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Niacin
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Summary
Niacin and its derivative nicotinamide are dietary precursors of nicotinamide adenine dinucleotide
(NAD), which can be phosphorylated (NADP) and reduced (NADH and NADPH). NAD functions in
oxidation-reduction (redox) reactions and non-redox reactions (More information).
Pellagra is the disease of severe niacin deficiency. It is characterized by symptoms affecting the skin,
the digestive system, and the nervous system and can lead to death if left untreated (More
information).
Dietary tryptophan can be converted to niacin, although the efficiency of conversion is low in humans
and affected by deficiencies in other nutrients (More information).
Causes of niacin deficiency include inadequate oral intake, poor bioavailability from unlimed grains,
defective tryptophan absorption, metabolic disorders, and the long-term use of chemotherapeutic
treatments (More information).
The requirements for niacin are based on the urinary excretion of niacin metabolites (More
information).
NAD is the sole substrate for PARP enzymes involved in DNA repair activity in response to DNA strand
breaks; thus, NAD is critical for genome stability. Several studies, mostly using in vitro and animal
models, suggest a possible role for niacin in cancer prevention. Nevertheless, large studies are
needed to investigate the association between niacin deficiency and cancer risk in human populations
(More information).
Despite promising initial results, nicotinamide administration has failed to prevent or delay the onset
of type 1 diabetes in high-risk relatives of type 1 diabetics. Future research might explore the use of
nicotinamide in combined therapy and evaluate activators of NAD-dependent enzymes (More
information).
At pharmacologic doses, niacin, but not nicotinamide, improves the lipid profile and reduces coronary
events and total mortality in patients at high risk for coronary heart disease. Several clinical trials
have explored the cardiovascular benefit of niacin in combination with other lipid-lowering
medications (More information).
Elevated tryptophan breakdown and niacin deficiency have been reported in HIV-positive people. This
population is also at high risk for cardiovascular diseases, and current data show that they could
benefit from niacin supplementation (More information).
The tolerable upper intake level (UL) for niacin is based on skin flushing, niacin's most prominent side
effect. A new drug, laropiprant, has been developed to reduce skin flushing. Adverse effects have also
been reported with pharmacologic doses of niacin administrated alone or in combination with other
lipid-lowering medications (More information).
Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B
3
. Nicotinamide is the
derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD)
and nicotinamide adenine dinucleotide phosphate (NADP). The chemical structures of the various forms of
niacin are shown in the figure. None of the forms are related to the nicotine found in tobacco, although their
names are similar (1).
Function
Oxidation-reduction (redox) reactions
Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes
involving the transfer of electrons. Over 400 enzymes require the niacin coenzymes, NAD and NADP, mainly
to accept or donate electrons for redox reactions (2). NAD functions most often in energy-producing
reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP
functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of all macromolecules,
including fatty acids and cholesterol (1, 3).
Non-redox reactions
The niacin coenzyme, NAD, is the substrate (reactant) for at least four classes of enzymes that separate the
nicotinamide moiety from NAD and transfer ADP-ribose to acceptors.
Mono-ADP-ribosyltransferase enzymes were first discovered in certain bacteria, where they mediate the
action of toxins, such as cholera and diptheria. In mammalian cells, these enzymes transfer an ADP-ribose
residue from NAD to a specific amino acid of a target protein, with the creation of an ADP-ribosylated protein
and the release of nicotinamide. Mono ADP-ribosylation reactions reversibly modify the activity of acceptor
proteins, such as G-proteins that bind guanosine-5'-triphosphate (GTP) and act as intermediaries in a
number of cell-signaling pathways (4).
Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze the transfer of polymers of ADP-ribose
from NAD to acceptor proteins. PARPs appear to function in DNA repair and stress responses, cell signaling,
transcription, regulation, apoptosis, chromatin structure, and cell differentiation, suggesting a role for NAD in
cancer prevention (3). At least six different PARPs have been identified, and although their functions are not
yet fully understood, their existence indicates a potential for considerable consumption of NAD (5, 6).
A new nomenclature has been proposed for enzymes catalyzing ADP-ribosylation: The PARP family was
renamed ARTD, while ARTC designates the mono ADP-ribosyltransferase family (6).
ADP-ribosylcyclases catalyze the formation of cyclic ADP-ribose from ADP-ribose. Cyclic ADP-ribose works
within cells to provoke the release of calcium ions from internal storage sites and probably also plays a role
in cell signaling (1).
Sirtuins are a class of NAD-dependent deacetylase enzymes that remove acetyl groups from the acetylated
lysine residues of target proteins. During the deacetylation process, an ADP-ribose is added to the acetyl
group to produce O-acetyl-ADP-ribose. Both acetylation and ADP-ribosylation are known post-translational
modifications that affect protein activities. The initial interest in sirtuins followed the discovery that their
activation could mimic calorie restriction, which has been shown to increase lifespan in lower organisms.
