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

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 based on 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.