Metformin Repurposing in Neurological Disorders: A Clinical Trial Landscape

Abstract

Background

Neurological disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS) involve progressive nerve cell loss and current treatments mainly provide symptomatic relief without stopping disease progression. Drug repurposing offers a promising approach to address this gap. Metformin, a widely used oral anti-diabetic drug, is being studied in central nervous system (CNS) disorders due to its multiple effects, including activating the adenosine monophosphate–activated protein kinase (AMPK) pathway, supporting neuroprotection and promoting remyelination.

Purpose

To systematically analyse the current clinical trial landscape of metformin repurposing in CNS disorders.

Methods

Data were collected exclusively from ClinicalTrials.gov. The search focused on neurological, neurodegenerative and neurodevelopmental conditions while excluding trials mainly targeting type 2 diabetes or cancer. After screening, 23 clinical studies were selected. Extracted data emphasised disease types, therapeutic goals and measurable neurobiological and functional outcomes.

Results

Research on metformin in CNS disorders is active, with over two-thirds of trials being completed (N = 7, 30.4%) or recruiting (N = 9). Most studied conditions include MS (N = 5), schizophrenia/psychosis (N = 4) and fragile X syndrome (FXS) (N = 4), highlighting interest in neurodevelopmental and demyelinating repair. Trials use functional outcomes such as the Timed 25-Foot Walk Test (T25FWT) and the MATRICS Consensus Cognitive Battery (MCCB), along with advanced biomarkers such as diffusion tensor imaging (DTI) for white matter integrity and molecular markers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).

Conclusion

This analysis shows growing interest in repurposing metformin as a potential disease-modifying therapy for CNS disorders, with a focus on neurorepair and biomarker-based assessment. Larger, well-designed randomised controlled trials are still needed to confirm efficacy in humans.

Keywords

Metformin ClinicalTrials.gov drug repurposing adenosine monophosphate–activated protein kinase (AMPK) pathway systematic review

Introduction

Millions of people worldwide suffer from neurological disorders, which include neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS) and Huntington’s disease (HD). These conditions are characterised by progressive degeneration and death of nerve cells.^1–3 Current treatment options are frequently confined to symptomatic improvement, failing to prevent the underlying disease development.^{1, 2} Intense research into drug repurposing is motivated by this unmet therapeutic need, with the goal of finding well-established drugs with proven safety profiles that may be efficiently applied to neurological treatment.⁴

Metformin (1,1-dimethylbiguanide hydrochloride) is the most often prescribed oral anti-diabetic drug in the world and it is the primary treatment for type 2 diabetes mellitus (T2DM).^{2, 3, 5} Biguanides have been used to treat diabetes since the Middle Ages, when Galega officinalis (French lilac) was used.^{2, 3} The main clinical advantage of metformin is its capacity to reduce blood glucose levels by enhancing peripheral insulin sensitivity and inhibiting the synthesis of glucose by the liver.^2–4

The current knowledge of the pathophysiological similarities between metabolic illnesses and neurodegeneration, often termed as ‘type 3 diabetes’ in the context of AD, has led to interest in repurposing metformin for CNS disorders.⁶ Metformin targets several conserved molecular pathways that are essential for the survival of neurons.¹

The majority of neurological conditions manifest metabolic abnormalities related to mitochondria.¹ By directly affecting complex I of the respiratory chain, metformin is known to slow mitochondrial respiration.^{1, 2, 6} Significantly, it stimulates adenosine monophosphate–activated protein kinase (AMPK), an essential cellular energy sensor that improves energy metabolism, increases mitochondrial biogenesis (via peroxisome proliferator-activated receptor gamma coactivator 1-alpha or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)) and promotes cellular energy metabolism.^1,3,6–8 Metformin’s ‘classic’ molecular route is perceived to be AMPK activation.⁹

