Niacin also known as nicotinic acid, is an organic compound and is,
depending on the definition used, one of the 20 to 80 essential human
nutrients. Together with nicotinamide it makes up the group known as
vitamin B3 complex. It has the formula C
2 and belongs to the group of the pyridinecarboxylic acids.
Medication and supplemental niacin are primarily used to treat high
blood cholesterol and pellagra (niacin deficiency). Insufficient
niacin in the diet can cause nausea, skin and mouth lesions, anemia,
headaches, and tiredness. The lack of niacin may also be observed in
pandemic deficiency disease, which is caused by a lack of five crucial
vitamins (niacin, vitamin C, thiamin, vitamin D, and vitamin A) and is
usually found in areas of widespread poverty and malnutrition. Niacin
is provided in the diet from a variety of whole and processed foods,
with highest contents in fortified packaged foods, tuna, some
vegetable and other animal sources. Some countries require its
addition to grains.
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the carboxyl group has been replaced by a carboxamide group (CONH
2), as well as more complex amides and a variety of esters. Nicotinic
acid and niacinamide are convertible to each other with steady world
demand rising from 8,500 tonnes per year in the 1980s to 40,000 in
Niacin cannot be directly converted to nicotinamide, but both
compounds are precursors of the coenzymes nicotinamide adenine
dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate
(NADP) in vivo. NAD converts to NADP by phosphorylation in the
presence of the enzyme NAD+ kinase. NADP and NAD are coenzymes for
many dehydrogenases, participating in many hydrogen transfer
processes. NAD is important in catabolism of fat, carbohydrate,
protein, and alcohol, as well as cell signaling and DNA repair, and
NADP mostly in anabolism reactions such as fatty acid and cholesterol
synthesis. High energy requirements (brain) or high turnover rate
(gut, skin) organs are usually the most susceptible to their
Niacin supplementation has not been found useful for decreasing the
risk of cardiovascular disease in those already on a statin, but
appears to be effective in those not taking a statin. Although
niacin and nicotinamide 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. As the precursor for NAD and NADP, niacin is
also involved in DNA repair.
1 Dietary recommendations
1.1 Food sources
2 Medical uses
2.1 Abnormal lipids
2.2 Treatment of deficiency
4 Side effects
4.1 Facial flushing
4.2 Gastrointestinal and hepatic
7 Physical and chemical properties
7.1 Laboratory synthesis
8.1 Extended release
12 External links
Institute of Medicine
Institute of Medicine (IOM) updated Estimated Average
Requirements (EARs) and Recommended Dietary Allowances (RDAs) for B
vitamins in 1998. The current EARs for niacin for women and men ages
14 and up are 11 mg/day and 12 mg/day, respectively; the
RDAs are 14 and 16 mg/day, respectively. RDAs are higher than
EARs so as to identify amounts that will cover people with higher than
average requirements. RDA for pregnancy is 18 mg/day. RDA for
lactation is 17 mg/day. For infants up to 12 months the Adequate
Intake (AI) is 2–4 mg/day. For children ages 1–13 years the
RDA increases with age from 6 to 12 mg/day. As for safety, the
IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals
when evidence is sufficient. In the case of niacin the UL is set at
35 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred
to as Dietary Reference Intakes (DRIs).
European Food Safety Authority
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. AI and UL defined the same as in United States. For women
(including those pregnant or lactating), men and children the PRI is
1.6 mg niacin per megajoule (MJ) of energy consumed. As the
conversion is 1 MJ = 238.8 kcal, an adult consuming 2388 calories
should be consuming 16 mg niacin. This is comparable to U.S.
RDAs. The niacin UL is set at 10 mg/day, which is much less
than the U.S. value. The UL applies to niacin as a supplement consumed
as one dose, and in intended to avoid the skin flush reaction. This
explains why the PRI 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 was 20 mg, but as of
May 27, 2016 it was revised to 16 mg to bring it into agreement
with the RDA. A table of the old and new adult Daily Values is
provided at Reference Daily Intake. The original deadline to be in
compliance was July 28, 2018, but on September 29, 2017 the FDA
released a proposed rule that extended the deadline to January 1, 2020
for large companies and January 1, 2021 for small companies.
