From ... in Biology Health — Oct 27, 2021

Is Niacin a Missing Piece of the COVID Puzzle?

This article was previously published January 20, 2021, and has been updated with new information.

While vitamins C and D have garnered much attention in the ght against COVID-19, B vitamins can also play an important role, according to two recent papers niacin (B3) in particular. Is Niacin a Missing Piece of the COVID Puzzle? Analysis by Dr. Joseph Mercola B vitamins may play an important role in COVID-19 prevention and treatment, according to two recent papers Based on B vitamins effects on your immune system, immune-competence and red blood cells (which help ght infection), supplementation may be a useful adjunct to other prevention and treatment strategies B vitamins can inuence several COVID-19-specic disease processes, including viral replication and invasion, cytokine storm induction, adaptive immunity and hypercoagulability Niacin appears particularly important. According to one published paper, there appears to be a causative link between low niacin status and SARS-CoV-2 infection SARS-CoV-2s ability to invade your body is dependent on calcium signaling, which in turn is dependent on the presence of NAADP, which is formed from niacin. NAADP-dependent calcium signaling is responsible both for the inhibition of viral entry into cells and driving the virus out of already infected cells The rst, "Be Well: A Potential Role for Vitamin B in COVID-19," was published in the February 2021 issue of the journal Maturitas.

The paper is the result of a joint collaboration between researchers at the University of Oxford, United Arab Emirates University and the University of Melbourne, Australia. While no studies using B vitamins have been performed on COVID-19 patients, the researchers stress that, based on B vitamins' effects on your immune system, immune- competence and red blood cells (which help ght infection), supplementation may be a useful adjunct to other prevention and treatment strategies. As noted by the authors: "There is a need to highlight the importance of vitamin B because it plays a pivotal role in cell functioning, energy metabolism, and proper immune function. Vitamin B assists in proper activation of both the innate and adaptive immune responses, reduces pro-inammatory cytokine levels, improves respiratory function, maintains endothelial integrity, prevents hypercoagulability and can reduce the length of stay in hospital.

Therefore, vitamin B status should be assessed in COVID-19 patients and vitamin B could be used as a non-pharmaceutical adjunct to current treatments Vitamin B not only helps to build and maintain a healthy immune system, but it could potentially prevent or reduce COVID-19 symptoms or treat SARS-CoV-2 infection. Poor nutritional status predisposes people to infections more easily; therefore, a balanced diet is necessary for immuno-competence." B Vitamins Play Many Roles in COVID-19 Disease Process Importantly, B vitamins can inuence several COVID-19-specic disease processes, including: Viral replication and invasion Cytokine storm induction 1,2 3 4 Adaptive immunity Hypercoagulability The paper goes on to detail how each of the B vitamins can help manage various COVID- 19 symptoms: Vitamin B1 (thiamine) Thiamine improves immune system function, protects cardiovascular health, inhibits inammation and aids in healthy antibody responses. Vitamin B1 deciency can result in an inadequate antibody response, thereby leading to more severe symptoms.

There's also evidence suggesting B1 may limit hypoxia. Vitamin B2 (riboavin) Riboavin in combination with ultraviolet light has been shown to decrease the infectious titer of SARS-CoV-2 below the detectable limit in human blood, plasma and platelet products. Vitamin B3 (niacin/nicotinamide) Niacin is a building block of NAD and NADP, which are vital when combating inammation. Vitamin B5 (pantothenic acid) Vitamin B5 aids in wound healing and reduces inammation. Vitamin B6 (pyridoxal 5-phosphate/pyridoxine) Pyridoxal 5-phosphate (PLP), the active form of vitamin B6, is a cofactor in several inammatory pathways. Vitamin B6 deciency is associated with dysregulated immune function. Inammation increases the need for PLP, which can result in depletion. According to the authors, in COVID-19 patients with high levels of inammation, B6 deciency may be a contributing factor. What's more, B6 may also play an important role in preventing the hypercoagulation seen in some COVID-19 patients. Vitamin B9 (folate/folic acid) Folate, the natural form of B9 found in food, is required for the synthesis of DNA and protein in your adaptive immune response. 5 Folic acid, the synthetic form typically found in supplements, was recently found to inhibit furin, an enzyme associated with viral infections, thereby preventing the SARS-CoV-2 spike protein from binding to and gaining entry into your cells.

