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Niacin: chemical forms, bioavailability, and health effects

Douglas MacKay, John Hathcock, Erminia Guarneri
DOI: http://dx.doi.org/10.1111/j.1753-4887.2012.00479.x 357-366 First published online: 1 June 2012


Elevated low-density lipoprotein cholesterol (LDL-C) has been the main target of lipid-altering therapy to reduce cardiovascular risk associated with dyslipidemia. Residual cardiovascular risk remains, however, after achievement of goal LDL-C levels and is associated in part with other risk markers of cardiovascular disease, including low high-density lipoprotein cholesterol (HDL-C), high lipoprotein a, and hypertriglyceridemia. Niacin is considered a valuable agent for therapy to modify high LDL-C as well as low HDL-C, high lipoprotein a, and hypertriglyceridemia. The forms of niacin available in the marketplace include unbound niacin, or free nicotinic acid (NA); extended-release NA, a form of NA that is released gradually over a period of time; inositol hexanicotinate, six molecules of NA covalently bonded to one molecule of inositol; and nicotinamide, or niacinamide, the amide form of NA, which is readily bioavailable. This review is designed to assist healthcare professionals in evaluating the form(s) of niacin best suited for a particular therapeutic goal. Further, it provides a literature-based evaluation of risk for NA, extended-release NA, inositol hexanicotinate, and nicotinamide.

  • adverse effects
  • bioavailability
  • inositol hexanicotinate
  • niacin
  • serum lipids


The term “niacin” is often defined as nicotinic acid (NA),1 although it can be defined more expansively as “nicotinamide (nicotinic acid amide), nicotinic acid (pyridine-3-carboxylic acid), and derivatives that exhibit the biological activity of nicotinamide.”2 Whether other compounds that are converted to NA or that contain NA, nicotinamide (NM), or their releasable moieties should be referred to as “niacin” depends on the biological effects that are attributed to the compound, the interpretation of the evidence for the rates of uptake and metabolism, and/or the release of the chemical components (apparent bioavailability) that produce biological effects similar to the primary forms of niacin. In doses large enough to produce pharmacological effects, NA and extended-release nicotinic acid (ER-NA) are potent lipid-modifying agents with a broad spectrum of effects, including effects aimed at attenuating the risks associated with low high-density lipoprotein cholesterol (HDL-C), high low-density lipoprotein cholesterol (LDL-C), high lipoprotein a, and hypertriglyceridemia.3 The landmark study by Altschul et al.4 was the first to report the cholesterol-lowering effects of niacin. Since then, numerous clinical trials have demonstrated that niacin reduces the risk of coronary artery disease and is the most potent lipid-regulating agent for increasing levels of HDL-C.5 Although the various forms of niacin available on the market have long been considered bioequivalent with respect to certain cardiovascular health benefits, this is the first extensive review of the literature comparing the efficacy and safety of the different chemical forms of niacin.

The objective of this review is to conduct a comprehensive analysis of the literature on the four primary forms of niacin available in the marketplace as either over-the-counter or prescription products, including free NA, ER-NA, inositol hexanicotinate (IHN), and NM (Table 1). A few other forms have been studied and are briefly mentioned in the discussion of specific research evidence, but they will not be a focus in this review. The analysis examines the bioavailability of each of these primary forms of niacin (assessed by plasma levels of NA), the efficacy of each form in meeting the nutritional requirement for niacin, the efficacy of each form with respect to effects on serum lipids and several disease conditions, and the dose-related adverse effects of each form. Briefly, relevant articles were identified through a literature search of the PubMed database (1960 to present) and through bibliographic tracing for older articles. Articles involving one or more of the four niacin forms (NA, ER-NA, NM, and IHN) and including assessments of bioavailability, metabolism, efficacy, and adverse effects were selected for review. To review the safety of the four forms, past safety and risk assessments published by authoritative bodies, including the US Institute of Medicine (IOM),2 the European Commission's Scientific Committee on Food (SCF),6 and the UK Expert Group on Vitamins and Minerals (EVM),7 were consulted in addition to other selected reviews.8,9

View this table:
Table 1

Different forms of supplemental niacin.