Such a role in mammals is controversial, although sirtuins are energy-sensing regulators involved in signaling
pathways that could play important roles in delaying the onset of age-related diseases (e.g., cardiovascular
diseases, cancer, dementia, arthritis). To date, the spectrum of their biological functions include gene
silencing, DNA damage repair, cell cycle regulation, and cell differentiation (7).
Deficiency
Pellagra
The late stage of severe niacin deficiency is known as pellagra. Early records of pellagra followed the
widespread cultivation of corn in Europe in the 1700s (1). The disease is generally associated with poorer
social classes whose chief dietary staple consisted of cereals like corn or sorghum. Pellagra was also common
in the southern United States during the early 1900s where income was low and corn products were a major
dietary staple (8). Interestingly, pellagra was not known in Mexico, where corn was also an important dietary
staple and much of the population was also poor. In fact, corn contains appreciable amounts of niacin, but it
is present in a bound form that is not nutritionally available to humans. The traditional preparation of corn
tortillas in Mexico involves soaking the corn in a lime (calcium oxide) solution, prior to cooking. Heating the
corn in an alkaline solution results in the release of bound niacin, increasing its bioavailability (9).
The most common symptoms of niacin deficiency involve the skin, the digestive system, and the nervous
system (3). The symptoms of pellagra are commonly referred to as the three D's: dermatitis, diarrhea, and
dementia. A fourth D, death, occurs if pellagra is left untreated (10). In the skin, a thick, scaly, darkly
pigmented rash develops symmetrically in areas exposed to sunlight. In fact, the word "pellagra" comes from
"pelle agra," the Italian phrase for rough or raw skin. Symptoms related to the digestive system include
inflammation of the mouth and tongue ("bright red tongue"), vomiting, constipation, abdominal pain, and
ultimately, diarrhea. Gastrointestinal disorders and diarrhea contribute to the ongoing malnourishment of the
subjects. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory
loss and are more consistent with delirium than with the historically described dementia (11). Disease
presentations vary in appearance since the classic triad rarely presents in its entirety. The absence of
dermatitis, for example, is known as pellagra sine pellagra.
Tryptophan metabolism
In addition to its synthesis from dietary niacin, NAD can be synthesized from the dietary amino acid
tryptophan via the kynurenine pathway (see figure). The relative ability to make this conversion varies
greatly from mice to humans. The first step is catalyzed by the extrahepatic enzyme indoleamine 2,3-
dioxygenase (IDO), which is responsible for the oxidative cleavage of tryptophan. The chronic stimulation of
tryptophan oxidation, mediated by an increased activity of IDO and/or inadequate niacin levels, is observed
in a number of diseases, including human immunodeficiency virus (HIV) infection (see HIV/AIDS below). In
healthy individuals, less than 2% of dietary tryptophan is converted to NAD by this tryptophan oxidation
pathway (12). Tryptophan metabolism plays an essential regulatory role by mediating immunological
tolerance of the fetus during pregnancy (13). It is now understood that tryptophan oxidation in the placenta
drives a physiologic tryptophan depletion that impairs the function of nearby maternal T-lymphocytes and
prevents the rejection of the fetus. However, the synthesis of niacin from tryptophan is a fairly inefficient
pathway that depends on enzymes requiring vitamin B
6
and riboflavin, as well as an enzyme containing heme
(iron). On average, 1 milligram (mg) of niacin can be synthesized from the ingestion of 60 mg of tryptophan.
The term "niacin equivalent" (NE) is used to describe the contribution to dietary intake of all the forms of
niacin that are available to the body. Thus, 60 mg of tryptophan are considered to be 1 mg NE. However,
studies of pellagra in the southern U.S. during the early twentieth century indicated that the diets of many
individuals who suffered from pellagra contained enough NE to prevent pellagra (10), challenging the idea
that 60 mg of dietary tryptophan are equivalent to 1 mg of niacin. In particular, one study in young men
found that the tryptophan content of the diet had no effect on the decrease in red blood cell niacin content
that resulted from low dietary niacin (14).
Causes of niacin deficiency
Niacin deficiency or pellagra may result from inadequate dietary intake of niacin and/or tryptophan. As
mentioned above, other nutrient deficiencies may also contribute to the development of niacin deficiency.
