046: Niacin, Part 1: What It Is and Why You Need It
Mastering Nutrition Episode 46
Niacin is vitamin B3. You use it to make NAD, the ultimate anti-aging molecule that repairs your DNA and lengthens your telomeres, and the most foundational molecule in our entire system of energy metabolism.
It is especially important to protecting your mind, your skin, and your gut.
You use it to release all your neurotransmitters. This is why depression sets in as the earliest sign of deficiency and why, when it gets bad enough, it leads to suicidality or schizophrenia-like psychosis.
You use constantly it to repair the microscopic damage done to your skin every time you step out into the sunlight. This is why red, inflamed skin appears on the backs of your hands or on your face when you’re deficient, but only if you get outdoors a lot.
You use it to fuel the rapid turnover of cells in your intestines (the cells that absorb the nutrients in our food are replaced every 2-3 days!), and to repair those cells from the constant barrage of insults they face (think of everything those cells *don’t* let in our body 💩and the fact that *they* need to stare all that stuff down!) This is why deficiency will give you diarrhea and make you deficient in lots of other nutrients.
You use it for lots of other things too, like participating with riboflavin to make the methyl group of methylfolate and recycle glutathione, the master antioxidant of the cell. You use it to recycle vitamin K, to support detoxification in the liver, and to synthesize cholesterol, fatty acids, neurotransmitters and nucleotides.
Who needs more? We all do!
Why? Because just aging alone depletes niacin and getting sick or developing diseases as we age depletes it all the more. Niacin repairs damage, so the more damage we face the more we consume.
In fact, this is why many people are taking supplements like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), to slow the onset of aging, or to age more gracefully. Some people are even injected NAD!
But should we be?
And what about the dark side of niacin? We all know the flush -- the redness and itching that accompanies high-dose niacin that people take to lower cholesterol. At high doses, niacin can even damage the liver. How? By sapping methyl groups. Sapping methyl groups can give you liver failure when it’s *really* bad, but sapping them just a little can leave you feeling weak, emotionally stuck, or tied up in a mental funk.
In this two-part podcast series, Alex Leaf and I tackle all of these questions. This is part 1, where we teach you what niacin is and why you need it.
In part 2, we’ll cover how to get niacin in foods, blood tests, and supplements.
00:37 Cliff Notes
5:31 The stories of Julie, John, and Jane
11:32 Symptoms of pellagra: the three Ds of dermatitis, dementia, and diarrhea, and the fourth D, death
18:02 Speculative signs and symptoms of suboptimal niacin status
19:10 Symptoms of excess niacin
20:45 Excess niacin will reduce the supply of methyl groups, which can lower creatine synthesis and affect neurotransmitters, and is probably what underlies niacin-induced liver damage.
24:30 Explaining the stories of Julie, John, and Jane in the context of niacin deficiency or toxicity
28:18 Chemical properties of niacin
31:08 How niacin and nicotinic acid derived their names
33:00 Chemical structures of nicotinic acid, nicotinamide, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide adenine dinucleotide (NAD)
37:05 The biochemistry of niacin
37:57 The differences between NAD(H) and NADP(H) in metabolism
41:07 NAD is often broken down to form ADP-ribose.
42:10 How PARPs (including PARP1 and tankyrase) and sirtuins use NAD to protect us from DNA damage, repair DNA damage, lengthen telomeres, and regulate gene expression
48:31 ADP-ribosyltransferases (ARTs)
50:47 The NAD metabolites cyclic ADP-ribose, linear ADP-ribose, O-acetyl-ADP-ribose, and NAADP are involved in regulating calcium transport, which is especially important for neurotransmitter release.
52:28 How the biochemistry of niacin explains the deficiency symptoms
57:37 The biochemistry of how we get niacin from foods and how we dispose of excess niacin
01:01:14 How the degradation pathways of niacin explain the liver toxicity and flushing reaction from different forms of niacin
01:16:12 Extended-release niacin
01:18:57 Rationale for nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) supplementation
01:27:39 Physiology of niacin absorption and circulation
01:35:04 Endogenous synthesis of niacin
01:35:37 Tracer studies of oral and intravenous nicotinamide riboside supplementation in mice
01:40:00 Estrogen is a strong regulator of the conversion of tryptophan to niacin.
