Fact Sheet: Folate (Vitamin B9) & Folic Acid

Overview

Folate is the generic term for water-soluble vitamin B9. The word folate comes from the Latin folium, meaning leaf. Leafy green vegetables are rich in folate.

When exploring folate’s health benefits, the discussion starts with DNA—the body’s instruction manual. DNA contains genetic information and is crucial for establishing and sustaining optimal health. Folate supports important body functions, including amino acid metabolism, proper cell division, and DNA synthesis, stability, repair, and methylation.¹Bo Y, Zhu Y, Tao Y, et al. Association between folate and health outcomes: an umbrella review of meta-analyses. Public Health Front. 2020;8. https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2020.550753/full Folate deficiency is a risk factor for heart disease and neural tube defects.²Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem. 2004;15:64.,³Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.

Folic acid, a synthetic version of folate, was formulated to fortify “enriched grain” products in response to growing concern about birth defects. The widespread availability of processed foods has made folic acid–fortified products easily accessible. However, the body must complete a multi-step process to biochemically convert folic acid. Enzyme-encoding genes and sufficient nutrients are needed to make a usable form, tetrahydrofolate. For most people, this isn’t a concern; however, it can pose challenges to those with genetic difficulties in enzyme conversion, who may struggle to safely and efficiently process folic acid. On the other hand, 5-methyltetrahydrofolate (5-MTHF), a natural form of folate, is well absorbed and fully participates in folate metabolism. The use of 5-MTHF as an alternative folate supplement has increased.

Uses

Reduced risk of birth defects is the most recognized benefit of folate supplementation. More than 30 years ago, the U.S. Public Health Service advised women of reproductive age to take 400 mcg of folic acid, a synthetic form of folate, as a daily substitute for naturally occurring folate. The campaign is widely considered a successful public health effort to prevent neural tube defects, which can affect a baby’s brain and spine.⁴Folic acid: facts for clinicians. Centers for Disease Control and Prevention. Published May 15, 2024. https://www.cdc.gov/folic-acid/hcp/clinical-overview/?CDC_AAref_Val=https://www.cdc.gov/ncbddd/folicacid/recommendations.html

Folic acid is commonly found in processed foods (enriched breads, flour, pasta, rice, cornmeal, cereal) and is a key ingredient in prenatal vitamins. As understanding of folic acid metabolism has advanced, some people may find the bioavailable form of folate, 5-MTHF, more beneficial.

Folate supplementation is important for the following individuals, given their increased risk for deficiency²Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem. 2004;15:64.:

• People with alcohol use disorder
• People with malabsorptive disorders
• Women of childbearing age and pregnant women
• Older adults with poor nutrition
• People taking certain medications that interfere with folate metabolism
• People with folate-deficiency anemia resulting from an unbalanced diet

People with folate-deficiency anemia may experience one or more of the following symptoms:

• Fatigue
• Digestive trouble
• Diarrhea
• Irritability
• Pale skin
• Smooth and tender tongue

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Benefits

Folate is effective in correcting and preventing deficiency. Low folate levels are a risk factor for cardiovascular disease and neural tube defects.

Additionally, folate is possibly effective for the following:

• Mental/behavioral health disorders such as depression, postpartum depression, post-menopausal depression, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, and bipolar affective disorder⁵Lam N, Long X, Li X, et al. The potential use of folate and its derivatives in treating psychiatric disorders: a systematic review. Biomed Pharmacother. 2022;146. https://www.sciencedirect.com/science/article/pii/S0753332221013287
• Reducing the risk of cardiovascular disease when combined with vitamins B6 and B12⁶Miao Y, Guo Y, Chen Y, et al. The effect of B-vitamins on the prevention and treatment of cardiovascular diseases: a systematic review and meta-analysis. Nutr Rev. 2023. https://pubmed.ncbi.nlm.nih.gov/37850302
• Reducing the risk of Alzheimer’s disease and cognitive decline⁷Ma F, Li Q, Zhou X, et al. Effects of folic acid supplementation on cognitive function and AB-related biomarkers in mild cognitive impairment: a randomized controlled trial. Eur J Nutr. 2019;58(1):345-356. https://pubmed.ncbi.nlm.nih.gov/29255930
• Reducing the risk of colorectal cancers⁸Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res. 2007 Mar;51(3):267-92. https://doi.org/10.1002/mnfr.200600191. PMID: 17295418.