The research suggests folic acid may therefore be helpful during the early stages of COVID-19. Another recent paper found folic acid has a strong and stable binding anity against SARS-CoV-2. This too suggests it may be a suitable therapeutic against COVID-19. Vitamin B12 (cobalamin) B12 is required for healthy synthesis of red blood cells and DNA. A deciency in B12 increases inammation and oxidative stress by raising homocysteine levels. Your body can eliminate homocysteine naturally, provided you're getting enough B9 (folate), B6 and B12. Hyperhomocysteinemia a condition characterized by abnormally high levels of homocysteine causes endothelial dysfunction, activates platelet and coagulation cascades and decreases immune responses. B12 deciency is also associated with certain respiratory disorders. Advancing age can diminish your body's ability to absorb B12 from food, so the need for supplementation may increase as you get older. According to "Be Well: A Potential Role for Vitamin D in COVID-19": "A recent study showed that methylcobalamin supplements have the potential to reduce COVID-19-related organ damage and symptoms. A clinical study conducted in Singapore showed that COVID-19 patients who were given vitamin B12 supplements (500 g), vitamin D (1000 IU) and magnesium had reduced COVID-19 symptom severity and supplements signicantly reduced the need for oxygen and intensive care support." Niacin A Missing Piece of the COVID-19 Puzzle? 6 7 8 9 10 11 The second paper, "Sucient Niacin Supply: The Missing Puzzle Piece to COVID-19 and Beyond?" (which is a preprint and has yet to undergo peer review), focuses specically on niacin (B3), raising the question of whether this vitamin might actually be a crucial player in the COVID-19 disease process. As noted in the abstract: "Denitive antiviral properties are evidenced for niacin, i.e., nicotinic acid (NA), as coronavirus disease 2019 (COVID-19) therapy for both disease recovery and prevention, to the level that reversal or progression of its pathology follows as an intrinsic function of NA supply. This detailed investigation provides a thorough disentanglement of how the downstream inammatory propagation of ensuing severe acute respiratory virus 2 (SARS-CoV-2) infection is entirely prohibited or reversed upstream out the body to expeditiously restore health with well-tolerated dynamic supplementation of sucient NA (i.e., ~1-3 grams per day)." As noted in this paper, a primary hallmark of COVID-19 pathology is the cytokine storm, which can lead to multiple organ failure and death. Marked elevations in proinammatory cytokines are to blame for this chain of events, most notable of which are interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor- (TNF-) and monocyte chemoattractant protein-1 (MCP-1). If you can decrease and control these damaging cytokines, you stand a good chance of thwarting the cytokine storm and the downstream damage it causes. Nicotinamide adenine dinucleotide (NAD+) plays an important role in this, and niacin is a building block of NAD. As explained in "Be Well: A Potential Role for Vitamin D in COVID-19": "NAD+ is released during the early stages of inammation and has immunomodulatory properties, known to decrease the pro-inammatory cytokines, IL-1, IL-6 and TNF-. Recent evidence indicates that targeting IL-6 could help control the inammatory storm in patients with COVID-19." Aside from markedly decreasing proinammatory cytokines, niacin has also been shown to: 12 13 14 Reduce the replication of a number of viruses, including vaccinia virus, human immunodeciency virus, enteroviruses and hepatitis B virus Reduce neutrophil inltration Have anti-inammatory effect in patients with ventilator-induced lung injury Niacin Modulates the Bradykinin Storm COVID-19 also triggers bradykinin storms. Bradykinin is a chemical that helps regulate your blood pressure and is controlled by your renin-angiotensin system (RAS).

The bradykinin hypothesis provides a model that helps explain some of the more unusual symptoms of COVID-19, including its bizarre effects on your cardiovascular system. Researchers have discovered SARS-CoV-2 downregulates your body's ability to degrade or break down bradykinin.

