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{{Wikipedia fork | article_name = Niacin }} {{Short description|Organic compound and a form of vitamin B3}} {{good article}} {{Use dmy dates|date=July 2019}} {{Chembox | Watchedfields = changed | verifiedrevid = 408767536 | ImageFileL1 = Niacin_structure.svg | ImageFileL1_Ref = {{chemboximage|correct|??}} | ImageClassL1 = skin-invert | ImageNameL1 = Kekulé, skeletal formula of niacin | ImageFileR1 = Niacin-3D-balls.png | ImageFileR1_Ref = {{chemboximage|correct|??}} | ImageNameR1 = Ball and stick model of niacin | PIN = Pyridine-3-carboxylic acid<ref name=iupac2013>{{cite book | title = Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Royal Society of Chemistry]] | date = 2014 | location = Cambridge | pages = 648–1047 | doi = 10.1039/9781849733069-00648 | isbn = 978-0-85404-182-4| chapter = Chapter P-6. Applications to Specific Classes of Compounds }}</ref> | pronounce = {{IPAc-en|ˈ|n|aɪ|ə|s|ɪ|n}} | OtherNames = {{ubl | Nicotinic acid ([[British Approved Name|BAN]] {{abbr|UK|United Kingdom}},<ref name="Martindale37">{{Cite book |last=Sweetman |first=Sean C. |url=https://archive.org/details/martindalecomple0000unse_37ed/page/2116/mode/2up?q=niacin <!-- ?q=niacin is required to unlock the page without login --> |title=Martindale: the complete drug reference |date=2011 |publisher=Pharmaceutical press |isbn=978-0-85369-933-0 |edition=37 |series=Martindale |location=London |page=2117 |language=en |oclc=1256529676}}</ref> [[International nonproprietary name|INN]], [[Japanese Accepted Name|JAN]] {{abbr|JP|Japan}}) | Bionic | Vitamin B<sub>3</sub> | Vitamin PP }} |Section1={{Chembox Identifiers | CASNo = 59-67-6 | CASNo_Ref = {{cascite|correct|CAS}} | PubChem = 938 | ChemSpiderID = 913 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | UNII = 2679MF687A | UNII_Ref = {{fdacite|correct|FDA}} | EINECS = 200-441-0 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00627 | KEGG = D00049 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG1_Ref = {{keggcite|correct|kegg}} | KEGG1 = C00253 | MeSHName = Niacin | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 15940 | ChEMBL = 573 | ChEMBL_Ref = {{ebicite|correct|EBI}} | IUPHAR_ligand = 1588 | RTECS = QT0525000 | Beilstein = 109591 | Gmelin = 3340 | 3DMet = B00073 | SMILES = OC(=O)c1cccnc1 | StdInChI = 1S/C6H5NO2/c8-6(9)5-2-1-3-7-4-5/h1-4H,(H,8,9) | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | InChI = 1/C6H5NO2/c8-6(9)5-2-1-3-7-4-5/h1-4H,(H,8,9) | StdInChIKey = PVNIIMVLHYAWGP-UHFFFAOYSA-N | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | InChIKey = PVNIIMVLHYAWGP-UHFFFAOYAA }} |Section2={{Chembox Properties | C=6 | H=5 | N=1 | O=2 | Appearance = White, translucent crystals | MeltingPtK = 510 | Density = 1.473 g cm<sup>−3</sup> | Solubility = 18 g L<sup>−1</sup> | LogP = 0.219 | pKa = 2.0, 4.85 | IsoelectricPt = 4.75 | RefractIndex = 1.4936 | Dipole = 0.1271305813 D{{citation needed|date=February 2023}} }} |Section5={{Chembox Thermochemistry | DeltaHf = −344.9 kJ mol<sup>−1</sup> | DeltaHc = −2.73083 MJ mol<sup>−1</sup> }} |Section6={{Chembox Pharmacology | ATCCode_prefix = C04 | ATCCode_suffix = AC01 | ATC_Supplemental = {{ATC|C10|BA01}} {{ATC|C10|AD02}} {{ATC|C10|AD52}} | Licence_EU=yes | INN_EMA=Nicotinic acid | AdminRoutes = Intramuscular, by mouth | HalfLife = 20–45 min }} |Section7={{Chembox Hazards | GHSPictograms = {{GHS07}} | GHSSignalWord = Warning | HPhrases = {{H-phrases|319}} | PPhrases = {{P-phrases|264|280|305+351+338|337+313|501}} | NFPA-H = 1 | NFPA-F = 1 | NFPA-R = 0 | FlashPtC = 193 | AutoignitionPtC = 365 }} }} {{Infobox drug | container_only = yes | drug_name = | INN = Nicotinic acid | type = <!-- empty --> | image = | width = | alt = | caption = | USAN = | INN_EMA = Nicotinic acid <!-- Clinical data --> | pronounce = | tradename = Niacor, Niaspan, others | Drugs.com = {{drugs.com|monograph|niacin}} | MedlinePlus = a682518 | licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) --> | licence_EU = yes | DailyMedID = Niacin | licence_US = <!-- FDA may use generic or brand name (generic name preferred) --> | pregnancy_AU = | pregnancy_AU_comment = Exempt<ref name="Drugs.com pregnancy">{{cite web | title=Niacin Use During Pregnancy | website=Drugs.com | date=29 July 2019 | url=https://www.drugs.com/pregnancy/niacin.html | access-date=4 May 2020 | archive-date=5 August 2020 | archive-url=https://web.archive.org/web/20200805024846/https://www.drugs.com/pregnancy/niacin.html | url-status=live }}</ref> | pregnancy_category= | dependency_liability = | addiction_liability = | routes_of_administration = Intramuscular, by mouth | class = | ATCvet = | ATC_supplemental = <!-- Legal status --> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_AU_comment = | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F--> | legal_BR_comment = | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA_comment = | legal_DE = <!-- Anlage I, II, III or Unscheduled--> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> | legal_UK_comment = | legal_US = OTC | legal_US_comment = / Rx-only | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV--> | legal_UN_comment = | legal_status = <!-- For countries not listed above --> <!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion = <!-- Identifiers --> | CAS_number_Ref = | CAS_number = | CAS_supplemental = | PubChem = | PubChemSubstance = | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = | UNII_Ref = | UNII = | KEGG_Ref = | KEGG = | KEGG2_Ref = | KEGG2 = | ChEBI_Ref = | ChEBI = | ChEMBL_Ref = | ChEMBL = | NIAID_ChemDB = | PDB_ligand = NIO | synonyms = <!-- Chemical and physical data --> | IUPAC_name = | chemical_formula = | molecular_weight = | SMILES = | Jmol = | StdInChI = | StdInChI_comment = | StdInChIKey = | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }} [[File:Vitamin B3 (Niacine) space filling model.jpg|thumb|Space-filling model of niacin]] '''Niacin''', also known as '''nicotinic acid''', is an organic compound and a form of{{spaces}}[[vitamin B3|vitamin B<sub>3</sub>]], an [[essential nutrient|essential human nutrient]].<ref name="NIH Fact Sheet">{{cite web |title=Niacin Fact Sheet for Health Professionals |publisher=Office of Dietary Supplements, US National Institutes of Health |date=18 November 2022 |url=https://ods.od.nih.gov/factsheets/Niacin-HealthProfessional/ |access-date=12 December 2024}}</ref><ref name="lpi">{{cite web |title=Niacin |url=https://lpi.oregonstate.edu/mic/vitamins/niacin |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR |access-date=16 September 2019 |date=8 October 2018 |archive-date=12 September 2019 |archive-url=https://web.archive.org/web/20190912214545/https://lpi.oregonstate.edu/mic/vitamins/niacin |url-status=live }}</ref> It is produced by plants and animals from the amino acid tryptophan.<ref name="DRItext" /> Niacin is obtained in the diet from a variety of [[whole food|whole]] and [[processed foods]], with highest contents in [[fortified food|fortified]] [[packaged food]]s, meat, poultry, red fish such as tuna and salmon, lesser amounts in nuts, legumes and seeds.<ref name=lpi/><ref name="NIH Fact Sheet" /> Niacin as a [[dietary supplement]] is used to treat pellagra, a disease caused by niacin deficiency. Signs and symptoms of pellagra include skin and mouth lesions, anemia, headaches, and tiredness.<ref name=Hegyi2004 /> Many countries mandate its addition to wheat flour or other food grains, thereby reducing the risk of pellagra.<ref name=lpi/><ref name=WhyFortify>{{Cite web|url=http://www.ffinetwork.org/why_fortify/index.html|publisher=Food Fortification Initiative|title=Why fortify?|date=2017|access-date=4 April 2017|archive-date=4 April 2017|archive-url=https://web.archive.org/web/20170404131451/http://www.ffinetwork.org/why_fortify/index.html|url-status=dead}}</ref> The amide derivative nicotinamide is a component of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP<sup>+</sup>). Although niacin and nicotinamide are identical in their vitamin activity, nicotinamide does not reduce cholesterol nor cause [[flushing (physiology)|flushing]].<ref>{{cite journal | vauthors = Jaconello P | title = Niacin versus niacinamide | journal = CMAJ | volume = 147 | issue = 7 | pages = 990 | date = October 1992 | pmid = 1393911 | pmc = 1336277 }}</ref><ref name="pmid22138132">{{cite journal | vauthors = Kirkland JB | title = Niacin requirements for genomic stability | journal = Mutation Research | volume = 733 | issue = 1–2 | pages = 14–20 | date = May 2012 | pmid = 22138132 | doi = 10.1016/j.mrfmmm.2011.11.008 | bibcode = 2012MRFMM.733...14K | url = https://zenodo.org/record/1143032 | access-date = 3 July 2019 | archive-date = 4 August 2020 | archive-url = https://web.archive.org/web/20200804183506/https://zenodo.org/record/1143032 | url-status = live }}</ref> Nicotinamide is therefore preferred as a treatment for niacin deficiency because it can be administered in remedial amounts without causing the flushing, considered an adverse effect.<ref name="Pellagra And Its Prevention" /> Niacin is also a prescription medication.<ref name=Drugs/> Amounts far in excess of the recommended dietary intake for vitamin functions will lower blood [[triglyceride]]s and [[low-density lipoprotein|low density lipoprotein cholesterol]] (LDL-C), and raise blood [[high density lipoprotein|high density lipoprotein cholesterol]] (HDL-C, often referred to as "good" cholesterol). There are two forms: immediate-release and sustained-release niacin. Initial prescription amounts are 500 mg/day, increased over time until a therapeutic effect is achieved. Immediate-release doses can be as high as 3,000 mg/day; sustained-release as high as 2,000 mg/day.<ref name=Drugs>{{cite web |url=https://www.drugs.com/niacin.html |title=Niacin |date=16 March 2019 |website=Drugs.com |access-date=27 April 2020 |archive-date=9 June 2020 |archive-url=https://web.archive.org/web/20200609134807/https://www.drugs.com/niacin.html |url-status=live }}</ref> Despite the proven lipid changes, niacin has not been found useful for decreasing the risk of cardiovascular disease in those already on a statin.<ref name=Kee2014/> A 2010 review had concluded that niacin was effective as a mono-therapy,<ref>{{cite journal | vauthors = Bruckert E, Labreuche J, Amarenco P | title = Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis | journal = Atherosclerosis | volume = 210 | issue = 2 | pages = 353–61 | date = June 2010 | pmid = 20079494 | doi = 10.1016/j.atherosclerosis.2009.12.023 }}</ref> but a 2017 review incorporating twice as many trials concluded that prescription niacin, while affecting lipid levels, did not reduce all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes.<ref name=Schand2017 /> Prescription niacin was shown to cause hepatotoxicity<ref name=LiverTox2014 /> and increase risk of [[type 2 diabetes]].<ref name=Ong2014 /><ref name=Goldie2016 /> Niacin prescriptions in the U.S. had peaked in 2009 at 9.4{{nbsp}}million, <!-- shown in archived version of ref --> declining to 800{{nbsp}}thousand by 2020.<ref name="ClinCalc Niacin">{{cite web | title = Niacin - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Niacin | access-date = 7 October 2022 | archive-date = 8 July 2020 | archive-url = https://web.archive.org/web/20200708061719/https://clincalc.com/DrugStats/Drugs/Niacin | url-status = live }}</ref> Niacin has the formula C<sub>6</sub>H<sub>5</sub>NO<sub>2</sub> and belongs to the group of the pyridinecarboxylic acids.<ref name=lpi/> As the [[precursor (chemistry)|precursor]] for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, niacin is involved in DNA repair.