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Nutrition in Clinical Care

Niacin: chemical forms, bioavailability, and health effects

Douglas MacKay, John Hathcock, and Erminia Guarneri

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.
© 2012 International Life Sciences Institute

INTRODUCTION a, and hypertriglyceridemia.3 The landmark study by

Altschul et al.4 was the first to report the cholesterol-
The term “niacin” is often defined as nicotinic acid (NA),1 lowering effects of niacin. Since then, numerous clinical
although it can be defined more expansively as “nicotina- trials have demonstrated that niacin reduces the risk of
mide (nicotinic acid amide), nicotinic acid (pyridine-3- coronary artery disease and is the most potent lipid-
carboxylic acid), and derivatives that exhibit the regulating agent for increasing levels of HDL-C.5
biological activity of nicotinamide.”2 Whether other com- Although the various forms of niacin available on the
pounds that are converted to NA or that contain NA, market have long been considered bioequivalent with
nicotinamide (NM), or their releasable moieties should respect to certain cardiovascular health benefits, this is
be referred to as “niacin” depends on the biological effects the first extensive review of the literature comparing the
that are attributed to the compound, the interpretation of efficacy and safety of the different chemical forms of
the evidence for the rates of uptake and metabolism, niacin.
and/or the release of the chemical components (apparent The objective of this review is to conduct a compre-
bioavailability) that produce biological effects similar to hensive analysis of the literature on the four primary
the primary forms of niacin. In doses large enough to forms of niacin available in the marketplace as either
produce pharmacological effects, NA and extended- over-the-counter or prescription products, including free
release nicotinic acid (ER-NA) are potent lipid-modifying NA, ER-NA, inositol hexanicotinate (IHN), and NM
agents with a broad spectrum of effects, including effects (Table 1). A few other forms have been studied and are
aimed at attenuating the risks associated with low high- briefly mentioned in the discussion of specific research
density lipoprotein cholesterol (HDL-C), high low- evidence, but they will not be a focus in this review. The
density lipoprotein cholesterol (LDL-C), high lipoprotein analysis examines the bioavailability of each of these

Affiliations: D MacKay and J Hathcock are with the Council for Responsible Nutrition, Washington, DC, USA. E Guarneri is with the Scripps
Center for Integrative Medicine, La Jolla, California, USA.
Correspondence: Douglas MacKay, Council for Responsible Nutrition, 1828 L Street NW, Suite 510, Washington, DC 20036, USA. E-mail:
dmackay@crnusa.org. Phone: +1-202-204-7664. Fax: +1-202-204-7701.
Key words: adverse effects, bioavailability, inositol hexanicotinate, niacin, serum lipids

doi:10.1111/j.1753-4887.2012.00479.x
Nutrition Reviews® Vol. 70(6):357–366 357
 Table 1 Different forms of supplemental niacin.
Form of niacin Biological effects Indications/effectiveness Flushing effect
Nicotinic acid At physiological amounts, the Physiological amounts Yes
effects of nicotinic acid and prevent vitamin B3 Prostaglandin
nicotinamide are deficiency D2-mediated
indistinguishable (see Supraphysiological vasodilatation of
nicotinamide) doses of nicotinic acid small cutaneous
Supraphysiological doses of are indicated for blood vessels that
nicotinic acid decrease total dyslipidemia, result in cutaneous
cholesterol, LDL cholesterol, atherosclerosis, and flush
and triglycerides and cardiovascular disease
increase HDL cholesterol
Nicotinamide Precursor to nicotinamide Prevents vitamin B3 None
adenine dinucleotide deficiency
phosphate (NADP), which is No effect on lipid levels
required for ATP synthesis, in individuals with
oxidation-reduction dyslipidemia
reactions, and ADP-ribose
transfer reactions
Inositol hexanicotinate Research suggests inositol Minimal to no effect on None
hexanicotinate metabolism lipid levels in
does not result in peak free individuals with
nicotinic acid levels high dyslipidemia
enough for a clinical effect Indicated for peripheral
on dyslipidemia vascular insufficiency
Other biological effects and symptomatic
include reduced fibrinogen relief of intermittent
levels, vasodilatory action, claudication and
improved blood viscosity, Raynaud’s
and oxygen transport phenomenon

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein.

