Vitamin B3 (niacin)

Vitamin B3 (Niacin): A Comprehensive Reference

1. Identity, Chemical Names, and Common Forms

Niacin, also known as vitamin B3, is one of the water-soluble B vitamins. The term "niacin" is the generic name for nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (niacinamide or pyridine-3-carboxamide), and related derivatives, such as nicotinamide riboside. The name "niacin" was coined when it was decided to enrich foods with the vitamin, since it was considered that "nicotinic acid" would be unacceptable as a food additive because of its chemical — but not metabolic — relationship with nicotine.

Niacin is naturally present in many foods, added to some food products, and available as a dietary supplement. The two principal dietary and supplemental forms are nicotinic acid and nicotinamide (niacinamide); these share equivalent activity as vitamins but differ substantially in their pharmacological profiles at high doses.

Natural Food Sources

Niacin in mature cereal grains is largely bound and thus is only about 30 percent available; alkali treatment of the grain increases the percentage absorbed. Niacin in the coenzyme NAD/NADP form in meats appears to be much more available. Niacin added during enrichment or fortification is in the free form and thus highly available.

Corn is naturally high in niacin, but it is bound to carbohydrates which makes it difficult for the human body to absorb. However, when corn is nixtamalized — a traditional process in tortilla making where corn is treated with calcium hydroxide, cooked, and ground — the niacin becomes absorbable because of the calcium hydroxide treatment.

Supplement Forms and Preparations

• Niacin is available in multivitamin/mineral products, in supplements containing other B-complex vitamins, and in supplements containing niacin only. Nicotinic acid and nicotinamide are the two most common forms of niacin in supplements.
• Some niacin-only supplements contain 500 mg or more per serving, which is much higher than the RDA. Nicotinic acid in supplemental amounts beyond nutritional needs can cause skin flushing, so some formulations are manufactured and labeled as prolonged, sustained, extended, or timed release to minimize this side effect. Nicotinamide does not produce skin flushing because of its slightly different chemical structure.
• Niacin supplements are also available in the form of inositol hexanicotinate, and these supplements are frequently labeled as being "flush free" because they do not cause flushing.

2. Traditional and Historical Use

Pellagra: The Disease That Led to the Discovery of Niacin

In humans, niacin was discovered through the niacin deficiency condition pellagra. The name "pellagra" traces to the Italian words "pella" (skin) and "agra" (rough), first appearing in Italy in the 1700s. It was initially described by the physician Gaspar Casal in Spain in 1735, soon after maize was introduced into Europe. The name of the disease was established in 1771 by the Italian physician Francesco Frapolli. Due to the great increase in the use of maize in northern Italy, pellagra became so widespread that a special hospital (known as Legano) was built in 1784, exclusively for pellagra patients.

Reports on the occurrence of pellagra appeared soon thereafter in France (1829), Romania (1858), and Egypt (1874). In the early 1900s, pellagra was prevalent in the Southern United States due to the low availability of corn, the primary dietary source of niacin. The disease was so pervasive that the U.S. Congress asked the Surgeon General to investigate.

Nixtamalization: A Traditional Practice that Prevented Pellagra

In Central and South America, the traditional method for making corn tortillas involves soaking the corn in limewater overnight. This process unbinds the niacin in the corn and makes it available to absorb. For this reason, pellagra has rarely been seen in these populations. Native people in North, Central, and South America used to consume maize treated with lime or wood ashes, which enhanced the bioavailability of niacin.

Scientific Identification and Fortification Era

In 1915, Goldberger conducted a series of experiments on 11 healthy volunteer prisoners in a Mississippi jail and found that he could induce pellagra by altering their diets. He concluded that the disease was caused by the absence of some factor lacking in corn but found in meat and milk, naming it the "P-P" (pellagra-preventative) factor.

In 1937, Elvehjem and his colleagues isolated the vitamin and demonstrated that pure nicotinic acid and nicotinic acid amide would reverse the black tongue and pellagra. Later studies by Dr. Tom Spies, Marion Blankenhorn, and Clark Cooper established that niacin also cured pellagra in humans, for which Time dubbed them its 1938 Men of the Year in comprehensive science.

