Hubbry Logo
logo
Nicotinamide avatar
Nicotinamide
Community hub

Nicotinamide

logo
0 subscribers
Read side by side
Nicotinamide
View on Wikipedia
from Wikipedia

Nicotinamide
Clinical data
Pronunciation/ĖŒnaÉŖəĖˆsÉŖnəmaÉŖd/, /ĖŒnÉŖkəĖˆtÉŖnəmaÉŖd/
Other namesNAM, 3-pyridinecarboxamide
niacinamide (USAN US)
nicotinic acid amide
vitamin PP
nicotinic amide
vitamin B3
AHFS/Drugs.comConsumer Drug Information
License data
Routes of
administration		oral, topical
ATC code
Legal status
Legal status
Identifiers
  • pyridine-3-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.002.467 Edit this at Wikidata
Chemical and physical data
FormulaC6H6N2O
Molar mass122.127 gĀ·molāˆ’1
3D model (JSmol)
Density1.40 g/cm3 g/cm3 [1]
Melting point129.5 Ā°C (265.1 Ā°F)
Boiling point334 Ā°C (633 Ā°F)
  • c1cc(cnc1)C(=O)N
  • InChI=1S/C6H6N2O/c7-6(9)5-2-1-3-8-4-5/h1-4H,(H2,7,9)
  • Key:DFPAKSUCGFBDDF-UHFFFAOYSA-N

Nicotinamide (INN, BAN UK[2]) or niacinamide (USAN US) is a form of vitamin B3 found in food and used as a dietary supplement and medication.[3][4][5] As a supplement, it is used orally (swallowed by mouth) to prevent and treat pellagra (niacin deficiency).[4] While nicotinic acid (niacin) may be used for this purpose, nicotinamide has the benefit of not causing skin flushing.[4] As a cream, it is used to treat acne, and has been observed in clinical studies to improve the appearance of aging skin by reducing hyperpigmentation and redness.[5][6] It is a water-soluble vitamin.

Side effects are minimal.[7][8] At high doses, liver problems may occur.[7] Normal amounts are safe for use during pregnancy.[9] Nicotinamide is in the vitamin B family of medications, specifically the vitamin B3 complex.[10][11] It is an amide of nicotinic acid.[7] Foods that contain nicotinamide include yeast, meat, milk, and green vegetables.[12]

Nicotinamide was discovered between 1935 and 1937.[13][14] It is on the World Health Organization's List of Essential Medicines.[15][16] Nicotinamide is available as a generic medication and over the counter.[10] Commercially, nicotinamide is made from either nicotinic acid (niacin) or nicotinonitrile.[14][17] In some countries, grains have nicotinamide added to them.[14]

Extra-terrestrial nicotinamide has been found in carbonaceous chondrite meteorites.[18]

Medical uses

[edit]

Niacin deficiency

[edit]

Nicotinamide is the preferred treatment for pellagra, caused by niacin deficiency.[4]

Acne

[edit]

Nicotinamide cream is used as a treatment for acne.[5] It has anti-inflammatory actions, which may benefit people with inflammatory skin conditions.[19]

Nicotinamide increases the biosynthesis of ceramides in human keratinocytes in vitro and improves the epidermal permeability barrier in vivo.[20] The application of 2% topical nicotinamide for 2 and 4 weeks has been found to be effective in lowering the sebum excretion rate.[21] Nicotinamide has been shown to prevent Cutibacterium acnes-induced activation of toll-like receptor 2, which ultimately results in the down-regulation of pro-inflammatory interleukin-8 production.[22]

Skin cancer

[edit]

Nicotinamide at doses of 500 to 1000 mg a day decreases the risk of skin cancers, other than melanoma, in those at high risk.[23]

Side effects

[edit]

Nicotinamide has minimal side effects.[7][8] At very high doses above 3 g per day acute liver toxicity has been documented in at least one case.[7] Normal doses are safe during pregnancy.[9]

Chemistry

[edit]

The structure of nicotinamide consists of a pyridine ring to which a primary amide group is attached in the meta position. It is an amide of nicotinic acid.[7] As an aromatic compound, it undergoes electrophilic substitution reactions and transformations of its two functional groups. Examples of these reactions reported in Organic Syntheses include the preparation of 2-chloronicotinonitrile by a two-step process via the N-oxide,[24][25]

from nicotinonitrile by reaction with phosphorus pentoxide,[26] and from 3-aminopyridine by reaction with a solution of sodium hypobromite, prepared in situ from bromine and sodium hydroxide.[27]

NAD+, the oxidized form of NADH, contains the nicotinamide moiety (highlighted in red)

Industrial production

[edit]

The hydrolysis of nicotinonitrile is catalysed by the enzyme nitrile hydratase from Rhodococcus rhodochrous J1,[28][29][17] producing 3500 tons per annum of nicotinamide for use in animal feed.[30] The enzyme allows for a more selective synthesis as further hydrolysis of the amide to nicotinic acid is avoided.[31][32] Nicotinamide can also be made from nicotinic acid. According to Ullmann's Encyclopedia of Industrial Chemistry, worldwide 31,000 tons of nicotinamide were sold in 2014.[14]

Biochemistry

[edit]
The active Nicotinamide group on the molecule NAD+ undergoes oxidation in many metabolic pathways.

Nicotinamide, as a part of the cofactor nicotinamide adenine dinucleotide (NADH / NAD+) is crucial to life. In cells, nicotinamide is incorporated into NAD+ and nicotinamide adenine dinucleotide phosphate (NADP+). NAD+ and NADP+ are cofactors in a wide variety of enzymatic oxidation-reduction reactions, most notably glycolysis, the citric acid cycle, and the electron transport chain.[33] If humans ingest nicotinamide, it will likely undergo a series of reactions that transform it into NAD, which can then undergo a transformation to form NADP+. This method of creation of NAD+ is called a salvage pathway. However, the human body can produce NAD+ from the amino acid tryptophan and niacin without our ingestion of nicotinamide.[34]

NAD+ acts as an electron carrier that mediates the interconversion of energy between nutrients and the cell's energy currency, adenosine triphosphate (ATP). In oxidation-reduction reactions, the active part of the cofactor is the nicotinamide. In NAD+, the nitrogen in the aromatic nicotinamide ring is covalently bonded to adenine dinucleotide. The formal charge on the nitrogen is stabilized by the shared electrons of the other carbon atoms in the aromatic ring. When a hydride atom is added onto NAD+ to form NADH, the molecule loses its aromaticity, and therefore a good amount of stability. This higher energy product later releases its energy with the release of a hydride, and in the case of the electron transport chain, it assists in forming adenosine triphosphate.[35]

When one mole of NADH is oxidized, 158.2 kJ of energy will be released.[35]

Biological role

[edit]

Nicotinamide occurs as a component of a variety of biological systems, including within the vitamin B family and specifically the vitamin B3 complex.[10][11] It is also a critically important part of the structures of NADH and NAD+, where the N-substituted aromatic ring in the oxidised NAD+ form undergoes reduction with hydride attack to form NADH.[33] The NADPH/NADP+ structures have the same ring, and are involved in similar biochemical reactions.

Nicotinamide can be methylated in the liver to biologically active 1-Methylnicotinamide when there are sufficient methyl donors.

