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From ... in Biology Research Health —

NAC’s Crucial Role in Preventing and Treating COVID-19

N-acetylcysteine (NAC) is a precursor to reduced glutathione, which appears to play a crucial role in COVID-19.

NAC’s Crucial Role in Preventing and Treating COVID-19

According to an April 2020 literature analysis, glutathione

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deficiency may be associated with COVID-19 severity, leading the author to conclude that NAC may be useful both for its prevention and treatment. NAC has a long history of use as a first-aid remedy for acetaminophen poisoning. It neutralizes the toxic effects of the drug by recharging glutathione, thereby preventing liver damage. But the idea that NAC can also be helpful against viral infections is not new. Previous studies have found it reduces viral replication of certain viruses, including the infiuenza virus. In one such study, the number needed to treat (NNT) was 0.5, which means for every two people treated with NAC, one will be protected against symptomatic infiuenza. That's significantly better than infiuenza vaccines, which have an NNV (number needed to vaccinate) of 71, meaning 71 people must be vaccinated to prevent a single case of confirmed infiuenza. It's even better than vitamin D, which has an NNT of 33. In the MedCram lecture above, pulmonologist Dr. Roger Seheult reviews the latest medical literature on NAC for COVID-19, starting with a paper published in the October 2020 issue of Clinical Immunology titled "Therapeutic Blockade of Infiammation in Severe COVID-19 Infection With Intravenous N-acetylcysteine."

G6PD Deficiency Worsens COVID-19 Outcomes

Previous research has shown NAC inhibits the expression of proinfiammatory cytokines in cells infected with highly pathogenic H5N1 infiuenza virus. Proinfiammatory cytokines also play a crucial role in COVID-19 severity. Researchers have confirmed that in severe COVID-19 cases, cytokines such as interleukin-6 (IL6), interleukin-10 (IL10) and TNF- ɑ are all elevated. Once they reach excessive levels, a so-called cytokine storm develops, causing significant tissue damage. NAC may be able to inhibit this damaging cascade. In the "Therapeutic Blockade of Infiammation in Severe COVID-19 Infection With Intravenous N-acetylcysteine" paper, the researchers focus on a specific group of patients, namely those with glucose 6-phosphate dehydrogenase (G6PD) deficiency,

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which has been shown to facilitate human coronavirus infection due to the fact that G6PD depletes glutathione. G6PD deficiency is a genetic disorder that typically affects males and is more prevalent among Black men and those from the Mediterranean area, Africa and Asia. (Women with this genetic anomaly are carriers and can pass it on to their children but rarely display symptoms.) G6PD is an enzyme needed for the proper function of red blood cells. It also protects your red blood cells from free radicals in your blood by limiting oxidative stress. When your body doesn't produce enough of this enzyme, hemolytic anemia — a condition in which red blood cells are broken down faster than they are made — can result due to unneutralized oxidative stress from insuficient amounts of NADPH being produced. As noted in "Therapeutic Blockade of Infiammation in Severe COVID-19 Infection With Intravenous N-acetylcysteine":

"G6PD deficiency may especially predispose to hemolysis upon coronavirusdisease-2019 (COVID-19) infection when employing pro-oxidant therapy.However, glutathione depletion is reversible by N-acetylcysteine (NAC)administration.We describe a severe case of COVID-19 infection in a G6PD-deficient patienttreated with hydroxychloroquine who benefited from intravenous (IV) NACbeyond reversal of hemolysis.NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein(CRP), and ferritin and allowed removal from respirator and veno-venousextracorporeal membrane oxygenator and full recovery of the G6PD-deficientpatient."

How G6PD Deficiency Impacts COVID-19 Disease Process

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In his lecture, Seheult goes through the nitty-gritty details of how G6PD infiuences the COVID-19 disease process, why a deficiency in this enzyme can worsen outcomes and how NAC supplementation short-circuits this harmful chain of events. In summary, hydrogen peroxide (H O ), a reactive oxygen species (ROS), needs to be converted to water (H O) as much as possible in your cells to avoid red blood cell hemolysis, i.e., the destruction of red blood cells. As noted by Seheult, there's concern that the drug hydroxychloroquine may increase this process in G6PD-deficient patients, thereby increasing the risk of red blood cell hemolysis. The evidence is not conclusive, however. One 2018 study looking at the incidence of hemolytic anemia in G6PD-deficient patients given hydroxychloroquine concluded the risk may be overblown, as "There were no reported episodes of hemolysis in more than 700 months of HCQ exposure among the 11 G6PDH-deficient patients." The enzyme responsible for the conversion of hydrogen peroxide to water is glutathione peroxidase (GPX). GPX does two things simultaneously. While reducing hydrogen peroxide into water, it also converts the reduced form of glutathione (GSH) into glutathione disulfide (GSSG), which is the oxidized form of glutathione. In other words, as GPX turns hydrogen peroxide into harmless water, glutathione becomes oxidized. To recycle GSSG back to its reduced form, GSH, you need an enzyme called GSH reductase. The reducing agent needed for this to occur is NADPH. NADPH is also simultaneously converted into NADP+. To recycle NADP+ back to NADPH, you need G6PD. The point here is this: Patients who have G6PD deficiency will also have lower NADPH, and therefore won't be able to reduce the GSSG (the oxidated form of glutathione) to its reduced GSH form. This in turn leads to a buildup of hydrogen peroxide, resulting in higher levels of hemolysis. As explained by Seheult, the two building blocks of glutathione are NAC and the amino acid glycine. Glycine is fairly abundant, whereas NAC is not, so the theory is that, if you