Voluntary food fortification and periods of mandatory fortification on the state and federal levels soon followed, coinciding with a continuous drop in pellagra deaths. By the 1950s, the disease was virtually eliminated from the US. By the mid-century, bread and cereal products in the United States were routinely fortified with niacin, a practice that continues today.

3. Key Constituents, Active Compounds, and Mechanisms of Action

NAD and NADP: The Central Metabolic Coenzymes

All tissues in the body convert absorbed niacin into its main metabolically active form, the coenzyme nicotinamide adenine dinucleotide (NAD). More than 400 enzymes require NAD to catalyze reactions in the body, which is more than for any other vitamin-derived coenzyme. NAD is also converted into another active form, the coenzyme nicotinamide adenine dinucleotide phosphate (NADP), in all tissues except skeletal muscle.

The nicotinamide moiety of NAD and NADP acts as a hydride ion acceptor or donor in many biological redox reactions. NAD has also been shown to be required for important non-redox adenosine diphosphate (ADP)–ribose transfer reactions involved in DNA repair and calcium mobilization.

NAD also serves as a cosubstrate for a large number of ADP-ribosylation enzymes with varied functions. Among the NAD-consuming enzymes identified are important genetic and epigenetic regulators, including poly(ADP-ribose)polymerases and sirtuins. There is rapidly growing knowledge of the close connection between dietary niacin intake, NAD(P) availability, and the activity of NAD(P)-dependent epigenetic regulator enzymes.

Biosynthesis from Tryptophan

The essential amino acid tryptophan can also be converted into NAD via the kynurenine pathway. On average, 60 milligrams (mg) of tryptophan are considered to correspond to 1 mg of niacin or 1 mg of niacin equivalent (NE). Mammals, including humans, can synthesize the vitamin nicotinamide from tryptophan in the liver, from where the resultant nicotinamide is distributed to non-hepatic tissues.

People who do not consume enough riboflavin (vitamin B2), pyridoxine (vitamin B6), or iron convert less tryptophan to niacin because enzymes in the metabolic pathway for this conversion depend on these nutrients to function.

Absorption and Metabolism

Ingested niacin is absorbed primarily in the small intestine, but some is also absorbed in the stomach. Even when taken in very high doses of 3–4 g, niacin is almost completely absorbed. Once absorbed, physiologic amounts of niacin are metabolized to NAD. Some excess niacin is taken up by red blood cells to form a circulating reserve pool. The liver methylates any remaining excess to N1-methyl-nicotinamide, N1-methyl-2-pyridone-5-carboxamide, and other pyridone oxidation products, which are then excreted in the urine.

Lipid-Modifying Mechanism at Pharmacological Doses

Therapeutically used for more than 50 years, niacin is the most effective clinically available agent for increasing high-density lipoprotein cholesterol (HDL-C) levels. In most patients, niacin increases HDL-C by 20–40%. At high doses (1.5 to 4 grams per day), niacin has been shown to improve VLDL levels through lowering Apolipoprotein B (ApoB) and raising HDL through increasing Apolipoprotein A1 (ApoA1) in the liver. Niacin can also inhibit diacylglycerol acyltransferase-2, a key enzyme for triglyceride synthesis.

4. Scientific Evidence by Area of Use

4.1 Niacin Deficiency and Pellagra

Niacin deficiency results in a condition known as pellagra, which includes the triad of dermatitis, dementia, and diarrhea and can result in death. Niacin deficiency can also occur through genetic disorders, malabsorptive conditions, and interaction with certain medications.

Clinical evidence confirms that treatment with nicotinamide and B-vitamin supplementation leads to rapid and sustained resolution of all pellagra symptoms. Today, niacin deficiencies are uncommon in industrialized nations primarily due to sufficient dietary intake; however, specific populations remain at risk of this mostly eradicated condition. Evidence for niacin treatment of pellagra is clinically well established based on decades of observational and interventional data.

