Physicians in India have recommended “the mass scale distribution and use of nicotinamide (NAM) supplementation to decrease COVID- 19 prevalence,” based on recent Phase II clinical studies observing that nicotinamide supplementation with the standard of care demonstrably reduced COVID-19 patient recovery time by nearly 30% compared to standard of care alone.
(By OMNS Contributing Editor W. Todd Penberthy, PhD)
Just 1,000 milligrams per day of niacinamide, which costs about 5 cents, has been shown to clearly reduce mortality in patients with COVID-19 related acute kidney injury (AKI) by 25% [1] Investigators observed that “niacinamide administered for the prevention of COVID-19-related AKI progression was safe and associated with reduced estimated risk of death or the need for renal replacement therapy compared with historical controls. The association was strongest in severe AKI.”
Given that niacinamide and/or niacin (vitamin B3) are routinely dosed at much higher levels, typically involving 1,000 mg taken 3x/d (T.I.D.) and also that these higher levels provide greater benefits, it is likely that even greater COVID-19 benefits may occur when using these higher niacin/niacinamide doses after regular administration for patients with COVID19. [2]
I personally take 2,000 mg T.I.D., totaling 6,000 mg/day niacin — and my lipids are always perfect and also my liver enzymes are fine. In fact, niacin is now known to reduce fatty liver and it is under development to treat non-alcoholic fatty liver disease. [3,4] So do not be misled by the myth that niacin is toxic to the liver. This was only shown for timed release formulations and not for the most common form, the less expensive immediate release form. [5]
As Stephen McConnell and I detailed in a previous orthomolecular publication, 500 mg of niacin 3x daily (TID) can effectively reverse the stages of chronic kidney disease, especially when used together with sodium bicarbonate (baking soda). [6] This activity has been proven in multiple clinical trials and in case studies. Still, the use of these common pennies-a-day agents are unfortunately not common in nephrology practice as somehow myths persist that it must be more complicated.
Without equivocation, the benefits of high doses of vitamin B3 as niacinamide or niacin for treating both COVID-19 and CKD are now proven. Moreover, these are safe therapeutics that have been used for over 50 years with unparalleled safety. In fact, niacin is so important to basic human health that the U.S. government mandated fortification of processed flour and rice in the 1940s, saving countless thousands of lives. [7]
In the emerging field of network pharmacology, the benefit of treating multi-morbidity with niacin has been identified as exceptionally promising. The network pharmacology and bioinformatics screen was performed with criteria set to identify small molecules that may have favorable anti-viral, anti-inflammatory, and immunomodulatory activities. Niacin treatment was prominently identified based on five core desirable targets and the expression of 14 genes that it favorably modified. [8] The investigators concluded that niacin may provide therapeutic benefit as a treatment for patients with COVID-19 based on favorable effects on important signaling pathways controlling outcome, thus paving the way for clinical trials.
Viral infectious disease like coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), stimulate an immune response that can have a disastrous effect when uncontrolled, leading to deadly cytokine storms. Ultimately this process actively depletes NAD (nicotinamide adenine dinucleotide) in infected cells. Accordingly, many NAD precursors have been tested to combat this virus-caused deficiency of the essential NAD molecule. [9]
Risk factors for increased susceptibility to COVID-19 are age, insulin resistance, and diabetes. Low NAD concentrations are commonly observed with aging and in diabetes. Depletion of NAD has been reported in severe COVID-19 patients. Moreover, the expression of genes controlling NAD biosynthesis from precursors (vitamin B3s) are known to be changed after infection with SARS-CoV-2. [10]
Many cellular enzymes utilize NAD in their biochemical reactions. When these enzymes are modulated with drugs, NAD can control the immune responses, so investigators conclude that boosting NAD is “an actionable component.” Pennies-a-day niacin administered in divided doses may serve best to prevent catastrophic NAD deficiency.
Unfortunately, in standard of care medicine there is often little scientific consideration of the possibility that we simply need more of what keeps most of us from even succumbing to COVID-19 sickness in the first place. Adequate amounts of essential nutrients and sufficient high quality sleep can enable the body to recover from virus-induced deficiencies of essential molecules and prevent death due to sepsis.
