Review A Perspective on the Role of Metformin in Treating [...] (ME/CFS) and Long COVID (2025) Fineberg et al

Ravn

Senior Member (Voting Rights)
Authors: David Fineberg, Alain Moreau, Elena K Schneider-Futschik, Christopher W. Armstrong

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID (LC) are increasingly recognized as debilitating postinfectious conditions that impact both individuals and society. Recent research highlights the potential of metformin, an antidiabetic agent, as a treatment for these syndromes by targeting their underlying mechanisms.

This review assesses the effectiveness of metformin in ME/CFS and LC, which involve complex dysfunctions related to cytokines, glycolysis, ATP generation, oxidative stress, gastrointestinal microbiomes, and vascular endothelial function.

Metformin, traditionally known for its antihyperglycemic properties may offer broader therapeutic benefits by influencing these pathological pathways. It works by inhibiting complexes I and IV of the electron transport chain, which reduces the strain on malfunctioning complex V and decreases the production of harmful free radicals.

Additionally, metformin’s impact on mTOR signaling could improve energy metabolism in ME/CFS and LC by downregulating an overactive but underperforming protein, thereby alleviating symptoms.

Beyond the impact on cellular metabolism, metformin has shown to have anti-inflammatory, vascular, gastrointestinal, neuroprotective and epigenetic effects.

We explore this impact of metformin and the potential role it could play to help people with ME/CFS. While metformin shows promise, it is unlikely to be a stand-alone solution. Instead, it may be part of a broader treatment strategy that includes other therapies targeting neurocognitive and autonomic impairments.

https://pubs.acs.org/doi/full/10.1021/acsptsci.5c00229

Open access
 
This review assesses the effectiveness of metformin in ME/CFS and LC, which involve complex dysfunctions related to cytokines, glycolysis, ATP generation, oxidative stress, gastrointestinal microbiomes, and vascular endothelial function.
That's a very confident assertion.

Key symptoms shared between ME/CFS and LC, such as fatigue, PEM, cognitive impairments, and sleep disturbances, contribute to the clinical heterogeneity of both conditions.
I've tried hard to understand that sentence, but haven't yet.

Heterogeneity, even seen among twin studies and genders complicates the ability to develop a single treatment that will provide unifying symptomatic relief. (79−81) Trials aimed at treating ME/CFS, such as rituximab, report failures when the diversity in larger populations begins to play a role. (82,83)
That is looking worryingly like a suggestion that there are treatments that are useful for ME/CFS, it's just that one treatment doesn't work for everyone. We've criticised that idea before. It's a problem when we don't have good evidence of any treatment being helpful; it sets people with ME/CFS off on an odyssey of searching for the promised treatment that will be the one that works for them. And the second sentence there makes it seems as though the reason for the failure of rituximab in the phase 3 trial was the diversity of the large sample - I don't think we have evidence to support that idea.

We suggest unifying the principle of aggressive symptom management in ME/CFS and LC clustered under affected systems (see Figure 5), whereby whole-of-person treatment should involve targeting of each domain. Although significant interplay between affected domains allows treatment of one domain to improve others, a multifaceted approach is likely to provide greater clinical benefit.
Metformin has a strong influence on cellular stress and microbiome derangement (see Figure 6), with medication targeting cardiac autonomic dysfunction in ME/CFS often reporting success in specific subgroups. (84−90) Similar responses in subgroups are found in psychostimulant medications targeting cognition, suggesting variable penetrance of each domain within individuals. (91,92) Using the new perspective on treatment, a future strategy might involve autonomic targeting with IV saline, (93,94) oral rehydration salts (95) and negative chronotropic medications, (96−98) coupled with neurocognitive and neuromuscular stimulants. (91,92,99−101)

This looks to be the manifesto of the ME/CFS specialist doctors. The senior author here, Chris Armstrong @MelbME is on the Australian ME/CFS Clinical Guideline Development Committee. Chris, are these ideas that you will be putting forward for inclusion in the clinical guideline?

Figure 5 tells us in a new sort of circular diagram that the overlapping etiological pathways of ME/CFS are
  • cardiac and vascular pathology
  • cellular stress
  • neurocognitive impairment
  • microbiome derangement
Screenshot 2025-09-14 at 10.58.30 pm.png
A simplified diagram demonstrates an overlapping interplay of the etiological pathologies and their contribution to symptomatic ME/CFS and LC.
 
Last edited:
Back
Top Bottom