Metformin has shown strong anti-inflammatory effects through modifying microglial activation and blocking NF-κB signalling, which is a major cause of neuroinflammation.^{1, 8, 10} By triggering the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, which is connected to cellular defence mechanisms and myelin regeneration, it also strengthens antioxidant defences.^{3, 8}

Metformin is able to impact brain function since it can pass across the blood–brain barrier (BBB).^{1, 4, 7, 8} Metformin activates several processes in the central nervous system (CNS), such as neuroprotection, neuronal regeneration and anti-inflammation.¹ Through the activation of the atypical protein kinase C (aPKC)–CREB-Binding Protein (CBP) pathway, it increases the generation of spatial memory and supports adult neurogenesis.^{1, 6} Metformin’s function as a brain regenerative and remyelinating agent in a variety of neurodegenerative disease models is further supported by preclinical research.^{1, 11}

Clinical and experimental data on metformin’s neuroprotective benefits are still unclear and frequently contradictory, despite the clear molecular justification.^{1, 4, 12} Metformin treatment may be linked to slower cognitive decline and a lower risk of dementia in diabetic individuals, according to several retrospective clinical investigations^{1, 4, 6, 12} However, some research has shown that using metformin may worsen cognitive function or raise the risk of AD/dementia.^{1, 4, 12} These conflicting results, observed in both animal models and human observational studies, underscore the complexity of the drug’s mechanism of action and the necessity of personalised biomarker-guided treatments.^{1, 3} To address this ambiguity and clarify the actual clinical translation efforts, we conducted a comprehensive analysis of the trials currently registered on ClinicalTrials.gov that specifically excluded T2DM and cancer, focusing on metformin’s repurposing potential for CNS illnesses.

Methods

Study Design and Search Strategy

Using data exclusively from the public registry ClinicalTrials.gov, we conducted a systematic analysis to assess the current clinical trial landscape of metformin repurposing in CNS diseases. While retaining specificity against the drug’s principal indications of cancer and diabetes, the search technique was created to be extremely sensitive to neurological, neurodegenerative and neurodevelopmental indications.¹³

The detailed search query used on ClinicalTrials.gov: Metformin AND (CNS OR Brain OR Neurodegeneration OR Neuroinflammation OR Remyelination OR Myelin OR Axonal OR Cognitive OR Neuroprotection OR Demyelinating OR ‘Multiple Sclerosis’ OR MS OR ‘Amyotrophic Lateral Sclerosis’ OR ALS OR ‘Frontotemporal Dementia’ OR FTD OR Stroke OR ‘Vascular Cognitive Impairment’ OR ‘Huntington Disease’ OR ‘Parkinson Disease’ OR ‘Myotonic Dystrophy’) NOT Diabetes NOT Cancer.

For the systematic search, we included trials listed on ClinicalTrials.gov that investigated metformin as an intervention specifically for CNS conditions. Eligible studies targeted neurodegenerative disorders such as AD, PD and HD; demyelinating conditions such as MS; neurovascular disorders, including stroke and aneurysms; neurodevelopmental disorders such as fragile X syndrome (FXS) and cerebral palsy (CP); and psychiatric conditions, including schizophrenia and psychosis. Studies were excluded if metformin was used primarily for the treatment of T2DM or cancer, if they were preclinical studies or review articles or if they lacked clearly defined clinical outcomes.

Data Extraction and Analysis

The data collected for each trial included: Study title, NCT number, acronym (if available), study status (e.g., unknown, completed, recruiting), details of the conditions studied and the intervention, primary outcome measures with an objective on neurobiological and functional efficacy parameters.

To evaluate the general trend of metformin repurposing, the gathered data were sorted by illness group and examined with attention to specific diseases, intervention phases and important measurable endpoints.

Results

The ClinicalTrials.gov database was searched from 2000 (ClinicalTrials.gov launched in 2000) to 28 October 2025. Out of 556,781 studies, this query initially provided 55 studies. After applying the eligibility criteria, 23 clinical trials were selected for the final analysis (Supplementary Table S1). The collected data were categorised by disease group and analysed with a focus on particular diseases, intervention stages and significant measurable endpoints to assess the overall trend of metformin repurposing. We conducted an electronic search again with the same query on 30 November 2025 and confirmed that no additional eligible trials meeting our inclusion criteria had been registered.