The majority of COVID-19 clinical drug trials are primarily profit-driven and involve patentable xenobiotic small molecules or biologics, with relatively little systemic investigation of the basics that are responsible for keeping the non-COVID-19-succumbing population resistant to developing disease.
With only a few exceptions, patients are served best if we start by following the acronym K.I.S.S. (“keep it simple, stupid”), making certain that all biochemical pathways are replete with all requisite co-factors and essential molecules. By following a basic K.I.S.S. orthomolecular approach, we are assisting all the steps in any given biochemical pathway needed to optimally fight pathogens in a manner consistent with a healthy functioning immune system. Monotherapeutic approaches are needed for making advances in basic science, but they rarely benefit patients, and are of ethical concern in clinical trial settings. Again, it is best to make sure adequate levels of all essential nutrients are present so multi-step biochemical pathways can function through to completion.
Niacin and niacinamide are precursors for the NAD molecule, which is required for over 400 different gene functions, many of which are essential for keeping the cell alive. [11] Genetic polymorphisms within the NAD-binding domain confer different vitamin B3 dependencies. Some individuals have genes that endow a lower than usual binding affinity for the enzyme binding to the NAD molecule. Accordingly, these individuals need higher amounts of vitamin B3 to achieve the higher levels of NAD required to achieve competent gene function. [12]
Vitamin B3 is unique and our knowledge of it distinguished compared to the other vitamins in the amount of relevant scientific research. Perhaps more is known about the molecular details of protein degradations actively causing acute and chronic depletion of NAD levels from vitamin B3 than for any other vitamin. In contrast, the consequences of vitamin B1 (thiamine) deficiency and the mechanisms thereof are woefully understudied. Much more attention should be devoted to these questions especially given that deficiencies of vitamin B1 clearly cause a clinical presentation that resembles Alzheimer’s disease, a condition for which we have almost no effective treatment.
One function of NAD is to serve as a substrate in the poly ADP-ribose polymerase (PARP) reaction, which is involved in many essential cell functions including repair of DNA in response to DNA damage. However, hyper-activation of PARP1 rapidly depletes NAD leading to catastrophic cell death. It has long been known that PARP1 hyper-activated cell death due to ischemic shock, DNA damage, or other stimuli can be prevented by pre-incubation or supplementation with vitamin B3 as NAD or niacin or niacinamide. This effect is particularly dramatic in neurons which are energetically demanding. SARS-CoV-2 has been shown experimentally to upregulate PARP enzymes, which degrade NAD. [10] Again, the most rational intervention would be to increase NAD+ supply. This may be accomplished inexpensively by supplemental niacin or niacinamide.
Knowledge of the mechanisms causing active depletion of NAD and even genetically inherited greater dependence on NAD is increasingly garnered as research on NAD biology advances. COVID-19 is a disease condition in which known pathways are activated to cause a greater requirement for vitamin B3. However, many other pathways requiring high levels of vitamin B3 are also known.
Three major mechanisms causing NAD depletion are well understood. Firstly, depletion of NAD is likely most acutely caused by hyper-activation of poly-ADP ribose polymerase (PARP1) enzyme, which can rapidly cause depletion of NAD in the PAR polymerization reaction, ultimately leading to quick cell death. PARP1 activity is stimulated by DNA damage. Many other stresses and under defined conditions cell death can be prevented by either increasing NAD levels or by inhibiting the PARP1 enzyme.
Secondly, a slower decrease in NAD levels is likely caused by persistent activation of the enzyme indoleamine 2,3-dioxygenase (IDO), which depletes the source of de novo NAD biosynthesis. IDO enzyme activity is elevated in COVID-19, sepsis, and severe inflammatory response syndrome with higher values predicting mortality. [13,14] IDO is also excessively and persistently activated in autoimmune diseases and cancer — and for these many IDO-targeted therapeutics are under development. [15] This pathway likely may be involved in some of the symptoms of long COVID-19.
Thirdly, NAD is depleted via activation of CD38 enzyme expressed on many white blood cells. Therefore, CD38 is likely to be exceptionally significant in the context of infectious disease and so investigators have been targeting it as a potential approach to treat a variety of conditions.