Food sources

[edit]

Nicotinamide occurs in trace amounts mainly in meat, fish, nuts, and mushrooms, as well as to a lesser extent in some vegetables.[36] It is commonly added to cereals and other foods. Many multivitamins contain 20ā€“30 mg of vitamin B3 and it is also available in higher doses.[37]

Compendial status

[edit]

Research

[edit]

A 2015 trial found nicotinamide to reduce the rate of new nonmelanoma skin cancers and actinic keratoses in a group of people at high risk for the conditions.[40]

Nicotinamide has been investigated for many additional disorders, including treatment of bullous pemphigoid and nonmelanoma skin cancers.[41]

Nicotinamide may be beneficial in treating psoriasis.[42]

There is tentative evidence for a potential role of nicotinamide in treating acne, rosacea, autoimmune blistering disorders, ageing skin, and atopic dermatitis.[41] Nicotinamide also inhibits poly(ADP-ribose) polymerases (PARP-1), enzymes involved in the rejoining of DNA strand breaks induced by radiation or chemotherapy.[43] ARCON (accelerated radiotherapy plus carbogen inhalation and nicotinamide) has been studied in cancer.[44]

Research has suggested nicotinamide may play a role in the treatment of HIV.[45]

Extra-terrestrial occurrence

[edit]

Extra-terrestrial nicotinamide has been found in carbonaceous chondrite meteorites.

Vitamin B3 vitamers from extra-terrestrial sources
Meteorite Nicotinic acid Nicotinamide
Orgueil[46] 715 ppb 214 ppb
Murray[18] 626 ppb 65 ppb
Murchison 2.4 nmol/g[47] 190 ppb[18] 16 ppb[18]
Tagish Lake[18] 108 ppb 5 ppb

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Nicotinamide

View on Grokipedia
from Grokipedia
Nicotinamide, also known as niacinamide, is the amide derivative of nicotinic acid (niacin) and a form of vitamin B3, a water-soluble essential nutrient that serves as a precursor to the coenzymes nicotinamide adenine dinucleotide (NADāŗ) and nicotinamide adenine dinucleotide phosphate (NADPāŗ), which are critical for cellular energy production, redox reactions, and metabolic processes. Discovered in the 1930s as a treatment for pellagra, it is chemically 3-pyridinecarboxamide with the molecular formula Cā‚†Hā‚†Nā‚‚O and a molecular weight of 122.12 g/mol; it appears as a white crystalline powder that is highly soluble in water (1 g/mL) and has a melting point of 128.8ā€“130 Ā°C.[1][2] Found naturally in foods such as fish, poultry, and yeast, nicotinamide prevents niacin deficiency diseases like pellagra in humans and blacktongue in animals by replenishing NADāŗ levels.[3][4] In biological systems, nicotinamide plays a pivotal role in over 500 enzymatic reactions involving NADāŗ and NADPāŗ, supporting glycolysis, the citric acid cycle, fatty acid oxidation, and DNA repair while also modulating inflammation and oxidative stress through inhibition of poly(ADP-ribose) polymerase 1 (PARP1) and sirtuins.[2][5] Its deficiency leads to dermatological, gastrointestinal, and neurological symptoms characteristic of pellagra, which it effectively treats at doses of 50ā€“500 mg/day.[4] Beyond nutrition, nicotinamide is widely used as a dietary supplement, food fortifier, and animal feed additive to ensure adequate vitamin B3 intake.[1] Therapeutically, nicotinamide exhibits multifaceted applications, particularly in dermatology, where topical formulations (2ā€“5%) improve skin barrier function by boosting ceramide synthesis, reduce acne vulgaris lesions, alleviate rosacea and atopic dermatitis symptoms, and enhance wound healing.[5] Oral supplementation (500 mg twice daily) has demonstrated efficacy in chemopreventing non-melanoma skin cancers by enhancing DNA repair and mitigating UV-induced immunosuppression, as shown in the ONTRAC phase 3 clinical trial with high-risk populations.[5][6] In anti-aging contexts, it diminishes fine wrinkles, hyperpigmentation, and photoaging signs via antioxidant effects and NADāŗ-dependent pathways.[5] Generally well-tolerated up to 3 g/day, it rarely causes mild gastrointestinal upset at higher doses, with no significant toxicity reported in standard use.[5][4]

Introduction

Definition and nomenclature

Nicotinamide, abbreviated as NAM, is the amide derivative of niacin (vitamin B3), a water-soluble vitamin essential for human metabolism.[1] Chemically known as 3-pyridinecarboxamide, it consists of a pyridine ring with a carboxamide group attached at the 3-position and has the molecular formula C6H6N2O.[1] This compound is classified as a pyridinecarboxamide, distinguishing it from other B vitamins by its role in coenzyme synthesis.[1] Unlike niacin, also called nicotinic acid, nicotinamide does not induce skin flushingā€”a vasodilatory side effect associated with high doses of the acid formā€”due to differences in their chemical structures and metabolic handling.[7] Both compounds function as precursors to nicotinamide adenine dinucleotide (NAD+), a critical coenzyme, but they are not fully interchangeable across all pathways, as niacin exhibits unique lipid-modulating effects at pharmacological doses that nicotinamide lacks.[8] Nicotinamide has been included on the World Health Organization's List of Essential Medicines since 1979, specifically for the treatment of pellagra, a deficiency disease historically linked to niacin shortfall.[9] The term "nicotinamide" originates from a blend of "nicotine" and "amide," referencing its structural relation to the pyridine-based alkaloid in tobacco, though nicotinamide is non-toxic and bears no connection to tobacco's addictive properties.[10]

History

Pellagra, a disease characterized by dermatitis, diarrhea, dementia, and often death, was first systematically described in the late 18th century in Spain and Italy, with epidemics emerging in the United States by the early 1900s, particularly among populations reliant on corn-based diets lacking sufficient niacin precursors.[11] In the 1910s, U.S. Public Health Service physician Joseph Goldberger demonstrated through epidemiological studies and controlled experiments on prisoners and orphans that pellagra was not infectious but resulted from dietary deficiencies, specifically linking it to monotonous corn-heavy diets common in the American South that failed to provide adequate tryptophan or niacin.[12] Goldberger's findings, published between 1915 and 1923, shifted medical understanding toward nutritional prevention, though the exact causative nutrient remained unidentified during his lifetime.[13] In 1937, biochemist Conrad Elvehjem at the University of Wisconsin isolated the anti-pellagra factor from liver extracts, identifying nicotinic acid and its amide form, nicotinamide, both effective in treating black tongue disease in dogs, a canine analog to human pellagra.[14] This breakthrough, building on earlier work with coenzyme fractions, confirmed the role of these compounds as the active pellagra-preventive factors, later designated vitamin B3 (with "niacin" coined from "nicotinic acid vitamin" to avoid nicotine associations), and paved the way for their commercial production.[15] During the 1940s, the biosynthetic pathways for nicotinamide adenine dinucleotide (NAD+), the coenzyme form of nicotinamide, were elucidated through enzymatic studies, with Arthur Kornberg identifying key synthesis enzymes like nicotinamide mononucleotide adenylyltransferase in 1948.[16] Concurrently, Otto Warburg and collaborators expanded on their earlier discoveries, detailing NAD+'s critical function as a redox coenzyme in cellular respiration and dehydrogenase reactions, essential for energy metabolism.[17] Following World War II, widespread enrichment of staple foods like flour and bread with nicotinamide and other B vitamins, mandated by U.S. legislation in the early 1940s, dramatically reduced pellagra incidence, leading to its near-eradication in the United States by the late 1940s through improved dietary intake among at-risk populations.[18][19]

