targets Download figure Open in new tab Figure S.1. Variations in Targets in tES/TMS Studies for Substance Use Disorders. This figure displays the number of studies tackling specific target areas. The studies are color-coded, with tES in red and TMS in blue. Note that some studies utilize multiple stimulation protocols, resulting in 275 total targets in this figure, exceeding the actual number of studies included. Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation, DLPFC: dorsolateral prefrontal cortex, FPC: frontopolar cortex, IFG: inferior frontal gyrus, TPC: temporoparietal cortex, ACC: anterior cingulate cortex, SFG: superior frontal gyrus, PCC: posterior cingulate cortex. Electrode/coil positioning system Of the 121 TMS studies reviewed, the majority focused on conventional repetitive transcranial magnetic stimulation (rTMS) (n=75). The remaining studies utilized intermittent theta burst stimulation (iTBS) (n=16), continuous theta burst stimulation (cTBS) (n=8), deep transcranial magnetic stimulation (dTMS) (n=13), or combinations of different TMS types, such as cTBS and iTBS (n=9). Among the 86 tES studies analyzed, the vast majority utilized transcranial direct current stimulation (tDCS) (n=83), while only three studies employed transcranial alternating current stimulation (tACS) (n=3). Among the tDCS studies, only one study utilized 4x1 high-definition (HD) electrodes (n=1), whereas the remaining tES studies employed large conventional electrode pads (n=78). For 7 tDCS studies, the type of electrodes used was not reported. Download figure Open in new tab Figure S.2. Types of Stimulation, Coils/Electrodes, Targets, and Positioning Systems in tES/TMS Studies for Substance Use Disorders. This Sankey diagram depicts the distribution of 207 tES/TMS studies, categorized by the type of stimulation, coil/electrode, target area, and positioning system used. The number of studies is indicated in parentheses within the boxes. Note: ’Multiple’ in the ’Type’ layer refers to studies that employed a combination of two different types of stimulation (e.g., cTBS and iTBS). ’Multiple’ in the ’Electrodes or Coil’ layer refers to studies that utilized a combination of two different coil shapes (e.g., deep and figure 8). ’Multiple’ in the ’Target’ layer refers to studies that employed a combination of different target areas. Abbreviations : TMS: transcranial magnetic stimulation, tES: transcranial electrical stimulation, rTMS: repetitive TMS, dTMS: deep TMS, iTBS: intermittent theta burst stimulation, cTBS: continuous theta burst stimulation, tDCS: transcranial direct current stimulation, tACS: transcranial alternating current stimulation, EEG: electroencephalography, MRI: magnetic resonance imaging, DLPFC: dorsolateral prefrontal cortex, FPC: frontopolar cortex, IFG: inferior frontal gyrus, TPC: temporoparietal cortex, SFG: superior frontal gyrus. In total, 207 TMS/tES studies were included in the analysis, employing various methods for positioning tES electrodes or TMS coils over the scalp. The most commonly utilized method was based on the EEG standard system (n=112). Additionally, other methods such as MRI-guided techniques (n=17) and Beam F3 methods (n=12) were used. Some studies utilized scalp measurements and applied different rules for electrode or coil placement using anatomical landmarks, including the 5 cm rule (n=26), 6 cm rule (n=13), 5.5 cm rule (n=4), and 4 cm rule (n=1). For 21 studies, the positioning system used was not reported. Outcome measures Each study included in our systematic review reported a diverse range of primary and secondary outcome measures. To organize and categorize these measures, we extracted data from the full text of the studies and identified seven main categories. We recorded both significant and non-significant results reported in the abstract for each outcome measure (see Figure S.6 .). The most commonly reported outcome measure across the majority of studies was "craving" (n=159), with 84 significant reductions and 39 non-significant changes in response to TMS/tES reported in the abstracts. Other frequently reported outcome measures included "consumption/relapse/abstinence" (n=111), "cognitive functions" (n=95), "physiological measures" (n=76), "negative valence" (n=59), "mental/general health" (n=33), and "positive valence" (n=8). Additionally, a few other outcome measures were reported, categorized as “other” (n=10). Across all studies, a total of 317 significant effects and 99 non-significant alterations in response to TMS/tES on the outcome measures were reported. Download figure Open in new tab Figure S.3. Reported Outcome Measures and Their Significance in tES/TMS Studies for Substance Use Disorders Considering Type of Substances. This figure