Metformin cut the incidence of long COVID by about 40%.

Metformin cut the incidence of long COVID by about 40%.

Another week – another fascinating drug connection pops up in long COVID. A preprint of a long-COVID study, “Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine – and the development of Long Covid over a 10-month follow-up”, recently reported that metformin decreased the risk of coming down with long COVID by about 40%.

The size and duration of the trial were unlike virtually anything that’s been done in ME/CFS or FM – which is exactly what we want to see. The large (n=1,125 overweight or obese adults) phase 3, randomized, quadruple-blinded, placebo-controlled trial followed the participants monthly for almost a year. People who’d had a positive coronavirus test result within three days and had fewer than 7 days of symptoms were eligible to participate. Immediate-release metformin was increased over time to 1,500mg per day.

The first thing to notice was the high incidence of long COVID – almost 11% – in this group. The second is the lack of definition for what a diagnosis of long COVID means. It appears that the doctors decided on their own who had long COVID.

Whatever type of long COVID some of the participants ultimately had, being able to prevent almost half of it from showing up, with what the authors called “a very safe medication”, was a very good thing. Since figuring out what metformin is doing to reduce the rate of long COVID could tell us much about long COVID – and therefore ME/CFS/FM – let’s check out what metformin is and what it’s possibly doing to keep a substantial number of coronavirus patients from emerging with long COVID.


Metformin turns out to be a most interesting drug. The first-line drug for type II diabetes, Metformin can do a lot more, though, than reduce insulin resistance, so much more that it’s hard to know what exactly it’s doing in long COVID. A good place to start is with pain and fibromyalgia.

The Fibromyalgia Connection

Metformin’s ability to boost immune functioning by activating AMPK and then the NLRP3 inflammasome appears to have significant pain-reducing potential. Many animal studies suggest the drug could provide a novel approach to pain reduction. At least five studies/papers on metformin and fibromyalgia/chronic pain have been published.

In a proof-of-concept, pilot trial, six women with FM received low-dose metformin (200 mg/daily) – a 6th of what the coronavirus study used). Significant improvements in pain, fatigue, morning tiredness, stiffness, anxiety, and depression were found.

Noting that AMPK appears to affect the sensory neurons via the mTOR and MAPK pathways – both of which impact the mitochondria – the authors proposed metformin might be enhancing the clearance of damaged mitochondria (autophagy). That’s an interesting connection given the recent finding of significant autophagy problems in ME/CFS.

Cleaning Crisis? Defective Mitochondrial Cleanup In ME/CFS May Be Impairing Energy Production

Another study found that the genes associated with metformin production were expressed big time in FM – suggesting a close connection between the two. They proposed that “metformin may regulate the axis of inflammation to improve pain, fatigue, and other symptoms in patients with FM”.

Similarly, reporting on a large number of animal studies, a recent review paper, “Metformin: A Prospective Alternative for the Treatment of Chronic Pain“, asserted, “Data strongly suggest that metformin could open a new avenue for the treatment of pathological pain and some of its associated comorbidities.. They believe that metformin’s ability to inhibit mTOR expression may be helping it regulate the activity of out-of-control sensory neurons that are causing so much pain in FM and other diseases.

Finally, one study suggests that metformin makes sense in fibromyalgia for an entirely different reason: it’s possible that many people with FM are in a pre-diabetic state without knowing it.

Fibromyalgia, Pre-Diabetes and Metformin: Could a Diabetes Drug Help with FM (and ME/CFS?)

A Chronic Fatigue Syndrome (ME/CFS) Connection?

Lower levels of autophagy (i.e. mitochondrial cleanup) can turn the mitochondria into ghosts – causing the cells to begin to deteriorate through lack of energy and start secreting pro-inflammatory cytokines. Autophagy, interestingly, also declines when cells become starved of resources – which has been proposed in ME/CFS – and plays an important role during exercise – a problematic area for ME/CFS and long COVID.

