Folic Acid

Also indexed as: Folate, Methylfolate, Vitamin B9

What is it?

Folic acid is a B vitamin needed for cell replication and growth. Folic acid helps form building blocks of DNA, the body’s genetic information, and building blocks of RNA, needed for protein synthesis in all cells. Therefore, rapidly growing tissues, such as those of a foetus, and rapidly regenerating cells, like red blood cells and immune cells, have a high need for folic acid. Folic acid deficiency results in a form of anaemia that responds quickly to folic acid supplementation.

The requirement for folic acid increases considerably during pregnancy.¹ Deficiencies of folic acid during pregnancy are associated with low birth weight and an increased incidence of neural tube defects in infants.² In one study, women who were at high risk of giving birth to babies with neural tube defects were able to lower their risk by 72% by taking folic acid supplements prior to and during pregnancy.³ Most doctors, many other healthcare professionals, and the March of Dimes recommend that all women of childbearing age supplement with 400 mcg per day of folic acid. Such supplementation would protect against the formation of neural tube defects during the time between conception and when pregnancy is discovered. If a woman waits until after pregnancy has been discovered to begin taking folic acid supplements, it will probably be too late to prevent a neural tube defect.

Other birth defects may be prevented with folic acid supplementation as well. Women who take folic acid-containing multivitamin supplements around the time they conceive may also reduce the risk of other congenital malformations, such as heart defects, defects of the upper lip and mouth,⁴ urinary tract defects,⁵ ⁶ and limb-reduction defects.⁷ ⁸ Rates of prevention of cleft lip and cleft palate may be improved by using very large amounts of folic acid (6 mg per day).⁹ A doctor should supervise anyone wishing to take this much folic acid.

Folic acid is needed to keep homocysteine (an amino acid by-product) levels in blood from rising. A growing body of evidence suggests that an elevated homocysteine level is a risk factor for heart disease¹⁰ and may also be linked to several other diseases. Folic acid and certain other B vitamins function as cofactors for enzymes that can lower homocysteine levels. Research has shown that supplementing with folic acid reduces homocysteine levels.¹¹ Of the B vitamins with a role in homocysteine metabolism, folic acid appears to be the most important in lowering homocysteine levels for the average person.¹² ¹³ A deficiency of folic acid has also been associated with peripheral vascular disease and coronary artery disease even in people with normal homocysteine levels, suggesting that the vitamin may have protective effects that extend beyond its role in maintaining normal homocysteine levels.¹⁴

In 1996, the FDA began to require that all enriched flour,rice, pasta, cornmeal, and other grain products contain 140 mcg of folic acid per 100 grams.¹⁵ Among people who do not take vitamin supplements, this amount of food fortification has been associated with increased folic acid levels in the blood and decreased blood levels of homocysteine.¹⁶ Nevertheless, evidence is mounting that the FDA-mandated level of folic acid fortification in food is inadequate to fully prevent neural tube defects.¹⁷ Until fortification rates are quadrupled, women who can possibly become pregnant are advised to take a folic acid supplement of 400 mcg per day.

A diet low in folic acid has been associated with a high incidence of pre-cancerous polyps in the colon, suggesting that folic acid may prevent the development of colon cancer.¹⁸ Two studies have shown that reduced folic acid levels are associated with an increase in the incidence of cancer in people with ulcerative colitis¹⁹ ²⁰ and a third study showed the degree of abnormal cell growth decreases as folic acid intake increases.²¹ Three large population studies showed that low folic acid intake is associated with an increased risk of colorectal cancer.²² ²³ ²⁴

In addition, decreased blood levels of folic acid are associated with an increased risk of colon cancer in women.²⁵ Long-term supplementation with folic acid from a multivitamin has been found in one large population study to be associated with a reduced risk of colon cancer. However, 15 years of supplementation was necessary before a significant reduction in colon-cancer risk became apparent. In that study, folic acid from dietary sources alone was associated with a modest reduction in the risk of colon cancer.²⁶

Total folic acid intake was not associated with overall risk of breast cancer in preliminary studies.²⁷ ²⁸ However, among women who consume at least one alcoholic beverage per day, the risk of breast cancer appears to be highest among those with low folic acid intake. Current use of a multivitamin supplement has also been associated with lower breast cancer risk among women who consume at least 1.5 alcoholic beverages per day, compared with those who never use a multivitamin supplement.

Where is it found?

Beans, leafy green vegetables, citrus fruits, beets, wheat germ, and meat are good sources of folic acid.