Nicotinic acid

Intestinal uptakes of NA are rapid and nearly stoichiometric,2 i.e., bolus doses of up to 3–4 g NA are almost completely absorbed by adults.10 Once absorbed in the intestine, 15–30% of the plasma NA is bound to protein.1 The overall dose-response relationships of NA are well known.11 Nutritional functions related to NM-containing coenzymes1 occur at lower levels of intake (15–18 mg/day), while the undesirable vasodilative flushing effect may occur when intakes exceed 50 mg/day.12,13 The beneficial effects on serum lipid profiles occur at much higher levels of intake (500–3,000 mg/day). These widely studied impacts on serum lipids are accompanied by low but significant risks of liver and intestinal pathologies.8

Extended-release nicotinic acid

ER-NA and various formulations of IHN, which minimize or avoid the undesirable flushing effect of NA, have been investigated for their potentially beneficial effects on serum lipids.14 Research on these compounds in relation to serum lipids has been performed under the assumption that the known effects of NA might be achieved without the flushing effect. For ER-NA, the potential impacts on serum lipid concentrations are directly related to the release of NA from the matrix in which it is presented. The uptake of NA from ER-NA formulations is dependent on the specific delivery matrix and is significantly slower than that of NA, but rapid enough to achieve effective plasma NA concentrations.15,16

Inositol hexanicotinate

In 2009, the European Food Safety Authority (EFSA) Scientific Panel on Food Additives and Nutrient Sources Added to Food concluded that nicotinate from IHN is a bioavailable source of niacin.17 The data available suggests that intestinal absorption of IHN varies widely, with an average of 70% of the administered dose being absorbed into the bloodstream.18 Although the fraction absorbed is not as high as for NA, the majority of IHN is absorbed and appears to remain intact. Possible direct actions of IHN after absorption have not been demonstrated but are plausible. Metabolism of IHN to release NA can result in the physiological actions of NA, depending on the rate and amount of release. The beneficial lipid-lowering effects of NA and ER-NA are well established, but the beneficial effects of IHN on serum lipids are dependent on the uptake of IHN and the substantial subsequent release of the NA moieties from the IHN molecule.

The available reports indicate that IHN does not produce plasma NA levels sufficient to lower lipids. Humans given oral doses of IHN obtain peak plasma levels of NA at 6–12 h,19,20 while oral doses of NA result in peak plasma levels of NA at 0.5–1 h.21 Interestingly, the peak plasma levels of NA after oral doses of IHN are dramatically lower when compared with those obtained after oral doses of NA; for example, a single oral dose of 1,000 mg NA resulted in a peak plasma level of 30 µg/mL NA,21 while 1,000 mg of IHN (weight equivalent to ∼910 mg NA) resulted in a peak plasma level of 0.2 µg/mL NA.22 Similarly, Kruse et al.23 gave 12 healthy young women 2,400 mg of IHN orally over a 3-hour period and achieved a peak plasma NA level of 0.1 µg/mL. Another experiment conducted in dogs compared the bioavailability of oral doses of 1 g of NA to the same amount of IHN and pentaerythritol tetranicotinate. The peak plasma level of NA was 130 times (approximately 65 µg/mL) greater than the peak plasma level of IHN (approximately 0.5 µg/mL) and 80 times greater than that of pentaerythritol tetranicotinate (0.8 µg/mL).22