primary forms of niacin (assessed by plasma levels of BIOAVAILABILITY

NA), the efficacy of each form in meeting the nutritional
requirement for niacin, the efficacy of each form with Nicotinic acid
respect to effects on serum lipids and several disease con-
ditions, and the dose-related adverse effects of each form. Intestinal uptakes of NA are rapid and nearly stoichio-
Briefly, relevant articles were identified through a litera- metric,2 i.e., bolus doses of up to 3–4 g NA are almost
ture search of the PubMed database (1960 to present) and completely absorbed by adults.10 Once absorbed in the
through bibliographic tracing for older articles. Articles intestine, 15–30% of the plasma NA is bound to pro-
involving one or more of the four niacin forms (NA, tein.1 The overall dose-response relationships of NA
ER-NA, NM, and IHN) and including assessments of bio- are well known.11 Nutritional functions related to
availability, metabolism, efficacy, and adverse effects were NM-containing coenzymes1 occur at lower levels of
selected for review. To review the safety of the four forms, intake (15–18 mg/day), while the undesirable vasodila-
past safety and risk assessments published by authorita- tive flushing effect may occur when intakes exceed
tive bodies, including the US Institute of Medicine 50 mg/day.12,13 The beneficial effects on serum lipid pro-
(IOM),2 the European Commission’s Scientific Commit- files occur at much higher levels of intake (500–
tee on Food (SCF),6 and the UK Expert Group on Vita- 3,000 mg/day). These widely studied impacts on serum
mins and Minerals (EVM),7 were consulted in addition to lipids are accompanied by low but significant risks of
other selected reviews.8,9 liver and intestinal pathologies.8

358 Nutrition Reviews® Vol. 70(6):357–366

Extended-release nicotinic acid (approximately 0.5 mg/mL) and 80 times greater than that
of pentaerythritol tetranicotinate (0.8 mg/mL).22
ER-NA and various formulations of IHN, which mini- Some reports indicate IHN produces a slight increase
mize or avoid the undesirable flushing effect of NA, have in the plasma level of NA but does not have any signifi-
been investigated for their potentially beneficial effects on cant effects on plasma lipid profiles.22–24 If IHN is, in fact,
serum lipids.14 Research on these compounds in relation absorbed intact and hydrolyzed in the body with the
to serum lipids has been performed under the assump- release of NA and inositol, the extent of hydrolysis
tion that the known effects of NA might be achieved appears to be very low, as evidenced by the low levels of
without the flushing effect. For ER-NA, the potential NA found in plasma after IHN ingestion. The significant
impacts on serum lipid concentrations are directly related differences in plasma levels of NA that are achieved after
to the release of NA from the matrix in which it is pre- similar oral doses of IHN and NA may account for the
sented. The uptake of NA from ER-NA formulations is different effects observed in clinical studies. In fact, the
dependent on the specific delivery matrix and is signifi- observed effects of IHN may not be related to its total NA
cantly slower than that of NA, but rapid enough to content but rather to a direct effect of IHN itself. Overall,
achieve effective plasma NA concentrations.15,16 the evidence indicates that IHN produces only slight
increases in plasma NA, but these changes are not large
Inositol hexanicotinate enough to significantly alter plasma lipid profiles.25

In 2009, the European Food Safety Authority (EFSA) Sci- Nicotinamide

entific Panel on Food Additives and Nutrient Sources
Added to Food concluded that nicotinate from IHN is a NM is readily bioavailable2 and is effective in preventing
bioavailable source of niacin.17 The data available suggests the classical signs of niacin deficiency (pellagra). Female
that intestinal absorption of IHN varies widely, with an college students were administered 51 mg of NM, of
average of 70% of the administered dose being absorbed which 52% was excreted as urinary metabolites.26 NM is
into the bloodstream.18 Although the fraction absorbed is not sufficiently converted to NA to produce either the
not as high as for NA, the majority of IHN is absorbed undesirable flushing effect or the beneficial changes in
and appears to remain intact. Possible direct actions of plasma lipids.27
IHN after absorption have not been demonstrated but are
plausible. Metabolism of IHN to release NA can result in
CLINICAL USE OF NIACIN
the physiological actions of NA, depending on the rate
and amount of release. The beneficial lipid-lowering Niacin therapy may be initiated with an extended-release
effects of NA and ER-NA are well established, but the nicotinic acid drug or an immediate-release preparation
beneficial effects of IHN on serum lipids are dependent such as free nicotinic acid. Niacin therapy should be
on the uptake of IHN and the substantial subsequent avoided in individuals with liver abnormalities, peptic
release of the NA moieties from the IHN molecule. ulcer disease, and gout. The adage “start low and go slow”
The available reports indicate that IHN does not is the most robust way to approach free nicotinic acid
produce plasma NA levels sufficient to lower lipids. therapy. Measurement of serum lipids and hepatic func-
Humans given oral doses of IHN obtain peak plasma tion should be evaluated as niacin is titrated. Although
levels of NA at 6–12 h,19,20 while oral doses of NA result in flushing is a common side effect with both the free nico-
peak plasma levels of NA at 0.5–1 h.21 Interestingly, the tinic acid and the extended-release forms, it is possible to
peak plasma levels of NA after oral doses of IHN are ameliorate this symptom by ingesting niacin with food,
dramatically lower when compared with those obtained avoiding alcohol, and, for those individuals on aspirin
after oral doses of NA; for example, a single oral dose of therapy, consuming aspirin one-half hour before ingest-
1,000 mg NA resulted in a peak plasma level of 30 mg/mL ing niacin. The free nicotinic acid form can be taken with
NA,21 while 1,000 mg of IHN (weight equivalent to multiple meals in divided doses, making it possible to
~910 mg NA) resulted in a peak plasma level of achieve therapeutic goals.
0.2 mg/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 mg/ BENEFICIAL EFFECTS
mL. Another experiment conducted in dogs compared
the bioavailability of oral doses of 1 g of NA to the same Nicotinic acid
amount of IHN and pentaerythritol tetranicotinate. The
peak plasma level of NA was 130 times (approximately This chemical form fully supports the NM-dependent
65 mg/mL) greater than the peak plasma level of IHN coenzyme activities and may properly be called niacin. In

