Vitamin B3

Niacin, also known as vitamin B₃, is a vitamin family that includes three forms or vitamers: nicotinamide (niacinamide), niacin (nicotinic acid), and nicotinamide riboside. All three forms of vitamin B₃ are converted within the body to nicotinamide adenine dinucleotide (NAD). NAD is required for human life and people are unable to make it within their bodies without either vitamin B₃ or tryptophan. Nicotinamide riboside was identified as a form of vitamin B₃ in 2004.

Niacin (the nutrient) can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variety of whole and processed foods, with highest contents in fortified packaged foods, meat, poultry, red fish such as tuna and salmon, lesser amounts in nuts, legumes and seeds. Niacin as a dietary supplement is used to treat pellagra, a disease caused by niacin deficiency. Signs and symptoms of pellagra include skin and mouth lesions, anemia, headaches, and tiredness. Many countries mandate its addition to wheat flour or other food grains, thereby reducing the risk of pellagra.

The amide derivative nicotinamide (niacinamide) is a component of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP+). Although niacin and nicotinamide are identical in their vitamin activity, nicotinamide does not have the same pharmacological, lipid-modifying effects or side effects as niacin, i.e., when niacin takes on the -amide group, it does not reduce cholesterol nor cause flushing. Nicotinamide is recommended as a treatment for niacin deficiency because it can be administered in remedial amounts without causing the flushing, considered an adverse effect.

In the past, the group was loosely referred to as vitamin B₃ complex.

Mechanism of action

NAD, along with its phosphorylated variant nicotinamide adenine dinucleotide phosphate (NADP), are utilized in transfer reactions within DNA repair and calcium mobilization. NAD also plays a critical role in human metabolism, acting as a coenzyme in both glycolysis and the Krebs cycle.

Vitamin deficiency

Main article: Pellagra

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

Severe deficiency of niacin in the diet causes the disease pellagra, characterized by diarrhea, sun-sensitive dermatitis involving hyperpigmentation and thickening of the skin (see image), inflammation of the mouth and tongue, delirium, dementia, and if left untreated, death. Common psychiatric symptoms include irritability, poor concentration, anxiety, fatigue, loss of memory, restlessness, apathy, and depression. The biochemical mechanism(s) for the observed deficiency-caused neurodegeneration are not well understood, but may rest on: A) the requirement for nicotinamide adenine dinucleotide (NAD+) to suppress the creation of neurotoxic tryptophan metabolites, B) inhibition of mitochondrial ATP generation, resulting in cell damage; C), activation of the poly (ADP-ribose) polymerase (PARP) pathway, as PARP is a nuclear enzyme involved in DNA repair, but in the absence of NAD+ can lead to cell death; D) reduced synthesis of neuro-protective brain-derived neurotrophic factor or its receptor tropomyosin receptor kinase B; or E) changes to genome expression directly due to the niacin deficiency.

Niacin deficiency is rarely seen in developed countries, and it is more typically associated with poverty, malnutrition or malnutrition secondary to chronic alcoholism. It also tends to occur in less developed areas where people eat maize (corn) as a staple food, as maize is the only grain low in digestible niacin. A cooking technique called nixtamalization i.e., pretreating with alkali ingredients, increases the bioavailability of niacin during maize meal/flour production. For this reason, people who consume corn as tortillas or hominy are at less risk of niacin deficiency.

For treating deficiency, the World Health Organization (WHO) recommends administering niacinamide(i.e. nicotinamide) instead of niacin, to avoid the flushing side effect commonly caused by the latter. Guidelines suggest using 300 mg/day for three to four weeks. Dementia and dermatitis show improvement within a week. Because deficiencies of other B-vitamins may be present, the WHO recommends a multi-vitamin in addition to the niacinamide.

Hartnup disease is a hereditary nutritional disorder resulting in niacin deficiency. It is named after an English family with a genetic disorder that resulted in a failure to absorb the essential amino acid tryptophan, tryptophan being a precursor for niacin synthesis. The symptoms are similar to pellagra, including red, scaly rash and sensitivity to sunlight. Oral niacin or niacinamide is given as a treatment for this condition in doses ranging from 50 to 100 mg twice a day, 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.