Chemical properties

Molecular structure

Nicotinamide, with the IUPAC name pyridine-3-carboxamide, is a derivative of pyridine featuring a carboxamide functional group attached at the 3-position.[1] The molecule consists of a six-membered aromatic ring containing one nitrogen atom (pyridine), where the -C(=O)NHā‚‚ group is bonded to the carbon atom meta to the ring nitrogen.[1] This amide linkage (-CONHā‚‚) replaces the carboxylic acid group (-COOH) found in niacin (nicotinic acid), resulting in nicotinamide being neutral and non-acidic, unlike the acidic niacin.[1][20] The canonical SMILES notation for nicotinamide is C1=CC(=CN=C1)C(=O)N, representing the ring connectivity and the amide substituent.[1] Structurally, it can be visualized as a flat, planar pyridine ring with alternating double bonds, the nitrogen at position 1, and the carboxamide protruding from position 3, enabling resonance within the aromatic system.[1] Nicotinamide lacks chiral centers, as confirmed by its defined atom stereocenter count of zero, and its aromatic ring adopts a planar conformation due to spĀ² hybridization of the ring atoms.[1]

Physical and chemical characteristics

Nicotinamide is a white crystalline powder that is odorless.[1] It exhibits high solubility in water (691 g/L at 20 Ā°C), ethanol (660 g/L at 20 Ā°C), and glycerol; it is sparingly soluble in diethyl ether.[1][21][22] The melting point ranges from 128Ā°C to 131Ā°C.[1] Chemically, the pKa of its conjugate acid is approximately 3.3, corresponding to the pyridine nitrogen.[1] Nicotinamide remains stable under neutral conditions but undergoes hydrolysis to nicotinic acid in strongly acidic or basic environments. For analytical purposes, it shows characteristic UV absorption at around 262 nm in alcohol (log Īµ = 3.4).[1]

Synthesis and production

Industrial production

Nicotinamide is primarily produced on an industrial scale through chemical synthesis routes starting from 3-picoline (3-methylpyridine), with the most common method involving gas-phase ammoxidation followed by hydrolysis of the intermediate 3-cyanopyridine.[23] This process achieves high purity levels exceeding 95%, suitable for pharmaceutical and supplement applications.[23] An alternative route directly hydrolyzes 3-cyanopyridine, which can be sourced from other ammoxidation processes.[24] The key ammoxidation step reacts 3-picoline with ammonia and oxygen in a fluidized bed reactor, catalyzed by metal oxides such as vanadium pentoxide (Vā‚‚Oā‚…) combined with antimony oxide (Sbā‚‚Oā‚…), chromium oxide (Crā‚‚Oā‚ƒ), and titanium dioxide (TiOā‚‚).[23] The reaction occurs at temperatures of 300ā€“400Ā°C and pressures around 0.5 MPa, selectively converting the methyl group to a cyano group to form 3-cyanopyridine with yields up to 99%.[23] The overall reaction can be represented as:
3-picoline+NH3+O2ā†’metal oxide catalysts, 300-400Ā°C3-cyanopyridine+H2O \text{3-picoline} + \text{NH}_3 + \text{O}_2 \xrightarrow{\text{metal oxide catalysts, 300-400Ā°C}} \text{3-cyanopyridine} + \text{H}_2\text{O}
This step is preferred for its efficiency and atom economy in large-scale operations.[24] Subsequent hydrolysis of 3-cyanopyridine to nicotinamide typically employs alkaline conditions using 10% sodium hydroxide at 190Ā°C and 1.5ā€“2 MPa, followed by purification via ion exchange and crystallization to isolate the amide product.[23] The process yields nicotinamide with minimal impurities, and the main byproduct is water, contributing to its relatively low environmental footprint compared to older methods.[23] Major global producers include Lonza Group and BASF SE.[25] Overall worldwide production exceeded 75,000 metric tons as of 2024, directed toward supplements, animal feed, and medicinal formulations.[26] Production has grown significantly due to increasing demand in pharmaceuticals and cosmetics. Environmental considerations in nicotinamide production have driven shifts toward catalytic ammoxidation routes since the early 2000s, phasing out cyanide-intensive processes that generated hazardous byproducts like NOx from nitric acid oxidations. Modern methods emphasize byproduct management and greener catalysis to minimize waste, with water as the predominant effluent and reduced emissions of volatile organics.[23]

Biosynthesis

Nicotinamide is primarily synthesized in living organisms through two main enzymatic pathways: the de novo pathway and the salvage pathway, both contributing to the production of nicotinamide adenine dinucleotide (NADāŗ), from which nicotinamide is derived upon degradation.[27] In mammals, the de novo pathway begins with the amino acid tryptophan and proceeds via the kynurenine pathway, where tryptophan is oxidized to N-formylkynurenine by tryptophan 2,3-dioxygenase in the liver, followed by subsequent steps involving kynurenine 3-monooxygenase and kynureninase to form anthranilic acid and eventually quinolinic acid.[28] Quinolinic acid is then converted to nicotinic acid mononucleotide by quinolinate phosphoribosyltransferase, leading to nicotinic acid adenine dinucleotide and finally NADāŗ, which can be hydrolyzed to release nicotinamide.[27] This pathway accounts for the majority of de novo NADāŗ synthesis in mammals, with approximately 60 mg of tryptophan yielding about 1 mg of niacin equivalent (nicotinamide or nicotinic acid), and typical daily dietary tryptophan intake supporting around 10-15 mg of such equivalents.[29] The salvage pathway recycles nicotinamide generated from NADāŗ degradation, which occurs through enzymatic hydrolysis by sirtuins, poly(ADP-ribose) polymerases, and CD38 during cellular processes like DNA repair and signaling.[27] The rate-limiting step is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT), which uses phosphoribosyl pyrophosphate (PRPP) to convert nicotinamide into nicotinamide mononucleotide (NMN).[30] NMN is then adenylated by nicotinamide mononucleotide adenylyltransferase (NMNAT) to form NADāŗ, closing the recycling loop and preventing nicotinamide accumulation.[31] This pathway is predominant in most tissues, especially under conditions of limited de novo synthesis, and can sustain up to 85% of NADāŗ pools in mammals by reutilizing nicotinamide from dietary or endogenous sources.[27] In microorganisms, nicotinamide biosynthesis can be enhanced through metabolic engineering, particularly in bacteria like Escherichia coli. Engineered strains overexpressing NAMPT homologs (such as NadV) and optimizing PRPP availability have achieved high-yield fermentation, with NMN production reaching up to 16.2 g/L in bioreactors under optimized conditions like supplemented nicotinamide and lactose media.[32] These microbial systems leverage the salvage pathway for efficient biotransformation, offering scalable production alternatives to chemical synthesis.[33] Biosynthesis of nicotinamide is tightly regulated to maintain cellular NADāŗ homeostasis, with NAMPT and NMNAT as key control points. High NADāŗ levels indirectly inhibit the pathway through feedback mechanisms, including allosteric modulation of NAMPT by energy status (e.g., AMP/ATP ratios) and transcriptional repression of salvage enzymes during NADāŗ abundance.[34] In mammals, the de novo kynurenine pathway is primarily active in the liver and inhibited by excess NADāŗ via reduced expression of tryptophan dioxygenase, while the salvage pathway responds to NADāŗ depletion by upregulating NAMPT under stress conditions like inflammation or aging.[27]