The current status of the 23 studies demonstrates a highly active research pipeline (Figure 1). Over two-thirds of the cohort is comprised of completed (N = 7) and recruiting /) trials, indicating a substantial number of ongoing research (Table 1). The NCT05590676 trial mentioned ‘low recruitment’ as the primary reason on ClinicalTrials.gov for termination. No safety concerns or drug-related issues were reported by the investigators. The geographical distribution of the included clinical trials is illustrated in Figure 2, highlighting the global research activity across multiple regions.

Figure 1.

Source: Based on data extracted from ClinicalTrials.gov and synthesized from the included studies.

Figure 2.

Source: Based on data extracted from ClinicalTrials.gov and synthesized from the included studies.

Table 1.

Distribution of Clinical Trial Status (N = 23).

Study Status	Number of Trials (N)	%	NCT
Recruiting	5	21.7	NCT06405971, NCT05900466, NCT05838573, NCT05120505, NCT04121468
Completed	7	30.4	NCT05722951, NCT05349474, NCT04826692, NCT03710343, NCT03479476, NCT03451734, NCT02593097
Active: Not recruiting	3	13.04	NCT07055958, NCT05893225, NCT03862950
Not-yet-recruiting	5	21.7	NCT07001878, NCT06965868, NCT06429007, NCT06463743, NCT05532813
Unknown	2	8.7	NCT04930471, NCT03271866
Terminated	1	4.3	NCT05590676
Total	23	100	–

Source: Based on data extracted from ClinicalTrials.gov and synthesized from the included studies.

Metformin’s potential pleiotropic effects are demonstrated by the 23 trials, which cover seven key categories of CNS disease (Table 2). MS, schizophrenia/psychosis and FXS are the most frequently studied conditions, suggesting a high translational interest in demyelinating diseases, complex psychiatric disorders and neurodevelopmental repair.

Table 2.

Distribution of Clinical Trials by CNS Condition (N = 23).

CNS Condition Category	Specific Conditions	Count (N)	Therapeutic Goal Focus
Demyelinating/MS	Multiple sclerosis (MS, PMS, SPMS)	5	Remyelination, neurodegeneration, neural progenitor cells
Psychiatric/Cognitive	Schizophrenia, psychosis, stress resilience	4	Cognitive impairment (MCCB), brain white matter, BBB integrity
Neurodevelopmental	Fragile X syndrome (FXS), cerebral palsy (CP)	4	Language deficits, motor/cognitive improvement, behaviour problems
Neurodegenerative	Parkinson’s disease (PD), Huntington’s disease (HD)	3	Motor aspects of daily living, cognitive decline, oxidative stress
Neurovascular/Injury	Hypoxic-ischaemic encephalopathy (HIE), vertebrobasilar aneurysms (VBDAs)	3	Safety/feasibility in infants (brain injury), vascular morphology
Chronic Pain/Syndromic	Fibromyalgia syndrome (FMS), myotonic dystrophy type 1 (DM1)	2	Neuroinflammatory pathways, muscle function (motor deficit correction)
Other Neurological	Epilepsy, episodic migraine	2	Efficacy/safety with antiepileptic drugs, prevention of headache days

Source: Based on data extracted from ClinicalTrials.gov and synthesized from the included studies.

Across the 23 included studies, metformin doses ranged from 500 to 2,000 mg/day, depending on the disease condition and study protocol. Monotherapy was used in trials for MS, FXS, CP, migraine, fibromyalgia and myotonic dystrophy. Adjunct therapy was used in schizophrenia/psychosis, epilepsy and some PD trials. Trial durations ranged from 8 to 96 weeks, according to the disease-specific design and outcome measures. Completed studies reported actual enrolment ranging from 18 to 57 participants, depending on the disease area. Recruiting and not-yet-recruiting trials had planned sample sizes ranging from 30 to 120 participants, reflecting variability in study design and disease prevalence. Supplementary Table S1 represents these variables NCT-wise for clarity and transparency. The table also includes the inclusion and exclusion criteria for each trial.