illustrates the various outcome measures from past tES and TMS studies, color-coded by the type of stimulation—tES in red and TMS in blue—and categorized by the type of substance use disorder. Colors range from light yellow to purple, with darker shades indicating a higher number of publications. Note that some studies have included more than one type of substance and outcome measures, resulting in the total items in this figure equaling 551 and exceeding the actual number of 207 studies included. The number of significant and non-significant outcome measures is depicted in line bar graphs, which are color-coded by significance: dark colors indicate significant, and light colors indicate non-significant results. Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation. Outcome measures based on stimulation targets To examine the impact of the stimulation target, type of stimulation (excitatory or inhibitory), and coil/electrode positioning system on the reported results (significant or non-significant alterations), our analysis revealed noteworthy findings. Specifically, for TMS studies, the most significant responses were observed in high-frequency stimulation of either the left or right DLPFC. Left DLPFC stimulation yielded 153 significant and 32 non-significant responses, while right DLPFC high-frequency stimulation resulted in 50 significant and 14 non-significant responses. Similar patterns were identified in tES studies, where excitatory DLPFC stimulation proved to be the most effective protocol. Notably, anodal tDCS targeting the right DLPFC exhibited 61 significant and 25 non-significant responses, while anodal tDCS targeting the left DLPFC produced 53 significant and 28 non-significant alterations. Download figure Open in new tab Figure S.4-1. Reported Outcome Measures and Their Significance in tES/TMS Studies for Substance Use Disorders Considering Target Location and Stimulation Type. This figure illustrates the various outcome measures from 207 tES and TMS studies, color-coded by the type of stimulation—tES in red and TMS in blue—and categorized by the target location and type of stimulation (excitatory: anodal tES or HF TMS, inhibitory: cathodal tES or LF TMS). It is important to note that the total numbers reported for outcome measures do not add up to 207, as some studies reported multiple outcome measures. The number of significant and non-significant outcome measures is depicted in line bar graphs, color-coded by significance: dark colors indicate significant, and light colors indicate non-significant results. Abbreviations : tES: transcranial electrical stimulation, tDCS: transcranial direct current stimulation, tACS: transcranial alternating stimulation, TMS: transcranial magnetic stimulation, HF TMS: high-frequency TMS (≥ 5 Hz), LF TMS: low-frequency TMS (≤ 1 Hz), DLPFC: dorsolateral prefrontal cortex, FPC: frontopolar cortex, IFG: inferior frontal gyrus, TPC: temporoparietal cortex, ACC: anterior cingulate cortex, SFG: superior frontal gyrus, PCC: posterior cingulate cortex. Considering that DLPFC stimulation emerged as the most frequently utilized target, yielding a substantial number of significant outcomes, we further explored the influence of electrode/coil positioning systems on the reported results. In TMS studies, several positioning methods demonstrated effectiveness in targeting the left DLPFC with high-frequency stimulation. The EEG standard system resulted in 39 significant and 9 non-significant responses, the 5 cm rule yielded 33 significant and 9 non-significant responses, MRI-guided techniques showed 20 significant and 1 non-significant responses, and the 6 cm rule resulted in 26 significant and 3 non-significant responses. In targeting the right DLPFC, the EEG standard system resulted in 15 significant and 7 non-significant responses. For tES studies, the EEG standard system proved to be the most effective positioning method for both right DLPFC (54 significant and 23 non-significant responses) and left DLPFC (44 significant and 24 non-significant responses) for anodal tDCS over DLPFC. Download figure Open in new tab Figure S.4-2. Relationship Between Stimulation Type, Positioning Method, and Significant Outcomes in DLPFC-Targeted tES/TMS Studies. This figure illustrates the various outcome measures from 207 tES and TMS studies that targeted DLPFC, color-coded by the type of stimulation—tES in red and TMS in blue—and categorized by the type of stimulation (excitatory: anodal tES or HF TMS, inhibitory: cathodal tES or LF TMS) and electrode/coil positioning system. The number of significant and non-significant outcome measures is depicted in line bar graphs, color-coded by significance: dark colors indicate significant, and light colors indicate non-significant