Editing Folate

{{Short description|Vitamin B9; nutrient essential for DNA synthesis}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Good article}}
{{Use dmy dates|date=September 2024}}
{{Infobox drug
| drug_name = Folic acid
| image = Folic acid.svg
| image_class = skin-invert-image
| width = 260
| alt = Skeletal formula
| caption = 
| image2 = Folic-acid-from-xtal-3D-bs-17.png
| image_class2 = bg-transparent
| width2 = 280
| alt2 = <!-- Clinical data -->
| pronounce = {{IPAc-en|ˈ|f|oʊ|l|ɪ|k|,_|ˈ|f|ɒ|l|ɪ|k}}
| tradename = Folicet, Folvite
| Drugs.com = {{drugs.com|monograph|folic-acid}}
| MedlinePlus = a682591
| DailyMedID = Folic acid
| pregnancy_AU = A
| pregnancy_AU_comment = 
| pregnancy_category = 
| routes_of_administration = [[Oral administration|By mouth]], [[Intramuscular injection|intramuscular]], [[Intravenous therapy|intravenous]], [[Subcutaneous injection|subcutaneous]]
| class = 
| ATC_prefix = B03
| ATC_suffix = BB01
| ATC_supplemental = {{ATC|V04|CX02}} {{ATC|B03|AE02}} {{ATC|B03|AE01}} {{ATC|B03|BB51}}

<!-- Legal status -->| legal_AU = S4
| legal_AU_comment = /&nbsp;S2
| 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 = Rx-only
| legal_US_comment = /&nbsp;OTC
| legal_EU = 
| legal_EU_comment = 
| 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 = 50–100%<ref name=AHFS2016/>
| protein_bound = 
| metabolism = [[Liver]]<ref name=AHFS2016/>
| metabolites = 
| onset = 
| elimination_half-life = 
| duration_of_action = 
| excretion = Urine<ref name=AHFS2016/>

<!-- Identifiers -->| index2_label = as salt
| CAS_number = 59-30-3
| CAS_number2 = 6484-89-5
| CAS_supplemental = 
| PubChem = 6037
| IUPHAR_ligand = 4563
| DrugBank = DB00158
| DrugBank2 = DBSALT001918
| ChemSpiderID = 5815
| ChemSpiderID2 = 21512
| UNII = 935E97BOY8
| UNII2 = 9P9W8GGU78
| KEGG = D00070
| KEGG2 = D07985
| ChEBI = 27470
| ChEMBL = 1622
| NIAID_ChemDB = 
| PDB_ligand = FOL
| synonyms = Wills factor, FA, ''N''-(4-<nowiki/>{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-<small>L</small>-glutamic acid, pteroyl-L-glutamic acid, folacin, vitamin B<sub>9</sub>;<ref name=NIH/> formerly, vitamin B<sub>c</sub> and vitamin M<ref name=Welch1983/>

<!-- Chemical and physical data -->| IUPAC_name = (2''S'')-2-<nowiki>[[</nowiki>4-[(2-Amino-4-oxo-1''H''-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid<ref>{{cite web|title=Folic Acid|url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6037|publisher=The PubChem Project|url-status=live|archive-url=https://web.archive.org/web/20140407091703/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6037|archive-date=7 April 2014}}</ref>
| C = 19
| H = 19
| N = 7
| O = 6
| SMILES = n1c2C(=O)NC(N)=Nc2ncc1CNc3ccc(cc3)C(=O)N[C@H](C(O)=O)CCC(O)=O
| StdInChI = 1S/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1
| StdInChI_comment = 
| StdInChIKey = OVBPIULPVIDEAO-LBPRGKRZSA-N
| density = 1.6±0.1
| density_notes = <ref name="chemsrc">{{Cite web|url=https://www.chemsrc.com/en/cas/59-30-3_1191873.html|title=Folic Acid|website=ChemSrc|access-date=12 April 2018|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828090610/https://www.chemsrc.com/en/cas/59-30-3_1191873.html|url-status=live}}</ref>
| melting_point = 250
| melting_high = 
| melting_notes = (decomposition)
| boiling_point = 
| boiling_notes = 
| solubility = 1.6
| sol_units = mg/L (25 °C)<ref name="chemsrc">{{Cite web|url=https://www.chemsrc.com/en/cas/59-30-3_1191873.html|title=Folic Acid|website=ChemSrc|access-date=12 April 2018|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828090610/https://www.chemsrc.com/en/cas/59-30-3_1191873.html|url-status=live}}</ref>
| specific_rotation = 
}}

<!-- Definition and uses -->
'''Folate''', also known as '''vitamin B<sub>9</sub>''' and '''folacin''',<ref name="lpi">{{cite web|title=Folate|url=http://lpi.oregonstate.edu/mic/vitamins/folate|publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University|access-date=17 March 2018|date=2014|quote=Folate is a water-soluble B-vitamin, which is also known as vitamin B9 or folacin.|archive-date=19 August 2021|archive-url=https://web.archive.org/web/20210819075234/https://lpi.oregonstate.edu/mic/vitamins/folate|url-status=live}}</ref> is one of the [[B vitamins]].<ref name=AHFS2016>{{cite web|title=Folic Acid|url=https://www.drugs.com/monograph/folic-acid.html|website=Drugs.com|publisher=American Society of Health-System Pharmacists|access-date=1 September 2016|date=1 January 2010|url-status=live|archive-url=https://web.archive.org/web/20170808233930/https://www.drugs.com/monograph/folic-acid.html|archive-date=8 August 2017}}</ref> Manufactured '''folic acid''', which is converted into folate by the body, is used as a [[dietary supplement]] and in [[food fortification]] as it is more stable during processing and storage.<ref name=Choi2014>{{cite journal |vauthors=Choi JH, Yates Z, Veysey M, Heo YR, Lucock M |title=Contemporary issues surrounding folic Acid fortification initiatives |journal=Prev Nutr Food Sci |volume=19 |issue=4 |pages=247–60 |date=December 2014 |pmid=25580388 |pmc=4287316 |doi=10.3746/pnf.2014.19.4.247}}</ref> Folate is required for the body to make [[DNA]] and [[RNA]] and metabolise [[amino acids]] necessary for [[cell division]] and maturation of [[blood cell]]s.<ref name=NIH/><ref name=PKIN2020Folate>{{cite book |vauthors=West AA, Caudill MA, Bailey LB |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Folate |editor=BP Marriott |editor2=DF Birt |editor3=VA Stallings|editor4=AA Yates |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 273–88 |isbn=978-0-323-66162-1}}</ref> As the human body cannot make folate, it is required in the diet, making it an [[Nutrient#Essential nutrients|essential nutrient]].<ref>{{cite book|url=https://books.google.com/books?id=fedRNr2-UVAC&pg=PA551|title=Alcamo's Fundamentals of Microbiology: Body Systems|date=2009|publisher=Jones & Bartlett Publishers|isbn=978-0-7637-8712-7|page=511| vauthors = Pommerville JC |url-status=live|archive-url= https://web.archive.org/web/20170908213409/https://books.google.com/books?id=fedRNr2-UVAC&pg=PA551 |archive-date=8 September 2017 }}</ref> It occurs naturally in many foods.<ref name=lpi/><ref name=NIH/> The recommended adult daily intake of folate in the U.S. is 400 [[microgram]]s from foods or [[dietary supplement]]s.<ref name=NIH/>

<!-- Medical uses -->
Folate in the form of folic acid is used to treat [[anemia]] caused by [[folic acid deficiency|folate deficiency]].<ref name=AHFS2016 /> Folic acid is also used as a supplement by women during [[pregnancy]] to reduce the risk of [[neural tube defect]]s (NTDs) in the baby.<ref name=AHFS2016 /><ref>{{cite journal|vauthors=Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, García FA, Kemper AR, Krist AH, Kurth AE, Landefeld CS, Mangione CM, Phillips WR, Phipps MG, Pignone MP, Silverstein M, Tseng CW|s2cid=205077749|title=Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement|journal=JAMA|volume=317|issue=2|pages=183–189|date=January 2017|pmid=28097362|doi=10.1001/jama.2016.19438}}</ref> NTDs include [[anencephaly]] and [[spina bifida]], among other defects. Low levels in early [[pregnancy]] are believed to be the cause of more than half of babies born with NTDs.<ref name=NIH/> More than 80 countries use either mandatory or voluntary fortification of certain foods with folic acid as a measure to decrease the rate of NTDs.<ref name=Wald2018/> Long-term supplementation with relatively large amounts of folic acid is associated with a small reduction in the risk of [[stroke]]<ref name=Li2016>{{cite journal|vauthors=Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB|title=Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials|journal=Journal of the American Heart Association|volume=5|issue=8|pages=e003768|date=August 2016|pmid=27528407|pmc=5015297|doi=10.1161/JAHA.116.003768|url=https://dash.harvard.edu/bitstream/handle/1/29407892/5015297.pdf?sequence=1|access-date=4 November 2018|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427034202/https://dash.harvard.edu/bitstream/handle/1/29407892/5015297.pdf?sequence=1|url-status=live}}</ref> and an increased risk of prostate cancer.<ref name=Wien2012/>  Maternal folic acid supplementation reduces [[autism]] risk, and [[folinic acid]] improves symptoms in autism with [[cerebral folate deficiency]]. Folate deficiency is linked to higher depression risk; folate supplementation serves as a beneficial [[Combination therapy|adjunctive]] treatment for depression. There are concerns that large amounts of supplemental folic acid can hide [[vitamin B12 deficiency|vitamin B<sub>12</sub> deficiency]].<ref name=NIH/>

<!-- Deficiency -->
Not consuming enough folate can lead to folate deficiency.<ref name=NIH/> This may result in [[megaloblastic anemia|a type of anemia]] in which red blood cells become abnormally large.<ref name=NIH/> Symptoms may include [[fatigue (medical)|feeling tired]], [[heart palpitations]], [[shortness of breath]], open sores on the tongue, and changes in the color of the skin or hair.<ref name=NIH/> Folate deficiency in children may develop within a month of poor dietary intake.<ref>{{cite book|vauthors=Marino BS, Fine KS|title=Blueprints Pediatrics|date=2009|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-8251-7|page=131|url=https://books.google.com/books?id=oqpSRIOcd8MC&pg=PA131|language=en|url-status=live|archive-url=https://web.archive.org/web/20170908213408/https://books.google.com/books?id=oqpSRIOcd8MC&pg=PA131|archive-date=8 September 2017}}</ref> In adults, normal total body folate is between 10 and 30&nbsp;mg with about half of this amount stored in the liver and the remainder in blood and body tissues.<ref name=NIH/> In plasma, the natural folate range is 150 to 450&nbsp;nM.<ref>{{cite journal | vauthors = Fardous AM, Heydari AR | title = Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review | journal = Nutrients | volume = 15 | issue = 21 | page = 4699 | date = November 2023 | pmid = 37960352 | pmc = 10648405 | doi = 10.3390/nu15214699 | doi-access = free }}</ref>

<!-- History and culture -->
Folate was discovered between 1931 and 1943.<ref name=Pond>{{cite book| vauthors = Pond WG, Nichols BL, Brown DL |title=Adequate Food for All: Culture, Science, and Technology of Food in the 21st Century |date=2009 |publisher=CRC Press |isbn=978-1-4200-7754-4 |page=148 |url=https://books.google.com/books?id=wbS5FogT1-4C&pg=PA148 |language=en |quote=Folic acid's discovery started in 1931...}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 2022, it was the 65th most commonly prescribed medication in the United States, with more than 10{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Folic Acid Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/FolicAcid | access-date = 30 August 2024 | archive-date = 8 July 2020 | archive-url = https://web.archive.org/web/20200708065613/https://clincalc.com/DrugStats/Drugs/FolicAcid | url-status = live }}</ref> The term "folic" is from the Latin word {{lang|la|[[wikt:folium|folium]]}} (which means leaf) because it was found in dark-green leafy vegetables.<ref name=Chambers>{{cite book|title=Chambers Concise Dictionary|date=2004|publisher=Allied Publishers|isbn=978-81-86062-36-4|page=451|url=https://books.google.com/books?id=iwWuY9tAVq8C&pg=PA451|url-status=live|archive-url=https://web.archive.org/web/20170908213408/https://books.google.com/books?id=iwWuY9tAVq8C&pg=PA451|archive-date=8 September 2017}}</ref>
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==Definition==
[[Image:Folate family.svg|thumb|left|250px|class=skin-invert-image|Chemical structure of the folate family]]
''Folate'' (vitamin B<sub>9</sub>) refers to the many forms of folic acid and its [[Congener (chemistry)|related compounds]], including [[tetrahydrofolic acid]] (the active form), [[methyltetrahydrofolate]] (the primary form found in blood), [[5,10-Methenyltetrahydrofolate|methenyltetrahydrofolate]], [[folinic acid]], folacin, and pteroylglutamic acid.<ref name=lpi/><ref>{{cite web|title=Folic Acid|url=https://livertox.nlm.nih.gov//FolicAcid.htm|publisher=NIH LiverTox|date=2 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170107010702/https://livertox.nlm.nih.gov/FolicAcid.htm|archive-date=7 January 2017}}</ref><ref name=CDCFAQ>{{cite web|title=FAQ's Folic Acid|url=https://www.cdc.gov/ncbddd/folicacid/faqs.html|publisher=CDC|date=16 December 2016|archive-url=https://web.archive.org/web/20170710114350/https://www.cdc.gov/ncbddd/folicacid/faqs.html|archive-date=10 July 2017|access-date=7 July 2017}}</ref><ref name = "IUPAC_folic_acid" /> Historic names included ''L.&nbsp;⁠casei'' factor, vitamin B<sub>c</sub> and vitamin M.<ref name=Welch1983>{{cite journal |vauthors=Welch AD |s2cid=31993927 |title=Folic acid: discovery and the exciting first decade |journal=Perspect. Biol. Med. |volume=27 |issue=1 |pages=64–75 |date=1983 |pmid=6359053 |doi=10.1353/pbm.1983.0006 }}</ref>

