A curious paper published this spring by Russian medical researcher Alexey Polonikov at the height of the coronavirus pandemic looked at a sampling of four COVID-19-positive patients at Kursk State Medical University: two with moderate to severe symptoms that persisted, and two with mild symptoms that disappeared without treatment within days.
All four patients were women, nonsmokers with no previously diagnosed underlying chronic conditions. The women were part of a healthy control group in a separate study of oxidation status in type 2 diabetes at the university's Research Institute for Genetic and Molecular Epidemiology.
One 33-year-old woman developed a fever of 38°C (100°F) and mild muscle aches eight days after she had contact with someone infected with SARS-CoV-2, the virus that causes COVID-19. Her symptoms disappeared without treatment six days after they began.
The second patient, a 47-year-old woman, developed a low-grade fever (37.3°C/99°F) and mild fatigue 10 days after she was exposed to the novel coronavirus via an infected person. Her symptoms resolved without treatment four days later.
A third woman in the study was 44 years old and developed severe COVID-19 symptoms four days after coming into contact with an infected person. Her fever ranged from 37.1°C to 38.5°C (99-101°F), her voice became hoarse, and she developed a dry cough along with significant muscle aches and fatigue. Pneumonia was confirmed by radiography.
Twenty-four days after her symptoms began, when the study was published in May, they had not yet resolved.
The fourth woman in the study was 56 and developed COVID-19 symptoms a week after exposure to an infected person. Her fever peaked at 39°C (102°F). She developed a severe dry cough, with difficulty breathing and an elevated heart rate. Lung X-ray confirmed that she, too, had pneumonia. Her symptoms lasted a total of 16 days, but eventually she fully recovered.
What was it about these women that made them react so differently to the virus?
Polonikov had data from blood tests taken two months before the women had become infected with the SARS-CoV-2 virus that made them ill with COVID-19. The two women who recovered quickly on their own had previously shown high blood levels of the potent, natural antioxidant glutathione (GSH) and a low ratio of damaging free radicals (also called reactive oxygen species or ROS) to GSH.
Before becoming ill, the two women who developed pneumonia had tested with low blood levels of GSH and high ratios of damaging free radical levels relative to GSH levels.
In fact, the measurements were inversely proportional to their degree of sickness: the woman who had not recovered had a prior ROS/GSH ratio of 34.6, the woman who was sick but recovered from pneumonia had a ratio of 6.9, the one who was sick for six days had a ratio of 2.9 and the one who recovered after just four days of mild sickness had a ratio of 1.2. The sicker the patient, the lower her GSH.
High glutathione, low viral load
"Long-term and severe manifestations of COVID-19 infection in one of our patients with marked glutathione deficiency suggest that the degree of glutathione decrease correlates negatively with viral replication rate and that an increasing viral load exacerbates oxidative damage of the lung," Polonikov hypothesized.
"This finding suggests that the virus cannot actively replicate at higher levels of cellular glutathione, and therefore, milder clinical symptoms are observed with lower viral loads."
He goes on to propose clinical trials of GSH and its precursor N-acetylcysteine (NAC), which raises GSH levels, for the treatment and prevention of COVID-19. 1
Four cases do not make a scientific dogma, of course, but Polonikov's hypothesis about GSH in COVID is grounded in his prior research into its role in diabetes and in an extensive medical literature that clearly links low GSH, the body's most important antioxidant, to disease. And he is not alone in proposing GSH and NAC as prevention and treatment for COVID-19.
Hundreds of recent studies have shown an association between low levels of GSH and chronic illnesses related to oxidative stress including obesity, cardiovascular disease, AIDS, cystic and pulmonary fibrosis, respiratory disease, cancer and mental illnesses like schizophrenia and depression.
Autopsies have also revealed that GSH is greatly depleted in the brains of patients with Alzheimer's and Parkinson's diseases.2
A review of the medical literature from 1980 to 2016 on the role of oxidative stress and GSH in ear, nose, and throat conditions concluded that many conditions such as rhinitis, allergic rhinitis, chronic rhinosinusitis with or without polyps, chronic earaches, tonsillitis, Ménière's disease, laryngeal conditions and chronic cough are associated with oxidative stress and decreased GSH, both at the site of infection and in the blood serum.3
Research has also found that healthy elderly women have higher blood serum levels of GSH than those with a chronic illness, though GSH is generally highest in young, healthy populations and declines with age.