The trial, which was titled Metformin for the Prevention of Episodic Migraine (MPEM) (NCT02593097), was one of the seven completed studies with results published. The results were not yet published for the other six completed studies. This study, MPEM, employed a randomised, quadruple-masked, crossover design, enrolling 34 participants with episodic migraine to receive either metformin (500 mg twice daily) or a matching placebo for 12 weeks, separated by a four-week washout period. The analysis population for the primary outcome consisted of the 30 subjects who completed both intervention periods. The primary outcome measured the total number of moderate and severe headache days over the study period. Treatment with metformin resulted in a mean of 23.64 days (SD = 2.15), compared to 24.33 days (SD = 2.19) for the matching placebo group. The statistical test of the hypothesis (Hills–Armitage method) yielded a P value of .83, indicating no statistically significant difference between metformin and placebo in reducing headache days. Regarding the secondary efficacy outcome, only 10.1% of subjects achieved a 50% or greater reduction in migraine days when on metformin (mean 95% CI: −3.46%–23.66%), with a statistical P value of .16 (McNemar test). In terms of safety and tolerability, there were no reported cases of all-cause mortality or serious adverse events (AEs). However, the frequency of non-serious, treatment-related AEs was higher in the metformin group, affecting 40.0% (12/30) of participants, compared to 12.5% (4/32) in the matching placebo group. The most common AEs systematically collected and reported in the metformin arm included gastrointestinal disorders such as diarrhoea (10.0%) and other issues such as dry mouth (10.0%), dry hair (10.0%) and hair loss (10.0%).

Key Clinical Endpoints and Biomarker Utilisation

The reported studies show a sophisticated approach to clinical endpoint measurement that goes beyond simple functional scores to quantify biological changes, which supports the push for biomarker-guided therapies.¹

Using the Movement Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) (Part 2), the main result of PD is changes in motor aspects of daily living. The Unified Huntington’s Disease Rating Scale motor score is the main focus of HD trials. Standardised tests such as the Expanded Disability Status Score (EDSS) and the Timed 25-Foot Walk Test (T25FWT) that correlate with the progression of disability are used in MS trials.¹⁴

The main cognitive endpoint for schizophrenia is the MATRICS Consensus Cognitive Battery (MCCB) Composite score. Information processing speed is measured in MS trials using the Symbol Digit Modalities Test.¹⁴ Memory, learning and executive functioning are also assessed in HD and other psychiatric trials.

Several studies employ sophisticated MRI methods to evaluate effectiveness, with a concentration on neuroprotection and neurorepair. These include assessing white matter integrity and myelin using diffusion tensor imaging (DTI) metrics (fractional anisotropy, mean diffusivity and radial diffusivity) and quantifying changes in brain volumetry.¹⁴ Changes in cerebral blood flow are measured using arterial spin labelling.

Certain biochemical markers are being measured in trials exploring PD and fibromyalgia. This includes levels of the antioxidant glutathione in erythrocytes and the oxidative stress marker plasma malondialdehyde for PD. Metformin is expected to reduce inflammatory markers such as the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and nociceptive cytokines (interleukin 1β and interleukin 18) in peripheral immune cells, according to the fibromyalgia study. In MS, exploratory objectives include assessing neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), which are indicators for axonal damage and astrogliosis, respectively.¹⁴

Discussion

ClinicalTrials.gov’s comprehensive review of clinical studies reveals a strong and expanding effort to repurpose metformin for CNS-related illnesses.^{3, 4} Researchers are taking advantage of metformin’s well-established safety profile and exploring its potential to function as a disease-modifying agent rather than just a symptomatic treatment, as seen by the findings from the 23 recognised trials.³

Metformin’s known pleiotropic processes, which closely correspond with the underlying diseases of neurodegeneration and neuroinflammation, are reflected in the range of illnesses treated (Figure 3).^{1, 3}

Figure 3.