<ref name="pmid26828517">{{cite journal | vauthors = Kennedy DO | title = B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review | journal = Nutrients | volume = 8 | issue = 2 | pages = 68 | date = January 2016 | pmid = 26828517 | pmc = 4772032 | doi = 10.3390/nu8020068 | doi-access = free | title-link = doi }}</ref> {{TOC limit}} ==Definition== Niacin is both a vitamin, i.e., an essential nutrient, marketed as a dietary supplement, and in the US, a prescription medicine. As a vitamin, it is precursor of the coenzymes [[nicotinamide adenine dinucleotide]] (NAD) and [[nicotinamide adenine dinucleotide phosphate]] (NADP). These compounds are coenzymes for many dehydrogenases, participating in many hydrogen transfer processes. NAD is important in [[catabolism]] of fat, carbohydrate, protein, and alcohol, as well as cell signaling and DNA repair, and NADP mostly in [[anabolism]] reactions such as fatty acid and cholesterol synthesis.<ref name=PKIN2020Niacin/> Vitamin intake recommendations made by several countries are that intakes of 14–18 mg/day are sufficient to meet the needs of healthy adults.<ref name="DRItext" /><ref name="EFSAtext" /><ref name=AusNZ /> Niacin but also [[nicotinamide]] are used for prevention and treatment of [[pellagra]], a disease caused by lack of the vitamin.<ref name=Hegyi2004>{{cite journal | vauthors = Hegyi J, Schwartz RA, Hegyi V | title = Pellagra: dermatitis, dementia, and diarrhea | journal = International Journal of Dermatology | volume = 43 | issue = 1 | pages = 1–5 | date = January 2004 | pmid = 14693013 | doi = 10.1111/j.1365-4632.2004.01959.x | s2cid = 33877664 | doi-access = free }}</ref><ref name=PKIN2020Niacin>{{cite book |vauthors=Penberthy WT, Kirkland JB |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Niacin |editor=BP Marriott |editor2=DF Birt |editor3=VA Stallings|editor4=AA Yates |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 209–24 |isbn=978-0-323-66162-1}}</ref> When niacin is used as a medicine to treat [[hyperlipidemia|elevated cholesterol and triglycerides]], daily doses range from 500 to 3,000 mg/day.<ref name=DailyMed /><ref name=Niaspan /> High-dose nicotinamide does not have this medicinal effect.<ref name=PKIN2020Niacin /> ==Vitamin deficiency== {{Main|Pellagra}} [[File:Pellagra2.jpg|thumb|left|A man with [[pellagra]], which is caused by a chronic lack of vitamin B<sub>3</sub> in the diet]] Severe deficiency of niacin in the diet causes the disease [[pellagra]], characterized by [[diarrhea]], sun-sensitive [[dermatitis]] involving hyperpigmentation and thickening of the skin (see image), inflammation of the mouth and tongue, delirium, dementia, and if left untreated, death.<ref name=Hegyi2004 /> Common psychiatric symptoms include irritability, poor concentration, anxiety, fatigue, loss of memory, restlessness, apathy, and depression.<ref name=PKIN2020Niacin /> The biochemical mechanism(s) for the observed deficiency-caused neurodegeneration are not well understood, but may rest on: A) the requirement for [[nicotinamide adenine dinucleotide]] (NAD+) to suppress the creation of neurotoxic tryptophan metabolites, B) inhibition of mitochondrial ATP generation, resulting in cell damage; C), activation of the [[poly (ADP-ribose) polymerase]] (PARP) pathway, as PARP is a nuclear enzyme involved in DNA repair, but in the absence of NAD+ can lead to cell death; D) reduced synthesis of neuro-protective [[brain-derived neurotrophic factor]] or its receptor [[tropomyosin receptor kinase B]]; or E) changes to genome expression directly due to the niacin deficiency.<ref name="niacin review 2014">{{cite journal | vauthors = Fu L, Doreswamy V, Prakash R | title = The biochemical pathways of central nervous system neural degeneration in niacin deficiency | journal = Neural Regeneration Research | volume = 9 | issue = 16 | pages = 1509–13 | date = August 2014 | pmid = 25317166 | pmc = 4192966 | doi = 10.4103/1673-5374.139475 | doi-access = free }}</ref> Niacin deficiency is rarely seen in developed countries, and it is more typically associated with poverty, malnutrition or malnutrition secondary to chronic [[alcoholism]].<ref>{{cite journal |vauthors = Pitsavas S, Andreou C, Bascialla F, Bozikas VP, Karavatos A |s2cid = 29070525 |title = Pellagra encephalopathy following B-complex vitamin treatment without niacin |journal = International Journal of Psychiatry in Medicine |volume = 34 |issue = 1 |pages = 91–5 |date = March 2004 |pmid = 15242145 |doi = 10.2190/29XV-1GG1-U17K-RGJH |url = http://baywood.metapress.com/link.asp?id=29xv1gg1u17krgjh |access-date = 27 November 2009 |archive-url = https://archive.today/20120710191340/http://baywood.metapress.com/link.asp?id=29xv1gg1u17krgjh |archive-date = 10 July 2012 |url-status = dead }}</ref> It also tends to occur in less developed areas where people eat [[maize]] (corn) as a staple food, as maize is the only grain low in digestible niacin. A cooking technique called [[nixtamalization]] i.e., pretreating with alkali ingredients, increases the bioavailability of niacin during maize meal/flour production.<ref>{{cite journal |vauthors=Bressani R, Gomez-Brenes R, Scrimshaw NS |title=Effect of processing on distribution and in vitro availability of niacin of corn (Zea mays) |journal=Food Technol|date=1961 |volume=15 |pages=450–4 }}</ref> For this reason, people who consume maize as tortillas or [[hominy]] are at less risk of niacin deficiency. For treating deficiency, the World Health Organization (WHO) recommends administering nicotinamide, instead of nicotinic acid, to avoid the flushing side effect commonly caused by the latter. Guidelines suggest using 300 mg/day for three to four weeks.<ref name="Pellagra And Its Prevention" /> Dementia and dermatitis show improvement within a week. Because deficiencies of other B-vitamins may be present, the WHO recommends a multi-vitamin in addition to the nicotinamide.<ref name="Pellagra And Its Prevention" /> [[Hartnup disease]] is a [[hereditary]] nutritional disorder resulting in niacin deficiency.<ref name=HartnupMerck>{{cite web |url=https://www.merckmanuals.com/professional/pediatrics/congenital-renal-transport-abnormalities/hartnup-disease?query=Hartnup%20Disease |title=Hartnup Disease |vauthors=LaRosa CJ |date=January 2020 |access-date=6 July 2020 |archive-date=8 July 2020 |archive-url=https://web.archive.org/web/20200708204521/https://www.merckmanuals.com/professional/pediatrics/congenital-renal-transport-abnormalities/hartnup-disease?query=Hartnup%20Disease |url-status=dead }}</ref> It is named after an English family with a genetic disorder that resulted in a failure to absorb the essential amino acid [[tryptophan]], tryptophan being a precursor for niacin synthesis. The symptoms are similar to pellagra, including red, scaly rash and sensitivity to sunlight. Oral nicotinic acid or nicotinamide is given as a treatment for this condition in doses ranging from 50 to 100 mg twice a day, with a good prognosis if identified and treated early.<ref name=HartnupMerck /> Niacin synthesis is also deficient in [[carcinoid syndrome]], because of metabolic diversion of its [[precursor (chemistry)|precursor]] [[tryptophan]] to form [[serotonin]].<ref name="lpi" /> ===Measuring vitamin status=== Plasma concentrations of niacin and niacin metabolites are not useful markers of niacin status.<ref name="DRItext"/> Urinary excretion of the methylated metabolite N1-methyl-nicotinamide is considered reliable and sensitive. The measurement requires a 24-hour urine collection. For adults, a value of less than 5.8 μmol/day represent deficient niacin status and 5.8 to 17.5 μmol/day represents low.<ref name="DRItext"/> According to the World Health Organization, an alternative mean of expressing urinary N1-methyl-nicotinamide is as mg/g creatinine in a 24-hour urine collection, with deficient defined as <0.5, low 0.5-1.59, acceptable 1.6-4.29, and high >4.3<ref name="Pellagra And Its Prevention" /> Niacin deficiency occurs before the signs and symptoms of pellagra appear.<ref name="DRItext"/> Erythrocyte [[nicotinamide adenine dinucleotide]] (NAD) concentrations potentially provide another sensitive indicator of niacin depletion, although definitions of deficient, low and adequate have not been established. Lastly, plasma [[tryptophan]] decreases on a low niacin diet because tryptophan converts to niacin. However, low tryptophan could also be caused by a diet low in this essential [[amino acid]], so it is not specific to confirming vitamin status.<ref name="DRItext"/> ==Dietary recommendations== {| class="wikitable" style="float: right; margin-left: 2em;" |+ Dietary recommendations | {| class="wikitable mw-collapsible mw-collapsed" style="font-size: 80%; text-align: center; width:406px" |- |+ style="background: blue; color: white; font-size: 110%; text-align: center;" | Australia and New Zealand |- ! scope="col" style="width:8em" | Age group ! scope="col" style="width:8em" | RDI for niacin (mg NE/day)<ref name=AusNZ /> ! scope="col" style="width:8em" | Upper level of intake<ref name=AusNZ>{{cite web|url = http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/n35.pdf|title = Nutrient reference values for Australia and New Zealand|access-date = 19 June 2018|date = 9 September 2005|work = National Health and Medical Research Council|archive-url = https://web.archive.org/web/20170121003340/https://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/n35.pdf|archive-date = 21 January 2017|url-status = dead}}</ref> |- | Infants 0–6 months || 2 mg/d preformed niacin* || rowspan="2"| ND |- | Infants 7–12 months || 4 mg/d NE* |- | 1–3 || 6 || 10 |- | 4–8 || 8 || 15 |- | 9–13 || 12 || 20 |- | 14–18 || – || 30 |- | 19+ || – || 35 |- | Females 14+ || 14 || rowspan=2 | – |- | Males 14+ || 16 |- | Pregnant females 14–50 || 18 || – |- | Pregnant females 14–18 || – || 30 |- | Pregnant females 19–50 || – || 35 |- | Lactating females 14–50 || 17 || – |- | Lactating females 14–18 || – || 30 |- | Lactating females 19–50 || – || 35 |- | colspan="3" style="text-align: center;" | * Adequate Intake for infants<ref name=DRItext /> |- |} {| class="wikitable mw-collapsible mw-collapsed" style="font-size: 80%; text-align: center; width:406px" |- |+ style="background: blue; color: white; font-size: 110%; text-align: center;" | Canada |- ! scope="col" style="width:8em" | Age group (years) ! scope="col" style="width:8em" | RDA of niacin (mg NE/d)<ref name=HealthCanada>{{cite web|author=Health Canada|title=Dietary Reference Intakes|url=https://www.canada.ca/en/health-canada/services/food-nutrition/healthy-eating/dietary-reference-intakes/tables/reference-values-vitamins-dietary-reference-intakes-tables-2005.html|publisher=Government of Canada|access-date=20 June 2018|date=2005-07-20|archive-date=14 June 2018|archive-url=https://web.archive.org/web/20180614052711/https://www.canada.ca/en/health-canada/services/food-nutrition/healthy-eating/dietary-reference-intakes/tables/reference-values-vitamins-dietary-reference-intakes-tables-2005.html|url-status=live}}</ref> ! scope="col" style="width:8em" | Tolerable upper intake level<ref name=HealthCanada /> |- | 0–6 months || 2 mg/d preformed niacin* || rowspan=2| ND |- | 7–12 months || 4 mg/d NE* |- | 1–3 || 6 || 10 |- | 4–8 || 8 || 15 |- | 9–13 || 12 || 20 |- | Females 14–18 || 14 || rowspan=2| 30 |- | Males 14–18 || 16 |- | Females 19+ || 14 || rowspan=2| 35 |- | Males 19+ || 16 |- | Pregnant females <18 || 18 || 30 |- | Pregnant females 18–50 || 18 || 35 |- | Lactating females <18 || 17 || 30 |- | Lactating females 18–50 || 17 || 35 |- |} {| class="wikitable mw-collapsible mw-collapsed" style="font-size: 80%; text-align: center; width:406px" |- |+ style="background: blue; color: white; font-size: 110%; text-align: center;" | European Food Safety Authority |- ! scope="col" width=8em | Gender ! colspan=2 width=16em | Adequate Intake (mg NE/MJ)<ref name=EFSA>{{cite web|url=http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf|title=Tolerable Upper Intake Levels for Vitamins and Minerals|date=February 2006|publisher=European Food Safety