Biological and metabolic roles

Coenzyme functions

Nicotinamide acts as a key precursor in the biosynthesis of the essential coenzymes nicotinamide adenine dinucleotide (NADāŗ) and its phosphorylated derivative, nicotinamide adenine dinucleotide phosphate (NADPāŗ), which are critical for cellular redox reactions and metabolism. Through the salvage pathway, nicotinamide is first converted to nicotinamide mononucleotide (NMN) by the enzyme nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting step that recycles nicotinamide derived from NADāŗ consumption. NMN is then transformed into NADāŗ by nicotinamide mononucleotide adenylyltransferases (NMNATs), a family of enzymes localized in different cellular compartments to ensure efficient NADāŗ production.[27][35] NADāŗ primarily functions as an electron acceptor in catabolic processes, undergoing reduction to NADH by accepting a hydride ion (Hā») from substrates in dehydrogenase reactions. This redox capability is exemplified by the half-reaction:
NADX++2ā€‰eXāˆ’+2ā€‰HX+ā‡ŒNADH+HX+ \ce{NAD+ + 2e- + 2H+ ā‡Œ NADH + H+}
with a standard reduction potential (EĀ°') of -0.32 V at pH 7, enabling the transfer of electrons to the mitochondrial electron transport chain.[36] NADāŗ-dependent dehydrogenases facilitate hydride transfer in central metabolic pathways, including glycolysis (e.g., glyceraldehyde-3-phosphate dehydrogenase), the tricarboxylic acid (TCA) cycle (e.g., isocitrate dehydrogenase and Ī±-ketoglutarate dehydrogenase), and Ī²-oxidation of fatty acids, ultimately supporting ATP production via oxidative phosphorylation. Approximately 500 enzymes across these and other pathways rely on NADāŗ/NADH as a cofactor for maintaining cellular energy homeostasis.[37][27] In contrast, NADPāŗ, formed by phosphorylation of NADāŗ via NADāŗ kinase, predominates in anabolic reactions where its reduced form, NADPH, supplies reducing equivalents. NADPH is crucial for biosynthetic processes such as fatty acid synthesis, where it powers the reductive steps catalyzed by fatty acid synthase, as well as cholesterol and nucleotide synthesis. This distinction allows cells to compartmentalize redox balance, with NADāŗ/NADH favoring oxidation and NADPāŗ/NADPH supporting reduction in pathways that build complex molecules.[27]

Deficiency effects

Nicotinamide deficiency, also known as niacin deficiency, leads to the clinical syndrome pellagra, characterized by the classic triad of symptoms: dermatitis, diarrhea, and dementia. Dermatitis manifests as a photosensitive rash, typically appearing as symmetrical, erythematous lesions on sun-exposed areas such as the face, neck (often forming a "Casal's necklace"), hands, and feet, which can progress to bullae, scaling, and hyperpigmentation in severe cases. Diarrhea presents as profuse, watery stools, sometimes accompanied by nausea, vomiting, abdominal pain, and glossitis. Dementia involves initial neuropsychiatric symptoms like irritability, anxiety, poor concentration, and depression, potentially advancing to confusion, hallucinations, delirium, and coma if untreated. Collectively, these are referred to as the "4 Ds" of pellagraā€”dermatitis, diarrhea, dementia, and deathā€”which can occur if the deficiency remains unaddressed.[38][39] The underlying mechanisms of pellagra stem from depletion of nicotinamide adenine dinucleotide (NAD+), a critical coenzyme derived from nicotinamide, which impairs cellular energy metabolism and other vital processes. NAD+ depletion disrupts over 500 enzymatic reactions, including those essential for ATP production through glucose, fat, and protein oxidation, leading to widespread metabolic dysfunction, particularly in high-energy tissues like the skin, gastrointestinal tract, and central nervous system.[38][37] Risk factors for nicotinamide deficiency include diets predominantly composed of maize or other staples low in bioavailable niacin and tryptophan (the amino acid precursor to niacin), as maize contains niacin in a bound form with limited digestibility unless processed with alkali. Chronic alcoholism increases susceptibility by promoting poor nutrition, impairing intestinal absorption, and interfering with tryptophan conversion to niacin. Genetic conditions like Hartnup disease, which impair tryptophan absorption in the intestines and kidneys, also heighten risk by limiting the substrate for endogenous niacin synthesis.[38][39] Subclinical nicotinamide deficiency can manifest as nonspecific symptoms such as fatigue, weakness, depression, and irritability, often preceding overt pellagra and affecting quality of life without the classic diagnostic signs. While pellagra has been largely eradicated in industrialized nations through food fortification, it persists in developing regions, particularly among vulnerable populations like refugees and those in low-income countries with maize-dependent diets; estimates suggest millions remain at risk globally, with historical outbreaks affecting tens of thousands in emergency settings.[38][39][40]

Sources and intake

Dietary sources

Nicotinamide, a form of vitamin B3, is obtained from dietary sources primarily as niacin equivalents, which include preformed niacin (nicotinic acid and nicotinamide) and tryptophan that the body converts to nicotinamide at a ratio of approximately 60 mg tryptophan yielding 1 mg niacin equivalent. Animal-based foods are rich sources, providing highly bioavailable forms mainly as nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). Beef, chicken, shrimp, fish like salmon and tuna, and milk (especially fresh milk, rich in nicotinamide riboside (NR)) are examples that help raise NAD+ levels. Beef liver contains about 17.5 mg niacin per 100 g, while poultry such as chicken breast offers around 12 mg per 100 g, and fish like tuna provides approximately 10ā€“13 mg per 100 g.[7][41] Plant-based foods contribute lower amounts of niacin equivalents, often in less bioavailable forms bound to plant matrices. Brewer's yeast (including beer yeast products) is an exception, delivering up to 40 mg per 100 g, and peanuts supply about 12 mg per 100 g; whole grains also provide moderate contributions. Green vegetables generally provide 0.5ā€“2 mg per 100 g, with examples like spinach at 0.7 mg per 100 g and broccoli at 0.6 mg per 100 g. The body's conversion of tryptophan from protein-rich plants further supports niacin status.[42][41] The recommended dietary allowance (RDA) for niacin equivalents is 16 mg per day for adult men and 14 mg per day for adult women, accounting for both preformed niacin and tryptophan conversion. Bioavailability varies by food type; animal sources offer near-complete absorption (over 90%), while plant sources range from 30ā€“70%, with niacin in some grains like corn being particularly low due to binding unless processed. In regions relying on corn as a staple, such as parts of Latin America and historically the southern United States, niacin intake is limited without nixtamalizationā€”a traditional alkali treatment that significantly enhances bioavailability through hydrolysis of bound forms.[7][42] In balanced diets worldwide, average daily niacin intake typically ranges from 20ā€“30 mg, exceeding the RDA and reflecting contributions from diverse foods; for instance, U.S. adults consume about 31 mg for men and 21 mg for women.[7][42]
Food CategoryExampleNiacin Equivalents (mg/100 g)Source
Animal (Liver)Beef liver, cooked17.5USDA FoodData Central
Animal (Fish)Tuna, canned in water10ā€“13USDA FoodData Central
Animal (Poultry)Chicken breast, cooked12NIH ODS
Plant (Yeast)Brewer's yeast, dried40Linus Pauling Institute
Plant (Nuts)Peanuts, raw12USDA FoodData Central
Plant (Vegetables)Spinach, raw0.7USDA FoodData Central

Supplements and fortification

Nicotinamide is available in various commercial supplement forms, primarily as oral capsules or tablets ranging from 100 mg to 500 mg per serving, with some products offering higher doses up to 500 mg or more for specific therapeutic needs.[7][43] Topical formulations, such as creams and gels typically containing 4-5% nicotinamide, are also marketed for skin applications. These supplements are frequently combined with other B vitamins, like thiamin, riboflavin, and pyridoxine, in multivitamin complexes to support overall nutritional balance, particularly for individuals at risk of deficiencies.[44][45] Food fortification with nicotinamide or niacin equivalents began in the 1940s to combat pellagra, with widespread adoption in the United States following voluntary enrichment programs for flour and cereals by 1942, driven initially by military procurement requirements. Under current U.S. Food and Drug Administration regulations, enriched flour must contain at least 24 mg of niacin per pound to meet standardization standards for nutrient restoration in milled grains. This practice has extended to cereals and other grain products, contributing significantly to population-level prevention of niacin deficiency.[46][47][48] Intake guidelines for nicotinamide, as part of niacin, establish a tolerable upper intake level of 35 mg per day for adults from all sources to minimize risks of minor adverse effects like gastrointestinal upset, though higher therapeutic doses are used under medical supervision. It is commonly incorporated into multivitamins at doses of 15-20 mg for at-risk groups, such as older adults or those with limited dietary variety, aligning with recommended dietary allowances of 14-16 mg niacin equivalents daily. Oral nicotinamide exhibits high bioavailability, with approximately 90% absorption in the gastrointestinal tract, facilitating efficient systemic uptake. The global vitamin B3 market, including nicotinamide, was valued at USD 372 million in 2023 and USD 380.2 million in 2024 (as of 2024), projected to grow at a CAGR of 2.2% from 2024 to 2030 due to increasing demand for nutritional and skin health products.[49][7][50]

