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A large-scale phase 3 randomized clinical trial demonstrated that mirtazapine, administered at 30 mg daily over 12 weeks, significantly reduces days of methamphetamine use in adults with moderate to severe methamphetamine use disorder. The reduction was modest but clinically relevant, with mirtazapine well-tolerated overall despite higher rates of drowsiness and weight gain. No significant improvements were observed in secondary domains including depression, insomnia, HIV risk behavior, or quality of life. This represents an important advance as no medication is currently approved for methamphetamine use disorder.