- 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 disease, 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 B3. 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 (Figure 1). None of the forms are related to the nicotine found in tobacco, although their names are similar (1).
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).
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 disease, cancer, dementia, arthritis). To date, the spectrum of their biological functions include gene silencing, DNA damage repair, cell cycle regulation, and cell differentiation (7).
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.
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 (12, 13). Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin B-complex preparation is advised.
In addition to its synthesis from dietary niacin, NAD can be synthesized from the dietary amino acid tryptophan via the kynurenine pathway (see Figure 2 below). 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). In healthy individuals, less than 2% of dietary tryptophan is converted to NAD by this tryptophan oxidation pathway (14). Tryptophan metabolism plays an essential regulatory role by mediating immunological tolerance of the fetus during pregnancy (15). 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 B6 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 US 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 (16).
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 (17-20). 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 (21, 22). 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 (23). 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 (13, 24), individuals suffering from chronic alcoholism (11), and people with HIV (see HIV/AIDS).
The Recommended Dietary Allowance (RDA)
The RDA for niacin, revised in 1998, is based on the prevention of deficiency (Table 1). 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 US Institute of Medicine chose to use the excretion of niacin metabolites as an indicator of niacin nutritional status rather than symptoms of pellagra (25). However, some researchers feel that cellular NAD and NADP content may be more relevant indicators of niacin nutritional status (16, 26, 27).
Table 1. Recommended Dietary Allowance (RDA) for Niacin
||Males (mg NE*/day)
||Females (mg NE/day)
||19 years and older
|*NE, niacin equivalent: 1 mg NE = 60 mg of tryptophan = 1 mg niacin
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 (27). 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.
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.
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).
Type 1 diabetes mellitus
Type 1 (insulin-dependent) diabetes mellitus in children is known to result from the autoimmune destruction of insulin-secreting β-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 β-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 β-cells in patients shortly after the onset of IDDM. An analysis of 10 published trials (5 placebo-controlled) found evidence of improved β-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 β-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).
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 disease, 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 trial—investigated 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.
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-γ (IFN-γ) 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 (14). 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 2 above). 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 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).
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 (25). Some foods with substantial amounts of niacin are listed in Table 2, 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 Table 2 are from this database (83).
Table 2. Some Food Sources of Niacin
|Chicken (light meat)
||3 ounces* (cooked without skin)
|Tuna (light, canned, packed in water)
|Turkey (light meat)
||3 ounces (cooked without skin)
||3 ounces (cooked)
|Beef (90% lean)
||3 ounces (cooked)
||1 ounce (dry-roasted)
||1 cup (cooked)
||1 cup (cooked)
||1 cup (cooked)
|*A 3-ounce serving of meat is about the size of a deck of cards.
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.
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 (25).
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 (25). 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 (25).
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 (25; Table 3). 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.
Table 3. Tolerable Upper Intake Level (UL) for Niacin
|Infants 0-12 months
||Not possible to establish*
|Children 1-3 years
|Children 4-8 years
|Children 9-13 years
|Adolescents 14-18 years
|Adults 19 years and older
|*Source of intake should be from food and formula only.
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 α-tocopherol, 100 mcg/d of selenium, and 25 mg/d of β-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.
Authors and Reviewers
Originally written in 2000 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in August 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in June 2007 by:
Victoria J. Drake, 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 2000-2015 Linus Pauling Institute
1. Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.
2. Penberthy WT, Kirkland JB. Niacin. In: Erdman JW, MacDonald I, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Ames: International Life Sciences Institute; 2012:293-306.
3. Cervantes-Laurean D, McElvaney NG, Moss J. Niacin. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:401-411.
4. Di Girolamo M, Dani N, Stilla A, Corda D. Physiological relevance of the endogenous mono(ADP-ribosyl)ation of cellular proteins. FEBS J. 2005;272(18):4565-4575. (PubMed)
5. Jacobson MK, Jacobson EL. Discovering new ADP-ribose polymer cycles: protecting the genome and more. Trends Biochem Sci. 1999;24(11):415-417.