Niacin deficiency, often associated with malnutrition, is observed in the homeless population, in individuals
suffering from anorexia nervosa or obesity, and in consumers of diets high in maize and poor in animal
proteins (15-18). Patients with Hartnup's disease, a hereditary disorder resulting in defective tryptophan
absorption, have developed pellagra (3). Other malabsorptive states that can lead to pellagra include Crohn's
disease and megaduodenum (19, 20). Carcinoid syndrome, a condition of increased secretion of serotonin
and other catecholamines by carcinoid tumors, may also result in pellagra due to increased utilization of
dietary tryptophan for serotonin rather than niacin synthesis. Further, prolonged treatment with the anti-
tuberculosis drug Isoniazid has resulted in niacin deficiency (21). Other pharmaceutical agents, including the
immunosuppressive drugs Azathioprine and 6-Mercaptopurine, the anti-cancer drug 5-Fluorouracil, and
Carbidopa, a drug given to people with Parkinson's disease, are known to increase the reliance on dietary
niacin by interfering with the tryptophan-kinurenine-niacin pathway. Finally, other populations at risk for
niacin deficiency include dialysis patients, cancer patients (22, 23), individuals suffering from chronic
alcoholism (11), and people with HIV (see HIV/AIDS below).
The Recommended Dietary Allowance (RDA)
The RDA for niacin, revised in 1998, is based on the prevention of deficiency. Pellagra can be prevented by
about 11 mg NE/day, but 12 mg to 16 mg/day has been found to normalize the urinary excretion of niacin
metabolites (breakdown products) in healthy young adults. Because pellagra represents severe deficiency,
the Food and Nutrition Board (FNB) of the U.S. Institute of Medicine chose to use the excretion of niacin
metabolites as an indicator of niacin nutritional status rather than symptoms of pellagra (24). However, some
researchers feel that cellular NAD and NADP content may be more relevant indicators of niacin nutritional
status (14, 25, 26).
Recommended Dietary Allowance (RDA) for Niacin
Life Stage Age Males (mg NE*/day) Females (mg NE/day)
Infants 0-6 months 2 (AI) 2 (AI)
Infants 7-12 months 4 (AI) 4 (AI)
Children 1-3 years 6 6
Children 4-8 years 8 8
Children 9-13 years 12 12
Adolescents 14-18 years 16 14
Adults 19 years and older 16 14
Pregnancy all ages - 18
Breast-feeding all ages - 17
*NE, niacin equivalent: 1 mg NE = 60 mg of tryptophan = 1 mg niacin
Treatment of pellagra
To treat pellagra, the World Health Organization (WHO) recommends administering nicotinamide to avoid the
flushing commonly caused by niacin (see Safety). Treatment guidelines suggest using 300 mg nicotinamide
per day orally in divided doses, or 100 mg per day parenterally in divided doses, for three to four weeks (23,
27). Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin
B-complex preparation is advised.
Disease Prevention
Cancer
Studies of cultured cells (in vitro) provide evidence that NAD content influences mechanisms that maintain
genomic stability. Loss of genomic stability, characterized by a high rate of damage to DNA and
chromosomes, is a hallmark of cancer (28). The current understanding is that the pool of NAD is decreased
during niacin deficiency and that it affects the activity of NAD-consuming enzymes rather than redox and
metabolic functions (29). Among NAD-dependent reactions, poly ADP-ribosylations catalyzed by PARP
enzymes are critical for the cellular response to DNA injury. After DNA damage, PARPs are activated. The
subsequent poly ADP-ribosylations of a number of signaling and structural molecules by PARPs were shown
to facilitate DNA repair at DNA strand breaks. Cellular depletion of NAD has been found to decrease levels of
the tumor suppressor protein p53, a target for poly ADP-ribosylation, in human breast, skin, and lung cells
(26). The expression of p53 was also altered by niacin deficiency in rat bone marrow cells (30). Impairment
of DNA repair caused by niacin deficiency could lead to genomic instability and drive tumor development in
rat models (31, 32). Both PARPs and sirtuins have been recently involved in the maintenance of
heterochromatin, a chromosomal domain associated with genome stability, as well as in transcriptional gene
silencing, telomere integrity, and chromosome segregation during cell division (33, 34). Neither the cellular
NAD content nor the dietary intake of NAD precursors (niacin and tryptophan) necessary for optimizing
protective responses following DNA damage has been determined, but both are likely to be higher than that
required for the prevention of pellagra.
Bone marrow
Cancer patients often suffer from bone marrow suppression following chemotherapy, given that bone marrow
is one of the most proliferative tissues in the body and thus a primary target for chemotherapeutic agents.
Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk
of chemically induced leukemia in rats (35). Conversely, a pharmacologic dose of niacin was able to increase
NAD and poly ADP-ribose in bone marrow and decrease the development of leukemia in rats (36). It has
been suggested that niacin deficiency often observed in cancer patients could sensitize bone marrow tissue
to the suppressive effect of chemotherapy. However, little is known regarding cellular NAD levels and the
prevention of DNA damage or cancer in humans. One study in two healthy individuals involved elevating NAD
levels in blood lymphocytes by supplementation with 100 mg/day niacin for eight weeks. Compared to non-
supplemented individuals, the supplemented individuals had reduced DNA strand breaks in lymphocytes
exposed to free radicals in a test tube assay (37). However, niacin supplementation of up to 100 mg/day in
21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage
in blood lymphocytes compared to placebo (38). More recently, the frequency of chromosome translocation
was used to evaluate DNA damage in peripheral blood lymphocytes of 82 pilots chronically exposed to
ionizing radiation, a known human carcinogen. In this observational study, the rate of chromosome
aberrations was significantly lower in subjects with high (28.4 mg/day) compared to low (20.5 mg/day)
dietary niacin intake (39).