Niacin is found in a variety of whole and processed foods, including
fortified packaged foods, meat from various animal sources, seafoods,
Among whole food sources with the highest niacin content per 100
cooked skipjack tuna, 18.8 mg
cooked light meat turkey, 11.8 mg
cooked, lean ground pork, 11.1 mg
cooked venison, 10.8 mg
cooked, lean veal, 8.0 mg
Plant foods and spices
sesame seed flour, 12.5 mg
ground ginger, 9.6 mg
dried tarragon, 9.0 mg
dried, green sweet peppers, 7.4 mg
grilled portabella mushrooms, 6.2 mg
roasted sunflower seeds, 4.1 mg
dehydrated apricots, 3.6 mg
baked potato, 3.1 mg
Fortified breakfast cereals have among the highest niacin contents
(more than 20 mg per 100 grams).
Whole grain flours, such as
from wheat, rice, barley or corn, and pasta have niacin contents in a
range of 3–10 mg per 100 grams.
Niacin has sometimes been used in addition to other lipid-lowering
medications. Systematic reviews found no effect of niacin on
cardiovascular disease or death, in spite of raising HDL cholesterol,
and reported side effects including an increased risk of
Treatment of deficiency
Niacin and niacinamide are used for prevention and treatment of
Niacin is contraindicated with active liver disease, persistent
elevated serum transaminases, active peptic ulcer disease, or arterial
The most common adverse effects are flushing (e.g., warmth, redness,
itching or tingling), headache, pain, abdominal pain, diarrhea,
dyspepsia, nausea, vomiting, rhinitis, pruritus and rash. These can be
minimized by initiating therapy at low dosages, increasing dosage
gradually, and avoiding administration on an empty stomach. High
doses of niacin often temporarily reduce blood pressure as a result of
acute vasodilation. In the longer term, high-dose niacin use may
persistently lower blood pressure in individuals with hypertension,
but more research is needed to determine the extent of this
Flushing usually lasts for about 15 to 30 minutes, though it can
sometimes last up to two hours. It is sometimes accompanied by a
prickly or itching sensation, in particular, in areas covered by
clothing. Flushing 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 niacin with meals also helps reduce this side
effect. Acquired tolerance will also help reduce flushing; after
several weeks of a consistent dose, most patients no longer experience
flushing. Reduction of flushing focuses on altering or blocking
the prostaglandin mediated pathway. 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.
Prostaglandin (PGD2) is the primary cause of the flushing reaction,
with serotonin appearing to have a secondary role in this
reaction. The effect is mediated by prostaglandin E2 and D2 due to
GPR109A activation of epidermal
Langerhans cells and
Langerhans cells use cyclooxygenase type 1
(COX-1) for PGE2 production and are more responsible for acute
flushing, while keratinocytes are COX-2 dependent and are in active
continued vasodilation. Flushing was often thought to involve
histamine, but histamine has been shown not to be involved in the
Gastrointestinal and hepatic
Gastrointestinal complaints, such as indigestion, nausea and liver
failure, have also been reported.
Hepatotoxicity is possibly related
to metabolism via amidation resulting in NAD production. The
time-release form has a lower therapeutic index for lowering serum
lipids relative to this form of toxicity.
The high doses of niacin used to improve the lipid profile have been
shown to elevate blood sugar by 5-10%, thereby worsening diabetes
Niacin therapy increases the risk of new-onset diabetes
by approximately 34%.
Hyperuricemia is another side effect of taking high-dose niacin and
may exacerbate gout.
Side effects of heart arrhythmias have also been
reported.[page needed] Increased prothrombin time and
decreased platelet count have been reported; therefore, these should
be monitored closely in patients who are also taking
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.
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.
Main article: Pellagra
A man with pellagra, which is caused by a chronic lack of vitamin B3
in the diet.
Between 1906 and 1940 more than 3 million Americans were affected by
pellagra with more than 100,000 deaths.