6. Hottiger MO, Hassa PO, Luscher B, Schuler H, Koch-Nolte F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem Sci. 2010;35(4):208-219. (PubMed)
7. Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013;56:133-171. (PubMed)
8. Park YK, Sempos CT, Barton CN, Vanderveen JE, Yetley EA. Effectiveness of food fortification in the United States: the case of pellagra. Am J Public Health. 2000;90(5):727-738. (PubMed)
9. Gregory JF, 3rd. Nutritional properties and significance of vitamin glycosides. Annu Rev Nutr. 1998;18:277-296. (PubMed)
10. Jacob R, Swenseid M. Niacin. In: Ziegler E, Filer L, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:185-190.
11. Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract. 2012;7(1):12. (PubMed)
12. World Health Organization, United Nations High Commissions for Refugees. Pellagra and its prevention and control in major emergencies. World Health Organization. 2000. Available at http://www.who.int/nutrition/publications/
emergencies/WHO_NHD_00.10/en/. Accessed 6/20/13.
13. Nogueira A, Duarte AF, Magina S, Azevedo F. Pellagra associated with esophageal carcinoma and alcoholism. Dermatol Online J. 2009;15(5):8. (PubMed)
14. Murray MF. Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. Lancet Infect Dis. 2003;3(10):644-652. (PubMed)
15. Hao K, Zhou Q, Chen W, et al. Possible role of the 'IDO-AhR axis' in maternal-foetal tolerance. Cell Biol Int. 2013;37(2):105-108. (PubMed)
16. Fu CS, Swendseid ME, Jacob RA, McKee RW. Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. J Nutr. 1989;119(12):1949-1955. (PubMed)
17. Dawson B, Favaloro EJ, Taylor J, Aggarwal A. Unrecognized pellagra masquerading as odynophagia. Intern Med J. 2006;36(7):472-474. (PubMed)
18. Jagielska G, Tomaszewicz-Libudzic EC, Brzozowska A. Pellagra: a rare complication of anorexia nervosa. Eur Child Adolesc Psychiatry. 2007;16(7):417-420. (PubMed)
19. Kertesz SG. Pellagra in 2 homeless men. Mayo Clin Proc. 2001;76(3):315-318. (PubMed)
20. Prakash R, Gandotra S, Singh LK, Das B, Lakra A. Rapid resolution of delusional parasitosis in pellagra with niacin augmentation therapy. Gen Hosp Psychiatry. 2008;30(6):581-584. (PubMed)
21. Rosmaninho A, Sanches M, Fernandes IC, et al. Letter: Pellagra as the initial presentation of Crohn disease. Dermatol Online J. 2012;18(4):12. (PubMed)
22. Zaraa I, Belghith I, El Euch D, et al. A case of pellagra associated with megaduodenum in a young woman. Nutr Clin Pract. 2013;28(2):218-222. (PubMed)
23. Bilgili SG, Karadag AS, Calka O, Altun F. Isoniazid-induced pellagra. Cutan Ocul Toxicol. 2011;30(4):317-319. (PubMed)
24. Dreizen S, McCredie KB, Keating MJ, Andersson BS. Nutritional deficiencies in patients receiving cancer chemotherapy. Postgrad Med. 1990;87(1):163-167, 170. (PubMed)
25. Food and Nutrition Board, Institute of Medicine. Niacin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:123-149. (National Academy Press)
26. Jacobson EL, Jacobson MK. Tissue NAD as a biochemical measure of niacin status in humans. Methods Enzymol. 1997;280:221-230.