The end result is a bradykinin storm, and this appears to be an important factor in many of COVID-19's lethal effects, perhaps even more so than the cytokine storms associated with the disease. As bradykinin accumulates, the more serious COVID-19 symptoms appear. Vitamin D has a signicant impact on the RAS, and can therefore help prevent a bradykinin storm, but niacin also plays an important role. As noted in "Sucient Niacin Supply: The Missing Puzzle Piece to COVID-19 and Beyond?": "Immediate-release NA [niacin] administration has been reported as highly effective in preventing the lung tissue damage involved in this pathology. As a matter of fact, authors of a March, 2020, paper in Nature for this very reason conclude with suggestion of niacin supplementation to COVID-19 patients as a 'wise approach.'" The paper also expounds on the role of NAD+, and why niacin is a useful strategy for boosting NAD+: "The major effects of COVID-19 are evidenced to involve tryptophan metabolism and the kynurenine pathway towards depletions of these 15 16 17 18 precursors of NAD+ Exclusively sucient dosage of immediate-release NA through its processing in the mammalian body to form NAADP [nicotinic acid adenine dinucleotide phosphate, a calcium mobilizer] leads to an inverse potential energy pump back upstream, from the core up and ultimately out the body, of the downstream ensuing propagation of such inammatory disease that spreads into the cells. This is made possible by the capability of NAADP to be readily formed by sucient NA supply to induce Ca2+ [calcium] channeling back upstream out the body of built-up or ensuing inammation, representing kinetic energy that by electron gradient, moves downstream into the body. Attempting to restore NAD+ with other NAD+-precursors aside from NA (e.g., nicotinamide, nicotinamide riboside, nicotinamide mononucleotide) only actually temporarily and in a sense, articially, raises NAD+ levels, until they imminently deplete back down with further ensuing inammation. NA is in fact the only compound to readily produce NAADP if needed in acidic environments (as is characteristic to ensuing inammatory disease pathology), which in turn provides a potential energy/H+ pump-out action of its inverse, downstream kinetic (heat) energy inammation to ultimately restore NAD+ to normal, pre-inammatory levels, as well as other inammatorily-depleted cofactors and biochemical pathways towards a more thermodynamically homeostatic health status The 'niacin red ush' in fact is this thermodynamic exfoliation of ensuing disease, toxins, and (restoration of) free radical-damaged compounds being H+ (potential energy) pumped out the body. It represents the anti-inammatory or thermodynamic (i.e., energy transfer-like) therapy in action that only and exclusively sucient oral intake of immediate- release NA is capable of (readily) accomplishing with potency." Recommended Use The paper goes deep into the biochemical aspects of how niacin works in your body, so if you're interested in that, you may want to read through it. In summary, as it pertains to COVID-19, the important thing to understand is that there appears to be a causative link between low niacin status and SARS-CoV-2 infection. Nothing outside of sufficiently supplied niacin is capable of readily leading to the NAADP supply needed for therapeutic action that counteracts inflammatory disease progression. According to the authors, SARS-CoV-2's ability to invade your body is dependent on whether calcium signaling can properly proceed, which in turn is dependent on the presence of NAADP. And, as explained in the quoted section above, niacin forms NAADP in your body. NAADP-dependent calcium signaling is responsible both for the inhibition of viral entry into cells and driving the virus out of already infected cells. And, again, the authors stress that "nothing outside of suciently, dynamically supplied niacin is capable of readily leading to the NAADP supply needed in these acidic environments for therapeutic action that counteracts inammatory disease progression." They also point out that the ushing you get from niacin is part of how the niacin drives inammatory free radicals out of the cells. As you continue to take the supplement at a consistent, suciently high dose, that ushing will gradually lessen, which is a sign that your body is reaching a healthy homeostasis. "This represents perhaps the ideal state that should be worked up to and maintained thereafter in terms of niacin dosing to respectively reverse out and prevent inammation," the authors state. 19 20 While the ushing can be uncomfortable, the authors stress that it is "indeed safe," and actually "should be sought when needed for its anti-inammatory properties." Suggested Dosing As a "health restorative therapy" for those diagnosed with SARS-CoV-2, they recommend starting with a dose of 500 milligrams of immediate-release niacin, two to three times a day, ideally within the rst 48 hours of symptom onset. As your ush response lessens, increase your dose to 1,000 mg, two to three times a day. "For the subgroup of patients still suffering with high cytokines proles from deep, remnant damage of previously experienced SARS-CoV-2 infection termed the 'long-haulers' alleviation from ailment(s) towards complete health restoration to pre-infection state from initiating and maintaining the aforementioned dosage regimen has consistently been reported to assume within two days and to incrementally follow further over the course of weeks." Although the authors suggest you can use niacin prophylactically, using that same dose, I disagree. According to the authors: "By readily providing sucient NAADP, this same NA dosage regimen is capable of serving as prophylaxis, which can be interpreted as the physical/biochemical inability of sucient progression of SARS-CoV-2 in order to enter into the body and/or thereafter induce replication, infection onset, or disease progression in a previously uninfected host." There may be some value to the high doses in acute COVID-19 infections but I am skeptical. I am a huge fan of NAD+ augmentation and have been using it for years. My research suggests you really only need about 25 mg per day of niacin, which will not cause ushing in nearly anyone. I believe most would benet from taking 25 mg of niacin daily, preferably in a well-balanced B complex, which would have thiamine (B1) that has also been shown to be useful in COVID-19. 21 22 23 Other alternatives to high-dose niacin would be nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which is my personal favorite. I believe that compounding these into rectal suppositories would avoid most of the methylation of the supplement and supply you with higher NAD+ tissue levels. Another downside of high-dose niacin is that it breaks down to nicotinamide and in high doses, nicotinamide will inhibit Sirt1, which is an important longevity protein. Personally, I believe a superior strategy to high-dose niacin in acute COVID-19 would be to use nebulized hydrogen peroxide at 0.1%. I have never seen or heard of this intervention failing in the treatment of COVID-19. How to Improve Your Vitamin B Status As a general rule, I recommend getting most if not all of your nutrition from real food. This will work well for most B vitamins, but not if you're using niacin therapeutically, as described above. For that, you will need to take a supplement. That said, the list below will show you which foods contain which B vitamins, as well as provide general guidance on dosage if you're taking a supplement. If you're trying to improve your vitamin B status, also consider limiting sugar and eating more fermented foods. The reason for this is because the entire B group vitamin series is produced within your gut, assuming you have healthy gut ora. Eating real food, including plenty of leafy greens and fermented foods, will provide your microbiome with important ber and benecial bacteria to help optimize your internal vitamin B production. Nutrient Dietary Sources Supplement Recommendations Vitamin B1 Pork, sh, nuts and seeds, beans, green peas, brown rice, squash, asparagus and seafood.