Some reports indicate IHN produces a slight increase in the plasma level of NA but does not have any significant effects on plasma lipid profiles.2224 If IHN is, in fact, absorbed intact and hydrolyzed in the body with the release of NA and inositol, the extent of hydrolysis appears to be very low, as evidenced by the low levels of NA found in plasma after IHN ingestion. The significant differences in plasma levels of NA that are achieved after similar oral doses of IHN and NA may account for the different effects observed in clinical studies. In fact, the observed effects of IHN may not be related to its total NA content but rather to a direct effect of IHN itself. Overall, the evidence indicates that IHN produces only slight increases in plasma NA, but these changes are not large enough to significantly alter plasma lipid profiles.25


NM is readily bioavailable2 and is effective in preventing the classical signs of niacin deficiency (pellagra). Female college students were administered 51 mg of NM, of which 52% was excreted as urinary metabolites.26 NM is not sufficiently converted to NA to produce either the undesirable flushing effect or the beneficial changes in plasma lipids.27


Niacin therapy may be initiated with an extended-release nicotinic acid drug or an immediate-release preparation such as free nicotinic acid. Niacin therapy should be avoided in individuals with liver abnormalities, peptic ulcer disease, and gout. The adage “start low and go slow” is the most robust way to approach free nicotinic acid therapy. Measurement of serum lipids and hepatic function should be evaluated as niacin is titrated. Although flushing is a common side effect with both the free nicotinic acid and the extended-release forms, it is possible to ameliorate this symptom by ingesting niacin with food, avoiding alcohol, and, for those individuals on aspirin therapy, consuming aspirin one-half hour before ingesting niacin. The free nicotinic acid form can be taken with multiple meals in divided doses, making it possible to achieve therapeutic goals.


Nicotinic acid

This chemical form fully supports the NM-dependent coenzyme activities and may properly be called niacin. In addition to supporting coenzyme functions, NA at high intakes is an effective antihyperlipidemic agent, and an ER-NA prescription drug product has been approved by the US Food and Drug Administration.28 NA not only lowers LDL-C and very low-density lipoprotein cholesterol and triglycerides, it also raises HDL-C. It is one of the few lipid-altering agents that have been shown to decrease mortality due to heart attacks.29 High-dose NA (above 50 mg) is marketed in the United States as a dietary supplement (which may not make drug claims) and also as a prescription drug (which may make approved therapeutic claims). The beneficial lipid-lowering effects of both NA and ER-NA are well established, with data showing reduction of total triglyceride levels by 20–50%, reduction of LDL-C levels by 10–25%, increases of HDL-C levels by 10–30%, and reduction of lipoprotein a levels by 10–30%,3035 which includes preferential reduction of the more atherogenic, small, dense LDL-C.36 Both NA and ER-NA are effective in treating a range of lipid disorders, but neither has become a first-line therapy because of the uncomfortable flushing side effect and the potential risk of liver and gastrointestinal side effects. Clearly, NA is a very effective and inexpensive agent for improving health outcomes in persons with elevated lipid levels at risk for heart disease, but its utility is limited by poor patient compliance due to the generally unacceptable flushing reaction.3739

Inositol hexanicotinate

This compound is marketed as “no-flush niacin.”24 The small amount of data available that suggests IHN does not produce a flushing reaction is consistent with the modest NA plasma response following IHN intake.2340 Few other adverse effects have been reported in clinical trials studying the use of dosages of IHN up to 4,000 mg/day.4043 There is debate about whether the bioavailability of NA from IHN is high enough to justify it being considered a form of niacin. Some publications support this classification,17 while others contradict it.14 The functional effect by which “niacin” is to be defined must be specified for the term to have meaning.