27. Jacobson EL, Shieh WM, Huang AC. Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. Mol Cell Biochem. 1999;193(1-2):69-74. (PubMed)
28. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability--an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11(3):220-228. (PubMed)
29. Kirkland JB. Niacin requirements for genomic stability. Mutat Res. 2012;733(1-2):14-20. (PubMed)
30. Spronck JC, Nickerson JL, Kirkland JB. Niacin deficiency alters p53 expression and impairs etoposide-induced cell cycle arrest and apoptosis in rat bone marrow cells. Nutr Cancer. 2007;57(1):88-99. (PubMed)
31. Spronck JC, Kirkland JB. Niacin deficiency increases spontaneous and etoposide-induced chromosomal instability in rat bone marrow cells in vivo. Mutat Res. 2002;508(1-2):83-97. (PubMed)
32. Kostecki LM, Thomas M, Linford G, et al. Niacin deficiency delays DNA excision repair and increases spontaneous and nitrosourea-induced chromosomal instability in rat bone marrow. Mutat Res. 2007;625(1-2):50-61. (PubMed)
33. Dantzer F, Santoro R. The expanding role of PARPs in the establishment and maintenance of heterochromatin. FEBS J. 2013;280(15):3508-3518. (PubMed)
34. El Ramy R, Magroun N, Messadecq N, et al. Functional interplay between Parp-1 and SirT1 in genome integrity and chromatin-based processes. Cell Mol Life Sci. 2009;66(19):3219-3234. (PubMed)
35. Boyonoski AC, Spronck JC, Gallacher LM, et al. Niacin deficiency decreases bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats. J Nutr. 2002;132(1):108-114. (PubMed)
36. Boyonoski AC, Spronck JC, Jacobs RM, Shah GM, Poirier GG, Kirkland JB. Pharmacological intakes of niacin increase bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats. J Nutr. 2002;132(1):115-120. (PubMed)
37. Weitberg AB. Effect of nicotinic acid supplementation in vivo on oxygen radical-induced genetic damage in human lymphocytes. Mutat Res. 1989;216(4):197-201. (PubMed)
38. Hageman GJ, Stierum RH, van Herwijnen MH, van der Veer MS, Kleinjans JC. Nicotinic acid supplementation: effects on niacin status, cytogenetic damage, and poly(ADP-ribosylation) in lymphocytes of smokers. Nutr Cancer. 1998;32(2):113-120. (PubMed)
39. Yong LC, Petersen MR. High dietary niacin intake is associated with decreased chromosome translocation frequency in airline pilots. Br J Nutr. 2011;105(4):496-505. (PubMed)
40. Jacobson EL. Niacin deficiency and cancer in women. J Am Coll Nutr. 1993;12(4):412-416. (PubMed)
41. Negri E, Franceschi S, Bosetti C, et al. Selected micronutrients and oral and pharyngeal cancer. Int J Cancer. 2000;86(1):122-127. (PubMed)
42. Franceschi S, Bidoli E, Negri E, et al. Role of macronutrients, vitamins and minerals in the aetiology of squamous-cell carcinoma of the oesophagus. Int J Cancer. 2000;86(5):626-631. (PubMed)
43. Gensler HL, Williams T, Huang AC, Jacobson EL. Oral niacin prevents photocarcinogenesis and photoimmunosuppression in mice. Nutr Cancer. 1999;34(1):36-41. (PubMed)
44. Jacobson EL, Kim H, Kim M, et al. A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function in photodamaged skin. Exp Dermatol. 2007;16(6):490-499. (PubMed)
45. Bermudez Y, Benavente CA, Meyer RG, Coyle WR, Jacobson MK, Jacobson EL. Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation. PLoS One. 2011;6(5):e20487. (PubMed)
46. Benavente CA, Jacobson EL. Niacin restriction upregulates NADPH oxidase and reactive oxygen species (ROS) in human keratinocytes. Free Radic Biol Med. 2008;44(4):527-537. (PubMed)
47. Benavente CA, Schnell SA, Jacobson EL. Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin. PLoS One. 2012;7(7):e42276. (PubMed)
