Niacinamide (nicotinamide) is one of the two principal forms of the B-complex vitamin niacin (see Niacin). The term niacin is used as a collective term to refer to both nicotinamide and nicotinic acid, the other principal form of niacin, or the term is used synonymously with nicotinic acid. Nicotinamide and nicotinic acid have identical vitamin activities, but they have very different pharmacological activities. Niacinamide has wide-reaching health effects, and the many niacinamide benefits are worth a close examination.
Niacinamide (nicotinamide) is one of the two principal forms of the B-complex vitamin niacin (see Niacin). The term niacin is used as a collective term to refer to both nicotinamide and nicotinic acid, the other principal form of niacin, or the term is used synonymously with nicotinic acid. Nicotinamide and nicotinic acid have identical vitamin activities, but they have very different pharmacological activities.
Niacinamide is a component of two related coenzymes—nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The principle function of these enzymes is to facilitate oxidation and reducing reactions in the form of dehydrogenases.
Nicotinamide, via its major metabolite NAD++ (nicotinamide adenine dinucleotide), is involved in a wide range of biological processes including the production of energy, the synthesis of fatty acids, cholesterol and steroids, signal transduction, and the maintenance of the integrity of the genome. Nicotinic acid, in pharmacological doses, is used as an antihyperlipidemic agent. It also causes vasodilatation of cutaneous blood vessels resulting in the so-called niacin flush. Nicotinamide in pharmacological doses does not have antihyperlipidemic activity, nor does it cause a niacin-flush. There is evidence, however, that pharmacological doses of nicotinamide may help prevent type 1 diabetes mellitus. Pyrazinamide, an important drug in the treatment of tuberculosis, is an analogue of and shares the same biochemical mechanism with nicotinamide.
Although niacinamide shares some characteristics of niacin, it has unique nutritional and pharmacological properties of its own and niacinamide has important benefits. The niacinamide form of B3 is literally required in hundreds of enzymatic reactions in the human body. Research has demonstrated remarkable niacinamide benefits for arthritis, asthma, diabetes, heart disease, stress, stroke, and recently as an anti-aging nutrient.
The traditional medical use of both forms of B3 is to treat the vitamin deficiency syndrome known as pellagra, a disease that occurs frequently among people who subsisted mainly on corn (maize). After the Spanish introduced corn to Europe, a condition began to be observed which was first called ‘Mal de la Rosa’ (redness of the rose) because of the red skin lesions frequently seen — caused by lack of niacinamide and one of the hallmarks of pellagra. In Italy, the condition was called pellagra, which meant rough skin. The name Pellagra was introduced into medical literature in 1771 by Frapoli.
Full-blown pellagra is a chronic wasting disease associated with dermatitis, dementia and diarrhea (the three Ds). Early symptoms include weakness, lassitude, anorexia, and indigestion. Mental changes include fatigue, insomnia, and apathy, which precede encephalopathy, characterized by confusion, disorientation, hallucination, loss of memory and frank organic psychosis.
Niacinamide is usually absorbed only in the small intestine, while nicotinic acid is absorbed in the stomach as well. Both niacinamide and nicotinic acid are present in blood plasma and are converted to the coenzyme form in the blood cells, kidney, brain and liver. Although niacinamide can be converted to nicotinic acid, there is no direct conversion back to niacinamide. Niacinamide is water soluble, and the body does not store a significant amount. Most of niacinamide is present in the tissues in the form of nicotinamide as NAD and NADP. Niacinamide converts twice as readily to NAD/NADP as does niacin. Tryptophan metabolism provides about two thirds of the nicotinamide the body utilizes (Fig. 1). A non-redox function involves transfer of the coenzyme to macromolecules that attach to ribosomes in mitochondria and in the nucleus where it affects the activity of DNA. The non-redox function is thought to account for the rapid turnover of NAD in the body.