IHN has been discussed as a better tolerated and safer alternative to NA and ER-NA,44,45 but data on the efficacy of IHN for lowering serum lipids do not support the hypothesis that the chemical forms are clinically interchangeable.1425

The relatively high intestinal absorption efficiency (70%) and partial release of NA from the IHN molecule after absorption should hypothetically allow sufficiently high intakes of IHN to be an adequate source of niacin for the conventional nutritional functions.17 There is very limited evidence of reduction in serum lipids by IHN, and it is doubtful that IHN could be an effective lipid control agent at any of the dosage levels tested. Although Welsh and Ede19 are cited in many reviews as supporting the use of IHN in controlling hyperlipidemia, serum lipid data were collected in only two patients (with “selected dermatoses”), and the study lacked a control group. In the study, total cholesterol decreased by 12% and 17% in patients 1 and 2, respectively.19 If validated, these results might be considered compelling on a population basis; however, with only two test subjects and no control group, the data cannot be considered representative. Even though the data presented by Welsh and Ede19 are suggestive of a beneficial effect, they are inconsistent with the majority of available evidence and are not convincing enough to serve as the basis of a general recommendation for the use of IHN in controlling blood lipids.

Another IHN clinical study included 41 hyperlipidemic individuals who showed a mean reduction in total cholesterol of 8.2%, but again there was no placebo group.46 In a report by Fischer and Falkensammer,47 250 mg of IHN in combination with 350 mg of magnesium chlorophenoxyisobutyrate resulted in a modest reduction in serum lipids. However, it is important to note that the same reduction in serum lipids has been observed in studies using chlorophenoxyisobutyrate alone.48 Therefore, attribution of the observed effect to IHN is speculative.

The limited evidence of reductions in serum lipids by IHN observed in published studies is offset by several reports of IHN having no effect on serum lipids. In a double-blind, placebo-controlled trial, 11 subjects received 1,500 mg/day IHN for 3 months and experienced no change in plasma lipid concentrations.24 In addition, Kruse et al.23 showed that 2,400 mg of IHN given in three divided oral doses over a 3-hour period had no effect on plasma triglyceride or cholesterol levels over the subsequent 24-hour period. Another study of 59 normolipidemic and dyslipidemic patients showed that IHN had no significant effect on total cholesterol.49

A published case report discusses a treatment failure using IHN titrated up to 2,000 mg/day for 6 months in a 49-year-old male with heart disease. No beneficial or adverse effects were observed after 6 months of treatment. The patient was switched to a prescription of 1,000 mg ER-NA and, after 3 months, experienced a 20% increase in HDL-C.14 Meyers et al.25 performed a comprehensive comparison of over-the-counter niacin preparations and concluded that IHN preparations are not an effective treatment for dyslipidemia. The strongest evidence that IHN does not reduce blood lipids comes from a recent 6-week, parallel three-arm (n = 120; 40 subjects per arm), double-blind, randomized clinical trial that used 1,500 mg/day (500 mg of ER-NA, IHN, and placebo 3 times per day with meals).50 ER-NA significantly reduced total cholesterol and LDL-C and significantly increased HDL-C. Triglycerides were not significantly reduced (−9%, P = 0.075). In contrast to the beneficial effects of ER-NA on blood lipids, IHN had no significant or nearly significant effects (total cholesterol: −1%; LDL: −1%; HDL: +1%; triglycerides: +2%).

Collectively, the available data show no significant effects of IHN on blood lipids following daily oral intakes of up to 2,000 mg/day (Table 2).

View this table:
Table 2

Evidence of the effects of inositol hexanicotinate (IHN) on blood lipids.