Folic acid has been used in connection with the following conditions (refer to the individual health concern for complete information):

Science Ratings	Health Concerns
	Birth defects prevention Cervical smear (abnormal) (in women taking oral contraceptives) Depression Gingivitis (periodontal disease) (rinse only) High homocysteine (in combination with vitamin B6 and vitamin B12) Pregnancy and postpartum support Schizophrenia (for deficiency)
	Anaemia (for thallasaemia if deficient) Atherosclerosis Breast cancer (reduces risk in women who consume alcohol) Coeliac disease (for deficiency only) Colon cancer (prevention) Heart attack Mouth ulcers (for deficiency only) Preeclampsia Sickle cell anaemia (for lowering homocysteine levels) Skin ulcers Ulcerative colitis
	Alzheimer’s disease Bipolar Disorder/Manic Depression Crohn’s disease Dermatitis herpetiformis (for deficiency) Diarrhoea Down’s syndrome Epilepsy Gingivitis (periodontal disease) (pill) Gout HIV support Lung cancer (reduces risk) Osteoporosis Peripheral vascular disease Psoriasis Restless legs syndrome Seborrheic dermatitis Stroke (for high homocysteine only) Vitiligo
Reliable and relatively consistent scientific data showing a substantial health benefit. Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit. For a herb, supported by traditional use but minimal or no scientific evidence. For a supplement, little scientific support and/or minimal health benefit.

Who is likely to be deficient?

Many people consume less than the recommended amount of folic acid. Scientists have found that people with heart disease commonly have elevated blood levels of homocysteine, a laboratory test abnormality often controllable with folic acid supplements. This suggests that many people in Western societies have a mild folic acid deficiency. In fact, it has been suggested that increasing folic acid intake could prevent an estimated 13,500 deaths from cardiovascular diseases each year.²⁹

Folic acid deficiency has also been common in alcoholics, people living at poverty level, those with malabsorption disorders or liver disease (e.g., cirrhosis), and women taking the birth control pill. Recently, elderly people with hearing loss have been reported to be much more likely to be folic acid deficient than healthy elderly people.³⁰ A variety of prescription drugs including cimetidine, antacids, some anticancer drugs, triamterene, sulfasalazine, and anticonvulsants interfere with folic acid.

Deficiency of folic acid can be precipitated by situations wherein the body requires greater than normal amounts of the vitamin, such as pregnancy, infancy, leukaemia, exfoliative dermatitis, and diseases that cause the destruction of blood cells.³¹

The relationship between folic acid and prevention of neural tube defects is partly thought to result from the high incidence of folate deficiency in many societies. To protect against neural tube defects, the U.S. Food and Drug Administration has mandated that some grain products provide supplemental folic acid at a level expected to increase the dietary intake by an average of 100 mcg per day per person. As a result of folic acid added to the food supply, fewer Americans will be depleted compared with the past. In 1999, scientific evidence began to demonstrate that the folic acid added to the U.S. food supply was having positive effects, including a partial lowering of homocysteine levels.³² In the same year, however, a report from the North Carolina Birth Defects Monitoring Programme suggested the current level of folic acid fortification has not reduced the incidence of neural-tube defects.³³ Many doctors and the Centres for Disease Control in Atlanta³⁴ believe that optimal levels of folic acid intake may still be higher than the amount now being added to food by several hundred micrograms per day. A low blood level of folate has also been associated with an increased risk of miscarriage.³⁵

People with kidney failure have an increased risk of folic acid deficiency.³⁶ Recipients of kidney transplants often have elevated homocysteine levels, which may respond to supplementation with folic acid.³⁷ The usual recommended amount of 400 mcg per day may not be enough for these people, however. Larger amounts (up to 2.4 mg per day) may produce a better outcome, according to one double-blind trial.³⁸

Folate deficiency is more prevalent among elderly African American women than among elderly white women.³⁹

Which form is best?

Folic acid naturally found in food is much less available to the body compared with synthetic folic acid found both in supplements and added to grain products in the United States. Women with a recent history of giving birth to babies with neural tube defects participated in a study to determine which form of folic acid is best absorbed—dietary folic acid or folic acid from supplements.⁴⁰ They received either orange juice containing 400 mcg of folic acid per day or a supplement containing the same amount. Overall, the supplement folic acid was better absorbed than the folic acid from orange juice.

How much is usually taken?

Many doctors recommend that all women who are or who could become pregnant take 400 mcg per day in order to reduce the risk of birth defects. Some doctors also extend this recommendation to other people in an attempt to reduce the risk of heart disease by lowering homocysteine levels. Since the FDA mandated addition of folic acid to grain products, many people who eat grains have followed the new recommendation of supplementing only 100 mcg of folic acid per day. However, studies have found that this amount of folic acid is inadequate to maintain normal folate levels in a significant percentage of the groups assessed.⁴¹ It now appears that, for pregnant women, supplementing with at least 300 mcg (and optimally 400 mcg) of folic acid per day is sufficient to prevent a folate deficiency, even if dietary intake is low.

Are there any side effects or interactions?

Folic acid is not generally associated with side effects.⁴² However, folic acid supplementation can interfere with the laboratory diagnosis of vitamin B12 deficiency, possibly allowing the deficiency to progress undetected to the point of irreversible nerve damage.⁴³ Although vitamin B12 deficiency is uncommon, no one should supplement with 1,000 mcg or more of folic acid without consulting a doctor.

