A couple of months ago, Health Rising reported on a metformin long-COVID study. In this blog, we take a deeper look at metformin and the study itself in light of recent results.
This 1,000-person-plus trial, “Outpatient treatment of Covid-19 and the development of Long Covid over 10 months: A 2 multi-center, quadruple-blind, parallel group randomized phase 3 trial“, assessed what happened when overweight but healthy people were given metformin (500 mg – 1 day, 2 500 mg for 4 days, 500 mg in the morning and 1,000 mg in the afternoon for 9 days) or placebo as they came down with COVID-19. Note how short the time period was – just two weeks. (The trial also assessed the effectiveness of ivermectin and fluvoxamine and did not find them helpful.)
They were followed monthly with a final assessment 9 months after receiving metformin. The patients were deemed to have long COVID if a physician had diagnosed them with it – suggesting that the incidence of long COVID may have been understated. While we don’t know what type of long COVID they had, studies that ask about the incidence of post-exertional malaise in long COVID find that a majority of long-COVID patients have it.
The study found that people receiving metformin early in the infection had a 42% reduction in the incidence of long COVID. Interestingly, during the acute stages of COVID-19, metformin was also found to prevent about 40% of emergency department visits, hospitalizations, and death. The drug was most effective when taken earlier in the infection (<4 days since symptom onset).
In his recent Ground Truths blog, Eric Topol was very high on the finding, calling it a “breakthrough” stating that given metformin’s cheapness and safety profile, if he came down with a coronavirus infection, he’d take the metformin at the doses recommended in the study.
The authors asserted that the fact that the drug was most effective when taken earlier in the infection (<4 days after symptoms) suggested that its antiviral properties may have played a major role in preventing long COVID.
They also suggested that metformin be tried in combination with drugs like Paxlovid. The possibility of using multiple drugs together to synergize their effects on viruses is welcome indeed given the mediocre drugs that have been used in ME/CFS to fight off the herpes viruses.
While Skip Pridgen has been trialing a two antiviral/anti-inflammatory drug combination in fibromyalgia, the antiviral avenue has hardly been touched in clinical trials of ME/CFS. Comparing this thousand-plus person trial to the one very small placebo-controlled antiviral trial that the ME/CFS field managed to get produced, despite years of interest in the Epstein-Barr virus, shows what a different world we’re in now.
Now for a deeper look at metformin and the ability of other drugs and supplements to impact a crucial energy regulator called AMPK.
Metformin, AMPK Activation/mTORC1 Inhibition
Metformin is an AMPK activator. Described as a cellular energy sensor and metabolic regulator, AMPK activation switches the body from being in an energy-consuming to an energy-producing state. AMPK is activated to respond to cellular conditions that reduce energy, and ensures that proper ATP levels are present in our cells. As ATP declines during say, exercise, AMPK triggers more ATP production. AMPK should, therefore, be activated in the muscles during exercise. Interestingly, given the recent findings of impaired fatty acid oxidation in ME/CFS, AMPK also promotes fatty acid oxidation.
In 2015, Julia Newton found greatly impaired production of AMPK and a cytokine (IL-6) involved in AMPK activation in ME/CFS, but when Newton whacked the muscle cells from ME/CFS patients with exercise, she found no evidence of AMPK activation. She proposed that the lack of AMPK activation impaired muscle contractions during exercise in ME/CFS, leading to exercise intolerance.
Newton followed up her 2015 study with a 2018 study that showed that metformin increased AMPK activation in cultured ME/CFS muscle cells. Unfortunately, that’s as far as we’ve gotten with metformin in ME/CFS.
AMPK activation and autophagy (see below) is inhibited by the coronavirus as well. In fact, many viruses, including herpesvirus and Coxsackie, modulate AMPK activity in order to impact autophagy, fat and lipid metabolism, glucose metabolism, etc., and facilitate viral replication.