Upper digestive tract
Generally, relationships between dietary factors and cancer are established first in epidemiological studies
and followed up by basic cancer research at the cellular level. In the case of niacin, research on biochemical
and cellular aspects of DNA repair has stimulated an interest in the relationship between niacin intake and
cancer risk in human populations (40). A large case-control study found increased consumption of niacin,
along with antioxidant nutrients, to be associated with decreased incidence of oral (mouth), pharyngeal
(throat), and esophageal cancers in northern Italy and Switzerland (41, 42). An increase in daily niacin
intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth and throat,
while a 5.2 mg increase in daily niacin intake was associated with a similar decrease in cases of esophageal
cancer.
Skin
Niacin deficiency can lead to severe sunlight sensitivity in exposed skin. Given the implication of NAD-
dependent enzymes in DNA repair, there has been some interest in the effect of niacin on skin health. In
vitro and animal experiments have helped gather information, but human data on niacin/NAD status and skin
cancer are severely limited. One study reported that niacin supplementation decreased the risk of ultraviolet
light (UV)-induced skin cancers in mice, despite the fact that mice convert tryptophan to NAD more
efficiently than rats and humans and thus do not get severely deficient (43). Hyper-proliferation and
impaired differentiation of skin cells can alter the integrity of the skin barrier and increase the occurrence of
pre-malignant and malignant skin conditions. A protective effect of niacin was suggested by topical
application of myristyl nicotinate, a niacin derivative, which successfully increased the expression of
epidermal differentiation markers in subjects with photodamaged skin (44). The activation of the "niacin
receptors," GPR109A and GPR109B, by pharmacologic doses of niacin could be involved in improving skin
barrier function. Conversely, differentiation defects in skin cancer cells were linked to the abnormal cellular
localization of defective "niacin receptors" (45). Nicotinamide restriction with subsequent depletion of cellular
NAD was shown to increase oxidative stress-induced DNA damage in a precancerous skin cell model,
implying a protective role of NAD-dependent pathways in cancer (46). Altered NAD availability also affects
sirtuin expression and activity in UV-exposed human skin cells. Along with PARPs, NAD-consuming sirtuins
could play an important role in the cellular response to photodamage and skin homeostasis (47).
Insulin-dependent diabetes mellitus (IDDM)
Insulin-dependent diabetes mellitus in children, often called type 1 diabetes, is known to result from the
autoimmune destruction of insulin-secreting beta-cells in the pancreas. Prior to the onset of symptomatic
diabetes, specific antibodies, including islet cell antibodies (ICA), can be detected in the blood of high-risk
individuals. The ability to detect individuals at high risk for the development of IDDM led to the enrollment of
high-risk siblings of children with IDDM into trials designed to prevent its onset. Evidence from in vitro and
animal research indicates that high levels of nicotinamide protect beta-cells from damage by toxic chemicals,
inflammatory white blood cells, and reactive oxygen species. Pharmacologic doses of nicotinamide (up to 3
grams/day) were first used to protect beta-cells in patients shortly after the onset of IDDM. An analysis of 10
published trials (5 placebo-controlled) found evidence of improved beta-cell function after one year of
treatment with nicotinamide, but the analysis failed to find any clinical evidence of improved glycemic (blood
glucose) control (48). However, high doses of nicotinamide could decrease insulin sensitivity in high-risk
relatives of IDDM patients (49), which might explain the finding of improved beta-cell function without
concomitant improvement in glycemic control.
Several pilot studies for the prevention of IDDM in ICA-positive relatives of patients with IDDM yielded
conflicting results, whereas a large randomized trial in school children that was not placebo-controlled found
a significantly lower incidence of IDDM in the nicotinamide-treated group. A large, multicenter randomized
controlled trial of nicotinamide in ICA-positive siblings of IDDM patients between 3 and 12 years of age also
failed to find a difference in the incidence of IDDM after three years (48). A randomized, double-blind,
placebo-controlled, multicenter trial of nicotinamide (maximum of 3 grams/day) was conducted in 552 ICA-
positive relatives of patients with IDDM. The proportion of relatives who developed IDDM within five years
was comparable whether they were treated with nicotinamide or placebo (50). Although inflammation-related
parameters were decreased in high-risk subjects, nicotinamide was ineffective in the prevention of IDDM
(51). Recently, preliminary data have examined the combination of nicotinamide with acetyl-L-carnitine and
warrant further investigation (52). Interestingly, resveratrol, a sirtuin agonist, was shown to be more potent
than nicotinamide in preventing chemically induced IDDM in a rat model (53).
