In 2021, nearly 296 million people worldwide used psychoactive substances, highlighting a significant need for effective interventions for disorders such as Methamphetamine Use Disorder (MUD). Despite existing treatments, including behavioral therapies and medications, the relapse rates remain high, signaling the need for more potent and targeted approaches. This clinical trial investigates high-intensity transcranial alternating current stimulation (Hi-tACS), a non-invasive method that applies 15mA electrical currents with a patented frequency of 77.5Hz to modulate brain activity. Hi-tACS has shown promise in preliminary studies for its ability to reduce drug cravings significantly by influencing brain regions crucial in addiction. The primary aim of this study is to evaluate the effectiveness of Hi-tACS in curbing cravings in individuals with MUD. As secondary objectives, the trial will also explore the potential benefits of Hi-tACS in alleviating other clinical symptoms, enhancing cognitive performance, and positively influencing brain activity. This study seeks to establish Hi-tACS as a more effective treatment option that could lead to substantially lower relapse rates for individuals with MUD.

The study will be conducted at multiple drug rehabilitation centers in China. The procedure includes screening, pre-intervention evaluation (baseline), a 2-week intervention (twice daily sessions, 40 minutes each, totaling 20 sessions), post-intervention evaluation, and follow-up evaluations at 2 weeks and 3 months.

During the screening phase, participants are recruited and undergo a health interview to determine eligibility. If eligible, participants sign informed consent and are randomly assigned to one of two groups (active or sham).

At baseline, participants report demographic information and complete various questionnaires, cognitive tasks, and electroencephalogram (EEG) recordings to assess craving, clinical symptoms, and cognitive abilities.

During the intervention phase, tACS stimulates the scalp with three Nexalin electrodes (Nexalin Technology, Inc., Houston, TX, USA): electrodes are placed according to the international 10/20 system for EEG recording. A 4.45 × 9.53 cm electrode is placed above the forehead (Fpz, Fp1, and Fp2), and two 3.18 × 3.81 cm electrodes are placed above both mastoid areas. The active group receives 77.5 Hz tACS for 40 minutes per session. The sham group receives treatment with identical technical parameters, which induce scalp sensations but without penetration of the electric field into the brain. After each session, any side effects reported by participants are recorded to ensure safety and feasibility.

Post-intervention evaluation, as well as the 2-week and 3-month follow-up evaluations, mirror the pre-intervention assessments.

Sample size was calculated using GPower 3.1.9.4. Since Hi-tACS has not been previously investigated in drug addiction, an effect size of 0.15 was chosen. The power is set at 80%, and a two-tailed significance level is maintained at 5%. The calculations suggest a total sample size of 62. Considering potential dropout during treatment, the sample size was set at 70 (35 per group).

Throughout the intervention, patients, operators, and raters remain blinded to treatment conditions. To ensure study quality, researchers and drug rehabilitation staff will collaborate throughout the process, and data will be converted to electronic versions after each evaluation.

The inclusion criteria include:

1. ages between 18 and 70;
2. education level of at least primary school;
3. confirmed diagnosis of MUD as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5);
4. a subjective craving score of 30 or higher;
5. absence of any other behavioral, pharmacological, or physical treatments during the trial.

The exclusion criteria include:

1. significant neurological or serious psychiatric disorders;
2. concurrent substance use disorders;
3. previous treatments with electroconvulsive therapy, transcranial magnetic stimulation, or transcranial direct current stimulation;
4. presence of a cochlear implant, cardiac pacemaker, implanted neurological device, or cerebral metal;
5. current pregnancy or lactation;
6. severe withdrawal symptoms;
7. engagement in other clinical studies.

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