The many niacinamide benefits are worth noting. Nicotinamide, unlike nicotinic acid, does not have significant effects on lipids, but it has been shown to be useful for some with type 1 (insulin-dependent) diabetes. There is preliminary evidence showing that it might help individuals with generalized granuloma annular and osteoarthritis. There is little evidence that it is helpful in rheumatoid arthritis, schizophrenia or tinnitus. It has been suggested that niacinamide might aid in some cancer therapies.
Nicotinamide is being investigated as an agent for the possible prevention or delaying of the onset of type 1 diabetes mellitus (insulin-dependent diabetes mellitus or IDDM). The rationale for using nicotinamide in the prevention of type 1 diabetes mellitus is derived from human and animal studies as well as in vitro investigations. Nicotinamide has been found to prevent diabetes in alloxan- and streptozotocin-treated mice and rats and in non-obese diabetic (NOD) mice. In vitro studies have shown that nicotinamide can prevent macrophage- orinterleukin-1beta-induced beta-cell damage. An inter-vention study in New Zealand using nicotinamide treatment showed a 50 reduction in the development of IDDM over a five-year period. However, the use of nicotinamide in connection with diabetes is at best experimental.
Nicotinamide has been shown to have antioxidant activity. In vitro, it has been found to inhibit protein oxidation and lipid peroxidation. It has also been found to inhibit reactive oxygen species-induced apoptosis, to inhibit phagocytic generation of reactive oxygen species, to scavenge reactive oxygen species and to inhibit the oxidative activity of nitric oxide.
Nicotinamide has demonstrated a number of anti-inflammatory activities. Nicotinamide has been shown to inhibit lipopolysaccharide-induced TNF-alpha in mice, in a dose-dependent manner. It is thought that this inhibition of TNF-alpha is mediated via inhibition, at the gene transcription level, of NF-Kappa B, which in turn inhibits TNF-alpha. Nicotinamide has also been shown to decrease the production of IL-12 and TNF-alpha in cultures of whole blood from prediabetic and diabetic subjects and also in healthy subjects.
Dosage and Administration
Typical supplemental dosage ranges from 20 to 100 milligrams daily. Pre- and postnatal vitamin/mineral supplements typically deliver a dose of 20 milligrams daily. Most people need more especially if illness is present related to circulatory or cardiovascular issues including elevated cholesterol. The correct dosage for Cholest, Niacinamide B3 and NAC are on the labels. A patient may be tested monthly by their health provider for dosage change and more niacinamide information is available through the provider.
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Gene Silencing and Anti-Aging
Genes and gene therapy are proving to be a powerful tool in the latest frontier in the fight against aging. Genes are actually a small part of the DNA structure and cellular differentiation depends on not only gene expression but also on gene silencing. In other words, which genes are ‘expressed’ determines the cell purpose and activity. Recent research has identified genes that influence longevity. In particular, a gene labeled, Sir2, for silent information regulator 2, has been shown to produce a protein, Sir2p, that extends cell life. Recent research has shown that Sir2p is a NAD-dependent histone deacetylase that connects metabolism, gene silencing, and cellular life extension (Imai, et.al. 2000). Niacinamide, by increasing NAD, enhances Sir2p activity.
Caloric restricted diets have long been known for their ability to extend the lifespan by slowing metabolism. NAD is essential in cellular metabolism. It was proposed by MIT researchers that by slowing metabolism NAD is spared, thereby enhancing Sir2p activity. Increasing intracellular NAD not only mimics the metabolic benefits of calorie restricted diets, but also helps maintain a balance of silent and active genes.
Nutritional supplementation with niacinamide, as mentioned earlier, is an effective way to increase intracellular NAD levels. Additionally, Sir2 activity is also thought to have ADP-ribosyltransferase activity (Tanny, et al. 1999). Could it be that increased intracellular NAD positively influences ADP-ribosyltransferase activity in favor of Sir2p activity over nitric oxide synthase? This could explain the inhibition of nitric oxide and account for niacinamide’s benefit in the treatment of arthritis and diabetes, as well as protection of the brain.
