Folic Acid

Overview

Folic acid is a member of the water-soluble B vitamin group. Isolated in 1946 from spinach leaves, its name comes from folium, the Latin word for leaf. In the body, folic acid is converted to its biologically active form tetrahydrofolic acid (THFA). Niacin and vitamin C are necessary for this conversion. Structurally, folic acid consists of a pteridine nucleus (containing two rings), conjugated with para-aminobenzoic acid, and glutamic acid. Hence, its chemical name is pteroylmonoglutamate.

Dosage Info

Dosage Range

200-800mcg daily. However, physicians may occasionally administer doses to severely deficient patients ranging from 5,000-15,000mcg daily. (1)

Most Common Dosage

400mcg daily.

Dosage Forms

Tablets, capsules, liquids, liposomal sprays, and effervescent tablets.

Adult RDI

400mcg

Adult ODA

400-800mcg

RDA

• RDA listed as dietary folate:
• Infants 14 years: 400mcg
• Pregnancy: 600mcg
• Lactation: 500mcg

Interactions and Depletions

Interactions

• Aluminum and magnesium containing antacids
• Bile acid sequestrants
• H-2 receptor antagonists
• Potassium-sparing diuretics

Depletions

• Alcoholic beverages
• Anticonvulsants
• Salicylates
• Corticosteroid medications
• Nonsteroidal anti-inflammatory medications (NSAIDs)
• Oral contraceptives
• metformin
• methotrexate
• Trimethoprim-containing antibiotics
• sulfasalazine

Active Forms

Folic acid (also known as folate) and folinic acid (also known as 5-methyl tetrahydro-folate).

Absorption

Folic acid absorption occurs primarily in the first part of the small intestine via two separate mechanisms, which include:
a) active transport, which requires a folate-binding protein (FBP)
b) passive diffusion, which accounts for 20 to 30 percent of folate absorption

Toxicities & Precautions

General

There are no known toxicities associated with folic acid.

Large doses of folic acid can mask an underlying vitamin B₁₂ deficiency, which if undetected, could result in irreversible nerve damage. (2) Consequently, folic acid is limited to 800mcg in OTC nutritional supplements and 1mg in prescription products.

Functions in the Body

DNA and RNA Synthesis:

Like vitamin B12, folic acid is necessary for the synthesis of both DNA and RNA. Hence, it is essential for proper cellular division and the transmission of the genetic code to all newly formed cells.

Pregnancy:

Necessary for decreased incidence of neural tube defects during pregnancy. (3) , (4)

Red Blood Cells:

Essential for the healthy maturation of red blood cells. (5)

Methylation Reactions:

Required for some methylation reactions such as the conversion of homocysteine to methionine.

Protein and Amino Acid Synthesis:

Involved in the synthesis of proteins and various amino acids.

Clinical Applications

Alzheimer’s Disease

Relative folate deficiency may precede Alzheimer disease and vascular dementia onset. (6)

Depression

Many patients with major depression and schizophrenia improve with folic acid therapy. (7)

Pregnancy And Lactation

Doubles the requirements for folic acid. (8)

Atherosclerosis.

Homocysteine concentrations, when elevated, are a risk factor for atherosclerotic disease. Folic acid lowers homocysteine levels, which decreases atherogenesis. (9) , (10) , (11) , (12) , (13) , (14) . The same effect has been noted when folic acid is given in conjunction with vitamin B6 and vitamin B12. (15) , (16) , (17) Lipid lowering medications known as “fibrates” have been shown to increase homocysteine levels. A study was conducted in which fenofibrate was given either with placebo or with vitamins including vitamin B6, vitamin B12 and folic acid. The homocysteine measurements with the vitamins were significantly lower than the measurements taken without the vitamins. (18) Dietary supplementation with the B-vitamins prevented hyperhomocysteinemia but did not prevent the development of vascular dysfunction or atherosclerotic lesions. (19)

In patients who have undergone angioplasty, benefit has been documented with therapy consisting of vitamin B6, vitamin B12 and folic acid. In a prospective, double-blind, randomized trial, 205 patients who had undergone a successful coronary angioplasty were given a combination of folic acid, vitamin B12 and pyridoxine or placebo for six months. Treatment significantly lowered plasma homocysteine levels and at follow-up, the minimal luminal diameter was significantly larger in the treatment group, the degree of stenosis was less severe, the rate of restenosis was significantly lower and the need for revascularization of the target lesion was less in patients assigned to folate treatment. (20)