results. In the square panels, studies are color-coded by the type of intervention: tES in red and TMS in blue and darker shades indicating a higher number of studies. Abbreviations: tES: transcranial electrical stimulation, tDCS: transcranial direct current stimulation, tACS: transcranial alternating stimulation, TMS: transcranial magnetic stimulation, HF TMS: high-frequency TMS (≥ 5 Hz), LF TMS: low-frequency TMS (≤ 1 Hz), DLPFC: dorsolateral prefrontal cortex. Study design and control condition The study designs in our systematic review were categorized into two main types, parallel and crossover, and excluded all studies without a control condition. The most commonly utilized control condition across both TMS (n=62) and tES (n=48) studies was "sham control." However, other control methods were also employed, including active control, therapy other than TMS/tES, healthy control, other types of clinical populations, or combinations of different control conditions. Download figure Open in new tab Figure S.5. Variations in Study Design and Control Conditions in tES/TMS Studies for Substance Use Disorders. This figure presents the number of tES/TMS studies in substance use disorders, categorized by the type of randomization and divided by the control condition. The studies are color-coded according to the type of intervention, with tES in red and TMS in blue. Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation. Dosage, number of sessions, and follow-up Considering the stimulation dose, our analysis revealed the utilization of various pulse frequencies in the included TMS studies. The most commonly used pulse frequency was 10 Hz (n=57). Additionally, other stimulation frequencies were employed, including 50 Hz (n=39), 20 Hz (n=21), 1 Hz (n=12), 15 Hz (n=8), and 5 Hz (n=1) which can be assigned to excitatory (high-frequency TMS (≥ 5 Hz)), or inhibitory (low-frequency TMS (≤ 1 Hz)) stimulation. Among the tES studies, the dominant stimulation dose was found to be 2 mA (n=65). The second most frequently used dose was 1 mA, with 11 trials reporting its utilization. Additionally, 1.5 mA (n=8) and 0.45 mA (n=2) were employed in previous studies. Out of the 86 tES studies, 3 used tACS. Among the remaining 83 tDCS studies, 75 used anodal electrodes (excitatory), while 7 used cathodal electrodes (inhibitory) over their main brain target. One study employed both anodal and cathodal electrodes over their target across two different study arms. One TMS and one tES study did not report the stimulation frequency/intensity. Download figure Open in new tab Figure S.6-1. Variations in Stimulation Parameters in tES/TMS Studies for Substance Use Disorders. This figure displays the number of studies with different stimulation frequencies, which serve as an indicator of TMS dose, and electrical current intensity, which indicates the dose in tES studies (for tACS studies, the peak-to-peak current amplitude is considered). The studies are color-coded, with tES in red and TMS in blue. Abbreviations : tES: transcranial electrical stimulation; TMS: transcranial magnetic stimulation. In terms of the number of sessions included in the studies analyzed, we found that 30 TMS studies and 37 tES studies comprised single-session trials. For multi-session trials, 22 TMS and 15 tES studies applied 10 active stimulation sessions. 24 TMS and 2 tES studies applied 20 sessions of stimulation. 1 TMS trial applied 44 active stimulation sessions. Most of these studies had no follow-up, however, the most common duration for follow-up was less than one month (TMS: n=14, tES: n=10). Download figure Open in new tab Figure S.6-2. Variation in the Number of Sessions and Follow-Ups in tES/TMS Studies for Substance Use Disorders. This figure illustrates the follow-up durations, categorized by the number of stimulation sessions, with TMS represented in blue and tES in red. The follow-up durations are organized into 9 main groups to summarize the results succinctly. Abbreviations: tES: transcranial electrical stimulation; TMS: transcranial magnetic stimulation. Risk of bias Download figure Open in new tab Figure S.7-1. Risk of Bias of tES studies using the Cochrane Risk of Bias (RoB) 2 tool. The figures summarize the judgments across key domains of bias, including (1) bias due to the randomization process and timing of identification or recruitment of participants, (2) deviation from intended intervention, (3) missing outcome data, (4) measurement of outcomes, (5) selection of the reported result. Each domain is categorized as “Low risk”, “Some concerns”, or “High risk” bias. The overall judgment for risk of bias is shown in the last column. Download figure Open in new tab Figure S.7-2. Risk of Bias of TMS studies using the Cochrane