Better for Arthritis than NSAIDS
Niacinamide has been known for over fifty years for its benefit in the treatment of arthritis. Niacinamide, glucosamine, SAMe, selenium and fish oil may all provide significantly superior alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs). These supplements act as modulators at multiple points in the signal transduction pathways that promote synthesis and mediate the activity of the cytokine interleukin-1 (IL-1). IL-1, so crucial to the pathogenesis of osteoarthritis, is also involved in B and T cell proliferation, cytokine production by macrophages and T cells, prostaglandin release, bone reabsorption and fever. IL-1 contributes to arthritis by stimulating nitric oxide (NO) production.
Inhibiting NO has been proposed as a desirable therapeutic approach in osteoarthritis (Amin, Abramson 1998). NO is a highly reactive, cytotoxic (cell-killing) free radical. NO has long been implicated in a variety of tissue injury related diseases, and is thought to play a significant role in the breakdown of articular (joint) cartilage, resulting in osteoarthritis. Niacinamide blunts the anti-catabolic effects of IL-1 which is generated by the synovium (the membrane which surrounds the joint). IL-1 induces the production of increased nitric oxide synthase. Nitric oxide synthase, in turn inhibits chondrocyte synthesis of substances that are essential for the repair of cartilage. This results in the inefficient repair of articular cartilage. Niacinamide, by inhibiting ADP-ribosylation, is thought to suppress the cytokine-mediated induction of nitric oxide synthase by IL-1 (McCarty, Russell 1999). In fact, the progression of collagen II-induced arthritis is inhibited by niacinamide and this inhibition is enhanced when co-supplemented with N-acetyl cysteine (Kroger H, et.al. 1999).
The Wellness Center offers the most effective and purest Niacinamide B.3 and N.A.C. in the marketplace.
Niacinamide and Diabetes
Niacinamide has three major benefits for diabetics. First, it reduces nitric oxide synthase which helps retard beta cell death. Beta cells are the pancreatic cells that produce insulin. Second, it enhances ox/redox function through restoration of NAD levels which help prevent cellular damage and improve regeneration. Third, it reduces glycosylated hemoglobin levels which reduces the peripheral organ and blood vessel oxidation load and damage from sugar metabolites. In type I diabetics, niacinamide supplementation may slow down pancreatic beta cell destruction (where insulin is formed) and enhance the cells’ regeneration. Niacinamide can suppress ADP-ribosylation reactions in beta cells as well as in immune cells and the endothelium. Cell death pathways and gene expression patterns are modified with high niacinamide doses leading to improved beta cell survival and an enhanced immunoregulatory balance (Kolb, Burkhart 1999). In another earlier study, nicotinamide supplementation was shown to result in lower glycosylated hemoglobin along with lower insulin doses. The authors concluded that niacinamide may be successful in improving metabolic control in recent onset type I diabetes, probably by increasing residual islet B-cell (beta cell) function (Pozzilli, et.al. 1989). Additional information on niacinamide is coming forth. Complete remissions of young adult type I diabetics lasting over two years are rare, yet a 1987 French study found two complete remissions out of seven patients given 3gm/day. They also found the mean dose of insulin was lower in the niacinamide-treated group than the placebo group. (Vague, et.al 1987)
Niacinamide may also be of benefit in type II adult onset diabetes and chronic pancreatitis.
Researchers observed improved glycemic parameters and other benefits by the addition of niacinamide to nutritional therapies of type II diabetics. It is reasoned that reduction of glycosylated hemoglobin and enhancement of beta cell survival and function is beneficial in Type II diabetes as well. In a study of alcoholics with chronic pancreatitis, niacinamide significantly increased basal secretion of insulin, slightly improved glucose-stimulated secretion and promoted reduction of hypercoagulation and time to remission (Loginov et.al. 1999). Niacinamide may also retard nephropathy in diabetics and reduce liver toxicity in drug therapies (Kroger, et. al. 1999).