The AMPK/mTORC1 Connection
By inhibiting mTORC1, AMPK also provides other benefits including reducing lactate production, increasing ATP levels, improving cognition, and inducing autophagy – a process the cell uses to clean defective mitochondria up – and which a recent Simmaron study suggests may be impaired in ME/CFS. If defective mitochondria are not cleaned up, the cells they are embedded in can become senescent, start deteriorating and begin secreting pro-inflammatory cytokines.
Autophagy is also induced by the muscle contractions that occur during exercise and is necessary for maintaining muscle activity. Mice deficient in stress-induced autophagy exhibit less endurance during exercise.
Metformin and Chronic Pain
mTORC1 also regulates the activity of sensory neurons in the periphery and central nervous system, including the A-fiber neurons that have been shown to be damaged in FM, ME/CFS, and long-COVID patients with small fiber neuropathy. Given the many, many symptoms – including sensitivity to light, sound, and touch as well as the odd, hard-to-describe symptoms – reported in FM, ME/CFS, and long COVID, it would seem odd indeed if the sensory neurons were not affected in some way.
That brings us to the question of whether metformin and similar AMPK-activating / mTORC1 inactivating compounds might help with pain.
A rather meaty 2020 review, “Metformin: A Prospective Alternative for the Treatment of Chronic Pain“, proposed, in fact, that metformin could be a new pain drug and might even be helpful with anxiety, cognition, and sleep as well.
The review indicated that researchers have been studying the effects of metformin on pain in the lab and animal models for over ten years. One animal study, which found that metformin suppressed “aberrant translation pathways”, and neuronal excitability, and inhibited pain, made it seem like metformin might be just the thing for overstimulated and tweaked pain pathways in FM.
Another study found that metformin was able to reverse allodynia (extreme sensitivity to touch) – a nightmarish treatment-resistant problem. Further studies suggested metformin may be able to diminish a form of allodynia associated with fructose (chronic fructose-induced tactile allodynia).
Plus, metformin’s apparent ability to impact the dorsal root ganglia – a primary sensory processing center and the putative source of “chronic inflammatory pain”, as well as a common hiding place for herpesviruses – adds another possible dimension to this interesting drug, given its antiviral properties.
Finally, metformin has positive effects on the gut, including increasing the levels of butyrate and short-chain fatty acids and bulking up the integrity of the gut wall. 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. Despite this it can produce some negative symptoms in some people.
Despite a decade of successful animal and laboratory studies, few human studies have assessed metformin’s ability to reduce pain.
Metformin and other AMPK Activators and mTORC1 Inhibitors in Fibromyalgia (FM) and Chronic Fatigue Syndrome (ME/CFS)
Given the mitochondrial aberrations seen in fibromyalgia (diminished AMPK activity, decreased mitochondrial production, reduced oxygen consumption), metformin’s ability to enhance mitochondrial activity and reduce oxidative stress would make it seem like a good possibility for FM.
Indeed, a 2015 FM study found that the reduced AMPK activation found in FM tissues (fibroblasts) was reversed by metformin in a laboratory study. (Note that AMPK activation = mTORC1 inhibition = possibly increased ATP production, reduced lactate, reduced activation of pain nerves). The authors stated, “these results suggest that AMPK plays an essential role in FM pathophysiology and could represent the basis for a valuable new therapeutic target/strategy.”
That was followed by a 2016 study that again found “deficient AMPK activation” in FM. In a small treatment study, metformin treatment (200 mg/daily) “increased AMPK activation, restored all biochemical alterations… and significantly improved clinical symptoms, such as pain, fatigue, depression, disturbed sleep, and tender points” in six people with FM.
In the 2020 paper, “Is insulin resistance the cause of fibromyalgia? A preliminary report“, the authors reported that metformin completely resolved the pain of half (8/16) of the FM patients and that some responded only to metformin. (Others were getting drugs like amitriptyline and gabapentin). Plus, the metformin treatment effects seemed to stick over time. (This study was retracted by PLOS ONE because it had not received a proper ethics review. PLOS ONE was also concerned that the control group was not sufficient.)