Risk of Bias (RoB) 2 tool. The figures summarize the judgments across key domains of bias, including (1) bias due to the randomization process and timing of identification or recruitment of participants, (2) deviation from intended intervention, (3) missing outcome data, (4) measurement of outcomes, (5) selection of the reported result. Each domain is categorized as “Low risk”, “Some concerns”, or “High risk” bias. The overall judgement for risk of bias is shown in the last column. Funnel plot Download figure Open in new tab Figure S.8-1. Funnel Plots for tES and TMS Studies on Craving and Consumption/Relapse This figure presents funnel plots illustrating the heterogeneity across studies on craving and consumption/relapse for both tES and TMS protocols. Panel A (upper left) shows the funnel plot for tES studies on craving, while Panel B (upper right) displays the funnel plot for tES studies on consumption/relapse. Panel C (lower left) illustrates the funnel plot for TMS studies on craving, and Panel D (lower right) shows the funnel plot for TMS studies on consumption/relapse. In each plot, dots represent individual studies, with the y-axis representing study precision (standard error) and the x-axis representing the study’s estimated effect size (Hedges’ g). Larger studies with greater precision are shown at the top, while smaller, less precise studies scatter more widely at the bottom. Abbreviations: tES: transcranial electrical stimulation; TMS: transcranial magnetic stimulation. Forest plots Download figure Open in new tab Figure S.8-2. Forest plot for tES effects on Craving. Hedges’ g values for studies that reported craving in response to transcranial electrical stimulation (tES, with a total number of n=45 studies and 55 experiments). This forest plot provides a detailed analysis of the influence of tES on craving in various studies. Each horizontal line represents a specific study, with squares denoting effect sizes and horizontal lines indicating confidence intervals. Positive values indicate that active stimulation was effective in reducing craving. The diamond at the bottom illustrates the overall effect size across all studies, with the width representing the confidence interval. Units of analysis are added to studies with multiple experiments to highlight differences in study design. Abbreviations : tES: transcranial electrical stimulation, tDCS: transcranial direct current stimulation, tACS: transcranial alternating stimulation, DLPFC: dorsolateral prefrontal cortex, IFG: inferior frontal gyrus, CBM: cognitive bias modification, ABM: attentional bias modification, CCAT: computerized cognitive addiction therapy, Exp: experimental. Download figure Open in new tab Figure S.8-3. Forest plot for tES effects on Consumption/Relapse. Hedges’ g values for studies that reported consumption/relapse in response to transcranial electrical stimulation (tES, with a total number of n=31 studies and 55 experiments). This forest plot provides a detailed analysis of the influence of tES on consumption/relapse in various studies. Each horizontal line represents a specific study, with squares denoting effect sizes and horizontal lines indicating confidence intervals. Positive values indicate that active stimulation was effective in reducing consumption/relapse. The diamond at the bottom illustrates the overall effect size across all studies, with the width representing the confidence interval. Units of analysis are added to studies with multiple experiments to highlight differences in study design. Abbreviations: tES: transcranial electrical stimulation, tDCS: transcranial direct current stimulation, CBM: cognitive bias modification, ABM: attentional bias modification, AICT: alcohol cue inhibitory control training, NICT: neutral inhibitory control training, PE: psycho-education, Exp: experiment, mA: milliampere. Download figure Open in new tab Figure S.8-4. Forest plot for TMS effects on Craving. Hedges’ g values for studies that reported craving in response to transcranial magnetic stimulation (TMS, with a total number of n=50 studies and 69 experiments). This forest plot provides a detailed analysis of the influence of TMS on craving in various studies. Each horizontal line represents a specific study, with squares denoting effect sizes and horizontal lines indicating confidence intervals. Positive values indicate that active stimulation was effective in reducing craving. The diamond at the bottom illustrates the overall effect size across all studies, with the width representing the confidence interval. Units of analysis are added to studies with multiple experiments to highlight differences in study design. Abbreviations : TMS: transcranial magnetic stimulation, cTBS: continuous theta burst