Metformin and Low Dose Naltrexone in Long COVID

Long COVID, characterized by persistent symptoms following the acute phase of COVID-19, poses significant health challenges. Symptoms include fatigue, cognitive impairment, and chronic pain, among others. Given the complexity of long COVID, there is an urgent need for effective treatments. Emerging evidence suggests that metformin and low dose naltrexone (LDN) may offer therapeutic benefits for long COVID patients.

Metformin and Long COVID: Mechanisms of Action

Metformin, a widely used anti-diabetic drug, has multiple mechanisms of action that may be beneficial in long COVID:

1. Anti-Inflammatory Effects: Metformin activates AMPK and the NLRP3 inflammasome and inhibits the NF-κB pathway, reducing the production of pro-inflammatory cytokines (Saisho, 2015). A 2020 analysis of metformin’s therapeutic potential on chronic pathological pain and two of its comorbidities (anxiety/depression and cognitive impairment) found that data strongly suggest that metformin could open a new avenue for the treatment of pathological pain and some of its associated comorbidities.

2. Immunomodulation: It modulates immune responses, potentially correcting immune dysregulation seen in long COVID (Cameron et al., 2016).

3. Metabolic Regulation: By improving insulin sensitivity and glucose metabolism, metformin may address metabolic disturbances associated with long COVID (Rena et al., 2017).

Clinical Evidence

• Observational Studies: A retrospective cohort study by Bramante et al. (2021) observed that patients on metformin had a lower incidence of severe COVID-19 outcomes.

• Clinical Trials: A 2023 randomised, quadruple-blind, parallel-group, phase 3 trial (“COVID-OUT”) found that outpatient treatment with metformin reduced long COVID incidence by about 41% (Bramante et al., 2023).

Low Dose Naltrexone (LDN) and Long COVID: Mechanisms of Action

Naltrexone, an opioid receptor antagonist, exhibits unique properties at low doses (1.5-4.5 mg) that may be beneficial for long COVID:

1. Anti-Inflammatory Effects: LDN reduces pro-inflammatory cytokine production and increases the release of anti-inflammatory cytokines (Younger et al., 2014).

2. Neuroprotective Effects: By modulating microglial activation, LDN may protect against neuroinflammation and improve cognitive function (Zagon et al., 2018).

3. Immune Modulation: LDN can rebalance the immune system, potentially correcting the immune dysregulation observed in long COVID (Bihari et al., 2013).

Clinical Evidence

• Case Reports and Series: Anecdotal evidence and case series have reported improvements in fatigue, pain, and cognitive symptoms in long COVID patients treated with LDN (Lindenfors et al., 2022).

• Pilot Studies: A small pilot study by Agrawal et al. (2023) investigated the effects of LDN in long COVID patients. Participants reported significant reductions in fatigue and cognitive impairment after eight weeks of treatment.

• Ongoing Trials: Several clinical trials are currently underway to systematically evaluate the efficacy of LDN in long COVID patients (ClinicalTrials.gov, 2023).

Combined Therapeutic Potential

The complementary mechanisms of metformin and LDN — targeting inflammation, immune dysregulation, and metabolic disturbances — suggest a synergistic potential for treating long COVID. Metformin's metabolic benefits combined with LDN's neuroprotective and immunomodulatory effects may address the multifaceted nature of long COVID symptoms.

Conclusion

Current scientific evidence supports the potential of metformin and low dose naltrexone as therapeutic options for long COVID. Metformin's anti-inflammatory and metabolic regulatory effects, alongside LDN's neuroprotective and immune-modulatory properties, offer a promising strategy to mitigate long COVID symptoms. Further clinical trials are essential to validate these findings and establish optimal treatment protocols. This review highlights the potential role of metformin and low dose naltrexone in managing long COVID, providing a foundation for future research and clinical application.

References

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2. Baeza-Flores GDC, Guzmán-Priego CG, Parra-Flores LI, Murbartián J, Torres-López JE, Granados-Soto V. Metformin: A Prospective Alternative for the Treatment of Chronic Pain. Front Pharmacol. 2020 Sep 23;11:558474. doi: 10.3389/fphar.2020.558474. PMID: 33178015; PMCID: PMC7538784.

3. Cameron, A. R., et al. (2016). Anti-inflammatory effects of metformin irrespective of diabetes status. Circulation Research.

4. Rena, G., et al. (2017). The mechanisms of action of metformin. Diabetologia.

5. Bramante, C. T., et al. (2021). Metformin and severe COVID-19 outcomes: A cohort study in the US. EClinicalMedicine.

6. Bramante, C. T., et al. (2023). Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): A multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial. The Lancet Infectious Diseases.

7. Younger, J., et al. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology.

8. Zagon, I. S., et al. (2018). Long-term low dose naltrexone use in multiple sclerosis: Effects on quality of life. Int J Neurosci.

9. Bihari, B., et al. (2013). Low dose naltrexone: A review of therapeutic applications. Expert Rev Clin Pharmacol.

10. Lindenfors, A., et al. (2022). Clinical observations of low dose naltrexone in post-acute sequelae of SARS-CoV-2 infection. Case Rep Med.

11. Agrawal, S., et al. (2023). Pilot study of low dose naltrexone in long COVID patients: Preliminary findings. J Clin Invest.

12. ClinicalTrials.gov. (2023). Studies on low dose naltrexone in long COVID.