Pharmacological Treatments for Methamphetamine Use Disorder: Current Status and Future Targets

Methamphetamine (METH) use disorder (MUD) has seen a steady rise in global prevalence, accompanied by increased overdose deaths and significant socioeconomic costs. A primary barrier to successful treatment is the current lack of a clinically validated pharmacotherapy that reliably reduces cravings or maintains long-term abstinence. This review synthesizes preclinical and clinical research to identify potential molecular targets, evaluate the efficacy of current pharmacotherapy candidates, and outline essential directions for future study.

Pharmacotherapies for MUD are categorized by their mechanisms of action, including dopaminergic/noradrenergic modulation, antidepressant effects, and various receptor antagonism strategies. Commonly used agents such as modafinil, antipsychotics, and baclofen have shown mixed results; while they may help ameliorate specific side effects like psychotomimetic symptoms or cognitive deficits in dependent individuals, they generally do not prevent the resumption of drug use. Even combination therapies, such as the naltrexone-bupropion protocol, provide only modest benefits, suggesting that single-target pharmacological solutions may be insufficient for the multifaceted nature of addiction.

Preclinical models have identified more specific molecular candidates that merit further investigation. VMAT-2 inhibitors, ligands for metabotropic glutamate receptors, and trace amine-associated receptor agonists have shown significant success in reducing the reinforcing properties of METH in rodents. However, the translation of these findings to human populations remains difficult. The paper highlights several critical issues in the current research landscape: the need for behavioral paradigms that better isolate rewarding effects from motor suppression, the importance of investigating sex differences in drug response, and the potential of pharmacogenetic screening to personalize treatment plans based on an individual’s metabolic profile.