Niacinamide Abstracts 9


Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin.
            (Bissett et al., 2004) Download
Previous clinical testing of topical niacinamide (vitamin B3) has revealed a broad array of improvements in the appearance of aging facial skin. The study reported here was done to confirm some of those previous observations and to evaluate additional end points such as skin anti-yellowing. Caucasian female subjects (n = 50, aged 40-60 years) participated in a 12-week, double-blind, placebo-controlled, split-face, left-right randomized clinical study assessing two topical products: moisturizer control product versus the same moisturizer product containing 5% niacinamide. Niacinamide was well tolerated by the skin and provided significant improvements versus control in end points evaluated previously: fine lines/wrinkles, hyperpigmentation spots, texture, and red blotchiness. In addition, skin yellowing (sallowness) versus control was significantly improved. The mechanism by which this array of benefits is achieved with niacinamide is discussed.

A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients.
            (Cheng et al., 2008) Download
BACKGROUND AND OBJECTIVES:  Niacinamide inhibits intestinal sodium/phosphorus transporters and reduces serum phosphorus in open-label studies. A prospective, randomized, double-blind, placebo-controlled crossover trial was performed for assessment of the safety and efficacy of niacinamide. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:  Hemodialysis patients with phosphorus levels > or =5.0 mg/dl were randomly assigned to 8 wk of niacinamide or placebo, titrated from 500 to 1500 mg/d. After a 2-wk washout period, patients switched to 8 wk of the alternative therapy. Vitamin D analogs and calcimimetics were held constant; phosphorus binders were not changed unless safety criteria were met. RESULTS:  Thirty-three patients successfully completed the trial. Serum phosphorus fell significantly from 6.26 to 5.47 mg/dl with niacinamide but not with placebo (5.85 to 5.98 mg/dl). A concurrent fall in calcium-phosphorus product was seen with niacinamide, whereas serum calcium, intact parathyroid hormone, uric acid, platelet, triglyceride, LDL, and total cholesterol levels remained stable in both arms. Serum HDL levels rose with niacinamide (50 to 61 mg/dl but not with placebo. Adverse effects were similar between both groups. Among patients who were > or =80% compliant, results were similar, although the decrease in serum phosphorus with niacinamide was more pronounced (6.45 to 5.28 mg/dl) and the increase in HDL approached significance (49 to 58 mg/dl). CONCLUSIONS:  In hemodialysis patients, niacinamide effectively reduces serum phosphorus when co-administered with binders and results in a potentially advantageous increase in HDL cholesterol. Further study in larger randomized trials and other chronic kidney disease populations is indicated.

Antilipaemic effect of nicotinamide.
            (Dalton, 1967) Download
The antilipaemic effect of nicotinic acid is well known1 and the clinical value of this compound as an agent for lowering the content of cholesterol has been demonstrated. Although many explanations have been offered, the mechanism by which nicotinic acid exerts its antilipaemic effect is not known. It is generally agreed, however, that the effect of decreasing cholesterol is unrelated to this compound's known vitamin role as a precursor of pyridine nucleotides, because nicotinamide, which is more readily incorporated into pyridine nucleotides, has little effect on serum cholesterol concentrations in man.

Relationship of nicotinamide and nicotinic acid to hypolipidemia.
            (Dalton et al., 1970) Download
Acute administration of nicotinamide-like nicotinic acid caused a decrease of serum cholesterol, triglycerides and free-fatty acids in the fasted rat. However, the dose of nicotinamide required for these effects was much larger than that of nicotinic acid. The serum half-life of nicotinamide was found to be three times greater than nicotinic acid. The duration of hypolipidemic activity of nicotinamide was longer than that of nicotinic acid. Nicotinic acid was found to accumulate in the serum in amounts proportional to the injected dose of nicotinamide. The concentration of nicotinic acid in the serum after nicotinamide treatment was larger than minimal serum concentrations necessary to produce free-fatty acid lowering. It was concluded that the lipopenic action of nicotin- amide was indirect and was dependent upon deamidation to nicotinic acid. It seems from these observations that NAM might offer some therapeutic advantage over NA as a hypolipidemic agent. Clinically, 3-6 g/day of nicotinic acid are used. At these doses, it appears to lower all serum lipid constituents. Hypolipidemic data in vivo showed an effective dose ratio for NAM to NA of about three. Extrapolation of this ratio to man would necessitate a dose of 9-18 g/day. It is of interest to note that the dosage of either NA and NAM recommended by Hoffe? is 3-18 g/day for treatment of schizophrenia. Such a large dose, if tolerated, would have the advantage of less frequent administration because of the longer half-life of nicotinamide. Nicotinamide administration may also eliminate many of the distressing side effects observed after nicotinic acid therapy.


Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.
            (Goldberg et al., 2000) Download
This multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase. Significant decreases from baseline in levels of LDL cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%, respectively, at the 3,000-mg/day dose. Significant increases from baseline in levels of high-density lipoprotein cholesterol became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching 30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000-mg dose. The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo. Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile.

Niacin: antipellagra factor, hypocholesterolemic agent. Model of nutrition research yesterday and today.
            (Goldsmith, 1965) Download
It appeared possible that the action of niacin might be related to an increased demand for the production of aminoacetic acid (glycine). Niacin is conjugated with aminoacetic acid to form nicotinuric acid, which is a major excretory product.

Use of nicotinic acid and/or nicotinamide in high doses to treat schizophrenia.
            (Hoffer, 1966) Download
In 1952, with Dr. H. Osmond, I developed the adrenochrome hypothesis of schizophrenia. Briefly, we believe that adrenochrome, the oxidatiion product of adrenaline, had something to do with the genesis of schizophrenia. In order to develop a therapy, we decided to give massive doses of nicotinic acid to cut down the production of adrenaline. Today it seems clear that nicotinic acid works by other mechanisms. I also use nicotinamide.

The effect of niacinamide on osteoarthritis: a pilot study.
            (Jonas et al., 1996) Download
OBJECTIVE:  To evaluate the effect of niacinamide, on selected parameters of osteoarthritis using a double-blind, placebo controlled study design. METHODS:  Seventy two patients with osteoarthritis were randomized for treatment with niacinamide or an identical placebo for 12 weeks. Outcome measures included global arthritis impact and pain, joint range of motion and flexibility, erythrocyte sedimentation rate, complete blood count, liver function tests, cholesterol, uric acid, and fasting blood sugar. Compliance was monitored with a pill record sheet and interview. RESULTS:  Global arthritis impact improved by 29% (95% confidence interval [CI] 6, 46) in subjects on niacinamide and worsened by 10% in placebo subjects (p = 0.04). Pain levels did not change but those on niacinamide reduced their anti-inflammatory medications by 13% (95% CI 9, 94; p = 0.01). Niacinamide reduced erythrocyte sedimentation rate by 22% (95% CI 6, 51; p < 0.005) and increased joint mobility by 4.5 degrees over controls (8 degrees vs 3.5 degrees; p = 0.04). Side effects were mild but higher in the niacinamide group (40% vs 27%, p = 0.003). CONCLUSION:  This study indicates that niacinamide may have a role in the treatment of osteoarthritis. Niacinamide improved the global impact of osteoarthritis, improved joint flexibility, reduced inflammation, and allowed for reduction in standard anti-inflammatory medications when compared to placebo. More extensive evaluation of niacinamide in arthritis is warranted.

Randomized, double-blinded, placebo controlled study to assess the effect of topical 1% nicotinamide on actinic keratoses.
(Moloney et al., 2010) Download
Participants were randomized to apply 1% nicotinamide or vehicle twice daily. Primary endpoints were AK count at 3 and 6 months compared with baseline. Of 41 patients screened, four developed skin cancers before commencement, five failed to attend and two were ineligible. The remaining 26 men and four women were randomized to receive nicotinamide (n = 13) or vehicle (n = 17). Two men (vehicle) discontinued at 3 months (one developed melanoma, one liver failure). A basal cell carcinoma (BCC) occurred in one nicotinamide-treated patient and three SCCs, three BCCs and a melanoma were identified in four vehicle-treated patients. At 3 months there was a 10.0 ± 12.0% reduction in AKs with vehicle (P = 0.3) compared with 21.8 ± 10.0% with nicotinamide (P = 0.04; Fig. 1). This difference was not maintained at 6 months (reduction from baseline 22.4 ± 9.6%, P = 0.06 with vehicle; 24.6 ± 15.4% with nicotin- amide, P = 0.1). No site-specific differences were seen. In men, there was a 1.0 ± 13.0% reduction in AKs with vehicle (n = 14, P = 0.8) and a reduction of 17.7 ± 9.5% with nicotinamide (n = 12, P < 0.05) at 3 months. This difference was less marked at 6 months (10.4 ± 9.2%, n = 12, P = 0.4; and 19.5 ± 15.1%, n = 12, P = 0.1 with vehicle and nicotinamide, respectively).  This study found a more rapid rate of AK resolution with nicotinamide compared with vehicle in a group of heavily sun-damaged individuals.

Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme.
            (Pissios, 2017) Download
Nicotinamide (NAM) N-methyltransferase (NNMT) was originally identified as the enzyme responsible for the methylation of NAM, one of the forms of vitamin B3. Methylated NAM is eventually excreted from the body. Recent evidence has expanded the role of NNMT beyond clearance of excess vitamin B3. NNMT has been implicated in the regulation of multiple metabolic pathways in tissues such as adipose and liver as well as cancer cells through the consumption of methyl donors and generation of active metabolites. This review examines recent findings regarding the function of NNMT in physiology and disease and highlights potential new avenues for therapeutic intervention. Finally, key gaps in our knowledge about this enzymatic system and future areas of investigation are discussed.

Testing a mechanism of control in human cholesterol metabolism: relation of arginine and glycine to insulin and glucagon.
            (Sanchez et al., 1988) Download
Eight men were given 2 casein meals, one with and one without a supplement of arginine and glycine, to measure the effect on plasma amino acids, insulin and glucagon. Supplementation resulted in increased levels of plasma glucagon, glycine and arginine, a tendency to decreased insulin and significantly lower insulin/glucagon ratio, tryptophan and tyrosine. The data suggest that insulin and glucagon, which control cholesterol metabolism, respond to dietary and postprandial plasma amino acid levels of arginine and glycine.

Plasma amino acids and the insulin/glucagon ratio as an explanation for the dietary protein modulation of atherosclerosis.
            (Sanchez and Hubbard, 1991) Download
The amino acid composition of the diet influences the postprandial levels of plasma amino acids along with the hormones insulin and glucagon in humans fed single test meals identical in composition except for protein source. Soy protein (hypocholesterolemic), versus casein (hypercholesterolemic), contains a higher amount of arginine and glycine and induces an increase in postprandial arginine and glycine. Soy protein induces a low postprandial insulin/glucagon ratio in both hypercholesterolemic and normocholesterolemic subjects. Casein induces a high postprandial insulin/glucagon ration among hypercholesterolemic subjects. Amino acids such as arginine and glycine are associated with a decrease, while lysine and branched-chain amino acids are associated with increased serum cholesterol levels. Our data are consistent with the hypothesis that the control of cholesterol by insulin and glucagon is regulated by dietary and plasma amino acids. From this hypothesis the insulin/glucagon ratio is proposed as an early metabolic index of the effect of dietary proteins on serum cholesterol levels, a risk factor and a common mechanism through which dietary and lifestyle factors influence cardiovascular disease.

Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials.
(Surjana et al., 2012) Download
Healthy, immune-competent volunteers with >4 palpable AKs (face, scalp and upper limbs) were recruited. Participants were randomly assigned (1:1) to take nicotinamide 500 mg (Nature’s Own, Virginia, Queensland, Australia) or matched placebo twice daily (Study 1) or once daily (Study 2) for 4 months. At baseline, 2 and 4 months, palp- able AKs were identified visually and by touch by a blinded observer (DS), counted and documented on a body grid chart. At baseline and 2 months, full blood count, creatinine, and liver function were assessed. A total of 35 patients were enrolled in Study 1. One withdrew (nicotinamide) at 2 months because of invasive squamous cell carcinoma (SCC), but returned for his 4-month AK count. A total of 41 patients were enrolled in Study 2; two withdrew from treatment (placebo) soon after their baseline counts because of nursing-home placement, but agreed to follow up AK counts. Two nicotinamide participants withdrew from follow-up for personal reasons soon after enrolment. A 35% relative reduction in AK count at 4 months (95% confidence interval (CI): 18–48%; P 1⁄4 0.0006) was estimated from Study 1 (with similar results at 2 months). A 29% relative reduction in AK count at 4 months (95% CI: 11–44%; P 1⁄4 0.005) was estimated from Study 2 (with smaller but significant differences observed at 2 months). The results of these phase II studies suggest nicotinamide is effective in reducing AKs and shows promise for skin cancer chemoprevention.

