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

BackgroundTranscranial 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. MethodTo 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. FindingsThe 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. InterpretationOur 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.