Medical applications

Niacin deficiency treatment

Nicotinamide serves as the primary therapeutic agent for treating pellagra and other manifestations of niacin deficiency, preferred over nicotinic acid due to its lack of vasodilatory side effects such as flushing. The standard oral regimen involves administering 300 mg of nicotinamide daily in divided doses, typically 100 mg three times per day, for 3 to 4 weeks to replenish depleted stores and reverse symptoms. In severe cases, particularly those involving malabsorption or inability to tolerate oral intake, intravenous or intramuscular administration may be initiated at doses of 50 to 100 mg up to five times daily, transitioning to oral therapy as the patient's condition stabilizes.[39][51][43] Treatment with nicotinamide demonstrates high efficacy, leading to rapid resolution of acute symptoms; gastrointestinal issues like diarrhea typically improve within days, while dermatological manifestations such as dermatitis begin to resolve within one to two weeks, and neurological symptoms like early dementia are often prevented from progressing with prompt intervention. Full recovery in chronic cases may require several weeks to months, but early administration significantly reduces mortality risk, which can exceed 50% in untreated advanced pellagra. This therapeutic approach has been consistently effective across diverse populations, including those in resource-limited settings.[52][53][38] Adjunctive measures are essential to optimize outcomes and prevent recurrence, including dietary enhancements with niacin-rich foods such as lean meats, fish, nuts, and fortified grains to support long-term intake, alongside a protein-rich diet to aid tryptophan conversion to niacin. Underlying causes, such as malabsorption syndromes (e.g., due to chronic diarrhea or alcoholism), must be addressed concurrently through targeted interventions like managing gastrointestinal disorders or providing additional B-vitamin supplements, given frequent co-deficiencies.[51][38][39] Historically, widespread nicotinamide supplementation programs, combined with food fortification initiatives following the 1937 identification of niacin as the anti-pellagra factor, dramatically reduced pellagra incidence in the United States, eradicating endemic cases by the 1950s and averting thousands of deaths in the American South. These efforts, led by public health measures including enriched flour distribution, demonstrated the scalability of niacin-based interventions in controlling deficiency epidemics.[54][55][38]

Dermatological uses

Nicotinamide has demonstrated efficacy in treating various dermatological conditions through its anti-inflammatory, DNA repair-enhancing, and barrier-strengthening properties. In acne vulgaris, topical formulations such as 4% nicotinamide gel reduce inflammatory lesions by modulating immune responses and decreasing sebum production, which controls oiliness particularly beneficial for oily skin, minimizes the appearance of large pores through sebum regulation, improved skin elasticity, and barrier strengthening, and improves rough skin texture, showing comparable effectiveness to 1% clindamycin gel in randomized double-blind trials involving patients with moderate inflammatory acne; such topical applications are suitable for daily use in the morning and evening. Higher concentrations, such as 10% topical nicotinamide, are effective for hyperpigmentation, providing skin brightening and evening skin tone; in brightening skincare routines with actives like kojic acid, it enhances overall brightening by reducing hyperpigmentation, controls oil production beneficial for combination skin, reduces inflammation, and strengthens the skin barrier to counteract dryness from other actives, and is generally well-tolerated, particularly for tolerant skin when introduced gradually, as shown in clinical use for melasma.[56][57][58] Oral nicotinamide at 750 mg daily, often combined with zinc, leads to significant lesion reduction, with approximately 55% of patients reporting moderate to substantial improvement in appearance after 8 weeks in clinical outcomes studies.[59] For skin aging, oral nicotinamide at 500 mg daily supports cellular energy metabolism, enhancing ATP levels to promote DNA repair and mitigate UV-induced damage, which contributes to reduced wrinkle formation and improved skin elasticity over time.[5] Topically, nicotinamide stimulates de novo synthesis of ceramides and other stratum corneum lipids, bolstering the epidermal barrier function and improving hydration, as evidenced by decreased transepidermal water loss in human skin models.[60] In skin cancer prevention, particularly for high-risk individuals, oral nicotinamide at 500 mg twice daily reduces the incidence of new non-melanoma skin cancers by 23% and actinic keratoses by 13-20% over 12 months, according to the phase 3 ONTRAC randomized controlled trial.[6] A 2025 retrospective cohort study of U.S. veterans further confirmed a 14% overall risk reduction in skin cancers among those taking nicotinamide for over 30 days, escalating to 54% when initiated post-initial diagnosis, with the strongest effects against squamous cell carcinoma (up to 34% reduction).[61] These dermatological benefits stem from nicotinamide's role in replenishing NAD+ pools, which fuel ATP-dependent DNA repair pathways like nucleotide excision repair, thereby counteracting UV-induced photolesions and maintaining genomic stability in keratinocytes.[62] Additionally, it inhibits oxidative stress by scavenging reactive oxygen species and modulating sirtuin activity, reducing inflammation and cellular senescence without the flushing associated with niacin.[63] Nicotinamide is generally safe for high-risk patients, including those with prior skin cancers, exhibiting minimal adverse effects at these doses in large-scale trials.[6]

Ocular and other uses

Nicotinamide has shown potential in treating glaucoma, a leading cause of irreversible blindness, by supporting mitochondrial function in retinal ganglion cells and improving inner retinal function. In randomized controlled trials, oral doses escalating from 1.5 to 3 grams per day have demonstrated enhancements in visual field sensitivity and electroretinogram responses in patients with open-angle and normal-tension glaucoma. In prominent clinical trials such as the crossover randomized trial by Hui et al. (2020) and The Glaucoma Nicotinamide Trial, the nicotinamide supplement used was produced by Blackmores Ltd. (Blackmores, NSW, Australia); other trials (e.g., U.S.-based) do not always specify a brand. For instance, a 2020 crossover trial involving patients with treated glaucoma found that 1.5 grams daily for 6 weeks escalating to 3.0 grams daily for the subsequent 6 weeks significantly improved inner retinal function compared to placebo, with benefits attributed to boosted NAD+ levels aiding energy metabolism in optic nerve cells.[64][65] The Glaucoma Nicotinamide Trial similarly employs escalating doses from 1.5 to 3.0 g/day. Ongoing phase III trials, such as the NAMinG study, continue to evaluate nicotinamide escalating to 3 grams daily for slowing visual field loss in early-stage disease.[66][67] Beyond ocular applications, nicotinamide is used in managing bullous pemphigoid, an autoimmune blistering disorder, often in combination with tetracycline to reduce lesion formation through immunomodulatory effects that stabilize immune responses and inhibit inflammatory pathways. A landmark 1994 randomized trial reported that 500 mg three times daily (1.5 grams total) alongside tetracycline led to faster blister resolution and lower disease activity scores in 57 patients compared to prednisone alone, with sustained remission in many cases. Subsequent studies have supported this regimen as a steroid-sparing option, particularly for elderly patients intolerant to systemic corticosteroids.[68] In patients undergoing dialysis, nicotinamide addresses hyperphosphatemia by inhibiting intestinal phosphate absorption, achieving serum phosphate reductions without the vasodilatory flushing associated with niacin. Randomized trials have tested doses of 500 to 1000 mg daily, showing 10-20% phosphate lowering over 8-12 weeks, comparable to phosphate binders but with better tolerability. A 2017 randomized double-blind trial in 33 hemodialysis patients found nicotinamide (500 mg three times daily) equally effective as sevelamer in lowering serum phosphorus, though with inferior patient tolerance; evidence remains promising but limited by smaller sample sizes in recent studies, warranting further long-term validation.[69][70][71]