01:42:07 Pharmacokinetic study of Niagen (nicotinamide riboside) supplementation in humans
Niacin Links and Research
Yvan-Charvet L, Kling J, Pagler T, Li H, Hubbard B, Fisher T, Sparrow CP, Taggart AK, Tall AR. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol [Internet]. 2010 Jul;30(7):1430–1438. Available from: http://dx.doi.org/10.1161/ATVBAHA.110.207142 PMCID: PMC2917780
Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol [Internet]. 2013 Nov 12;62(20):1909–1910. Available from: http://dx.doi.org/10.1016/j.jacc.2013.07.025 PMID: 23933538
Kamanna VS, Ganji SH, Kashyap ML. Recent advances in niacin and lipid metabolism. Curr Opin Lipidol [Internet]. 2013 Jun;24(3):239–245. Available from: http://dx.doi.org/10.1097/MOL.0b013e3283613a68 PMID: 23619367
Garg A, Sharma A, Krishnamoorthy P, Garg J, Virmani D, Sharma T, Stefanini G, Kostis JB, Mukherjee D, Sikorskaya E. Role of Niacin in Current Clinical Practice: A Systematic Review. Am J Med [Internet]. 2017 Feb;130(2):173–187. Available from: http://dx.doi.org/10.1016/j.amjmed.2016.07.038 PMID: 27793642
Wang W, Basinger A, Neese RA, Christiansen M, Hellerstein MK. Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women. Am J Physiol Endocrinol Metab [Internet]. 2000 Jul;279(1):E50–9. Available from: http://dx.doi.org/10.1152/ajpendo.2000.279.1.E50 PMID: 10893322
Goldie C, Taylor AJ, Nguyen P, McCoy C, Zhao X-Q, Preiss D. Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials. Heart [Internet]. 2016 Feb;102(3):198–203. Available from: http://dx.doi.org/10.1136/heartjnl-2015-308055 PMCID: PMC4752613
Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT. Langerhans cells release prostaglandin D2 in response to nicotinic acid. J Invest Dermatol [Internet]. 2006 Dec;126(12):2637–2646. Available from: http://dx.doi.org/10.1038/sj.jid.5700586 PMID: 17008871
Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen BE, Ahmed K, Tunaru S, Wirth A, Offermanns S. Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest [Internet]. 2010 Aug;120(8):2910–2919. Available from: http://dx.doi.org/10.1172/JCI42273 PMCID: PMC2912194
Dunbar RL, Gelfand JM. Seeing red: flushing out instigators of niacin-associated skin toxicity. J Clin Invest [Internet]. 2010 Aug;120(8):2651–2655. Available from: http://dx.doi.org/10.1172/JCI44098 PMCID: PMC2912206
Stern RH, Spence JD, Freeman DJ, Parbtani A. Tolerance to nicotinic acid flushing. Clin Pharmacol Ther [Internet]. 1991 Jul;50(1):66–70. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1855354 PMID: 1855354
Stern RH, Freeman D, Spence JD. Differences in metabolism of time-release and unmodified nicotinic acid: explanation of the differences in hypolipidemic action? Metabolism [Internet]. 1992 Aug;41(8):879–881. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1640866 PMID: 1640866
Kourtzidis IA, Dolopikou CF, Tsiftsis AN, Margaritelis NV, Theodorou AA, Zervos IA, Tsantarliotou MP, Veskoukis AS, Vrabas IS, Paschalis V, Kyparos A, Nikolaidis MG. Nicotinamide riboside supplementation dysregulates redox and energy metabolism in rats: Implications for exercise performance. Exp Physiol [Internet]. 2018 Oct;103(10):1357–1366. Available from: http://dx.doi.org/10.1113/EP086964 PMID: 30007015
Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol [Internet]. 2000 Dec 21;86(12A):35L–40L. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11374854 PMID: 11374854
Poddar SK, Sifat AE, Haque S, Nahid NA, Chowdhury S, Mehedi I. Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules [Internet]. 2019 Jan 21;9(1). Available from: http://dx.doi.org/10.3390/biom9010034 PMCID: PMC6359187
Fricker RA, Green EL, Jenkins SI, Griffin SM. The Influence of Nicotinamide on Health and Disease in the Central Nervous System. Int J Tryptophan Res [Internet]. 2018 May 21;11:1178646918776658. Available from: http://dx.doi.org/10.1177/1178646918776658 PMCID: PMC5966847
Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Curr Opin Clin Nutr Metab Care [Internet]. 2013 Nov;16(6):657–661. Available from: http://dx.doi.org/10.1097/MCO.0b013e32836510c0 PMID: 24071780
Dollerup OL, Christensen B, Svart M, Schmidt MS, Sulek K, Ringgaard S, Stødkilde-Jørgensen H, Møller N, Brenner C, Treebak JT, Jessen N. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr [Internet]. 2018 Aug 1;108(2):343–353. Available from: http://dx.doi.org/10.1093/ajcn/nqy132 PMID: 29992272
Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun [Internet]. 2018 Mar 29;9(1):1286. Available from: http://dx.doi.org/10.1038/s41467-018-03421-7 PMCID: PMC5876407
Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O’Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One [Internet]. 2017 Dec 6;12(12):e0186459. Available from: http://dx.doi.org/10.1371/journal.pone.0186459 PMCID: PMC5718430
Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol [Internet]. 1998 Dec 17;82(12A):29U–34U; discussion 39U–41U. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9915660 PMID: 9915660
Keenan JM. Wax-matrix extended-release niacin vs inositol hexanicotinate: a comparison of wax-matrix, extended-release niacin to inositol hexanicotinate “no-flush” niacin in persons with mild to moderate dyslipidemia. J Clin Lipidol [Internet]. 2013 Jan;7(1):14–23. Available from: http://dx.doi.org/10.1016/j.jacl.2012.10.004 PMID: 23351578
Soudijn W, van Wijngaarden I, Ijzerman AP. Nicotinic acid receptor subtypes and their ligands. Med Res Rev [Internet]. 2007 May;27(3):417–433. Available from: http://dx.doi.org/10.1002/med.20102 PMID: 17238156
Ellinger P, Kader MM. Nicotinamide metabolism in mammals. Biochem J [Internet]. 1949;44(1):77–87. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16748483 PMCID: PMC1274811
Stratford MR, Dennis MF, Hoskin P, Phillips H, Hodgkiss RJ, Rojas A. Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring. Br J Cancer [Internet]. 1996 Jul;74(1):16–21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8679452 PMCID: PMC2074616
Dragovic J, Kim SH, Brown SL, Kim JH. Nicotinamide pharmacokinetics in patients. Radiother Oncol [Internet]. 1995 Sep;36(3):225–228. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8532910 PMID: 8532910
McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA [Internet]. 1994 Mar 2;271(9):672–677. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8309029 PMID: 8309029
Pieper JA. Understanding niacin formulations. Am J Manag Care [Internet]. 2002 Sep;8(12 Suppl):S308–14. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12240702 PMID: 12240702
Wallace TC, McBurney M, Fulgoni VL 3rd. Multivitamin/mineral supplement contribution to micronutrient intakes in the United States, 2007-2010. J Am Coll Nutr [Internet]. 2014;33(2):94–102. Available from: http://dx.doi.org/10.1080/07315724.2013.846806 PMID: 24724766
Moreschi I, Bruzzone S, Nicholas RA, Fruscione F, Sturla L, Benvenuto F, Usai C, Meis S, Kassack MU, Zocchi E, De Flora A. Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes. J Biol Chem [Internet]. 2006 Oct 20;281(42):31419–31429. Available from: http://dx.doi.org/10.1074/jbc.M606625200 PMID: 16926152
Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O’Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One [Internet]. journals.plos.org; 2017 Dec 6;12(12):e0186459. Available from: http://dx.doi.org/10.1371/journal.pone.0186459 PMCID: PMC5718430
Jacobson EL, Jacobson MK.  Tissue NAD as a biochemical measure of niacin status in humans. Methods in Enzymology [Internet]. Academic Press; 1997. p. 221–230. Available from: http://www.sciencedirect.com/science/article/pii/S0076687997801139
Jacobson EL, Jacobson MK. Biochemical method to measure niacin status in a biological sample [Internet]. US Patent. 6287796, 2001 [cited 2019 Feb 16]. Available from: https://patentimages.storage.googleapis.com/19/41/2d/a1de97bc17d927/US6287796.pdf
Fu CS, Swendseid ME, Jacob RA, McKee RW. Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. J Nutr [Internet]. academic.oup.com; 1989 Dec;119(12):1949–1955. Available from: http://dx.doi.org/10.1093/jn/119.12.1949 PMID: 2621487
Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids : Health and Medicine Division [Internet]. [cited 2019 Feb 16]. Available from: http://www.nationalacademies.org/hmd/Reports/2002/Dietary-Reference-Intakes-for-Energy-Carbohydrate-Fiber-Fat-Fatty-Acids-Cholesterol-Protein-and-Amino-Acids.aspx
Dölle C, Skoge RH, Vanlinden MR, Ziegler M. NAD biosynthesis in humans--enzymes, metabolites and therapeutic aspects. Curr Top Med Chem [Internet]. ingentaconnect.com; 2013;13(23):2907–2917. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24171775 PMID: 24171775