Genetic aspect of greater dependency
Everyone has their own unique needs for vitamin B3 and, by extension, the NAD needed to enable approximately 400 gene functions. Some individuals need much greater doses of vitamin B3 to achieve the higher levels of NAD required to achieve competent gene function. [12] These individuals are said to have a greater “dependency on vitamin B3” in order to avoid symptoms of deficiency. This biochemical aspect of genetics is an advanced concept — at the peak of western biomedical scientific achievements — but it is not generally taught in medical schools with only a few exceptions, such as with glucose-6-phosphate dehydrogenase.
However, with advances in genetics and associated biochemistry, more examples of the variety of vitamin B3 dependencies are regularly discovered. One of the most impressive and important to consider is the mitochondrial aldehyde dehydrogenase (ALDH2) enzyme, which functions to remove toxic acetaldehyde after drinking alcohol. As many as 50% of the Asian population have the Glu487→Lys variant, which confers a roughly 150-fold reduced affinity for NAD. Accordingly, the ALDH2 Glu487→Lys variant enzyme requires much higher NAD concentrations to function at a healthy level and ultimately prevent hyper-sensitivity to drinking alcohol.
Abram Hoffer, MD. PhD treated thousands of patients with schizophrenia by using high doses of niacin in over 40 years of clinical practice (1950s-1990s). Hoffer finally settled on the observation that some patients required as much as 18,000 mg of niacin a day to avoid schizophrenic symptoms. [16] He described this genetic response as an inter-individual dependence. This dose of 18,000 mg for good health is more than one-thousand-fold higher than the RDA of 16 mg for adult males. Accordingly, we can expect that these inter-individual variations may play prominent roles in controlling COVID-19 susceptibility.
Not surprisingly, schizophrenia has been determined to be the second highest risk factor for dying of COVID-19, just after age. [17,18] Again, the evidence strongly supports that high doses of niacin should be administered after a COVID-19 or related diagnosis. It is safe and may be the difference that saves lives.
One of the potential catastrophic activities initiated by SARS-CoV-2 infection is a cytokine storm. The levels of circulating proinflammatory factors IL-1, IL-6, and TNFα are strongly associated with mortality in COVID-19 patients. Niacin (pennies-a-day doses) is well known to reduce IL-6 and TNF alpha. Meanwhile, IL-6 antibodies costing thousands of dollars are being tested for use against COVID-19. [19]
A great amount of focus has been devoted to the NAD precursors nicotinamide mononucleotide (NMN) and/or nicotinamide riboside (NR) in many clinical trials owing to their potential for return on financial investments. However, the truth is that in the rare occasions that plain old niacin or niacinamide (both discovered in the 1930s) are tested alongside these precursors, these older largely non-patentable forms of NAD precursor often give superior results.
In my own experience directing research comparing all NAD precursors, I observed the most impressive ischemic stress-associated zebrafish embryo life-saving activities using preincubations with niacin as compared to NMN, NR, tryptophan, quinolinic acid, or NAD itself (unpublished experimental observations). These various molecules cross the intestinal mucosa. Their molecular sizes, cell-specific transporters, ability to cross the blood-brain barrier, and more are all factors controlling their ultimate activities in addressing disease that must be empirically compared and tested. Biochemical evolutionary studies of niacin suggest that it is among the oldest of all NAD precursors.