Pharmacology and safety

Mechanisms of action

Nicotinamide serves as a precursor to nicotinamide adenine dinucleotide (NAD+), thereby elevating cellular NAD+ levels, which in turn activates sirtuin enzymes such as SIRT1 that promote DNA repair processes and exert anti-inflammatory effects by deacetylating key transcription factors like NF-ĪŗB and FOXO proteins.[72] This NAD+ boosting mechanism is particularly relevant in therapeutic contexts, where nicotinamide supplementation restores depleted NAD+ pools to support sirtuin-mediated genomic stability and reduce inflammatory signaling.[73] A key aspect of nicotinamide's NAD+-sparing action involves its competitive inhibition of poly(ADP-ribose) polymerase 1 (PARP1), an enzyme that consumes NAD+ during DNA damage repair, thereby preventing excessive NAD+ depletion and allowing more substrate availability for sirtuin activation.[74] By binding to the catalytic site of PARP1 in competition with NAD+, nicotinamide limits PARP1-mediated poly(ADP-ribosyl)ation without fully abolishing the enzyme's role in DNA repair, thus maintaining a balance that favors sirtuin-dependent anti-inflammatory and reparative functions.[75] In its anti-inflammatory role, nicotinamide suppresses the NF-ĪŗB signaling pathway, a central regulator of immune responses, by inhibiting its translocation to the nucleus and subsequent activation of pro-inflammatory genes in skin keratinocytes and immune cells such as macrophages and dendritic cells.[76] This suppression leads to reduced production of cytokines like interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-Ī±), and IL-6, mitigating inflammatory cascades triggered by stimuli such as bacterial antigens or UV exposure in cutaneous and systemic contexts.[77][78] Nicotinamide also exhibits antioxidant properties by enhancing glutathione synthesis through upregulation of Ī³-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione production, which helps neutralize reactive oxygen species and protect cellular components from oxidative damage.[79] In skin cells, this mechanism contributes to defense against UV-induced oxidative stress, where nicotinamide bolsters glutathione levels to prevent lipid peroxidation and DNA strand breaks, thereby reducing immunosuppression and carcinogenesis risk.[80] The therapeutic effects of nicotinamide are dose-dependent, with low doses (50-500 mg daily) primarily supporting NAD+ maintenance and general anti-inflammatory actions in dermatological applications, while higher doses (1-3 g daily) promote neuroprotection by stimulating mitochondrial biogenesis via PGC-1Ī± activation and improving oxidative phosphorylation in neuronal models of metabolic stress.[81] At these elevated doses, nicotinamide enhances mitochondrial function and reduces reactive oxygen species accumulation, offering benefits in conditions involving neurodegeneration without inducing significant toxicity in preclinical studies.[82]

Side effects and toxicity

Nicotinamide is generally well-tolerated at therapeutic doses, with a favorable safety profile compared to nicotinic acid, as it does not cause the characteristic skin flushing associated with the latter.[7] Common adverse effects are mild and primarily gastrointestinal, including nausea, vomiting, and upset stomach, which typically occur at doses exceeding 3 g per day, particularly when taken on an empty stomach.[83][7] Rare but more serious side effects include hepatotoxicity, characterized by elevated liver enzymes such as alanine aminotransferase (ALT), observed with chronic intake above 6 g per day.[84][83] In 2025, ophthalmology guidelines highlighted potential risks of liver toxicity at high doses (ā‰„3 g/day) and unknown long-term safety, advising caution and monitoring in patients with glaucoma or liver conditions, as nicotinamide is not approved for glaucoma treatment.[85][86] The median lethal dose (LD50) for nicotinamide is greater than 2.5 g/kg via oral administration in rats, indicating low acute toxicity.[83] For humans, unlike nicotinic acid, nicotinamide does not have an established tolerable upper intake level (UL) due to the absence of flushing and low toxicity at higher doses; however, therapeutic doses up to 3 g per day are generally safe without significant toxicity in most individuals, as confirmed by meta-analyses and clinical trials.[7][87][6] Drug interactions with nicotinamide are minimal at standard doses, but caution is recommended during chemotherapy involving PARP inhibitors, as nicotinamide's structural similarity to these agents may competitively inhibit their binding to PARP enzymes, potentially reducing therapeutic efficacy.[88][89]

Regulatory status

Nicotinamide is affirmed as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration (FDA) for use as a direct human food ingredient, including in infant formulas, based on its established safety profile as a form of vitamin B3.[90] It is widely available over-the-counter as a dietary supplement and is FDA-approved in prescription formulations specifically for the prevention and treatment of pellagra, a deficiency disease caused by inadequate niacin intake.[91][92] The United States Pharmacopeia (USP) monograph establishes purity standards for pharmaceutical-grade nicotinamide, requiring not less than 98.5% and not more than 101.0% of C6H6N2O on a dried basis, with limits on key impurities such as nicotinic acid not exceeding 0.1%.[93] Similarly, the European Pharmacopoeia (EP) monograph mandates a content of not less than 99.0% and not more than 101.0% of pyridine-3-carboxamide, calculated with reference to the dried substance, alongside tests for heavy metals, loss on drying (not more than 0.5%), and other contaminants to ensure quality.[94] Nicotinamide is listed on the World Health Organization (WHO) Model List of Essential Medicines as a core (Level 1) therapeutic agent, particularly for addressing niacin deficiencies like pellagra, with recommended oral doses of 50 mg tablets.[9] It is also incorporated into global standards for infant formulas, as endorsed by WHO through Codex Alimentarius guidelines, to provide essential niacin equivalents at levels supporting daily requirements (e.g., 6.6 mg per 1000 kcal for infants).[95][7] Internationally, regulatory frameworks affirm nicotinamide's safety for various applications, though restrictions apply in specific contexts. In the European Union, it is permitted in cosmetic products for topical use at concentrations up to 5% without specific prohibitions at higher levels, provided overall product safety is demonstrated under the Cosmetics Regulation (EC) No 1223/2009.[96] For wrinkle-related claims, regulations differ: in Japan, the Ministry of Health, Labour and Welfare approves nicotinamide as an effective ingredient in quasi-drugs, permitting direct "improves wrinkles" claims on packaging; in contrast, overseas markets such as the US (FDA) and EU lack pharmacological approval for such efficacy, limiting claims to cosmetic descriptions like "reduces the appearance of wrinkles," supported by substantiation rather than direct regulatory endorsement.[97] As of 2025, updated clinical evidence from cohort studies has further supported its safety profile for skin cancer prevention, reinforcing approvals for supplemental and topical uses without necessitating changes to existing regulatory limits.[98]