The terms ''folate'' and ''folic acid'' have somewhat different meanings in different contexts, although sometimes used interchangeably.<ref>{{cite web | title = Folic Acid | url = https://medlineplus.gov/folicacid.html | work = MedlinePlus | publisher = U.S. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services | access-date = 15 December 2019 | archive-date = 31 July 2020 | archive-url = https://web.archive.org/web/20200731221822/https://medlineplus.gov/folicacid.html | url-status = live }}</ref> Within the field of [[organic chemistry]], folate refers to the [[conjugate base]] of folic acid.<ref>{{cite web | title = Folic acid | url = https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:27470 | work = Chemical Entities of Biological Interest (ChEBI) | publisher = European Bioinformatics Institute | access-date = 15 December 2019 | archive-date = 31 July 2020 | archive-url = https://web.archive.org/web/20200731171418/https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:27470 | url-status = live }}</ref><ref name="IUPAC_folic_acid">{{cite web | vauthors = Moss GP | title = Nomenclature and symbols for folic acid and related compounds | url = https://www.qmul.ac.uk/sbcs/iupac/misc/folic.html | quote = Folate and folic acid are the preferred synonyms for pteroylglutamate and pteroylglutamic acid, respectively. | work = IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) | date = 1986 | access-date = 15 December 2019 | archive-date = 30 November 2020 | archive-url = https://web.archive.org/web/20201130112000/https://www.qmul.ac.uk/sbcs/iupac/misc/folic.html | url-status = live }}</ref> Within the field of [[biochemistry]], folates refer to a class of biologically active compounds related to and including folic acid.<ref>{{cite book |vauthors=Combs JR GF, McClung JP |chapter=Chapter 17: Folate |title=The Vitamins: Fundamental Aspects in Nutrition and Health |date=2016 |isbn=978-0-12-802983-1 |pages=400–401 |publisher=Academic Press |edition=Fifth |chapter-url=https://books.google.com/books?id=UEy0DAAAQBAJ&pg=PA400 |quote=The term folate is the generic descriptor for folic acid (pteroylmonoglutamic acid or pteroylglutamic acid) and related compounds exhibiting the biological activity of folic acid. |access-date=15 December 2019 |archive-date=12 January 2023 |archive-url=https://web.archive.org/web/20230112173407/https://books.google.com/books?id=UEy0DAAAQBAJ&pg=PA400 |url-status=live }}</ref> Within the field of [[nutrition]], the ''folates'' are a family of essential nutrients related to folic acid obtained from natural sources whereas the term ''folic acid'' is reserved for the manufactured form that is used as a dietary supplement.<ref>{{cite web | title = Folic acid in diet | url = https://medlineplus.gov/ency/article/002408.htm | work = MedlinePlus | publisher = U.S. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services | access-date = 15 December 2019 | archive-date = 31 July 2020 | archive-url = https://web.archive.org/web/20200731180118/https://medlineplus.gov/ency/article/002408.htm | url-status = live }}</ref>

Chemically, folates consist of three distinct chemical moieties linked together. A [[pterin]] (2-amino-4-hydroxy-pteridine) [[heterocyclic]] ring is linked by a [[methylene bridge]] to a [[p-aminobenzoic acid|p-aminobenzoyl]] group that in turn is bonded through an amide linkage to either [[glutamic acid]] or poly-glutamate. One-carbon units in a variety of [[oxidation state]]s may be attached to the N5 nitrogen atom of the pteridine ring and/or the N10 nitrogen atom of the p-aminobenzoyl group.<ref name="Zheng_2019">{{cite journal | vauthors = Zheng Y, Cantley LC | title = Toward a better understanding of folate metabolism in health and disease | journal = The Journal of Experimental Medicine | volume = 216 | issue = 2 | pages = 253–266 | date = February 2019 | pmid = 30587505 | pmc = 6363433 | doi = 10.1084/jem.20181965 }}</ref>

==Health effects==
Folate is especially important during periods of frequent cell division and growth, such as infancy and pregnancy. Folate deficiency hinders [[DNA]] synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of their greater frequency of cell division. [[RNA]] transcription and subsequent protein synthesis are less affected by folate deficiency, as the [[mRNA]] can be recycled and used again (as opposed to DNA synthesis, where a new genomic copy must be created).

===Birth defects===
Deficiency of folate in pregnant women has been implicated in [[neural tube defects]] (NTDs), with an estimate of 300,000 cases worldwide prior to the implementation in many countries of mandatory food fortification.<ref name=Berry2010>{{cite journal |vauthors=Berry RJ, Bailey L, Mulinare J, Bower C |s2cid=36706350 |title=Fortification of flour with folic acid |journal=Food Nutr Bull |volume=31 |issue=1 Suppl |pages=S22–S35 |date=2010 |pmid=20629350 |doi=10.1177/15648265100311S103 |doi-access=free }}</ref> NTDs occur early in pregnancy (first month), therefore women must have abundant folate upon conception and for this reason there is a recommendation that any woman planning to become pregnant consume a folate-containing dietary supplement before and during pregnancy.<ref>{{cite journal|vauthors=Wilson RD, Wilson RD, Audibert F, Brock JA, Carroll J, Cartier L, Gagnon A, Johnson JA, Langlois S, Murphy-Kaulbeck L, Okun N, Pastuck M, Deb-Rinker P, Dodds L, Leon JA, Lowel HL, Luo W, MacFarlane A, McMillan R, Moore A, Mundle W, O'Connor D, Ray J, Van den Hof M|title=Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies|journal=Journal of Obstetrics and Gynaecology Canada|volume=37|issue=6|pages=534–52|date=June 2015|pmid=26334606|doi=10.1016/s1701-2163(15)30230-9|doi-access=free}}</ref> The [[Centers for Disease Control and Prevention|Center for Disease Control and Prevention (CDC)]] recommends a daily amount of 400 micrograms of folic acid for the prevention of NTDs.<ref>{{Cite web|title=Folic Acid|url=https://www.cdc.gov/ncbddd/folicacid/about.html#:~:text=CDC%20recommends%20that%20women%20of,of%20folate%20through%20diet%20alone.|website=CDC|date=19 April 2021|access-date=20 December 2021|archive-date=15 July 2023|archive-url=https://web.archive.org/web/20230715011206/https://www.cdc.gov/ncbddd/folicacid/about.html#:~:text=CDC%20recommends%20that%20women%20of,of%20folate%20through%20diet%20alone.|url-status=live}}</ref> Many women take this medication less than the CDC recommends, especially in cases where the pregnancy was unplanned, or in countries that lack healthcare resources and education. Some countries have implemented either mandatory or voluntary food fortification of wheat flour and other grains,<ref name="Map" /> but many others rely on public health education and one-on-one healthcare practitioner advice. A [[meta-analysis]] of global birth prevalence of [[spina bifida]] showed that when a national, mandatory program to fortify the diet with folate was compared to countries without such a fortification program, there was a 30% reduction in live births with spina bifida.<ref name="Atta2016">{{cite journal|vauthors=Atta CA, Fiest KM, Frolkis AD, Jette N, Pringsheim T, St Germaine-Smith C, Rajapakse T, Kaplan GG, Metcalfe A|title=Global Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis|journal=American Journal of Public Health|volume=106|issue=1|pages=e24-34|date=January 2016|pmid=26562127|pmc=4695937|doi=10.2105/AJPH.2015.302902}}</ref> Some countries reported a greater than 50% reduction.<ref name="Castillo2013">{{cite journal |vauthors=Castillo-Lancellotti C, Tur JA, Uauy R |title=Impact of folic acid fortification of flour on neural tube defects: a systematic review |journal=Public Health Nutr |volume=16 |issue=5 |pages=901–911 |date=2013 |pmid=22850218 |doi=10.1017/S1368980012003576 |doi-access=free |pmc=10271422 }}</ref> The [[United States Preventive Services Task Force]] recommends folic acid as the supplement or fortification ingredient, as forms of folate other than folic acid have not been studied.<ref name=CDCFAQ/>

A meta-analysis of folate supplementation during pregnancy reported a 28% lower relative risk of newborn [[congenital heart defect]]s.<ref>{{cite journal|vauthors=Feng Y, Wang S, Chen R, Tong X, Wu Z, Mo X|title=Maternal folic acid supplementation and the risk of congenital heart defects in offspring: a meta-analysis of epidemiological observational studies|journal=Scientific Reports|volume=5|page=8506|date=February 2015|pmid=25687545|pmc=4330542|doi=10.1038/srep08506|bibcode=2015NatSR...5.8506F}}</ref> Prenatal supplementation with folic acid did not appear to reduce the risk of preterm births.<ref>{{cite journal|vauthors=Fekete K, Berti C, Trovato M, Lohner S, Dullemeijer C, Souverein OW, Cetin I, Decsi T|title=Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation|journal=Nutrition Journal|volume=11|page=75|date=September 2012|pmid=22992251|pmc=3499376|doi=10.1186/1475-2891-11-75|doi-access=free}}</ref><ref>{{cite journal|vauthors=Saccone G, Berghella V|title=Folic acid supplementation in pregnancy to prevent preterm birth: a systematic review and meta-analysis of randomized controlled trials|journal=European Journal of Obstetrics, Gynecology, and Reproductive Biology|volume=199|pages=76–81|date=April 2016|pmid=26901401|doi=10.1016/j.ejogrb.2016.01.042}}</ref> One [[systematic review]] indicated no effect of folic acid on mortality, growth, body composition, respiratory, or cognitive outcomes of children from birth to 9 years old.<ref>{{cite journal|vauthors=Devakumar D, Fall CH, Sachdev HS, Margetts BM, Osmond C, Wells JC, Costello A, Osrin D|title=Maternal antenatal multiple micronutrient supplementation for long-term health benefits in children: a systematic review and meta-analysis|journal=BMC Medicine|volume=14|page=90|date=June 2016|pmid=27306908|pmc=4910255|doi=10.1186/s12916-016-0633-3|doi-access=free}}</ref> There was no relation between maternal folic acid supplementation and an increased risk for childhood asthma.<ref>{{cite journal|vauthors=Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ|title=Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis|journal=The American Journal of Clinical Nutrition|volume=98|issue=5|pages=1272–81|date=November 2013|pmid=24004895|pmc=5369603|doi=10.3945/ajcn.113.065623}}</ref>

===Fertility===
Folate contributes to [[spermatogenesis]].<ref name=Ebisch2007 /> In women, folate is important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development.<ref name=Ebisch2007>{{cite journal|vauthors=Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP|title=The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility|journal=Human Reproduction Update|volume=13|issue=2|pages=163–74|date=Mar–Apr 2007|pmid=17099205|doi=10.1093/humupd/dml054|doi-access=free}}</ref>

===Heart disease===
One meta-analysis reported that multi-year folic acid supplementation, in amounts in most of the included clinical trials at higher than the upper limit of 1,000&nbsp;μg/day, reduced the [[relative risk]] of cardiovascular disease by a modest 4%.<ref name=Li2016/> Two older meta-analyses, which would not have incorporated results from newer clinical trials, reported no changes to the risk of cardiovascular disease.<ref>{{cite journal |vauthors=Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL |title=Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials |journal=Eur. J. Intern. Med. |volume=23 |issue=8 |pages=745–54 |date=December 2012 |pmid=22884409 |doi=10.1016/j.ejim.2012.07.004 }}</ref><ref>{{cite journal|vauthors=Bazzano LA|s2cid=20470125|title=No effect of folic acid supplementation on cardiovascular events, cancer or mortality after 5 years in people at increased cardiovascular risk, although homocysteine levels are reduced|journal=Evidence-Based Medicine|volume=16|issue=4|pages=117–8|date=August 2011|pmid=21402567|doi=10.1136/ebm1204}}</ref>