ReferenceNo. of subjectsDoseDurationStudy designFindingAuthor comment
Welsh and Ede (1961)1921,200 mg IHN/day10 monthsPublished case report12% and 17% reduction in total cholesterolCited by review articles as supporting the use of IHN in controlling hyperlipidemia
Fischer and Falkensammer (1977)4716350 mg Mg-chlorphenoxyisobutyrate + 250 mg mesoinositol-hexanicotinate/day60 daysOpen labela16–20% reduction in serum cholesterolReduction in serum cholesterol is consistent with 350 mg Mg-chlorphenoxyisobutyrate alone
Ziliotto et al. (1977)49591,500 mg IHN/day compared with 1,500 mg pentaerythritol tetranticotinate/day7 daysCOTIHN had a slight effect on total blood lipidsEffect of pentaerythritol tetranticotinate on normalization of lipids similar to that observed with NA
Agusti et al. (1978)46414,500 mg IHN/day15–120 daysOpen labela8–12% reduction in total cholesterol for 64.2% of participantsTreatment duration with IHN varied significantly
Kruse et al. (1979)23122,400 mg IHN divided into 3 equal doses3 hoursCOTAcute, but not sustained, reduction of nocturnal levels of free fatty acidsTherapeutic potential of any niacin preparation depends on its ability to exhibit a sustained inhibition of free fatty acid levels
Norris (2006)141≤2,000 mg IHN/day6 monthsPublished case reportNo effectSignificant improvements in serum lipids after switching to 1,000 mg ER-NA for 12 weeks
Benjo et al. (2006)24221,500 mg IHN/day3 monthsRCTNo change in plasma lipidsSubjects showed improvements in vascular reactivity
Keenan (2010)50121,500 mg IHN/day or 1,500 mg ER-NA/day6 weeksRCTIHN had no effect; ER-NA significantly improved serum lipidsStrongest evidence that IHN does not reduce serum lipids
  • a No control group.

  • Abbreviations: COT, crossover trial; ER-NA, extended-release nicotinic acid; IHN, inositol hexanicotinate; NA, nicotinic acid; RCT, randomized double-blind placebo-controlled trial.

While the evidence to support the use of IHN for dyslipidemic disorders is weak to contradictory, there are reports suggesting that IHN may have a beneficial effect on endothelium-dependent vasodilatation. Benjo et al.24 observed no improvements in serum lipids after 3 months of 1,500 mg/day IHN but did observe improvements in flow-mediated dilation of the brachial artery, indicating an improved endothelial function.

Blood flow improvements are therapeutically important in conditions resulting from peripheral vascular insufficiency, such as Raynaud's disease and intermittent claudication. The clinical research literature includes promising results from several studies on the use of IHN for improving blood flow in these conditions.5153 IHN is prescribed in Europe as a patented drug known as Hexopal, which is therapeutically indicated for the symptomatic relief of severe intermittent claudication and Raynaud's phenomenon. The usual adult dose of IHN for these conditions is 3 g/day and is increased to 4 g/day if necessary. IHN is not recommended for use in children.54 The mode of action of IHN in Raynaud's phenomenon and in intermittent claudication is not known. However, IHN does not appear to work solely via general peripheral vasodilatation, and it is hypothesized that its activity may also be mediated through a reduction in fibrinogen, improvements in blood viscosity, and resultant improvement in oxygen transport.34


Like NA, this chemical form fully supports the classic niacin function of providing NM coenzymes and preventing pellagra. Higher doses of NM have been tested for a variety of possible benefits related to several disease conditions such as depression,55 but results are inconsistent and NM is not generally recognized as an effective treatment for clinical depression or high plasma triglyceride and cholesterol levels.


Nicotinic acid

This form of niacin has the potential to produce several different adverse effects, depending on the intake.2 Intakes of 1 g or more per day not only provide pharmacological benefits but also carry a significant risk of adverse effects, thus requiring medical monitoring and supervision. High intakes of NA produce a vasodilative effect that can result in an intense itching or burning sensation of the skin known as the “niacin flush.” Flushing may be classified as a nuisance effect. It is initiated via prostaglandin D2-mediated vasodilatation of small subcutaneous blood vessels. The vasodilatation is associated with an unpleasant sensation of intense warmth and itching that commonly starts in the face and neck and can proceed down through the body. Some individuals may experience a rash, hypotension, and/or dizziness.56 Flushing appears about 30 minutes after intake of NA, and 2–4 hours after intake of ER-NA. Skin-flushing reactions usually persist over only a few doses until the body develops a natural tolerance. The daily dose is generally administered over several hours in three parts to reduce flushing. Each portion may be increased gradually until the desired total dose is achieved. Liver function tests and tests for uric acid, fasting blood glucose, and lipid levels should be conducted as the dose is administered. When used as an antihyperlipidemic agent, adverse reactions may require decreased dosage or discontinuation in favor of other agents.