Measuring vitamin status

Plasma concentrations of niacin and niacin metabolites are not useful markers of niacin status. Urinary excretion of the methylated metabolite N1-methyl-nicotinamide is considered reliable and sensitive. The measurement requires a 24-hour urine collection. For adults, a value of less than 5.8 μmol/day represent deficient niacin status and 5.8 to 17.5 μmol/day represents low. According to the World Health Organization, an alternative mean of expressing urinary N1-methyl-nicotinamide is as mg/g creatinine in a 24-hour urine collection, with deficient defined as <0.5, low 0.5-1.59, acceptable 1.6-4.29, and high >4.3 Niacin deficiency occurs before the signs and symptoms of pellagra appear. Erythrocyte nicotinamide adenine dinucleotide (NAD) concentrations potentially provide another sensitive indicator of niacin depletion, although definitions of deficient, low and adequate have not been established. Lastly, plasma tryptophan decreases on a low niacin diet because tryptophan converts to niacin. However, low tryptophan could also be caused by a diet low in this essential amino acid, so it is not specific to confirming vitamin status.

Dietary recommendations

Dietary recommendations

Australia and New Zealand Age group RDI for niacin (mg NE/day) Upper level of intake Infants 0–6 months 2 mg/d preformed niacin* ND Infants 7–12 months 4 mg/d NE* 1–3 6 10 4–8 8 15 9–13 12 20 14–18 – 30 19+ – 35 Females 14+ 14 – Males 14+ 16 Pregnant females 14–50 18 – Pregnant females 14–18 – 30 Pregnant females 19–50 – 35 Lactating females 14–50 17 – Lactating females 14–18 – 30 Lactating females 19–50 – 35 * Adequate Intake for infants Canada Age group (years) RDA of niacin (mg NE/d) Tolerable upper intake level 0–6 months 2 mg/d preformed niacin* ND 7–12 months 4 mg/d NE* 1–3 6 10 4–8 8 15 9–13 12 20 Females 14–18 14 30 Males 14–18 16 Females 19+ 14 35 Males 19+ 16 Pregnant females <18 18 30 Pregnant females 18–50 18 35 Lactating females <18 17 30 Lactating females 18–50 17 35 European Food Safety Authority Gender Adequate Intake (mg NE/MJ) Females 1.3 Males 1.6 Age (years) Tolerable upper limit of Nicotinic acid (mg/day) Tolerable upper limit of Nicotinamide (mg/day) 1–3 2 150 4–6 3 220 7–10 4 350 11–14 6 500 15–17 8 700 United States Age group RDA for niacin (mg NE/day) Tolerable upper intake level Infants 0–6 months 2* ND** Infants 6–12 months 4* 1–3 6 10 4–8 8 15 9–13 12 20 Females 14–18 14 30 Males 14–18 16 30 Females 19+ 14 35 Males 19+ 16 35 Pregnant females 14–18 18 30 Pregnant females 19–50 18 35 Lactating females 14–18 17 30 Lactating females 19–50 17 35 * Adequate intake for infants, as an RDA has yet to be established ** Not possible to establish; source of intake should be formula and food only

The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for niacin in 1998, also Tolerable upper intake levels (ULs). In lieu of an RDA, Adequate Intakes (AIs) are identified for populations for which there is not sufficient evidence to identify a dietary intake level that is sufficient to meet the nutrient requirements of most people. (see table).

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values (DRV), with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. For the EU, AIs and ULs have the same definition as in the US, except that units are milligrams per megajoule (MJ) of energy consumed rather than mg/day. For women (including those pregnant or lactating), men and children the PRI is 1.6 mg per megajoule. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories should be consuming 16 mg niacin. This is comparable to US RDAs (14 mg/day for adult women, 16 mg/day for adult men).

ULs are established by identifying amounts of vitamins and minerals that cause adverse effects, and then selecting as an upper limit amounts that are the "maximum daily intake unlikely to cause adverse health effects." Regulatory agencies from different countries do not always agree. For the US, 30 or 35 mg for teenagers and adults, less for children. The EFSA UL for adults is set at 10 mg/day - about one-third of the US value. For all of the government ULs, the term applies to niacin as a supplement consumed as one dose, and is intended as a limit to avoid the skin flush reaction. This explains why for EFSA, the recommended daily intake can be higher than the UL.

Both the DRI and DRV describe amounts needed as niacin equivalents (NE), calculated as 1 mg NE = 1 mg niacin or 60 mg of the essential amino acid tryptophan. This is because the amino acid is utilized to synthesize the vitamin.

