Nicotinamide (NAM)

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    • Nicotinamide (NAM) and nicotinic acid (NA) are already available on the world market as dietary supplements. However, high oral doses of NAM and NA have been reported to be hepatotoxic to humans [1][2], and an adverse effect of vasodilative flushing due to high NA intake has been shown[3]. The upper tolerable dose of NAM and NA for humans established by the European Commission and the UK Vitamin and Mineral Expert are 900 mg/day and 10 mg/day, respectively[4].
    • 2017, Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels [5]

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    1. Ito TK, et al. A single oral supplementation of nicotinamide within the daily tolerable upper level increases blood NAD+ levels in healthy subjects. Transl. Med. Aging. 2021;5:43–51. doi: 10.1016/j.tma.2021.09.001.
    2. Knip M et al.: Safety of high-dose nicotinamide: a review. Diabetologia 2000. (PMID 11126400) [PubMed] [DOI] Nicotinamide, the amide derivative of nicotinic acid, has over the past forty years been given at high doses for a variety of therapeutic applications. It is currently in trial as a potential means of preventing the onset of Type I (insulin-dependent) diabetes mellitus in high-risk, first-degree relatives. Nicotinamide is for regulatory purposes classed as a food additive rather than a drug and has not therefore required the formal safety evaluation normally expected of a new therapy. Because the safety of treatment with megadoses of vitamins cannot be assumed, a full literature review has been undertaken. The therapeutic index of nicotinamide is wide but at very high doses reversible hepatotoxicity has been reported in animals and humans. Minor abnormalities of liver enzymes can infrequently occur at the doses used for diabetes prevention. There is no evidence of teratogenicity from animal studies and nicotinamide is not in itself oncogenic; at very high doses it does however potentiate islet tumour formation in rats treated with streptozotocin or alloxan. There is no evidence of oncogenicity in man. Growth inhibition can occur in rats but growth in children is unaffected. Studies of its effects on glucose kinetics and insulin sensitivity are inconsistent but minor degrees of insulin resistance have been reported. The drug is well tolerated, especially in recent studies which have used relatively pure preparations of the vitamin. Experience to date therefore suggests that the ratio of risk to benefit of long-term nicotinamide treatment would be highly favourable, should the drug prove efficacious in diabetes prevention. High-dose nicotinamide should still, however, be considered as a drug with toxic potential at adult doses in excess of 3 gm/day and unsupervised use should be discouraged.
    3. MacKay D et al.: Niacin: chemical forms, bioavailability, and health effects. Nutr Rev 2012. (PMID 22646128) [PubMed] [DOI] Elevated low-density lipoprotein cholesterol (LDL-C) has been the main target of lipid-altering therapy to reduce cardiovascular risk associated with dyslipidemia. Residual cardiovascular risk remains, however, after achievement of goal LDL-C levels and is associated in part with other risk markers of cardiovascular disease, including low high-density lipoprotein cholesterol (HDL-C), high lipoprotein a, and hypertriglyceridemia. Niacin is considered a valuable agent for therapy to modify high LDL-C as well as low HDL-C, high lipoprotein a, and hypertriglyceridemia. The forms of niacin available in the marketplace include unbound niacin, or free nicotinic acid (NA); extended-release NA, a form of NA that is released gradually over a period of time; inositol hexanicotinate, six molecules of NA covalently bonded to one molecule of inositol; and nicotinamide, or niacinamide, the amide form of NA, which is readily bioavailable. This review is designed to assist healthcare professionals in evaluating the form(s) of niacin best suited for a particular therapeutic goal. Further, it provides a literature-based evaluation of risk for NA, extended-release NA, inositol hexanicotinate, and nicotinamide.
    4. Scientific Committee on Food. Tolerable Upper Intake Levels for Vitamin S and Minerals (2006). https://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf.
    5. Sun WP et al.: Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels. Clin Nutr 2017. (PMID 27567458) [PubMed] [DOI] AIM: The present study was to compare the effects of nicotinic acid and nicotinamide on the plasma methyl donors, choline and betaine. METHODS: Thirty adult subjects were randomly divided into three groups of equal size, and orally received purified water (C group), nicotinic acid (300 mg, NA group) or nicotinamide (300 mg, NM group). Plasma nicotinamide, N1-methylnicotinamide, homocysteine, betaine and choline levels before and 1.5-h and 3-h post-dosing, plasma normetanephrine and metanephrine concentrations at 3-h post-dosing, and the urinary excretion of N1-methyl-2-pyridone-5-carboxamide during the test period were examined. RESULTS: The level of 3-h plasma nicotinamide, N1-methylnicotinamide, homocysteine, the urinary excretion of N1-methyl-2-pyridone-5-carboxamide and pulse pressure (PP) in the NM group was 221%, 3972%, 61%, 1728% and 21.2% higher than that of the control group (P < 0.01, except homocysteine and PP P < 0.05), while the 3-h plasma betaine, normetanephrine and metanephrine level in the NM group was 24.4%, 9.4% and 11.7% lower (P < 0.05, except betaine P < 0.01), without significant difference in choline levels. Similar but less pronounced changes were observed in the NA group, with a lower level of 3-h plasma N1-methylnicotinamide (1.90 ± 0.20 μmol/l vs. 3.62 ± 0.27 μmol/l, P < 0.01) and homocysteine (12.85 ± 1.39 μmol/l vs. 18.08 ± 1.02 μmol/l, P < 0.05) but a higher level of betaine (27.44 ± 0.71 μmol/l vs. 23.52 ± 0.61 μmol/l, P < 0.05) than that of the NM group. CONCLUSION: The degradation of nicotinamide consumes more betaine than that of nicotinic acid at identical doses. This difference should be taken into consideration in niacin fortification.