Closed-loop transcranial alternating current stimulation (tACS) reduces cue reactivity and improves inhibitory control in methamphetamine use disorder with frequency and timing specificity.

Methamphetamine use disorder (MUD) involves persistent cue reactivity and impaired inhibitory control, posing major treatment challenges. Closed-loop noninvasive neuromodulation can tailor stimulation to dynamic brain states, but its application in MUD remains largely unexplored. This study developed a cue reactivity biomarker-guided closed-loop transcranial alternating current stimulation (tACS) system, examined its optimal stimulation frequency, and preliminarily evaluated its efficacy in improving inhibitory control and reducing cue reactivity. Three cohorts of individuals with severe MUD were enrolled. Drug-cue exposure increased parietal-occipital theta power in Cohort 1. Based on this biomarker, a closed-loop tACS system targeting the left dorsolateral prefrontal cortex was developed. In Cohort 2, a within-subject crossover design examined closed-loop tACS at 6, 10, and 40 Hz. Random-time and open-loop continuous stimulation at the identified optimal frequency served as controls. In Cohort 3, an open-label, single-arm study of five consecutive daily closed-loop stimulation sessions assessed preliminary clinical efficacy. The results showed that closed-loop tACS at 40 Hz was the only condition that simultaneously reduced cue-related electroencephalographic (EEG) activity (P = 0.007) and improved inhibitory control (P = 0.031). Random-time stimulation reduced cue-related activity but did not improve inhibitory control, whereas open-loop continuous stimulation showed no significant effects. Repeated 40 Hz closed-loop tACS over five days in severe MUD significantly reduced craving and improved inhibitory control. These findings suggest that biomarker-guided 40 Hz closed-loop tACS can modulate neural and behavioral dysfunction in MUD and support the feasibility, safety, and preliminary efficacy of this neuromodulation strategy.