Nicotinamide suppresses hyperphosphatemia in hemodialysis patients.
            (Takahashi et al., 2004) Download
BACKGROUND:  The use of calcium- or aluminum-based phosphate binders against hyperphosphatemia is limited by the adverse effects of hypercalcemia or aluminum toxicity in long-term hemodialysis. Because nicotinamide is an inhibitor of sodium-dependent phosphate cotransport in rat renal tubule and small intestine, we examined whether nicotinamide reduces serum levels of phosphorus and intact parathyroid hormone (iPTH) in patients undergoing hemodialysis. METHODS:  Sixty-five hemodialysis patients with a serum phosphorus level of more than 6.0 mg/dL after a 2-week washout of calcium carbonate were enrolled in this study. Nicotinamide was administered for 12 weeks. The starting dose was 500 mg/day, and the dose was increased by 250 mg/day every 2 weeks until serum phosphorus levels were well controlled at less than 6.0 mg/dL. A 2-week posttreatment washout period followed the cessation of nicotinamide. Blood samples were collected every week for measurement of serum calcium, phosphorus, lipids, iPTH, and blood nicotinamide adenine dinucleotide (NAD). RESULTS:  The mean dose of nicotinamide was 1080 mg/day. The mean blood NAD concentration increased from 9.3 +/- 1.9 nmol/105 erythrocytes before treatment to 13.2 +/- 5.3 nmol/105 erythrocytes after treatment (P < 0.01). The serum phosphorus concentration increased from 5.4 +/- 1.5 mg/dL to 6.9 +/- 1.5 mg/dL with the pretreatment washout, then decreased to 5.4 +/- 1.3 mg/dL after the 12-week nicotinamide treatment (P < 0.0001), and rose again to 6.7 +/- 1.6 mg/dL after the posttreatment washout. Serum calcium levels decreased during the pretreatment washout from 9.1 +/- 0.8 mg/dL to 8.7 +/- 0.7 mg/dL with the cessation of calcium carbonate. No significant changes in serum calcium levels were observed during nicotinamide treatment. Median serum iPTH levels increased with pretreatment washout from 130.0 (32.8 to 394.0) pg/mL to 200.0 (92.5 to 535.0) pg/mL and then decreased from the maximum 230.0 (90.8 to 582.0) pg/mL to 150.0 (57.6 to 518.0) pg/mL after the 12-week nicotinamide treatment (P < 0.05). With nicotinamide, serum high-density lipoprotein (HDL) cholesterol concentrations increased from 47.4 +/- 14.9 mg/dL to 67.2 +/- 22.3 mg/dL (P < 0.0001) and serum low-density lipoprotein (LDL) cholesterol concentrations decreased from 78.9 +/- 18.8 mg/dL to 70.1 +/- 25.3 mg/dL (P < 0.01); serum triglyceride levels did not change significantly. CONCLUSION:  Nicotinamide may provide an alternative for controlling hyperphosphatemia and hyperparathyroidism without inducing hypercalcemia in hemodialysis patients.



Bissett, DL, et al. (2004), ‘Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin.’, Int J Cosmet Sci, 26 (5), 231-38. PubMed: 18492135
Cheng, SC, et al. (2008), ‘A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients.’, Clin J Am Soc Nephrol, 3 (4), 1131-38. PubMed: 18385391
Dalton, C (1967), ‘Antilipaemic effect of nicotinamide.’, Nature, 216 (5117), 825. PubMed: 4229354
Dalton, C, TC VanTrabert, and JX Dwyer (1970), ‘Relationship of nicotinamide and nicotinic acid to hypolipidemia.’, Biochem Pharmacol, 19 (9), 2609-19. PubMed: 4249087
Goldberg, A, et al. (2000), ‘Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.’, Am J Cardiol, 85 (9), 1100-5. PubMed: 10781759
Goldsmith, GA (1965), ‘Niacin: antipellagra factor, hypocholesterolemic agent. Model of nutrition research yesterday and today.’, JAMA, 194 (2), 167-73. PubMed: 5319581
Hoffer, A (1966), ‘Use of nicotinic acid and/or nicotinamide in high doses to treat schizophrenia.’, Can J Psychiatr Nurs, 7 (8), 5-6. PubMed: 4224196
Jonas, WB, CP Rapoza, and WF Blair (1996), ‘The effect of niacinamide on osteoarthritis: a pilot study.’, Inflamm Res, 45 (7), 330-34. PubMed: 8841834
Moloney, F., et al. (2010), ‘Randomized, double-blinded, placebo controlled study to assess the effect of topical 1% nicotinamide on actinic keratoses’, Br J Dermatol, 162 (5), 1138-39. PubMed: 20199551
Pissios, P (2017), ‘Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme.’, Trends Endocrinol Metab, 28 (5), 340-53. PubMed: 28291578
Sanchez, A, et al. (1988), ‘Testing a mechanism of control in human cholesterol metabolism: relation of arginine and glycine to insulin and glucagon.’, Atherosclerosis, 71 (1), 87-92. PubMed: 3288227
Sanchez, A and RW Hubbard (1991), ‘Plasma amino acids and the insulin/glucagon ratio as an explanation for the dietary protein modulation of atherosclerosis.’, Med Hypotheses, 35 (4), 324-29. PubMed: 1943885
Surjana, D., et al. (2012), ‘Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials’, J Invest Dermatol, 132 (5), 1497-500. PubMed: 22297641
Takahashi, Y, et al. (2004), ‘Nicotinamide suppresses hyperphosphatemia in hemodialysis patients.’, Kidney Int, 65 (3), 1099-104. PubMed: 14871431