Nutrition Reviews® Vol. 70(6):357–366 359

addition to supporting coenzyme functions, NA at high agent at any of the dosage levels tested. Although Welsh
intakes is an effective antihyperlipidemic agent, and an and Ede19 are cited in many reviews as supporting the use
ER-NA prescription drug product has been approved by of IHN in controlling hyperlipidemia, serum lipid data
the US Food and Drug Administration.28 NA not only were collected in only two patients (with “selected der-
lowers LDL-C and very low-density lipoprotein choles- matoses”), and the study lacked a control group. In the
terol and triglycerides, it also raises HDL-C. It is one of study, total cholesterol decreased by 12% and 17% in
the few lipid-altering agents that have been shown to patients 1 and 2, respectively.19 If validated, these results
decrease mortality due to heart attacks.29 High-dose NA might be considered compelling on a population basis;
(above 50 mg) is marketed in the United States as a however, with only two test subjects and no control
dietary supplement (which may not make drug claims) group, the data cannot be considered representative. Even
and also as a prescription drug (which may make though the data presented by Welsh and Ede19 are sugges-
approved therapeutic claims). The beneficial lipid- tive of a beneficial effect, they are inconsistent with the
lowering effects of both NA and ER-NA are well estab- majority of available evidence and are not convincing
lished, with data showing reduction of total triglyceride enough to serve as the basis of a general recommendation
levels by 20–50%, reduction of LDL-C levels by 10–25%, for the use of IHN in controlling blood lipids.
increases of HDL-C levels by 10–30%, and reduction of Another IHN clinical study included 41 hyperlipi-
lipoprotein a levels by 10–30%,30–35 which includes pref- demic individuals who showed a mean reduction in total
erential reduction of the more atherogenic, small, dense cholesterol of 8.2%, but again there was no placebo
LDL-C.36 Both NA and ER-NA are effective in treating a group.46 In a report by Fischer and Falkensammer,47
range of lipid disorders, but neither has become a first- 250 mg of IHN in combination with 350 mg of magne-
line therapy because of the uncomfortable flushing side sium chlorophenoxyisobutyrate resulted in a modest
effect and the potential risk of liver and gastrointestinal reduction in serum lipids. However, it is important to
side effects. Clearly, NA is a very effective and inexpensive note that the same reduction in serum lipids has been
agent for improving health outcomes in persons with observed in studies using chlorophenoxyisobutyrate
elevated lipid levels at risk for heart disease, but its utility alone.48 Therefore, attribution of the observed effect to
is limited by poor patient compliance due to the generally IHN is speculative.
unacceptable flushing reaction.37–39 The limited evidence of reductions in serum lipids by
IHN observed in published studies is offset by several
Inositol hexanicotinate reports of IHN having no effect on serum lipids. In
a double-blind, placebo-controlled trial, 11 subjects
This compound is marketed as “no-flush niacin.”24 The received 1,500 mg/day IHN for 3 months and experi-
small amount of data available that suggests IHN does not enced no change in plasma lipid concentrations.24 In
produce a flushing reaction is consistent with the modest addition, Kruse et al.23 showed that 2,400 mg of IHN
NA plasma response following IHN intake.23,24,40 Few given in three divided oral doses over a 3-hour period had
other adverse effects have been reported in clinical trials no effect on plasma triglyceride or cholesterol levels over
studying the use of dosages of IHN up to 4,000 mg/ the subsequent 24-hour period. Another study of 59 nor-
day.40–43 There is debate about whether the bioavailability molipidemic and dyslipidemic patients showed that IHN
of NA from IHN is high enough to justify it being con- had no significant effect on total cholesterol.49
sidered a form of niacin. Some publications support this A published case report discusses a treatment failure
classification,17 while others contradict it.14 The func- using IHN titrated up to 2,000 mg/day for 6 months in a
tional effect by which “niacin” is to be defined must be 49-year-old male with heart disease. No beneficial or
specified for the term to have meaning. adverse effects were observed after 6 months of treat-
IHN has been discussed as a better tolerated and ment. The patient was switched to a prescription of
safer alternative to NA and ER-NA,44,45 but data on the 1,000 mg ER-NA and, after 3 months, experienced a 20%
efficacy of IHN for lowering serum lipids do not support increase in HDL-C.14 Meyers et al.25 performed a compre-
the hypothesis that the chemical forms are clinically hensive comparison of over-the-counter niacin prepara-
interchangeable.14,23–25 tions and concluded that IHN preparations are not an
The relatively high intestinal absorption efficiency effective treatment for dyslipidemia. The strongest evi-
(70%) and partial release of NA from the IHN molecule dence that IHN does not reduce blood lipids comes from
after absorption should hypothetically allow sufficiently a recent 6-week, parallel three-arm (n = 120; 40 subjects
high intakes of IHN to be an adequate source of niacin for per arm), double-blind, randomized clinical trial that
the conventional nutritional functions.17 There is very used 1,500 mg/day (500 mg of ER-NA, IHN, and placebo
limited evidence of reduction in serum lipids by IHN, and 3 times per day with meals).50 ER-NA significantly
it is doubtful that IHN could be an effective lipid control reduced total cholesterol and LDL-C and significantly

