Roles of NAC and glutathione in promising COVID-19 treatment
By Dr. Joseph Mercola , Mercola , May 25, 2020.
- Research has shown that NAC can mitigate flu symptoms and improve cellular immunity. For every two people treated with NAC, one will be protected against symptomatic influenza
- NAC also inhibits viral replication and the expression of pro-inflammatory cytokines, such as interleukin-6 (IL-6), in cells infected with the pathogenic H5N1 influenza virus, and reduces acute respiratory distress syndrome (ARDS).
- NAC may protect against COVID-19-related clotting problems by counteracting hypercoagulation and destroying blood clots
- According to a case report, two COVID-19 patients treated with 2 grams of glutathione intravenously experienced less shortness of breath after one hour of use
N-Acetylcysteine (NAC) is a necessary precursor for glutathione biosynthesis, and both play an important role in health and fitness. NAC has been used as a first aid remedy for acetaminophen poisoning (known as paracetamol in Europe).
It is administered in cases of overdose by Tylenol or other acetaminophen products. Prevents liver damage by neutralizing the toxic effects of the drug and recharging glutathione.
NAC and glutathione may also be important in treating COVID-19, as explained by pulmonologist Dr. Roger Seheult at the MedCram conferences. It’s because they play an important role in fighting oxidative stress, which is the leading cause of inflammation and disease in general, and the COVID-19-related cytokine storm. NAC also decreases abnormal blood clotting that has been seen in many cases.
Biochemistry Manual
As Seheult explains and illustrates, when you add an electron to an oxygen molecule (O2), you get superoxide (O2), a kind of reactive oxygen (ROS). When you add another electron (for a total of two electrons), you get hydrogen peroxide (H2O2). An oxygen molecule with three added electrons turns into hydroxyl (O3), and oxygen with four electrons turns into water (H2O).
Oxygen is the most oxidized form, while water is the lowest form. Your body has built-in defenses against oxidative stress, as does the enzyme superoxide dismutase (SOD). SOD converts harmful superoxide to hydrogen peroxide. Another is catalase, which converts hydrogen peroxide into oxygen and water. A third is glutathione peroxidase (GSHPX).
The GSHPX does two things at once. While reducing hydrogen peroxide in water, it also converts the reduced form of glutathione (GSH) to glutathione disulfide (GSSG), which is the oxidized form of glutathione. In other words, as GSHPX converts hydrogen peroxide to harmless water, glutathione is oxidized.
The oxidized GSSG is “recharged” or regenerated by NADPH (the reduced form of NADP +), and converts it to GSH (the reduced form of glutathione). NADPH is also converted to NADP + through an enzyme called GSH reductase.
This is important because superoxide plays an important role in oxidative stress that is characteristic of chronic diseases identified as comorbidities that predispose you to COVID-19, such as obesity, heart disease, and diabetes.
As Seheult noted, complications from COVID-19 trigger a perfect storm of superoxide-driven oxidative stress, as SARS-CoV-2 binds to the ACE2 receptor, triggering angiotensin 2 (AT-2) and subsequently stimulating superoxide. Simultaneously, there is a deficiency of AT-1,7, which inhibits superoxide. So this deficiency allows more superoxide to build up.
SARS-CoV-2 also attracts polymorphonuclear leukocytes (PMNs), a type of white blood cell, which produce superoxide in its efforts to destroy pathogens. All that superoxide is converted to other ROS that destroy endothelial cells.
This effect can be avoided with N-acetylcysteine (NAC), which increases GSSG. As demonstrated in Seheult’s illustration, when two molecules of GSH and hydrogen peroxide are added, it results in oxidized glutathione and harmless water, thereby alleviating oxidative stress.
NAC increases GSH and protects against influenza
Seheult cites research showing that low GSH levels and oxidative stress are linked to many nose, ear, and throat conditions, which affect tissues, both locally and systemically. The good news is that glutathione can be recharged with NAC, a cheap, commercially available over-the-counter supplement.
In fact, research has shown that NAC can mitigate flu symptoms and improve cellular immunity. As the study authors indicate:
“N-acetylcysteine (NAC), is an analog and precursor of reduced glutathione, which has been used for more than 30 years as a mucolytic drug. It has also been recommended and used as therapy or for the prevention of various respiratory diseases related to oxidative stress.
The aim of the present study was to evaluate the effect of long-term treatment with NAC with influenza and similar illnesses. A total of 262 people of both genders were enrolled in a randomized, double-blind trial to receive placebo or NAC tablets (600 mg) twice daily for 6 months.
They did not select patients with chronic respiratory diseases to avoid possible confusion from the effect of NAC with respiratory symptoms. Patients tolerated NAC treatment and decreased flu-like episode frequency, severity, and bed time.
