Therapeutic potential of agmatine in alcohol use disorder: Preclinical insights and future directions

Alcohol Use Disorder (AUD) is a major global health challenge characterized by the recurrence of alcohol consumption, withdrawal symptoms, and significant social, economic, and health-related burdens. Despite conventional treatments such as cognitive behavioral therapy and medications like disulfiram and naltrexone, the majority of patients do not achieve adequate relief due to the multifactorial nature of this disorder, including mental health issues and neuroadaptive changes. Recent studies demonstrated that chronic alcohol consumption results in the disruption of both the production and signaling of endogenous agmatine, a neuromodulator synthesized from L-arginine. Agmatine modulates the neurotransmitter systems, particularly at NMDA and imidazoline sites, which are associated with neuroinflammation and neuroplasticity. Moreover, in preclinical models, altered agmatine metabolism is related to changes in alcohol seeking behavior, highlighting its potential as a novel therapeutic candidate. Furthermore, agmatine may mitigate the behavioral and biochemical effects of alcohol-induced neurotoxicity, indicating its potential role in improving tolerance management and withdrawal symptoms. Integration of agmatine into a multimodal treatment strategy could lead to comprehensive personalized interventions in patients with AUD, addressing both neurochemical imbalances and the psychosocial complexity associated with this disorder. Thus, this review explores the potential of agmatine in addressing psychological factors underlying AUD, offering a novel and optimistic treatment option for advancing future therapeutic approaches. However, comprehensive clinical trials are essential to confirm these benefits and to establish optimal dosing regimens and a long-term safety profile in human settings.