The total serum GSH levels of elderly people with multiple chronic illnesses were inversely proportional with their number of illnesses, a long-term study of Swedish elderly people reported in 2019. The more medical conditions a person suffered from, the lower their corresponding GSH levels, which led the Swedish researchers to conclude that GSH serum level is a reliable "biomarker of multisystem dysregulation" that eventually leads to multiple diseases and death.4
"Death is a glutathione deficiency"
"Death is basically a glutathione deficiency syndrome," says Edward Fogarty, a radiologist from North Dakota who has published on the role of mitochondria and hyperbaric oxygen therapy in brain disorders. Required for 144 major molecular pathways in the body, GSH has been called the "mother of all antioxidants."
Furthermore, GSH can bend DNA in order to repair it and is a "master detoxifier" that disables myriad pollutants in the body, from those produced inside cells as a result of basic energy production to heavy metals, pesticides, drugs, food preservatives, radiation and other environmental toxins.
"When you're thinking about the human cell as a symphony," Fogarty says, "the production is energy, oxygen is the conductor and the baton of the conductor
"When there's a lot more glutathione in the cell, there is actually higher energy," adds Dr Fogarty. "The more energy you have, the less susceptibility you have at the cellular level. That, he says, is why "all cells on the planet need glutathione and the key vital amines of life are those that form glutathione."
The mother of all antioxidants
Cleveland Clinic functional doctor Mark Hyman dubbed glutathione (GSH) the "mother of all antioxidants" because the molecule's chief job is taking care of damaging free radicals in the body.
Free radicals are generated as a byproduct of energy metabolism but also from exercise and environmental toxins. They are highly reactive particles that bounce around the cell causing damage, like burning embers, singeing everything they touch.
As our mitochondria, the energy powerhouses in each of our cells, constantly belt out the energy we need for all of our bodily functions, from thinking to synthesizing enzymes and contracting our muscles, GSH is continuously mopping up disease-causing free radicals generated by this energy production.
GSH is unique because it is the only antioxidant found inside every cell in our bodies, and unlike other antioxidants such as vitamins C and E, after it neutralizes a free radical, it pairs with another oxidized GSH molecule to be neutralized itself.
What's more, GSH acts synergistically with other antioxidants, including vitamins C and E, coenzyme Q10 and alpha-lipoic acid, by recycling these antioxidants to keep them in action longer.GSH is concentrated in the liver, spleen and skin at thousands of times higher concentrations than other antioxidants.
Among its myriad other functions besides antioxidant and detoxifier, GSH also acts as a transporter of proteins between cells and among the compartments of a cell, it signals the immune system to respond to invading pathogens, and it repairs damaged DNA.
So what is GSH and why is it apparently so critical to health? What's more, can we increase it to prevent disease and stay healthy?
As it is in such high demand in every cell, our bodies are continuously making their own GSH from three widespread amino acids: cysteine, glycine and glutamate. Of these, cysteine has been shown to be the rate-limiting factor in the production of GSH.5
If we get low on cysteine, we get low on GSH, and cysteine can boost low levels of GSH. That's why for decades doctors have used the supplement N-acetylcysteine (or NAC for short) to treat overdoses of acetaminophen (also known as paracetamol, or trade name Tylenol).
High doses of acetaminophen are believed to exert their toxicity by rapidly depleting the liver of its GSH stores. NAC is used to ramp GSH back up, and its use dramatically cuts the risk of overdose mortality.
NAC also has a history of use as a mucus-breaking agent in respiratory diseases because it can break up the double sulfur bonds in mucus, making it thinner and easier to expel.6
It is these properties of NAC—its GSH boosting and sulfur bond-breaking abilities—that have made it of special interest in dozens of studies on diseases from schizophrenia to COVID-19.
Side-effects of NAC
Researchers at the Whole Systems Research Institute in Portland, Oregon, also published a paper about NAC's anti-inflammatory potential in the fight against COVID-19. Importantly, the supplement's risks are very low. "NAC has an excellent safety record in clinical trials," the authors noted.
Some people have experienced side-effects of oral NAC, however, including mouth ulcers, nausea and acid reflux. Nebulized NAC may cause airway constriction, prolonged coughing and may worsen asthma. Serious adverse reactions with intravenous NAC are rare and documented only in cases of drug overdose treatment.1
It's the same anti-inflammatory and GSH-raising antioxidant properties of NAC that have sparked interest in its use to counteract neurodegenerative and mental health diseases including addiction, schizophrenia, Alzheimer's and Parkinson's diseases, to prevent cognitive decline in aging and to address neuropathic pain and stroke.2
At least as far back as 1991, researchers at the National Institutes for Health, including the current head of the US COVID-19 task force, Dr Anthony Fauci, were reporting how GSH and NAC could shut down HIV replication in cells. They recommended that GSH therapy may be useful for AIDS.7
Since then, numerous studies have demonstrated the antiviral properties of GSH and NAC.