360 Nutrition Reviews® Vol. 70(6):357–366

increased HDL-C. Triglycerides were not significantly Intakes of 1 g or more per day not only provide pharma-
reduced (-9%, P = 0.075). In contrast to the beneficial cological benefits but also carry a significant risk of
effects of ER-NA on blood lipids, IHN had no significant adverse effects, thus requiring medical monitoring and
or nearly significant effects (total cholesterol: -1%; LDL: supervision. High intakes of NA produce a vasodilative
-1%; HDL: +1%; triglycerides: +2%). effect that can result in an intense itching or burning
Collectively, the available data show no significant sensation of the skin known as the “niacin flush.” Flushing
effects of IHN on blood lipids following daily oral intakes may be classified as a nuisance effect. It is initiated via
of up to 2,000 mg/day (Table 2). prostaglandin D2-mediated vasodilatation of small sub-
While the evidence to support the use of IHN for cutaneous blood vessels. The vasodilatation is associated
dyslipidemic disorders is weak to contradictory, there are with an unpleasant sensation of intense warmth and
reports suggesting that IHN may have a beneficial effect itching that commonly starts in the face and neck and can
on endothelium-dependent vasodilatation. Benjo et al.24 proceed down through the body. Some individuals may
observed no improvements in serum lipids after 3 experience a rash, hypotension, and/or dizziness.56 Flush-
months of 1,500 mg/day IHN but did observe improve- ing appears about 30 minutes after intake of NA, and 2–4
ments in flow-mediated dilation of the brachial artery, hours after intake of ER-NA. Skin-flushing reactions
indicating an improved endothelial function. usually persist over only a few doses until the body devel-
Blood flow improvements are therapeutically impor- ops a natural tolerance. The daily dose is generally admin-
tant in conditions resulting from peripheral vascular istered over several hours in three parts to reduce
insufficiency, such as Raynaud’s disease and intermittent flushing. Each portion may be increased gradually until
claudication. The clinical research literature includes the desired total dose is achieved. Liver function tests and
promising results from several studies on the use of IHN tests for uric acid, fasting blood glucose, and lipid levels
for improving blood flow in these conditions.51–53 IHN is should be conducted as the dose is administered. When
prescribed in Europe as a patented drug known as used as an antihyperlipidemic agent, adverse reactions
Hexopal, which is therapeutically indicated for the symp- may require decreased dosage or discontinuation in favor
tomatic relief of severe intermittent claudication and of other agents.
Raynaud’s phenomenon. The usual adult dose of IHN for
these conditions is 3 g/day and is increased to 4 g/day if Flushing effect. The recommended dietary intakes of
necessary. IHN is not recommended for use in children.54 15–18 mg/day carry no known risk of adverse effects, but
The mode of action of IHN in Raynaud’s phenomenon the vasodilative flushing effect can be quite pronounced
and in intermittent claudication is not known. However, at intakes as low as 50 mg/day and may occur infre-
IHN does not appear to work solely via general peripheral quently at intakes as low as 30 mg/day, depending on the
vasodilatation, and it is hypothesized that its activity may circumstances of the intake. Important modifiers of
also be mediated through a reduction in fibrinogen, flushing risk include empty or full stomach; dissolved
improvements in blood viscosity, and resultant improve- versus crystalline form of NA; and bolus administration
ment in oxygen transport.34 versus intake spread over several hours. The flushing
effect can be managed effectively in most patients, pro-
Nicotinamide vided they are given proper instructions and the dose is
slowly titrated upward to reach therapeutic levels.56
Like NA, this chemical form fully supports the classic In the original studies cited by the IOM as the source
niacin function of providing NM coenzymes and pre- of data to identify flushing as the critical effect for the risk
venting pellagra. Higher doses of NM have been tested for assessment to establish a tolerable upper intake level
a variety of possible benefits related to several disease (UL),2 NA was administered in bolus doses, which may
conditions such as depression,55 but results are inconsis- have little relevance to NA consumed in food. Further-
tent and NM is not generally recognized as an effective more, the flushing effect, while definitely a nuisance, may
treatment for clinical depression or high plasma triglyc- or may not qualify as a hazard in risk assessment and thus
eride and cholesterol levels. 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
ADVERSE EFFECTS at much higher intake levels.