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are G6PD deficient, you may be able to bypass this detrimental spiral by supplying high levels of NAC. This will allow your body to produce its own glutathione (GSH). This theory is what was investigated in "Therapeutic Blockade of Infiammation in Severe COVID-19 Infection With Intravenous N-acetylcysteine," and the answer is yes. When given hydroxychloroquine, the G6PD-deficient patient developed severe hemolysis, which was successfully reversed by giving intravenous NAC. In the end, the patient fully recovered. As for the dosage, the G6PD-deficient patient was given 30,000 milligrams of intravenous NAC divided into three doses over 24 hours, after which the patient began showing immediate improvement in hemolysis indices. About a week later, IV NAC was restarted at a dose of 600 mg every 12 hours for one week.

NAC Blocks Infiammation

In addition to that G6PD-deficient patient, NAC was also given to nine other COVID-19 patients who were on respirators but did not have G6PD deficiency. In these patients, "NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients." The authors hypothesize that NAC's mechanism of action "may involve the blockade of viral infection and the ensuing cytokine storm." That said, they point out that it's dificult to discern whether these anti-infiammatory effects were specific to the use of NAC, as steroids and other anti-infiammatory drugs were sporadically used. Still, they believe NAC does have the ability to reduce infiammation in patients with COVID-19. As explained in the paper:

"We propose that NAC restrains the pro-infiammatory metabolic pathways thatcontrol oxidative stress and mTOR-dependent generation of cytokine stormemanating from the immune system …IL-6, the primary cytokine that drives infiammation in COVID-19 infectedpatients, elicits mitochondrial oxidative stress at complex I of the mitochondrial
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electron transport chain (ETC). In turn, this leads to redox-dependent activationof mTORC1.Further downstream, uncontrolled activation of mTORC1 promotesinfiammation. NAC inhibits oxidative stress by serving as a cell-permeableamino acid precursor of the main intracellular antioxidant, GSH.Acting outside the cell, NAC may break disulfide bonds within ACE2 that servesas the cellular receptor for COVID-19. NAC may also block COVID-19 binding bydisrupting disulfide bind within its receptor-binding domain …Several anti-infiammatory medications have been shown to mitigate thecytokine storm in COVID-19 infection, such as corticosteroids, colchicine,imatinib, and complement C3 inhibitor AMY-101. However, the safety of mTORblockade stands out based on its propensity to extend overall lifespan.IV NAC has long been used to safely treat patients with acetaminophenoverdose, or ARDS [acute respiratory distress syndrome]. NAC was also foundto reduce CRP levels in several controlled clinical trials. CRP elevation is aprominent risk factor for disease progression in patients infected with COVID-19."

NAC Also Protects Against Blood Clots

Importantly, NAC may also protect against other problems associated with COVID-19, including the hypercoagulation that can result in stroke and/or blood clots that impair the ability to exchange oxygen in the lungs. Many COVID-19 patients experience serious blood clots, and NAC counteracts hypercoagulation, as it has both anticoagulant and platelet-inhibiting properties. A 2017 paper also found NAC has potent thrombolytic effects, meaning it breaks down blood clots once they've formed.

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This is largely thanks to the sulfur in NAC (from cysteine). The sulfur reduces the intrachain disulfide bonds by von Willebrand factors that have polymerized by dissociating the sulfur bonds holding them together, thus contributing to the clot. Once von Willebrand factor sulfur bonds are broken, the clots start to dissolve and the blood vessels open up again allowing for exchange of oxygen and carbon dioxide. According to the authors, "NAC is an effective and safe alternative to currently available antithrombotic agents to restore vessel patency after arterial occlusion." (Restoring vessel patency means the blood vessel is now unobstructed so that blood can fiow freely.) Two additional papers show the same thing.

High-dose intravenous NAC may be expected toplay an adjuvant role in the treatment of severeCOVID-19 cases and in the control of its lethalcomplications … including pulmonary andcardiovascular adverse events. ~ FASEB JournalAugust 11, 2020

Importantly, NAC's mechanism of action does not appear to increase bleeding disorders like heparin does, so it would likely be a safer alternative to the heparin used in the MATH+ protocol.