Joseph Goldberger was assigned
to study pellagra by the Surgeon General of the United States and
produced good results. In the late 1930s, studies by Tom Spies, Marion
Blankenhorn, and Clark Cooper established that niacin cured pellagra
in humans. The disease was greatly reduced as a result.
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
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 not at risk of niacin deficiency.
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 Casal's 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 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 (an essential amino acid that is
utilized to synthesize niacin). 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.
Niacin's therapeutic effects are partly mediated through the
activation of G protein-coupled receptors, including niacin receptor 1
(NIACR1) and niacin receptor 2 (NIACR2) which are highly expressed in
adipose tissue, spleen, immune cells and keratinocytes but not in
other expected organs such as liver, kidney, heart or
NIACR1 and NIACR2 inhibit cyclic adenosine
monophosphate (cAMP) production and thus fat breakdown in adipose
tissue and free fatty acids available for liver to produce
triglycerides and very-low-density lipoproteins (VLDL) and
consequently low-density lipoprotein (LDL) or "bad"
cholesterol. Decrease in free fatty acids also suppress
hepatic expression of apolipoprotein C3 (APOC3) and PPARg
coactivator-1b (PGC-1b) thus increase VLDL turn over and reduce its
production. It also inhibits diacylglycerol acyltransferase-2
(important hepatic TG synthesis).
The mechanism behind increasing HDL is not totally understood but it
seems to be done in various ways.
Niacin increases apolipoprotein A1
levels due to anti catabolic effects resulting in higher reverse
cholesterol transport. It also inhibits HDL hepatic uptake,
down-regulating production of the cholesterol ester transfer protein
(CETP) gene. Finally, it stimulates the
ABCA1 transporter in
monocytes and macrophages and up-regulates peroxisome
proliferator-activated receptor γ results in reverse cholesterol
It reduces secondary outcomes associated with atherosclerosis, such as
low density lipoprotein cholesterol (LDL), very low-density
lipoprotein cholesterol (VLDL-C), and triglycerides (TG), but
increases high density lipoprotein cholesterol (HDL). Despite the
importance of other cardiovascular risk factors, high HDL was
associated with fewer cardiovascular events independent of LDL
reduction. Other effects include anti-thrombotic and vascular
inflammation, improving endothelial function, and plaque
stability. Adipokines are the adipocytes’ produced mediators.
Some adipokines such as tumor necrosis factor (TNF)-a, interleukins
and chemokines, have pro-inflammatory effect and some others such as
adiponectin have anti-inflammatory effect that regulates inflammatory
process, decrease vascular progression and atherosclerosis.
Niacin also appears to upregulate brain-derived neurotrophic factor
(BDNF) and tropomyosin receptor kinase B (TrkB) expression.
Research has been able to show the function of niacin in the pathway
lipid metabolism. It is seen that this vitamin can decrease the
synthesis of apoB-containing lipoproteins such as VLDL, LDL, IDL and
Lipoprotein (a) via several mechanisms: (1) Directly inhibiting the
action of DGAT2, a key enzyme for triglyceride synthesis; (2) It has
the ability to bind to the receptor HCAR2 thereby decreasing lipolysis
and FFA flux to the liver for triglyceride synthesis; and (3)
increased apoB catabolism. On the other hand, HDL cholesterol levels
are increased by niacin through direct and indirect pathways. (4)
Niacin decreases CETP mass and activity, and this synergistic effect
with the decrease in triglyceride levels, can indirectly raise HDL
cholesterol levels. The study has also been able to show direct
effects on the beta chain of ATP synthase (5) and on production (6)
and hepatic uptake (7) of apoA-I also increase HDL cholesterol levels.
Thus by affecting the pathway reducing lipid levels help in reducing
This section needs expansion. You can help by adding to it. (September
Niacin, serotonin (5-hydroxytryptamine), and melatonin biosynthesis
The liver can synthesize niacin from the essential amino acid
tryptophan, requiring 60 mg of tryptophan to make 1 mg of
niacin. Riboflavin, vitamin B6 and iron are required in some of
the reactions involved in the conversion of tryptophan to NAD.