Flushing effect.  The recommended dietary intakes of 15–18 mg/day carry no known risk of adverse effects, but the vasodilative flushing effect can be quite pronounced at intakes as low as 50 mg/day and may occur infrequently at intakes as low as 30 mg/day, depending on the circumstances of the intake. Important modifiers of flushing risk include empty or full stomach; dissolved versus crystalline form of NA; and bolus administration versus intake spread over several hours. The flushing effect can be managed effectively in most patients, provided they are given proper instructions and the dose is slowly titrated upward to reach therapeutic levels.56

In the original studies cited by the IOM as the source of data to identify flushing as the critical effect for the risk assessment to establish a tolerable upper intake level (UL),2 NA was administered in bolus doses, which may have little relevance to NA consumed in food. Furthermore, the flushing effect, while definitely a nuisance, may or may not qualify as a hazard in risk assessment and thus as an appropriate basis for the UL. Certainly, a UL based on the flushing effect would have no implication for risk related to hepatic and intestinal effects, which occur only at much higher intake levels.

Hepatotoxicity and gastrointestinal toxicity.  These adverse effects, which can be severe, definitely provide cause for concern about the safety of daily intakes of 1 g NA or higher, the level at which toxicity usually occurs. Hepatotoxicity is detected most often as increases in serum levels of selected liver enzymes,39 but the severity of hepatotoxicity can range from elevated liver enzymes to acute liver failure.57 Although the likelihood of liver toxicity is significant, it is nevertheless low enough that NA at intakes of up to 2–4 g/day may be used safely and effectively as an antihyperlipidemia drug under medical monitoring and supervision. Although available on the market as a dietary supplement in tablets of 500 mg and 750 mg, NA should not be used at gram dosages without medical supervision. There is a strong correlation between the minimal adverse effects identified through clinical trials and those suggested by the published anecdotal case reports. Many severe reactions to NA, especially liver toxicity, have involved ill-advised or uninformed switching from NA preparations to ER-NA formulations without adjusting the dose.12

Most reported adverse reactions to NA have occurred with intakes of 2–6 g/day. There are only two anecdotal cases reported in which intake levels below 1,000 mg/day produced an adverse effect: in one, ER-NA was administered at 500 mg/day, and in the other, NA was given at 750 mg/day.12 The clinical trial of McKenney et al.31 investigated two groups of adult subjects, one given NA and the other ER-NA, each containing subgroups that covered a range of doses. These two treatment groups were observed for 6 weeks at dosage levels of 500, 1,000, 1,500, 2,000, and 3,000 mg/day. The data showed no adverse reactions at 500 mg/day for either form of NA but did show statistically significant effects beginning at 1,000 mg/day (gastrointestinal effects for NA, and mild liver toxicity for ER-NA). The gastrointestinal side effects ranged in severity from nausea to, in the extreme, recurrence of peptic ulcer that had been asymptomatic for 7 years.31 Quantities of NA above 1 g should not be self-administered as a dietary supplement but may be safely used under the care and monitoring of a healthcare provider. Such an application, it should be noted, constitutes a pharmaceutical use, not a dietary supplement use.

Extended-release nicotinic acid

The flushing reaction may be substantially reduced through the use of ER-NA instead of NA, but ER-NA preparations carry a greater risk of liver toxicity, as indicated by the reported cases of hepatotoxicity after unsupervised switching from crystalline NA to ER-NA forms. Furthermore, the ER-NA forms may also provide greater pharmacological benefit at any given dose.12 There may be wide differences in the pharmacokinetics of different ER-NA formulations, but the prescription products and some of the ER-NA dietary supplements have known and predictable characteristics.28,32 In general, the ER-NA forms produce lower peak serum concentrations, but these are sustained for longer periods. The data for a direct quantitative comparison of the ER-NA and NA forms are not robust, but the risk of hepatotoxicity seems approximately twice as high with the ER-NA forms compared with the crystalline NA form.8 If this is taken into account to help ensure the beneficial effects and avoid the more serious types of toxicity, the ER-NA forms have significant advantage in lowering the tendency to cause flushing effects, which should lead to better acceptance and compliance by the patient.