Research directions

Skin cancer and dermatology

Recent cohort studies have demonstrated the potential of oral nicotinamide in reducing skin cancer risk among high-risk populations. A large 2025 Veterans Affairs (VA) study involving approximately 34,000 patients found that nicotinamide supplementation was associated with a 14% overall reduction in skin cancer incidence compared to non-users, with the effect strengthening to a 54% risk reduction when initiated after a first skin cancer diagnosis.[99] This benefit was particularly pronounced for squamous cell carcinoma, highlighting nicotinamide's role in preventing recurrence in veterans with prior non-melanoma skin cancers.[100] Building on earlier evidence, ongoing trials continue to explore nicotinamide's chemopreventive effects. Extensions and follow-up analyses of the phase III ONTRAC trial, which originally showed a 23% reduction in new non-melanoma skin cancers and actinic keratoses with oral nicotinamide, have informed real-world applications and safety assessments in 2025 reviews.[101][102] Additionally, clinical investigations into topical nicotinamide formulations for actinic keratosis include comparisons with oral dosing, showing modest lesion reduction, while research examines combinations with photodynamic therapy (PDT) to enhance clearance rates in field cancerization.[103][104] In preclinical and mechanistic studies, nicotinamide's protective effects against ultraviolet (UV) radiation-induced skin damage are linked to enhanced nucleotide excision repair (NER), a key DNA repair pathway. Nicotinamide boosts unscheduled DNA synthesis and accelerates the removal of UV-induced cyclobutane pyrimidine dimers and oxidative lesions in keratinocytes and melanocytes, thereby reducing mutagenesis and cancer progression.[62][105] This mechanism underpins its UV-protective role without altering photosensitivity.[106] Despite these advances, research gaps persist, particularly in long-term data for melanoma prevention, where evidence remains limited compared to non-melanoma skin cancers.[100] The 2025 VA findings, while robust for squamous cell carcinoma, underscore the need for extended trials to clarify sustained efficacy across all skin cancer types.[99]

Aging and neurodegeneration

Nicotinamide, a precursor to nicotinamide adenine dinucleotide (NAD+), plays a key role in counteracting age-related NAD+ decline, which can drop by up to 50% by middle age across various tissues. This decline contributes to mitochondrial dysfunction and impaired cellular repair mechanisms associated with aging. Through the NAD+ salvage pathway, nicotinamide is converted back to NAD+ via nicotinamide phosphoribosyltransferase (NAMPT), helping to replenish levels and support sirtuin activation, which promotes longevity by enhancing mitochondrial unfolded protein response and FOXO signaling.[107][27][108] Recent studies highlight nicotinamide's potential in mitigating age-related metabolic changes. For instance, supplementation with nicotinamide mononucleotide (NMN), a direct precursor to NAD+ derived from nicotinamide, improved muscle insulin sensitivity and signaling in overweight or obese prediabetic postmenopausal women, suggesting benefits for age-associated insulin resistance. Additionally, nicotinamide derivatives have demonstrated protection of the blood-brain barrier against oxidative stress-induced dysfunction in preclinical models, positioning them as candidates for addressing vascular aspects of brain aging.[109] In neurodegeneration, nicotinamide shows promise through NAD+ restoration and mitochondrial support. Preclinical evidence indicates it reduces tau hyperphosphorylation in Alzheimer's disease models by acting as a histone deacetylase inhibitor, potentially slowing pathological protein accumulation. For glaucoma, a form of optic neuropathy linked to aging, nicotinamide provides neuroprotection by enhancing retinal ganglion cell metabolism, boosting oxidative phosphorylation, and preserving mitochondrial morphology against dysfunction.[110][111] Despite these findings, human trials on nicotinamide for aging and neurodegeneration remain limited, with most evidence from preclinical studies or small-scale interventions lacking long-term efficacy data. Ongoing phase II trials, such as those testing nicotinamide for tau reduction in early Alzheimer's, have not yet shown clear clinical benefits, underscoring the need for larger, well-powered studies.[112][110]

Infectious diseases

Nicotinamide, a form of vitamin B3 and precursor to nicotinamide adenine dinucleotide (NAD+), has emerged in recent research as a potential adjunct therapy for viral infections, particularly through its role in modulating immune responses and microbial ecosystems. A 2025 clinical study demonstrated that targeted oral administration of high-dose nicotinamide in patients with mild-to-moderate COVID-19 led to faster recovery of physical performance, with improvements observed in symptoms and functional capacity compared to standard care alone. This effect was linked to nicotinamide's modulation of the gut microbiome, where it altered fecal microbial composition and metabolic potential, potentially enhancing antiviral defenses by promoting beneficial bacterial shifts during infection.[113][114] Furthermore, NAD+ dysregulation has been associated with COVID-19 severity, as evidenced by a 2024 analysis showing modestly reduced blood NAD+ levels and substantially increased NAD+ turnover in hospitalized patients, driven by upregulated genes in NAD+ synthesis and consumption pathways. This metabolic imbalance correlates with worse outcomes, including prolonged inflammation and organ dysfunction, highlighting nicotinamide's potential to replenish NAD+ pools and mitigate disease progression. Preclinical studies in 2025 further elucidated mechanisms, where nicotinamide riboside (NR), another NAD+ precursor, boosted antiviral immunity by enhancing T-cell function and inhibited SARS-CoV-2 replication in cell models through restoration of NAD+-dependent signaling.[115][116][117] In a small 2020 case series, an NMN-based cocktail (combining nicotinamide mononucleotide with other supplements) was administered to nine elderly patients with severe COVID-19, resulting in rapid clinical improvements, including reversal of cytokine storms and resolution of acute symptoms within days, suggesting NAD+ boosting as a supportive intervention in vulnerable populations. Beyond COVID-19, nicotinamide has shown promise as an adjunct in HIV management; a 2020 clinical report indicated that combining nicotinamide with auranofin reduced HIV reservoirs in antiretroviral-suppressed individuals, potentially aiding immune recovery without added toxicity. For sepsis, nicotinamide's inhibition of poly(ADP-ribose) polymerase (PARP) enzymes has been proposed to limit excessive inflammation and NAD+ depletion, with preclinical models demonstrating reduced cytokine release and improved survival rates in endotoxemia.[118][119][120] Ongoing research addresses gaps in understanding NAD+-COVID-19 links, particularly in the elderly; for instance, the NR-SAFE trial (NCT04407390) is evaluating 1 g daily NR supplementation in patients over 70 with SARS-CoV-2 to assess impacts on clinical outcomes like hospitalization duration and mortality, building on evidence of NAD+ decline with age exacerbating infection severity. These findings underscore nicotinamide's role in immune modulation during acute infections, though larger randomized trials are needed to confirm efficacy and optimal dosing.[121][122]

Extraterrestrial occurrence

Nicotinamide has been detected in carbonaceous chondrite meteorites, including the Orgueil and Murchison meteorites, where it occurs alongside its precursor nicotinic acid, though typically in lower abundances.[123][124] These findings support the hypothesis that vitamin B3 precursors were delivered to early Earth via extraterrestrial sources, potentially contributing to the origins of life. Laboratory simulations have also demonstrated that nicotinamide can form under interstellar ice conditions through photochemical reactions.[125]