Physical and chemical properties
Several thousand tons of niacin are manufactured each year, starting
Niacin is available as a prescription product, and in the United
States as a dietary supplement. Prescription products can be immediate
release (Niacor, 500 mg tablets) or extended release (Niaspan,
500 and 1000 mg tablets).
Dietary supplement products can be
immediate or slow release, the latter including inositol
Over-the-counter niacin is not federally regulated in the United
States. Some “no flush” types, such as inositol hexanicotinate
contain convertible niacin compounds, but have little clinical
efficacy in reducing cholesterol levels.
A prescription extended release niacin, Niaspan, has a film coating
that delays release of the niacin, resulting in an absorption over a
period of 8–12 hours. The extended release formulations generally
reduce vasodilation and flushing side effects, but increase the risk
of hepatotoxicity compared to the immediate release forms.
A formulation of laropiprant (Merck & Co., Inc.) and niacin had
previously been approved for use in Europe and marketed as Tredaptive.
Laropiprant is a prostaglandin D2 binding drug shown to reduce
vasodilatation and flushing up to 73%. The HPS2-THRIVE
study, a study sponsored by Merck, showed no additional efficacy
of Tredaptive in lowering cholesterol when used together with other
statin drugs, but did show an increase in other side effects. The
study resulted in the complete withdrawal of Tredaptive from the
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 disputed. 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.
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).
Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for
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. For the first time,
niacin was extracted by Casimir Funk, but he thought that it was
thiamine and due to the discovered amine group he coined the term
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.
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", "vitamin P-P" and "PP-factor", that are derived from the
term "pellagra-preventive factor". 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
In 1955, Altschul and colleagues described niacin as having a lipid
lowering property. As such, niacin is the oldest lipid lowering
In animal models and in vitro, niacin produces marked
anti-inflammatory effects in a variety of tissues – including
the brain, gastrointestinal tract, skin, and vascular tissue –
through the activation of NIACR1.
Niacin has been
shown to attenuate neuroinflammation and may have efficacy in treating
neuroimmune disorders such as multiple sclerosis and Parkinson's
disease. Unlike niacin, nicotinamide does not activate NIACR1,
however both niacin and nicotinamide activate the G protein-coupled
estrogen receptor (GPER) in vitro.
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Vitamin B3 MS Spectrum
Niacin bound to proteins in the PDB
Pyridoxine#, Pyridoxal phosphate
‡Withdrawn from market
§Never to phase III
Peripheral vasodilators (C04)
Niacin and derivatives
Other peripheral vasodilators
Lipid modifying agents (C10)
Cholesterol absorption inhibitors, NPC1L1
Bile acid sequestrants/resins (LDL)
Statins (HMG-CoA reductase, LDL)
Niacin and derivatives (HDL and LDL)
MTTP inhibitors (VLDL)
CETP inhibitors (HDL)
PCSK9 inhibitors (LDL)
Magnesium pyridoxal 5-phosphate glutamate
‡Withdrawn from market
§Never to phase III
GABAA receptor positive modulators
Ethanol (alcohol) (alcoholic drink)
Skullcap constituents (e.g., baicalin)
Certain anabolic-androgenic steroids
Acetylglycinamide chloral hydrate
Trichloroethane (methyl chloroform)
Avermectins (e.g., ivermectin)
Bromide compounds (e.g., lithium bromide, potassium bromide, sodium
Dihydroergolines (e.g., dihydroergocryptine, dihydroergosine,
dihydroergotamine, ergoloid (dihydroergotoxine))
Fenamates (e.g., flufenamic acid, mefenamic acid, niflumic acid,
Lignans (e.g., 4-O-methylhonokiol, honokiol, magnolol, obovatol)
Menthyl isovalerate (validolum)
Sulfonylalkanes (e.g., sulfonmethane (sulfonal), tetronal, trional)
Terpenoids (e.g., borneol)
Valerian constituents (e.g., isovaleric acid, isovaleramide, valerenic
Unsorted benzodiazepine site positive modulators: α-Pinene
See also: Receptor/signaling modulators • GABA receptor modulators
• GABA metabolism/tr