Vitamins – Vitamin B3 (Niacin) – part 13

Niacin (also known as vitamin B3, nicotinic acid and vitamin PP) is an organic compound with the formula C6H5NO2 and, depending on the definition used, one of the 40 to 80 essential human nutrients.

Niacin is one of five vitamins (when lacking in human diet) associated with a pandemic deficiency disease: niacin deficiency (pellagra), vitamin C deficiency (scurvy), thiamin deficiency (beriberi), vitamin D deficiency (rickets), vitamin A deficiency (night blindness and other symptoms). Niacin has been used for over 50 years to increase levels of HDL in the blood and has been found to modestly decrease the risk of cardiovascular events in a number of controlled human trials.

This colorless, water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B3 include the corresponding amide, nicotinamide (“niacinamide”), where the carboxyl group has been replaced by a carboxamide group (CONH2), as well as more complex amides and a variety of esters.

Niacin cannot be directly converted to nicotinamide, but both compounds could be converted to NAD and NADP in vivo. Although the two are identical in their vitamin activity, nicotinamide does not have the same pharmacological effects (lipid modifying effects) as niacin. Nicotinamide does not reduce cholesterol or cause flushing. Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults. Niacin is a precursor to NAD+/NADH and NADP+/NADPH, which play essential metabolic roles in living cells.Niacin is involved in both DNA repair, and the production of steroid hormones in the adrenal gland.

CAS number 59-67-6 
PubChem 938
ChemSpider 913 
UNII 2679MF687A 
EC number 200-441-0
DrugBank DB00627
KEGG D00049 
MeSH Niacin
ChEBI CHEBI:15940 
IUPHAR ligand 1588
RTECS number QT0525000
ATC code C04AC01,C10AD02
Beilstein Reference 109591
Gmelin Reference 3340
3DMet B00073
Jmol-3D images Image 1
Image 2
Molecular formula C6NH5O2
Molar mass 123.1094 g mol-1
Appearance White, translucent crystals
Density 1.473 g cm-3
Melting point 237 °C, 510 K, 458 °F
Solubility in water 18 g L-1
log P 0.219
Acidity (pKa) 2.201
Basicity (pKb) 11.796
Isoelectric point 4.75
Refractive index (nD) 1.4936
Dipole moment 0.1271305813 D
Std enthalpy of
-344.9 kJ mol-1
Std enthalpy of
-2.73083 MJ mol-1
Routes of
Intramuscular, Oral
20-45 min
EU classification Irritant Xi
R-phrases R36/37/38
S-phrases S26, S36
NFPA 704
NFPA 704.svg
Flash point 193 °C
365 °C

Dietary needs

One recommended daily allowance of niacin is 2–12 mg/day for children, 14 mg/day for women, 16 mg/day for men, and 18 mg/day for pregnant or breast-feeding women. Tolerable upper intake levels (UL) for adult men and women is considered to be 35 mg/day by the Dietary Reference Intake system to avoid flushing. In general, niacin status is tested through urinary biomarkers, which are believed to be more reliable than plasma levels.


A man with pellagra, which is caused by a chronic lack of vitamin B3 in the diet

At present, niacin deficiency is sometimes seen in developed countries, and it is usually apparent in conditions of poverty, malnutrition, and chronic alcoholism. It also tends to occur in areas where people eat maize (corn, the only grain low in digestible niacin) as a staple food. A special cooking technique called nixtamalization is needed to increase the bioavailability of niacin during maize meal/flour production.

Mild niacin deficiency has been shown to slow metabolism, causing decreased tolerance to cold.

Severe deficiency of niacin in the diet causes the disease pellagra, which is characterized by diarrhea, dermatitis, and dementia, as well as “necklace” lesions on the lower neck, hyperpigmentation, thickening of the skin, inflammation of the mouth and tongue, digestive disturbances, amnesia, delirium, and eventually death, if left untreated. Common psychiatric symptoms of niacin deficiency include irritability, poor concentration, anxiety, fatigue, restlessness, apathy, and depression. Studies have indicated that, in patients with alcoholic pellagra, niacin deficiency may be an important factor influencing both the onset and severity of this condition. Patients with alcoholism typically experience increased intestinal permeability, leading to negative health outcomes.

Hartnup’s disease is a hereditary nutritional disorder resulting in niacin deficiency. This condition was first identified in the 1950s by the Hartnup family in London. It is due to a deficit in the intestines and kidneys, making it difficult for the body to break down and absorb dietary tryptophan. The resulting condition is similar to pellagra, including symptoms of red, scaly rash, and sensitivity to sunlight. Oral niacin is given as a treatment for this condition in doses ranging from 40–200 mg, with a good prognosis if identified and treated early. Niacin synthesis is also deficient in carcinoid syndrome, because of metabolic diversion of its precursor tryptophan to form serotonin.