Nicotinic acid Hepatotoxicity and gastrointestinal toxicity. These

adverse effects, which can be severe, definitely provide
This form of niacin has the potential to produce several cause for concern about the safety of daily intakes of 1 g
different adverse effects, depending on the intake.2 NA or higher, the level at which toxicity usually occurs.

Nutrition Reviews® Vol. 70(6):357–366 361

362
Table 2 Evidence of the effects of inositol hexanicotinate (IHN) on blood lipids.
Reference No. of Dose Duration Study design Finding Author comment
subjects
Welsh and Ede 2 1,200 mg IHN/day 10 months Published case 12% and 17% reduction in Cited by review articles as
(1961)19 report total cholesterol supporting the use of IHN in
controlling hyperlipidemia
Fischer and 16 350 mg Mg- 60 days Open labela 16–20% reduction in serum Reduction in serum cholesterol
Falkensammer chlorphenoxyisobutyrate cholesterol is consistent with 350 mg
(1977)47 + 250 mg Mg-chlorphenoxyisobutyrate
mesoinositol- alone
hexanicotinate/day
Ziliotto et al. 59 1,500 mg IHN/day 7 days COT IHN had a slight effect on Effect of pentaerythritol
(1977)49 compared with total blood lipids tetranticotinate on
1,500 mg normalization of lipids
pentaerythritol similar to that observed
tetranticotinate/day with NA
Agusti et al. 41 4,500 mg IHN/day 15–120 days Open labela 8–12% reduction in total Treatment duration with IHN
(1978)46 cholesterol for 64.2% of varied significantly
participants
Kruse et al. 12 2,400 mg IHN divided 3 hours COT Acute, but not sustained, Therapeutic potential of any
(1979)23 into 3 equal doses reduction of nocturnal niacin preparation depends
levels of free fatty acids on its ability to exhibit a
sustained inhibition of free
fatty acid levels
Norris (2006)14 1 ⱕ2,000 mg IHN/day 6 months Published case No effect Significant improvements in
report serum lipids after switching
to 1,000 mg ER-NA for 12
weeks
Benjo et al. 22 1,500 mg IHN/day 3 months RCT No change in plasma lipids Subjects showed
(2006)24 improvements in vascular
reactivity
Keenan 12 1,500 mg IHN/day or 6 weeks RCT IHN had no effect; ER-NA Strongest evidence that IHN
(2010)50 1,500 mg ER-NA/day significantly improved does not reduce serum
serum lipids 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.