Local and systemic symptoms were greatly reduced in people who received NAC treatment. The frequency of seroconversion to the June 1986 influenza A / H1N1 virus in Singapore was similar in the two groups, but only 25% of people infected with the virus with CAP treatment developed a symptomatic form, in comparison with 79% of the placebo group …
Therefore, it appears that the administration of N-acetylcysteine during the winter provides a significant mitigation of influenza and similar episodes, especially in older people at high risk of infection. N-acetylcysteine did not prevent infection by the influenza A / H1N1 virus, but it did reduce the incidence of disease.
NAC is a powerful antiviral
As Seheult pointed out, the number needed to treat (NNT) in that study is 0.5, which means that for every two people treated with NAC, only one will be protected against symptomatic influenza. (Remember, you can get infected with a virus, but not get sick, that is, symptomatic, if your immune system is very strong.)
That’s better than flu vaccines, which have an NNT of 71, which means 71 people must get vaccinated to prevent a single case of flu. It’s even better than vitamin D, which has an NNT of 33. (Among those who were severely deficient in vitamin D at the start of the study, taking vitamin D still had an NNT of 4.)
NAC has also been shown to prevent viral reproduction and the expression of pro-inflammatory cytokines, such as interleukin-6 (IL-6), in cells infected with the highly pathogenic H5N1 influenza virus. As the study authors indicate:
“The antiviral and anti-inflammatory mechanisms of NAC included the inhibition of the activation of oxidant-sensitive pathways, including the transcription factor NF-kappaB and the mitogen-activated protein kinase p38…
NAC prevents the reproduction of H5N1 and the H5N1-induced production of pro-inflammatory molecules. Therefore, antioxidants such as NAC represent an additional treatment option that could be considered in an influenza A virus pandemic ”.
The relationship of CAP and acute respiratory distress syndrome
NAC has also been shown to reduce acute respiratory distress syndrome (ARDS), which is a complication related to acute lung injury (ALI). A meta-analysis of five randomized controlled trials found a significant reduction in intensive care unit (ICU) stays among patients treated with NAC, despite the fact that there were no large differences in the risk of short-term mortality.
Another earlier study found that NAC improves ARDS by “increasing intracellular glutathione and extracellular thiol molecules” along with overall antioxidant effects. According to the study:
“In acute respiratory distress syndrome (ARDS), there is an overproduction of free radicals to the extent that endogenous antioxidants experience a degree of oppression, allowing oxidative cell damage.
The present study examined the benefit of the antioxidant compound N-acetylcysteine (NAC) with the treatment of ARDS by measuring the patient’s intracellular glutathione (within red blood cells), extracellular antioxidant defense biomarkers (plasma), and outcome.
27 ARDS patients were admitted to the intensive care unit of a university hospital and divided into two groups. Both groups were treated similarly with regular treatments, but only 17 patients received NAC 150 mg / kg on the first day, followed by 50 mg / kg / day for three days, and 10 patients received no NAC.
NAC treatment increased extracellular antioxidant power, total thiol molecules, and also improved intracellular glutathione and patient outcome. In conclusion, ARDS patients have a poor oxidant-antioxidant balance that can benefit from supplementation with NAC ”.
NAC improves lung function
Other studies that have shown NAC to be good at treating lung-related problems, including the following:
• A 1994 study found that NAC improves recovery from ALI, greatly reversing the degree of lung injury during the first 10 days of treatment and reducing the need for ventilation.
After three days of treatment, only 17% of those who received NAC required ventilation, compared with 48% in the placebo group. According to the authors, “Treatment with intravenous NAC for 72 hours improved systemic oxygenation and reduced the need for respiratory support in patients with mild but moderate acute lung injury subsequent to other underlying diseases.”
• A 2018 study found that NAC reduces oxidative and inflammatory damage in patients with community-acquired pneumonia.
• Another 2018 study found that NAC also improves postoperative lung function in liver transplant patients.
NAC prevents blood clots and stroke
Importantly, with regards to COVID-19, NAC could protect you against health problems caused by blood clotting. Many COVID-19 patients experience blood clotting problems , and NAC counteracts hypercoagulation in the blood.
As noted in one of these studies, “NAC has anticoagulant and platelet inhibitory properties.” And another study notes that:
“… diabetes exacerbates stroke-induced brain injury, and that correlates with the brain state of methylglyoxal (MG) to glutathione (GSH).” N-acetylcysteine (NAC) reversed the brain injury.
Here we analyze whether the pro-thrombotic phenotype, found in the systemic circulation and brains of people with diabetes, was related to increased protein glycosylation by MG, and if NAC could reverse this …
Treatment with NAC partially or completely reversed the effects of diabetes. Together, these results demonstrate that the blood and brains of people with diabetes become more susceptible to platelet activation and thrombosis.
