N-acetylcysteine (NAC) has a long history of use to help prevent liver damage, and more recently as a treatment for flu viruses. Now researchers have discovered its lifesaving value for COVID-19.
N-acetylcysteine (NAC) is a precursor to reduced glutathione, which appears to play a crucial role in COVID-19. According to an April 2020 literature analysis, glutathione 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 influenza 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 influenza. That’s significantly better than influenza vaccines, which have an NNV (number needed to vaccinate) of 71, meaning 71 people must be vaccinated to prevent a single case of confirmed influenza. It’s even better than vitamin D, which has an NNT of 33.
G6PD Deficiency Worsens COVID-19 Outcomes
Previous research has shown NAC inhibits the expression of proinflammatory cytokines in cells infected with highly pathogenic H5N1 influenza virus. Proinflammatory 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 Inflammation 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, 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 insufficient amounts of NADPH being produced.
“G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration.
How G6PD Deficiency Impacts COVID-19 Disease Process
In his lecture, Seheult goes through the nitty-gritty details of how G6PD influences 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 (H2O2), a reactive oxygen species (ROS), needs to be converted to water (H2O) 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 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 Inflammation 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.
NAC Blocks Inflammation
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.”“We propose that NAC restrains the pro-inflammatory metabolic pathways that control oxidative stress and mTOR-dependent generation of cytokine storm emanating from the immune system …
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.
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.
“High-dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID-19 cases and in the control of its lethal complications … including pulmonary and cardiovascular adverse events.” ~ FASEB Journal August 11, 2020Importantly, 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 inflammatory damage in patients with community-acquired pneumonia.
- 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 ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID-19 patients.
“T cell exhaustion, high viral load, and high levels of TNF-ɑ, IL1β, IL6, IL10 have been associated with severe SARS-CoV-2. Cytokine and antigen overstimulation are potentially responsible for poor humoral response to the virus. Lower cellular redox status, which leads to pro-inflammatory states mediated by TNF-ɑ is also potentially implicated.