Source: Based on data extracted from ClinicalTrials.gov and synthesized from the included studies and generated using AI (Napkin).

Mitochondria-related metabolic disruptions are central to the pathophysiology of several CNS illnesses, such as AD and PD.^{1, 3} By directly inhibiting mitochondrial complex I, metformin activates the AMPK signalling pathway.^1–3,6 The advantages of metformin are primarily due to this AMPK activation, which improves energy metabolism and lowers oxidative stress in dopaminergic neurons in PD models.^{3, 7} Metformin has been demonstrated to reduce alpha-synuclein phosphorylation and aggregation in PD.⁷ Additionally, in cuprizone-induced MS models, its capacity to restore mitochondrial homeostasis is reported as an oligoprotective action.^{1, 14}

Utilising metformin’s neurorepair potential is a significant goal of the present trials, especially in MS (NCT05893225, NCT05349474).¹⁴ Metformin appears to stimulate brain remyelination and regeneration, according to preclinical data.^{1, 11} By rejuvenating old stem cells, such as oligodendrocyte precursor cells (OPCs), it restores the ability of the CNS to remyelinate.^{1, 3, 11} Metformin accomplishes this by stimulating the AMPK-Nrf2-mTOR signalling pathway, which promotes endogenous oligodendrogenesis during the brain’s self-repair process.^{1, 3, 11} Additionally, by triggering an epigenetic mechanism involving AMPK-aPKC-CBP, metformin improves spatial memory and supports adult neurogenesis.^{1, 6} This focus is evident in MS trials that assess neurodegeneration and remyelination using DTI and brain volumetry (NCT05893225).¹⁴

Neurodegenerative disorders frequently exhibit oxidative stress and chronic neuroinflammation.^{3, 8} Metformin functions as a neuroprotective drug by reducing oxidative stress and neuroinflammation, mainly by blocking NF-κB activation (pro-inflammatory signalling) and activating the Nrf2 pathway (antioxidant defence).^{3, 8, 10} The central hypothesis of the fibromyalgia trial (NCT05900466) is based solely on metformin’s ability to modify these neuroinflammatory pathways by reducing important inflammatory cytokines such as IL-1β and IL-18. Metformin pretreatment reduces inflammatory responses by inducing AMPK and activating Nrf2 antioxidant pathways in cerebral ischaemia models.^{10, 15}

Translational Focus on Specific Disease Groups

Multiple Sclerosis

The largest number of metformin repurposing trials found (N = 5) are a target for neurorepair MS. This special focus is based on robust preclinical results showing metformin’s capacity to reduce inflammation, protect myelin integrity and stimulate immunometabolic reprogramming in MS animal models.^{3, 14} Remyelination and neurodegeneration are the main objectives of the MACSiMiSE-BRAIN trial (NCT05893225), which focuses on progressive MS (PMS), a subtype with substantial unmet requirements.¹⁴ A focus on identifying significant clinical change over the course of 96 weeks is demonstrated by the adoption of T25FWT as the primary endpoint rather than the less sensitive EDSS.¹⁴

Stroke and Vascular Cognitive Impairment

Several clinical meta-analyses supporting metformin’s repurposing in neurovascular illnesses show that it is associated with improved post-stroke clinical outcomes and decreased death rates in T2DM patients who used metformin before stroke.^{15, 16} A higher rate of favourable modified Rankin Scale (mRS 0–2) ratings at discharge (OR 1.56) is associated with pre-stroke metformin use.^{15, 16} Metformin protects the brain from ischaemia/reperfusion injury by modulating pathways such as PI3K/Akt and AMPK/mTOR.^{1, 8, 17} Metformin improves cognitive impairment and reduces white matter damage in mouse models of vascular cognitive impairment caused by chronic cerebral hypoperfusion by restoring OPC function, along with reducing the burden of cerebral small vessel disease.¹¹