48 Lampeter EF, Klinghammer A, Scherbaum WA, et al. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group. Diabetes. 1998;47(6):980-984. (PubMed)
49. Greenbaum CJ, Kahn SE, Palmer JP. Nicotinamide's effects on glucose metabolism in subjects at risk for IDDM. Diabetes. 1996;45(11):1631-1634. (PubMed)
50. Gale EA, Bingley PJ, Emmett CL, Collier T, European Nicotinamide Diabetes Intervention Trial Group. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet. 2004;363(9413):925-931. (PubMed)
51. Hedman M, Ludvigsson J, Faresjo MK. Nicotinamide reduces high secretion of IFN-γ in high-risk relatives even though it does not prevent type 1 diabetes. J Interferon Cytokine Res. 2006;26(4):207-213. (PubMed)
52. Fernandez IC, Del Carmen Camberos M, Passicot GA, Martucci LC, Cresto JC. Children at risk of diabetes type 1. Treatment with acetyl-L-carnitine plus nicotinamide - Case reports. J Pediatr Endocrinol Metab. 2013;26(3-4):347-355. (PubMed)
53. Ku CR, Lee HJ, Kim SK, Lee EY, Lee MK, Lee EJ. Resveratrol prevents streptozotocin-induced diabetes by inhibiting the apoptosis of pancreatic β-cell and the cleavage of poly (ADP-ribose) polymerase. Endocr J. 2012;59(2):103-109. (PubMed)
54. Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341(7):498-511.
55. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8(6):1245-1255. (PubMed)
56. Guyton JR, Capuzzi DM. Treatment of hyperlipidemia with combined niacin-statin regimens. Am J Cardiol. 1998;82(12A):82U-84U; discussion 85-86U. (PubMed)
57. Bays HE, Shah A, Lin J, Sisk CM, Dong Q, Maccubbin D. Consistency of extended-release niacin/laropiprant effects on Lp(a), ApoB, non-HDL-C, Apo A1, and ApoB/ApoA1 ratio across patient subgroups. Am J Cardiovasc Drugs. 2012;12(3):197-206. (PubMed)
58. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592. (PubMed)
59. Vittone F, Chait A, Morse JS, Fish B, Brown BG, Zhao XQ. Niacin plus Simvastatin Reduces Coronary Stenosis Progression Among Patients with Metabolic Syndrome Despite a Modest Increase in Insulin Resistance: A Subgroup Analysis of the HDL-Atherosclerosis Treatment Study (HATS). J Clin Lipidol. 2007;1(3):203-210. (PubMed)
60. Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study). Am J Cardiol. 2004;93(3):307-312. (PubMed)
61. Sazonov V, Maccubbin D, Sisk CM, Canner PL. Effects of niacin on the incidence of new onset diabetes and cardiovascular events in patients with normoglycaemia and impaired fasting glucose. Int J Clin Pract. 2013;67(4):297-302. (PubMed)
62. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110(23):3512-3517. (PubMed)
63. Taylor AJ, Zhu D, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Relationship between glycemic status and progression of carotid intima-media thickness during treatment with combined statin and extended-release niacin in ARBITER 2. Vasc Health Risk Manag. 2007;3(1):159-164. (PubMed)
64. Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol. 2010;55(24):2721-2726. (PubMed)
65. McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med. 2004;164(7):697-705. (PubMed)
66. Wink J, Giacoppe G, King J. Effect of very-low-dose niacin on high-density lipoprotein in patients undergoing long-term statin therapy. Am Heart J. 2002;143(3):514-518. (PubMed)
67. Brown RR, Ozaki Y, Datta SP, Borden EC, Sondel PM, Malone DG. Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDS. Adv Exp Med Biol. 1991;294:425-435. (PubMed)
68. Taylor EW. The oxidative stress-induced niacin sink (OSINS) model for HIV pathogenesis. Toxicology. 2010;278(1):124-130. (PubMed)