===Stroke===
The [[absolute risk]] of stroke with supplementation decreases from 4.4% to 3.8% (a 10% decrease in relative risk).<ref name=Li2016/> Two other meta-analyses reported a similar decrease in relative risk.<ref name=Tian2017>{{cite journal |vauthors=Tian T, Yang KQ, Cui JG, Zhou LL, Zhou XL |s2cid=3500861 |title=Folic Acid Supplementation for Stroke Prevention in Patients With Cardiovascular Disease |journal=Am. J. Med. Sci. |volume=354 |issue=4 |pages=379–387 |date=October 2017 |pmid=29078842 |doi=10.1016/j.amjms.2017.05.020 }}</ref><ref name=Zhao2017>{{cite journal |vauthors=Zhao M, Wu G, Li Y, Wang X, Hou FF, Xu X, Qin X, Cai Y |s2cid=325155 |title=Meta-analysis of folic acid efficacy trials in stroke prevention: Insight into effect modifiers |journal=Neurology |volume=88 |issue=19 |pages=1830–1838 |date=May 2017 |pmid=28404799 |doi=10.1212/WNL.0000000000003909 }}</ref> Two of these three were limited to people with pre-existing cardiovascular disease or coronary heart disease.<ref name=Li2016/><ref name=Tian2017/> The beneficial result may be associated with lowering circulating [[homocysteine]] concentration, as stratified analysis showed that risk was reduced more when there was a larger decrease in homocysteine.<ref name=Li2016/><ref name=Tian2017/> The effect was also larger for the studies that were conducted in countries that did not have mandatory grain folic acid fortification.<ref name=Tian2017/><ref name=Zhao2017/> The beneficial effect was larger in the subset of trials that used a lower folic acid supplement compared to higher.<ref name=Tian2017/><ref name=Zhao2017/>

===Cancer===
Chronically insufficient intake of folate may increase the risk of colorectal, breast, ovarian, pancreatic, brain, lung, cervical, and prostate cancers.<ref name=lpi/><ref>{{cite journal|vauthors=Jägerstad M|title=Folic acid fortification prevents neural tube defects and may also reduce cancer risks|journal=Acta Paediatrica|volume=101|issue=10|pages=1007–12|date=October 2012|pmid=22783992|doi=10.1111/j.1651-2227.2012.02781.x|s2cid=3458384|doi-access=free}}</ref><ref name="cebp.aacrjournals">{{cite journal|vauthors=Weinstein SJ, Hartman TJ, Stolzenberg-Solomon R, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D|title=Null association between prostate cancer and serum folate, vitamin B(6), vitamin B(12), and homocysteine|journal=Cancer Epidemiology, Biomarkers & Prevention|volume=12|issue=11 Pt 1|pages=1271–2|date=November 2003|pmid=14652294|url=http://cebp.aacrjournals.org/content/12/11/1271.long|url-status=live|archive-url=https://web.archive.org/web/20170222201134/http://cebp.aacrjournals.org/content/12/11/1271.long|archive-date=22 February 2017}}</ref>

Early after fortification programs were implemented, high intakes were theorized to accelerate the growth of preneoplastic lesions that could lead to cancer, specifically colon cancer.<ref name=Chustecka2009>{{cite web|url=http://www.medscape.com/viewarticle/591111|vauthors=Chustecka Z|title=Folic-acid fortification of flour and increased rates of colon cancer|year=2009|website=Medscape|access-date=9 November 2009|archive-date=25 November 2010|archive-url=https://web.archive.org/web/20101125195847/http://www.medscape.com/viewarticle/591111|url-status=live}}</ref><ref name=Mason2007/> Subsequent meta-analyses of the effects of low versus high dietary folate, elevated serum folate, and supplemental folate in the form of folic acid have reported at times conflicting results. Comparing low to high dietary folate showed a modest but [[statistical significance|statistically significant]] reduced risk of colon cancer.<ref>{{cite journal |vauthors=Kim DH, Smith-Warner SA, Spiegelman D, Yaun SS, Colditz GA, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Harnack L, Jacobs EJ, Leitzmann M, Mannisto S, Miller AB, Potter JD, Rohan TE, Schatzkin A, Speizer FE, Stevens VL, Stolzenberg-Solomon R, Terry P, Toniolo P, Weijenberg MP, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter DJ |title=Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer |journal=Cancer Causes Control |volume=21 |issue=11 |pages=1919–30 |date=November 2010 |pmid=20820900 |pmc=3082430 |doi=10.1007/s10552-010-9620-8}}</ref> For prostate cancer risk, comparing low to high dietary folate showed no effect.<ref name=Wang2014>{{cite journal|vauthors=Wang R, Zheng Y, Huang JY, Zhang AQ, Zhou YH, Wang JN|title=Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies|journal=BMC Public Health|volume=14|issue=1|page=1326|date=December 2014|pmid=25543518|pmc=4320532|doi=10.1186/1471-2458-14-1326 |doi-access=free }}</ref><ref name=Tio2014>{{cite journal |vauthors=Tio M, Andrici J, Cox MR, Eslick GD |s2cid=27184844 |title=Folate intake and the risk of prostate cancer: a systematic review and meta-analysis |journal=Prostate Cancer Prostatic Dis. |volume=17 |issue=3 |pages=213–9 |date=September 2014 |pmid=24819234 |doi=10.1038/pcan.2014.16 |doi-access=free }}</ref> A review of trials that involved folic acid dietary supplements reported a statistically significant 24% increase in prostate cancer risk.<ref name=Wien2012>{{cite journal|vauthors=Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M|title=Cancer risk with folic acid supplements: a systematic review and meta-analysis|journal=BMJ Open|volume=2|issue=1|pages=e000653|date=January 2012|pmid=22240654|pmc=3278486|doi=10.1136/bmjopen-2011-000653}}</ref> It was shown that supplementation with folic acid at 1,000 to 2,500&nbsp;μg/day – the amounts used in many of the cited supplement trials<ref name=Wien2012/><ref name="Qin2013">{{cite journal |vauthors=Qin X, Cui Y, Shen L, Sun N, Zhang Y, Li J, Xu X, Wang B, Xu X, Huo Y, Wang X |date=September 2013 |title=Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials |journal=Int. J. Cancer |volume=133 |issue=5 |pages=1033–41 |doi=10.1002/ijc.28038 |pmid=23338728 |s2cid=19830376|doi-access=free }}</ref> – would result in higher concentrations of serum folate than what is achieved from diets high in food-derived folate. The second supplementation review reported no significant increase or decrease in total cancer incidence, colorectal cancer, other gastrointestinal cancer, genitourinary cancer, lung cancer or hematological malignancies in people who were consuming folic acid supplements.<ref name=Qin2013/> A third supplementation meta-analysis limited to reporting only on colorectal cancer incidence showed that folic acid treatment was not associated with colorectal cancer risk.<ref>{{cite journal |vauthors=Qin T, Du M, Du H, Shu Y, Wang M, Zhu L |title=Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials |journal=Sci Rep |volume=5 |page=12044 |date=July 2015 |pmid=26131763 |pmc=4487230 |doi=10.1038/srep12044 |bibcode=2015NatSR...512044Q }}</ref>

====Anti-folate chemotherapy====
Folate is important for cells and tissues that divide rapidly.<ref name="Oldref_2">{{cite journal | vauthors = Kamen B | title = Folate and antifolate pharmacology | journal = Seminars in Oncology | volume = 24 | issue = 5 Suppl 18 | pages = S18-30-S18-39 | date = October 1997 | pmid = 9420019 }}</ref> Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate drug [[methotrexate]] is often used to treat cancer because it inhibits the production of the active tetrahydrofolate (THF) from the inactive dihydrofolate (DHF).<ref name="Gonen_2012">{{cite journal | vauthors = Gonen N, Assaraf YG | title = Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance | journal = Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy | volume = 15 | issue = 4 | pages = 183–210 | date = August 2012 | pmid = 22921318 | doi = 10.1016/j.drup.2012.07.002 }}</ref> However, methotrexate can be toxic,<ref>{{cite journal | vauthors = Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS | title = Effect of glutamine on methotrexate efficacy and toxicity | journal = Annals of Surgery | volume = 227 | issue = 5 | pages = 772–8; discussion 778–80 | date = May 1998 | pmid = 9605669 | pmc = 1191365 | doi = 10.1097/00000658-199805000-00018 }}</ref><ref>{{cite journal | vauthors = Wolff JE, Hauch H, Kühl J, Egeler RM, Jürgens H | title = Dexamethasone increases hepatotoxicity of MTX in children with brain tumors | journal = Anticancer Research | volume = 18 | issue = 4B | pages = 2895–9 | year = 1998 | pmid = 9713483 }}</ref><ref>{{cite journal | vauthors = Kepka L, De Lassence A, Ribrag V, Gachot B, Blot F, Theodore C, Bonnay M, Korenbaum C, Nitenberg G | title = Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure | journal = Leukemia & Lymphoma | volume = 29 | issue = 1–2 | pages = 205–9 | date = March 1998 | pmid = 9638991 | doi = 10.3109/10428199809058397 }}</ref> producing side effects such as inflammation in the digestive tract that make eating normally more difficult. Bone marrow depression (inducing leukopenia and thrombocytopenia) and acute kidney and liver failure have been reported.

[[Folinic acid]], under the drug name [[leucovorin]], a form of folate (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate.<ref>{{cite journal | vauthors = Branda RF, Nigels E, Lafayette AR, Hacker M | title = Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats | journal = Blood | volume = 92 | issue = 7 | pages = 2471–6 | date = October 1998 | pmid = 9746787 | doi = 10.1182/blood.V92.7.2471 | doi-access = free }}</ref> Folic acid supplements have little established role in cancer chemotherapy.<ref>{{cite journal | vauthors = Shiroky JB | title = The use of folates concomitantly with low-dose pulse methotrexate | journal = Rheumatic Disease Clinics of North America | volume = 23 | issue = 4 | pages = 969–80 | date = November 1997 | pmid = 9361164 | doi = 10.1016/S0889-857X(05)70369-0 }}</ref><ref>{{cite journal | vauthors = Keshava C, Keshava N, Whong WZ, Nath J, Ong TM | title = Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells | journal = Mutation Research | volume = 397 | issue = 2 | pages = 221–8 | date = February 1998 | pmid = 9541646 | doi = 10.1016/S0027-5107(97)00216-9 | bibcode = 1998MRFMM.397..221K }}</ref> The supplement of folinic acid in people undergoing methotrexate treatment is to give less rapidly dividing cells enough folate to maintain normal cell functions. The amount of folate given is quickly depleted by rapidly dividing (cancer) cells, so this does not negate the effects of methotrexate.