4.2 Cardiovascular Disease and Dyslipidemia

For more than 40 years, niacin in the form of nicotinic acid has been given to patients to treat dyslipidemia, a major risk factor for cardiovascular diseases (CVD) such as coronary artery disease, heart attack, and strokes.

The evidence for niacin's lipid-modifying effects versus its translation into cardiovascular outcomes requires careful separation:

Lipid Effects (Well Established): Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25% and was shown in multiple surrogate endpoint studies to reduce CV risk.

The Coronary Drug Project (CDP): The findings of later large trials are consistent with earlier randomized trial data. In the Coronary Drug Project (CDP), conducted before effective LDL cholesterol-lowering agents were available, niacin reduced total cholesterol by 26 mg/dL from a high baseline of 253 mg/dL. It can be estimated that LDL cholesterol was reduced by at least 30 mg/dL and HDL increased by approximately 5 mg/dL, which is compatible with the 19% reduction in myocardial infarction or coronary death observed in the CDP.

AIM-HIGH Trial: The AIM-HIGH study enrolled 3,414 high-risk patients adding extended-release (ER) niacin 1.5–2.0 g daily to statin therapy. The trial was stopped prematurely because of perceived lack of benefit (hazard ratio 1.02; 95% CI 0.87–1.21), but the observed mean lipid differences were small (0.12 mmol/L lower LDL-C and 0.13 mmol/L higher HDL-C in the niacin group).

HPS2-THRIVE Trial: The HPS2-THRIVE study was a randomized, multicenter, double-blind, prospective, controlled clinical trial recruiting patients at 245 sites in the United Kingdom, Scandinavia, and China. A total of 25,673 high-risk patients aged 50 to 80 years with prior CV disease were enrolled. This trial was stopped early after 3.9 years due to lack of reduction in major vascular events in the niacin group. In addition, significantly increased adverse effects were noted with niacin use.

Overall Assessment: Niacin is a lipid-modifying therapy with proven efficacy for reducing cardiovascular events as monotherapy and, when used in combination with other lipid-modifying medications, impacts rates of atherosclerotic disease progression. However, large outcome trials using niacin against a background of statin therapy with optimal control of atherogenic lipoprotein burden were unable to demonstrate incremental benefit of niacin beyond statin therapy. In HPS2-THRIVE, niacin–laropiprant was associated with highly significant increases in the rates of various serious adverse events, including diabetes-related, gastrointestinal, musculoskeletal, and skin-related disorders. New diagnoses of diabetes were increased by one third, corresponding to 13 new cases per 1,000 patients treated for approximately 4 years.

4.3 Non-Melanoma Skin Cancer Chemoprevention (Nicotinamide)

Clinical trials over the past decade have reported mixed findings regarding nicotinamide's clinical utility for NMSC reduction.

ONTRAC Phase 3 Trial (2015): In this phase 3, double-blind, randomized, controlled trial, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years were randomly assigned in a 1:1 ratio to receive 500 mg of nicotinamide twice daily or placebo for 12 months, with dermatologist evaluations at 3-month intervals for 18 months. At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% CI, 4 to 38) in the nicotinamide group (P=0.02). Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients.

A pilot double-blind randomized trial in renal transplant patients evaluated oral nicotinamide (500 mg twice daily) for prevention of NMSCs and actinic keratoses. Over 6 months, nicotinamide showed a nonsignificant 35% relative reduction in NMSC rate (P=0.36) and a 16% reduction in actinic keratoses (P=0.15) compared to placebo. However, the beneficial effects observed in these studies have not been consistent throughout the literature. A recent phase 3 randomized trial by Allen et al. (2023) evaluated oral nicotinamide for skin cancer chemoprevention in organ transplant recipients. Despite previous promising results in immunocompetent individuals, the study found no significant reduction in new actinic keratoses with oral nicotinamide over 12 months compared to placebo.