Flu symptom reduction
A 1997 randomized double-blind trial of 262 people who took either a placebo or 600 mg NAC tablets twice daily (total dose of 1,200 mg/day) for six months found that, on blood tests, both groups were infected by H1N1 influenza at the same rate. However, 79 percent of those infected in the placebo group had a symptomatic form of the flu compared to just 25 percent of those taking NAC, corresponding to a roughly three-fold drop in the likelihood of developing clinical symptoms.8
By contrast, the 2017-2018 influenza vaccine was at most 40 percent effective, which means you'd have to treat 100 people to prevent 40 symptomatic cases of flu (and a sizable number of recipients would experience unpleasant symptoms from the vaccine as well).
In another study, researchers at Georgia State University developed an "amino acid cocktail" to encourage cellular production of GSH—consisting of three free-form amino acids, cysteine, glycine and glutamate, plus selenium—and tested its ability to combat Zika virus replication. They found the mixture "reduces Zika virus replication up to 90 percent at doses that are completely safe for cells."9
A 2018 study showed that one week of supplementation with NAC improved oxidative status and inflammatory markers in pneumonia patients.10
Another randomized, double-blind trial comparing NAC against a placebo in 60 patients on a ventilator found that those treated with NAC were "significantly less likely to develop clinically confirmed VAP [ventilator-associated pneumonia] compared with patients treated with placebo" (26.6 percent vs. 46.6 percent).
NAC-treated patients also had significantly shorter stays in an intensive care unit (ICU; 14 days vs. 17 days) and fewer days hospitalized overall (19 days vs. 24 days). The rate of complete recovery was significantly higher in the NAC group as well (56.6 percent vs. 30 percent).11
This and other NAC research has grabbed the attention of Roger Seheult, cofounder of the medical education company MedCram, whose YouTube videos about treating COVID at two of the hospital ICUs where he works in Southern California have drawn tens of thousands of views, along with other researchers who are increasingly convinced NAC could play a role in preventing and treating the SARS-CoV-2 infection that leads to COVID-19.
From early on in the pandemic, some doctors noticed that COVID-19 wasn't behaving like a typical respiratory syndrome but more like "acute mountain sickness," with some patients showing unusually severe immune responses.
Doctors increasingly became convinced that many cases of severe COVID occur when the patient's immune system hyper-responds to the virus. When the immune system overreacts, it can create what is called a "cytokine storm" in which immune signaling molecules called cytokines cause more collateral damage fighting the virus than the virus causes itself.
New York physician Richard Horowitz published case studies of two patients with coronavirus-related shortness of breath who responded well within one hour of treatment with oral and intravenous GSH.12
Swedish researchers cited previous studies of the anti-inflammatory effects of NAC and called for clinical trials of the supplement in COVID-19 infection for tamping down a runaway immune response and the tandem oxidative stress it creates.13
Doctors and researchers have additionally pointed to the mitigating effects of NAC on blood clotting or coagulation, which may also have a potent anti-COVID effect.
Anna Aksenova, a senior research associate at the Laboratory of Amyloid Biology at St Petersburg University in Russia, has proposed that severe SARS-CoV-2 infection may be associated with von Willebrand factor, one of the main components of the blood coagulation system.
According to this hypothesis, the virus stimulates inflammation of blood vessel walls. The body consequently releases von Willebrand factor as a repair response, but this elevates the risk of thromboses—clots that can clog or block the blood vessels. A number of COVID-19 deaths are attributed to blood clotting causing heart attacks and strokes.14
In one of his videos, viewed more than 150,000 times since May, Seheult describes the broad medical literature explaining how NAC's anti-mucosal action, snipping double-sulfide bonds in mucus, also snips double-sulfur bonds in von Willebrand factor, which explains its anticoagulant and anticlotting effects.15
He cited a number of studies on the anticoagulant properties of the inexpensive, over-the-counter supplement NAC, including a 2017 study in the journal Circulation titled, "Potent thrombolytic effect of N-acetylcysteine on arterial thrombi," which describes NAC breaking sulfur bonds in von Willebrand factor and reopening the arteries. "We provide evidence that NAC is an effective and safe alternative to currently available antithrombotic agents to restore vessel patency after arterial occlusion," the paper concludes.16
"These are the same kind of thrombi that might be acting in COVID-19 in the pulmonary vasculature [lung vessels]," said Seheult.