Disease Treatment
High cholesterol and cardiovascular disease
Pharmacologic doses of niacin, but not nicotinamide, have been known to reduce serum cholesterol since
1955 (54). Today, niacin is commonly prescribed with other lipid-lowering medications. However, one
randomized, placebo-controlled, multicenter trial examined the effect of niacin acid therapy, alone, on
outcomes of cardiovascular disease. Specifically, the Coronary Drug Project (CDP) followed over 8,000 men
with a previous myocardial infarction (heart attack) for six years (55). Compared to the placebo group,
patients who took 3 grams of niacin daily experienced an average 10% reduction in total blood cholesterol, a
26% decrease in triglycerides, a 27% reduction in recurrent nonfatal myocardial infarction, and a 26%
reduction in cerebrovascular events (stroke and transient ischemic attacks). Although niacin therapy did not
decrease total deaths or deaths from cardiovascular disease during the six-year study period, post-trial follow
up nine years later revealed a 10% reduction in total deaths with niacin treatment. Four out of five major
cardiovascular outcome trials found niacin in combination with other therapies to be of statistically significant
benefit in men and women (56). Niacin therapy markedly increases HDL-cholesterol levels, decreases serum
Lp(a) (lipoprotein-a) concentrations, and shifts small, dense LDL particles to large, buoyant LDL particles. All
of these changes in the blood lipid profile are considered cardioprotective. Low levels of HDL-cholesterol are
one major risk factor for coronary heart disease (CHD), and an increase in HDL levels is associated with a
reduction of that risk (57).
Because of the adverse side effects associated with high doses of niacin (see Safety), it has most often been
used in combination with other lipid-lowering medications in slightly lower doses (54). In particular, LDL
cholesterol-lowering statins like simvastatin form the cornerstone of treatment of hyperlipidemia, a major
risk factor for CHD. The HDL-Atherosclerosis Treatment Study (HATS), a three-year randomized controlled
trial in 160 patients with documented CHD and low HDL levels found that a combination of simvastatin and
niacin (2 to 3 grams/day) increased HDL levels, inhibited the progression of coronary artery stenosis
(narrowing), and decreased the frequency of cardiovascular events, including myocardial infarction and
stroke (58). Patients with metabolic syndrome display a number of metabolic disorders, including
dyslipidemia and insulin resistance, that put them at increased risk for type 2 diabetes mellitus,
cardiovascular diseases, and mortality. A subgroup analysis of the HATS patients with metabolic syndrome
showed a reduction in rate of primary clinical events even though glucose and insulin metabolism were
moderately impaired by niacin (59). Moreover, a review of niacin safety and tolerability among the HATS
subjects showed glycemic control in diabetic patients returned to pretreatment values following eight months
of disease management with medication and diet (60). Similarly, the cardiovascular benefit of long-term
niacin therapy outweighed the modest increase in risk of newly onset type 2 diabetes in patients from the
CDP study (61).
The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study
a double-blind, placebo-controlled trialinvestigated the incremental effect of adding niacin (1 gram daily)
to statin therapy in 167 patients with known CHD and low HDL levels (62) on carotid intima-media thickness
(CIMT), a surrogate endpoint for the development of atherosclerosis. The addition of extended-release niacin
prevented the increase in CIMT compared to simvastatin monotherapy. A post-hoc analysis of data from
ARBITER2 showed that the blockade of atherosclerotic progression was related to the increase in HDL levels
in patients with normal glycemic status. However, in the presence of additional risk factors, such as impaired
fasting glucose or diabetes, the increase in HDL levels was not predictive of CIMT reduction and
atherosclerotic retardation (63). A comparative efficacy trial (ARBITER6) also showed a significant reduction
of baseline CIMT with extended-release niacin (2 grams daily for 14 months), as opposed to ezetimibe (a
cholesterol-lowering drug), in patients on statins (64). Additional studies are needed to address the impact of
niacin in combination with statins on clinical outcomes.
The effects of niacin are dose-dependent (65). Doses of niacin higher than 1 gram/day are typically used to
treat hyperlipidemia. A placebo-controlled study in 39 patients taking statins (cerivastatin, atorvastatin, or
simvastatin) found that a very low dose of niacin, 100 mg daily, increased HDL cholesterol by only 2.1
mg/dL, and the combination had no effect on LDL cholesterol, total cholesterol, or triglyceride levels (66). At
the pharmacologic dose required for cholesterol-lowering effects, the use of niacin should be approached as if
it were a drug. Individuals should only undertake cholesterol-lowering therapy with niacin under the
supervision of a qualified health care provider in order to minimize potentially adverse effects and maximize
therapeutic benefits.
