I irritated some readers (as I often do) in February when I shared some thoughts from another reader about the possible importance of glucosamine in helping pneumonia patients survive. I'm not sure about the mechanisms proposed by that reader, a certain CT, but to her credit, there was a significant peer-reviewed study supporting the claim that people with respiratory illnesses such as pneumonia and lung cancer had a higher survival rate if they had been taking glucosamine: see Griffith A. Bell et al., "Use of glucosamine and chondroitin in relation to mortality," European Journal of Epidemiology, 27/8 (2012): 593-603; https://www.jstor.org/stable/23272500.  When I shared her tentative research results and proposals, I sought for feedback from the medical community just in case there might be something to glucosamine that could help with our current crisis. But the scant private feedback I received suggested the medical community felt that there was no serious reason to accept CT's proposals regarding glucosamine and diet on pneumonia survival or survival of COVID-19. The studies I cited were not the double-blind clinical tests that the medical profession is looking for in assessing efficacy of a treatment, but observational studies where various random factors and bias can be a problem. All fair points. So I didn't push the issue any more, but, just in case, I did buy some glucosamine and also N-acetyl cysteine, a nutriceutical known as an antioxidant but also an effective aid in treating cystic fibrosis because it reduces the viscosity of the mucous-like biofilm in the lungs of patients. I figured if it helps there, maybe it could be useful with the pneumonia COVID-19 can bring. I don't think I was alone because the price for N-acetyl cysteine has about tripled in the past couple of months and some suppliers are out of stock. But glucosamine prices seem more stable.

Last night, I came back to reflecting upon the puzzling and frustrating events related to my post on glucosamine in February (I won't discuss them here), and I felt it was time to see if there were any updates in the literature. Within seconds I spotted an intriguing post on Science Blog that led me to a new study:

In a compelling article in Progress in Cardiovascular Diseases, published by Elsevier, Mark McCarty of the Catalytic Longevity Foundation, San Diego, CA, USA, and James DiNicolantonio, PharmD, a cardiovascular research scientist at Saint Luke’s Mid America Heart Institute, Kansas City, MO, USA, propose that certain nutraceuticals may help provide relief to people infected with encapsulated RNA viruses such as influenza and coronavirus.

The new study is M.F. McCarty and J.J. DiNicolantonio, "Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus," Progress in Cardiovascular Diseases (in press, available online Feb. 12, 2020), https://doi.org/10.1016/j.pcad.2020.02.007. The full report is available both as a web page and as a PDF document. This peer-reviewed report reviews a variety of other studies and proposes specific mechanisms in light of recent research to explain why several nutriceuticals, including glucosamine and N-acetyl cysteine, may be helpful aids in coping with the Corona virus. The nutraceuticals discussed include glucosamine, N-acetyl cysteine, sulforophane (found in broccoli and other cruciferous vegetables), spirulina, lipoic acid, ferrulic acid (found in many foods), and selenium (high in Brazil nuts, but don't take really high doses of selenium supplements because this essential nutrient can be carcinogenic in excess -- it was once said to be carcinogenic in high doses, but that may not be correct, as you can see on the CDC's page on selenium). Yes, I know, the whole area of nutrition and medicine is filled with irresponsible claims and con artists. Get 50 pounds of vegetable and fruit nutrition in a single pill! Eat this oregano concentrate and you'll prevent cancer, foot odor, acne, hair loss, and inflamed navel disorder. Lots of claims, rumors, and little science. On the other hand, the impact of nutrition seems too zealously ignored in the medical community. When I ask questions of my doctors, I've been told things like, "We don't study nutrition. We don't get into that."