References

  1. Nicotinamide
  2. Nicotinamide - an overview | ScienceDirect Topics
  3. Nicotinamide - Memorial Sloan Kettering Cancer Center
  4. Nicotinamide: Uses, Interactions, Mechanism of Action - DrugBank
  5. Nicotinamide: A Multifaceted Molecule in Skin Health and Beyond
  6. Niacin - Health Professional Fact Sheet
  7. Pharmacological doses of nicotinic acid and nicotinamide ... - PubMed
  8. Nicotinamide - eEML - Electronic Essential Medicines List
  9. NICOTINAMIDE Definition & Meaning | Dictionary.com
  10. History of Pellagra - UAB Libraries
  11. Joseph Goldberger's research on the prevention of pellagra - PMC
  12. Pellagra: Definition, Symptoms & Treatment - Cleveland Clinic
  13. Role of Nicotinamide Adenine Dinucleotide and Related Precursors ...
  14. [PDF] CONRAD ARNOLD ELVEHJEM - Biographical Memoirs
  15. NAD+ metabolism: Bioenergetics, signaling and manipulation for ...
  16. Regulation of Stem Cell Function by NAD+ | Physiology
  17. Effectiveness of food fortification in the United States: the case of ...
  18. Food Fortification Spurred By Military Purchases | Johns Hopkins
  19. Nicotinic Acid
  20. Nicotinamide - Enzo
  21. Methods to Produce Nicotinic Acid with Potential Industrial ... - NIH
  22. Technology development in nicotinate production - ScienceDirect.com
  23. https://www.lonza.com/
  24. NAD+ metabolism: pathophysiologic mechanisms and therapeutic ...
  25. Kynurenine pathway, NAD+ synthesis, and mitochondrial function
  26. Nutritional Aspect of Tryptophan Metabolism - PMC - NIH
  27. Nicotinamide phosphoribosyltransferase in NAD+ metabolism
  28. Mechanisms of the NAD+ salvage pathway in enhancing ... - Frontiers
  29. De novo biosynthesis and nicotinamide biotransformation of ... - NIH
  30. Biosynthesis of Nicotinamide Mononucleotide: Current Metabolic ...
  31. A mechanism of allosteric modulation of nicotinamide ...
  32. NAD+ metabolism and its roles in cellular processes during ageing
  33. Standard Reduction Potentials (E 0' ), 25 o C - csbsju
  34. Article Nicotinic acid riboside maintains NAD + homeostasis and ...
  35. Niacin Deficiency - StatPearls - NCBI Bookshelf
  36. [PDF] PELLAGRA - CDC
  37. Big Brains, Meat, Tuberculosis, and the Nicotinamide Switches
  38. [PDF] USDA National Nutrient Database-Niacin
  39. Niacin | Linus Pauling Institute | Oregon State University
  40. Niacin - StatPearls - NCBI Bookshelf - NIH
  41. Nicotinamide - DermNet
  42. B Vitamins: Functions and Uses in Medicine - PMC - PubMed Central
  43. A Brief History of Food Fortification in the U.S. - IFIC
  44. [PDF] Converting Units of Measure for Folate, Niacin, and Vitamins ... - FDA
  45. Overview of Food Fortification in the United States and Canada - NCBI
  46. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin ...
  47. Vitamin B3 Market Size, Share, Trends Analysis Report, 2030
  48. Pellagra - MSF Medical Guidelines
  49. Pellagra (vitamin B3 or niacin deficiency) - DermNet
  50. The Rise and Fall of Pellagra in the American South
  51. [PDF] The Rise and Fall of Pellagra in the American South
  52. Topical 4% nicotinamide vs. 1% clindamycin in moderate ... - PubMed
  53. The Nicomide Improvement in Clinical Outcomes Study (NICOS)
  54. Nicotinamide increases biosynthesis of ceramides as well ... - PubMed
  55. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer ...
  56. Nicotinamide Linked to Lower Skin Cancer Risk - JAMA Network
  57. Nicotinamide enhances repair of ultraviolet radiation-induced DNA ...
  58. Nicotinamide Prevents UVB- and Oxidative Stressā€’Induced ...
  59. American Glaucoma Society, American Academy of Ophthalmology
  60. Study Details | NCT05405868 | Nicotinamide in Glaucoma (NAMinG ...
  61. Nicotinamide and tetracycline therapy of bullous pemphigoid
  62. Efficacy and safety of nicotinamide in haemodialysis patients
  63. Oral nicotinamide reduces serum phosphorus, increases HDL, and ...
  64. Modified-release nicotinamide for the treatment of ... - NIH
  65. Sirtuins and NAD+ in the Development and Treatment of Metabolic ...
  66. Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor ...
  67. Poly(ADP-ribose) polymerase inhibitors as promising cancer ...
  68. PARP Inhibitors in Cancer Therapy: Promise, Progress and Puzzles
  69. The mechanism of nicotinamide on reducing acute lung injury by ...
  70. Nicotinamide inhibits Propionibacterium acnes-induced IL-8 ...
  71. Nicotinamide is a potent inhibitor of proinflammatory cytokines - PMC
  72. Nicotinamide increases glutathione and anthocyanin in tissue ...
  73. Mechanistic Basis and Clinical Evidence for the Applications of ... - NIH
  74. High doses of nicotinamide prevent oxidative mitochondrial ...
  75. Nicotinamide provides neuroprotection in glaucoma by protecting ...
  76. Possible Adverse Effects of High-Dose Nicotinamide - PubMed Central
  77. Safety of high-dose nicotinamide: a review - PubMed
  78. American Glaucoma Society-American Academy of Ophthalmology
  79. Nicotinamide Safety Concerns - American Academy of Ophthalmology
  80. Safety of high-dose nicotinamide: a review
  81. PARP Inhibitors: Clinical Relevance, Mechanisms of Action and ...
  82. Mechanism of PARP inhibitor resistance and potential overcoming ...
  83. [PDF] Inert Reassessment - Nicotinamide CAS 98-92-0, OPP, US EPA
  84. NICOTINAMIDE - DailyMed
  85. [PDF] 208751Orig1s000 - accessdata.fda.gov
  86. USP Monographs: Niacinamide - USP29-NF24
  87. [PDF] NICOTINAMIDE Nicotinamidum NICOTINE Nicotinum
  88. 21 CFR 107.100 -- Nutrient specifications. - eCFR
  89. Final Report of the Safety Assessment of Niacinamide and Niacin1
  90. Nicotinamide for Skin Cancer Chemoprevention | Dermatology
  91. Nicotinamide for Skin Cancer Chemoprevention - PubMed
  92. Nicotinamide Reduces New Skin Cancer Risk in Large Veteran Study
  93. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer ...
  94. Examining the safety of nicotinamide for skin cancer prevention
  95. Comparison of Nicotinamide Treatments for Actinic Keratosis
  96. Randomized, double-blinded, placebo controlled study to assess ...
  97. Nicotinamide enhances repair of ultraviolet radiationā€induced DNA ...
  98. Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair
  99. Nicotinamide mononucleotide (NMN) supplementation ameliorates ...
  100. The NAD+/Sirtuin Pathway Modulates Longevity through Activation ...
  101. Nicotinamide derivatives protect the blood-brain barrier against ...
  102. Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo ...
  103. Nicotinamide provides neuroprotection in glaucoma by protecting ...
  104. NAD augmentation as a disease-modifying strategy for ...
  105. Nicotinamide modulates gut microbial metabolic potential ... - PubMed
  106. (PDF) Nicotinamide modulates gut microbial metabolic potential and ...
  107. Dysregulated nicotinamide adenine dinucleotide metabolome in ...
  108. Dysregulated nicotinamide adenine dinucleotide metabolome in ...
  109. Nicotinamide Riboside May Inhibit Coronavirus Replication
  110. Dramatic Cytokine Storm Reversal with an Over the Counter NMN ...
  111. How an NMN Cocktail Treatment Affected COVID-19 Patients
  112. New HIV remission case report at AIDS 2020: full report - HIV i-Base
  113. Effects of Nicotinamide Riboside on the Clinical Outcome of Covid ...
  114. Why does COVID-19 disproportionately affect older people? | Aging
  115. The effect of 2% niacinamide on facial sebum production
  116. Supramolecular salicylic acid combined with niacinamide in chloasma
  117. The long reign of Japanese beauty
  118. The Glaucoma Nicotinamide Trial (TGNT)
User Avatar
No comments yet.