Another randomized, double-blind placebo-controlled trial involving 553 patients was designed to evaluate the effect of homocysteine-lowering therapy on clinical outcome after percutaneous coronary intervention. After successful angioplasty of at least 1 significant coronary stenosis, patients were enrolled and randomized to either a combination of folic acid, vitamin B12, and vitamin B6 or a placebo for 6 months. After 1 year, the endpoints (death, nonfatal myocardial infarction, or revascularization) were lower in patients receiving the homocysteine lowering therapy. (21)

Birth Defects

Adequate folic acid is necessary to prevent neural tube birth defects such as spina bifida. (22)

Cervical Dysplasia

Often due to a folic acid deficiency, many hysterectomies can be prevented with adequate folic acid supplementation. (23)

Osteoporosis

Folic acid lowers homocysteine levels. Homocysteine interferes with collagen crosslinking, which leads to a defective bone matrix. (24)

Alcoholism

Alcohol inhibits folate absorption and alcoholics are usually deficient. (25)

Cognitive Enhancement

A literature review of recent research has noted subclinical differences in nutritional status of certain B vitamins among older adults may influence certain aspects of cognitive performance. Supplementation with folate, vitamin B12 and vitamin B6 has been effective in enhancing cognitive performance in older adults. (26)

Of note, a study evaluating 370 nondemented people 75 years old or older for three years, noted that subjects with low levels of vitamin B12 or folate had twice the risk of developing Alzheimer’s disease. A clearer association was noted when both vitamins were taken into consideration. (27)

Gingivitis

Effectively treated using 0.1% folate solution as a mouthwash. (28)

Symptoms and Causes of Deficiency

Folic acid deficiency disrupts DNA metabolism, which causes abnormal cellular development, especially in cells with the most rapid rates of turnover which includes red blood cells, leukocytes, and epithelial cells of the stomach, intestine, vagina, and uterine cervix.

Folic acid is one of the most common vitamin deficiencies. Substantial destruction occurs during food processing and heat, light, and oxygen easily destroy it. Folic acid needs are greatly increased during pregnancy. (29) Megaloblastic anemia (abnormally large red blood cells) is a result of a folic acid or vitamin B₁₂ deficiency. Symptoms of folic acid deficiency include headache, fatigue, hair loss, insomnia, birth defects, cervical dysplasia, and elevated homocysteine. The following drugs can cause folic acid depletion: oral contraceptives, triamterene, anticonvulsants, H-2 receptor antagonists, trimethoprim, cholestyramine, anti-inflammatory drugs, methotrexate, aspirin, antacids, and alcohol.

Dietary Sources

Folic acid occurs in a wide variety of foods. Best sources include dark green leafy vegetables, brewer’s yeast, liver, and eggs. Other good sources are beets, broccoli, brussels sprouts, orange juice, cabbage, cauliflower, cantaloupe, kidney and lima beans, wheat germ, and whole grain cereals and breads. The “friendly” intestinal bacteria also synthesize folic acid.