Neurodevelopmental Disorders

The inclusion of trials focused on CP and FXS (NCT05120505, NCT03862950, NCT03710343) indicates the potential of metformin’s significant impact on neurogenesis and synaptic plasticity. In models of infantile brain injury, preclinical research revealed that metformin activates endogenous neural precursor cells, resulting in neural regeneration and functional recovery.^{1, 9} The FXS trials are designed to evaluate their effectiveness in treating behavioural issues and language impairments.¹

Biomarker-guided Personalised Medicine

The successful adoption of personalised, biomarker-guided treatments relies on specific markers across various neurological diseases, including:

Neuroimaging and Fluid Biomarkers

The application of quantitative indicators is considered vital for guiding personalised therapeutic methods. In metformin trials for MS, specifically non-active PMS, the biological efficacy is being investigated using brain MRI volumetry and DTI metrics.¹⁴ DTI is listed among the advanced quantitative indicators used in CNS trials. Furthermore, exploratory measures include monitoring changes in paramagnetic rim lesions, which, along with DTI, provide valuable insights into MS disease mechanisms beyond simple brain volume assessment. Molecular markers such as NfL and GFAP are essential for guiding personalised methods. Biobanking samples for later analysis of biomarkers is also a crucial component of clinical trials to improve the understanding of disease and therapeutic mechanisms.¹⁴

Disease-specific Molecular and Functional Biomarkers

To identify patient subpopulations that will respond to the medication, it is crucial to identify disrupted molecular functions that metformin can target.

Alzheimer’s Disease

The dysregulated expression of monoacylglycerol lipase (Mgll), resulting from an impaired aPKC mediated CBP phosphorylation, can serve as a marker to guide targeted metformin therapy in AD models. Metformin treatment is postulated to be effective in AD patients exhibiting low aPKC activity, as it represses Mgll expression by activating the aPKC-CBP pathway.¹

Studies using phosphoproteomics identified altered phosphorylation of two key proteins, regucalcin and gelsolin, across preclinical AD, amnestic mild cognitive impairment (aMCI) and late-stage AD, which could potentially be targeted therapeutically in early stages.¹⁸

Redox proteomics has been instrumental in identifying oxidatively or nitrosatively modified brain proteins in AD and aMCI, including those related to glucose metabolism such as GAPDH and pyruvate dehydrogenase.¹⁸

Metformin’s ability to activate chaperone-mediated autophagy (CMA), leading to the degradation of Aβ and possibly acetylated tau, suggests CMA activity could be a functional target for AD treatment.⁶

Ischaemic Stroke

The AMPK activity status is a critical biomarker for treatment timing. Since AMPK activity is immediately increased after acute injury (which can contribute to cell death) but reduced during the chronic phase, measuring brain AMPK activity can stratify patients: Metformin, as an AMPK activator, would yield better outcomes when given to stroke patients exhibiting reduced brain AMPK activity.¹

Multiple Sclerosis

Metformin treatment stratification for MS patients could potentially use biomarkers reflecting reduced mitochondrial respiration.

Molecular markers of autophagy and mitophagy, such as autophagy-related gene 5 (ATG5) and Parkin, are found elevated in the cerebral spinal fluid of MS patients during active disease phases, suggesting they may function as biomarkers of disease activity.¹

The evolution of metformin use for neurological disorders relies on translating the concept of personalised medicine from benchwork to clinical settings to ensure precise and effective targeted therapy. Ongoing research also focuses on integrating genetic profiling with established treatments to optimise individualised therapy.³

Clinical Trial Limitations and Future Directions

While current registry data show potential study opportunities, several constraints associated with the drug and trial landscape must be considered. Despite the inclusion of observational studies to improve clinical relevance, their results were inconsistent and diverse in terms of methodology. This makes it impossible to draw clear conclusions about the translational efficacy of metformin in neurological illnesses, especially when combined with the lack of published results from the majority of completed trials.