===Neurological disorders===
Conversion of homocysteine to methionine requires folate and vitamin B<sub>12</sub>. Elevated plasma homocysteine and low folate are associated with cognitive impairment, dementia and [[Alzheimer's disease]].<ref>{{cite journal |vauthors=Shen L, Ji HF |title=Associations between Homocysteine, Folic Acid, Vitamin B12 and Alzheimer's Disease: Insights from Meta-Analyses |journal=J. Alzheimers Dis. |volume=46 |issue=3 |pages=777–90 |date=2015 |pmid=25854931 |doi=10.3233/JAD-150140}}</ref><ref name=Ford2012/> Supplementing the diet with folic acid and vitamin B<sub>12</sub> lowers plasma homocysteine.<ref name=Ford2012/> However, several reviews reported that supplementation with folic acid alone or in combination with other B vitamins did not prevent development of cognitive impairment nor slow cognitive decline.<ref name=Li2014>{{cite journal |vauthors=Li MM, Yu JT, Wang HF, Jiang T, Wang J, Meng XF, Tan CC, Wang C, Tan L |title=Efficacy of vitamins B supplementation on mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis |journal=Curr Alzheimer Res |volume=11 |issue=9 |pages=844–52 |date=2014 |pmid=25274113 }}</ref><ref name=Ford2012>{{cite journal |vauthors=Ford AH, Almeida OP |title=Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials |journal=J. Alzheimers Dis. |volume=29 |issue=1 |pages=133–49 |date=2012 |pmid=22232016 |doi=10.3233/JAD-2012-111739}}</ref><ref>{{cite journal |vauthors=Wald DS, Kasturiratne A, Simmonds M |title=Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials |journal=Am. J. Med. |volume=123 |issue=6 |pages=522–527.e2 |date=June 2010 |pmid=20569758 |doi=10.1016/j.amjmed.2010.01.017}}</ref>

Relative risk of [[autism spectrum disorder]]s (ASDs) was reported reduced by 23% when the maternal diet was supplemented with folic acid during pregnancy. Subset analysis confirmed this among Asian, European and American populations.<ref>{{cite journal |vauthors=Wang M, Li K, Zhao D, Li L |title=The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis |journal=Mol Autism |volume=8 |page=51 |date=2017 |pmid=29026508 |pmc=5625821 |doi=10.1186/s13229-017-0170-8 |doi-access=free }}</ref> Cerebral folate deficiency (CFD) has been associated with ASDs. The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate into the brain. One cause of CFD is autoantibodies that interfere with FRa, and FRa autoantibodies have been reported in ASDs. For individuals with ASD and CFD, meta-analysis reported improvements with treatment with [[folinic acid]], a 5-formyl derivative of [[tetrahydrofolic acid]], for core and associated ASD symptoms.<ref name="Rossignol2021">{{cite journal |vauthors=Rossignol DA, Frye RE |title=Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: A systematic review and meta-analysis |journal=J Pers Med |volume=11 |issue=11 |date=November 2021 |page=1141 |pmid=34834493 |pmc=8622150 |doi=10.3390/jpm11111141 |doi-access=free |url=}}</ref>

Some evidence links a shortage of folate with [[clinical depression]].<ref name="dep_coppen">{{cite journal|vauthors=Coppen A, Bolander-Gouaille C|s2cid=4828454|title=Treatment of depression: time to consider folic acid and vitamin B12|journal=Journal of Psychopharmacology|volume=19|issue=1|pages=59–65|date=January 2005|pmid=15671130|doi=10.1177/0269881105048899}}</ref>  An 2024 umbrella meta-analysis concluded that folate supplementation alleviates depression symptoms, while folate deficiency is associated with an increased risk of depression, suggesting folate as a beneficial [[Combination therapy|adjunctive]] treatment in managing depression.<ref>{{cite journal | vauthors = Gao S, Khalid A, Amini-Salehi E, Radkhah N, Jamilian P, Badpeyma M, Zarezadeh M | title = Folate supplementation as a beneficial add-on treatment in relieving depressive symptoms: A meta-analysis of meta-analyses | journal = Food Science & Nutrition | volume = 12 | issue = 6 | pages = 3806–3818 | date = June 2024 | pmid = 38873435 | pmc = 11167194 | doi = 10.1002/fsn3.4073 }}</ref> Other research also found a link between depression and low levels of folate.<ref>{{cite journal|vauthors=Gilbody S, Lewis S, Lightfoot T|title=Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review|journal=American Journal of Epidemiology|volume=165|issue=1|pages=1–13|date=January 2007|pmid=17074966|doi=10.1093/aje/kwj347|doi-access=free}}</ref><ref>{{cite journal|vauthors=Gilbody S, Lightfoot T, Sheldon T|title=Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity|journal=Journal of Epidemiology and Community Health|volume=61|issue=7|pages=631–7|date=July 2007|pmid=17568057|pmc=2465760|doi=10.1136/jech.2006.050385}}</ref> The exact mechanisms involved in the development of schizophrenia and depression are not entirely clear, but the bioactive folate, [[Levomefolic acid|methyltetrahydrofolate]] (5-MTHF), a direct target of methyl donors such as [[S-adenosyl methionine]] (SAMe), recycles the inactive [[dihydrobiopterin]] (BH<sub>2</sub>) into [[tetrahydrobiopterin]] (BH<sub>4</sub>), the necessary [[Cofactor (biochemistry)|cofactor]] in various steps of monoamine synthesis, including that of [[dopamine]] and [[serotonin]]. BH<sub>4</sub> serves a regulatory role in monoamine neurotransmission and is required to mediate the actions of most antidepressants.<ref>{{cite journal|vauthors=Krebs MO, Bellon A, Mainguy G, Jay TM, Frieling H|title=One-carbon metabolism and schizophrenia: current challenges and future directions|journal=Trends in Molecular Medicine|volume=15|issue=12|pages=562–70|date=December 2009|pmid=19896901|doi=10.1016/j.molmed.2009.10.001}}</ref>

===Folic acid, B<sub>12</sub> and iron===
A complex interaction occurs between folic acid, [[Vitamin B12|vitamin B<sub>12</sub>]], and [[Human iron metabolism|iron]]. A deficiency of folic acid or vitamin B<sub>12</sub> may mask the deficiency of iron; so when taken as dietary supplements, the three need to be in balance.<ref>{{cite journal|vauthors=Vreugdenhil G, Wognum AW, van Eijk HG, Swaak AJ|title=Anaemia in rheumatoid arthritis: the role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness|journal=Annals of the Rheumatic Diseases|volume=49|issue=2|pages=93–8|date=February 1990|pmid=2317122|pmc=1003985|doi=10.1136/ard.49.2.93}}</ref><ref>{{cite journal|vauthors=Allen RH, Stabler SP, Savage DG, Lindenbaum J|date=June 1990|title=Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations|journal=American Journal of Hematology|volume=34|issue=2|pages=90–8|doi=10.1002/ajh.2830340204|pmid=2339683|s2cid=23092095}}</ref><ref>{{cite journal|vauthors=Reynolds E|s2cid=2165819|title=Vitamin B12, folic acid, and the nervous system|journal=The Lancet. Neurology|volume=5|issue=11|pages=949–60|date=November 2006|pmid=17052662|doi=10.1016/S1474-4422(06)70598-1}}</ref>

===Malaria===
Some studies show iron–folic acid supplementation in children under five may result in increased mortality due to [[malaria]]; this has prompted the World Health Organization to alter their iron–folic acid supplementation policies for children in malaria-prone areas, such as India.<ref>{{cite journal|vauthors=Pasricha S, Shet A, Sachdev HP, Shet AS|title=Risks of routine iron and folic acid supplementation for young children|journal=Indian Pediatrics|volume=46|issue=10|pages=857–66|date=October 2009|pmid=19887691|url=http://www.indianpediatrics.net/oct2009/857.pdf|archive-url=https://web.archive.org/web/20100612030831/http://indianpediatrics.net/oct2009/857.pdf|url-status=live|archive-date=12 June 2010}}</ref>

== Absorption, metabolism and excretion ==
Folate in food is roughly one-third in the form of monoglutamate and two-thirds polyglutamate; the latter is hydrolyzed to monoglutamate via a reaction mediated by [[folate conjugase]] at the brush border of enterocytes in the proximal small intestine.<ref name="Alpers2016">{{cite journal |vauthors=Alpers DH |title=Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations |journal=Biochimie |volume=126 |issue= |pages=52–6 |date=July 2016 |pmid=26586110 |pmc=4867132 |doi=10.1016/j.biochi.2015.11.006 |url=}}</ref> Subsequently, intestinal absorption is primarily accomplished by the action of the [[proton-coupled folate transporter]] (PCFT) protein coded for by the ''SLC46A1'' gene. This functions best at [[pH]] 5.5, which corresponds to the acidic status of the proximal small intestine. PCFT binds to both reduced folates and folic acid. A secondary folate transporter is the [[reduced folate carrier]] (RFC), coded for by the ''SLC19A1'' gene. It operates optimally at pH 7.4 in the [[ileum]] portion of the small intestine. It has a low affinity for folic acid. Production of the receptor proteins is increased in times of folate deficiency.<ref name="Said2011"/> In addition to a role in intestinal absorption, RFC is expressed in virtually all tissues and is the major route of delivery of folate to cells within the systemic circulation under physiological conditions. When pharmacological amounts of folate are taken as a dietary supplement, absorption also takes place by a passive diffusion-like process.<ref name=PKIN2020Folate /><ref name="Visentin2014">{{cite journal |vauthors=Visentin M, Diop-Bove N, Zhao R, Goldman ID |title=The intestinal absorption of folates |journal=Annu Rev Physiol |volume=76 |issue= |pages=251–74 |date=2014 |pmid=24512081 |pmc=3982215 |doi=10.1146/annurev-physiol-020911-153251 |url=}}</ref> In addition, bacteria in the distal portion of the small intestine and in the large intestine synthesize modest amounts of folate, and there are RFC receptors in the large intestine, so this in situ source may contribute to toward the cellular nutrition and health of the local colonocytes.<ref name="Said2011">{{cite journal |vauthors=Said HM |title=Intestinal absorption of water-soluble vitamins in health and disease |journal=Biochem J |volume=437 |issue=3 |pages=357–72 |date=August 2011 |pmid=21749321 |pmc=4049159 |doi=10.1042/BJ20110326 |url=}}</ref><ref name="Visentin2014"/>

The biological activity of folate in the body depends upon [[dihydrofolate reductase]] action in the liver which converts folate into [[tetrahydrofolate]] (THF). This action is rate-limiting in humans leading to elevated blood concentrations of unmetabolized folic acid when consumption from dietary supplements and fortified foods nears or exceeds the U.S. [[Dietary Reference Intake#Parameters|Tolerable Upper Intake Level]] of 1,000&nbsp;μg per day.<ref name=PKIN2020Folate /><ref name = "Bailey">{{cite journal | vauthors = Bailey SW, Ayling JE | title = The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 36 | pages = 15424–9 | date = September 2009 | pmid = 19706381 | pmc = 2730961 | doi = 10.1073/pnas.0902072106 | bibcode = 2009PNAS..10615424B| doi-access = free }}</ref>

The total human body content of folate is estimated to be approximately 15–30 milligrams, with approximately half in the liver.<ref name=PKIN2020Folate /> Excretion is via urine and feces. Under normal dietary intake, urinary excretion is mainly as folate cleavage products, but if a dietary supplement is being consumed then there will be intact folate in the urine. The liver produces folate-containing bile, which if not all absorbed in the small intestine, contributes to fecal folate, intact and as cleavage products, which under normal dietary intake has been estimated to be similar in amount to urinary excretion. Fecal content includes what is synthesized by intestinal microflora.<ref name=PKIN2020Folate />

=== Biosynthesis ===
Animals, including humans, cannot synthesize (produce) folate and therefore must obtain folate from their diet. All plants and fungi and certain protozoa, bacteria, and [[archaea]] can synthesize folate [[de novo synthesis|de novo]] through variations on the same [[biosynthesis|biosynthetic]] pathway.<ref name="Rossi_2011">{{cite journal | vauthors = Rossi M, Amaretti A, Raimondi S | title = Folate production by probiotic bacteria | journal = Nutrients | volume = 3 | issue = 1 | pages = 118–34 | date = January 2011 | pmid = 22254078 | pmc = 3257725 | doi = 10.3390/nu3010118 | doi-access = free }}</ref> The folate molecule is synthesized from pterin pyrophosphate, [[para-aminobenzoic acid|''para''-aminobenzoic acid]] (PABA), and [[glutamate]] through the action of [[dihydropteroate synthase]] and [[dihydrofolate synthase]]. Pterin is in turn derived in a series of enzymatically catalyzed steps from [[guanosine triphosphate]] (GTP), while PABA is a product of the [[shikimate pathway]].<ref name="Rossi_2011" />

=== Bioactivation ===
[[File:Folic Acid Biotransformations.svg|thumb|400px|class=skin-invert-image|Biotransformation of folic acid into [[folinic acid]]s where R = ''para''-aminobenzoate-glutamate<ref name = "Carmen_2008" />]]

All of the biological functions of folic acid are performed by [[tetrahydrofolate|THF]] and its [[methylated]] derivatives. Hence folic acid must first be [[redox|reduced]] to THF. This four electron reduction proceeds in two chemical steps both catalyzed by the same enzyme, [[dihydrofolate reductase]].<ref name = "Carmen_2008">{{cite book | vauthors = Carmen AJ, Carlos M | title = Medicinal Chemistry of Anticancer Drugs | date = 2008 | chapter = Chapter 2 – Antimetabolites | pages = 9–52 | isbn = 978-0-444-52824-7 | doi = 10.1016/B978-0-444-52824-7.00002-0 | quote = Figure 2.27: Biotransformation of folic acid into folinic acids }}</ref> Folic acid is first reduced to [[dihydrofolate]] and then to tetrahydrofolate. Each step consumes one molecule of [[NADPH]] ([[biosynthesis|biosynthetically]] derived from [[Niacin (nutrient)|vitamin B<sub>3</sub>]]) and produces one molecule of [[NADP]].<ref name=PKIN2020Folate /><ref>{{cite web | url = http://us.expasy.org/enzyme/1.5.1.3 | title = EC 1.5.1.3 | publisher = Us.expasy.org | access-date = 9 September 2012 | url-status = live | archive-url = https://web.archive.org/web/20110613191819/http://us.expasy.org/enzyme/1.5.1.3 | archive-date = 13 June 2011}}</ref> Mechanistically, hydride is transferred from NADPH to the C6 position of the pteridine ring.<ref>{{cite journal | vauthors = Benkovic SJ, Hammes-Schiffer S | s2cid = 7899320 | title = A perspective on enzyme catalysis | journal = Science | volume = 301 | issue = 5637 | pages = 1196–202 | date = August 2003 | pmid = 12947189 | doi = 10.1126/science.1085515 | bibcode = 2003Sci...301.1196B}}</ref>