This form of niacin has been tested at multigram intakes, with inconsistent evidence of adverse effects.7,58 One study reported a range of adverse effects, including headache, heartburn, nausea, gastrointestinal disturbances, and fatigue at a dose of 3,000 mg/day supplemental NM for 3–36 months59; however, few details were provided and no controls were included for comparison. Although these effects might have been caused by NM, they are not unique to any specific substance or condition. Other supplementation trials6064 have reported no adverse effects at NM intake levels of up to 3,000 mg/day. However, the studies in which the highest doses were administered primarily looked for possible beneficial effect in patients with type 1 diabetes mellitus, and it is unclear how the possible adverse effects were evaluated. Because of the small database, the EVM applied an uncertainty factor of 3 and adjusted to a standard body weight of 60 kg to set a total dietary intake guidance level of 600 mg/day NM, or 560 mg/day of supplemental NM.7

Inositol hexanicotinate

The 70% intestinal absorption of IHN11 suggests that this compound could produce the flushing reaction if hydrolysis released a significant amount of NA at a sufficiently fast rate. There are no reports of flushing associated with IHN, but evidence demonstrating a meager increase in serum NA after administration and the lack of substantial evidence of the typical NA effects on serum lipids suggest that release of NA from IHN is very limited or extremely slow. Irrespective of the metabolic and pharmacokinetic pathways, IHN has not been associated with significant adverse effects at intake levelss up to 4 g/day.5153


Nicotinic acid

The IOM, SCF, and EVM have each set UL or similar values for NA based on its dermal vasodilative flushing effect, with the values being 35, 10, and 17 mg/day, respectively.27 The SCF argued that the flushing effect is the appropriate basis for the UL because of the possibility that hypotension induced by “high doses” of NA could lead to major adverse effects resulting from falls, particularly in the elderly. However, there is no evidence to support such speculated effects. The UL value of NA was not based on studies using “high-dose” NA, which hypothetically could lead to hypotension, but instead was derived using results related to 30-mg single doses and an uncertainty factor. In fact, the evidence that NA may cause systemic hypotension that might lead to falls is related to doses of more than 1,000 mg/day. NA intakes in that range may lead to the risk of hepato- and gastrointestinal toxicity,39 and the development of these effects, rather than the low-dose dermal vasodilatation that may be judged to be a nuisance rather than a hazard, would be the critical effect for assessing risk and establishing a UL value. It is suggested that the safe upper limit for supplemental NA formulations be set at 500 mg/day, a level associated with neither adverse effects in clinical trials nor anecdotal reports of adverse reactions, other than vasodilative dermal flushing.8 Supplemental products should carry label statements to inform consumers of the annoying but apparently otherwise harmless flushing effect.

Extended-release nicotinic acid

Although the data are not as robust for ER-NA, this form seems to be approximately twice as hepatotoxic as the free form of NA; thus, 250 mg/day has been recommended as the safe upper limit for supplemental ER-NA.8


Because NM does not produce a vasodilative dermal flush, the SCF and EVM established separate UL values for this compound on bases that are different from those for NA. These values are 900 mg/day and 500 mg/day, respectively. Inexplicably, the IOM did not establish a UL for NM separately from that for NA, even though NM does not produce the vasodilative flushing that was the basis of the UL for NA.2 Instead, the IOM applied the 35 mg UL to all forms of “niacin.” The IOM provided no discussion to address this anomaly. Previous risk analysis suggested a safe upper limit of supplemental NM of 1,500 mg/day,8 as well as the 900 mg/day and 500 mg/day values in the SCF and EVM reports.