69. Dunham RM, Gordon SN, Vaccari M, et al. Preclinical evaluation of HIV eradication strategies in the simian immunodeficiency virus-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenase. AIDS Res Hum Retroviruses. 2013;29(2):207-214. (PubMed)
70. Tang AM, Graham NM, Saah AJ. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. Am J Epidemiol. 1996;143(12):1244-1256. (PubMed)
71. Murray MF, Langan M, MacGregor RR. Increased plasma tryptophan in HIV-infected patients treated with pharmacologic doses of nicotinamide. Nutrition. 2001;17(7-8):654-656. (PubMed)
72. Dube MP, Lipshultz SE, Fichtenbaum CJ, et al. Effects of HIV infection and antiretroviral therapy on the heart and vasculature. Circulation. 2008;118(2):e36-40. (PubMed)
73. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12(7):F51-58. (PubMed)
74. Giannarelli C, Klein RS, Badimon JJ. Cardiovascular implications of HIV-induced dyslipidemia. Atherosclerosis. 2011;219(2):384-389. (PubMed)
75. Chow DC, Stein JH, Seto TB, et al. Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy. AIDS. 2010;24(7):1019-1023. (PubMed)
76. Balasubramanyam A, Coraza I, Smith EO, et al. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. J Clin Endocrinol Metab. 2011;96(7):2236-2247. (PubMed)
77. Hoffer LJ. Vitamin therapy in schizophrenia. Isr J Psychiatry Relat Sci. 2008;45(1):3-10. (PubMed)
78. Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(3825):265-271. (PubMed)
79. Seybolt SE. Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia? Med Hypotheses. 2010;75(6):572-575. (PubMed)
80. Zell M, Grundmann O. An orthomolecular approach to the prevention and treatment of psychiatric disorders. Adv Mind Body Med. 2012;26(2):14-28. (PubMed)
81. Messamore E. Niacin subsensitivity is associated with functional impairment in schizophrenia. Schizophr Res. 2012;137(1-3):180-184. (PubMed)
82. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res. 1998;30(3):193-208. (PubMed)
83. US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 25. 2012. Available at: http://ndb.nal.usda.gov/. Accessed 6/24/13.
84. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.
85. Vitamins. Drug Facts and Comparisons. St. Louis: Facts and Comparisons; 2000:6-33.
86. Knopp RH. Evaluating niacin in its various forms. Am J Cardiol. 2000;86(12A):51L-56L. (PubMed)
87. Kar S, Chockalingam A. Statin-associated rhabdomyolysis with acute renal failure complicated by intradialytic NSTEMI: a review of lipid management considerations. Am J Ther. 2013;20(1):57-60. (PubMed)
88. Cziraky MJ, Willey VJ, McKenney JM, et al. Risk of hospitalized rhabdomyolysis associated with lipid-lowering drugs in a real-world clinical setting. J Clin Lipidol. 2013;7(2):102-108. (PubMed)
89. Maccubbin DL, Chen F, Anderson JW, et al. Effectiveness and safety of laropiprant on niacin-induced flushing. Am J Cardiol. 2012;110(6):817-822. (PubMed)
90. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34(17):1279-1291. (PubMed)
91. Lewey J, Shrank WH, Bowry AD, Kilabuk E, Brennan TA, Choudhry NK. Gender and racial disparities in adherence to statin therapy: a meta-analysis. Am Heart J. 2013;165(5):665-678, 678 e661. (PubMed)
92. Cheung MC, Zhao XQ, Chait A, Albers JJ, Brown BG. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol. 2001;21(8):1320-1326. (PubMed)
93. Brown BG, Cheung MC, Lee AC, Zhao XQ, Chait A. Antioxidant vitamins and lipid therapy: end of a long romance? Arterioscler Thromb Vasc Biol. 2002;22(10):1535-1546. (PubMed)