Between 1945 and 1961 several studies found vitamin B3 to be useful in the treatment of TB of the lung, but this potential role was superseded by modern antibiotics. More recently it has been investigated and found to be promising for the treatment of HIV. A recent paper stated, “… this small molecule could emerge at the beginning of the 21st century either as a therapeutic agent in itself or as the lead compound for a new class of agents with activity against both TB and HIV.” [20]
Metabolic analysis of SARS-CoV-2 of COVID-19 patients determined that there is a tryptophan deficiency caused by infection with a correlative increase in pathogenic interleukin-6 (IL-6) levels. [21] Decreased tryptophan causes decreased NAD biosynthesis with concomitant NAD deficiency. High dose niacin supplementation can correct this NAD+ deficiency and the multitude of associated clinical presentations. Chronic fatigue syndrome may be an IDO trap, the result of constant NAD deficiency causing symptoms similar to long COVID-19 that are likely to be preventable with regular high doses of niacin taken in divided doses. [22]
Investigators based in South Africa reviewed changes of macrophages in the context of sepsis with consideration of COVID-19 and pointed out the important role of the immunosuppressive molecule IDO in depleting vitamin B3-derived NAD concluding “…we strongly suggest that vitamin B3 be investigated as a therapy for sepsis, including that caused by COVID-19, ideally as a single agent at high dose rather than within a multivitamin,” which is likely to be insufficient. [13]
Hallmark features of pathological SARS-CoV-2 infection are marked elevations in pro-inflammatory cytokines and chemokines-including, most notably, interleukin-6 (IL-6), in addition to interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). Thus, a commonly proposed effective treatment of COVID-19 is targeting the blockade of IL-6, through inhibition of its most prominent transcription factor, nuclear factor kappa B (NF-κB) ). [23]
Sufficient doses of niacin have consistently been shown to markedly reduce production of pro-inflammatory cytokines (IL-6, TNF-α, MCP-1) in human monocytes, and can substantially inhibit TNF-α-induced NF-κB activation along with MCP-1 secretion in cultured human aortic endothelial cells. Niacin also suppresses TNF-α and IL-6 expressions through down-regulation of the NF-κB pathway. [24] Since vitamin B3 is highly lung protective, it should be used as soon as coughing begins.
Physicians in India have recommended “the mass scale distribution and use of nicotinamide (NAM) supplementation to decrease COVID- 19 prevalence,” based on recent Phase II clinical studies observing that nicotinamide supplementation with the standard of care demonstrably reduced COVID-19 patient recovery time by nearly 30% compared to standard of care alone. [25]
In a mouse model COVID-19 study, injected NAD kept them alive. [26] Investigators examining the effect of treatment with NAD+ found that the pneumonia phenotypes, including excessive inflammatory cell infiltration and embolization in SARS-CoV-2 infected lungs were significantly rescued by boosting NAD+ levels. Most notably, cell death was suppressed by greater than 65% with NAD+ supplementation!
Niacin attenuates lung inflammation and improves survival during sepsis by down-regulating the nuclear factor-κB pathway. A pilot phase of the COVID-19 trial showed an effect of nicotinamide on the time to complete resolution of COVID-19 symptoms.
Landmark clinical trials completed recently in Finland proved that niacin cures systemic NAD deficiency, reduces fatty liver, and also improves muscle performance. [27] Why this study isn’t yet common knowledge in clinical practice may be due to the unfortunate excessive distraction of life in 2022. However, the results of this Finnish study were unparalleled in their positive outcome — the data supporting once again that more research needs to be focused on better determining the full range of clinical indications that respond favorably to high doses of niacin, e.g. 1,000 mg taken 2-3x/d.
Conclusion and doses
The ideal niacin dosage varies depending on an individual’s genetics and their infections and/or stresses. Ultimately, perhaps the best gauge of the most effective niacin dosage regimen may involve the flush response. The niacin-eliciting flush pathway is known to be independent of the NAD biosynthetic pathway in our understanding thus far, and the niacin dose that just causes flushing is currently known to be exceptionally therapeutic for several indications. Still, some will flush with as little as 50 mg while others still do not even experience a flush after taking 4,000 mg at one time! The latter situation is expected to involve an individual with other health problems.
A simple straightforward recommendation is to take whatever dosage of niacin that elicits a flush response, starting with low doses and increasing gradually over several days to weeks until a flush appears. Remember that 1,000 mg taken 3 times a day in the plain old immediate release form has been successfully used in medical practice for over 50 years. It reproducibly corrects the lipodystrophic profile favorably, to reduce cardiovascular events and is expected to provide benefits in the context of COVID-19 — and much more!
(OMNS Contributing Editor W. Todd Penberthy received his PhD in biochemistry from the University of Tennessee College of Medicine in 1997. He then conducted research and taught at the university level. He is presently a continuing medical education writer https://https://www.cmescribe.com/resume/ who prepares courses for physicians to maintain their certification.)