Although it is a nutrient, at the pharmacologic dose required for cholesterol-lowering effects, the use of
nicotinic acid should be approached as if it were a drug. Individuals should only undertake cholesterol-
lowering therapy with nicotinic acid under the supervision of a qualified health care provider in order to
minimize potentially adverse effects and maximize therapeutic benefits.
HIV/AIDS
It has been hypothesized that infection with human immunodeficiency virus (HIV), the virus that causes
acquired immmunodeficiency syndrome (AIDS), increases the risk of niacin deficiency. Interferon-gamma
(IFN-g) is a cytokine produced by cells of the immune system in response to infection. IFN-g levels are
elevated in individuals infected with HIV, and higher IFN-g levels have been associated with poorer
prognoses. By stimulating the enzyme indoleamine 2,3-dioxygenase (IDO), IFN-g increases the breakdown
of tryptophan, thus supporting the finding that the average tryptophan levels in blood are significantly lower
in HIV patients compared to uninfected subjects (12). The increase in tryptophan degradation that leads to
de novo niacin synthesis and NAD production paralleled niacin deficiency in HIV infection (67). An
explanatory model for these paradoxical observations incriminates the oxidative stress induced by multiple
nutrient deficiencies in HIV patients (68). In particular, the activation of PARP enzymes by oxidative damage
to DNA could be responsible for inducing niacin/NAD depletion (see figure). The breakdown of tryptophan
would then be a compensatory response to inadequate niacin/NAD levels.
Some metabolites derived from the oxidation of tryptophan in the kynurenine pathway regulate specific T-
lymphocyte subgroups. As mentioned above, circulating IFN-g, but also viral and bacterial products, can
activate IDO during HIV infection. The overstimulation of the tryptophan pathway has been involved in the
loss of normal T-lymphocyte function, which is characteristic of HIV. The increased IDO activity has been
linked to the altered immune response that contributes to the persistence of HIV in patients receiving
antiviral therapy. One therapeutic option consisting of blocking IDO using IDO inhibitor 1-methyl tryptophan
was tested in a monkey model for HIV infection, the simian immunodeficiency virus (SIV)-infected rhesus
macaque. However, a partial and transient blockade of the enzyme proved ineffective to reduce the viral load
in plasma and intestinal tissues beyond the level achieved by antiretroviral therapy (69). Other molecules
that inhibit the IDO pathway (e.g., INCB024360 and Indoximod) are being currently tested in oncology trials
and could be of relevance against HIV.
An observational study of 281 HIV-positive men found that higher levels of niacin intake were associated with
decreased progression rate to AIDS and improved survival (70). In a very small, uncontrolled study,
treatment of four HIV positive individuals with 1 to 1.5 grams/day of nicotinamide for two months resulted in
40% increases in plasma tryptophan levels (71). Nicotinamide supplementation may prove to be useful
adjunct to HIV treatment although the clinical implications are still poorly understood.
Cardiovascular disease (CVD) is the second most frequent cause of deaths in the HIV population, and the
rate of CVD is predicted to increase further as patients are living longer due to successful antiretroviral
therapies. Abnormal lipid profiles observed in patients have been attributed to the HIV infection and to the
highly active antiretroviral treatment (HAART) (72). Moreover, insulin resistance was detected together with
dyslipidemia in HAART-treated patients (73). As for the general population, statin-based therapy appears to
benefit HIV patients in terms of atherogenic protection and CVD risk reduction, although contraindications
exist due to drug interactions with HAART. Other first-line treatments include lipid-lowering fibrates, which
are preferred to niacin due to the increased risk of glucose intolerance and insulin resistance (74).
Nevertheless, an unblinded, controlled pilot study showed that extended-release niacin (0.5-1.5 grams/day
for 12 weeks) could effectively improve endothelial function of the brachial artery in HAART-treated HIV
subjects with low HDL and no history of CVD (75). Damaged endothelial function is an early sign of
atherosclerosis before structural changes of the endothelial wall occur and has prognostic value in predicting
adverse CVD outcomes. Finally, a combined treatment of fibrates, niacin, and lifestyle changes (low-fat diet
and exercise) was effective in normalizing lipid parameters in a cohort of 191 HAART-treated patients.
Increased risk of liver dysfunction was detected in subjects receiving both fibrates and niacin, but insulin
sensitivity was not affected by niacin treatment given alone or when combined with fibrates (76).
Schizophrenia
Schizophrenia is a neurologic disorder with unclear etiology that is diagnosed purely from its clinical
presentation. Because neurologic disorders associated with pellagra resemble acute schizophrenia, niacin-
based therapy for the condition was investigated during the 1950s-70s (reviewed in 77). The adjunctive use
of nutrients like niacin to correct deficiencies associated with neurologic symptoms is called orthomolecular
psychiatry (78). Such an approach has not been included in psychiatric practice; practitioners have instead
relied solely on antipsychotic drugs to eliminate the clinical symptoms of schizophrenia. Nevertheless, recent
scientific advances and new hypotheses on the benefit of nutrient supplementation in the treatment of
psychiatric disorders have suggested the re-assessment of orthomolecular medicine by the medical
community (79, 80).