Authority|access-date=18 June 2018|archive-date=16 March 2016|archive-url=https://web.archive.org/web/20160316225123/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf|url-status=live}}</ref> |- | Females || colspan=2 width="8em"| 1.3 |- | Males || colspan=2 width="8em"| 1.6 |- ! scope="col" style="width:8em" | Age (years) ! scope="col" style="width:8em" | Tolerable upper limit of Nicotinic acid (mg/day)<ref name=EFSA /> ! scope="col" style="width:8em" | Tolerable upper limit of Nicotinamide (mg/day)<ref name=EFSA /> |- | 1–3 || 2 || 150 |- | 4–6 || 3 || 220 |- | 7–10 || 4 || 350 |- | 11–14 || 6 || 500 |- | 15–17 || 8 || 700 |- |} {| class="wikitable mw-collapsible mw-collapsed" style="font-size: 80%; text-align: center; width:406px" |- |+ style="background: blue; color: white; font-size: 110%; text-align: center;" | United States |- ! scope="col" style="width:8em" | Age group ! scope="col" style="width:8em" | RDA for niacin (mg NE/day) ! scope="col" style="width:8em" | Tolerable upper intake level<ref name="DRItext">{{cite book |last1= Institute of Medicine |title= Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline |chapter= Niacin |publisher= The National Academies Press |year= 1998 |location= Washington, DC |pages= 123–149 |chapter-url= https://www.nap.edu/read/6015/chapter/8 |access-date= 29 August 2018 |isbn= 978-0-309-06554-2 |archive-date= 1 September 2018 |archive-url= https://web.archive.org/web/20180901175650/https://www.nap.edu/read/6015/chapter/8 |url-status= live }}</ref> |- | Infants 0–6 months || 2* || rowspan="2"| ND** |- | Infants 6–12 months || 4* |- | 1–3 || 6 || 10 |- | 4–8 || 8 || 15 |- | 9–13 || 12 || 20 |- | Females 14–18 || 14 || 30 |- | Males 14–18 || 16 || 30 |- | Females 19+ || 14 || 35 |- | Males 19+ || 16 || 35 |- | Pregnant females 14–18 || 18 || 30 |- | Pregnant females 19–50 || 18 || 35 |- | Lactating females 14–18 || 17 || 30 |- | Lactating females 19–50 || 17 || 35 |- | colspan="3" style="text-align: center;" | * Adequate intake for infants, as an RDA has yet to be established<br />** Not possible to establish; source of intake should be formula and food only<ref name=DRItext /> |- |} |} The U.S. Institute of Medicine (renamed [[National Academy of Medicine]] in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for niacin in 1998, also [[Tolerable upper intake levels]] (ULs). In lieu of an RDA, Adequate Intakes (AIs) are identified for populations for which there is not sufficient evidence to identify a dietary intake level that is sufficient to meet the nutrient requirements of most people.<ref name=DRIExplain /> (see table). The [[European Food Safety Authority]] (EFSA) refers to the collective set of information as Dietary Reference Values (DRV), with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. For the EU, AIs and ULs have the same definition as in the US, except that units are milligrams per megajoule (MJ) of energy consumed rather than mg/day. For women (including those pregnant or lactating), men and children the PRI is 1.6 mg per megajoule. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories should be consuming 16 mg niacin. This is comparable to US RDAs (14 mg/day for adult women, 16 mg/day for adult men).<ref name="EFSAtext">{{cite web| title = Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies| year = 2017| url = https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| access-date = 31 August 2017| archive-date = 28 August 2017| archive-url = https://web.archive.org/web/20170828082247/https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| url-status = live}}</ref> ULs are established by identifying amounts of vitamins and minerals that cause adverse effects, and then selecting as an upper limit amounts that are the "maximum daily intake unlikely to cause adverse health effects."<ref name=DRIExplain>{{cite web |url=https://ods.od.nih.gov/Health_Information/Dietary_Reference_Intakes.aspx |title=Nutrient Recommendations: Dietary Reference Intakes (DRI) |website=National Institutes of Health, Office of Dietary Supplements |access-date=30 June 2020 |archive-date=2 July 2020 |archive-url=https://web.archive.org/web/20200702082029/https://ods.od.nih.gov/Health_Information/Dietary_Reference_Intakes.aspx |url-status=live }}</ref> Regulatory agencies from different countries do not always agree. For the US, 30 or 35 mg for teenagers and adults, less for children.<ref name="DRItext"/> The EFSA UL for adults is set at 10 mg/day - about one-third of the US value. For all of the government ULs, the term applies to niacin as a supplement consumed as one dose, and is intended as a limit to avoid the skin flush reaction. This explains why for EFSA, the recommended daily intake can be higher than the UL.<ref>{{cite web| title = Tolerable Upper Intake Levels For Vitamins And Minerals| publisher = European Food Safety Authority| year = 2006| url = http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| access-date = 9 March 2016| archive-date = 16 March 2016| archive-url = https://web.archive.org/web/20160316225123/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| url-status = live}}</ref> Both the DRI and DRV describe amounts needed as niacin equivalents (NE), calculated as 1 mg NE = 1 mg niacin or 60 mg of the essential amino acid tryptophan. This is because the amino acid is utilized to synthesize the vitamin.<ref name="DRItext" /><ref name="EFSAtext" /> For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of [[Daily Value]] (%DV). For niacin labeling purposes 100% of the Daily Value is 16 mg. Prior to 27 May 2016 it was 20 mg, revised to bring it into agreement with the RDA.<ref name="FedReg">{{cite web|url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |archive-date=2022-10-09 |url-status=live |title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels}}</ref><ref>{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=16 May 2020 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp | url-status=dead }}</ref> Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with [[US$]]10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales.<ref name="FDAdelay">{{cite web | title=Changes to the Nutrition Facts Label | website=U.S. [[Food and Drug Administration]] (FDA) | date=27 May 2016 | url=https://www.fda.gov/food/food-labeling-nutrition/changes-nutrition-facts-label | access-date=16 May 2020 | archive-date=6 May 2018 | archive-url=https://web.archive.org/web/20180506080421/https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm385663.htm | url-status=live }} {{PD-notice}}</ref><ref>{{cite web | title=Industry Resources on the Changes to the Nutrition Facts Label | website=U.S. [[Food and Drug Administration]] (FDA) | date=21 December 2018 | url=https://www.fda.gov/food/food-labeling-nutrition/industry-resources-changes-nutrition-facts-label | access-date=16 May 2020 | archive-date=25 December 2020 | archive-url=https://web.archive.org/web/20201225063145/https://www.fda.gov/food/food-labeling-nutrition/industry-resources-changes-nutrition-facts-label | url-status=live }} {{PD-notice}}</ref> A table of the old and new adult daily values is provided at [[Reference Daily Intake]]. ==Sources== Niacin is found in a variety of [[whole food|whole]] and [[processed foods]], including [[fortified food|fortified]] [[packaged food]]s, [[meat]] from various animal sources, [[seafoods]], and [[spices]].<ref name=lpi/><ref name="usda">{{cite web|url=https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=406&nutrient2=&nutrient3=&subset=1&fg=13&fg=1&fg=15&fg=17&fg=10&fg=5&fg=2&fg=11&sort=c&measureby=g|title=Niacin content per 100 grams; select food subset, abridged list by food groups|publisher=United States Department of Agriculture, Agricultural Research Service, USDA Branded Food Products Database v.3.6.4.1|date=17 January 2017|access-date=23 January 2017|archive-date=2 February 2017|archive-url=https://web.archive.org/web/20170202032221/https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=406&nutrient2=&nutrient3=&subset=1&fg=13&fg=1&fg=15&fg=17&fg=10&fg=5&fg=2&fg=11&sort=c&measureby=g|url-status=dead}}</ref> In general, animal-sourced foods provide about 5–10 mg niacin per serving, although dairy foods and eggs have little. Some plant-sourced foods such as nuts, legumes and grains provide about 2–5 mg niacin per serving, although in some grain products this naturally present niacin is largely bound to polysaccharides and glycopeptides, making it only about 30% bioavailable. Fortified food ingredients such as wheat flour have niacin added, which is bioavailable.<ref name="NIH Fact Sheet" /> Among whole food sources with the highest niacin content per 100 grams: <div style="float:left; padding: 1em;"> {|class="wikitable" |- !Source<ref name=USDANiacin>{{cite web |url=https://www.nal.usda.gov/sites/www.nal.usda.gov/files/niacin.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://www.nal.usda.gov/sites/www.nal.usda.gov/files/niacin.pdf |archive-date=2022-10-09 |url-status=live |title= USDA National Nutrient Database for Standard Reference Legacy: Niacin |date=2018 |website=U.S. Department of Agriculture, Agricultural Research Service |access-date=12 May 2020}}</ref> !Amount<br /> (mg / 100g) |- |[[Nutritional yeast]]<ref>{{cite web |url=https://nutritiondata.self.com/facts/custom/1323565/2 |title=Nutritional Yeast Flakes (two tablespoons = 16 grams |website=NutritionData.Self.com |access-date=13 May 2020 |archive-date=11 April 2020 |archive-url=https://web.archive.org/web/20200411162516/https://nutritiondata.self.com/facts/custom/1323565/2 |url-status=live }}</ref><br />Serving = 2 Tbsp (16 g) contains 56 mg || 350 |- |[[Tuna]], yellowfin || 22.1 |- |[[Peanut]]s || 14.3 |- |[[Peanut butter]] || 13.1 |- |[[Bacon]] || 10.4 |- |[[Tuna]], light, canned || 10.1 |- |[[Salmon]] || 10.0 |- |[[Turkey (bird)|Turkey]] depending on what part, how cooked || 7-12 |- |[[Chicken as food|Chicken]] depending on what part, how cooked || 7-12 |} </div> <div style="float:left; padding: 1em;"> {|class="wikitable" |- !Source<ref name=USDANiacin /> !Amount<br /> (mg / 100g) |- |[[Beef]] depending on what part, how cooked || 4-8 |- |[[Pork]] depending on what part, how cooked || 4-8 |- |[[Sunflower seeds]] || 7.0 |- |[[Tuna]], white, canned || 5.8 |- |[[Almond]]s || 3.6 |- |[[Mushroom]]s, white || 3.6 |- |[[Cod as food|Cod fish]] || 2.5 |- |[[Brown rice|Rice, brown]] || 2.5 |- |[[Hot dog]]s || 2.0 |} </div> <div style="float:left; padding: 1em;"> {|class="wikitable" |- !Source<ref name=USDANiacin /> !Amount<br /> (mg / 100g) |- |[[Avocado]] || 1.7 |- |[[Potato]], baked, with skin || 1.4 |- |[[Maize]] (corn) || 1.0 |- |[[White rice|Rice, white]] || 0.5 |- |[[Kale]] || 0.4 |- |[[Egg as food|Eggs]] || 0.1 |- |[[Milk]] || 0.1 |- |[[Cheese]] || 0.1 |- |[[Tofu]] || 0.1 |} </div>{{Clear}} [[Vegetarianism|Vegetarian]] and [[Veganism|vegan]] diets can provide adequate amounts if products such as nutritional yeast, peanuts, peanut butter, tahini, brown rice, mushrooms, avocado and sunflower seeds are included. Fortified foods and dietary supplements can also be consumed to ensure adequate intake.<ref name="NIH Fact Sheet" /> ===Food preparation=== Niacin naturally found in food is susceptible to destruction from high heat cooking, especially in the presence of acidic foods and sauces. It is soluble in water, and so may also be lost from foods boiled in water.<ref>{{cite web|url=http://www.beyondveg.com/tu-j-l/raw-cooked/raw-cooked-2e.shtml|title=Effects of Cooking on Vitamins (Table)|publisher=Beyondveg|access-date=30 April 2019|url-status=live|archive-url=https://web.archive.org/web/20121016010351/http://beyondveg.com/tu-j-l/raw-cooked/raw-cooked-2e.shtml|archive-date=16 October 2012|df=dmy-all}}</ref> ===Food fortification=== Countries fortify foods with nutrients to address known deficiencies.