References
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2. Pieper JA (2002) Understanding niacin formulations. Am J Manag Care 8:S308-S314. https://pubmed.ncbi.nlm.nih.gov/12240702
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8. Li R, Li Y, Liang X, et al. (2021) Network Pharmacology and bioinformatics analyses identify intersection genes of niacin and COVID-19 as potential therapeutic targets. Brief Bioinform. 22:1279-1290. https://pubmed.ncbi.nlm.nih.gov/33169132
9. Zheng M, Schultz MB, Sinclair DA. (2022) NAD+ in COVID-19 and viral infections. Trends Immunol. 43:283-295. https://pubmed.ncbi.nlm.nih.gov/35221228
10. Heer CD, Sanderson DJ, Voth LS, et al. (2020) Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity. J Biological Chem. 295:17986-17996. https://pubmed.ncbi.nlm.nih.gov/33051211
11. Penberthy WT, Axelsen KB. (2022) Table of NAD-Utilizing Enzymes. https://www.cmescribe.com/vitamin-dependent-gene-databases
12. Ames BN, Elson-Schwab I, Silver EA. (2002) High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 75:616-658. https://pubmed.ncbi.nlm.nih.gov/11916749
13. Suchard MS, Savulescu DM. (2022) Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts. FEBS J. 289:955-964. https://pubmed.ncbi.nlm.nih.gov/33686748
14. de Assis Barros D’Elia Zanella LGF, de Lima Galvão L (2021) The COVID-19 Burden or Tryptophan Syndrome: Autoimmunity, Immunoparalysis and Tolerance in a Tumorigenic Environment. J Infect Dis Epidemiol. 7:195. https://doi.org/10.23937/2474-3658/1510195
15. Penberthy WT. (2007) Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. Curr Drug Metab. 8:245-66. https://pubmed.ncbi.nlm.nih.gov/17430113
16. Hoffer A, Prousky J. (2008) Successful treatment of schizophrenia requires optimal daily doses of vitamin B3. Altern Med Rev. 13:287-291. https://www.researchgate.net/publication/24036385_The_proper_treatment_of_schizophrenia_requires_optimal_daily_doses_of_vitamin_B3
17. Nemani K, Li C, Olfson M, et al. (2021) Association of Psychiatric Disorders With Mortality Among Patients With COVID-19. JAMA Psychiatry 78:380-386. https://pubmed.ncbi.nlm.nih.gov/33502436
18. Dembosky A. (2022) Having schizophrenia is the second biggest risk factor for dying from COVID-19. NPR. https://www.npr.org/2022/03/20/1087766160/having-schizophrenia-is-the-second-biggest-risk-factor-for-dying-from-covid-19
19. NIH COVID-19 Treatment Guidelines. (2022) Interleukin-6 Inhibitors. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/interleukin-6-inhibitors
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21. Thomas T, Stefanoni D, Reisz JA, et al. (2020) COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight 5:e140327. https://pubmed.ncbi.nlm.nih.gov/32559180
22. Kashi AA, Davis RW, Phair RD. (2019) The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. Diagnostics (Basel) 9:82. https://pubmed.ncbi.nlm.nih.gov/31357483
23. Kats D. (2021) Sufficient Niacin Supply: The Missing Puzzle Piece to COVID-19, and beyond? Preprint. https://doi.org/10.31219/osf.io/uec3r
24. Kwon WY, Suh GJ, Kim KS, et al. (2011) Niacin attenuates lung inflammation and improves survival during sepsis by downregulating the nuclear factor-κB pathway. Crit Care Med. 39:328-334. https://pubmed.ncbi.nlm.nih.gov/20975550
25. Gharote M. (2021) POTENTIAL ROLE OF NICOTINAMIDE SUPPLEMENTATION IN PREVENTION OF COVID-19 TRANSMISSION-A PERSPECTIVE. https://www.researchgate.net/publication/350800103_POTENTIAL_ROLE_OF_NICOTINAMIDE_SUPPLEMENTATION_IN_PREVENTION_OF_COVID-19_TRANSMISSION-A_PERSPECTIVE
26. Jiang Y, Deng Y, Pang H, et al. (2022) Treatment of SARS-CoV-2-induced pneumonia with NAD+ and NMN in two mouse models. Cell Discov. 8:38. https://pubmed.ncbi.nlm.nih.gov/35487885
27. Pirinen E, Auranen M, Khan NA, et al. (2020) Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metab. 31:1078-1090.e5. https://pubmed.ncbi.nlm.nih.gov/32386566
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