Nutrition Reviews® Vol. 70(6):357–366

Hepatotoxicity is detected most often as increases in these are sustained for longer periods. The data for a
serum levels of selected liver enzymes,39 but the severity direct quantitative comparison of the ER-NA and NA
of hepatotoxicity can range from elevated liver enzymes forms are not robust, but the risk of hepatotoxicity seems
to acute liver failure.57 Although the likelihood of liver approximately twice as high with the ER-NA forms com-
toxicity is significant, it is nevertheless low enough that pared with the crystalline NA form.8 If this is taken into
NA at intakes of up to 2–4 g/day may be used safely and account to help ensure the beneficial effects and avoid the
effectively as an antihyperlipidemia drug under medical more serious types of toxicity, the ER-NA forms have
monitoring and supervision. Although available on the significant advantage in lowering the tendency to cause
market as a dietary supplement in tablets of 500 mg and flushing effects, which should lead to better acceptance
750 mg, NA should not be used at gram dosages without and compliance by the patient.
medical supervision. There is a strong correlation
between the minimal adverse effects identified through Nicotinamide
clinical trials and those suggested by the published anec-
dotal case reports. Many severe reactions to NA, espe- This form of niacin has been tested at multigram intakes,
cially liver toxicity, have involved ill-advised or with inconsistent evidence of adverse effects.7,58 One
uninformed switching from NA preparations to ER-NA study reported a range of adverse effects, including head-
formulations without adjusting the dose.12 ache, heartburn, nausea, gastrointestinal disturbances,
Most reported adverse reactions to NA have and fatigue at a dose of 3,000 mg/day supplemental NM
occurred with intakes of 2–6 g/day. There are only two for 3–36 months59; however, few details were provided
anecdotal cases reported in which intake levels below and no controls were included for comparison. Although
1,000 mg/day produced an adverse effect: in one, ER-NA these effects might have been caused by NM, they are not
was administered at 500 mg/day, and in the other, NA was unique to any specific substance or condition. Other
given at 750 mg/day.12 The clinical trial of McKenney supplementation trials60–64 have reported no adverse
et al.31 investigated two groups of adult subjects, one effects at NM intake levels of up to 3,000 mg/day.
given NA and the other ER-NA, each containing sub- However, the studies in which the highest doses were
groups that covered a range of doses. These two treatment administered primarily looked for possible beneficial
groups were observed for 6 weeks at dosage levels of 500, effect in patients with type 1 diabetes mellitus, and it is
1,000, 1,500, 2,000, and 3,000 mg/day. The data showed unclear how the possible adverse effects were evaluated.
no adverse reactions at 500 mg/day for either form of NA Because of the small database, the EVM applied an uncer-
but did show statistically significant effects beginning at tainty factor of 3 and adjusted to a standard body weight
1,000 mg/day (gastrointestinal effects for NA, and mild of 60 kg to set a total dietary intake guidance level of
liver toxicity for ER-NA). The gastrointestinal side effects 600 mg/day NM, or 560 mg/day of supplemental NM.7
ranged in severity from nausea to, in the extreme, recur-
rence of peptic ulcer that had been asymptomatic for 7 Inositol hexanicotinate
years.31 Quantities of NA above 1 g should not be self-
The 70% intestinal absorption of IHN11 suggests that
administered as a dietary supplement but may be safely
this compound could produce the flushing reaction if
used under the care and monitoring of a healthcare pro-
hydrolysis released a significant amount of NA at a suffi-
vider. Such an application, it should be noted, constitutes
ciently fast rate. There are no reports of flushing associ-
a pharmaceutical use, not a dietary supplement use.
ated with IHN, but evidence demonstrating a meager
increase in serum NA after administration and the lack of
Extended-release nicotinic acid
substantial evidence of the typical NA effects on serum
lipids suggest that release of NA from IHN is very limited
The flushing reaction may be substantially reduced
or extremely slow. Irrespective of the metabolic and
through the use of ER-NA instead of NA, but ER-NA
pharmacokinetic pathways, IHN has not been associated
preparations carry a greater risk of liver toxicity, as indi-
with significant adverse effects at intake levelss up to
cated by the reported cases of hepatotoxicity after unsu-
4 g/day.51–53
pervised 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 ASSESSMENT OF RISK
be wide differences in the pharmacokinetics of different
ER-NA formulations, but the prescription products and Nicotinic acid
some of the ER-NA dietary supplements have known
and predictable characteristics.28,32 In general, the ER-NA The IOM, SCF, and EVM have each set UL or similar
forms produce lower peak serum concentrations, but values for NA based on its dermal vasodilative flushing

Nutrition Reviews® Vol. 70(6):357–366 363

 Table 3 Tolerable upper intake levels and related values for nicotinic acid, nicotinamide, and inositol
hexanicotinate.
Reference Upper level of Upper level of Upper level
nicotinic acid; basis nicotinamide; basis of IHN; basis
Institute of Medicine 35 mg; flushing 35 mg; flushing –
(1998)2
Scientific Committee on 10 mg; flushing 900 mg; hepatotoxicity –
Food (2002)6
Expert Group on Vitamins 17 mg; flushing 500 mg; hepatotoxicity –
and Minerals (2003)7
Hathcock (2004)8 500 mg; hepatotoxicity (250 mg 1,500 mg; hepatotoxicity –
ER-NA formulations)
Current review 500 mg (NA); hepatotoxicity (250 mg 1,500 mg; hepatotoxicity 3,000 mg; highest
(ER-NA formulations) observed intake
Abbreviations: ER-NA, extended-release nicotinic acid; IHN, inositol hexanicotinate.