Lipid-modifying effects

Niacin binds to and stimulates a G-protein-coupled receptor, GPR109A, which causes the inhibition of fat breakdown in adipose tissue. Nicotinamide does not bind this receptor which explains why it does not affect blood lipid levels. Lipids that are liberated from adipose tissue are normally used to build very-low-density lipoproteins (VLDL) in the liver, which are precursors of low-density lipoprotein (LDL) or “bad” cholesterol. Because niacin blocks the breakdown of fats, it causes a decrease in free fatty acids in the blood and, as a consequence, decreases the secretion of VLDL and cholesterol by the liver.

By lowering VLDL levels, niacin also increases the level of high-density lipoprotein (HDL) or “good” cholesterol in blood, and therefore it is sometimes prescribed for people with low HDL, who are also at high risk of a heart attack.

The ARBITER 6-HALTS study, reported at the 2009 annual meeting of the American Heart Association and in the New England Journal of Medicine concluded that, when added to statins, 2000 mg/day of extended-release niacin was more effective than ezetimibe (Zetia) in reducing carotid intima-media thickness, a marker of atherosclerosis. Additionally, a recent meta-analysis covering 11 randomized controlled clinical trials found positive effects of niacin alone or in combination on all cardiovascular events and on atherosclerosis evolution.

However, a 2011 study (AIM-HIGH) was halted early because patients showed no decrease in cardiovascular events, but did experience an increase in the risk of stroke. These patients already had LDL levels well controlled by a statin drug, and the aim of the study was to evaluate extended-release niacin (2000 mg per day) to see if raising HDL levels had an additional positive effect on risk. In this study, it did not have such an effect, and appeared to increase stroke risk. The role of niacin in patients whose LDL is not well-controlled (as in the majority of previous studies with niacin) is still under study and debate. However, it does not seem to offer benefits via raising HDL, in patients already lowering LDL by taking a statin.


Pharmacological doses of niacin (1.5 – 6 g per day) lead to side effects that can include dermatological conditions such as skin flushing and itching, dry skin, and skin rashes including eczema exacerbation and acanthosis nigricans. Some of these symptoms are generally related to niacin’s role as the rate limiting cofactor in the histidine decarboxylase enzyme which converts l-histidine into histamine. H1 and H2 receptor mediated histamine is metabolized via a sequence of mono (or di-) amine oxidase and COMT into methylhistamine which is then conjugated through the liver’s CYP450 pathways. Persistent flushing and other symptoms may indicate deficiencies in one or more of the cofactors responsible for this enzymatic cascade. Gastrointestinal complaints, such as dyspepsia (indigestion), nausea and liver toxicity fulminant hepatic failure, have also been reported. Side effects of hyperglycemia, cardiac arrhythmias and “birth defects in experimental animals” have also been reported.

Flushing lasts for about 15 to 30 minutes, and is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing. This effect is mediated by GPR109A-mediated prostaglandin release from the Langerhans cells of the skin and can be blocked by taking 300 mg of aspirin half an hour before taking niacin, by taking one tablet of ibuprofen per day or by co-administering the prostaglandin receptor antagonist laropiprant. Taking the niacin with meals also helps reduce this side effect. After several weeks of a consistent dose, most patients no longer flush. Slow- or “sustained”-release forms of niacin have been developed to lessen these side effects. One study showed the incidence of flushing was significantly lower with a sustained release formulation though doses above 2 g per day have been associated with liver damage, in particular, with slow-release formulations. Flushing is often thought to involve histamine, but histamine has been shown not to be involved in the reaction.Prostaglandin (PGD2) is the primary cause of the flushing reaction, with serotonin appearing to have a secondary role in this reaction.

Although high doses of niacin may elevate blood sugar, thereby worsening diabetes mellitus, recent studies show the actual effect on blood sugar to be only 5–10%. Patients with diabetes who continued to take anti-diabetes drugs containing niacin did not experience major blood glucose changes. Thus looking at the big picture, niacin continues to be recommended as a drug for preventing cardiovascular disease in patients with diabetes.

Hyperuricemia is another side effect of taking high-dose niacin, and may exacerbate gout.

Niacin in doses used to lower cholesterol levels has been associated with birth defects in laboratory animals, with possible consequences for infant development in pregnant women.