stimulation, iTBS: intermittent theta burst stimulation, HF TMS: high-frequency TMS (≥ 5 Hz), LF TMS: low-frequency TMS (≤ 1 Hz), DLPFC: dorsolateral prefrontal cortex, FPC: frontopolar cortex, MA: methamphetamine, C0: cognitive behavioral therapy treatment without fixed schedule, C1: cognitive behavioral therapy treatment with fixed schedule. Download figure Open in new tab Figure S.8-5. Forest plot for TMS effects on Consumption/Relapse. Hedges’ g values for studies that reported consumption/relapse in response to transcranial magnetic stimulation (TMS, with a total number of n=29 studies and 64 experiments). This forest plot provides a detailed analysis of the influence of TMS on consumption/relapse in various studies. Each horizontal line represents a specific study, with squares denoting effect sizes and horizontal lines indicating confidence intervals. Positive values indicate that active stimulation was effective in reducing consumption. The diamond at the bottom illustrates the overall effect size across all studies, with the width representing the confidence interval. Units of analysis are added to studies with multiple experiments to highlight differences in study design. Abbreviations: TMS: transcranial magnetic stimulation, HF TMS: high-frequency TMS (≥ 5 Hz), LF TMS: low-frequency TMS (≤ 1 Hz), d: day, Obj: objective, Subj: subjective, DDD: drinks per drinking day, TLFB: timeline follow back, d: day. Subgroup analysis Download figure Open in new tab Figure S.9-1. Exploring Overall Effects and Subgroup Analyses. This figure presents the results of a subgroup analysis on craving and consumption, featuring forest plots that detail the effect sizes by type of substance. These plots offer an in-depth look at the impact of tES/TMS on craving and consumption by examining the role of the type of stimulation. Each horizontal line within the plots represents a distinct substance use disorder, with dots for effect sizes and horizontal lines for confidence intervals. Additionally, bar plots show the number of participants in the active (dark colors) and sham (light colors) arms. The total number of experiments is noted in parentheses adjacent to the related moderator. The final four rows illustrate the cumulative effects of stimulation on craving and consumption, with bars color-coded by the type of stimulation: tES studies in red and TMS studies in blue. Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation. Download figure Open in new tab Figure S.9-2. Exploring Subgroup Analyses of tES Effects on Craving. This figure displays the results of a subgroup analysis focusing on craving, featuring forest plots that illustrate the effect sizes by different types of moderators. These plots provide a comprehensive analysis of the impact of tES on craving, considering key factors such as number of sessions, randomization, hemisphere, target, polarity, symmetry in DLPFC stimulation (in minutes), intensity (in mA), and stimulation duration. Each horizontal line within the plots signifies a specific moderator, with dots representing effect sizes and horizontal lines denoting confidence intervals. In addition, bar plots indicate the number of participants in the active (dark colors) and sham (light colors) arms, with the total number of experiments mentioned in parentheses next to each relevant moderator. Note that two studies did not report tES intensity. The hemisphere subgroup pertains to studies targeting the DLPFC. The left/right refers to tACS studies. Abbreviations: tES: transcranial electrical stimulation, tACS: transcranial alternating stimulation, DLPFC: dorsolateral prefrontal cortex. Download figure Open in new tab Figure S.9-3. Exploring Subgroup Analyses of tES Effects on Consumption. This figure displays the results of a subgroup analysis focusing on consumption, featuring forest plots that illustrate the effect sizes by different types of moderators. These plots provide a comprehensive analysis of the impact of tES on consumption, considering key factors such as the type of outcome measurement, outcome assessment timepoint, number of sessions, randomization, hemisphere, target, polarity, symmetry in DLPFC stimulation, intensity, and stimulation duration. Each horizontal line within the plots signifies a specific moderator, with dots representing effect sizes and horizontal lines denoting confidence intervals. In addition, bar plots indicate the number of participants in the active (dark colors) and sham (light colors) arms, with the total number of experiments mentioned in parentheses next to each relevant moderator. The hemisphere subgroup pertains to studies targeting the DLPFC. Abbreviations: tES: transcranial electrical stimulation, DLPFC: dorsolateral prefrontal cortex. Download