<ref name=WhyFortify /> As of 2020, 54 countries required food fortification of wheat flour with nicotinic acid or nicotinamide; 14 also mandate fortification of maize flour, and 6 mandate fortification of rice.<ref name=Map>{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Map: Count of Nutrients In Fortification Standards|website=Global Fortification Data Exchange|access-date=4 July 2020|archive-date=11 April 2019|archive-url=https://web.archive.org/web/20190411123853/https://fortificationdata.org/map-number-of-nutrients/|url-status=live}}</ref> From country to country, niacin fortification ranges from 1.3 to 6.0 mg/100 g.<ref name=Map /> ===As a dietary supplement=== In the United States, niacin is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving. These products often have a Structure/Function health claim<ref name=SFclaim>{{cite web |url=https://www.fda.gov/food/food-labeling-nutrition/structurefunction-claims |title=Structure/Function Claims |date=December 2017 |website=U.S. Food & Drug Administration |access-date=30 June 2020 |archive-date=10 June 2020 |archive-url=https://web.archive.org/web/20200610032745/https://www.fda.gov/food/food-labeling-nutrition/structurefunction-claims |url-status=live }}</ref> allowed by the US Food & Drug Administration (FDA). An example would be "Supports a healthy blood lipid profile." The American Heart Association strongly advises against the substitution of dietary supplement niacin for prescription niacin because of potentially serious side effects, which means that niacin should only be used under the supervision of a health care professional, and because manufacture of dietary supplement niacin is not as well-regulated by the FDA as prescription niacin.<ref name=AHA>{{cite web |url=https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia/cholesterol-medications |title=Cholesterol Medications |date=10 November 2018 |website=American Heart Association |access-date=8 May 2020 |archive-date=5 April 2020 |archive-url=https://web.archive.org/web/20200405090134/https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia/cholesterol-medications |url-status=live }}</ref> More than 30 mg niacin consumed as a dietary supplement can cause skin flushing. Face, arms and chest skin turns a reddish color because of vasodilation of small subcutaneous blood vessels, accompanied by sensations of heat, tingling and itching. These signs and symptoms are typically transient, lasting minutes to hours; they are considered unpleasant rather than toxic.<ref name="NIH Fact Sheet" /> ==As lipid-modifying medication== In the United States, prescription niacin, in immediate-release and slow-release forms, is used to treat primary [[hyperlipidemia]] and [[hypertriglyceridemia]].<ref name=DailyMed /><ref name=Niaspan /> It is used either as a monotherapy or in combination with other lipid-modifying drugs. Dosages start at 500 mg/day and are often gradually increased to as high as 3000 mg/day for immediate release or 2000 mg/day for slow release (also referred to as sustained release) to achieve the targeted lipid changes (lower LDL-C and triglycerides, and higher HDL-C).<ref name=DailyMed>{{cite web |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ce739d68-d89c-437c-90fb-3c0c45140f22 |title=NIACOR-niacin tablet |date=March 2020 |website=DAILYMED, US National Library of Medicine |access-date=9 May 2020 |archive-date=9 August 2020 |archive-url=https://web.archive.org/web/20200809105743/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ce739d68-d89c-437c-90fb-3c0c45140f22 |url-status=live }}</ref><ref name=Niaspan>{{cite web |url=http://www.rxabbott.com/pdf/niaspan.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.rxabbott.com/pdf/niaspan.pdf |archive-date=2022-10-09 |url-status=live |title=Niaspan Patient Package and Product Information (PPPI) |date= December 2018 |access-date=9 May 2020}}</ref> Prescriptions in the US peaked in 2009, at 9.4{{nbsp}}million{{citation needed|date=November 2022}} and had declined to 800{{nbsp}}thousand by 2020.<ref name="ClinCalc Niacin" /> Systematic reviews found no effect of prescription niacin on all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes despite raising [[high-density lipoprotein|HDL]] cholesterol in patients already taking statins.<ref name=Kee2014>{{cite journal | vauthors = Keene D, Price C, Shun-Shin MJ, Francis DP | title = Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients | journal = BMJ | volume = 349 | pages = g4379 | date = July 2014 | pmid = 25038074 | pmc = 4103514 | doi = 10.1136/bmj.g4379 }}</ref><ref name=Mani2015>{{cite journal |vauthors=Mani P, Rohatgi A |title=Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct? |journal=Curr Atheroscler Rep |volume=17 |issue=8 |pages=43 |date=August 2015 |pmid=26048725 |pmc=4829575 |doi=10.1007/s11883-015-0521-x }}</ref> Reported side effects include an increased risk of new-onset type 2 diabetes.<ref name=Schand2017>{{cite journal | vauthors = Schandelmaier S, Briel M, Saccilotto R, Olu KK, Arpagaus A, Hemkens LG, Nordmann AJ | title = Niacin for primary and secondary prevention of cardiovascular events | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD009744 | date = June 2017 | issue = 6 | pmid = 28616955 | doi = 10.1002/14651858.CD009744.pub2 | pmc = 6481694 }}</ref><ref name=Ong2014 /><ref name=Goldie2016 /><ref>{{cite journal | vauthors = Garg A, Sharma A, Krishnamoorthy P, Garg J, Virmani D, Sharma T, Stefanini G, Kostis JB, Mukherjee D, Sikorskaya E | title = Role of Niacin in Current Clinical Practice: A Systematic Review | journal = The American Journal of Medicine | volume = 130 | issue = 2 | pages = 173–187 | date = February 2017 | pmid = 27793642 | doi = 10.1016/j.amjmed.2016.07.038 | doi-access = free }}</ref> ===Mechanisms=== Niacin reduces synthesis of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), [[lipoprotein(a)]] and [[triglycerides]], and increases [[high-density lipoprotein]] cholesterol (HDL-C).<ref name="Villines, T. C. 2012 p 14">{{cite journal | vauthors = Villines TC, Kim AS, Gore RS, Taylor AJ | s2cid = 27925461 | title = Niacin: the evidence, clinical use, and future directions | journal = Current Atherosclerosis Reports | volume = 14 | issue = 1 | pages = 49–59 | date = February 2012 | pmid = 22037771 | doi = 10.1007/s11883-011-0212-1 }}</ref> The lipid-therapeutic effects of niacin are partly mediated through the activation of [[G protein-coupled receptor]]s, including [[hydroxycarboxylic acid receptor 2]] (HCA<sub>2</sub>)and [[hydroxycarboxylic acid receptor 3]] (HCA<sub>3</sub>), which are highly expressed in [[adipose tissue|body fat]].<ref>{{cite journal | vauthors = Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K |title = Molecular identification of nicotinic acid receptor | journal = Biochemical and Biophysical Research Communications | volume = 303 | issue = 1 | pages = 364–9 | date = March 2003 | pmid = 12646212 | doi = 10.1016/S0006-291X(03)00342-5 }}</ref><ref>{{cite journal | vauthors = Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB | title = Molecular identification of high and low affinity receptors for nicotinic acid | journal = The Journal of Biological Chemistry | volume = 278 | issue = 11 | pages = 9869–74 | date = March 2003 | pmid = 12522134 | doi = 10.1074/jbc.M210695200 | doi-access = free }}</ref> HCA<sub>2</sub> and HCA<sub>3</sub> inhibit [[cyclic adenosine monophosphate]] (cAMP) production and thus suppress the release of free [[fatty acids]] (FFAs) from body fat, reducing their availability to the liver to synthesize the blood-circulating lipids in question.<ref name="Gille, A. 2008">{{cite journal | vauthors = Gille A, Bodor ET, Ahmed K, Offermanns S | title = Nicotinic acid: pharmacological effects and mechanisms of action | journal = Annual Review of Pharmacology and Toxicology | volume = 48 | issue = 1 | pages = 79–106 | year = 2008 | pmid = 17705685 | doi = 10.1146/annurev.pharmtox.48.113006.094746 }}</ref><ref>{{cite journal | vauthors = Wanders D, Judd RL | title = Future of GPR109A agonists in the treatment of dyslipidaemia | journal = Diabetes, Obesity & Metabolism | volume = 13 | issue = 8 | pages = 685–91 | date = August 2011 | pmid = 21418500 | doi = 10.1111/j.1463-1326.2011.01400.x | s2cid = 205536280 }}</ref><ref name=Costet2010>{{cite journal |vauthors=Costet P |title=Molecular pathways and agents for lowering LDL-cholesterol in addition to statins |journal=Pharmacol Ther |volume=126 |issue=3 |pages=263–78 |date=June 2010 |pmid=20227438 |doi=10.1016/j.pharmthera.2010.02.006 }}</ref> A decrease in free fatty acids also suppresses liver expression of [[apolipoprotein C3]] and [[PPARGC1B|PPARg coactivator-1b]], thus increasing VLDL-C turnover and reducing its production.<ref>{{cite journal | vauthors = Hernandez C, Molusky M, Li Y, Li S, Lin JD | title = Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid | journal = Cell Metabolism | volume = 12 | issue = 4 | pages = 411–9 | date = October 2010 | pmid = 20889132 | pmc = 2950832 | doi = 10.1016/j.cmet.2010.09.001 }}</ref> Niacin also directly inhibits the action of [[diacylglycerol O-acyltransferase 2]] (DGAT2) a key enzyme for triglyceride synthesis.<ref name=Costet2010/> The mechanism behind niacin increasing HDL-C is not totally understood, but seems to occur in various ways. Niacin increases [[apolipoprotein A1]] levels by inhibiting the breakdown of this protein, which is a component of HDL-C.<ref>{{cite journal |vauthors=Malik S, Kashyap ML |s2cid=27918392 |title=Niacin, lipids, and heart disease |journal=Curr Cardiol Rep |volume=5 |issue=6 |pages=470–6 |date=November 2003 |pmid=14558989 |doi=10.1007/s11886-003-0109-x }}</ref><ref>{{cite journal | vauthors = Creider JC, Hegele RA, Joy TR | s2cid = 22526314 | title = Niacin: another look at an underutilized lipid-lowering medication | journal = Nature Reviews. Endocrinology | volume = 8 | issue = 9 | pages = 517–28 | date = September 2012 | pmid = 22349076 | doi = 10.1038/nrendo.2012.22 }}</ref> It also inhibits HDL-C hepatic uptake by suppressing production of the [[cholesterol ester transfer protein]] (CETP) gene.<ref name="Villines, T. C. 2012 p 14"/> It stimulates the [[ABCA1|ABCA1 transporter]] in monocytes and macrophages and [[Downregulation and upregulation|upregulates]] [[peroxisome proliferator-activated receptor gamma]], resulting in reverse cholesterol transport.<ref>{{cite journal | vauthors = Rubic T, Trottmann M, Lorenz RL | title = Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin | journal = Biochemical Pharmacology | volume = 67 | issue = 3 | pages = 411–9 | date = February 2004 | pmid = 15037193 | doi = 10.1016/j.bcp.2003.09.014 }}</ref> ===Combined with statins=== Extended release niacin was combined with [[lovastatin]] (Advicor), and with [[simvastatin]] (Simcor), as prescription drug combinations. The combination niacin/lovastatin was approved by the U.S. [[Food and Drug Administration]] (FDA) in 2001.<ref name=Advicor>{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-249_Advicor.cfm |title=Drug Approval Package: Advicor (Niacin Extended-Release & Lovastatin) NDA #21-249 |date=13 September 2002 |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=17 May 2020 |archive-date=4 August 2020 |archive-url=https://web.archive.org/web/20200804174117/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-249_Advicor.cfm |url-status=live }}</ref> The combination niacin/simvastatin was approved by the FDA in 2008.