Metformin for fatigue and cognitive dysfunction associated with postCOVID-19 condition and other suspected mitochondrial dysfunction: a case series

Technical Summary: Metformin for Fatigue and Cognitive Dysfunction in Post-COVID-19 and Suspected Mitochondrial Dysfunction

Problem Statement
Post–COVID-19 condition (long COVID) and similar post-infectious syndromes, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), are characterized by persistent, debilitating fatigue, cognitive dysfunction ("brain fog"), and dysautonomia. The etiology is heterogeneous, involving immunologic, metabolic, and neurologic mechanisms, potentially including mitochondrial bioenergetic failure. Currently, evidence-based therapies for these conditions are limited, and management is largely supportive. While metformin, a biguanide used for type 2 diabetes, modulates immune-metabolic pathways (including AMPK signaling and mitochondrial bioenergetics) that offer biological plausibility for treating such disorders, its efficacy in established long COVID or suspected mitochondrial dysfunction remains uncertain due to mixed results in prior clinical trials.

Methodology
This report presents a case series of three women with severe fatigue and cognitive dysfunction. The methodology relies on retrospective clinical observation and temporal association analysis rather than a controlled experimental design.

• Patient Selection:
  • Patient 1: A 50-year-old woman with post–COVID-19 cardio-neuropathy and small fiber/sudomotor neuropathy, experiencing worsening fatigue and cognitive symptoms following a respiratory infection in 2025.
  • Patient 2: A 60-year-old woman with a history of severe SARS-CoV-2 infection (2020) presenting with progressive fatigue, cognitive dysfunction, thermoregulation issues, and mucocutaneous lesions. She had concurrent vitamin B12 deficiency and low morning cortisol.
  • Patient 3: A 50-year-old woman with ovarian cancer history who developed severe fatigue and cognitive dysfunction while on letrozole (an aromatase inhibitor), suspected to be medication-associated mitochondrial dysfunction.
• Intervention: Metformin was initiated as an empiric trial for severe fatigue and cognitive dysfunction in the context of suspected mitochondrial impairment.
  • Patient 1 received extended-release (ER) metformin 500 mg once daily.
  • Patient 2 was titrated to 1500 mg daily over two weeks.
  • Patient 3 received ER metformin 500 mg once daily.
• Evaluation: Outcomes were assessed via patient-reported symptoms regarding energy levels and cognitive clarity. The study utilized a "stop-start" approach to evaluate causality: symptoms were monitored upon drug initiation, discontinuation, and re-initiation.

Key Results

• Rapid Improvement: All three patients reported rapid, clinically meaningful improvement in fatigue and cognitive dysfunction following metformin initiation.
  • Patient 1 and Patient 3 reported marked improvement within 48 hours to one week.
  • Patient 2 reported improvement within 10–14 days of reaching the 1500 mg dose, with cognitive symptoms resolving by six weeks.
• Withdrawal and Re-challenge:
  • In all three cases, symptoms partially or fully recurred upon discontinuation of metformin.
  • Re-initiation of the drug led to the return of improvement, supporting a temporal association between the drug and symptom relief.
• Safety: Patient 1 experienced no gastrointestinal adverse effects or hypoglycemia. Patient 2 successfully tapered off the medication after approximately 18 months without relapse, though residual peripheral neuropathy persisted.
• Concurrent Therapies: Patient 1 was on multiple concurrent therapies (melatonin, physical therapy, pyridostigmine, etc.), while Patients 2 and 3 were not described as having similar complex concurrent regimens during the metformin trial.

Significance and Claims
The paper claims that these observations support the hypothesis that metformin may be beneficial for fatigue and cognitive dysfunction in selected patients with post-viral syndromes or suspected mitochondrial impairment.

• Biological Plausibility: The authors note that metformin's activation of AMPK, influence on mitochondrial bioenergetics, and modulation of inflammatory pathways (e.g., NLRP3 inflammasome) provide a mechanistic basis for its potential efficacy in disorders characterized by altered energy metabolism and immune dysfunction.
• Clinical Signal: The consistency of response across different clinical contexts (post-COVID and aromatase inhibitor-associated), the rapidity of response, and the reproducible symptom recurrence upon withdrawal suggest a potential treatment signal worthy of further investigation.
• Limitations and Modesty: The authors explicitly state that causality cannot be established due to the lack of a control group, the small sample size (n=3), and the reliance on patient-reported outcomes rather than validated instruments. They acknowledge that spontaneous improvement or regression to the mean cannot be excluded.
• Future Direction: The paper does not propose immediate clinical guidelines but rather motivates the generation of hypotheses for prospective studies. It emphasizes the need for standardized outcome measures and mechanism-informed patient selection to determine optimal dosing, duration, and discontinuation strategies, noting that previous randomized trials with mixed results may have suffered from differences in case definitions and treatment duration.

In conclusion, the authors assert that while this uncontrolled case series cannot prove efficacy, the reproducible pattern of improvement and withdrawal recurrence supports further evaluation of metformin for these specific symptom clusters.