Accumulating evidence suggests that nicotinamide plays a role in cancer prevention and therapy. Phase III clinical trials have confirmed its clinical efficacy for non-melanoma skin cancer chemoprevention, but evidence for other cancers has mostly been collected through preclinical research and is not yet evidence-based.

4.4 Brain Health and Cognitive Function

A large prospective study of 3,718 men and women aged 65 and older, followed for 6 years using dietary questionnaires and cognitive assessments, found a protective effect from Alzheimer's disease and cognitive decline when comparing the highest to lowest intakes of niacin.

The Coronary Artery Risk Development in Young Adults (CARDIA) study followed 3,136 men and women aged 18–30 for up to 25 years and measured dietary and supplemental B vitamin intake and cognitive function. A higher intake of B vitamins, particularly niacin, throughout young adulthood was associated with better cognitive function scores in midlife. However, cognitive function was only assessed at the end of the study, so any changes in cognitive function over time were not known. Research in this area is limited and several clinical trials are underway that may shed further light on niacin's effects on brain health. The evidence in this area is currently preliminary and observational.

4.5 Niacin Flush Response and Schizophrenia Research

Niacin, a B-complex vitamin, induces prostaglandin synthesis, vasodilatation, and skin flushing when applied to the skin or taken orally. In schizophrenia, diminished or absent skin response to niacin represents a robust finding. Attenuated niacin skin-flush response has been analyzed as a potential biochemical marker of impaired prostaglandin signaling in schizophrenia.

Twelve (42.9%) of 28 schizophrenic subjects did not vasodilate in response to a 200-mg niacin challenge dose, whereas only 1 of 18 (6%) bipolar disorder subjects and none of 28 controls showed impaired response (Fisher's Exact Test, p < 0.0001).

Reported findings indicate that a reduced niacin sensitivity is associated with greater severity of schizophrenia symptoms (evaluated via Brief Psychiatric Rating Scale); worse global functioning; cognitive impairment; and illness progression. This research area is primarily diagnostic in nature; niacin itself is not established as a treatment for schizophrenia, and the evidence is exploratory.

4.6 Type 1 Diabetes Prevention (Nicotinamide)

The European Nicotinamide Diabetes Intervention Trial (ENDIT) was a large-scale, randomized controlled trial investigating whether high-dose nicotinamide could prevent or delay the onset of type 1 diabetes in at-risk individuals. The ENDIT study (n=552), involving patients at risk of developing type 1 diabetes mellitus, showed no difference in patient tolerability and laboratory adverse events between nicotinamide (1–3 g/day) and placebo. The ENDIT trial did not demonstrate that nicotinamide successfully prevented type 1 diabetes onset in the at-risk population studied.

5. Body Systems and Health Areas

• Cellular energy metabolism: Niacin helps turn the food you eat into the energy you need and is important for the development and function of the cells in your body.
• Digestive system, skin, and nervous system: Niacin helps the digestive system, skin, and nerves to function, and is important for changing food to energy.
• Lipid metabolism (pharmacological doses): In large doses, niacin can cause a modest increase in the level of HDL cholesterol in the blood. It can also bring down the amount of triglycerides in the blood.
• DNA repair and epigenetic regulation: Among NAD-consuming enzymes are important genetic and epigenetic regulators including poly(ADP-ribose)polymerases and sirtuins. There is rapidly growing knowledge of the connection between dietary niacin intake, NAD(P) availability, and the activity of these regulatory enzymes, pointing to an exciting role of dietary niacin in the maintenance of genetic stability and epigenetic control mechanisms modulating metabolism and aging.
• Skin integrity and photoprotection: Supplementation of nicotinamide restores the cellular NAD+ pool and mitochondrial energetics, attenuates oxidative stress and inflammatory response, and enhances the extracellular matrix and skin barrier. Topical treatment of nicotinamide reduces the progression of skin aging and hyperpigmentation in clinical trials.