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For niacin labeling purposes 100% of the Daily Value is 16 mg. Prior to 27 May 2016 it was 20 mg, revised to bring it into agreement with the RDA. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at Reference Daily Intake.

Sources

Niacin is found in a variety of whole and processed foods, including fortified packaged foods, meat from various animal sources, seafoods, and spices. In general, animal-sourced foods provide about 5–10 mg niacin per serving, although dairy foods and eggs have little. Some plant-sourced foods such as nuts, legumes and grains provide about 2–5 mg niacin per serving, although in some grain products this naturally present niacin is largely bound to polysaccharides and glycopeptides, making it only about 30% bioavailable. Fortified food ingredients such as wheat flour have niacin added, which is bioavailable. Among whole food sources with the highest niacin content per 100 grams:

Source	Amount (mg / 100g)
Nutritional yeast Serving = 2 Tbsp (16 g) contains 56 mg	350
Tuna, yellowfin	22.1
Peanuts	14.3
Peanut butter	13.1
Bacon	10.4
Tuna, light, canned	10.1
Salmon	10.0
Turkey depending on what part, how cooked	7-12
Chicken depending on what part, how cooked	7-12

Source	Amount (mg / 100g)
Beef depending on what part, how cooked	4-8
Pork depending on what part, how cooked	4-8
Sunflower seeds	7.0
Tuna, white, canned	5.8
Almonds	3.6
Mushrooms, white	3.6
Cod fish	2.5
Rice, brown	2.5
Hot dogs	2.0

Source	Amount (mg / 100g)
Avocado	1.7
Potato, baked, with skin	1.4
Corn (maize)	1.0
Rice, white	0.5
Kale	0.4
Eggs	0.1
Milk	0.1
Cheese	0.1
Tofu	0.1

Vegetarian and vegan diets can provide adequate amounts if products such as nutritional yeast, peanuts, peanut butter, tahini, brown rice, mushrooms, avocado and sunflower seeds are included. Fortified foods and dietary supplements can also be consumed to ensure adequate intake.

Food preparation

Niacin naturally found in food is susceptible to destruction from high heat cooking, especially in the presence of acidic foods and sauces. It is soluble in water, and so may also be lost from foods boiled in water.

Food fortification

Countries fortify foods with nutrients to address known deficiencies. As of 2020, 54 countries required food fortification of wheat flour with niacin or niacinamide; 14 also mandate fortification of maize flour, and 6 mandate fortification of rice. From country to country, niacin fortification ranges from 1.3 to 6.0 mg/100 g.

As a dietary supplement

In the United States, niacin is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving. These products often have a Structure/Function health claim allowed by the US Food & Drug Administration (FDA). An example would be "Supports a healthy blood lipid profile." The American Heart Association strongly advises against the substitution of dietary supplement niacin for prescription niacin because of potentially serious side effects, which means that niacin should only be used under the supervision of a health care professional, and because manufacture of dietary supplement niacin is not as well-regulated by the FDA as prescription niacin. More than 30 mg niacin consumed as a dietary supplement can cause skin flushing. Face, arms and chest skin turns a reddish color because of vasodilation of small subcutaneous blood vessels, accompanied by sensations of heat, tingling and itching. These signs and symptoms are typically transient, lasting minutes to hours; they are considered unpleasant rather than toxic.

Toxicity

The daily limit for vitamin B₃ has been set at 35 mg. At daily doses of as low as 30 mg, flushing has been reported, always starting in the face and sometimes accompanied by skin dryness, itching, paresthesia, and headache. Liver toxicity is the most serious toxic reaction and it occurs at doses >2 grams/day. Fulminant hepatitis has been reported at doses between 3-9 grams/day with needs for liver transplantation. Other reactions include glucose intolerance, hyperuricemia, macular edema, and macular cysts.

Deficiency

Vitamin B₃ deficiency can cause pellagra, a disease found in many alcoholics in North America. Symptoms include vomiting, loss of appetite, abdominal pain, and general fatigue. Drinking too much alcohol can lead to vitamin B3 deficiency. Chronic alcoholism can cause vitamin B3 deficiency because it affects both the intake and absorption of vitamin B3. Drinking excessive amounts of alcohol blunts the appetite, so people who are chronic alcoholics may not be eating enough food to sustain a healthy level of vitamin B3. Over time, chronic alcohol intake also affects the body's ability to absorb and use niacin. Some doctors routinely prescribe niacin to people with alcohol use disorders.