A one-carbon (1C) methyl group is added to tetrahydrofolate through the action of [[serine hydroxymethyltransferase]] (SHMT) to yield [[5,10-methylenetetrahydrofolate]] (5,10-CH<sub>2</sub>-THF). This reaction also consumes [[serine]] and [[pyridoxal phosphate]] (PLP; vitamin B<sub>6</sub>) and produces [[glycine]] and [[pyridoxal]].<ref name = "Carmen_2008" /> A second enzyme, [[methylenetetrahydrofolate dehydrogenase (NADP+)|methylenetetrahydrofolate dehydrogenase]] ([[MTHFD2]])<ref name="Christensen_2008">{{cite journal | vauthors = Christensen KE, Mackenzie RE | title = Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases | journal = Vitamins and Hormones | volume = 79 | pages = 393–410 | date = 2008 | pmid = 18804703 | doi = 10.1016/S0083-6729(08)00414-7 }}</ref> oxidizes 5,10-methylenetetrahydrofolate to an [[iminium]] cation which in turn is [[hydrolyzed]] to produce [[5-formyltetrahydrofolate|5-formyl-THF]] and [[10-formyltetrahydrofolate|10-formyl-THF]].<ref name = "Carmen_2008" /> This series of reactions using the [[alpha and beta carbon|β-carbon]] atom of serine as the carbon source provide the largest part of the one-carbon units available to the cell.<ref name = Stover1990>{{cite journal | vauthors = Stover P, Schirch V | title = Serine hydroxymethyltransferase catalyzes the hydrolysis of 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate | journal = The Journal of Biological Chemistry | volume = 265 | issue = 24 | pages = 14227–33 | date = August 1990 | doi = 10.1016/S0021-9258(18)77290-6 | pmid = 2201683 | doi-access = free }}</ref>

Alternative carbon sources include [[formate]] which by the catalytic action of [[formate–tetrahydrofolate ligase]] adds a 1C unit to THF to yield 10-formyl-THF. Glycine, [[histidine]], and [[sarcosine]] can also directly contribute to the THF-bound 1C pool.<ref name="Ducker_2017">{{cite journal | vauthors = Ducker GS, Rabinowitz JD | title = One-Carbon Metabolism in Health and Disease | journal = Cell Metabolism | volume = 25 | issue = 1 | pages = 27–42 | date = January 2017 | pmid = 27641100 | pmc = 5353360 | doi = 10.1016/j.cmet.2016.08.009 }}</ref>

== Drug interference ==
A number of drugs interfere with the biosynthesis of THF from folic acid. Among them are the [[antifolate]] [[:Category:Dihydrofolate reductase inhibitors|dihydrofolate reductase inhibitors]] such as the antimicrobial, [[trimethoprim]], the antiprotozoal, [[pyrimethamine]] and the chemotherapy drug [[methotrexate]],<ref name=Rajagopalan2002>{{cite journal | vauthors = Rajagopalan PT, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG | title = Interaction of dihydrofolate reductase with methotrexate: Ensemble and single-molecule kinetics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 21 | pages = 13481–6 | date = October 2002 | pmid = 12359872 | pmc = 129699 | doi = 10.1073/pnas.172501499 | bibcode = 2002PNAS...9913481R | doi-access = free }}</ref><ref name=McGuire2003>{{cite journal | vauthors = McGuire JJ | title = Anticancer antifolates: current status and future directions | journal = Current Pharmaceutical Design | volume = 9 | issue = 31 | pages = 2593–613 | year = 2003 | pmid = 14529544 | doi = 10.2174/1381612033453712 }}</ref> and the [[Sulfonamide (medicine)|sulfonamides]] (competitive inhibitors of PABA in the reactions of [[dihydropteroate synthetase]]).<ref>{{Cite web | vauthors = Boothe DM | title = Sulfonamides and Sulfonamide Combinations | work = Merck Veterinary Manual | publisher = Merck & Co., Inc. | location = Kenilworth, NJ | access-date = 10 October 2019 | url = http://www.merckvetmanual.com/pharmacology/antibacterial-agents/sulfonamides-and-sulfonamide-combinations | archive-date = 7 August 2020 | archive-url = https://web.archive.org/web/20200807020526/https://www.merckvetmanual.com/pharmacology/antibacterial-agents/sulfonamides-and-sulfonamide-combinations | url-status = live }}</ref>

[[Valproic acid]], one of the most commonly prescribed epilepsy treatment drugs, also used to treat certain psychological conditions such as bipolar disorder, is a known inhibitor of folic acid, and as such, has been shown to cause birth defects, including neural tube defects, plus increased risk for children having cognitive impairment and autism. There is evidence that folate consumption is protective.<ref>{{cite journal |vauthors=Verrotti A, Tana M, Pelliccia P, Chiarelli F, Latini G |title=Recent advances on neural tube defects with special reference to Valproic Acid |journal=Endocr Metab Immune Disord Drug Targets |volume=6 |issue=1 |pages=25–31 |date=March 2006 |pmid=16611162|doi=10.2174/187153006776056657 }}</ref><ref>{{cite journal |vauthors=Tanoshima M, Kobayashi T, Tanoshima R, Beyene J, Koren G, Ito S |title=Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis |journal=Clin. Pharmacol. Ther. |volume=98 |issue=4 |pages=417–41 |date=October 2015 |pmid=26044279 |doi=10.1002/cpt.158|s2cid=205715968 }}</ref><ref>{{cite journal |vauthors=Veroniki AA, Rios P, Cogo E, Straus SE, Finkelstein Y, Kealey R, Reynen E, Soobiah C, Thavorn K, Hutton B, Hemmelgarn BR, Yazdi F, D'Souza J, MacDonald H, Tricco AC |title=Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis |journal=BMJ Open |volume=7 |issue=7 |pages=e017248 |date=July 2017 |pmid=28729328 |pmc=5642793 |doi=10.1136/bmjopen-2017-017248}}</ref>

Folate deficiency is common in alcoholics, attributed to both inadequate diet and an inhibition in intestinal processing of the vitamin. Chronic alcohol use inhibits both the digestion process of dietary folate polyglutamates and the uptake phase of liberated folate monoglutamates. The latter is associated with a significant reduction in the level of
expression of RFC.<ref name="Said2011"/>

== Function ==
Tetrahydrofolate's main function in metabolism is transporting single-carbon groups (i.e., a [[methyl group]], [[methylene group]], or [[formyl group]]). These carbon groups can be transferred to other molecules as part of the modification or biosynthesis of a variety of biological molecules. Folates are essential for the synthesis of [[DNA]], the modification of DNA and [[RNA]], the synthesis of [[methionine]] from [[homocysteine]], and various other chemical reactions involved in cellular metabolism.<ref name=Naderi>{{cite journal|journal=Advances in Food and Nutrition Research |volume=83 |date=2018 |pages=195–213 |title=Chapter Five – Recent Developments in Folate Nutrition |vauthors=Naderi N, House JD |doi=10.1016/bs.afnr.2017.12.006 |pmid=29477222 |publisher=Elsevier}}</ref> These reactions are collectively known as folate-mediated one-carbon metabolism.<ref name=PKIN2020Folate /><ref name = Lan2018>{{cite journal | vauthors = Lan X, Field MS, Stover PJ | title = Cell cycle regulation of folate-mediated one-carbon metabolism | journal = Wiley Interdiscip Rev Syst Biol Med | volume = 10 | issue = 6 | pages = e1426 | date = November 2018 | pmid = 29889360 | doi = 10.1002/wsbm.1426 | s2cid = 47014043 | pmc = 11875019 }}</ref>

=== DNA synthesis ===
{{main|Purine metabolism|Pyrimidine metabolism}}
Folate derivatives participate in the biosynthesis of both purines and pyrimidines.

Formyl folate is required for two of the steps in the biosynthesis of [[inosine monophosphate]], the precursor to GMP and AMP. Methylenetetrahydrofolate donates the C1 center required for the biosynthesis of [[dTMP]] (2{{prime}}-deoxythymidine-5{{prime}}-phosphate) from [[dUMP]] (2{{prime}}-deoxyuridine-5{{prime}}-phosphate). The conversion is catalyzed by [[thymidylate synthase]].<ref name=PKIN2020Folate />

=== Vitamin B<sub>12</sub> activation ===
[[File:Folate methionine cycle.svg|thumb|class=skin-invert-image|Simplified schematic diagram of the folate methionine cycle<ref name="Froese_2019">{{cite journal | vauthors = Froese DS, Fowler B, Baumgartner MR | title = Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation | journal = Journal of Inherited Metabolic Disease | volume = 42 | issue = 4 | pages = 673–685 | date = July 2019 | pmid = 30693532 | doi = 10.1002/jimd.12009 | doi-access = free }}</ref>|360px]]
Methyl-THF converts vitamin B<sub>12</sub> to methyl-B<sub>12</sub> ([[methylcobalamin]]). Methyl-B<sub>12</sub> converts homocysteine, in a reaction catalyzed by [[homocysteine methyltransferase]], to [[methionine]]. A defect in homocysteine methyltransferase or a deficiency of B<sub>12</sub> may lead to a so-called "methyl-trap" of THF, in which THF converts to methyl-THF, causing a deficiency in folate.<ref name = Hoffbrand2001/> Thus, a deficiency in B<sub>12</sub> can cause accumulation of methyl-THF, mimicking folate deficiency.

==Dietary recommendations==
Because of the difference in bioavailability between supplemented folic acid and the different forms of folate found in food, the dietary folate equivalent (DFE) system was established. One DFE is defined as 1&nbsp;μg of dietary folate. 1&nbsp;μg of folic acid supplement counts as 1.7&nbsp;μg DFE. The reason for the difference is that when folic acid is added to food or taken as a dietary supplement with food it is at least 85% absorbed, whereas only about 50% of folate naturally present in food is absorbed.<ref name=NIH/>

{| class="wikitable"
|+[[National Institutes of Health]] (U.S.) nutritional recommendations<ref name=NIH>{{cite web|publisher=Office of Dietary Supplements, US [[National Institutes of Health]]|title=Folate – Fact Sheet for Health Professionals|url=http://ods.od.nih.gov/factsheets/folate/|date=29 March 2021|access-date=29 April 2022|archive-date=2 April 2011|archive-url=https://web.archive.org/web/20110402200837/http://ods.od.nih.gov/factsheets/Folate/|url-status=live}}</ref><br />μg DFE per day for RDA, μg folic acid for [[Tolerable upper intake levels]] (UL)
|-
!  rowspan="2"|Age
!colspan="2"|Infants
! colspan="2"|Children and adults
! colspan="2"|Pregnant women
! colspan="2"|Lactating women
|-
! (AI)
! (UL)
! (RDA)
! (UL)
! (RDA)
! (UL)
! (RDA)
! (UL)
|-
| 0–6 months
| 65
| None set
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
|-
| 7–12 months
| 80
| None set
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
|-
| 1–3 years
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" |150
| style ="text-align: center;" |300
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
|-
| 4–8 years
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" |200
| style ="text-align: center;" |400
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" |&nbsp;–
|-
| 9–13 years
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" |300
| style ="text-align: center;" |600
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" | –
|-
| 14–18
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" |400
| style ="text-align: center;" |800
| style ="text-align: center;" |600
| style ="text-align: center;" |800
| style ="text-align: center;" |500
| style ="text-align: center;" |800
|-
| 19+
| style ="text-align: center;" | –
| style ="text-align: center;" | –
| style ="text-align: center;" |400
| style ="text-align: center;" |1000
| style ="text-align: center;" |600
| style ="text-align: center;" |1000
| style ="text-align: center;" |500
| style ="text-align: center;" |1000
|}