A Safe Alternative for Fighting Stress and Anxiety
Niacinamide reduces the psychological effects of stress and anxiety. Niacinamide has been shown to be effective in alleviating anxiety, elevating the aggressive reaction threshold, and decreasing fighting (Akhundov et.al. 1993). It may be an effective natural alternative to benzodiazepines. Niacinamide has demonstrated benzodiazepine-like actions (Mohler et.al. 1979). Niacinamide is thought to be an endogenous ligand for the benzodiazepine-GABA receptor complex. It potentiates the anticonvulsant effects of diazepam (Kryzhanovskii, Shandra 1985). Study participants report they sleep better when taking niacinamide.
There now appears to be almost an epidemic of Ritalin prescriptions among school children. Unfortunately medicine has not fully considered Ritalin’s profound adverse effects on brain chemistry and energy. There is little focus on the role played by amphetamines and other mood-altering prescription or illicit drugs in childhood violence. Xenobiotic (synthetic) drug therapy, combined with biochemical imbalances resulting from situational stress and dietary induced nutritional deficiencies must be considered as a significant contributing factors in childhood violence.
Niacinamide is a potentially highly effective treatment for many childhood and adolescent behavioral problems.
Niacinamide helps maintain brain ATP/ADP ratios and thereby maintains brain energy and amine levels. Amphetamine-induced depletion of dopamine and energy stores can often be alleviated by niacinamide (Wan, et.al. 1999). Niacinamide, at the very least, would appear to be an inexpensive primary intervention tool due to its benefit of significantly reducing the aggression threshold. Niacinamide has yet another benefit for students. It was shown to have nootropic effects greater than piracetam! Niacinamide also beat piracetam as an antihypoxic, antiamnestic, and anxiolytic (Akhundov, et. al., 1990). Perhaps administrators and psychologists should be dispensing niacinamide rather than amphetamines and mood altering xenobiotics in our schools.
Niacinamide’s Other Diverse Benefits
Niacinamide may have therapeutic benefit in a wide range of disease processes because of its potent anti-inflammatory and anti-tumor properties. In asthma, niacinamide supplementation reduced mast cell degranulation and histamine release. Niacinamide has consequently been recommended for relief of bronchial asthma and urticaria (Werbach 1987). Niacinamide may be beneficial in the fight against cancer. It has been shown to inhibit gene transcription of NF-kappa B, which regulates inflammation, and which in turn inhibits NF-kappa A and induces apoptosis of tumor cells (Pero, et.al. 1999).
Niacinamide has been studied as a useful adjunct in the early treatment of stroke. If taken within two hours of onset of a stroke, niacinamide was shown to reduce the infarction in a dose dependent manner (Ayoub, et.al. 1999). Niacinamide has been shown to reduce damage in arterial occlusion largely by enhancing NAD+ (which increases ATP concentrations) and by inhibiting cell death through nitric oxide inhibition.
The most common side effect of high-dose niacinamide is sedation. High doses of niacinamide as well as timed-release niacin have raised questions about hepatotoxicity. This may be an overstated caution. Niacinamide at therapeutic doses of up to 3 grams a day for an adult and 100 – 500 mg for a child in 2-3 divided doses is usually well tolerated. Lower levels of niacinamide were shown to actually protect against hepatotoxicity, as noted earlier. Two to three grams daily is recommended for an anti-aging program with a corresponding decrease in niacin. It should be given with a complete B complex or multivitamin. Niacinamide doses often can be reduced once therapeutic effects are achieved if taken solely for stress and anxiety.