Vitamin B12 deficiencies often occur without anaemia (even in people who do not take folic acid supplements). Some doctors do not know that the absence of anaemia does not rule out a B12 deficiency. If this confusion delays diagnosis of a vitamin B12 deficiency, the patient could be injured, sometimes permanently. This problem is rare and should not happen with doctors knowledgeable in this area using correct testing procedures.

Folic acid is needed by the body to utilise vitamin B12. Proteolytic enzymes inhibit folic acid absorption.⁴⁴ People taking proteolytic enzymes are advised to supplement with folic acid.

Are there any drug interactions?
Certain medicines may interact with folic acid. Refer to drug interactions for a list of those medicines.

References
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3. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338(8760):131-7.

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6. Werler MM, Hayes C, Louik C, et al. Multivitamin supplementation and risk of birth defects. Am J Epidemiol 1999;150:675-82.

7. Shaw GM, O’Malley CD, Wasserman CR, et al. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 1995;59:536-45.

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9. Czeizel AE, Timar L, Sarkozi A. Dose-dependent effect of folic acid on the prevention of orofacial clefts. Pediatrics 1999;104:e66.

10. Bostom AG, Silbershatz H, Rosenberg IH, et al. Non-fasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 1999;159:1077-80.

11. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B12, vitamin B6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993;57:47-53.

12. Dierkes J, Kroesen M, Pietrzik K. Folic acid and vitamin B6 supplementation and plasma homocysteine concentrations in healthy young women. Int J Vitam Nutr Res 1998;68:98-103.

13. Stein JH, McBride PE. Hyperhomocysteinemia and atherosclerotic vascular disease. Arch Intern Med 1998;158:1301-6.

14. Bunout D, Petermann M, Hirsch S, et al. Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls. Nutrition 2000;16:434-8.

15. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist 1996;61:8781-97.

16. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-54.

17. Meyer RE, Oakley Jr GP. Folic acid fortification. Lancet 1999;354:2168 [letter].

18. Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875-84.

19. Lashner BA, Heidenreich PA, Su GL, et al. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology 1989;97:255-9.

20. 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.

21. Lashner BA, Provencher KS, Seidner DL, et al. The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology 1997;112:29-32.

22. Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991;20:368-74.

23. Benito E, Stiggelbout A, Bosch FX, et al. Nutritional factors in colorectal cancer risk: a case-control study in Majorca. Int J Cancer 1991;49:161-7.

24. Meyer F, White E. Alcohol and nutrients in relation to colon cancer in middle-aged adults. Am J Epidemiol 1993;138:225-36.

25. Kato I, Dnistrian AM, Schwartz M, et al. Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. Br J Cancer 1999;79:1917-21.

26. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate and colon cancer in women in the Nurse’s Health Study. Ann Intern Med 1998;129:517-24.

27. Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281:1632-7.

28. Rohan TE, Jain MG, Howe GR, Miller AB. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:266-9.

29. Russel RM. A minimum of 13,500 deaths annually from coronary artery disease could be prevented by increasing folate intake to reduce homocysteine levels. JAMA 1996;275:1828–9.

30. Houston DK, Johnson MA, Nozza RJ, et al. Age-related hearing loss, vitamin B-12, and folate in elderly women. Am J Clin Nutr 1999;69:564–71.

31. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency. A Guide for the primary care physician. Arch Intern Med 1999;159:1289–98 [review].

32. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449–54.

33. Meyer RE, Oakley GP Jr. Folic acid fortification. Lancet 1999;354:2168 [letter].

34. Oakley GP Jr. Eat right and take a multivitamin. N Engl J Med 1998;338:1060–1 [editorial].

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36. Makoff R. Vitamin replacement therapy in renal failure patients. Miner Electrolyte Metab 1999;25:349–51 [review].

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38. Beaulieu AJ, Gohh RY, Han H, et al. Enhanced reduction of fasting total homocysteine levels with supraphysiological versus standard multivitamin dose folic acid supplementation in renal transplant recipients. Arterioscler Thromb Vasc Biol 1999;19:2918–21.

39. Stabler SP, Allen RH, Fried LP, et al. Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women. Am J Clin Nutr 1999;70:911–9.

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43. Wald NJ, Bower C. Folic acid, pernicious anaemia, and prevention of neural tube defects. Lancet 1994;343:307.

44. Russell RM, Dutta SK, Oaks EV, et al. Impairment of folic acid absorption by oral pancreatic extracts. Dig Dis Sci 1980;25:369–73.

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The information presented in Healthnotes is for informational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, or traditional usage as cited in each article. The results reported may not necessarily occur in all individuals. For many of the conditions discussed, treatment with prescription or over the counter medication is also available. Consult your doctor, practitioner, and/or chemist for any health problem and before using any supplements or before making any changes in prescribed medications. Information expires March 2007.