The recommended daily allowance for B1 is 1.2 mg/day for men and 1.1 mg/day for women. Vitamin B2 Eggs, organ meats, lean meats, green vegetables such as asparagus, broccoli and spinach.

The RDA is 1.1 mg for adult women and 1.3 mg for men. Your body cannot absorb more than about 27 mg at a time, and some multivitamins or B- complex supplements may contain unnecessarily high amounts. 24 25 26 27 Nutrient Dietary Sources Supplement Recommendations Vitamin B3 Liver, chicken, veal, peanuts, chili powder, bacon and sun-dried tomatoes have some of the highest amounts of niacin per gram. Other niacin-rich foods include baker's yeast, paprika, espresso coffee, anchovies, spirulina, duck, shiitake mushrooms and soy sauce.

The dietary reference intake established by the Food and Nutrition Board ranges from 14 to 18 mg per day for adults. Higher amounts are recommended depending on your condition. For a list of recommended dosages, see the Mayo Clinic's website.

The dosage recommended as an anti- inammatory, health- restorative therapy in "Sucient Niacin Supply: The Missing Puzzle Piece to COVID-19 and Beyond?" is 500 mg two to three times a day, working your way up to 1,000 mg, two to three times a day as the ushing lessens. 28 29 30 31 Nutrient Dietary Sources Supplement Recommendations Vitamin B5 Beef, poultry, seafood, organ meats, eggs, milk, mushrooms, avocados, potatoes, broccoli, peanuts, sunower seeds, chickpeas and brown rice.