"And the articles just keep coming," he adds, citing a host of studies on the anticoagulant properties of NAC supplement: an in vitro study of NAC in plasma samples from healthy subjects demonstrating its ability to significantly decrease coagulation factors, making the blood thinner and less able to clot,17 another study showing that NAC use in patients undergoing surgery for abdominal aortic aneurysm has platelet-inhibiting and anticoagulant properties,18 and a study showing that NAC "reversed stroke-induced brain injury," which was correlated to GSH status, in the mouse brain.19
Referring to Russian researcher Polonikov's hypothesis of reduced GSH levels increasing susceptibility to more severe infections, Seheult said: "The good professor comes up with very similar conclusions that we do, which is that N-acetylcysteine as a preventative measure may be very effective.
"The nice thing about NAC is that it could act here to reduce oxidative stress and can potentially reduce the amount of von Willebrand factor monomers and polymers coming together and forming these clots and the thrombosis that is associated with it. We have no evidence that this would work in COVID-19 because we haven't done the trials, but if we connect the dots it looks promising.
"If people took NAC orally as a preventative, could this prevent serious forms of COVID-19 just as we saw with influenza? If given in high enough doses intravenously in the hospital, can it prevent patients from progressing to intubation and ventilation?" Seheult asked.
Seheult may soon have the answers he is looking for. As of July 2020, at least four clinical trials were recruiting COVID-19 patients to assess the performance of NAC against placebo. One of the trials, conducted by Memorial Sloan Kettering Cancer Center, stated that it intended to administer 6 grams of intravenous NAC against placebo in severe COVID-19 cases. The results, which may not be available until late 2021, will be worth waiting for.20
Boost your glutathione naturally
Glutathione (GSH) is a critical molecule in our bodies, performing many functions from quenching free radicals to neutralizing environmental toxins. High levels of GSH are linked to youth and vitality, and hundreds of studies have associated low levels of GSH with disease.
Smoking, drinking alcohol, bad diets, exposure to environmental pollutants, lack of sleep and stress all gobble up GSH. What's more, when you hit the age of 30, your body's production of GSH will typically start to flag.
"I now use it routinely in any complicated case and as people age," says UK doctor Sarah Myhill, author of Sustainable Medicine: Whistle-Blowing on 21st Century Medical Practice (Chelsea Green Publishing, 2018). Here are some things to consider for keeping your GSH tank topped up:
Dr Myhill said that 250 mg of "bog standard" or ordinary oral GSH would raise red blood cell GSH levels in her patients, and she does not recommend the more expensive liposomal version, which she says works just as well. If you do opt for a supplement of GSH, make sure it's a product made of L-glutathione, the only active form.
NAC does a "similar job" to GSH supplements, says Dr Myhill, in raising GSH levels in the blood. Some researchers say there is even evidence to prefer NAC, because NAC increases plasma cysteine levels that eventually raise plasma GSH. What's more, animal studies have described NAC's ability to penetrate the blood-brain barrier to raise GSH levels in the brain.1 NAC is inexpensive and widely available over the counter.
Recommended dose: 600 mg, twice daily
As a side note, Dr Joseph Mercola has recommended "pre-toxing" alcohol by taking at least 200 mg of NAC about 30 minutes before drinking alcohol to offset the depletion of GSH that contributes to hangover effects.2
Other glutathione boosters
Selenium. Selenium is a trace element and known antiviral
agent that your body needs to make the antioxidant glutathione (GSH). Selenium-rich foods include organ meats, chicken, brown rice and brazil nuts.
Recommended dose: 140-200 mcg/day as seleno-methionine
Whey protein. Studies point to whey protein as a supplement that increases GSH.1
Sulfur-rich foods. GSH contains sulfur, which is the third most abundant mineral in the human body. GSH production is dependent on the presence of amino acids containing sulfur, notably cysteine, which you
can get by eating sulfur-rich foods including: most high-protein foods such as meat, fish, eggs, seeds and yogurt, broccoli, cabbage, kale, onions, garlic, green onions, Brussels sprouts and cauliflower. Some people choose to supplement sulfur via methylsulfonylmethane (MSM), which should be used according to the directions on the product.
Vitamins C and E. Vitamins C and E are both antioxidants that work in tandem with GSH. Researchers have known for decades that vitamin C can raise GSH levels in red blood cells in healthy people.2 Vitamin E protects GSH-dependent enzymes that are essential for its antioxidant functions.3 Food sources of vitamin C include citrus fruits and kiwi. Food sources of vitamin E include nuts and seeds, avocados and fish.
Recommended maintenance dose of vitamin C: 1-2 grams twice a day. Vitamin E: 400 mg/day. When supplementing, look for tocotrienols rather than tocopherols if possible and follow the label for dosing