While the publication is in a peer-reviewed journal, please note that it is not based on original clinical work and the author's own double-blind studies, but looks at numerous related studies and pulls together bits and pieces to offer a hypothesis that several specific nutriceuticals may be effective in coping with influenza and the Corona virus. This study, like almost anything related to health and nutrition, will not meet the criteria physicians want to see in a new drug. The nutriceuticals discussed may not do any good or even if they are helpful, it may require extensive further studies that may never happen before they can be generally accepted. However, from the perspective of a potential Corona virus victim, there may be little harm to making sure we have some cruciferous vegetables like broccoli and a few Brazil nuts in your diet. Further, both glucosamine and N-acetyl cysteine are already popular nutriceuticals that are low in toxicity and known to have some benefits. However, I've also seen a warning that excess anti-oxidants like N-acetyl cysteine can also increase cancer risk since our body's defenses against cancer cells often can involve oxidative reactions that can be hindered when anti-oxidants are too high. See Derek Lowe, "N-Acetyl Cysteine: A Warning Shot," Science Translational Medicine at ScienceMag.com, October, 4 2019. He reasonably warns that anti-oxidants aren't always good for you. However, N-acetyl cysteine is well known as a treatment for cystic fibrosis because it reduces the viscosity of the biofilm mucous in the lungs, so using it  for COVID-19 doesn't seem like an outrageous stretch. But I am not a medical expert nor a nutritionist (in fact, I can also say, "I don't study nutrition; I don't get into that"), so get advice from competent sources before you do anything unusual based on the new publication on nutriceuticals and the Corona virus.

One of the authors appears to be a nutritionist and may not have the expertise needed to really understand the horrifically complicated mechanisms involved, and some of the studies he cites may not be that great. So this could all be a mistake. If they are wrong and you follow their advice by taking safe levels of nutriceuticals, you may be just be wasting your money. But if there is a benefit, it may help. Would appreciate any further feedback, pro or con. 

Here are a couple of excerpts from the report by McCarty and DiNicolantonio:

Glutathione production can also be promoted by administration of N-acetylcysteine (NAC), which has been shown to be protective in rodents infected with influenza.16., 17., 18. In a little-noticed 6-month controlled clinical study enrolling 262 primarily elderly subjects, those receiving 600 mg NAC twice daily, as opposed to those receiving placebo, experienced significantly fewer influenza-like episodes and days of bed confinement.¹⁹ Although the rate of seroconversion to influenza A was comparable in the two groups – indicating that they were exposed at the same frequency – only 25% of the virus-infected subjects in the NAC group developed symptoms, as contrasted to 79% of those of placebo. (Given the carnage that influenza wreaks among the elderly, it is most regrettable that no effort has been made to replicate this study, conducted over 20 years ago.) The particular utility of NAC in the elderly might reflect the fact that plasma cysteine levels and cellular glutathione levels tend to decline with advancing age.²⁰

The downstream consequences of hydrogen peroxide production might also be addressed by phase 2-inductive nutraceuticals, as these induce various peroxidase enzymes and promote the synthesis of glutathione, a cofactor for certain peroxidases and a catalyst in reactions that reconvert oxidized cysteine groups to their native form.¹⁵ Glutathione production can also be promoted by administration of N-acetylcysteine (NAC), which has been shown to be protective in rodents infected with influenza.16., 17., 18. In a little-noticed 6-month controlled clinical study enrolling 262 primarily elderly subjects, those receiving 600 mg NAC twice daily, as opposed to those receiving placebo, experienced significantly fewer influenza-like episodes and days of bed confinement.¹⁹ Although the rate of seroconversion to influenza A was comparable in the two groups – indicating that they were exposed at the same frequency – only 25% of the virus-infected subjects in the NAC group developed symptoms, as contrasted to 79% of those of placebo. (Given the carnage that influenza wreaks among the elderly, it is most regrettable that no effort has been made to replicate this study, conducted over 20 years ago.) The particular utility of NAC in the elderly might reflect the fact that plasma cysteine levels and cellular glutathione levels tend to decline with advancing age....²⁰

