COVID-19: Any Role for Acetaminophen, Glycine, Glutathione, or Cysteine (NAC)?

Should We Avoid Acetaminophen in COVID-19?

I recently listened to an ZDoggMD interview of Dr Marty Makary. Makary, a pancreas surgeon at Johns Hopkins, said that acetaminophen (aka paracetamol) enhances the cytokine storm linked to serious or fatal COVID-19. This was news to me. If true, it could lead to a worse disease outcome, so maybe we shouldn’t enhance it.

(I think it was this video.)

On the other hand, we know our bodies have evolved many ways to fight infection, so perhaps we shouldn’t interfere. For instance, there is active debate about whether we should try to reduce fevers caused by infection. Some experimental evidence indicates that many germs are less virulent when fever is present. As uncomfortable as it is, could the COVID-19 cytokine storm be an effective infection fighter, even thought it doesn’t always work?

So I tried to find a some articles via DuckDuckGo that would support Makary’s statement.

See The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. That’s the only pertinent article I found in 15 minutes of DuckDuckGoing. It is tangentially related to acetaminophen. Some quotes:

“Glutathione (GSH) has the function of “master antioxidant” in all tissues; the high concentration of the reduced form (millimolar) highlights its central role in the control of many processes such as detoxification, protein folding, antiviral defense and immune response.”

“A common denominator in all conditions associated with COVID-19 appears to be the impaired redox homeostasis responsible for reactive oxygen species (ROS) accumulation; therefore, levels of glutathione (GSH), the key anti-oxidant guardian in all tissues, could be critical in extinguishing the exacerbated inflammation that triggers organ failure in COVID-19. The present review provides a biochemical investigation of the mechanisms leading to deadly inflammation in severe COVID-19, counterbalanced by GSH…. Drawing on evidence from literature that demonstrates the reduced levels of GSH in the main conditions clinically associated with severe disease, we highlight the relevance of restoring GSH levels in the attempt to protect the most vulnerable subjects from severe symptoms of COVID-19.”

“Oxidative stress constitutes a failure of anti-oxidation defense systems to keep ROS and reactive nitrogen species in check. ROS are signaling molecules that induce the release of pro-inflammatory cytokines, and the dysregulation of this response plays an essential role in the development of inflammation.”

Glutathione (GSH) could be a key player in counteracting or avoiding the super-inflamatory cytokine storm.

“Glutathione, a tripeptide composed of glutamate, cysteine and glycine, is an antioxidant molecule ubiquitous in most living organisms. Intracellular GSH balance is maintained by de novo synthesis, regeneration from the oxidized form, GSSG, and extracellular GSH uptake.”

BTW, vitamin D increases levels of GSH.

Acetaminophen is the best-known drug that lowers GSH levels, by joining GSH to many drugs, thereby taking active GSH out of the picture. So finally we have the explanation of how acetaminophen could enhance cytokine storm.

“Anti-oxidant therapies exert beneficial effects on many diseases characterized by inflammation consequent to impaired redox homeostasis. In the context of inflammatory diseases, systemic oxidative stress is detected as decreased total free thiol levels (free sulfhydryl groups of cysteine in proteins such as albumin as well as low-molecular-weight free thiols, for example cysteine, glutathione, homocysteine and related species). A recent study has concluded that low molecular mass systemic thiols might play a role in the inflammatory and oxidative stress pathways involved in both chronic obstructive pulmonary disease (COPD) and cardiovascular disease. The levels of systemic free thiols can be influenced by nutritional or therapeutic intervention. For these reasons, many clinical trials have evaluated the efficacy of N-acetylcysteine (NAC) administration, and many are still ongoing (714 studies, 349 completed), as well as the effects of GSH supplementation (162 studies, 100 completed).”

“NAC is both a thiol with antioxidant properties and one of the substrates in GSH biosynthesis.”

“Body GSH concentration may be increased with oral intake of either GSH, or proteins enriched in the amino acid constituents of GSH, or the supplementation of the two limiting amino acids cysteine and glycine, as the body availability of glutamate is usually not limiting. Oral administration of GSH is more expensive than supplements with cysteine and glycine, and its systemic bioavailability may be poor due to degradation in the gut; therefore, its suitability for use on a large population could be limited. Interestingly, a case report study has shown that the repeated use of both 2000 mg of oral administration and intravenous injection of glutathione was effective in relieving the severe respiratory symptoms of COVID-19, showing for the first time the efficacy of this antioxidant therapy for COVID-19.

“Dietary supplementation with the glutathione precursors cysteine and glycine, in proper conditions, fully restores glutathione synthesis and concentrations.”

What About Glycine?

You read above that glycine is one of the three amino acid building blocks of glutathione, the master anti-oxidant. My brother told me a physician he trusted told him that COVID-19 is a glycine deficiency disease. If so, taking supplemental glycine can prevent or treat it.

This is the only evidence I found: full text Journal of Functional Foods Jan 2021.

Abstract

“The extracellular matrix, mainly composed of collagen, is a mechanical barrier against infective agents, including viruses. High glycine availability is needed for a healthy collagen turnover. Glycine produced by human metabolism is much lower than the cell’s needs giving a general glycine deficiency of 10 g/day in humans. This effect was tested for three years in 127 volunteers who had virus infections usually once or more times every year. 85 of them took glycine 10 g/day; 42 did not take glycine. Among those who took glycine, only 16 (12 of whom had infections two or more times each year) had the flu just in the first year –but much reduced in severity and duration– while those who did not take glycine, were infected as often and as severely as before. Glycine intake at the afore-mentioned dose prevents the spread of viruses by strengthening the extracellular matrix barriers against their advance.”

From the body of report:

“These results confirm our proposition of the need for glycine to regenerate and strengthen collagen. Invasive agents (bacteria, fungi, protozoa, or viruses) advance in the body to invade new areas through the extracellular matrix, which acts as a mechanical barrier that prevents their expansion within the body. As this matrix consists mainly of collagen, whose renewal and regeneration is difficult due to the lack of glycine, its reinforcement thanks to an increase in glycine in the diet helps to prevent the entry and advance of infectious agents.”

A clinical trial in 2020 was looking for COVID-19 patients on ventilators for treatment with glycine. I imagine it’s difficult to get informed consent from someone about to be intubated or already on a ventilator. The study should have been completed by now but I haven’t seen the write-up.

I think my brother’s physician friend is getting ahead of the science.

The Bottom Line

Should we avoid acetaminophen in COVID-19? Theoretically, maybe. Need more data.

The author of the “COVID-19 is a glycine deficiency disease” idea probably figured that optimal or high glutathione levels will prevent or treat the disease. And oral supplemental glycine can raise glutathione levels. Maybe he’s right. Too soon to tell. Need more data.

Would a cocktail of glutathione, glycine, and cysteine prevent or treat COVID-19? Maybe. Need more data.

Remember, proposed anti-COVID supplements are supposed to work on the theory the anti-oxidant glutathione needs to be boosted. Since the 1990s we’ve had suspicions that anti-oxidants can have serious adverse effects. From Scientific American:

“Antioxidants are supposed to keep your cells healthy. That is why millions of people gobble supplements like vitamin E and beta-carotene each year. Today, however, a new study adds to a growing body of research suggesting these supplements actually have a harmful effect in one serious disease: cancer.”

Steve Parker, M.D.

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