Editing Folate (section)

==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>