Recommended Dietary Allowance (RDA)

Side Effects

The biggest concern with folate is getting too much through diet and supplements. Potential side effects of excessive folate include immune dysregulation and cancer.⁹Fardous AM, Heydari AR. Uncovering the hidden dangers of molecular mechanisms of excessive folate: a narrative review. Nutrients. 2023;15(21). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648405 Children whose mothers have taken unnecessary folic acid may also experience detrimental health effects.⁷Ma F, Li Q, Zhou X, et al. Effects of folic acid supplementation on cognitive function and AB-related biomarkers in mild cognitive impairment: a randomized controlled trial. Eur J Nutr. 2019;58(1):345-356. https://pubmed.ncbi.nlm.nih.gov/29255930

Unmetabolized folic acid (UMFA) can accumulate when folic acid from fortified foods and supplements¹⁰Obeid R, Herrmann W. The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab. 2012 Oct;13(8):1184-95. https://doi.org/10.2174/138920012802850137. PMID: 22746304. exceeds 200 μg/day.¹¹Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997;65:1790. UMFA accumulation poses health risks that include masking vitamin B12 deficiency and inhibiting enzymes involved in cell division, DNA repair, and homeostasis, and may lead to functional folate deficiency.¹²Obeid R, Herrmann W. The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab. 2012 Oct;13(8):1184-95. https://doi.org/10.2174/138920012802850137 There is no link between UMFA accumulation and bioactive folate (5-MTHF), making it a beneficial alternative.

Interactions

Folate may reduce the efficacy of methotrexate as a cancer treatment. However, when the drug is taken at a lower dose (e.g., for autoimmune conditions), folate can reduce gastrointestinal side effects.²Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem. 2004;15:64.

Anticonvulsants, sulfamethoxazole–trimethoprim, oral contraceptives, and pancreatic enzymes can potentially deplete folate levels.¹³Mospan CM. Drug-induced nutrient depletions: what pharmacists need to know. US Pharmacist. 2019;44(12):18-24. https://www.uspharmacist.com/article/druginduced-nutrient-depletions-what-pharmacists-need-to-know

Food Sources 

Leafy green vegetables such as spinach, asparagus, and Brussels sprouts are major sources of folate. Fruits, nuts, beans, peas, chickpeas, and whole grains also provide folate. Meat and meat products, excluding liver, have minimal amounts of the vitamin.

The U.S. Food and Drug Administration requires manufacturers of bread, cereal, flour, corn meal, pasta, rice, and other grains to fortify their products with folic acid.²Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem. 2004;15:64.

Footnotes

• 1
  Bo Y, Zhu Y, Tao Y, et al. Association between folate and health outcomes: an umbrella review of meta-analyses. Public Health Front. 2020;8. https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2020.550753/full
• 2
  Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem. 2004;15:64.
• 3
  Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.
• 4
  Folic acid: facts for clinicians. Centers for Disease Control and Prevention. Published May 15, 2024. https://www.cdc.gov/folic-acid/hcp/clinical-overview/?CDC_AAref_Val=https://www.cdc.gov/ncbddd/folicacid/recommendations.html
• 5
  Lam N, Long X, Li X, et al. The potential use of folate and its derivatives in treating psychiatric disorders: a systematic review. Biomed Pharmacother. 2022;146. https://www.sciencedirect.com/science/article/pii/S0753332221013287
• 6
  Miao Y, Guo Y, Chen Y, et al. The effect of B-vitamins on the prevention and treatment of cardiovascular diseases: a systematic review and meta-analysis. Nutr Rev. 2023. https://pubmed.ncbi.nlm.nih.gov/37850302
• 7
  Ma F, Li Q, Zhou X, et al. Effects of folic acid supplementation on cognitive function and AB-related biomarkers in mild cognitive impairment: a randomized controlled trial. Eur J Nutr. 2019;58(1):345-356. https://pubmed.ncbi.nlm.nih.gov/29255930
• 8
  Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res. 2007 Mar;51(3):267-92. https://doi.org/10.1002/mnfr.200600191. PMID: 17295418.
• 9
  Fardous AM, Heydari AR. Uncovering the hidden dangers of molecular mechanisms of excessive folate: a narrative review. Nutrients. 2023;15(21). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648405
• 10
  Obeid R, Herrmann W. The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab. 2012 Oct;13(8):1184-95. https://doi.org/10.2174/138920012802850137. PMID: 22746304.
• 11
  Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997;65:1790.
• 12
  Obeid R, Herrmann W. The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab. 2012 Oct;13(8):1184-95. https://doi.org/10.2174/138920012802850137
• 13
  Mospan CM. Drug-induced nutrient depletions: what pharmacists need to know. US Pharmacist. 2019;44(12):18-24. https://www.uspharmacist.com/article/druginduced-nutrient-depletions-what-pharmacists-need-to-know