Other AMPK activators/mTORC1 Inhibitors
Some evidence suggests that other AMPK activators/mTORC1 inhibitors might help in diseases like FM and ME/FS. Rapamycin – which returned one person with ME/CFS to health – inhibits mTORC1 as well and has been shown to reduce pain hypersensitivity in animal studies.
Similarly, Jarred Younger recently reported that two other AMPK activators – resveratrol (200-600 mg/day; more is better) and curcumin (500 -1,000 mg;) – were helpful in Gulf War Illness.
- A couple of months ago, Health Rising published a post on a study that found when given for a short time during the initial coronavirus infection, metformin was able to reduce the incidence of long COVID by about 40%.
- This post goes over that study once again and then dives deeper into the possibility that metformin may be able to reduce pain and increase its ability to turn on a crucial energy regulator called AMPK.
- How metformin is working to reduce the incidence of long COVID is not clear but could be due to its antiviral, anti-inflammatory, blood vessel-protective, and energy-enhancing properties.
- Activating the AMPK enzyme switches the body from being in an energy-consuming to an energy-producing state. As ATP declines during, for instance, exercise, AMPK triggers more ATP production. AMPK should, therefore, be activated in the muscles during exercise.
- When Julia Newton whacked the muscle cells from ME/CFS patients with exercise, though, she found no evidence of AMPK activation. Giving the cells metformin, though, revived AMPK.
- AMPK also inhibits something called mTORC1. By doing so, it can reduce lactate production, increase ATP or energy levels, improve cognition, and induce something autophagy, which a recent Simmaron study suggests may be impaired in ME/CFS.
- Autophagy is a process cells use to clean up defective mitochondria. Problems with autophagy can cause cells to decline and start pumping our pro-inflammatory compounds called cytokines.
- mTORC1 activation on the other hand also appears to increase pain sensitivity. Over the past ten years, laboratory studies suggest metformin may be an effective pain drug.
- Human studies are rare, but a few small fibromyalgia studies in metformin and other AMPK activators suggest they might be helpful. Rapamycin, for instance, returned one ME/CFS patient to health, and Jarred Younger found that two other AMPK activators, resveratrol and cucumin, when used in the right dosages, were helpful in Gulf War Illness (see blog). Oxymatrine, used by Dr. John Chia in the form of Equilibrant, is another AMPK activator that’s proven helpful in ME/CFS.
- Many other possible AMPK activators are present. We don’t know which ones in which doses and in which combinations are most helpful, but much effort is going into finding ways to activate this crucial enzyme in the energy production pathway. It’s something to keep an eye on.
- For ME/CFS/FM and long-COVID patients, a big remaining question is whether the RECOVER Initiative or some other group will produce a metformin trial in long COVID.
Other AMPK Activators
Given the many ways that AMPK inactivation could be impacting diseases like ME/CFS, FM, and long COVID, finding ways to activate AMPK has to be considered. Thankfully, the interest that AMPK activation is sparking in cancer and other diseases has made finding ways to activate AMPK a growth field.
The Self-Hacked website lists an enormous number of possible AMPK-enhancing compounds including berberine (an antiviral), R-Lipoic Acid, Glucosamine, Resveratrol, Curcumin, Gynostemma (often used in AMPK activating supplements), Cod liver/Fish Oil, Anthocyanins, Cannabinoids, Astragalus, Reishi, Creatine, CoQ10, Bitter melon, etc.
Compounds are being tested regularly. Magnolol, for instance, is a plant-derived Chinese compound available as a supplement that was recently found to increase AMPK activation, downregulate MTORC1, and improve autophagy in a Parkinson’s mouse study. Astragalan, another Chinese compound (China is a world center of plant diversity) restored AMPK activity and improved energy metabolism in diabetic mice. A Chinese fungus, Cordyceps sinensis, helped to treat lung injury by activating AMPK. Two yogurt strains, Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131, not only improved gut integrity but increased AMPK activity.
Many attempts, then, are being made to find effective AMPK activators. Which ones might work best in the context of diseases like ME/CFS, FM, and long COVID is unclear, but the growth of the field is encouraging. AMPK activation is something to keep an eye on.