Folate

• How It Works

  Folate is used to prevent certain types of anemia and birth defects. Studies of increased folate intake or supplements to reduce cancer risk produced mixed results.

  Folate is a member of the vitamin B complex that must be obtained from food sources like grains, leafy vegetables, and liver. It is important for cell division, and if not consumed enough from food, can lead to anemia and birth defects. Folic acid is a form of folate used as a supplement to correct deficiencies. It is also added to some processed foods to increase dietary consumption.

  Some studies suggest adequate folate intake can help reduce the risk of Alzheimer’s disease, heart disease, and certain types of cancer, but other studies find increased colon and skin cancer risks with higher intake levels. Excess folate or folic acid may mask vitamin B12 deficiency.

• Purported Uses
  • To treat Alzheimer’s disease
    Studies have linked low dietary folate and low folate levels in the blood with Alzheimer’s disease.
  • To prevent cancer
    Some studies have shown that higher levels of folate reduce the risk for various cancers, but other studies found it may increase precancerous colon abnormalities or skin cancer risk. Therefore, more research is needed to understand the relationships between folate levels, supplementation, and cancer risks or prevention.
  • To prevent heart disease
    Low folic acid levels have been linked to higher homocysteine levels, a risk factor for heart disease-related death. However, further studies are needed to understand this association.
  • To prevent neural tube birth defects
    Studies have shown a significant decrease in risk of some types of birth defects with increased dietary folate.
• Do Not Take If
  • You are taking anticonvulsants: Using folic acid may reduce their effectiveness.
  • Black or green tea: May decrease folic acid absorption.
• Side Effects
  • Increased risk of toxicity with overconsumption.
  • In a 43-year-old man with low haemoglobin and multiorgan dysfunction syndrome (MODS), folate supplementation was associated with promoting lymphoma progression.
• Scientific Name

  Pteroylglutamic acid

• Clinical Summary

  Folate is an essential member of the vitamin B complex family that is naturally present in grains, green leafy vegetables, and liver. Folic acid and the L-methylfolate (5-MTHF) derivative are synthetic supplemental forms that have higher bioavailability ⁽¹⁾. Folate is important in cell growth and division and involved in the methylation process and DNA synthesis. Inadequate intake can cause deficiency leading to megaloblastic anemia. Folate is essential during pregnancy, with supplementation shown to reduce risks of neural tube birth defects ⁽¹⁰⁾ and medulloblastoma in offspring ⁽¹¹⁾. A study among South American populations suggests the protective effect against neural tube defects may be greater in female than male infants ⁽⁶⁵⁾. In high doses (5 mg/day), it reduced homocysteine levels at time of delivery and may lessen pregnancy complications ⁽⁴³⁾. Supplementation may also benefit women with polycystic ovary syndrome (PCOS) ⁽⁴²⁾, and high folate intake reduced chromosomal aberrations in sperm of healthy men ⁽¹²⁾. But supplements taken beyond the first trimester did not prevent pre-eclampsia in women at high risk for this disorder ⁽⁷²⁾.

  In other studies, folic acid decreased homocysteine levels, a risk factor for cardiovascular disease mortality ^{(13) (14) (15)}, along with lowering blood pressure in smokers ^(5) (16). Among hypertensive adults, folic acid therapy reduced risk of first stroke ^{(44) (45) (66)}, but smoking status may affect efficacy ⁽⁶⁷⁾. Other trials on stroke risk have yielded mixed results ^{(17) (18) (19) (20)}, with a meta analysis indicating moderate to low evidence for preventive benefits of folic acid for total cardiovascular disease; and folic acid and B-vitamins for stroke ⁽⁷³⁾. Folic acid supplementation has been shown to improve cognitive function in older adults ⁽²⁶⁾. In patients with Alzheimer’s disease, it improved response to cholinesterase inhibitors ⁽²⁷⁾, cognition, and inflammatory markers ⁽⁴⁶⁾. In individuals chronically exposed to arsenic, it lowered blood arsenic concentrations by facilitating urinary excretion ⁽²⁸⁾. There is limited evidence on whether supplementation can increase serum folate levels, or has an effect on anemia in patients with sickle cell disease ⁽⁶⁸⁾. But a combination of folic acid and vitamin B12 supplements decreased serum homocysteine levels and improved anemia in patients with multiple sclerosis ⁽⁷⁴⁾; and folic acid added to antipsychotics may improve symptoms in schizophrenic patients ⁽⁷⁵⁾.

  Studies on increased folate intake or supplements to reduce cancer risk are mixed. In young children, folic acid fortification was associated with reduced incidence of Wilms tumor and primitive neuroectodermal tumors (PNET) ⁽³⁶⁾. Folate supplementation also helps cervical intraepithelial neoplasia (CIN 1) regression ⁽⁴⁷⁾. Low levels of folate in the blood are associated with certain forms of cancer ⁽⁹⁾, whereas higher levels of dietary folate have been shown to reduce the risk of breast ⁽²⁾ and pancreatic cancers ⁽³⁾, but not prostate cancer ⁽⁷⁾. Studies on colorectal cancer risk produced mixed results ^{(4) (5) (32) (35) (48)} and some even suggest a negative effect ^{(6) (8) (49) (71)}. A large population study suggested an association between dietary folate intake and increased risk for overall skin cancer, basal cell carcinoma, and nonmelanoma skin cancer, particularly in women ⁽⁵⁰⁾. Overconsumption of folic acid may also increase risk of toxicity ⁽⁵¹⁾ and some cancers ⁽⁵²⁾. Therefore, more research is needed to examine the relationships between folate levels, supplementation, and cancer risks or prevention.

