Exploring the impact of metformin on the central nervous system and neurotransmission: A systematic review
Abstract
BACKGROUND
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.
METHODS
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.
RESULTS
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…
How strong is the evidence?
Evidence Hub reads this as a systematic review, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid.
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