<ref>{{cite web | title=Drug Approval Package: Simcor (Niacin/Simvastatin) NDA #022078 | website=U.S. [[Food and Drug Administration]] (FDA) | date=31 July 2008 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022078s000TOC.cfm | access-date=14 November 2022 | archive-date=14 November 2022 | archive-url=https://web.archive.org/web/20221114011457/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022078s000TOC.cfm | url-status=live }}</ref><ref name=Simcor>{{Cite press release |url=https://www.drugs.com/newdrugs/abbott-receives-fda-approval-simcor-niaspan-simvastatin-novel-combination-medicine-comprehensive-846.html | work = Drugs.com | title = Abbott Receives FDA Approval for Simcor (Niaspan / simvastatin), a Novel Combination Medicine for Comprehensive Cholesterol Management |access-date=2008-03-15 |archive-date=5 August 2020 |archive-url=https://web.archive.org/web/20200805074725/https://www.drugs.com/newdrugs/abbott-receives-fda-approval-simcor-niaspan-simvastatin-novel-combination-medicine-comprehensive-846.html |url-status=live }}</ref> Subsequently, large outcome trials using these niacin and statin therapies were unable to demonstrate incremental benefit of niacin beyond statin therapy alone.<ref>{{cite journal |vauthors=Toth PP, Murthy AM, Sidhu MS, Boden WE |title=Is HPS2-THRIVE the death knell for niacin? |journal=J Clin Lipidol |volume=9 |issue=3 |pages=343–50 |date=2015 |pmid=26073392 |doi=10.1016/j.jacl.2015.01.008 }}</ref> The FDA withdrew approval of both drugs in 2016. The reason given: "Based on the collective evidence from several large cardiovascular outcome trials, the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." The drug company discontinued the drugs.<ref name=FDAWithdrawal>{{cite web |url=https://www.federalregister.gov/documents/2016/04/18/2016-08894/abbvie-inc-withdrawal-of-approval-of-new-drug-applications-for-advicor-and-simcor |title=AbbVie Inc.; Withdrawal of Approval of New Drug Applications for Advicor and Simcor |date=18 April 2016 |website=U.S. Federal Register |access-date=17 May 2020 |archive-date=5 August 2020 |archive-url=https://web.archive.org/web/20200805003411/https://www.federalregister.gov/documents/2016/04/18/2016-08894/abbvie-inc-withdrawal-of-approval-of-new-drug-applications-for-advicor-and-simcor |url-status=live }}</ref> ===Contraindications=== Prescription immediate release (Niacor) and extended release (Niaspan) niacin are [[contraindicated]] for people with either active or a history of [[liver disease]] because both, but especially Niaspan, have been associated with instances of serious, on occasion fatal, liver failure.<ref name=Niaspan /><ref name="ReferenceB"/> Both products are contraindicated for people with existing [[peptic ulcer disease]], or other bleeding problems because niacin lowers platelet count and interferes with blood clotting.<ref name=DailyMed /><ref name=Niaspan /><ref name="ReferenceB"/> Both products are also contraindicated for women who are pregnant or expecting to become pregnant because safety during pregnancy has not been evaluated in human trials. These products are contraindicated for women who are lactating because it is known that niacin is excreted into human milk, but the amount and potential for adverse effects in the nursing infant are not known. Women are advised to either not nurse their child or discontinue the drug. High-dose niacin has not been tested or approved for use in children under 16 years.<ref name=DailyMed /><ref name=Niaspan /><ref name="ReferenceB">{{cite web | title=Niaspan- niacin tablet, film coated, extended release | website=DailyMed | date=20 August 2013 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dd18020-c211-423d-b3d8-a926ae626e14 | access-date=14 November 2022 | archive-date=14 November 2022 | archive-url=https://web.archive.org/web/20221114011459/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dd18020-c211-423d-b3d8-a926ae626e14 | url-status=live }}</ref> ===Adverse effects=== The most common adverse effects of medicinal niacin ({{nowrap|500–3000 mg}}) are flushing (e.g., warmth, redness, itching or tingling) of the face, neck and chest, headache, abdominal pain, diarrhea, [[dyspepsia]], nausea, vomiting, [[rhinitis]], [[pruritus]] and rash.<ref name=lpi/><ref name="NIH Fact Sheet" /><ref name="ReferenceB"/> These can be minimized by initiating therapy at low dosages, increasing dosage gradually, and avoiding administration on an empty stomach.<ref name="ReferenceB"/> The acute adverse effects of high-dose niacin therapy ({{nowrap|1–3 grams per day}}) – which is commonly used in the treatment of [[hyperlipidemia]]s – can further include [[hypotension]], fatigue, [[glucose intolerance]] and [[insulin resistance]], heartburn, blurred or impaired vision, and [[macular edema]].<ref name=lpi/><ref name="NIH Fact Sheet" /> With long-term use, the adverse effects of high-dose niacin therapy (750 mg per day) also include [[liver failure]] (associated with fatigue, nausea, and [[loss of appetite]]), [[hepatitis]], and [[acute liver failure]];<ref name=lpi/><ref name="NIH Fact Sheet" /> these hepatotoxic effects of niacin occur more often when extended-release [[dosage form]]s are used.<ref name=lpi/><ref name="NIH Fact Sheet" /> The long-term use of niacin at greater than or equal to 2 grams per day also significantly increases the [[risk ratio|risk]] of [[cerebral hemorrhage]], [[ischemic stroke]], [[gastrointestinal ulcer]]ation and [[gastrointestinal bleeding|bleeding]], [[diabetes]], [[dyspepsia]], and diarrhea.<ref name="NIH Fact Sheet"/> ====Flushing==== [[Flushing (physiology)|Flushing]] – a short-term [[vasodilation|dilatation]] of skin [[arteriole]]s, causing reddish skin color – usually lasts for about 15 to 30 minutes, although sometimes can persist for weeks. Typically, the face is affected, but the reaction can extend to neck and upper chest. The cause is blood vessel dilation<ref name=lpi/><ref name="NIH Fact Sheet" /> due to elevation in prostaglandin GD<sub>2</sub> ([[PGD2]]) and [[serotonin]].<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S | title = GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing | journal = The Journal of Clinical Investigation | volume = 115 | issue = 12 | pages = 3634–40 | date = December 2005 | pmid = 16322797 | pmc = 1297235 | doi = 10.1172/JCI23626 }}</ref><ref>{{cite journal | vauthors = Benyó Z, Gille A, Bennett CL, Clausen BE, Offermanns S | s2cid = 30199951 | title = Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells | journal = Molecular Pharmacology | volume = 70 | issue = 6 | pages = 1844–9 | date = December 2006 | pmid = 17008386 | doi = 10.1124/mol.106.030833 }}</ref><ref>{{cite journal | vauthors = Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT | title = Langerhans cells release prostaglandin D2 in response to nicotinic acid | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 12 | pages = 2637–46 | date = December 2006 | pmid = 17008871 | doi = 10.1038/sj.jid.5700586 | doi-access = free }}</ref> Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction.<ref name="ReferenceA">{{cite journal | vauthors = Papaliodis D, Boucher W, Kempuraj D, Michaelian M, Wolfberg A, House M, Theoharides TC | s2cid = 5609632 | title = Niacin-induced "flush" involves release of prostaglandin D2 from mast cells and serotonin from platelets: evidence from human cells in vitro and an animal model | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 3 | pages = 665–72 | date = December 2008 | pmid = 18784348 | doi = 10.1124/jpet.108.141333 }}</ref> Flushing is sometimes accompanied by a prickly or [[itching]] sensation, in particular, in areas covered by clothing.<ref name="NIH Fact Sheet" /> Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway.<ref name="NIH Fact Sheet" /><ref name="kamanna">{{cite journal | vauthors = Kamanna VS, Kashyap ML | title = Mechanism of action of niacin | journal = The American Journal of Cardiology | volume = 101 | issue = 8A | pages = 20B–26B | date = April 2008 | pmid = 18375237 | doi = 10.1016/j.amjcard.2008.02.029 }}</ref> [[Aspirin]] taken half an hour before the niacin prevents flushing, as does [[ibuprofen]]. Taking niacin with meals also helps reduce this side effect.<ref name="NIH Fact Sheet" /> Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most people no longer experience flushing.<ref name="NIH Fact Sheet" /> Slow- or "sustained"-release forms of niacin have been developed to lessen these side effects.<ref name=autogenerated1>{{cite book |author=Katzung, Bertram G. |title=Basic and clinical pharmacology |publisher=McGraw-Hill Medical Publishing Division |location=New York |year=2006 |isbn=978-0-07-145153-6 }}</ref><ref>{{cite journal | title = Options for therapeutic intervention: How effective are the different agents? | journal = European Heart Journal Supplements | volume = 8 | pages = F47–F53 | doi = 10.1093/eurheartj/sul041 | vauthors = Barter P | date = October 2006 | issue = F| doi-access = free }}</ref> ====Liver damage==== Niacin in medicinal doses can cause modest elevations in serum [[transaminase]] and unconjugated [[bilirubin]], both biomarkers of liver injury. The increases usually resolve even when drug intake is continued.<ref name=LiverTox2014>{{cite book |title = IN: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury (Internet) |chapter = Niacin |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |pmid=31643504 |date=February 2014 |location = Bethesda, MD }}</ref><ref name="bil1" /><ref name="bil2" /> However, less commonly, the sustained release form of the drug can lead to serious [[hepatotoxicity]], with onset in days to weeks. Early symptoms of serious liver damage include nausea, vomiting and abdominal pain, followed by [[jaundice]] and [[Itch|pruritus]]. The mechanism is thought to be a direct toxicity of elevated serum niacin. Lowering dose or switching to the immediate release form can resolve symptoms. In rare instances the injury is severe, and progresses to liver failure.<ref name=LiverTox2014 /> ====Diabetes==== The high doses of niacin used to treat [[hyperlipidemia]] have been shown to elevate [[blood sugar|fasting blood glucose]] in people with type 2 [[diabetes mellitus|diabetes]].<ref name=Ong2014>{{cite journal |vauthors=Ong KL, Barter PJ, Waters DD |title=Cardiovascular drugs that increase the risk of new-onset diabetes |journal=Am. Heart J. |volume=167 |issue=4 |pages=421–8 |date=April 2014 |pmid=24655688 |doi=10.1016/j.ahj.2013.12.025 |s2cid=205306912 |url=http://www.escholarship.org/uc/item/6gd606b1 |access-date=27 June 2020 |archive-date=28 June 2020 |archive-url=https://web.archive.org/web/20200628180527/https://escholarship.org/uc/item/6gd606b1 |url-status=live |hdl=1959.4/unsworks_43825 |hdl-access=free }}</ref> Long-term niacin therapy was also associated with an increase in the risk of new-onset type 2 diabetes.<ref name=Ong2014 /><ref name=Goldie2016>{{cite journal | vauthors = Goldie C, Taylor AJ, Nguyen P, McCoy C, Zhao XQ, Preiss D | title = Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials | journal = Heart | volume = 102 | issue = 3 | pages = 198–203 | date = February 2016 | pmid = 26370223 | pmc = 4752613 | doi = 10.1136/heartjnl-2015-308055 }}</ref> ====Other adverse effects==== High doses of niacin can also cause niacin [[maculopathy]], a thickening of the [[macula]] and [[retina]], which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases.<ref>{{cite journal |vauthors=Domanico D, Verboschi F, Altimari S, Zompatori L, Vingolo EM |title=Ocular Effects of Niacin: A Review of the Literature |journal=Med Hypothesis Discov Innov Ophthalmol |volume=4 |issue=2 |pages=64–71 |date=2015 |pmid=26060832 |pmc=4458328 }}</ref> Niaspan, the slow-release product, has been associated with a reduction in platelet content and a modest increase in prothrombin time.<ref name=Niaspan /> ==In schizophrenia== In 1954, researchers [[Abram Hoffer]] and [[Humphry Osmond]] claimed that [[adrenochrome]], a chemical compound produced by the oxidation of adrenaline (epinephrine), is a [[neurotoxin|neurotoxic]], [[psychotomimetic]] substance and may play a role in [[schizophrenia]] and other mental illnesses.