Skin flushing is one major side effect of the therapeutic use of niacin and the primary reason for non-
adherence to treatment (see Toxicity). Flushing is caused by the activation of phospholipase A2, an enzyme
that stimulates the production of specific lipids called prostanoids. These molecules can induce the dilation of
blood vessels in the skin and trigger a flushing response. Interestingly, patients with schizophrenia tend not
to flush following treatment with niacin. This blunted skin flushing response suggests abnormal prostanoid
signaling in schizophrenic patients. An association has been found between the altered niacin sensitivity and
greater functional impairment in schizophrenic subjects (81), which supports other findings that suggest
altered lipid metabolism could critically impair brain development and contribute to the disease (82).
Sources
Food sources
Good sources of niacin include yeast, meat, poultry, red fish (e.g., tuna, salmon), cereals (especially fortified
cereals), legumes, and seeds. Milk, green leafy vegetables, coffee, and tea also provide some niacin (10). In
plants, especially mature cereal grains like corn and wheat, niacin may be bound to sugar molecules in the
form of glycosides, which significantly decrease niacin bioavailability (9).
In the United States, the average dietary intake of niacin is about 30 mg/day for young adult men and 20
mg/day for young adult women. In a sample of adults over the age of 60, men and women were found to
have an average dietary intake of 21 mg/day and 17 mg/day, respectively (24). Some foods with substantial
amounts of niacin are listed in the table below along with their niacin content in milligrams (mg). Food
composition tables generally list niacin content without including niacin equivalents (NE) from tryptophan, or
any adjustment for niacin bioavailability. For more information on the nutrient content of specific foods,
search the USDA food composition database; data included in the table below are from this database (83).
Food Serving Niacin (mg)
Chicken (light meat) 3 ounces* (cooked without skin) 7.3-11.7
Tuna (light, canned, packed in water) 3 ounces 8.6-11.3
Turkey (light meat) 3 ounces (cooked without skin) 10.0
Salmon (chinook) 3 ounces (cooked) 8.5
Beef (90% lean) 3 ounces (cooked) 4.4-5.8
Cereal (unfortified) 1 cup 5-7
Cereal (fortified) 1 cup 20-27
Peanuts 1 ounce (dry-roasted) 3.8
Pasta (enriched) 1 cup (cooked) 1.9-2.4
Lentils 1 cup (cooked) 2.1
Lima beans 1 cup (cooked) 0.8-1.8
Bread (whole-wheat) 1 slice 1.3
Coffee (brewed) 1 cup 0.5
*A 3-ounce serving of meat is about the size of a deck of cards.
Supplements
Niacin supplements are available as nicotinamide or nicotinic acid. Nicotinamide is the form of niacin typically
used in nutritional supplements and in food fortification. Niacin is available over the counter and with a
prescription as a cholesterol-lowering agent (84). The nomenclature for niacin formulations can be confusing.
Niacin is available over the counter in an "immediate-release" (crystalline), and a "slow-release" or "timed-
release form." A shorter acting timed-release preparation referred to as "intermediate release" or "extended
release" niacin is available by prescription (85, 86). Due to the potential for side effects, medical supervision
is recommended for the use of niacin as a cholesterol-lowering agent.
Safety
Toxicity
Niacin from foods is not known to cause adverse effects. Although one study noted adverse effects following
consumption of bagels with 60 times the normal amount of niacin fortification, most adverse effects have
been reported with pharmacologic preparations of niacin (24).
Niacin
Common side effects of niacin include flushing, itching, and gastrointestinal disturbances, such as nausea
and vomiting. Hepatotoxicity (liver cell damage), including elevated liver enzymes and jaundice, has been
observed at intakes as low as 750 mg of niacin per day for less than three months (84, 85). Hepatitis has
been observed with timed-release niacin at dosages as little as 500 mg/day for two months, although almost
all reports of severe hepatitis have been associated with the timed-release form of niacin at doses of 3 to 9
grams per day used to treat high cholesterol for months or years (24). Immediate-release (crystalline) niacin
appears to be less toxic to the liver than extended-release forms. Immediate-release niacin is often used at
higher doses than timed-release forms, and severe liver toxicity has occurred in individuals who substituted
timed-release niacin for immediate-release niacin at equivalent doses (84). Skin rashes and dry skin have
been noted with niacin supplementation. Transient episodes of low blood pressure (hypotension) and
headache have also been reported. Large doses of niacin have been observed to impair glucose tolerance,
likely due to decreased insulin sensitivity. Impaired glucose-tolerance in susceptible (pre-diabetic) individuals
could result in elevated blood glucose levels and clinical diabetes. Elevated blood levels of uric acid,
occasionally resulting in attacks of gout in susceptible individuals, have also been observed with high-dose
niacin therapy (85). Niacin at doses of 1.5 to 5 grams/day has resulted in a few case reports of blurred vision
and other eye problems, which have generally been reversible upon discontinuation. People with abnormal
liver function or a history of liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias,
inflammatory bowel disease, migraine headaches, and alcoholism may be more susceptible to the adverse
effects of excess niacin intake than the general population (24).