Glucosamine administration may up-regulate MAVS activation

Another key mediator of type 1 interferon response is the mitochondrial antiviral-signaling protein (MAVS), which oligomerizes in response to activation of cytosolic RNA virus detectors RIG-1 and MDA5, and subsequently participates in the activation of the transcription factor interferon regulatory factor 3 (IRF3).²⁵ (TLR7 signaling likewise contributes to activation of this factor; both pathways promote the K63-linked polyubiquitination and activation of the tank-binding kinase-1 – TBK1 – which in turn activates IRF3 via phosphorylation.26., 27., 28.) Duan and colleagues have recently shown that RNA virus infection promotes O-GlcNacylation of MAVS on multiple sites, and that this renders MAVS susceptible to the K63-linked ubiquitination that enables it to activate IRF3.²⁹ Moreover, they show that, the more extensive this O-GlcNacylation is, the more effectively MAVS is activated. Hence, they are able to demonstrate that measures which suppress or amplify the cellular pool of UDP-N-acetylglucosamine – the substrate for O-GlcNacylation – correspondingly suppress or amplify the activation of MAVS. They then proceed to demonstrate that feeding mice a glucosamine-enriched diet (2.5% by weight) markedly enhances the survival of wild-type mice infected with influenza virus, whereas this provided no protection in mice in which MAVS, type 1 interferons, or O-GlcNac transferase (the mediator of O-GlcNacylation) were genetically absent.

This striking new finding points to the possibility that high-dose glucosamine supplementation might aid prevention and control of RNA virus infections. Whereas the hexosamine biosynthesis pathway is capable of generating UDP-N-acetylglucosamine in the absence of exogenous glucosamine, glucosamine administration can further enhance the intracellular pool of this compound, thereby boosting the extent of O-GlcNacylation evoked by viral infection.³⁰ The dietary dose employed in this study is quite high in the context of previous clinical experience – 2.5% of a human diet providing 400 g dry weight daily would correspond to 10 g glucosamine – but an intake of 3 g daily would be practical and is within the range of previous clinical experience.³¹ Rather high intakes may be required for significant clinical benefit, inasmuch as this compound is rather inefficiently absorbed after oral administration.³²

Any merit to this work? I'd still love to have further input from the medical community. Meanwhile, would it be dangerous to include a bottle of glucosamine and some N-acetyl cysteine in your medical supplies? Along with face masks, by the way. The top dog of our medical community, the US Surgeon General, the one who warned us that we should not use face masks because they are ineffective in preventing the spread of COVID-19 among us ordinary folks (and might even make things worse!) but urgently needed to protect medical workers, might not have been very accurate in his statement.  Other nations that are doing a much better job in taming the virus (Taiwan, for example, where schools are still in session and business is moving ahead with our draconian lockdowns) encourage widespread wearing of facemasks. Having a barrier is better than no barrier -- in fact, the CDC is now telling medical workers to at least use a bandana or some other material because a barrier is helpful, even a poor one. Who would have guessed?  Also see C. Raina MacIntyre et al.,  "Face Mask Use and Control of Respiratory Virus Transmission in Households," Emerging Infectious Diseases, Volume 15, Number 2 (February 2009) as one of several studies on this matter. Masks work. Maybe it's time we start wearing them here. Yesterday, for the first time since returning to America, hanging out in Minnesota and Wisconsin, I saw multiple people wearing masks when I went to Walmart to pick up some things. A good sign. Maybe I'll dare to wear one now. Have been afraid of stirring added panic and worry among others.

Don't panic, and don't let your local officials panic either (I know, a bit late to say this!). We'll get through this health crisis. But the economic and social consequences of the our nation's response may be felt for years to come, so keep preparing for more trouble ahead.

Update 1: One more thing to watch out for is that the main clinical study cited in this report, a study that found N-acetyl cysteine to be helpful,  was written by two professors and an employee of the Zambon Group, an Italian pharma company that I happen to know is a leading producer of -- can you guess? -- N-acetyl cysteine. Now this kind of thing happens a lot in academia because it takes funding to do studies and companies interested in the effects of their products are likely to want to fund relevant research. It doesn't mean the data are bad, but it's a factor to weigh.  The study is

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