<ref name="pmid13152519">{{cite journal | last1 = Hoffer | first1 = Abram | author-link1 = Abram Hoffer | last2 = Osmond | first2 = Humphrey | author-link2 = Humphry Osmond | first3 = John | last3 = Smythies| author-link3 = John Raymond Smythies | title = Schizophrenia: A New Approach. II. Result of a Year's Research | journal = [[British Journal of Psychiatry|The Journal of Mental Science]] | volume = 100 | issue = 418 | pages = 29–45 | date = January 1954 | pmid = 13152519 | doi = 10.1192/bjp.100.418.29 | eissn = 1472-1465 | issn = 0007-1250 | lccn = 89649366 | oclc = 1537306 | s2cid = 42531852 | df = dmy-all }}</ref> In what Hoffer called the "adrenochrome hypothesis",<ref name="Hoffer2">{{cite journal | last1 = Hoffer | first1 = Abram | author-link1 = Abram Hoffer | last2 = Osmond | first2 = Humphrey | author-link2 = Humphry Osmond | title = The Adrenochrome Hypothesis and Psychiatry | url = http://www.orthomolecular.org/library/jom/1999/articles/1999-v14n01-p049.shtml | access-date = 2024-03-15 | journal = [[The Journal of Orthomolecular Medicine]] | volume = 14 | issue = 1 | date = First Quarter 1999 | pages = 49–62 | archive-url = https://web.archive.org/web/20240220043758/http://www.orthomolecular.org/library/jom/1999/articles/1999-v14n01-p049.shtml | archive-date = 2024-02-20 | url-status = live | issn = 0834-4825 | oclc = 15726974 | s2cid = 41468628 | df = dmy-all}}</ref> he and Osmond in 1967 speculated that [[Megavitamin therapy|megadoses]] of [[vitamin C]] and [[niacin (nutrient)|niacin]] could cure schizophrenia by reducing brain adrenochrome.<ref name="hallucinogens">{{cite book | last1 = Hoffer | first1 = Abram | author-link1 = Abram Hoffer | last2 = Osmond | first2 = Humphrey | author-link2 = Humphry Osmond | date = 1968-01-01 | title = The Hallucinogens | url = https://archive.org/details/hallucinogens0000hoff/ | url-access = registration | language = en | edition = First | publisher = [[Academic Press]] | isbn = 978-0123518507 | lccn = 66030086 | oclc = 332437 | ol = OL35255701M | access-date = 2024-03-15 | via = [[Internet Archive]] | quote= | quote-page= | quote-pages= | df = dmy-all}}</ref><ref name=hoffer94>{{cite journal | vauthors = Hoffer A | date = 1994 | title = Schizophrenia: An Evolutionary Defense Against Severe Stress | journal = Journal of Orthomolecular Medicine | volume = 9 | issue = 4 | pages = 205–2221 | url = http://orthomolecular.org/library/jom/1994/pdf/1994-v09n04-p205.pdf }}</ref> He tested this in small numbers of patients and claimed that it was frequently impressively successful. The treatment of schizophrenia with such potent anti-oxidants is highly contested. In 1973, the [[American Psychiatric Association]] reported methodological flaws in Hoffer's work on niacin as a schizophrenia treatment and referred to follow-up studies that did not confirm any benefits of the treatment.<ref name="APA">{{cite web | vauthors = Lipton MA, Ban TA, Kane FJ, Levine J, Mosher LR, Wittenborn R | title = Task Force Report on Megavitamin and Orthomolecular Therapy in Psychiatry | publisher = American Psychiatric Association | year = 1973 | url = https://www.old.quackwatch.org/01QuackeryRelatedTopics/apa_megavitamin.pdf | access-date = 7 September 2020 | archive-date = 23 February 2021 | archive-url = https://web.archive.org/web/20210223194022/https://www.old.quackwatch.org/01QuackeryRelatedTopics/apa_megavitamin.pdf | url-status = dead }}</ref> Multiple additional studies in the United States,<ref name="ArchGenPsy">{{cite journal | doi = 10.1001/archpsyc.1973.01750330010002 |vauthors=Wittenborn JR, Weber ES, Brown M | title = Niacin in the Long-Term Treatment of Schizophrenia | journal = Archives of General Psychiatry | year = 1973 | volume = 28 | issue = 3 | pages = 308–315 | pmid = 4569673 | url = http://archpsyc.ama-assn.org/cgi/content/abstract/28/3/308}}</ref> Canada,<ref name="SZ Bull">{{cite journal | vauthors = Ban TA, Lehmann HE | title = Nicotinic Acid in the Treatment of Schizophrenia: A Summary Report | journal = Schizophrenia Bulletin | year = 1970 | volume = 1 | issue = 3 | pages = 5–7 | doi = 10.1093/schbul/1.3.5 | doi-access = free }}</ref> and Australia<ref name="ANZJP">{{cite journal |vauthors=Vaughan K, McConaghy N | s2cid = 38857700 | title = Megavitamin and dietary treatment in schizophrenia: a randomised, controlled trial | journal = Australian and New Zealand Journal of Psychiatry | year = 1999 | volume = 33 | issue = 1 | pages = 84–88 | pmid = 10197889 | doi =10.1046/j.1440-1614.1999.00527.x}}</ref> similarly failed to find benefits of megavitamin therapy to treat [[History of schizophrenia|schizophrenia]]. Hoffer, in a lengthy review article, replied that the follow-up studies were poorly designed, using incorrect doses and illogical measures of whether the patients had recovered or not, and voiced suspicions that they had been deliberately set up to make the niacin protocol look bad by doctors who had spoken publicly in support of the use of tranquillizers and wanted to make it look as if they were right. The adrenochrome theory of schizophrenia waned, despite some evidence that it may be [[psychotomimetic]], as adrenochrome was not detectable in people with schizophrenia.{{citation needed|date=March 2021}} In the early 2000s, interest was renewed by the discovery that adrenochrome may be produced normally as an intermediate in the formation of [[neuromelanin]].<ref name=Smythies>{{cite journal | last1 = Smythies | first1 = John | author-link1 = John Raymond Smythies | s2cid = 37594882 | title = The adrenochrome hypothesis of schizophrenia revisited | journal = [[Neurotoxicity Research]] | volume = 4 | issue = 2 | pages = 147–150 | date = January 2002 | pmid = 12829415 | doi = 10.1080/10298420290015827 | citeseerx = 10.1.1.688.3796 | issn = 1029-8428 | eissn = 1476-3524 | oclc = 50166444 }}</ref> This finding may be significant because adrenochrome is detoxified at least partially by [[glutathione-S-transferase]]. Some studies have found genetic defects in the gene for this enzyme.<ref>{{cite book | vauthors = Smythies J | veditors = Smythies J |title=Disorders of Synaptic Plasticity and Schizophrenia |date=2004 |publisher=Elsevier Academic Press |isbn=978-0-12-366860-8 |pages=xv |edition=1st}}</ref> ==Pharmacology== ===Pharmacodynamics=== Activating HCA<sub>2</sub> has effects other than lowering serum cholesterol and triglyceride concentrations: antioxidative, anti-inflammatory, antithrombotic, improved [[endothelium|endothelial]] function and [[atheroma|plaque]] stability, all of which counter development and progression of atherosclerosis.<ref name=Zeman2015>{{cite journal |vauthors=Zeman M, Vecka M, Perlík F, Hromádka R, Staňková B, Tvrzická E, Žák A |title=Niacin in the Treatment of Hyperlipidemias in Light of New Clinical Trials: Has Niacin Lost its Place? |journal=Med. Sci. Monit. |volume=21 |pages=2156–62 |date=July 2015 |pmid=26210594 |pmc=4523006 |doi=10.12659/MSM.893619 }}</ref><ref>{{cite journal | vauthors = Wu BJ, Yan L, Charlton F, Witting P, Barter PJ, Rye KA | title = Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 30 | issue = 5 | pages = 968–75 | date = May 2010 | pmid = 20167660 | doi = 10.1161/ATVBAHA.109.201129 | doi-access = free }}</ref> Niacin [[Enzyme inhibitor|inhibits]] [[cytochrome P450]] enzymes [[CYP2E1]], [[CYP2D6]] and [[CYP3A4]].<ref name = "Gaudineau_2004">{{cite journal | vauthors = Gaudineau C, Auclair K | title = Inhibition of human P450 enzymes by nicotinic acid and nicotinamide | journal = Biochemical and Biophysical Research Communications | volume = 317 | issue = 3 | pages = 950–6 | date = May 2004 | pmid = 15081432 | doi = 10.1016/j.bbrc.2004.03.137 }}</ref> Niacin produces a rise in serum [[Bilirubin#Indirect (unconjugated)|unconjugated bilirubin]] in normal individuals and in those with [[Gilbert's Syndrome]]. However, in the Gilbert's Syndrome, the rise in bilirubin is higher and clearance is delayed longer than in normal people.<ref>{{cite book |title=Nathan and Oski's Hematology of Infancy and Childhood |pages=118–119 |isbn=9781416034308| vauthors = Orkin SH, Nathan DG |date=January 2009 |publisher=Elsevier Health Sciences }}</ref> One test used to aid in diagnosing Gilbert's Syndrome involves intravenous administration of nicotinic acid (niacin) in a dose of 50 mg over a period of 30 seconds.<ref name="bil1">{{cite journal | vauthors = Dickey W, McAleer JJ, Callender ME | title = The Nicotinic Acid Provocation Test and Unconjugated Hyperbilirubinaemia | journal = The Ulster Medical Journal | volume = 60 | issue = 1 | pages = 49–52 | date = April 1991 | pmid = 1853497 | pmc = 2448612 }}</ref><ref name="bil2">{{cite journal | vauthors = Röllinghoff W, Paumgartner G, Preisig R | title = Nicotinic Acid Test in the Diagnosis of Gilbert's Syndrome: Correlation With Bilirubin Clearance | journal = Gut | volume = 22 | issue = 8 | pages = 663–668 | date = August 1981 | pmid = 7286783 | pmc = 1420060 | doi = 10.1136/gut.22.8.663 }}</ref> {{See also|Niacin#Liver_damage}} ===Pharmacokinetics=== Both nicotinic acid and nicotinamide are rapidly absorbed from the stomach and small intestine.<ref>{{cite journal | vauthors = Said HM | title = Intestinal absorption of water-soluble vitamins in health and disease | journal = The Biochemical Journal | volume = 437 | issue = 3 | pages = 357–372 | date = August 2011 | pmid = 21749321 | pmc = 4049159 | doi = 10.1042/BJ20110326 }}</ref> Absorption is facilitated by sodium-dependent diffusion, and at higher intakes, via passive diffusion. Unlike some other vitamins, the percent absorbed does not decrease with increasing dose, so that even at amounts of 3-4 grams, absorption is nearly complete.<ref name=PKIN2020Niacin /> With a one gram dose, peak plasma concentrations of 15 to 30 μg/mL are reached within 30 to 60 minutes. Approximately 88% of an oral pharmacologic dose is eliminated by the kidneys as unchanged niacin or nicotinuric acid, its primary metabolite. The plasma elimination half-life of niacin ranges from 20 to 45 minutes.<ref name=DailyMed /> Niacin and nicotinamide are both converted into the [[coenzyme]] NAD.<ref name="isbn1-57259-153-6">{{cite book | vauthors = Cox M, Lehninger AL, Nelson DR | title = Lehninger principles of biochemistry | publisher = Worth Publishers | location = New York | year = 2000 | isbn = 978-1-57259-153-0 | url-access = registration | url = https://archive.org/details/lehningerprincip01lehn }}</ref> NAD converts to NADP by phosphorylation in the presence of the enzyme [[NAD+ kinase]]. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency.<ref>{{cite journal | vauthors = Ishii N, Nishihara Y | title = Pellagra among chronic alcoholics: clinical and pathological study of 20 necropsy cases | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 44 | issue = 3 | pages = 209–15 | date = March 1981 | pmid = 7229643 | pmc = 490893 | doi = 10.1136/jnnp.44.3.209 }}</ref> In the liver, nicotinamide is converted to storage [[nicotinamide adenine dinucleotide]] (NAD). As needed, liver NAD is hydrolyzed to nicotinamide and niacin for transport to tissues, there reconverted to NAD to serve as an enzyme cofactor.<ref name=PKIN2020Niacin /> Excess niacin is methylated in the liver to N<sup>1</sup>-methylnicotinamide (NMN) and excreted in urine as such or as the oxidized metabolites [[N1-Methyl-2-pyridone-5-carboxamide|N<sup>1</sup>-methyl-2-pyridone-5-carboxamide]] and [[N1-Methyl-4-pyridone-3-carboxamide]] (2PY and 4PY). Decreased urinary content of these metabolites is a measure of niacin deficiency.<ref name=PKIN2020Niacin /> ==Production== ===Biosynthesis=== [[Image:Tryptophan metabolism.svg|thumb|300px|class=skin-invert-image|Niacin, [[serotonin]] (5-hydroxytryptamine), and [[melatonin]] [[biosynthesis]] from [[tryptophan]]]] In addition to absorbing niacin from diet, niacin can be synthesized from the [[Essential amino acid|essential]] [[amino acid]] [[tryptophan]], a five-step process with the penultimate compound being [[quinolinic acid]] (see figure). Some bacteria and plants utilize [[aspartic acid]] in a pathway that also goes to quinolinic acid.