NAC Also Improves Variety of Lung-Related Problems

Studies have also demonstrated that NAC helps improve a variety of lung-related problems, including pneumonia and ARDS, both of which are common characteristics of COVID-19. For example: Research published in 2018 found NAC reduces oxidative and infiammatory damage in patients with community-acquired pneumonia.

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Another 2018 study found NAC improves post-operative lung function in patients undergoing liver transplantation. A 2017 meta-analysis found a significant reduction in ICU stays among ARDS patients treated with NAC (although there was no significant difference in short-term mortality risk). A 2007 study concluded NAC improves ARDS by "increasing intracellular glutathione and extracellular thiol molecules" along with general antioxidant effects. A 1994 study found NAC enhances recovery from acute lung injury, significantly regressing patients' lung injury score during the first 10 days of treatment, and significantly reducing the need for ventilation. After three days of treatment, only 17% of those receiving NAC needed ventilation, compared to 48% in the placebo group. NAC is also a well-known mucolytic used to help clear mucus out of the airways of cystic fibrosis patients. Some studies also suggest NAC can help reduce symptoms of COPD and prevent exacerbation of the condition.

Standard of Care for COVID-19 Should Include NAC

Considering many COVID-19 cases involve blood clots in addition to excessive oxidative stress, and NAC effectively addresses both, I believe NAC should be included in standard of care for COVID-19. As noted in "Rationale for the Use of N-acetylcysteine in Both Prevention and Adjuvant Therapy of COVID-19," published August 11, 2020, in the FASEB Journal:

"COVID-19 may cause pneumonia, acute respiratory distress syndrome,cardiovascular alterations, and multiple organ failure, which have been ascribedto a cytokine storm, a systemic infiammatory response, and an attack by theimmune system. Moreover, an oxidative stress imbalance has beendemonstrated to occur in COVID-19 patients.
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N- Acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH). Due toits tolerability, this pleiotropic drug has been proposed not only as a mucolyticagent, but also as a preventive/therapeutic agent in a variety of disordersinvolving GSH depletion and oxidative stress …Thiols block the angiotensin-converting enzyme 2 thereby hamperingpenetration of SARS-CoV-2 into cells. Based on a broad range of antioxidantand anti-infiammatory mechanisms … the oral administration of NAC is likely toattenuate the risk of developing COVID-19, as it was previously demonstratedfor infiuenza and infiuenza-like illnesses.Moreover, high-dose intravenous NAC may be expected to play an adjuvant rolein the treatment of severe COVID-19 cases and in the control of its lethalcomplications … including pulmonary and cardiovascular adverse events."

In the same vein, an even more recent paper, published in the October 2020 issue of Medical Hypotheses, points out that:

"T cell exhaustion, high viral load, and high levels of TNF-ɑ, IL1β, IL6, IL10 havebeen associated with severe SARS-CoV-2. Cytokine and antigen overstimulationare potentially responsible for poor humoral response to the virus. Lowercellular redox status, which leads to pro-infiammatory states mediated by TNF-ɑ is also potentially implicated.In vivo, in vitro, and human clinical trials have demonstrated N-acetylcysteine(NAC) as an effective method of improving redox status, especially when underoxidative stress.In human clinical trials, NAC has been used to replenish glutathione stores andincrease the proliferative response of T cells. NAC has also been shown toinhibit the NLRP3 infiammasome pathway (IL1β and IL18) in vitro, and decreaseplasma TNF-ɑ in human clinical trials.Mediation of the viral load could occur through NAC's ability to increase cellularredox status via maximizing the rate limiting step of glutathione synthesis, and
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thereby potentially decreasing the effects of virally induced oxidative stress andcell death.We hypothesize that NAC could act as a potential therapeutic agent in thetreatment of COVID-19 through a variety of potential mechanisms, includingincreasing glutathione, improving T cell response, and modulatinginfiammation."

FDA Cracks Down on NAC and Wants to Prevent You From UsingIt

At present, 11 studies involving NAC for COVID-19 are listed on Clinicaltrials.gov. Ironically, just as we're starting to realize its benefits against this pandemic virus, the U.S. Food and Drug Administration is suddenly cracking down on NAC, claiming it is excluded from the definition of a dietary supplement. They point out that NAC was approved as a new drug in 1985, and therefore cannot be marketed as a supplement. This is not refiected in the supplement market, however. As reported by Natural Products Insider, there are at least 1,170 NAC-containing products in the National Institutes of Health's Dietary Supplement Label Database. As of yet, the FDA has not taken action against NAC due to anything related to COVID- 19. They've primarily targeted companies that market NAC as a remedy for hangovers. Still, members of the Council for Responsible Nutrition have expressed concern the FDA may end up targeting NAC more widely. Hopefully, the FDA will not end up blocking access to NAC supplements in the same way hydroxychloroquine access has been stified.

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