Nicotinamide
Nicotinamide is generally better tolerated than niacin. It does not generally cause flushing. However, nausea,
vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed at doses of 3
grams/day (84). Nicotinamide has resulted in decreased insulin sensitivity at doses of 2 grams/day in adults
at high risk for insulin-dependent diabetes (49).
The tolerable upper intake level (UL)
Flushing of the skin primarily on the face, arms, and chest is a common side effect of niacin and may occur
initially at doses as low as 30 mg/day. Although flushing from nicotinamide is rare, the Food and Nutrition
Board set the UL for niacin (nicotinic acid and nicotinamide) at 35 mg/day to avoid the adverse effect of
flushing (24). The UL applies to the general population and is not meant to apply to individuals who are
being treated with a nutrient under medical supervision, as should be the case with high-dose niacin for
elevated blood cholesterol levels.
Tolerable Upper Intake Level (UL) for Niacin
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 10
Children 4-8 years 15
Children 9-13 years 20
Adolescents 14-18 years 30
Adults 19 years and older 35
*Source of intake should be from food and formula only.
Drug interactions
The occurrence of rhabdomyolysis is increased in patients treated with HMG-CoA reductase inhibitors
(statins). Rhabdomyolysis is a relatively uncommon condition in which muscle cells are broken down,
releasing enzymes and electrolytes into the blood, and sometimes resulting in kidney failure (87). Co-
administration of niacin with a statin seems to enhance the risk of rhabdomyelosis (88). A new drug,
laropiprant, blocks prostanoid receptors and reduces niacin-induced flushing (89). A randomized, placebo-
controlled trial was designed to identify possible adverse effects of the niacin/laropiprant combination in over
25,000 simvastatin-treated subjects (90). When added to the statin therapy, niacin/laropiprant increased the
risk of myopathy and rhabdomyelosis, particularly in Asian subjects. It is possible that the niacin/laropiprant
combination further reduces the poor tolerability to statin treatment observed in certain populations (91).
In the three-year, randomized controlled HATS study, concurrent therapy with antioxidants (1,000 mg/day of
vitamin C, 800 IU/day of alpha-tocopherol, 100 mcg/d of selenium, and 25 mg/d of beta-carotene)
diminished the protective effects of the simvastatin-niacin combination (92). Although the mechanism for
these effects is not known, some scientists have questioned the benefit of concurrent antioxidant therapy in
patients on lipid-lowering agents (93).
Several other medications may interact with niacin therapy or with absorption and metabolism of the
vitamin. Sulfinpyrazone is a medication for the treatment of gout that promotes excretion of uric acid from
the blood into urine. Niacin may inhibit this "uricosuric" effect of sulfinpyrazone (84). Further, estrogen and
estrogen-containing oral contraceptives increase the efficiency of niacin synthesis from tryptophan, resulting
in a decreased dietary requirement for niacin (3). Long-term administration of chemotherapy agents has
been reported to cause symptoms of pellagra, and thus niacin supplementation may be needed (see Causes
of niacin deficiency).
Linus Pauling Institute Recommendation
The optimum intake of niacin for health promotion and chronic disease prevention is not yet known. The RDA
(16 mg NE/day for men and 14 mg NE/day for women) is easily obtainable in a varied diet and should
prevent deficiency in most people. Following the Linus Pauling Institute recommendation to take a daily
multivitamin/mineral supplement, containing 100% of the Daily Value (DV) for niacin, will provide at least 20
mg of niacin daily.
Older adults (> 50 years)
Dietary surveys indicate that 15% to 25% of older adults do not consume enough niacin in their diets to
meet the RDA (16 mg NE/day for men and 14 mg NE/day for women), and that dietary intake of niacin
decreases between the ages of 60 and 90 years. Thus, it is advisable for older adults to supplement their
dietary intake with a multivitamin/mineral, which will generally provide at least 20 mg of niacin daily.
References
Written in August 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in July 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in July 2013 by:
Elaine L. Jacobson, Ph.D., Professor (Retired)
Department of Pharmacology and Toxicology
College of Pharmacy and Arizona Cancer Center
University of Arizona
Copyright 2000-2014 Linus Pauling Institute
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