I. Basic Pharmacological Effects and Diverse Potential Benefits of Metformin

Metformin is a first-line core agent for the clinical management of type 2 diabetes mellitus. Owing to its low cost and favorable safety profile, it has been widely prescribed clinically for nearly six decades. Its classic hypoglycemic mechanism boasts unique advantages: it regulates blood glucose via multiple pathways, including inhibiting intestinal glucose absorption, enhancing glucose uptake and utilization in peripheral tissues, lowering fasting plasma insulin levels, and improving systemic insulin sensitivity. Unlike most antihyperglycemic medications, metformin does not stimulate insulin secretion from pancreatic β-cells; therefore, hypoglycemia will not occur when used as monotherapy, laying a solid foundation for its clinical safety.

With the advancement of pharmacological research, the medicinal value of metformin has extended beyond its conventional hypoglycemic indications, and a wide array of potential pharmacological effects have been successively discovered. Existing evidence confirms its anti-tumor, anti-aging, anti-inflammatory and osteogenic effects, among which the osteogenic activity specifically manifests in the regulation of alveolar bone growth. At present, numerous domestic and international research teams have conducted extensive investigations into the non-glycemic effects of metformin. Several researchers have attempted to translate its osteogenic mechanism into clinical interventions for patients with periodontitis, paving new research avenues for multidisciplinary disease treatment.

II. Clinical Status of Anxiety Disorder Treatment and Demand for New Drug Development

Driven by the fast-paced lifestyle in modern society, public mental stress has continued to rise, leading to a year-on-year increase in the clinical incidence of anxiety disorders. Characterized by long disease courses and high recurrence risks, anxiety disorders persistently or intermittently disrupt patients' daily lives, work and social interactions, while exerting adverse impacts on the quality of life of their family members.

The clinical diagnosis and treatment of anxiety disorders remain fraught with challenges. The disease features complex etiologies and diverse triggering factors, and its exact pathogenesis has not been fully elucidated, resulting in a lack of precise and curative clinical regimens. Functional abnormalities or altered expression of gamma-aminobutyric acid type A (GABAₐ) receptors are widely recognized by the medical community as the core mechanism closely linked to the onset of anxiety.

Benzodiazepines, the first-line anti-anxiety drugs widely used in clinical practice, possess prominent limitations. Long-term administration induces progressive drug tolerance with sustained attenuation of therapeutic efficacy, accompanied by escalating side effects such as dizziness, drowsiness and drug dependence/addiction, which severely compromise long-term therapeutic outcomes and patients' physical and mental health. Accordingly, developing novel anti-anxiety agents with superior safety, high efficacy and minimal adverse reactions has become a key research priority in psychiatry. In light of metformin's multiple pharmacological activities, its anxiolytic potential has garnered growing academic attention over the past two years.

III. Research on the Anxiolytic Effects and Molecular Mechanisms of Metformin

Latest animal studies have clearly validated the remarkable anxiolytic potential of metformin, providing experimental evidence for its application in anxiety disorder treatment. Dual in vitro and in vivo experimental models were established in relevant research: in vitro cell cultures were treated with metformin at a concentration of 10 μM, while anxious rats received intraperitoneal injection of metformin at a dosage of 100 mg·kg⁻¹ in vivo. Behavioral changes in rats were observed via open field tests and maze assays, and transcriptional expression levels of GABAₐ receptors were detected to systematically explore the anxiolytic efficacy and underlying mechanisms of metformin.

Experimental results demonstrate that intraperitoneal administration of metformin at 100 mg·kg⁻¹ elicits rapid and robust anxiolytic effects in anxious rats. Its core signaling pathway operates as follows: metformin effectively upregulates the expression of GABAₐ receptors and increases miniature inhibitory postsynaptic currents (mIPSCs). Meanwhile, it activates AMP-activated protein kinase (AMPK), which further boosts the transcriptional activity of FoxO3a and stimulates the synthesis of GABAₐ receptor-associated proteins. This ultimately facilitates stable membrane embedding of GABAₐ receptors. By modulating the function and expression of this core anxiety-related receptor, metformin exerts anxiolytic therapeutic effects.

IV. Supporting Studies on the Neuromodulatory Properties of Metformin

Multiple preliminary studies corroborate the neuromodulatory effects of metformin, offering indirect theoretical support for its anxiolytic function. In 2015, a research team from Huazhong University of Science and Technology established SD rat models for experimentation. The study verified that metformin facilitates fear memory extinction in rats following short-term extinction training. This mechanism is highly consistent with metformin's anxiolytic pathway: both rely on activating GABAₐ receptor-associated proteins to promote the membrane trafficking of GABAₐ receptors, thereby regulating emotion-related neurological functions.

V. Controversies and Limitations in Research on Metformin's Anxiolytic Effects

Academic debates persist regarding the anxiolytic efficacy of metformin, with several controlled clinical studies yielding conflicting conclusions. In October 2018, a research team led by Yao Min from Hubei Provincial Hospital of Traditional Chinese Medicine conducted a clinical trial comparing acupuncture and metformin as interventions for obese patients with polycystic ovary syndrome (PCOS). The study revealed comparable efficacy between the two interventions in reducing body weight, alleviating clinical symptoms and regulating endocrine metabolism. Nevertheless, acupuncture exerted significantly superior effects over metformin in mitigating patients' anxiety and improving their quality of life, casting doubt on the clinical anxiolytic potency of metformin.

Beyond academic controversies, research on metformin's anxiolytic activity suffers from notable overall limitations. Current relevant investigations are confined to in vitro cellular assays and in vivo animal experiments, lacking supportive data from large-sample, multi-center, long-term clinical trials. To date, its anxiolytic efficacy, optimal therapeutic dosage and safety profile in human subjects remain unconfirmed.

VI. Summary and Prospects

As a classic hypoglycemic drug, metformin exerts pharmacological effects far beyond its established glucose-lowering function. Its diverse potential activities including anti-tumor, anti-inflammatory, osteogenic and neuromodulatory properties have rendered it a hot research candidate across multiple disciplines. By regulating the GABAₐ receptor signaling pathway, metformin produces anxiolytic effects and modulates fear memory, delivering innovative ideas for the development of novel anxiety disorder therapies.

Nevertheless, research in this field is still in its initial exploratory stage, plagued by inconsistent research conclusions and insufficient clinical evidence. Additionally, traditional drugs may exhibit divergent pharmacological actions and side effects under different disease conditions and physiological states. This reminds clinical practitioners to strictly monitor medication safety while exploring new indications for metformin. High-quality clinical trials should be continuously carried out to further clarify its specific anxiolytic mechanisms, applicable patient populations, therapeutic dosages and adverse reactions, so as to provide scientific evidence supporting its expanded clinical application.