<ref>{{cite journal |vauthors=Foster JW, Moat AG |title= Nicotinamide adenine dinucleotide biosynthesis and pyridine nucleotide cycle metabolism in microbial systems |journal= Microbiol. Rev. |volume= 44 |issue= 1 |pages= 83–105 |date= 1 March 1980 |doi= 10.1128/MMBR.44.1.83-105.1980 |pmid= 6997723 |pmc= 373235}}</ref> For humans, the efficiency of conversion is estimated as requiring 60{{nbsp}}[[gram#SI multiples|mg]] of tryptophan to make 1{{nbsp}}mg of niacin. [[Riboflavin]], [[Vitamin B6|vitamin B<sub>6</sub>]] and [[iron]] are required for the process.<ref name=PKIN2020Niacin /> Pellagra is a consequence of a corn-dominant diet because the niacin in corn is poorly bioavailable and corn proteins are low in tryptophan compared to wheat and rice proteins.<ref name=Carpenter1983>{{cite book |doi=10.1007/978-3-0348-6540-1_12 |chapter=The Relationship of Pellagra to Corn and the Low Availability of Niacin in Cereals |title=Nutritional Adequacy, Nutrient Availability and Needs |series=Experientia Supplementum |year=1983 | vauthors = Carpenter KJ |volume=44 |pages=197–222 |pmid=6357846 |isbn=978-3-0348-6542-5 }}</ref> ===Industrial synthesis=== Nicotinic acid was first synthesized in 1867 by oxidative degradation of [[nicotine]] with [[potassium chromate]] and [[sulfuric acid]]<ref name=Ullmann2015/> — this is the origin of the name.<ref name=JAMA1942a>{{cite journal|title=Niacin and Nicotinic Acid|date=7 March 1942|volume=118|issue=10|doi=10.1001/jama.1942.02830100053014|journal=Journal of the American Medical Association|page=823}}</ref> Niacin is prepared by hydrolysis of [[nicotinonitrile]], which, as described above, is generated by oxidation of 3-picoline. Oxidation can be effected by air, but [[ammoxidation]] is more efficient. In the latter process, nicotinonitrile is produced by ammoxidation of [[3-methylpyridine]]. [[Nitrile hydratase]] is then used to catalyze nicotinonitrile to nicotinamide, which can be converted to niacin.<ref>{{Ullmann|vauthors=Abe N, Ichimura H, Kataoka T, Morishita S, Shimizu S, Shoji T, Watanabe N |year=2007 |doi=10.1002/14356007.a22_399|title=Pyridine and Pyridine Derivatives|isbn=978-3527306732}}</ref> Alternatively, ammonia, acetic acid and paraldehyde are used to make [[5-Ethyl-2-methyl-pyridine|5-ethyl-2-methyl-pyridine]], which is then oxidized to niacin.<ref name=LONZA>{{cite journal | vauthors = Eschenmooser W |title=100 Years of Progress with LONZA |journal=CHIMIA |date=June 1997 |volume=51 |issue=6 |pages=259–69 |doi=10.2533/chimia.1997.259 |s2cid=100485418 |doi-access=free }}</ref> New "greener" catalysts are being tested using manganese-substituted aluminophosphates that use acetyl peroxyborate as non-corrosive oxidant, avoiding producing nitrogen oxides as do traditional ammoxidations.<ref>{{cite journal| author = Sarah Everts| title = Clean Catalysis: Environmentally friendly synthesis of niacin generates less inorganic waste| journal = Chemical & Engineering News| year = 2008| issn = 0009-2347}}</ref> The demand for commercial production includes for animal feed and for food fortification meant for human consumption. According to ''[[Ullmann's Encyclopedia of Industrial Chemistry]]'', worldwide 31,000 tons of nicotinamide were sold in 2014.<ref name=Ullmann2015>{{cite encyclopedia|encyclopedia = Ullmann's Encyclopedia of Industrial Chemistry|year = 2015|publisher = [[Wiley-VCH]]|location = Weinheim|isbn = 978-3-527-30385-4|edition = 6th|title = Vitamins, 11. Niacin (Nicotinic Acid, Nicotinamide|pages = 1–9| vauthors = Blum R |doi = 10.1002/14356007.o27_o14.pub2|chapter = Vitamins, 11. Niacin (Nicotinic Acid, Nicotinamide)}}</ref> ===Climate impact=== The production of niacin creates [[nitrous oxide]] as a by-product, which is a potent greenhouse gas. In 2018, it was discovered that a niacin factory in [[Visp]], Switzerland, was responsible for around one percent of the country's greenhouse gas emissions.<ref>{{cite web | vauthors = Lenz C | title = The climate disgrace of Visp | newspaper = European Press Prize | year = 2021 | url = https://www.europeanpressprize.com/article/the-climate-disgrace-of-visp/ | access-date = 8 September 2023 | archive-date = 8 September 2023 | archive-url = https://web.archive.org/web/20230908132352/https://www.europeanpressprize.com/article/the-climate-disgrace-of-visp/ | url-status = live }}</ref> Eventually, catalytic scrubbing technology that eliminates most of the emissions was installed in 2021.<ref>{{cite journal | vauthors = Davidson EA, Winiwarter W |title=Urgent abatement of industrial sources of nitrous oxide |journal=Nature Climate Change |date=July 2023 |volume=13 |issue=7 |pages=599–601 |doi=10.1038/s41558-023-01723-3|bibcode=2023NatCC..13..599D }}</ref> ==Chemistry== This colorless, water-soluble solid is a derivative of [[pyridine]], with a [[carboxyl group]] (COOH) at the 3-position.<ref name=PKIN2020Niacin/> Other forms of vitamin B<sub>3</sub> include the corresponding [[amide]] [[nicotinamide]], where the carboxyl group has been replaced by a [[carboxamide]] group ({{chem|CONH|2}}).<ref name=PKIN2020Niacin/> ==Preparations== [[File:Inositol nicotinate.png|thumb|class=skin-invert-image|[[Inositol]] hexanicotinate]] Niacin is incorporated into multi-vitamin and sold as a single-ingredient dietary supplement. The latter can be immediate or slow release.<ref name=Dunatchik>{{cite journal | vauthors = Dunatchik AP, Ito MK, Dujovne CA | title = A systematic review on evidence of the effectiveness and safety of a wax-matrix niacin formulation | journal = Journal of Clinical Lipidology | volume = 6 | issue = 2 | pages = 121–31 | date = 1 March 2012 | pmid = 22385545 | doi = 10.1016/j.jacl.2011.07.003 }}</ref> [[Nicotinamide]] is used to treat niacin deficiency because it does not cause the flushing adverse reaction seen with niacin. Nicotinamide may be toxic to the liver at doses exceeding 3{{nbsp}}g/day for adults.<ref>{{cite journal | vauthors = Knip M, Douek IF, Moore WP, Gillmor HA, McLean AE, Bingley PJ, Gale EA | title = Safety of high-dose nicotinamide: a review | journal = Diabetologia | volume = 43 | issue = 11 | pages = 1337–45 | date = November 2000 | pmid = 11126400 | doi = 10.1007/s001250051536 | doi-access = free }}</ref> Prescription products can be immediate release (Niacor, 500 mg tablets) or [[extended release]] (Niaspan, 500 and 1000 mg tablets). Niaspan has a film coating that delays release of the niacin, resulting in an absorption over a period of 8–12 hours. This reduces [[vasodilation]] and [[flushing (physiology)|flushing]] side effects, but increases the risk of [[hepatotoxicity]] compared to the immediate release drug.<ref>{{cite journal | vauthors = Bassan M | title = A case for immediate-release niacin | journal = Heart & Lung | volume = 41 | issue = 1 | pages = 95–8 | year = 2012 | pmid = 21414665 | doi = 10.1016/j.hrtlng.2010.07.019 }}</ref><ref>{{cite journal | vauthors = Reiche I, Westphal S, Martens-Lobenhoffer J, Tröger U, Luley C, Bode-Böger SM | title = Pharmacokinetics and dose recommendations of Niaspan in chronic kidney disease and dialysis patients | journal = Nephrology, Dialysis, Transplantation | volume = 26 | issue = 1 | pages = 276–82 | date = January 2011 | pmid = 20562093 | doi = 10.1093/ndt/gfq344 | doi-access = free }}</ref> Prescription niacin preparations in combination with statin drugs (discontinued) are described above. A combination of niacin and [[laropiprant]] had been approved for use in Europe and marketed as Tredaptive. Laropiprant is a [[prostaglandin D2]] binding drug shown to reduce niacin-induced vasodilation and flushing side effects.<ref name="Villines, T. C. 2012 p 14"/><ref>{{cite journal | vauthors = Lai E, De Lepeleire I, Crumley TM, Liu F, Wenning LA, Michiels N, Vets E, O'Neill G, Wagner JA, Gottesdiener K | title = Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1 | journal = Clinical Pharmacology and Therapeutics | volume = 81 | issue = 6 | pages = 849–57 | date = June 2007 | pmid = 17392721 | doi = 10.1038/sj.clpt.6100180 | s2cid = 2126240 }}</ref><ref>{{cite journal | vauthors = Paolini JF, Bays HE, Ballantyne CM, Davidson M, Pasternak R, Maccubbin D, Norquist JM, Lai E, Waters MG, Kuznetsova O, Sisk CM, Mitchel YB | title = Extended-release niacin/laropiprant: reducing niacin-induced flushing to better realize the benefit of niacin in improving cardiovascular risk factors | journal = Cardiology Clinics | volume = 26 | issue = 4 | pages = 547–60 | date = November 2008 | pmid = 19031552 | doi = 10.1016/j.ccl.2008.06.007 }}</ref> A clinical trial showed no additional efficacy of Tredaptive in lowering cholesterol when used together with other statin drugs, but did show an increase in other side effects.<ref>{{cite journal |vauthors=Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J |title=Effects of extended-release niacin with laropiprant in high-risk patients |journal=N. Engl. J. Med. |volume=371 |issue=3 |pages=203–12 |date=July 2014 |pmid=25014686 |doi=10.1056/NEJMoa1300955 |s2cid=23548060 |doi-access=free }}</ref> The study resulted in the withdrawal of Tredaptive from the international market.<ref>{{Cite web|url=http://www.medscape.com/viewarticle/777519|title=Niacin/Laropiprant Products to Be Suspended Worldwide|vauthors=Nainggolan L|date=11 January 2013|website=Medscape|access-date=20 February 2017|archive-date=26 April 2015|archive-url=https://web.archive.org/web/20150426032404/http://www.medscape.com/viewarticle/777519|url-status=live}}</ref><ref>{{cite news | url=https://www.reuters.com/article/us-merck-cholesteroldrug-withdrawal-idUSBRE90A0MB20130111?feedType=RSS&feedName=healthNews | work=Reuters | title=Merck begins overseas recall of HDL cholesterol drug | date=11 January 2013 | access-date=6 July 2021 | archive-date=21 April 2023 | archive-url=https://web.archive.org/web/20230421215022/https://www.reuters.com/article/us-merck-cholesteroldrug-withdrawal-idUSBRE90A0MB20130111?feedType=RSS&feedName=healthNews | url-status=live }}</ref> One form of dietary supplement sold in the US is inositol hexanicotinate (IHN), also called [[inositol nicotinate]]. This is [[inositol]] that has been [[ester]]ified with niacin on all six of inositol's alcohol groups.<ref name="efsa.europa.eu">{{cite journal | journal = The EFSA Journal | date = January 2009 | volume = 949 | pages = 1–20 | title = Inositol hexanicotinate (inositol hexaniacinate) as a source of niacin (vitamin B3) added for nutritional purposes in food supplements | vauthors = Aguilar F, Charrondiere UR, Dusemund B, Galtier PM, Gilbert J, Gott DM, Grilli S, Guertler R, Kass GE, Koenig J, Lambré C, Larsen JC, Mortensen A, Parent-Massin D, Pratt I, Rietjens IM, Stankovic I, Tobback P, Verguieva T, Woutersen RA | url = https://www.efsa.europa.eu/en/efsajournal/pub/949 | access-date = 4 March 2017 | archive-date = 5 March 2017 | archive-url = https://web.archive.org/web/20170305035332/https://www.efsa.europa.eu/en/efsajournal/pub/949 | url-status = live }}</ref> IHN is usually sold as "flush-free" or "no-flush" niacin in units of 250, 500, or 1000 mg/tablets or capsules. In the US, it is sold as an over-the-counter formulation, and often is marketed and labeled as niacin, thus misleading consumers into thinking they are getting an active form of the medication. While this form of niacin does not cause the flushing associated with the immediate-release products, there is not enough evidence to recommend IHN to treat hyperlipidemia.