The U.S. Institute of Medicine defines Estimated Average Requirements (EARs), Recommended Dietary Allowances (RDAs), Adequate Intakes (AIs), and Tolerable upper intake levels (ULs) – collectively referred to as [[Dietary Reference Intake]]s (DRIs).<ref name=NIH/><ref name="DRItext">{{cite book|author=Institute of Medicine|title=Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline|chapter=Folate|publisher=The National Academies Press|year=1998|location=Washington, DC|pages=196–305|chapter-url=https://www.nap.edu/read/6015/chapter/10|access-date=25 September 2019|isbn=978-0-309-06554-2|author-link=Institute of Medicine|archive-date=25 September 2019|archive-url=https://web.archive.org/web/20190925102802/https://www.nap.edu/read/6015/chapter/10|url-status=live}}</ref> The [[European Food Safety Authority]] (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For women and men over age 18, the PRI is set at 330&nbsp;μg/day. PRI for pregnancy is 600&nbsp;μg/day, for lactation 500&nbsp;μg/day. For children ages 1–17 years, the PRIs increase with age from 120 to 270&nbsp;μg/day. These values differ somewhat from the U.S. RDAs.<ref>{{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|url-status=live|archive-url=https://web.archive.org/web/20170828082247/https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf|archive-date=28 August 2017}}</ref> The United Kingdom's Dietary Reference Value for folate, set by the Committee on Medical Aspects of Food and Nutrition Policy in 1991, is 200&nbsp;μg/day for adults.<ref>{{cite web|title=Nutrition Requirements|url=https://www.nutrition.org.uk/attachments/article/234/Nutrition%20Requirements_Revised%20Oct%202016.pdf|publisher=British Nutrition Foundation|access-date=8 July 2018|archive-date=11 February 2019|archive-url=https://web.archive.org/web/20190211104805/https://www.nutrition.org.uk/attachments/article/234/Nutrition%20Requirements_Revised%20Oct%202016.pdf}}</ref>

===Safety===
The risk of toxicity from folic acid is low because folate is a water-soluble vitamin and is regularly removed from the body through urine. One potential issue associated with high doses of folic acid is that it has a masking effect on the diagnosis of [[pernicious anaemia]] due to vitamin B<sub>12</sub> deficiency, and may even precipitate or exacerbate neuropathy in vitamin B12-deficient individuals. This evidence justified development of a UL for folate.<ref name="DRItext" /> In general, ULs are set for vitamins and minerals when evidence is sufficient. The adult UL of 1,000&nbsp;μg for folate (and lower for children) refers specifically to folic acid used as a supplement, as no health risks have been associated with high intake of folate from food sources. The EFSA reviewed the safety question and agreed with United States that the UL be set at 1,000&nbsp;μg.<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=16 May 2016|archive-date=19 September 2017|archive-url=https://web.archive.org/web/20170919040144/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf|url-status=live}}</ref> The Japan National Institute of Health and Nutrition set the adult UL at 1,300 or 1,400&nbsp;μg depending on age.<ref name=JapanDRI>{{cite journal |vauthors=Shibata K, Fukuwatari T, Imai E, Hayakawa T, Watanabe F, Takimoto H, Watanabe T, Umegaki K |title=Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins |journal=Journal of Nutritional Science and Vitaminology |volume=2013 |issue=59 |pages=S67–S82 |year=2013 |url=https://www.jstage.jst.go.jp/article/jnsv/59/Supplement/59_S67/_pdf |doi=10.3177/jnsv.59.S67 |doi-access=free |access-date=27 September 2018 |archive-date=14 September 2019 |archive-url=https://web.archive.org/web/20190914033244/https://www.jstage.jst.go.jp/article/jnsv/59/Supplement/59_S67/_pdf |url-status=live }}</ref>

Reviews of clinical trials that called for long-term consumption of folic acid in amounts exceeding the UL have raised concerns. Excessive amounts derived from supplements are more of a concern than that derived from natural food sources and the relative proportion to vitamin B<sub>12</sub> may be a significant factor in adverse effects.<ref>{{cite web | title=Folic Acid Overload? | website=Tufts Health & Nutrition Letter | date=10 September 2019 | url=https://www.nutritionletter.tufts.edu/vitamins-supplements/folic-acid-overload/ | access-date=18 October 2021}}</ref> One theory is that consumption of large amounts of folic acid leads to detectable amounts of unmetabolized folic acid circulating in blood because the enzyme [[dihydrofolate reductase]] that converts folic acid to the biologically active forms is rate limiting. Evidence of a negative health effect of folic acid in blood is not consistent, and folic acid has no known cofactor function that would increase the likelihood of a causal role for free folic acid in disease development.<ref name=Obeid2012>{{cite journal | vauthors = Obeid R, Herrmann W | title = The emerging role of unmetabolized folic acid in human diseases: myth or reality? | journal = Current Drug Metabolism | volume = 13 | issue = 8 | pages = 1184–95 | date = October 2012 | pmid = 22746304 | doi = 10.2174/138920012802850137 }}</ref> However, low vitamin B<sub>12</sub> status in combination with high folic acid intake, in addition to the previously mentioned neuropathy risk, appeared to increase the risk of cognitive impairment in the elderly.<ref name="adavidsmith"/> Long-term use of folic acid dietary supplements in excess of 1,000&nbsp;μg/day has been linked to an increase in prostate cancer risk.<ref name=Wien2012/>

===Food labeling===
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For folate labeling purposes, 100% of the Daily Value was 400&nbsp;μg. As of the 27 May 2016 update, it was kept unchanged at 400&nbsp;μg.<ref name="FedReg">{{cite web|url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf|title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982.|access-date=30 August 2017|archive-date=7 October 2021|archive-url=https://web.archive.org/web/20211007100633/https://www.govinfo.gov/content/pkg/FR-2016-05-27/pdf/2016-11867.pdf|url-status=live}}</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 }}</ref> Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with [[US$]]10&nbsp;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=dead }} {{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=dead }} {{PD-notice}}</ref> A table of the old and new adult daily values is provided at [[Reference Daily Intake]].

European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of Daily Values, amounts are shown as percent of Reference Intakes (RIs). For folate, 100% RI was set at 200&nbsp;μg in 2011.<ref>{{cite journal|title=Regulation (EU) No 1169/2011 of the European Parliament and of the Council|journal=Official Journal of the European Union|volume=22|issue=11|pages=18–63|year=2011|url=http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:304:0018:0063:EN:PDF|access-date=26 September 2018|archive-date=26 July 2017|archive-url=https://web.archive.org/web/20170726215901/http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ%3AL%3A2011%3A304%3A0018%3A0063%3AEN%3APDF|url-status=live}}</ref>

==Deficiency==
{{main|Folate deficiency}}
Folate deficiency can be caused by unhealthy diets that do not include enough vegetables and other folate-rich foods; diseases in which folates are not well absorbed in the digestive system (such as [[Crohn's disease]] or [[celiac disease]]); some genetic disorders that affect levels of folate; and certain medicines (such as phenytoin, [[sulfasalazine]], or trimethoprim-sulfamethoxazole).<ref name="nlm.nih.gov">{{Cite web|title=Folate deficiency: MedlinePlus Medical Encyclopedia|url=https://www.nlm.nih.gov/medlineplus/ency/article/000354.htm|website=nlm.nih.gov|access-date=16 November 2015|url-status=live|archive-url=https://web.archive.org/web/20151117023226/https://www.nlm.nih.gov/medlineplus/ency/article/000354.htm|archive-date=17 November 2015}}</ref> Folate deficiency is accelerated by alcohol consumption, possibly by interference with folate transport.<ref>{{cite journal|vauthors=Hamid A, Wani NA, Kaur J|title=New perspectives on folate transport in relation to alcoholism-induced folate malabsorption–association with epigenome stability and cancer development|journal=The FEBS Journal|volume=276|issue=8|pages=2175–91|date=April 2009|pmid=19292860|doi=10.1111/j.1742-4658.2009.06959.x|s2cid=8591709|doi-access=free}}</ref>

Folate deficiency may lead to [[glossitis]], diarrhea, depression, confusion, anemia, and fetal neural tube and brain defects.<ref name="DRItext"/> Other symptoms include fatigue, gray hair, mouth sores, poor growth, and swollen tongue.<ref name="nlm.nih.gov"/> Folate deficiency is diagnosed by analyzing a [[complete blood count]] (CBC) and plasma vitamin B<sub>12</sub> and folate levels. A serum folate of 3&nbsp;μg/L or lower indicates deficiency.<ref name="DRItext"/> Serum folate level reflects folate status, but erythrocyte folate level better reflects tissue stores after intake. An erythrocyte folate level of 140&nbsp;μg/L or lower indicates inadequate folate status. Serum folate reacts more rapidly to folate intake than erythrocyte folate.<ref>{{cite journal|vauthors=Lohner S, Fekete K, Berti C, Hermoso M, Cetin I, Koletzko B, Decsi T|s2cid=26868696|title=Effect of folate supplementation on folate status and health outcomes in infants, children and adolescents: a systematic review|journal=International Journal of Food Sciences and Nutrition|volume=63|issue=8|pages=1014–20|date=December 2012|pmid=22574624|doi=10.3109/09637486.2012.683779}}</ref>

Since folate deficiency limits cell division, [[erythropoiesis]] (production of red blood cells) is hindered. This leads to [[megaloblastic anemia]], which is characterized by large, immature red blood cells. This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division, and produces abnormally large red cells called megaloblasts (and hypersegmented neutrophils) with abundant cytoplasm capable of RNA and protein synthesis, but with clumping and fragmentation of nuclear chromatin. Some of these large cells, although immature (reticulocytes), are released early from the marrow in an attempt to compensate for the anemia.<ref>{{cite book|title=Marks' Essential Medical Biochemistry, First edition|vauthors=Lieberman M, Marks AD, Smith C|publisher=Lippincott Williams & Wilkins|year=2007|isbn=978-0-7817-9340-7|location=Hagerstwon, MD}}{{page needed|date=May 2013}}</ref> Both adults and children need folate to make normal red and white blood cells and prevent anemia, which causes fatigue, weakness, and inability to concentrate.<ref name="Oldref_4">{{cite journal|vauthors=Zittoun J|title=Anémies par trouble du métabolisme des folates, de la vitamine B12 et des transcobalamines|trans-title=Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism|language=fr|journal=La Revue du Praticien|volume=43|issue=11|pages=1358–63|date=June 1993|pmid=8235383}}</ref><ref>{{cite web|url=http://www.healthlinkbc.ca/healthfiles/hfile68g.stm|title=Folate and Your Health – HealthLinkBC File #68g|publisher=Healthlink British Columbia|access-date=9 September 2012|url-status=live|archive-url=https://web.archive.org/web/20120709211636/http://www.healthlinkbc.ca/healthfiles/hfile68g.stm|archive-date=9 July 2012}}</ref>

Increased homocysteine levels suggest tissue folate deficiency, but homocysteine is also affected by vitamin B<sub>12</sub> and vitamin B<sub>6</sub>, renal function, and genetics. One way to differentiate between folate deficiency and vitamin B<sub>12</sub> deficiency is by testing for [[methylmalonic acid]] (MMA) levels. Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B<sub>12</sub> deficiency.<ref name="DRItext"/> Elevated MMA levels may also be due to the rare metabolic disorder [[combined malonic and methylmalonic aciduria]] (CMAMMA).<ref>{{cite journal |vauthors=Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C, Carrillo-Carrasco N, Chandrasekaran SD, Sysol JR, O'Brien K, Hauser NS, Sapp JC, Dorward HM, Huizing M, Barshop BA, Berry SA, James PM, Champaigne NL, de Lonlay P, Valayannopoulos V, Geschwind MD, Gavrilov DK, Nyhan WL, Biesecker LG, Venditti CP  |title=Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria |journal=Nat Genet |volume=43 |issue=9 |pages=883–86 |date=August 2011 |pmid=21841779 |pmc=3163731 |doi=10.1038/ng.908 |url=}}</ref><ref>{{cite journal |vauthors=de Sain-van der Velden MG, van der Ham M, Jans JJ, Visser G, Prinsen HC, Verhoeven-Duif NM, van Gassen KL, van Hasselt PM  |title=A New Approach for Fast Metabolic Diagnostics in CMAMMA |journal=JIMD Rep |series=JIMD Reports |volume=30 |issue= |pages=15–22 |date=February 2016 |pmid=26915364 |pmc=5110436 |doi=10.1007/8904_2016_531 |isbn=978-3-662-53680-3 |url=}}</ref>

Folate deficiency is treated with supplemental oral folic acid of 400 to 1000&nbsp;μg per day. This treatment is very successful in replenishing tissues, even if deficiency was caused by malabsorption. People with megaloblastic anemia need to be tested for vitamin B<sub>12</sub> deficiency before treatment with folic acid, because if the person has vitamin B<sub>12</sub> deficiency, folic acid supplementation can remove the anemia, but can also worsen neurologic problems.<ref name="DRItext"/> Cobalamin (vitamin B<sub>12</sub>) deficiency may lead to folate deficiency, which, in turn, increases homocysteine levels and may result in the development of cardiovascular disease or birth defects.<ref>{{cite journal|vauthors=Varela-Moreiras G, Murphy MM, Scott JM|title=Cobalamin, folic acid, and homocysteine|journal=Nutrition Reviews|volume=67|pages=S69-72|date=May 2009|issue=Suppl 1 |pmid=19453682|doi=10.1111/j.1753-4887.2009.00163.x|hdl=2262/34510|hdl-access=free}}</ref>

==Sources==
The [[United States Department of Agriculture]], [[Agricultural Research Service]] maintains a food composition database from which folate content in hundreds of foods can be searched as shown in the table.<ref name=USDA-NDL /> The Food Fortification Initiative lists all countries in the world that conduct fortification programs,<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=30 April 2019|archive-date=4 April 2017|archive-url=https://web.archive.org/web/20170404131451/http://www.ffinetwork.org/why_fortify/index.html}}</ref> and within each country, what nutrients are added to which foods, and whether those programs are voluntary or mandatory. In the US, mandatory fortification of enriched breads, cereals, flours, corn meal, pastas, rice, and other grain products began in January 1998. As of 2023, 140 countries require food fortification with one or more vitamins,<ref name=Map/> with folate required in 69 countries. The most commonly fortified food is wheat flour, followed by maize flour and rice. From country to country, added folic acid amounts range from 0.4 to 5.1&nbsp;mg/kg, but the great majority are in a more narrow range of 1.0 to 2.5&nbsp;mg/kg, i.e. 100–250&nbsp;μg/100g.<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=30 April 2019|archive-date=11 April 2019|archive-url=https://web.archive.org/web/20190411123853/https://fortificationdata.org/map-number-of-nutrients/|url-status=live}}</ref> Folate 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 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.com|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}}</ref> For foods that are normally consumed cooked, values in the table are for folate naturally occurring in cooked foods.

