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

[Ravn]

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

 

[Ravn]

This recent paper out of Columbia mentions Metformin as a possible treatment strategy for some patients

 

[Hutan]

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

A simplified diagram demonstrates an overlapping interplay of the etiological pathologies and their contribution to symptomatic ME/CFS and LC.

 

[MelbME]

That's a very confident assertion.


I've tried hard to understand that sentence, but haven't yet.


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.




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

View attachment 28372

I can't discuss the guidelines AFAIK other than that I'm one voice among many and it's advisory to decision makers that will listen but may not action what we advise.

This review was primarily put together by Dr David Fineberg with input and guidance from myself. It was an exploration of how metformin might be useful.

I think it's important to try identify a management strategy for ME/CFS and comorbidities. It's true that some may not find anything that helps them and their search would be a waste of time and resources.

 

[Utsikt]

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

Are all of those established, though? Or are they just theorised?

 

[Ravn]

I haven’t read the paper, just speculating on metformin in general. It’s a very common drug. There must be thousands and thousands of pwME on it. If it did something for ME shouldn’t we be seeing more anecdotal reports of metformin use correlating with improvements in ME symptoms? There don’t seem to be many such reports (admittedly I haven’t looked very hard). Or are we talking much higher doses for ME than are used in diabetes?

Are you planning a metformin study @MelbME ?

 

[Art Vandelay]

I haven’t read the paper, just speculating on metformin in general. It’s a very common drug. There must be thousands and thousands of pwME on it. If it did something for ME shouldn’t we be seeing more anecdotal reports of metformin use correlating with improvements in ME symptoms? There don’t seem to be many such reports (admittedly I haven’t looked very hard). Or are we talking much higher doses for ME than are used in diabetes?

For what it's worth, I developed insulin resistance when I got ME/CFS so my doctor wanted me to try Metformin. My blood glucose levels dropped slightly over the years while I was on Metformin. My ME/CFS worsened over that same period (although I'm sure there were many factors that could be blamed for that worsening).

It was in very short supply here for quite some time, so I stopped taking it. I didn't notice any difference.

Metformin does seem to be one of the latest fads in the Covid Long Hauler communities.

 

[Trish]

I think it's important to try identify a management strategy for ME/CFS and comorbidities. It's true that some may not find anything that helps them and their search would be a waste of time and resources.

Can you clarify what you mean by this sentence please, @MelbME?

Given that there is no reliable clinical trial evidence of any medical, behavioural or psychological treatment being effective in treating ME/CFS, there should be no treatment recommendation, other than symptomatic treatment for symptoms such as pain, sleep and nausea, and of course pacing advice and care and financial or nutritional support where needed.

I hope your comment is not suggesting the guideline should list untested or unproven treatments such as metformin for ME/CFS. That would be unethical and no better than anecdotal Twitter 'guidance'.

 

[Hutan]

I think it's important to try identify a management strategy for ME/CFS and comorbidities. It's true that some may not find anything that helps them and their search would be a waste of time and resources.

It is important that our researchers try to identify the cause and treatments for ME/CFS. Probably, ideally, they would not be distracted from that task by working on clinical guidelines. Until researchers do find the answers, do you agree that Trish's paragraph summarises best practice ME/CFS care?

This review was primarily put together by Dr David Fineberg with input and guidance from myself. It was an exploration of how metformin might be useful.

Ah, looks like my observation that this paper sounded like something from a doctor who believes that they can treat ME/CFS was correct. So David is doing a PhD supervised by you, Chris?

This from Linked In:

Founder of the ME Research Clinic, GP and PhD Candidate researching precision medicine techniques in MECFS and LC

I'll make a thread for MERC in our Clinics subforum, if we don't have one already.
Edit: thread here: Australia: Dr David Fineberg, ME Research Clinic (MERC), Melbourne

 

[BrokenBeaktheBrave]

For what it's worth, I developed insulin resistance when I got ME/CFS so my doctor wanted me to try Metformin. My blood glucose levels dropped slightly over the years while I was on Metformin. My ME/CFS worsened over that same period (although I'm sure there were many factors that could be blamed for that worsening).

It was in very short supply here for quite some time, so I stopped taking it. I didn't notice any difference.

Metformin does seem to be one of the latest fads in the Covid Long Hauler communities.

I also developed insulin resistance when I got MECFS. One of the few abnormal results I got from blood tests. The others were elevated prolactin, elevated cholesterol and low cortisol.

 

[Jonathan Edwards]

I agree that this looks unhelpfully speculative. Identifying a treatment strategy requires well run trials and until then we have nothing to offer. Suggestions that different people may need different treatments is premature. You can only identify who is most likely to respond to one thing or another after you have shown that those things work, and is significantly more difficult even than doing that.

 

[Turtle]

I agree that this looks unhelpfully speculative. Identifying a treatment strategy requires well run trials and until then we have nothing to offer. Suggestions that different people may need different treatments is premature. You can only identify who is most likely to respond to one thing or another after you have shown that those things work, and is significantly more difficult even than doing that.

Well run trials; wouldn't that be nice!! Problem as always is the money to do such a trial.
Just anecdotal n=1.
When I got metformin for diabetes my muscle pain was less. Not 3 or 4 days, but half that. Really welcome.
I wouldn't want everyone to wait, 5 or 10 years, for good trials results with loads of participants.
I wish everyone less pain.
Who did not try way worse pills? Do ask your doctor first.