Exploring the impact of metformin on the central nervous system and neurotransmission: A systematic review

Metformin, a well-established antidiabetic agent, has emerging neuroactive properties extending beyond glycemic control. Evidence suggests effects on neurotransmission, neuroprotection, and neuroinflammatory pathways, offering potential in neurodegenerative disorders.

Following PRISMA 2020 guidelines and PROSPERO registration (CRD420251105355), we systematically searched PubMed, Scopus, Web of Science, and Google Scholar (November 2024-July 2025) for in vivo and clinical studies in humans or animals reporting CNS-related outcomes. Two reviewers independently screened and extracted data; risk of bias was assessed with validated tools appropriate to study design.

A total of 166 studies met inclusion criteria, including animal models, mechanistic experiments, and clinical observations. Metformin crosses the blood-brain barrier and modulates CNS pathways through anti-inflammatory and mitochondrial-supportive actions. Crucially, it regulates major neurotransmitter systems - serotonin, dopamine, glutamate, GABA, acetylcholine, and norepinephrine - restoring excitatory/inhibitory balance and enhancing synaptic plasticity. Most of the current evidence arises from preclinical studies, which consistently demonstrate neuroprotective and neuromodulatory effects of metformin in models of Alzheimer's disease, Parkinson's disease, stroke, and fragile X syndrome. Clinical data, while promising, remain limited and heterogeneous, mainly suggesting potential cognitive benefits.

Metformin shows promise for repurposing in CNS disorders via direct neurotransmitter regulation alongside mitochondrial and anti-inflammatory effects. Given that the majority of available data are preclinical, translational studies and well-designed clinical trials are essential to establish efficacy, dosing, and target populations. These findings underscore the metabolic-neurological interface and suggest a shift from viewing metformin solely as a metabolic therapy to recognizing its neurotherapeutic potential. Long-term use warrants vitamin B12 monitoring.