Abstract
BACKGROUND: Mood disorders are a severe symptom in patients with methamphetamine (MA) use disorder (MUD) during withdrawal and are closely associated with the risk of relapse. While both standalone repetitive transcranial magnetic stimulation (rTMS) and physical exercise (PE) have shown positive effects on regulating mood disorders, the potential synergistic benefits of their combined use remain unclear. This study aims to investigate the effects of high-frequency rTMS (10 Hz) combined with PE on mood disorders in patients with MUD and to identify the relevant factors associated with emotional regulation. METHODS: Using a randomized clinical trial design, 54 male patients with MUD were randomly assigned to a PE group, an rTMS combined with PE (rTMS + PE) group, and a control group (CG). All groups received interventions three times per week for a total of 12 weeks (8 weeks of intervention + 4 weeks of follow-up). The PE group received 10-min of health education and 35-min of exercise intervention, the rTMS + PE group received 10-min of 10 Hz rTMS administered over the left dorsolateral prefrontal cortex (DLPFC) and 35-min of exercise intervention, and the CG only received 45 min of health education. Measurements for depression, anxiety, MA craving, and blood neurotransmitters were taken from participants at baseline, the 8th week, and the follow-up period. RESULTS: (1) Compared with the CG, both intervention groups showed significant reductions in depression, anxiety, and MA craving after the 8-week intervention, and these improvements were accompanied by marked increases in the blood levels of dopamine (DA), β-EP, and 5-HT. Furthermore, these effects persisted for up to 1 month after the intervention concluded. (2) Compared to the PE group, the rTMS + PE group demonstrated significantly lower craving and higher DA levels at the 8th week, with the latter exhibiting superior sustained intervention effects during the follow-up period (such as negative emotions, craving, DA, and β-EP). (3) The reduction of negative emotions is not only related to the intervention increasing the release level of neurotransmitters in the blood but also to the decrease in MA craving. CONCLUSION: These findings indicate that adding high-frequency rTMS to moderate-intensity exercise can produce better therapeutic effects (such as emotion regulation and craving reduction) and increase the sustained impact on the rehabilitation of patients with MUD during the withdrawal period, thus providing a novel strategy for treatment of MUD. Trial Registration: ClinicalTrials.gov identifier: ChiCTR2500105315.