1. Imai S, Armstrong CM, Kaeberlein M, Guarente L; Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000 Feb
2. Tanny JC, Dowd GJ, Huang J, Hilz H, Moazed D; An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 1999 Dec 23;99(7):735-45
3. Kroger H, Hauschild A, Ohde M, Bache K, Voigt WP, Erlich W ; Enhancing the inhibitory effect of nicotinamide upon collagen II induced arthritis in mice using
N-acetylcysteine. Inflammation 1999 Apr;23(2):111-5
4. Amin AR, Abramson SB; The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Curr Opin Rheumatol 1998 May;10(3):263-8
5. McCarty MF, Russell AL; Niacinamide therapy for osteoarthritis—does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes? Med Hypotheses
1999 Oct; 53(4):350-60
6. Kolb H, Bukart V: Nicotinamide in type 1 diabetes. Mechanism of action revisited. Diabetes Care 1999 Mar;22 Suppl 2:B16-20
7. Pozzilli P, Visalli N, Ghirlanda G, Manna R, Andreani D; Nicotinamide increases C-peptide secretion in patients with recent onset type 1 diabetes. Diabet Med 1989 Sep-Oct;6(7):568-72
8. Vague P, Vialettes B, Lassmann-Vague V, Vallo J; Nicotinamide may extend remmision phase of insulin-dependent diabetes. The Lancet Mar 1987 ltr
9. Loginov AS, Matiushin BN, Astaf’eva OV, Nilova TV, Vinokurova LV; [Nicotinamide in combined treatment of chronic pancreatitis]. Ter Arkh 1999;71(8):43-6
10. Kroger H, Hauschild A, Ohde M, Bache K, Voigt WP, Thefeldt W, Kruger D; Nicotinamide and methionine reduce the liver toxic effect of methotrexate. Gen Pharmacol 1999 Aug;33(2):203-6
11. Hoffer A; Schizophrenia: an evolutionary defence against severe stress. J. of Orthomol Med 1994; Vol. 9(4):205-221
12. Burns DM, Ruddock MW, Walker MD, Allen JM, Kennovin GD, Hirst DG; Nicotinamide-inhibited vasoconstriction: lack of dependence on agonist signaling pathways. Eur J Pharmacol 1999 Jun 18;374(2):213-20
13. Akhundov RA, Sultanov AA, Gadzhily RA, Sadykhov RV; [Psychoregulating role of nicotinamide]. Biull Eksp Biol Med 1993 May;115(5):487-91
14. Mohler H, Pole P, Cumin R, Pieri L, Kettler R; Nicotinamide is a brain constituent with benzodiazepine-like actions. Nature 1979 Apr 5;278(5704):563-5
15. Kryzhanovskii GN, Shandra AA; Effect of diazepam and nicotinamide on convulsive activity of various types]. Farmakol Toksikol 1985 Jul-Aug;48(4):21-5
16. Wan FJ, Lin HC, Kang BH, Tseng CJ, Tung CS; D-amphetamine-induced depletion of energy and dopamine in the rat striatum is attenuated by nicotinamide pretreatment. Brain Res Bull 1999 Oct;50(3):167-71
17. Akhundov RA, Zagorevskii VA, Voronina TA; [Nootropic activity of nicotinamide and its structural analogs]. Biull Eksp Biol Med 1990 Oct;110(10):384-6
18. Werbach M. Nutritional Influences on Illness, 2nd ed., 1993 pp 114-115, 117 19.) Pero RW, Axelsson B, Siemann D, Chaplin D, Dougherty G; Newly discovered anti-inflammitory properties of the benzamides and nicotinamides. Mol Cell Biochem 1999 Mar;193(1-2):119-25
20. Ayoub IA, Lee EJ, Ogilvy CS, Beal MF, Maynard KI; Nicotinamide reduces infarction up to two hours after the onset of permanent focal cerebral ischemia in Wistar rats.
Neurosci Lett 1999 Jan 4;259(1):21-4
21. Paine AJ, Hockin LJ, Legg RF; Relationship between the ability of nicotinamide to maintain nicotinamide-adenine dinucleotide in rat liver cell culture and its effect on cytochrome P-450. Biochem J 1979 Nov 15; 184(2):461-3