6. Dosage Forms and Dosages Reported in Studies

Recommended Dietary Allowances (RDAs) and Tolerable Upper Intake Levels (ULs)

• The Recommended Dietary Allowance (RDA) for adults 19+ years is 16 mg NE for men, 14 mg NE for women, 18 mg NE for pregnant women, and 17 mg NE for lactating women.
• The Tolerable Upper Intake Level (UL) for niacin for adults is 35 mg/day, which was based on flushing as the critical adverse effect.
• The Food and Nutrition Board established tolerable upper intake levels for niacin of 10 mg for age 1–3 years, 15 mg for age 4–8 years, 20 mg for age 9–13 years, 30 mg for age 14–18 years, and 35 mg for age 19 years and up.

Pharmacological (Therapeutic) Doses Reported in Clinical Trials

• Nicotinic acid supplements in dyslipidemia studies contain high amounts, up to 1,000–2,000 mg of niacin taken daily.
• The AIM-HIGH study used ER niacin 1.5–2.0 g daily added to statin therapy.
• HPS2-THRIVE used ER niacin 2 g plus laropiprant 40 mg daily.
• The recommended daily dosage of niacin ER for hyperlipidemia ranges from 500 to 2,000 mg, generally given once daily at bedtime.
• The ONTRAC skin cancer trial used 500 mg of nicotinamide twice daily (1,000 mg/day total) for 12 months.
• At high doses of 1.5 to 4 grams per day, niacin has been shown to improve VLDL levels through lowering ApoB and raising HDL through increasing ApoA1 in the liver.

7. Safety Considerations and Drug Interactions

Flushing: Mechanism and Dose-Dependence

Niacin induces flushing through dermal Langerhans cells where the activation of G protein-coupled receptor 109A (GPR109A) increases arachidonic acid and prostaglandins, such as prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2), subsequently activating prostaglandin receptors in capillaries and causing cutaneous vasodilatation.

Flushing is a common side effect in people treated with 30 mg/day or more nicotinic acid by mouth and is characterized by a burning, tingling, and itching sensation primarily on the face, arms, and chest that can be accompanied by pruritus, headaches, and increased intracranial blood flow. Nicotinamide and inositol hexanicotinate do not appear to be associated with flushing.

Niacin extended-release (NER) formulations have reduced flushing incidence, duration, and severity relative to crystalline immediate-release niacin with similar lipid efficacy. Non-steroidal anti-inflammatory drugs (NSAIDs), notably aspirin given 30 min before NER at bedtime, further reduce flushing.

Hepatotoxicity

Niacin may be metabolized by either a conjugative or amidation pathway. The hepatotoxicity of niacin is most associated with the sustained-release formulation and the production of nicotinamide adenine dinucleotide via the amidation pathway. Nicotinamide adenine dinucleotide inhibits β-oxidation leading to mitochondrial dysfunction. This dysfunction leads to disruption in ATP production, which causes apoptosis, cytokine release, and necrosis.

Niacin-associated hepatotoxicity is generally related to ingestions of around 3 grams per day. In contrast, the more common symptom of flushing can occur at doses as low as 30 mg per day.

High doses of nicotinic acid taken over months or years can be hepatotoxic; effects can include increased levels of liver enzymes, hepatic dysfunction resulting in fatigue, nausea, and anorexia. When taken in pharmacologic doses of 1,000 to 3,000 mg/day, nicotinic acid can also cause more serious adverse effects. Many of these effects have occurred in patients taking high-dose nicotinic acid supplements to treat hyperlipidemias.

Adverse effects such as nausea, vomiting, and signs and symptoms of liver toxicity have been observed at nicotinamide intakes of 3,000 mg/day, compared with intakes of nicotinic acid of 1,500 mg/day.

Metabolic Adverse Effects at High Doses

Common side effects of niacin include nausea, fatigue, pruritus, and flushing; flushing being a major dose-limiting side effect. Less common but potentially severe adverse reactions with long-term use include an increased risk of serious bleeding, infections, myopathy, and hyperglycemia. Extended-release (ER) capsules and tablets of niacin are available in concentrations ranging from 125 to 1,000 mg and have not been associated with a higher rate of hepatotoxicity compared to regular niacin.