References

1. View Abstract: Kes P. Hyperhomocysteinemia in end-stage renal failure. Acta Med Croatica. 2000;54(4-5):175-81.
2. View Abstract: Stabler SP, et al. Vitamin B-12 deficiency in the elderly: current dilemmas. American Journal of Clinical Nutrition. 1997;Vol 66:741-749.
3. View Abstract: Evans MI, Llurba E, Landsberger EJ, OBrien JE, Harrison HH. Impact of folic acid fortification in the United States: markedly diminished high maternal serum alpha-fetoprotein values. Obstet Gynecol. Mar2004;103(3):474-9.
4. View Abstract: Norsworthy B, Skeaff CM, Adank C, Green TJ. Effects of once-a-week or daily folic acid supplementation on red blood cell folate concentrations in women. Eur J Clin Nutr. Mar2004;58(3):548-54.
5. View Abstract: Gutierrez Revilla JI, Perez Hernandez F, Tamparillas Salvador M, Calvo Martin MT. Influence of biochemical and genetic factors on homocysteine concentrations. An Pediatr (Barc). Mar2004;60(3):215-21.
6. View Abstract: Quadri P, Fragiacomo C, Pezzati R, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr. Jul2004;80(1):114-22.
7. View Abstract: Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry. Aug1991;159:271-2.
8. Truswell AS. ABC of Nutrition. Nutrition for Pregnancy. Br Med J. (Clin Res Ed) Jul1985;291(6490):263-66.
9. View Abstract: Brattstrom LE, et al. Folic Acid – An Innocuous Means to Reduce plasma Homocysteine. Scand J Clin Lab Invest. May1988;48(3):215-21.
10. View Abstract: Auer J, et al. Homocysteine and cardiovascular risk. Wien Med Wochenschr. 2001;151(1-2):25-8.
11. View Abstract: Stanford JL, et al. Oral folate reduces plasma homocyst(e)ine levels in hemodialysis patients with cardiovascular disease. Cardiovasc Surg. Dec2000;8(7):567-71.
12. View Abstract: Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol. Dec1999;34(7):2002-6.
13. View Abstract: Brouwer IA, van Dusseldorp M, Thomas CM, Duran M, Hautvast JG, Eskes TK, et al. Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Am J Clin Nutr. Jan1999;69(1):99-104.
14. View Abstract: Landgren F, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattstrom L. Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med. Apr1995;237(4):381-8.
15. View Abstract: Woodside JV, Yarnell JW, McMaster D, Young IS, Harmon DL, McCrum EE, et al. Effect of B-group vitamins and antioxidant vitamins on hyperhomocysteinemia: a double-blind, randomized, factorial-design, controlled trial. Am J Clin Nutr. May1998;67(5):858-66.
16. View Abstract: Nakhoul F, Abassi Z, Plawner M, et al. Comparative study of response to treatment with supraphysiologic doses of B-vitamins in hyperhomocysteinemic hemodialysis patients. Isr Med Assoc J. Apr2004;6(4):213-7.
17. View Abstract: Tavani A, et al. Folate and vitamin B6 intake and risk of acute myocardial infarction in Italy. EJCN. Sept 2004;58(9):1266-1272.
18. View Abstract: Dierkes J, Westphal S, Kunstmann S, Banditt P, Lossner A, Luley C. Vitamin supplementation can markedly reduce the homocysteine elevation induced by fenofibrate. Atherosclerosis. Sep2001;158(1):161-4.
19. View Abstract: Lentz SR, Piegors DJ, Malinow MR, Heistad DD. Supplementation of atherogenic diet with B vitamins does not prevent atherosclerosis or vascular dysfunction in monkeys. Circulation. Feb2001;103(7):1006-11.
20. View Abstract: Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med. Nov2001:345(22):1593-600.
21. View Abstract: Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic Acid, vitamin B12, and vitamin b6 on clinical outcome after percutaneous coronary intervention: the swiss heart study: a randomized controlled trial. JAMA. Aug2002;288(8):973-9.
22. View Abstract: Steegers-Theunissen RP. Folate Metabolism and Neural Tube Defects: A Review. Eur J Obstet Gynecol Reprod Biol. Jul1995;61(1):39-48.
23. View Abstract: Buckley DI, et al. Dietary Micronutrients and Cervical Dysplasia in Southwestern American Indian Women. Nutr Cancer. 1992;17(2):179-85.
24. View Abstract: Brattstrom LE, et al. Folic Acid Responsive Postmenopausal Homocysteinemia. Metabolism. Nov1985;34(11):1073-77.
25. View Abstract: Lindenbaum J, et al. Nutritional Anemia in Alcoholism. Am J Clin Nutr. Dec1980;33(12):2727-35.
26. View Abstract: Calvaresi E, Bryan J. B vitamins, cognition, and aging: a review. J Gerontol B Psychol Sci Soc Sci. Nov2001;56(6):P327-39.
27. View Abstract: Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology. May2001;56(9):1188-94.
28. Pack ARC. Folate Mouthwash: Effects on Established Gingivitis in Periodontal Patients. J Clin Periodontal. 1984;11:619-28.
29. View Abstract: Kondo A, Kimura K, Isobe Y, et al. Folic acid reduces risks of having fetus affected with neural tube defects: dietary food folate and plasma folate concentration. Nippon Hinyokika Gakkai Zasshi. Jul2003;94(5):551-9.