Plus, there’s an interesting possible Rapamycin connection given that both metformin and Rapamycin inhibit the mTOR pathway. Check a physician’s Rapamycin ME/CFS recovery story on Health Rising.

A Rapamycin Resurgence: An MD Moves the Needle on his ME/CFS

The Gist

  • Metformin is a type-11 diabetes drug that turns out to have lots of interesting possibilities for long COVID, fibromyalgia, and ME/CFS. 
  • A very large, well-constructed study found that metformin reduced the risk of coming down with long COVID by about 40% in people who were overweight. 
  • Numerous animal studies suggest that metformin may be an effective pain drug as well. A  pilot trial in FM found that low-dose metformin produced significant improvements in pain, fatigue, morning tiredness, stiffness, anxiety, and depression. 
  • Another study suggested that people with FM may be in a pre-diabetic state and that using metformin was able to take them out of that state may help to reduce pain. 
  • Like metformin, Rapamycin is an mTOR inhibitor that may be able to enhance autophagy – a process by which old, senescent mitochondria are removed so that the cell can function again. Rapamycin returned a physician with ME/CFS to health. 
  • Plus, metformin also appears to be able to improve gut health in ways that could be helpful in ME/CFS/FM. 
  • Unfortunately, metformin is still not being trialed in fibromyalgia or ME/CFS. After Paxlovid reduced the risk of long COVID, the NIH’s RECOVER Initiative started a Paxolivd trial in long COVID. Let’s hope this metformin finding produces the same result for this most interesting drug. 

Rapamycin, interestingly, appears to have the same impact on sensory neurons that metformin does. The effectiveness of both Rapamycin and metformin in laboratory studies has lead some to suggest that the mTOR pathway plays a key role in chronic pain.

It has been shown to be involved in the control of peripheral sensitization of nociceptors and inflammatory nociception. Based on this evidence, manipulations that provoke AMPK activation may be a novel and effective treatment for acute and chronic pain states.

Metformin has one other possible trick up its sleeve: it turns out that it also has many positive effects on the gut, including several that are pertinent to ME/CFS. They include increasing the levels of butyrate and short-chain fatty acids, and bulking up the integrity of the gut wall.

In fact, a recent article proposes repurposing metformin to reduce inflammation and oxidative stress, and enhance gut barrier integrity and the gut microbiome in inflammatory bowel disease.


One wonders if this long COVID finding will do for metformin what other studies have been unable to. For whatever reason, the ample positive animal studies that have explored its effects on chronic pain have not resulted in the kind of large clinical trials needed to get Rapamycin into wide distribution. (In fact, no clinical trials were reported underway in chronic pain or long COVID in the clinicaltrials.gov database.)

This quite large long-COVID study has gotten quite a bit of media attention, however, and the idea that a drug might be able to both reduce the risk of long COVID, reduce pain levels and even improve gut functioning in post-COVID diseases like fibromyalgia and ME/CFS seems pretty darn compelling.

NINDS chief Walter Koroshetz reported that the RECOVER Initiative is designed to avoid the scattershot approach that’s dominant in medical research – which produces lots of leads but provides few definitive results. Instead, the RECOVER Initiative is going to methodically assess treatments in a way that provides definitive results.

One imagines that this study has pushed metformin to the top of the potential treatment trial list. After Paxlovid was found to reduce the incidence of long COVID, the RECOVER Initiative started a trial of it in long COVID. Let’s hope the same thing happens with this intriguing drug.

BIG (Little) Drive Update

Thanks to the approximately 500 people who have supported Health Rising as we move into the last 10 days of our drive.

Scholar piggy

We do the work so you don’t have to.

When the metformin finding in long COVID came up, Health Rising was ready to provide linkages to fibromyalgia and ME/CFS as well because we’d already produced blogs on those topics and had done that work.

That’s why Health Rising is able to quickly clue you to the possibilities that this trial or that study provides for all these diseases. If that’s the kind of work that you want to see continue, please support us in a way that works for you. 🙂






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