figure Open in new tab Figure S.9-4. Exploring Subgroup Analyses of tES Effects on Relapse. This figure displays the results of a subgroup analysis focusing on relapse, featuring forest plots that illustrate the effect sizes by different types of moderators. These plots provide a comprehensive analysis of the impact of tES on relapse, considering key factors such as the type of outcome measurement, outcome assessment timepoint, number of sessions, randomization, hemisphere, target, polarity, symmetry in DLPFC stimulation, intensity, and stimulation duration. Each horizontal line within the plots signifies a specific moderator, with dots representing effect sizes and horizontal lines denoting confidence intervals. In addition, bar plots indicate the number of participants in the active (dark colors) and sham (light colors) arms, with the total number of experiments mentioned in parentheses next to each relevant moderator. The hemisphere subgroup pertains to studies targeting the DLPFC. Abbreviations: tES: transcranial electrical stimulation, DLPFC: dorsolateral prefrontal cortex. Download figure Open in new tab Figure S.9-5. Exploring Subgroup Analyses of TMS Effects on Craving. This figure presents the results of a subgroup analysis focused on craving, featuring forest plots that demonstrate the effect sizes across various moderators. These plots offer a thorough analysis of TMS’s impact on craving, considering key factors such as number of sessions, randomization, hemisphere in DLPFC stimulation, target, frequency, coil type, stimulation patterns, and type of TMS. ’Multi’ in the ’Target’ group refers to studies that employed a combination of different target areas. ’Multi’ in the ’Polarity’ group refers to studies that employed both HF and LF TMS simultaneously. Each horizontal line in the plots represents a specific moderator, with dots indicating effect sizes and horizontal lines showing confidence intervals. Additionally, bar plots display the number of participants in the active (dark colors) and sham (light colors) arms, with the total number of experiments indicated in parentheses alongside each moderator. Note that six studies did not report the type of TMS coil. The hemisphere subgroup pertains to standard TMS (classic or patterned) studies targeting the DLPFC. Abbreviations : TMS: transcranial magnetic stimulation, HF: high frequency, LF: low frequency, FPC: frontopolar cortex, DLPFC: dorsolateral prefrontal cortex. Download figure Open in new tab Figure S.9-6. Exploring Subgroup Analyses of TMS Effects on Consumption. This figure presents the results of a subgroup analysis focused on consumption, featuring forest plots that demonstrate the effect sizes across various moderators. These plots offer a thorough analysis of the impact of TMS on consumption, taking into account key factors such as the type of outcome measurement, outcome assessment timepoint, number of sessions, randomization, hemisphere in DLPFC stimulation, target, frequency, coil type, stimulation patterns, and type of TMS. Each horizontal line in the plots represents a specific moderator, with dots indicating effect sizes and horizontal lines showing confidence intervals. Additionally, bar plots display the number of participants in the active (dark colors) and sham (light colors) arms, with the total number of experiments indicated in parentheses alongside each moderator. The hemisphere subgroup pertains to standard TMS (classic or patterned) studies targeting the DLPFC. Abbreviations : TMS: transcranial magnetic stimulation, HF: high frequency, LF: low frequency, FPC: frontopolar cortex, DLPFC: dorsolateral prefrontal cortex. Download figure Open in new tab Figure S.9-7. Exploring Subgroup Analyses of TMS Effects on Relapse. This figure presents the results of a subgroup analysis focused on relapse, featuring forest plots that demonstrate the effect sizes across various moderators. These plots offer a thorough analysis of the impact of TMS on relapse, taking into account key factors such as type of outcome measurement, outcome assessment timepoint, number of sessions, randomization, hemisphere in DLPFC stimulation, target, frequency, coil type, stimulation patterns, and type of TMS. Each horizontal line in the plots represents a specific moderator, with dots indicating effect sizes and horizontal lines showing confidence intervals. Additionally, bar plots display the number of participants in the active (dark colors) and sham (light colors) arms, with the total number of experiments indicated in parentheses alongside each moderator. The hemisphere subgroup pertains to standard TMS (classic or patterned) studies targeting the DLPFC. Abbreviations : TMS: transcranial magnetic stimulation, HF: high frequency, LF: low frequency, FPC: frontopolar cortex, DLPFC: dorsolateral prefrontal cortex. Download figure Open in new tab Figure S.9-8. Exploring Subgroup Analyses of Substance on Relapse for tES/TMS. This figure presents the results of a subgroup analysis on relapse, featuring forest plots that detail the effect sizes by type of substance. These plots offer an in-depth look at the impact of tES/TMS on relapse by examining the role of the type of stimulation. Each horizontal line within the plots represents a distinct substance use disorder, with dots for effect sizes and horizontal lines for confidence intervals. Additionally, bar plots show the number of participants in the active (dark colors) and sham (light colors) arms. The total number of experiments is noted in parentheses adjacent to the related moderator. The final two rows illustrate the cumulative effects of stimulation on relapse, with bars color-coded by the type of stimulation: tES studies in red and TMS studies in blue. Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation. Heterogeneity of craving and consumption measures in the meta-analysis Download figure Open in new tab Figure S.10-1. Distribution of Craving Scales Used in tES and TMS Studies Included in the Meta-Analysis. This figure illustrates the various scales included in the meta-analysis, color-coded by the type of stimulation—tES in red and TMS in blue—and categorized by outcome measure (craving). Abbreviations : tES: transcranial electrical stimulation, TMS: transcranial magnetic stimulation. Download figure Open in new tab Figure S.10-2. Consumption/Relapse Outcome Measures Used in tES and TMS Studies Included in the Meta-Analysis. This figure illustrates the various scales used in the meta-analysis, color-coded by the type of stimulation—tES in red and TMS in blue—and categorized by outcome measure (consumption and relapse). 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Share Effectiveness of Noninvasive Brain Stimulation Protocols on Drug Craving and Consumption/Relapse in Substance Use Disorders: A Systematic Review and Meta-analysis of 208 Clinical Trials and 36 Protocols Ghazaleh Soleimani , Afra Souki , Sara Honari , Travis E Baker , Andre R Brunoni , Mohsen Ebrahimi , Eduardo A Garza-Villarreal , Tony P George , Rita Z Goldstein , Manish Kumar Jha , Tonisha Kearney-Ramos , Rayus Kuplicki , Bernard Le Foll , Kelvin O Lim , Martin P Paulus , Arash Rahmani , Gregory Sahlem , Victor M Tang , Hosna Tavakoli , Alireza Valyan , Ti-Fei Yuan , Mehran Zare-Bidoky , Marom Bikson , Colleen A Hanlon , Michael Nitsche , Hamed Ekhtiari medRxiv 2025.09.21.25335559; doi: https://doi.org/10.1101/2025.09.21.25335559 Share This Article: Copy Citation Tools Effectiveness of Noninvasive Brain Stimulation Protocols on Drug Craving and Consumption/Relapse in Substance Use Disorders: A Systematic Review and Meta-analysis of 208 Clinical Trials and 36 Protocols Ghazaleh Soleimani , Afra Souki , Sara Honari , Travis E Baker , Andre R Brunoni , Mohsen Ebrahimi , Eduardo A Garza-Villarreal , Tony P George , Rita Z Goldstein , Manish Kumar Jha , Tonisha Kearney-Ramos , Rayus Kuplicki , Bernard Le Foll , Kelvin O Lim , Martin P Paulus , Arash Rahmani , Gregory Sahlem , Victor M Tang , Hosna Tavakoli , Alireza Valyan , Ti-Fei Yuan , Mehran Zare-Bidoky , Marom Bikson , Colleen A Hanlon , Michael Nitsche , Hamed Ekhtiari medRxiv 2025.09.21.25335559; doi: https://doi.org/10.1101/2025.09.21.25335559 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Addiction Medicine Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (299) Cardiovascular Medicine (4426) Dentistry and Oral Medicine (443) Dermatology (382) Emergency Medicine (607) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1507) Epidemiology (15222) Forensic Medicine (30) Gastroenterology (1123) Genetic and Genomic Medicine (6589) Geriatric Medicine (667) Health Economics (997) Health Informatics (4525) Health Policy (1368) Health Systems and Quality Improvement (1612) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15910) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (145) Nephrology (667) Neurology (6588) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1143) Occupational and Environmental Health (956) Oncology (3331) Ophthalmology (971) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (663) Pediatrics (1690) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5440) Public and Global Health (9221) Radiology and Imaging (2195) Rehabilitation Medicine and Physical Therapy (1369) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (710) Sports Medicine (529) Surgery (711) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9fff3de5ef39c13d',t:'MTc3OTQ4ODc3OQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();