  Several studies that evaluated folic acid in combination with other B vitamins reported negative findings, with no overall effect on breast or invasive cancers  ⁽³³⁾, along with the potential for increased cancer incidence and mortality in patients with ischemic heart disease  ⁽³⁴⁾. Such interventions have also produced mixed results in studies for older adults with depression  ^(53) (54), and did not improve bone mineral density ⁽⁵⁵⁾ or reduce fracture risk or incidence ^(56) (69).

  Due to its antagonistic effects, folic acid can reduce the side effects of methotrexate when used for rheumatoid arthritis ^(22) (23). However, it may decrease the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia ⁽²⁴⁾ and psoriasis ⁽²⁵⁾. Excess folate or folic acid may mask vitamin B12 deficiency  ⁽⁷⁰⁾.

• Food Sources

  Main sources include fortified breakfast cereals and breads, liver, Brussels sprouts, potatoes, spinach, chickpeas, and brewer’s yeast.

• Purported Uses
  • Alzheimer’s disease
  • Cancer prevention
  • Cardiovascular disease
  • Neural tube defect prevention
• Mechanism of Action

  Folate acts as a co-enzyme during methylation. The bioactive form is tetrahydrofate, which can be converted from folic acid through the action of dihydrofolate reductase. Drugs that inhibit this enzyme can therefore reduce folic acid activity. The amino acid serine reacts with tetrahydrofolate, resulting in 5,10- methylenetetrahydrofolate, the derivative involved in nucleotide synthesis. In addition, 5-methyltetrahydrofolate transfers a methyl group to cobalamin (vitamin B12) and then to homocysteine, converting it to methionine, the precursor of methyl donor, S-adenosyl-methionine (SAMe) that plays a major role in neurological function and several biochemical pathways ⁽⁴¹⁾. Genetic polymorphisms that lower the production of methylenetetrahydrofolate reductase (MTHFR) can also reduce SAMe and increase homocysteine levels. Supplementation with folic acid can therefore reduce homocysteine levels and DNA oxidative damage ^(57) (58). This may in turn lower risk of cardiovascular and psychiatric diseases by increasing SAMe ^(59) (60). Folic acid supplementation also improves endothelial function ^(16) (31); and has a protective effect on retinal vascular endothelial cells from high glucose-induced injury via regulating proteins in the Hippo signaling pathway ⁽⁷⁶⁾.

  Although low folate status is associated with increased risk of cardiovascular disease and some cancers ⁽⁶¹⁾, increased intake from fortified foods may actually raise cancer risk ^{(49) (50) (62)}. There is also evidence that high levels of unmetabolized folic acid in plasma can reduce natural killer cell cytotoxicity ⁽⁶³⁾.

• Adverse Reactions
  • Increased risk of toxicity with overconsumption  ⁽⁵¹⁾
  • In a 43-year-old man with low haemoglobin and multiorgan dysfunction syndrome (MODS), folate supplementation was associated with promoting lymphoma progression ⁽⁷⁷⁾.
• Herb-Drug Interactions
  • Anticonvulsants: Concurrent use of folic acid may antagonize the effects of certain anticonvulsants ⁽²⁹⁾.
  • Black or green tea: May cause a decrease in folic acid absorption ⁽⁶⁴⁾.
• References

  1. Gregory JF, III. Case study: folate bioavailability. J Nutr 2001;131:1376S-82S.

  2. Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 2001;61:7136-41.

  3. Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol 2001;153:680-7.

  4. Fuchs CS, Willett WC, Colditz GA, Hunter DJ, Stampfer MJ, Speizer FE et al. The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiol Biomarkers Prev 2002;11:227-34.

  5. Su LJ,.Arab L. Nutritional status of folate and colon cancer risk: evidence from NHANES I epidemiologic follow-up study. Ann.Epidemiol 2001;11:65-72.

  6. Van Guelpen B, Hultdin J, Johansson I, et al. Low folate levels may protect against colorectal cancer. Gut 2006;55(10):1461-6.

  7. Stevens VL, et al. Folate nutrition and prostate cancer incidence in a large cohort of US men. Am J Epidemiology 2006; 163(11):989-996.

  8. Cole BF, Baron JA, Sandler RS. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007 ;297(21):2351-9.

  9. Lashner BA. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol 1993;119:549-54.

  10. Berry RJ, Li Z, Erickson D, et al. Prevention of neural-tube defects with folic acid in China. N Engl J Med 1999;341(20):1485-1490.

  11. Bunin GR, Gallagher PR, Rorke-Adams LB, et al. Maternal supplement, micronutrient, and cured meat intake during pregnancy and risk of medulloblastoma during childhood: A children’s oncology group study. Cancer Epidemiol Biomarkers Prev 2006; 15(9): 1660-7.

  12. Young SS, Eskenazi B, Marchetti FM, et al. The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men. Hum Reprod. 2008;23(5):1014-22. Epub 2008 Mar 19.

  13. Ducloux D, Aboubakr A, Motte G, Toubin G, Fournier V, Chalopin JM et al. Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12. Nephrol.Dial.Transplant. 2002;17:865-70.

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  22. Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology.(Oxford) 2000;39:1102-9.

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  45. Qin X, Li Y, He M, et al. Folic acid therapy reduces serum uric acid in hypertensive patients: a substudy of the China Stroke Primary Prevention Trial (CSPPT). Am J Clin Nutr. Apr 2017;105(4):882-889.

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