effect, with the values being 35, 10, and 17 mg/day, respec- for NA. These values are 900 mg/day and 500 mg/day,
tively.2,6,7 The SCF argued that the flushing effect is the respectively. Inexplicably, the IOM did not establish a UL
appropriate basis for the UL because of the possibility that for NM separately from that for NA, even though NM
hypotension induced by “high doses” of NA could lead to does not produce the vasodilative flushing that was the
major adverse effects resulting from falls, particularly in basis of the UL for NA.2 Instead, the IOM applied the
the elderly. However, there is no evidence to support such 35 mg UL to all forms of “niacin.” The IOM provided no
speculated effects. The UL value of NA was not based on discussion to address this anomaly. Previous risk analysis
studies using “high-dose” NA, which hypothetically could suggested a safe upper limit of supplemental NM of
lead to hypotension, but instead was derived using results 1,500 mg/day,8 as well as the 900 mg/day and 500 mg/day
related to 30-mg single doses and an uncertainty factor. In values in the SCF and EVM reports.
fact, the evidence that NA may cause systemic hypoten-
sion that might lead to falls is related to doses of more Inositol hexanicotinate
than 1,000 mg/day. NA intakes in that range may lead to
the risk of hepato- and gastrointestinal toxicity,39 and the No adverse effects have been attributed to this com-
development of these effects, rather than the low-dose pound; therefore, there is no basis to establish a UL under
dermal vasodilatation that may be judged to be a nuisance the method used by the IOM and the SCF (and later the
rather than a hazard, would be the critical effect for EFSA). An alternative method of risk assessment is to
assessing risk and establishing a UL value. It is suggested identify the highest intake that has adequate data to suf-
that the safe upper limit for supplemental NA formula- ficiently exclude a risk of adverse effects. The resulting
tions be set at 500 mg/day, a level associated with neither value is termed the highest observed intake,9 an intake
adverse effects in clinical trials nor anecdotal reports of with sufficient data to reasonably conclude that adverse
adverse reactions, other than vasodilative dermal flush- effects are not known at this intake. Several studies
ing.8 Supplemental products should carry label state- suggest that a justifiable highest observed intake value for
ments to inform consumers of the annoying but IHN is 3,000 mg/day51–53 (Table 3).
apparently otherwise harmless flushing effect.
CONCLUSION
Extended-release nicotinic acid
This analysis indicates that, contrary to the common and
Although the data are not as robust for ER-NA, this form mistaken perception, the four major forms of niacin in
seems to be approximately twice as hepatotoxic as the free the marketplace (NA, ER-NA, IHN, and NM) are not
form of NA; thus, 250 mg/day has been recommended as bioequivalent with respect to efficacy or safety. While all
the safe upper limit for supplemental ER-NA.8 four forms possess the ability to fulfill the nutritional
requirement for niacin in humans when intakes are suf-
Nicotinamide ficiently high, they have distinct dose-related effects per-
taining to cardiovascular benefits and adverse effects,
Because NM does not produce a vasodilative dermal including flushing and hepatotoxicity.
flush, the SCF and EVM established separate UL values NA and ER-NA are effective treatments for dyslipi-
for this compound on bases that are different from those demia. NA is strongly associated with an uncomfortable