<div style="float:left; padding: 1em;">
{|class="wikitable"
|-
!Plant sources<ref name=USDA-NDL>{{cite web|url=https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=432&nutrient2=&subset=0&sort=c&measureby=g|title=Folate content in micrograms per 100 g, All Foods; USDA Food Composition Databases|date=7 May 2019|publisher=United States Department of Agriculture, Agricultural Research Service. Release 28|access-date=27 May 2019}}{{dead link|date=October 2022|bot=medic}}{{cbignore|bot=medic}}</ref>
!Amount as<br />Folate<br /> (μg / 100&nbsp;g)
|-
|[[Peanut]]s || 246
|-
|[[Sunflower seed|Sunflower seed kernels]] || 238
|-
|[[Lentil]]s || 181
|-
|[[Chickpea]]s || 172
|-
|[[Asparagus]] || 149
|-
|[[Spinach]] || 146
|-
|[[Lettuce]] || 136
|-
|[[Peanut]]s (oil-roasted) || 125
|-
|[[Soybean]]s || 111
|-
|[[Broccoli]] || 108
|-
|[[Walnut]]s || 98
|}
</div>
<div style="float:left; padding: 1em;">
{|class="wikitable"
|-
!Plant sources<ref name=USDA-NDL />
!Amount as<br />Folate<br /> (μg / 100&nbsp;g)
|-
|[[Peanut butter]] || 92
|-
|[[Hazelnut]]s || 88
|-
|[[Avocado]]s || 81
|-
|[[Beets]] || 80
|-
|[[Kale]] || 65
|-
|[[Bread]] (not fortified) || 65
|-
|[[Cabbage]] || 46
|-
|[[Bell pepper|Red bell peppers]] || 46
|-
|[[Cauliflower]] || 44
|-
|[[Tofu]] || 29
|-
|[[Potato]]es || 28
|}
</div>
<div style="float:left; padding: 1em;">
{|class="wikitable"
|-
!Animal sources<ref name=USDA-NDL />
!Amount as<br />Folate<br /> (μg / 100&nbsp;g)
|-
|[[Chicken]] [[liver]] || 578
|-
|[[Calf (animal)|Calf]] liver || 331
|-
|[[Cheese]] || 20–60
|-
|[[Egg as food|Chicken eggs]] || 44
|-
|[[Salmon]] || 35
|-
|[[Chicken]] || 12
|-
|[[Beef]] || 12
|-
|[[Pork]] || 8
|-
|[[Yogurt]] || 8–11
|-
|[[Milk]], whole || 5
|-
|[[Butter]], salted || 3
|}
</div>{{Clear}}

==Food fortification==
{{See also|Food fortification}}
''Folic acid fortification'' is a process where synthetic folic acid is added to wheat flour or other foods with the intention of promoting public health through increasing blood folate levels in the populace. It is used as it is more stable during processing and storage.<ref name=Choi2014/><ref name="adavidsmith">{{cite journal|vauthors=Smith AD|title=Folic acid fortification: the good, the bad, and the puzzle of vitamin B-12|journal=The American Journal of Clinical Nutrition|volume=85|issue=1|pages=3–5|date=January 2007|pmid=17209170|doi=10.1093/ajcn/85.1.3|doi-access=free}}</ref> After the discovery of the link between insufficient folic acid and [[neural tube defects]], governments and health organizations worldwide made recommendations concerning folic acid [[dietary supplement|supplementation]] for women intending to become pregnant. Because the neural tube closes in the first four weeks of gestation, often before many women even know they are pregnant, many countries in time decided to implement mandatory food fortification programs. A meta-analysis of global birth prevalence of spina bifida showed that when mandatory fortification was compared to countries with voluntary fortification or no fortification program, there was a 30% reduction in live births with spina bifida,<ref name=Atta2016/> with some countries reporting a greater than 50% reduction.<ref name=Castillo2013 />

Folic acid is added to grain products in more than 80 countries, either as required or voluntary fortification,<ref name=Wald2018/><ref name=Map /> and these fortified products make up a significant source of the population's folate intake.<ref>{{cite journal|vauthors=Dietrich M, Brown CJ, Block G|title=The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States|journal=Journal of the American College of Nutrition|volume=24|issue=4|pages=266–74|date=August 2005|pmid=16093404|doi=10.1080/07315724.2005.10719474|s2cid=24699315}}</ref>  In the U.S., there is concern that the federal government mandates fortification but does not provide monitoring of potential undesirable effects of fortification.<ref name="adavidsmith" /> The Food Fortification Initiative lists all countries in the world that conduct fortification programs,<ref name=WhyFortify /> and within each country, what nutrients are added to which foods. The most commonly mandatory fortified vitamin – in 62 countries – is folate; the most commonly fortified food is wheat flour.<ref name=Map />

===Australia and New Zealand===
[[Australia]] and [[New Zealand]] jointly agreed to wheat flour fortification through the [[Food Standards Australia New Zealand]] in 2007. The requirement was set at 135&nbsp;μg of folate per 100&nbsp;g of bread. Australia implemented the program in 2009.<ref>{{cite web|url=http://www.foodstandards.gov.au/consumer/nutrition/folicmandatory/Pages/default.aspx|title=Folic Acid Fortification|date=2016|website=Food Standards Australia New Zealand|access-date=25 September 2018|archive-date=26 September 2018|archive-url=https://web.archive.org/web/20180926051839/http://www.foodstandards.gov.au/consumer/nutrition/folicmandatory/Pages/default.aspx}}</ref> New Zealand was also planning to fortify bread (excluding organic and unleavened varieties) starting in 2009, but then opted to wait until more research was done. The Association of Bakers and the [[Green Party of Aotearoa New Zealand|Green Party]] had opposed mandatory fortification, describing it as "mass medication".<ref>{{cite press release|title=Work Starts on Wilkinson's Mass Medication Plan|publisher=Association Of Bakers|date=8 July 2009|url=http://www.scoop.co.nz/stories/BU0907/S00210.htm|access-date=13 July 2009|url-status=live|archive-url=https://web.archive.org/web/20090710084803/http://www.scoop.co.nz/stories/BU0907/S00210.htm|archive-date=10 July 2009}}</ref><ref>{{cite press release|title=NZ should push pause on folic fortification|publisher=Green Party|date=9 July 2009|url=http://www.scoop.co.nz/stories/PA0907/S00132.htm|access-date=13 July 2009|url-status=live|archive-url=https://web.archive.org/web/20090710015728/http://www.scoop.co.nz/stories/PA0907/S00132.htm|archive-date=10 July 2009}}</ref> Food Safety Minister [[Kate Wilkinson (politician)|Kate Wilkinson]] reviewed the decision to fortify in July 2009, citing as reasons to oppose claims for links between over consumption of folate with increased risk of cancer.<ref>{{cite news|author=NZPA|title=Bakers, Govt battle over folic acid|publisher=[[The New Zealand Herald]] |date=8 July 2009|url=http://www.nzherald.co.nz/food/news/article.cfm?c_id=206&objectid=10583249|access-date=13 July 2009|archive-date=14 February 2012|archive-url=https://web.archive.org/web/20120214223246/http://www.nzherald.co.nz/food/news/article.cfm?c_id=206&objectid=10583249|url-status=live}}</ref> In 2012 the delayed mandatory fortification program was revoked and replaced by a voluntary program, with the hope of achieving a 50% bread fortification target.<ref>{{cite journal|vauthors=Houghton LA|title=A country left behind: folic acid food fortification policy in New Zealand|journal=The New Zealand Medical Journal|volume=127|issue=1399|pages=6–9|date=August 2014|pmid=25145300}}</ref>

===Canada===
Canadian public health efforts focused on promoting awareness of the importance of folic acid supplementation for all women of childbearing age and decreasing socio-economic inequalities by providing practical folic acid support to vulnerable groups of women.<ref>{{cite web|url=http://www.hc-sc.gc.ca|title=Welcome to the Health Canada Web site|publisher=Hc-sc.gc.ca|access-date=9 September 2012|url-status=live|archive-url=https://web.archive.org/web/20120910203617/http://www.hc-sc.gc.ca/|archive-date=10 September 2012}}</ref> Folic acid [[food fortification]] became mandatory in 1998, with the fortification of 150&nbsp;μg of folic acid per 100&nbsp;grams of [[enriched flour]] and uncooked [[cereal]] grains.<ref name=Mason2007>{{cite journal|vauthors=Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH|title=A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis|journal=Cancer Epidemiology, Biomarkers & Prevention|volume=16|issue=7|pages=1325–9|date=July 2007|pmid=17626997|doi=10.1158/1055-9965.EPI-07-0329|doi-access=free}}</ref> The results of folic acid fortification on the rate of neural tube defects in [[Canada]] have been positive, showing a 46% reduction in prevalence of NTDs; the magnitude of reduction was proportional to the prefortification rate of NTDs, essentially removing geographical variations in rates of NTDs seen in Canada before fortification.<ref>{{cite journal|vauthors=De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, Evans JA, Van den Hof MC, Zimmer P, Crowley M, Fernandez B, Lee NS, Niyonsenga T|title=Reduction in neural-tube defects after folic acid fortification in Canada|journal=The New England Journal of Medicine|volume=357|issue=2|pages=135–42|date=July 2007|pmid=17625125|doi=10.1056/NEJMoa067103|doi-access=free}}</ref>

===United Kingdom===
While the [[Food Standards Agency]] recommended folic acid fortification,<ref>{{cite web|url=http://www.food.gov.uk/news/newsarchive/2007/may/folatefort|title=Board recommends mandatory fortification|access-date=18 May 2007|author=FSA|date=17 May 2007|url-status=live|archive-url=https://web.archive.org/web/20070624183523/http://www.food.gov.uk/news/newsarchive/2007/may/folatefort|archive-date=24 June 2007}}</ref><ref>{{cite news|url=http://news.bbc.co.uk/1/hi/health/6665109.stm|title=Backing for folic acid in bread|access-date=18 May 2007|work=[[BBC News]] |date=17 May 2007|url-status=live|archive-url=https://web.archive.org/web/20070618010640/http://news.bbc.co.uk/1/hi/health/6665109.stm|archive-date=18 June 2007}}</ref><ref>BBC [http://news.bbc.co.uk/1/hi/health/6648059.stm Experts back folic acid in flour] {{webarchive|url=https://web.archive.org/web/20070818132738/http://news.bbc.co.uk/1/hi/health/6648059.stm|date=18 August 2007}} 11 May 2007</ref> and wheat flour is fortified with iron,<ref name=ffi>{{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|url-status=live|archive-url=https://web.archive.org/web/20170404131451/http://www.ffinetwork.org/why_fortify/index.html|archive-date=4 April 2017}}</ref> folic acid fortification of wheat flour is allowed voluntarily rather than required. A 2018 review by authors based in the United Kingdom strongly recommended that mandatory fortification be reconsidered as a means of reducing the risk of neural tube defects.<ref name=Wald2018>{{cite journal|vauthors=Wald NJ, Morris JK, Blakemore C|title=Public health failure in the prevention of neural tube defects: time to abandon the tolerable upper intake level of folate|journal=Public Health Reviews|volume=39|page=2|date=2018|pmid=29450103|pmc=5809909|doi=10.1186/s40985-018-0079-6 |doi-access=free }}</ref> In November 2024 the UK government announced legislation to require folic acid fortification in bread by the end of 2026.<ref>{{cite web|url=https://www.gov.uk/government/news/birth-defects-prevented-by-fortifying-flour-with-folic-acid |title=Birth defects prevented by fortifying flour with folic acid }}</ref>