Inositol hexanicotinate

No adverse effects have been attributed to this compound; therefore, there is no basis to establish a UL under the method used by the IOM and the SCF (and later the EFSA). An alternative method of risk assessment is to identify the highest intake that has adequate data to sufficiently exclude a risk of adverse effects. The resulting value is termed the highest observed intake,9 an intake with sufficient data to reasonably conclude that adverse effects are not known at this intake. Several studies suggest that a justifiable highest observed intake value for IHN is 3,000 mg/day5153 (Table 3).

View this table:
Table 3

Tolerable upper intake levels and related values for nicotinic acid, nicotinamide, and inositol hexanicotinate.

ReferenceUpper level of nicotinic acid; basisUpper level of nicotinamide; basisUpper level of IHN; basis
Institute of Medicine (1998)235 mg; flushing35 mg; flushing
Scientific Committee on Food (2002)610 mg; flushing900 mg; hepatotoxicity
Expert Group on Vitamins and Minerals (2003)717 mg; flushing500 mg; hepatotoxicity
Hathcock (2004)8500 mg; hepatotoxicity (250 mg ER-NA formulations)1,500 mg; hepatotoxicity
Current review500 mg (NA); hepatotoxicity (250 mg (ER-NA formulations)1,500 mg; hepatotoxicity3,000 mg; highest observed intake
  • Abbreviations: ER-NA, extended-release nicotinic acid; IHN, inositol hexanicotinate.


This analysis indicates that, contrary to the common and mistaken perception, the four major forms of niacin in the marketplace (NA, ER-NA, IHN, and NM) are not bioequivalent with respect to efficacy or safety. While all four forms possess the ability to fulfill the nutritional requirement for niacin in humans when intakes are sufficiently high, they have distinct dose-related effects pertaining to cardiovascular benefits and adverse effects, including flushing and hepatotoxicity.

NA and ER-NA are effective treatments for dyslipidemia. NA is strongly associated with an uncomfortable dermal flushing effect, which is decreased with ER-NA formulations. Both NA and ER-NA carry the risk of hepatotoxicity and gastrointestinal toxicity. However, NA and ER-NA are considered safe and effective antihyperlipidemic drugs for use under medical supervision and monitoring. ER-NA formulations substantially reduce the risk of flushing reactions but carry a greater risk of liver toxicity. ER-NA is approximately twice as hepatotoxic as NA, and clinicians and patients should be acutely aware of this distinction when considering a switch from NA to ER-NA. The recommended safe upper limit for dietary supplementation is 500 mg/day for NA and 250 mg/day or higher for ER-NA,8 as directed under medical supervision.

IHN is offered as a “no-flush” form of NA. Evidence suggests IHN may improve conditions associated with peripheral vascular insufficiency, such as Raynaud's phenomena and intermittent claudication, but it does not support the efficacy of IHN as a dyslipidemic agent. No adverse events or dermal flushing have been reported for IHN. A justifiable highest observed intake value for IHN is 3,000 mg/day.

NM is effective in fulfilling the nutritional requirement for niacin and preventing niacin deficiency. Evidence suggests NM has no effect on serum lipids and is not associated with dermal flushing effects. Other therapeutic effects of NM are under investigation. A recommended safe upper level of intake of NM is 1,500 mg/day.

Collectively, all forms of niacin perform essential biochemical functions and prevent niacin deficiency, but IHN has very limited supporting data. Full recognition of the unique effects of NA, ER-NA, IHN, and NM at higher doses can assist consumers and clinicians in choosing the correct agent while understanding the risks associated with each form. Furthermore, regulators and policymakers should consider the variable efficacy and safety profiles of these four agents when establishing public policy.


Declaration of interest.  DM and JH are employed by The Council for Responsible Nutrition, a trade association representing dietary supplement manufacturers and ingredient suppliers. There are no other relevant interests to declare.


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