364 Nutrition Reviews® Vol. 70(6):357–366

dermal flushing effect, which is decreased with ER-NA 3. Carleson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary
review. J Intern Med. 2005;258:94–114.
formulations. Both NA and ER-NA carry the risk of hepa- 4. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol
totoxicity and gastrointestinal toxicity. However, NA and in man. Arch Biochem Biophys. 1955;54:558–559.
5. Ganji SH, Zhang L-H, Kamanna VS, et al. Effect of niacin on lipoproteins and
ER-NA are considered safe and effective antihyperlipi- atherosclerosis. Future Lipidol. 2006;1:549–557.
demic drugs for use under medical supervision and 6. Scientific Committee on Food. European Commission. Opinion of the Scientific
Committee on Food on the Tolerable Upper Intake Levels of Nicotinic Acid and Nico-
monitoring. ER-NA formulations substantially reduce the tinamide (Niacin). SCF/CS/NUT/UPPLEV/39/Final. 2002; Available at: http://
risk of flushing reactions but carry a greater risk of liver ec.europa.eu/food/fs/sc/scf/out80j_en.pdf. Accessed 15 June 2011.
7. Expert Group on Vitamins and Minerals. Food Standards Agency. Safe Upper
toxicity. ER-NA is approximately twice as hepatotoxic as Levels for Vitamins and Minerals. 2003; Available at: http://cot.food.gov.uk/pdfs/
NA, and clinicians and patients should be acutely aware of vitmin2003.pdf. Accessed15 June 2011.
8. Hathcock JN. Niacin, nicotinic acid and nicotinamide. In: Hathcock JN, ed.
this distinction when considering a switch from NA to Vitamin and Mineral Safety, 2nd ed. Washington, DC: Council for Responsible
ER-NA. The recommended safe upper limit for dietary Nutrition; 2004:85–91.
9. Food and Agriculture Organization of the United Nations (FAO) and the World
supplementation is 500 mg/day for NA and 250 mg/day Health Organization (WHO). A Model for Establishing Upper Levels of Intake for
or higher for ER-NA,8 as directed under medical Nutrients and Related Substances: report of a Joint FAO/WHO Technical Workshop
supervision. on Food Nutrient Risk Assessment. 2006; Available at: http://www.who.int/ipcs/
highlights/full_report.pdf. Accessed15 June 2011.
IHN is offered as a “no-flush” form of NA. Evidence 10. Bechgaard H, Jespersen S. GI absorption of niacin in humans. J Pharm Sci.
suggests IHN may improve conditions associated with 1977;66:871–872.
11. Rader JI, Calvert RJ, Hathcock JN. Hepatic toxicity of unmodified and time-
peripheral vascular insufficiency, such as Raynaud’s phe- release preparations of niacin. Am J Med. 1992;92:77–81.
nomena and intermittent claudication, but it does not 12. Sebrell WH, Butler RE. A reaction to the oral administration of nicotinic acid.
JAMA. 1938;11:2286–2287.
support the efficacy of IHN as a dyslipidemic agent. No 13. Spies TD, Bean WB, Stone RE. The treatment of subclinical and classic pellagra.
adverse events or dermal flushing have been reported for Use of nicotinic acid, nicotinic acid amide and sodium nicotinate, with special
reference to the vasodilator action and the effect on mental symptoms. JAMA.
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not associated with dermal flushing effects. Other thera- release niacin and lovastatin fixed dose combination tablet versus extended-
release niacin tablet, lovastatin tablet and a combination of extended-release
peutic effects of NM are under investigation. A recom- niacin tablet and lovastatin tablet. Biopharm Drug Dispos. 2007;28:297–306.
mended safe upper level of intake of NM is 1,500 mg/day. 17. European Food Safety Authority (EFSA). Inositol hexanicotinate (inositol hexani-
Collectively, all forms of niacin perform essential acinate) as a source of niacin (vitamin B3) added for nutritional purposes in food
supplements. Scientific Opinion of the Panel on Food Additives and Nutrient
biochemical functions and prevent niacin deficiency, but Sources Added to Food. EFSA J. 2009;949:1–20.
IHN has very limited supporting data. Full recognition of 18. Harthon JG, Lindqvist JT. On the elimination of unabsorbed hexanicotinic acid
esters of meso-inositol in the feces. Arzneimittelforschung. 1964;14:1170–1171.
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doses can assist consumers and clinicians in choosing the Preliminary report. Int Record Med. 1961;174:9–15.
20. Sommer H. Nicotinic acid level in the blood and fibrinolysis under the influence
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Acknowledgment 23. Kruse W, Kruse W, Raetzer H, et al. Nocturnal inhibition of lipolysis in man by
nicotinic acid and derivatives. Eur J Clin Pharmacol. 1979;16:11–15.
24. Benjó AM, Maranhão RC, Coimbra SR, et al. Accumulation of chylomicron rem-
Declaration of interest. DM and JH are employed by The nants and impaired vascular reactivity occur in subjects with isolated low HDL
Council for Responsible Nutrition, a trade association cholesterol: effects of niacin treatment. Atherosclerosis. 2006;187:116–122.
25. Meyers CD, Carr MC, Park S, et al. Varying cost and free nicotinic acid content in
representing dietary supplement manufacturers and over-the-counter niacin preparations for dyslipidemia. Ann Intern Med. 2003;
ingredient suppliers. There are no other relevant interests 139:996–1002.
26. Parsons WB Jr. Use of nicotinic acid compounds in the treatment of hyperlipi-
to declare. demia. In: Casdorph HR, ed. Treatment of the Hyperlipidemic States. Springfield, IL:
Charles C. Thomas Press; 1971:336–374.
27. Fukuwatari T, Ebata M, Sasaki R, et al. Bioavailability of nicotinamide-rich
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