Nicotinamide undergoes hepatic metabolism via methylation, oxidation, and hydroxylation to yield renally excreted end-products. Reported adverse effects of these metabolites include diarrhea, rash, insulin insensitivity, hepatotoxicity, renal toxicity, thrombocytopenia, anemia, and lymphopenia.

Diabetes Risk

In HPS2-THRIVE, niacin–laropiprant therapy was associated with new diagnoses of diabetes increased by one third, corresponding to 13 new cases per 1,000 patients treated for approximately 4 years.

Drug Interactions

Statins: While high doses of vitamin B3 (niacin) can enhance cholesterol management when combined with statins, this combination carries a risk of rhabdomyolysis, a serious muscle condition. A growing body of evidence suggests that this risk is relatively slight in persons with healthy kidneys.

Alcohol: Alcohol can increase some of the side effects of niacin, causing nausea, dizziness, itching, vomiting, upset stomach, and flushing. Furthermore, consumption of large amounts of alcohol is associated with elevated cholesterol and triglycerides.

Conditions affecting niacin metabolism: Carcinoid syndrome is caused by slow-growing tumors in the gastrointestinal tract that release serotonin and other substances. It is characterized by facial flushing, diarrhea, and other symptoms. In those with carcinoid syndrome, tryptophan is preferentially oxidized to serotonin and not metabolized to niacin, leaving the body with less available tryptophan to convert to niacin.

There is no evidence of adverse effects from the consumption of naturally occurring niacin in foods.

References

• NIH Office of Dietary Supplements — Niacin: Health Professional Fact Sheet
• NIH Office of Dietary Supplements — Niacin: Consumer Fact Sheet
• Institute of Medicine (1998) — Dietary Reference Intakes: Niacin Chapter (NCBI Bookshelf)
• StatPearls — Niacin Deficiency (NCBI Bookshelf)
• LiverTox — Niacin (NCBI Bookshelf / NIH)
• StatPearls — Niacin Toxicity (NCBI Bookshelf)
• Harvard T.H. Chan School of Public Health — The Nutrition Source: Niacin – Vitamin B3
• Linus Pauling Institute, Oregon State University — Niacin Micronutrient Information Center
• Mani P, Uno K, Nair SV et al. — Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct? (PMC)
• HPS2-THRIVE, AIM-HIGH and dal-OUTCOMES: HDL-cholesterol under attack (PMC)
• HPS2-THRIVE Collaborative Group — Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients (NEJM, 2014)
• HPS2-THRIVE Trial Design Paper — European Heart Journal (2013)
• Chen AC et al. — A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention (NEJM, 2015)
• Chen AC et al. — A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention (PubMed abstract)
• Tummala R et al. — The Role of Nicotinamide in Cancer Chemoprevention and Therapy (PMC)
• Boo YC — Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide to Control Skin Aging and Pigmentation (PMC)
• Benyó Z et al. — The Mechanism and Mitigation of Niacin-Induced Flushing (PMC)
• Messamore E et al. — The niacin skin flush abnormality in schizophrenia: a quantitative dose-response study (PubMed)
• Glen AI et al. — The niacin challenge test: clinical manifestation of altered transmembrane signal transduction in schizophrenia? (PubMed)
• Nadalin S et al. — Niacin skin flush test: a research tool for studying schizophrenia (PubMed)
• News-Medical.net — Niacin History
• Cleveland Clinic — Pellagra: Definition, Symptoms & Treatment
• JAAD Reviews — Examining the safety of nicotinamide for skin cancer prevention (2025)
• Snaidr VA et al. — Nicotinamide for photoprotection and skin cancer chemoprevention (Experimental Dermatology, 2019)
• Pubmed — The discovery of niacin, biotin, and pantothenic acid
• National Academies Press — Dietary Reference Intakes: Niacin Chapter