<ref name=Taheri>{{cite web | url = http://www.medscape.com/viewarticle/447528 | title = No-Flush Niacin for the Treatment of Hyperlipidemia | vauthors = Taheri | website = [[Medscape]] | date = 15 January 2003 | access-date = 31 March 2008 | archive-date = 5 December 2008 | archive-url = https://web.archive.org/web/20081205051549/http://www.medscape.com/viewarticle/447528 | url-status = live }}</ref> ==History== {{Further|Vitamin#History}} Niacin as a chemical compound was first described by chemist [[Hugo Weidel]] in 1873 in his studies of [[nicotine]],<ref>{{cite journal | vauthors = Weidel H | title = Zur Kenntniss des Nicotins | journal = [[Justus Liebigs Annalen der Chemie und Pharmacie]] | year = 1873 | volume = 165 | pages = 330–49 | doi = 10.1002/jlac.18731650212 | issue = 2 | url = https://zenodo.org/record/1427317 | access-date = 3 July 2019 | archive-date = 4 August 2020 | archive-url = https://web.archive.org/web/20200804134952/https://zenodo.org/record/1427317 | url-status = live }}</ref> but that predated by many years the concept of food components other than protein, fat and carbohydrates that were essential for life. Vitamin nomenclature was initially alphabetical, with [[Elmer McCollum]] calling these fat-soluble A and water-soluble B.<ref name=Combs2007 /> Over time, eight chemically distinct, water-soluble B vitamins were isolated and numbered, with niacin as vitamin B<sub>3</sub>.<ref name=Combs2007>{{Cite book|url=https://books.google.com/books?id=1CMHiWum0Y4C&pg=PA16|title=The Vitamins: Fundamental Aspects in Nutrition and Health|edition=3rd|vauthors=Combs GF|date=2007|pages=7–33|publisher=Elsevier, Boston, MA|isbn=978-0-080-56130-1|access-date=30 June 2020|archive-date=13 January 2023|archive-url=https://web.archive.org/web/20230113023205/https://books.google.com/books?id=1CMHiWum0Y4C&pg=PA16|url-status=live}}</ref> {{Further|Pellagra#History}} Corn (maize) became a staple food in the southeast United States and in parts of Europe. A disease that was characterized by dermatitis of sunlight-exposed skin was described in Spain in 1735 by [[Gaspar Casal]]. He attributed the cause to poor diet.<ref>{{cite book | vauthors = Casal G |chapter=The natural and medical history of the principality of the Asturias |title=Classic Descriptions of Disease | veditors = Major RH |edition=3rd |location=Springfield |publisher=Charles C Thomas |year=1945 |pages=607–12}}</ref> In northern Italy it was named "pellagra" from the [[Lombard language]] (''agra'' = [[holly]]-like or [[Serous fluid|serum]]-like; ''pell'' = skin).<ref>F. Cherubini, ''Vocabolario Milanese-Italiano'', Imp. Regia Stamperia, 1840-43, vol. I, III.</ref><ref>{{cite web| title = Definition of Pellagra| work = MedicineNet.com| url = http://www.medterms.com/script/main/art.asp?articlekey=4821|access-date=2007-06-18|url-status = live|archive-url = https://web.archive.org/web/20070930155704/http://www.medterms.com/script/main/art.asp?articlekey=4821| archive-date = 2007-09-30}}</ref> In time, the disease was more closely linked specifically to corn.<ref>Cesare Lombroso, ''Studi clinici ed esperimentali sulla natura, causa e terapia delle pellagra'' (Bologna: Fava e Garagnani, 1869)</ref> In the US, [[Joseph Goldberger]] was assigned to study pellagra by the Surgeon General of the United States. His studies confirmed a corn-based diet as the culprit, but he did not identify the root cause.<ref>{{cite journal |vauthors=Evans BK,Feinstein AR | s2cid = 13226008 | title = Joseph Goldberger: an unsung hero of American clinical epidemiology | journal = Ann Intern Med | date=September 1994| volume = 121 | issue = 5 | pages = 372–75 | pmid = 8042827 | doi=10.7326/0003-4819-121-5-199409010-00010}}</ref><ref name=Kraut>{{Cite web|url=https://history.nih.gov/pages/viewpage.action?pageId=8883184|title=Dr. Joseph Goldberger and the War on Pellagra {{!}} Ashes on the Potomac|vauthors=Kraut A|website=history.nih.gov|access-date=20 February 2017|archive-date=9 May 2020|archive-url=https://web.archive.org/web/20200509172705/https://history.nih.gov/pages/viewpage.action?pageId=8883184|url-status=live}}</ref> Nicotinic acid was extracted from liver by biochemist [[Conrad Elvehjem]] in 1937. He later identified the active ingredient, referring to it as "pellagra-preventing factor" and the "anti-blacktongue factor."<ref name=Elvehjem>{{cite journal |vauthors=Elvehjem CA, Madden RJ, Strongandd FM, Woolley DW |year=1938 |title=The isolation and identification of the anti-blacktongue factor J |journal = J. Biol. Chem. |volume=123 |pages=137–49 |url=http://www.jbc.org/content/123/1/137.full.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.jbc.org/content/123/1/137.full.pdf |archive-date=2022-10-09 |url-status=live |issue=1|doi=10.1016/S0021-9258(18)74164-1 |doi-access=free }}</ref> It was also referred to as "vitamin PP", "vitamin P-P" and "PP-factor", all derived from the term "pellagra-preventive factor".<ref name="Pellagra And Its Prevention">{{cite report|vauthors=((World Health Organization)) | title=Pellagra And Its Prevention And Control In Major Emergencies|publisher=[[World Health Organization]] (WHO) | year=2000 | hdl=10665/66704 | hdl-access=free | id=WHO/NHD/00.10}}</ref> In the late 1930s, studies by [[Tom Douglas Spies]], Marion Blankenhorn, and Clark Cooper confirmed that niacin cured pellagra in humans. The prevalence of the disease was greatly reduced as a result.<ref>Ruth Hanna Sachs, [https://books.google.com/books?id=WOPfM-0hz1AC&dq=%22pellagra%3A+Drs.+Tom+Douglas%22&pg=PA630 ''White Rose History''.] {{Webarchive|url=https://web.archive.org/web/20230421215022/https://books.google.com/books?id=WOPfM-0hz1AC&dq=%22pellagra:+Drs.+Tom+Douglas%22&pg=PA630 |date=21 April 2023 }} Volume I. 2003. Appendix D, p. 2 {{ISBN|978-0-9710541-9-6}} "Men of the Year, outstanding in comprehensive science were three medical researchers who discovered that nicotinic acid was a cure for human pellagra: Drs. Tom Douglas Spies of Cincinnati General Hospital, Marion Arthur Blankenhorn of the University of Cincinnati, Clark Niel Cooper of Waterloo, Iowa."</ref> Nicotinic acid was initially synthesized by oxidizing [[nicotine]] with [[potassium chromate]] and [[sulfuric acid]].<ref name=JAMA1942a/> Hence, in 1942, when flour [[food fortification|enrichment]] with nicotinic acid began, a headline in the popular press said "Tobacco in Your Bread." In response, the Council on Foods and Nutrition of the [[American Medical Association]] approved of the [[Food and Nutrition Board]]'s new names ''niacin'' and ''niacin amide'' for use primarily by non-scientists. It was thought appropriate to choose a name to dissociate nicotinic acid from nicotine, to avoid the perception that vitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins. The resulting name ''niacin'' was derived from ''{{strong|ni}}cotinic {{strong|ac}}id'' + ''vitam{{strong|in}}''.<ref>{{cite journal|title=Niacin and Niacin Amide| date=7 March 1942|volume=118|issue=10|doi=10.1001/jama.1942.02830100049011|journal=Journal of the American Medical Association|page=819}}</ref><ref name=JAMA1942a/> Carpenter found in 1951, that niacin in corn is biologically unavailable, and can be released only in very alkaline [[Lime (material)|lime]] water of [[pH]] 11. This explains why a Latin-American culture that used [[Nixtamalization|alkali-treated cornmeal]] to make tortilla was not at risk for niacin deficiency.<ref>{{cite journal | vauthors = Laguna J, Carpenter KJ | title = Raw versus processed corn in niacin-deficient diets | journal = The Journal of Nutrition | volume = 45 | issue = 1 | pages = 21–8 | date = September 1951 | pmid = 14880960 | doi = 10.1093/jn/45.1.21 | doi-access = free }}</ref> In 1955, Altschul and colleagues described large amounts of niacin as having a lipid-lowering property.<ref>{{cite journal | vauthors = Altschul R, Hoffer A, Stephen JD | title = Influence of nicotinic acid on serum cholesterol in man | journal = Archives of Biochemistry and Biophysics | volume = 54 | issue = 2 | pages = 558–9 | date = February 1955 | pmid = 14350806 | doi = 10.1016/0003-9861(55)90070-9 }}</ref> As such, niacin is the oldest known [[Lipid-lowering agent|lipid-lowering drug]].<ref>{{cite journal |vauthors=Romani M, Hofer DC, Katsyuba E, Auwerx J |title=Niacin: an old lipid drug in a new NAD+ dress |journal=J. Lipid Res. |volume=60 |issue=4 |pages=741–6 |date=April 2019 |pmid=30782960 |pmc=6446705 |doi=10.1194/jlr.S092007 |doi-access=free }}</ref> [[Lovastatin]], the first '[[statin]]' drug, was first marketed in 1987.<ref name=Simons>{{cite journal | vauthors = Simons J | title = The $10 billion pill | journal = Fortune | volume = 147 | issue = 1 | pages = 58–62, 66, 68 | date = January 2003 | pmid = 12602122 | url = https://money.cnn.com/magazines/fortune/fortune_archive/2003/01/20/335643/index.htm }}</ref> ==Research== In [[animal model]]s and ''[[in vitro]]'', niacin produces marked anti-inflammatory effects in a variety of tissues – including the brain, gastrointestinal tract, skin, and [[Inflammation#Vascular component|vascular tissue]] – through the activation of [[hydroxycarboxylic acid receptor 2]] (HCA2), also known as niacin receptor 1 (NIACR1).<ref name="Niacin neuroinflammation">{{cite journal | vauthors = Offermanns S, Schwaninger M | title = Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation | journal = Trends in Molecular Medicine | volume = 21 | issue = 4 | pages = 245–55 | date = April 2015 | pmid = 25766751 | doi = 10.1016/j.molmed.2015.02.002}}</ref><ref name="Niacin vascular inflammation">{{cite journal | vauthors = Chai JT, Digby JE, Choudhury RP | title = GPR109A and vascular inflammation | journal = Current Atherosclerosis Reports | volume = 15 | issue = 5 | pages = 325 | date = May 2013 | pmid = 23526298 | pmc = 3631117 | doi = 10.1007/s11883-013-0325-9 }}</ref><ref name="NIACR1 anti-inflammatory effects">{{cite journal | vauthors = Graff EC, Fang H, Wanders D, Judd RL | title = Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2 | journal = Metabolism | volume = 65 | issue = 2 | pages = 102–13 | date = February 2016 | pmid = 26773933 | doi = 10.1016/j.metabol.2015.10.001 }}</ref><ref name="Niacin-NIACR1 in PD">{{cite journal | vauthors = Wakade C, Chong R | s2cid = 29760853 | title = A novel treatment target for Parkinson's disease | journal = Journal of the Neurological Sciences | volume = 347 | issue = 1–2 | pages = 34–8 | date = December 2014 | pmid = 25455298 | doi = 10.1016/j.jns.2014.10.024 }}</ref> Unlike niacin, nicotinamide does not activate NIACR1; however, both niacin and nicotinamide activate the [[G protein-coupled estrogen receptor]] (GPER) ''in vitro''.<ref name="Niacin-nicotinamide GPER primary">{{cite journal | vauthors = Santolla MF, De Francesco EM, Lappano R, Rosano C, Abonante S, Maggiolini M | title = Niacin activates the G protein estrogen receptor (GPER)-mediated signalling | journal = Cellular Signalling | volume = 26 | issue = 7 | pages = 1466–75 | date = July 2014 | pmid = 24662263 | doi = 10.1016/j.cellsig.2014.03.011 }}</ref> In 2024, it was reported that metabolites of niacin promote vascular inflammation and contribute to the risk of developing [[atherosclerosis]].<ref name="Mole2024">{{cite news | vauthors = Mole B |title=Surprising link found between niacin and risk of heart attack and stroke |url=https://arstechnica.com/science/2024/02/surprising-link-found-between-niacin-and-risk-of-heart-attack-and-stroke/ |access-date=24 May 2024 |publisher=Ars Technica |date=26 Feb 2024}}</ref> == References == {{Reflist}} {{Vitamin}} {{Peripheral vasodilators}} {{Lipid modifying agents}} {{Estrogen receptor modulators}} {{GABAA receptor positive allosteric modulators}} {{Portal bar | Medicine}} [[Category:Drugs developed by AbbVie]] [[Category:Aromatic acids]] [[Category:B vitamins]] [[Category:CYP2D6 inhibitors]] [[Category:CYP3A4 inhibitors]] [[Category:GABAA receptor positive allosteric modulators]] [[Category:GPER agonists]] [[Category:Hypolipidemic agents]] [[Category:3-Pyridyl compounds]] [[Category:Multiple Chemboxes|X]]
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