NAC, administered after diabetes, could protect against the risk of stroke by altering both systemic and vascular prothrombotic responses by enhancing the GSM platelet and by eliminating GSH-dependent MG, as well as correcting levels of antioxidants such as SOD1 and GPx- 1. “
A fourth article, published in 2017, found that NAC has potent thrombolytic effects, meaning that it destroys blood clots. The authors concluded that “NAC is an effective and safe alternative to current antithrombotic agents in terms of restoring vessel patency after arterial occlusion.” (Restoring the patency of the vessels means that the blood vessel will not be clogged and will allow the blood to flow freely.)
Seheult cites two additional documents that demonstrate the same. As Seheult noted, many COVID-19 cases feature blood clotting in addition to excessive oxidative stress, and NAC addresses both of these issues.
NAC for COVID-19 Treatment
Last but not least, the Oxford University Center for Evidence-Based Medicine released a report reviewing the evidence for the use of NAC in the treatment of COVID-19 on April 14, 2020.
This report focuses on acute respiratory disorders, and we now know that COVID-19 in addition to being a respiratory disorder is a blood disorder. This is a major shortcoming of this report, as there is evidence that NAC can destroy blood clots responsible for hypoxia (cellular oxygen deprivation) in COVID-19.
On May 5, 2020, a trial was published on ClinicalTrials.gov, for the study of NAC in COVID-19 patients, sponsored by the Memorial Sloan Kettering Cancer Center. The study aims to enroll 86 critically or critically ill patients to investigate whether CAP, in addition to other supportive treatments, can reduce ICU stay and avoid the need for mechanical ventilation. There they administer 6 grams (6,000 milligrams) of NAC per day for three weeks.
Seheult’s hypothesis for why NAC may be effective in treating COVID-19 can be summarized as follows:
SARS-CoV-2 binds to and reduces the ACE2 receptor, causing AT-2 to increase and AT-1,7 to decrease. This in turn increases the harmful superoxide that causes oxidative stress and endothelial cell dysfunction.
Then von Willebrand factor rises from the endothelial space, causing thrombosis (blood clots), and this is apparently what causes hypoxia in the lungs. NAC, which recharges glutathione, reduces superoxide (oxidative stress) and appears to also reduce the von Willebrand factors that form blood clots.
Glutathione for COVID-19 Treatment
Seheult also reviews aspects of blood clotting from COVID-19. It also looks at the potential effectiveness of just taking glutathione, rather than its precursor, NAC.
A recent case report, which reviews one or more medical cases and is not an actual study, reports that two COVID-19 patients and a history of Lyme disease (co-infection) treated with 2 grams of glutathione intravenously “improved their dyspnea within one hour of use “. Dyspnea is the medical term used to define shortness of breath. As the study authors indicate:
” Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a new treatment approach to block NF-κB and treat” cytokine storm syndrome “and difficulty respiratory disease in patients with COVID-19 pneumonia ″.
He also cites a Russian article that states that glutathione deficiency could be “the leading cause of serious problems and death” in COVID-19 patients. The document, which is a preprint and has not yet been reviewed, presents a hypothesis “based on an exhaustive analysis of the literature and on our own observations”.
According to the author:
“The major established risk factors for COVID-19 severity and relative glutathione deficiency found in COVID-19 infected patients with moderate to severe disease have led me to make two very important conclusions:
(1) oxidative stress contributes to hyperinflammation of the lung leading to adverse disease outcomes such as acute respiratory distress syndrome, multiple organ failure, and death;
(2) poor antioxidant defense due to endogenous glutathione deficiency as a result of decreased biosynthesis and increased GSH depletion is the most likely cause of increased oxidative lung damage, regardless of aging factors , comorbidity of chronic diseases, smoking or some others responsible for this deficit.
The hypothesis provides new insights into the etiology and mechanisms responsible for the severe manifestations of COVID-19 infection and justifies the promising opportunities for effective disease treatment and prevention by recovering glutathione with reduced N-acetylcysteine and glutathione. “
As Seheult pointed out, we don’t yet have trials showing that NAC will benefit COVID-19 patients, “but if we do an analysis, it looks promising,” says Seheult. In addition, NAC is a very safe treatment and many studies have shown that there are no serious adverse effects related to its use.
The same can be said for glutathione. Seheult points out that it would be interesting to know what the effect of a combination of glutathione and NAC could be. In general, the more we learn about this disease, the more we realize that there may be simple and inexpensive ways to treat it, and CAP in particular seems to be a good candidate.
Of course, both have many other important health benefits as well.