===United States===
[[File:GrainProducts.jpg|right|thumb|In the United States and many other countries, wheat flour is fortified with folic acid; some countries also fortify maize flour and rice.<ref name=Map/>]]

In 1996, the United States [[Food and Drug Administration]] (FDA) published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products.<ref>{{cite web |url=https://www.govinfo.gov/content/pkg/FR-1996-03-05/pdf/96-5014.pdf |title=Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Final Rule. 21 CFR Parts 136, 137, and 139. |date=March 1996 |volume=61 |issue=44 |pages=8781–89 |website=Federal Register |access-date=6 October 2019 |archive-date=6 October 2019 |archive-url=https://web.archive.org/web/20191006122713/https://www.govinfo.gov/content/pkg/FR-1996-03-05/pdf/96-5014.pdf |url-status=live }}</ref> This ruling took effect on 1 January 1998, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.<ref name=Crandall1998>{{cite journal|vauthors=Crandall BF, Corson VL, Evans MI, Goldberg JD, Knight G, Salafsky IS|title=American College of Medical Genetics statement on folic acid: fortification and supplementation|journal=American Journal of Medical Genetics|volume=78|issue=4|page=381|date=July 1998|pmid=9714444|doi=10.1002/(SICI)1096-8628(19980724)78:4<381::AID-AJMG16>3.0.CO;2-E}}</ref> There were concerns expressed that the amount of folate added was insufficient.<ref>{{cite news|url=http://www.boston.com/yourlife/health/women/articles/2004/01/06/fda_muffed_chance_to_prevent_birth_defects/?pages=full|title=FDA muffed chance to reduce birth defects|newspaper=Boston Globe|date=6 January 2004|url-status=live|archive-url=https://web.archive.org/web/20070313013804/http://www.boston.com/yourlife/health/women/articles/2004/01/06/fda_muffed_chance_to_prevent_birth_defects/?pages=full|archive-date=13 March 2007}}</ref>

The fortification program was expected to raise a person's folic acid intake level by 70–130&nbsp;μg/day;<ref name=Choumenkovitch2002>{{cite journal|vauthors=Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF|title=Folic acid intake from fortification in United States exceeds predictions|journal=The Journal of Nutrition|volume=132|issue=9|pages=2792–8|date=September 2002|pmid=12221247|doi=10.1093/jn/132.9.2792|doi-access=free}}</ref> however, an increase of almost double that amount was actually observed.<ref name="Quinlivan">{{cite journal|vauthors=Quinlivan EP, Gregory JF|title=Effect of food fortification on folic acid intake in the United States|journal=The American Journal of Clinical Nutrition|volume=77|issue=1|pages=221–5|date=January 2003|pmid=12499345|doi=10.1093/ajcn/77.1.221|doi-access=free}}</ref> This could be from the fact that many foods are fortified by 160–175% over the required amount.<ref name="Quinlivan"/> Much of the elder population take [[dietary supplement|supplements]] that add 400&nbsp;μg to their daily folic acid intake. This is a concern because 70–80% of the population have detectable levels of unmetabolized folic acid in their [[blood]], a consequence of folic acid supplementation and fortification.<ref name=Chustecka2009/> However, at blood concentrations achieved via food fortification, folic acid has no known cofactor function that would increase the likelihood of a causal role for free folic acid in disease development.<ref name=Obeid2012/>

The U.S. National Center for Health Statistics conducts the biannual National Health and Nutrition Examination Survey (NHANES) to assess the health and nutritional status of adults and children in the United States. Some results are reported as What We Eat In America. The 2013–2014 survey reported that for adults ages 20 years and older, men consumed an average of 249&nbsp;μg/day folate from food plus 207&nbsp;μg/day of folic acid from consumption of fortified foods, for a combined total of 601&nbsp;μg/day of dietary folate equivalents (DFEs because each microgram of folic acid counts as 1.7&nbsp;μg of food folate). For women, the values are 199, 153 and 459&nbsp;μg/day, respectively. This means that fortification led to a bigger increase in folic acid intake than first projected, and that more than half the adults are consuming more than the RDA of 400&nbsp;μg (as DFEs). Even so, fewer than half of pregnant women are exceeding the pregnancy RDA of 600&nbsp;μg/day.<ref>{{cite web|url=https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_1_NIN_GEN_13.pdf|title=TABLE 1: Nutrient Intakes from Food and Beverages|website=What We Eat In America, NHANES 2012–2014 (2016)|access-date=12 October 2018|archive-date=24 February 2017|archive-url=https://web.archive.org/web/20170224042515/https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_1_NIN_GEN_13.pdf|url-status=live}}</ref>

Before folic acid fortification, about 4,100 pregnancies were affected by a neural tube defect each year in the United States. The [[Centers for Disease Control and Prevention]] reported in 2015 that since the addition of folic acid in grain-based foods as mandated by the FDA, the rate of neural tube defects dropped by 35%. This translates to an annual saving in total direct costs of approximately $508 million for the NTD-affected births that were prevented.<ref>{{cite journal|title=Updated Estimates of Neural Tube Defects Prevented by Mandatory Folic Acid Fortification — United States, 1995–2011|journal=MMWR. Morbidity and Mortality Weekly Report|volume=64|issue=1|pages=1–5|date=16 January 2015|pmid=25590678|pmc=4584791|url=https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a2.htm|author=Centers for Disease Control Prevention (CDC)|access-date=15 September 2019|archive-date=31 July 2020|archive-url=https://web.archive.org/web/20200731174802/https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a2.htm|url-status=live}}</ref><ref name="cdc.gov">{{Cite web|title=Birth Defects COUNT {{!}} Folic Acid {{!}} NCBDDD {{!}} CDC|url=https://www.cdc.gov/ncbddd/folicacid/global.html#1|website=www.cdc.gov|access-date=16 November 2015|url-status=live|archive-url=https://web.archive.org/web/20151113191745/http://www.cdc.gov/ncbddd/folicacid/global.html#1|archive-date=13 November 2015}}</ref>

==History==
{{See|Vitamin#History}}
In the 1920s, scientists believed folate deficiency and anemia were the same condition.<ref name="Lanska">{{cite book|year=2009 |series=Handbook of Clinical Neurology|volume=95|pages=445–476|doi=10.1016/S0072-9752(08)02130-1|isbn=978-0-444-52009-8|pmid=19892133|vauthors=Lanska DJ|chapter=Chapter 30 Historical aspects of the major neurological vitamin deficiency disorders: The water-soluble B vitamins |title=History of Neurology}}</ref> In 1931, researcher [[Lucy Wills]] made a key observation that led to the identification of folate as the nutrient required to prevent [[anemia]] during pregnancy. Wills demonstrated that anemia could be reversed with [[brewer's yeast]].<ref name=Pond/><ref>{{cite journal | vauthors = Wills L | title = Nutrition Classics. British Medical Journal 1:1059–64, 1931. Treatment of "pernicious anaemia of pregnancy" and "tropical anaemia" with special reference to yeast extract as a curative agent. By Lucy Wills | journal = Nutrition Reviews | volume = 36 | issue = 5 | pages = 149–51 | date = May 1978 | pmid = 355948 | doi = 10.1111/j.1753-4887.1978.tb03735.x }}</ref> In the late 1930s, folate was identified as the corrective substance in brewer's yeast. It was first isolated via extraction from [[spinach]] leaves by [[Herschel K. Mitchell]], [[Esmond E. Snell]], and [[Roger J. Williams]] in 1941.<ref>{{cite journal|year=1941|title=The concentration of "folic acid"|journal=J Am Chem Soc|volume=63|issue=8|page=2284|doi=10.1021/ja01853a512|vauthors=Mitchell HK, Snell EE, Williams RJ|bibcode=1941JAChS..63.2284M }}</ref> The term "folic" is from the Latin word {{lang|la|[[wikt:folium|folium]]}} (which means leaf) because it was found in dark-green leafy vegetables.<ref name=Chambers/> Historic names included ''[[L. casei|L.&nbsp;casei]]'' factor, vitamin B<sub>c</sub> after research done in chicks and vitamin M after research done in monkeys.<ref name=Welch1983/>

Bob Stokstad isolated the pure crystalline form in 1943, and was able to determine its chemical structure while working at the Lederle Laboratories of the American Cyanamid Company.<ref name=Hoffbrand2001>{{cite journal | vauthors = Hoffbrand AV, Weir DG | title = The history of folic acid | journal = British Journal of Haematology | volume = 113 | issue = 3 | pages = 579–89 | date = June 2001 | pmid = 11380441 | doi = 10.1046/j.1365-2141.2001.02822.x | s2cid = 22925228 }}</ref> This historical research project, of obtaining folic acid in a pure crystalline form in 1945, was done by the team called the "folic acid boys", under the supervision and guidance of Director of Research Dr. [[Yellapragada Subbarow]], at the Lederle Lab, Pearl River, New York.<ref name="Paul2016">{{cite journal | vauthors = Paul C | title = Folic acid in pregnancy | journal = BJOG | volume = 123 | issue = 3 | page = 392 | date = February 2016 | pmid = 26810675 | doi = 10.1111/1471-0528.13602 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Angier RB, Boothe JH, Hutchings BL, Mowat JH, Semb J, Stokstad EL, Subbarow Y, Waller CW, Cosulich DB, Fahrenbach MJ, Hultquist ME, Kuh E, Northey EH, Seeger DR, Sickels JP, Smith JM | title = Synthesis of a Compound Identical with the L. Casei Factor Isolated from Liver | journal = Science | volume = 102 | issue = 2644 | pages = 227–8 | date = August 1945 | pmid = 17778509 | doi = 10.1126/science.102.2644.227 | bibcode = 1945Sci...102..227A }}</ref> This research subsequently led to the synthesis of the antifolate [[aminopterin]], which was used to treat [[childhood leukemia]] by [[Sidney Farber]] in 1948.<ref name="Hoffbrand2001"/><ref name="FarberDiamond1948">{{cite journal | vauthors = Farber S, Diamond LK | title = Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid | journal = The New England Journal of Medicine | volume = 238 | issue = 23 | pages = 787–93 | date = June 1948 | pmid = 18860765 | doi = 10.1056/NEJM194806032382301 }}</ref>

In the 1950s and 1960s, scientists began to discover the biochemical mechanisms of action for folate.<ref name="Lanska" /> In 1960, researchers linked folate deficiency to risk of neural tube defects.<ref name="Lanska" /> In the late 1990s, the U.S. and Canadian governments decided that despite public education programs and the availability of folic acid supplements, there was still a challenge for women of child-bearing age to meet the daily folate recommendations, which is when those two countries implemented folate fortification programs.<ref name=Crandall1998 /> As of December 2018, 62 countries mandated food fortification with folic acid.<ref name=Map/>

==Animals==
Veterinarians may test cats and dogs if a risk of folate deficiency is indicated. Cats with exocrine pancreatic insufficiency, more so than dogs, may have low serum folate. In dog breeds at risk for cleft lip and cleft palate dietary folic acid supplementation significantly decreased incidence.<ref>{{cite web |url=https://www.wedgewoodpetrx.com/learning-center/professional-monographs/folic-acid-for-veterinary-use.html |title=Folic Acid for Veterinary Use |vauthors=Forney B |date=2017 |website=Wedgewood Pharmacy |access-date=21 September 2019 |archive-date=21 September 2019 |archive-url=https://web.archive.org/web/20190921163133/https://www.wedgewoodpetrx.com/learning-center/professional-monographs/folic-acid-for-veterinary-use.html |url-status=live }}</ref>

==References==
{{Reflist}}

==External links==
Current versions from the [[International Union of Biochemistry and Molecular Biology]]'s ''Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology etc.'' [https://web.archive.org/web/20170804052444/http://iubmb.qmul.ac.uk/enzyme/reaction/misc/ Enzyme Nomenclature, Miscellaneous Reaction Schemes] section ''Pterins, Riboflavins, etc.'' formerly hosted by [[Queen Mary College]] (all archived by [[archive.org]]):
* [https://iubmb.qmul.ac.uk/enzyme/reaction/misc/folate1.html Folate biosynthesis (early stages)]
* [https://iubmb.qmul.ac.uk/enzyme/reaction/misc/folate2.html Folate biosynthesis (later stages)]
* [https://iubmb.qmul.ac.uk/enzyme/reaction/misc/folate3.html Folate coenzymes]
* [https://iubmb.qmul.ac.uk/enzyme/reaction/misc/folate4.html Formylation, hydroxymethylation and methylation using folate]
* [https://iubmb.qmul.ac.uk/enzyme/reaction/misc/folate5.html C<sub>1</sub> metabolism with folate]

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