The RDA is 5 mg for adults over the age of 19. Pantothenic acid in dietary supplements is often in the form of calcium pantothenate or pantethine. Vitamin B6 Turkey, beef, chicken, wild-caught salmon, sweet potatoes, potatoes, sunower seeds, pistachios, avocado, spinach and banana. Nutritional yeast is an excellent source of B vitamins, especially B6. One serving (2 tablespoons) contains nearly 10 mg of vitamin B6. Not to be confused with Brewer's yeast or other active yeasts, nutritional yeast is made from an organism grown on molasses, which is then harvested and dried to deactivate the yeast. It has a pleasant cheesy avor and can be added to a number of different dishes. 32 33 34,35 36 Nutrient Dietary Sources Supplement Recommendations Vitamin B9 Fresh, raw, organic leafy green vegetables, especially broccoli, asparagus, spinach and turnip greens, and a wide variety of beans, especially lentils, but also pinto beans, garbanzo beans, kidney beans, navy and black beans. Folic acid is a synthetic type of B vitamin used in supplements; folate is the natural form found in foods. (Think: Folate comes from foliage, edible leafy plants.) For folic acid to be of use, it must rst be activated into its biologically active form (L-5-MTHF). Nearly half the population has diculty converting folic acid into the bioactive form due to a genetic reduction in enzyme activity. For this reason, if you take a B-vitamin supplement, make sure it contains natural folate rather than synthetic folic acid. Nutritional yeast is an excellent source. 37 38 Nutrient Dietary Sources Supplement Recommendations Research also shows your dietary ber intake has an impact on your folate status. For each gram of ber consumed, folate levels increased by nearly 2%.

The researchers hypothesize that this boost in folate level is due to the fact that ber nourishes bacteria that synthesize folate in your large intestine. 39 Nutrient Dietary Sources Supplement Recommendations Vitamin B12 Vitamin B12 is found almost exclusively in animal tissues, including foods like beef and beef liver, lamb, snapper, venison, salmon, shrimp, scallops, poultry, eggs and dairy products.

The few plant foods that are sources of B12 are actually B12 analogs that block the uptake of true B12. Nutritional yeast is high in B12, and is highly recommended for vegetarians and vegans. One serving (2 tablespoons) provides nearly 8 mcg of natural vitamin B12. Sublingual (under-the- tongue) ne mist spray or vitamin B12 injections are also effective, as they allow the large B12 molecule to be absorbed directly into your bloodstream. Sources and References Maturitas 2021 Feb; 144: 108111 Yahoo August 27, 2020 Maturitas August 15, 2020 DOI: 10.1016/j.maturitas.2020.08.007 [Epub ahead of print] ChemRxiv March 30, 2020 DOI: 10.26434/chemrxiv.12034980.v1 (PDF) Research Square May 26, 2020 DOI: 10.21203/rs.3.rs-31775/v1 PLoS ONE 5(9): e12244 New York Times September 6, 2016 Maturitas August 15, 2020 DOI: 10.1016/j.maturitas.2020.08.007 [Epub ahead of print], 1.7. Vitamin B12 OSF Preprints Sucient Niacin Supply: The Missing Puzzle Piece to COVID-19? Vitamin D (Third Edition) 2011: 707-723 Cell Death and Differentiation 2020 May;27(5):1451-1454 My Food Data, Thiamine 40 1 2 3, 4, 5, 13, 14 6, 7 8 9 10 11 12, 16, 18, 19, 20, 21, 22, 23, 31 15 17 24 Dietary Reference Intakes for B Vitamins NIH.gov Riboavin Healthaliciousness.com, Top 10 High Niacin Foods Healthaliciousness.com, Niacin-Rich Foods Mayo Clinic Niacin Dosing NIH.gov Pantothenic Acid NIH Vitamin B6 Fact Sheet December 10, 2019 Healthalisciousness.com, Top 10 Foods High in Vitamin B6 Self Nutrition Data, Nutritional Yeast NIH Folate March 29, 2021 Chalkboard, Nutritional Yeast American Journal of Clinical Nutrition 1997 Dec;66(6):1414-21 25 26, 27 28 29 30 32, 33 34 35 36, 40 37 38 39 .

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