Clegg KM. BOUND NICOTINIC ACID IN DIETARY WHEATEN PRODUCTS. Br J Nutr [Internet]. cambridge.org; 1963;17:325–329. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14045335 PMID: 14045335
Adrian J, Frangne R. Synthesis and availability of niacin in roasted coffee. Adv Exp Med Biol [Internet]. Springer; 1991;289:49–59. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1897406 PMID: 1897406
Frederick DW, Loro E, Liu L, Davila A Jr, Chellappa K, Silverman IM, Quinn WJ 3rd, Gosai SJ, Tichy ED, Davis JG, Mourkioti F, Gregory BD, Dellinger RW, Redpath P, Migaud ME, Nakamaru-Ogiso E, Rabinowitz JD, Khurana TS, Baur JA. Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle. Cell Metab [Internet]. 2016 Aug 9;24(2):269–282. Available from: http://dx.doi.org/10.1016/j.cmet.2016.07.005 PMCID: PMC4985182
Liu L, Su X, Quinn WJ 3rd, Hui S, Krukenberg K, Frederick DW, Redpath P, Zhan L, Chellappa K, White E, Migaud M, Mitchison TJ, Baur JA, Rabinowitz JD. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab [Internet]. 2018 May 1;27(5):1067–1080.e5. Available from: http://dx.doi.org/10.1016/j.cmet.2018.03.018 PMCID: PMC5932087
Creeke PI, Dibari F, Cheung E, van den Briel T, Kyroussis E, Seal AJ. Whole blood NAD and NADP concentrations are not depressed in subjects with clinical pellagra. J Nutr [Internet]. academic.oup.com; 2007 Sep;137(9):2013–2017. Available from: http://dx.doi.org/10.1093/jn/137.9.2013 PMID: 17709435
Strohm D, Bechthold A, Isik N, Leschik-Bonnet E, Heseker H. Revised reference values for the intake of thiamin (vitamin B1), riboflavin (vitamin B2), and niacin. NFS Journal [Internet]. Elsevier; 2016 Aug 1;3:20–24. Available from: http://www.sciencedirect.com/science/article/pii/S2352364615300432
Pissios P. Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme. Trends Endocrinol Metab [Internet]. 2017 May;28(5):340–353. Available from: http://dx.doi.org/10.1016/j.tem.2017.02.004 PMCID: PMC5446048
Ongol MP, Niyonzima E, Gisanura I, Vasanthakaalam H, Others. Effect of germination and fermentation on nutrients in maize flour. Pakistan Journal of Food Sciences [Internet]. Pakistan Society of Food Scientists and Technologists; 2013;23(4):183–188. Available from: https://www.researchgate.net/profile/Niyonzima_Eugene2/publication/281554021_Effect_of_germination_and_fermentation_on_nutrients_in_maize_flour/links/55ed7ecd08ae21d099c759db.pdf
Carpenter KJ. The relationship of pellagra to corn and the low availability of niacin in cereals. Experientia Suppl [Internet]. Springer; 1983;44:197–222. Available from: https://www.ncbi.nlm.nih.gov/pubmed/6357846 PMID: 6357846
Ghosh HP, Sarkar PK, Guha BC. Distribution of the Bound Form of Nicotinic Acid in Natural Materials. J Nutr [Internet]. Oxford University Press; 1963 Apr 1 [cited 2019 Feb 14];79(4):451–453. Available from: https://academic.oup.com/jn/article-abstract/79/4/451/4779288
Lerner F, Niere M, Ludwig A, Ziegler M. Structural and functional characterization of human NAD kinase. Biochem Biophys Res Commun [Internet]. 2001 Oct 19;288(1):69–74. Available from: http://dx.doi.org/10.1006/bbrc.2001.5735 PMID: 11594753
Sorci L, Cimadamore F, Scotti S, Petrelli R, Cappellacci L, Franchetti P, Orsomando G, Magni G. Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis. Biochemistry [Internet]. 2007 Apr 24;46(16):4912–4922. Available from: http://dx.doi.org/10.1021/bi6023379 PMID: 17402747
Heimburger DC. Clinical Manifestations of Nutrient Deficiencies and Toxicities. In: Ross AC, editor. Modern Nutrition in Health and Disease [Internet]. Available from: https://chrismasterjohnphd.com/textbook
Kirkland JB. Niacin. In: Ross AC, editor. Modern Nutrition in Health and Disease [Internet]. Available from: https://chrismasterjohnphd.com/textbook
Niacin [Internet]. Linus Pauling Institute. 2014 [cited 2019 Feb 14]. Available from: https://lpi.oregonstate.edu/mic/vitamins/niacin
Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, its Panel on Folate, Vitamins OB, Choline. Niacin [Internet]. National Academies Press (US); 1998 [cited 2019 Feb 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114304/
Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, its Panel on Folate, Vitamins OB, Choline. Riboflavin [Internet]. National Academies Press (US); 1998 [cited 2019 Feb 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114322/
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