Niacin, particularly the time-release variety, at extremely high doses can cause acute toxic reactions. Extremely high doses of niacin can also cause niacin maculopathy, a thickening of the macula and retina, which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases.


Nicotinamide may be obtained from the diet where it is present primarily as NAD+ and NADP+. These are hydrolysed in the intestine and the resulting nicotinamide is absorbed either as such, or following its hydrolysis to nicotinic acid. Nicotinamide is present in nature in only small amounts. In unprepared foods, niacin is present mainly in the form of the cellular pyridine nucleotides NAD and NADP. Enzymatic hydrolysis of the co-enzymes can occur during the course of food preparation. Boiling releases most of the total niacin present in sweet corn as nicotinamide (up to 55 mg/kg).

Inositol hexanicotinate

One form of dietary supplement is inositol hexanicotinate (IHN), which is inositol that has been esterified with niacin on all six of inositol’s alcohol groups. IHN is usually sold as “flush-free” or “no-flush” niacin in units of 250, 500, or 1000 mg/tablets or capsules. It is sold as an over-the-counter formulation, and often is marketed and labeled as niacin, thus misleading consumers into thinking they are getting the active form of the medication. While this form of niacin does not cause the flushing associated with the immediate-release products, the evidence that it has lipid-modifying functions is contradictory, at best. As the clinical trials date from the early 1960s (Dorner, Welsh) or the late 1970s (Ziliotto, Kruse, Agusti), it is difficult to assess them by today’s standards. One of the last of those studies affirmed the superiority of inositol and xantinol esters of nicotinic acid for reducing serum free fatty acid, but other studies conducted during the same period found no benefit. Studies explain that this is primarily because “flush-free” preparations do not contain any free nicotinic acid. A more recent placebo-controlled trial was small (n=11/group), but results after three months at 1500 mg/day showed no trend for improvements in total cholesterol, LDL-C, HDL-C or triglycerides. Thus, so far there is not enough evidence to recommend IHN to treat dyslipidemia. Furthermore, the American Heart Association and the National Cholesterol Education Program both take the position that only prescription niacin should be used to treat dyslipidemias, and only under the management of a physician. The reason given is that niacin at effective intakes of 1500–3000 mg/day can also potentially have severe adverse effects. Thus liver function tests to monitor liver enzymes are necessary when taking therapeutic doses of niacin, including alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT).

Biosynthesis and chemical synthesis


The liver can synthesize niacin from the essential amino acid tryptophan, requiring 60 mg of tryptophan to make one mg of niacin.The 5-membered aromatic heterocycle of tryptophan is cleaved and rearranged with the alpha amino group of tryptophan into the 6-membered aromatic heterocycle of niacin. Riboflavin, vitamin B6 and iron are required in some of the reactions involved in the conversion of tryptophan to NAD.

Several million kilograms of niacin are manufactured each year, starting from 3-methylpyridine.


In addition to its effects as NAD and NADP, niacin may have additional effects by receptor activation. The receptor for niacin is a G protein-coupled receptor called HM74A. It couples to the Gi alpha subunit.

Food sources

Niacin is found in variety of foods, including liver, chicken, beef, fish, cereal, peanuts and legumes, and is also synthesized from tryptophan, an essential amino acid found in most forms of protein.

Animal products:

Fruits and vegetables:





Niacin was first described by chemist Hugo Weidel in 1873 in his studies of nicotine. The original preparation remains useful: The oxidation of nicotine using nitric acid. Niacin was extracted from livers by biochemist Conrad Elvehjem in 1937, who later identified the active ingredient, then referred to as the “pellagra-preventing factor” and the “anti-blacktongue factor.” Soon after, in studies conducted in Alabama and Cincinnati, Dr. Tom Spies found that nicotinic acid cured the sufferers of pellagra.

When the biological significance of nicotinic acid was realized, it was thought appropriate to choose a name to dissociate it from nicotine, to avoid the perception that vitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins. The resulting name ‘niacin’ was derived from nicotinic acid + vitamin.

Carpenter found in 1951 that niacin in corn is biologically unavailable, and can be released only in very alkaline lime water of pH 11. This process, known as nixtamalization, was discovered by the prehistoric civilizations of Mesoamerica.

Niacin is referred to as vitamin B3 because it was the third of the B vitamins to be discovered. It has historically been referred to as “vitamin PP” or “vitamin P-P”.


As of August 2008, a combination of niacin with laropiprant is being tested in a clinical trial. Laropiprant reduces facial flushes induced by niacin.


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