By Matthew Roberts, Ph.D.

NAD precursors — building blocks that cells use to make NAD — have always existed, including ones that may sound familiar. The B3 vitamins (niacin and nicotinamide) and the amino acid tryptophan are all used by cells to make more NAD. Humans have been eating foods containing these NAD boosting molecules for our entire history, and a minimum level of vitamin B3 consumption is required to avoid the deficiency disease Pellagra [1].

The B3 vitamins nicotinic acid and nicotinamide have both been the subject of clinical trials over the past several decades [2]. High doses of niacin have also been used therapeutically since the 1950s to treat dyslipidemia based on its ability to increase “good” HDL cholesterol and lower “bad” LDL cholesterol [3]. More than half a century of therapeutic niacin supplementation and clinical studies involving dietary administration of B3 vitamins have not led to an association between boosting NAD and an increased risk of cancer [2-4]. And published studies suggest that increased NAD could help reduce cancer risk [5-7].

NR has gained more recent awareness among scientists and supplement-seekers, in part because of unique properties that allow it to boost NAD without some of the drawbacks of niacin, such as skin flushing. The few preclinical studies that have directly compared NR to the B3 vitamins have also demonstrated differences in pharmacokinetics and cellular health benefits that give it an edge when it comes to the potential for supporting our health [8-10].

NR has been the subject of rigorous preclinical safety and toxicology studies [11]. Three studies demonstrated that NR does not alter DNA by introducing mutations or chromosome breaks, supporting that it would not lead to the formation of cancer through DNA damage. Another pivotal preclincial study demonstrated that NR has a similar toxicity profile as nicotinamide.

These safety studies laid the groundwork for the multiple clinical studies of NR that have now been published [8, 12-14]. At the time of writing, doses as high as 2 grams NR per day have been administered for as long as 12 weeks with no attributable adverse reactions. More than 20 additional NR clinical trials are registered with the National Institutes of Health and in various stages of completion.

Beyond conducting scientific research to establish safety, companies that introduce new dietary ingredients are required to notify the FDA before selling their product. This is called the new dietary ingredient notification (NDIN) process and was first introduced in 1994. NR, specifically in the form of Niagen, has been twice successfully notified to the FDA as a new dietary ingredient and successfully notified to the FDA as generally recognized as safe (GRAS).


Matthew Roberts, Ph.D. is the Chief Scientific Officer and Senior Vice President of Innovation at ChromaDex. He received his Ph.D. in Environmental and Comparative Toxicology from Cornell University, his M.B.A. from the Olin School of Business at Washington University, and his B.S. in Plant Molecular Biology and Physiology from Purdue University.


References

  1. Bogan, K.L. and C. Brenner, Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr, 2008. 28: p. 115-30.
  2. Knip, M., et al., Safety of high-dose nicotinamide: a review. Diabetologia, 2000. 43(11): p. 1337-45.
  3. Pieper, J.A., Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety. Am J Health Syst Pharm, 2003. 60(13 Suppl 2): p. S9-14; quiz S25.
  4. Kirkland, J.B., Niacin and carcinogenesis. Nutr Cancer, 2003. 46(2): p. 110-8.
  5. Snaidr, V.A., D.L. Damian, and G.M. Halliday, Nicotinamide for photoprotection and skin cancer chemoprevention: A review of efficacy and safety. Exp Dermatol, 2019. 28 Suppl 1: p. 15-22.
  6. Tummala, K.S., et al., Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell, 2014. 26(6): p. 826-839.
  7. Santidrian, A.F., et al., Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest, 2013. 123(3): p. 1068-81.
  8. Trammell, S.A., et al., Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun, 2016. 7: p. 12948.
  9. Diguet, N., et al., Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy. Circulation, 2017.
  10. Vannini, N., et al., The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Cell Stem Cell, 2019. 24(3): p. 405-418 e7.
  11. Conze, D.B., J. Crespo-Barreto, and C.L. Kruger, Safety assessment of nicotinamide riboside, a form of vitamin B3. Hum Exp Toxicol, 2016.
  12. Airhart, S.E., et al., 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, 2017. 12(12): p. e0186459.
  13. Martens, C.R., et al., Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun, 2018. 9(1): p. 1286.
  14. Dollerup, O.L., et al., A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr, 2018.