Many of the previous human studies that produced favourable or negative outcomes were observational, with potential biases due to confounding factors such as age, gender, cardio-metabolic diseases and the duration and timing of metformin therapy.^{3, 12} In particular, since B12 insufficiency is linked to the development of MCI and AD, the association between long-term metformin use and possible vitamin B12 deficiency complicates the interpretation of cognitive results.^{12, 19}

The 23 trials analysed primarily focus on MS, schizophrenia and FXS, rather than AD and PD, which have more extensive observational and preclinical evidence. The majority of current repurposing efforts appear to focus on disorders where metformin’s role in inflammation and cellular repair (such as remyelination) is more potent, even if some small pilot trials on AD suggest modest cognitive improvement in executive functioning.²⁰

Safety and feasibility are the main concerns of most completed trials included in this analysis (e.g., phase I trials in paediatric MS).¹⁴ Larger, definitive phase II/III randomised controlled trials (RCTs) are needed to show therapeutic efficacy, particularly for PMS and neurodevelopmental disorders, advancing translational research from promising preclinical models to concrete clinical benefit.^{3, 7, 14}

To strengthen the potential of metformin as an important part of multimodal precision medicine for neurodegenerative disorders, future research must concentrate on optimising drug delivery (e.g., intranasal delivery to avoid BBB concerns, though metformin is known to cross it) and combining metformin with other agents (e.g., clemastine in MS) to achieve synergistic beneficial effects.^{3, 14}

Conclusion

This comprehensive analysis of trials registered on ClinicalTrials.gov reveals that metformin is a leading candidate in the drug repurposing strategy for a wide range of CNS conditions. The drug’s potential in treating MS, schizophrenia and neurodevelopmental disorders is highlighted by the present pipeline, which consists of 23 carefully specified trials. Using advanced biomarkers such as DTI and molecular assays to measure biological efficacy, these trials are well-organised to explore certain neuroprotective pathways, such as remyelination, neurogenesis and anti-neuroinflammation.¹⁴ Large-scale RCTs are still required to overcome methodological challenges and confirm efficacy in humans, despite the abundance of preclinical evidence supporting metformin’s beneficial effects via the AMPK pathway and its pleiotropic actions on mitochondrial function and oxidative stress.^{3, 7} Current clinical trials significantly confirm metformin’s practical relevance as an adjuvant or preventive treatment, guiding the development of personalised therapeutic methods adapted to the particular molecular pathologies of CNS diseases.^{3, 16}

Footnotes

Acknowledgements

We highly appreciate the faculty of the Department of Pharmacology, AIIMS Mangalagiri, for formulating this review article.

Authors’ Contributions

Dr Yukesh R: Conceptualisation, data curation, formal analysis, methodology, writing original draft, writing review and editing.

Dr Sushil Sharma: Methodology, supervision.

Dr Madhavrao C: Supervision, validation.

Dr Gaurav Manikrao Rangari: Visualisation, supervision.

Dr Arup Kumar Misra: Formal analysis, resources.

Dr Srinivasa Rao Katiboina: Data curation, validation.

Dr Boda Srikanth Nayak: Conceptualisation, methodology.

Dr Jyothi Vennela: Resources.

Dr Sarikonda Sandhyarani: Formal analysis.

Data Availability

Data sharing is not applicable as no new datasets were generated or analysed during the current study.

Declaration of Competing Interest

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

ICMJE Statement

All authors contributed equally to the following:

Substantial contributions to the conception, design, data acquisition or analysis and interpretation.

Drafting and revising.

Final approval for publication.

Agreement to be accountable for all aspects of the work.

Statement of Ethics

Not applicable. This article does not involve studies with human participants or animals and no person’s data or images are included.

Supplemental Material

ORCID iDs

Yukesh R.

Jyothi Vennela

Sarikonda Sandhyarani

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