Folic Acid Information

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Requirements & Recommendations Deficiency Signs and Symptoms

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Populations w/ Special Needs Drug-Vitamin Interaction

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Facts

Folic acid is one of the B vitamins. It is found in various forms in common foods, especially green, leafy vegetables.
The vitamin is readily destroyed by air and heat, and appreciable amounts are lost when foods are improperly stored, overcooked, or reheated.
Folic acid and folate are both terms used to describe this vitamin. Folic acid describes the chemical compound, pteroylmono-glutamic acid, which is commonly used as a vitamin supplement. Folate is the general term used to refer to any of the protein-bound or other conjugated forms of folic acid, which are forms generally found in foods.
The body readily absorbs up to 90 percent of folic acid (supplement form). Folate or protein-bound folic acid compounds cannot be absorbed until they are modified by enzymes in the body. As little as 50 percent of folate (food form) can be absorbed.
Folic deficiency results in megaloblastic anemia.
Since January 1998, the FDA has required fortification of cereal grain products such as bread and cold cereals with folic acid (140 mcg/100 g product).

Functions Topic header down arrow

As a coenzyme, folate is essential for the synthesis of the purines, guanine, adenine, the pyrimidines and thymine.
Folic acid plays a role in the biosynthesis of heme and hemoglobin.
Aids in remethylation of homocysteine to methionine. Heart and arterial disease may be prevented and treated with folic acid supplementation to decrease blood homocysteine concentration.
Assists with conversion of ethanolamine to choline.
Assists with conversion of histidine to glutamic acid, and serine to glycine.
Essential for formation of red and white blood cells from stem cells in bone marrow and for their maturation.
Folic acid is involved in the synthesis of DNA and RNA. It is also necessary for DNA replication and repair, maintenance of the genome and regulation of gene expression.

Requirements & Recommendations Topic header down arrow

Folic acid: Dietary Reference Intake ⁴

	mcg/day	Tolerable Upper Intake Levels (UL)
Infants 0 to 6 months 7 to 12 months	65 80	ND ND
Children 1 to 3 years 4 to 8 years	150 200	300 400
Male 9 to 13 years 14 to 18 years 19+ years Female 13 to 19 years 14 to 18 years 19+ years	300 400 400 300 400 400	600 800 1000 600 800 1000
Pregnancy < = 18 years 19 to 50 years	600 600	800 1000
Lactation < = 18 years 19 to 50 years	500 500	800 1000

* Values for infants are Adequate Intake (AI), others are RDA.
ND=Not determinable due to lack of data concerning adverse effects in this age group and concern with regard to lack of ability to handles excess amounts.

Deficiency Signs and Symptoms Topic header down arrow

Folic acid deficiency may occur because of a lack of dietary intake or because of a failure to absorb the vitamin from the intestines. Failure to absorb folic acid can result from interactions with drugs (such as cholestyramine) or diseases such as ulcerative colitis or Crohn's disease.
Poor dietary intake of folic acid results in growth retardation, macrocytic anemia, glossitis, GI disorders, and neural tube defects.
Neural tube defects (NTDs) affect nearly 4,000 pregnancies in the United States each year. The Center for Disease Control (CDC) and the United States Public Health Service (USPHS) estimate that 400 mcg of folic acid per day could help to prevent nearly 70 percent of birth defects. Since NTDs occur very early in pregnancy (before the sixth week of gestation), folic acid supplements are recommended for any woman of child bearing age. Women at particular risk are those who have had a previous NTD-affected pregnancy and those who have a close relative affected by such a pregnancy (such as a sibling). Research is now focusing on how folic acid protects against NTDs.¹²
Homocysteine is the product of demethylation of methionine. It is also an intermediate in the synthesis of L-cysteine from L-methionine (building blocks for proteins). When folic acid concentrations are inadequate, these reactions slow and homocysteine concentrations may accumulate in the bloodstream. Studies have linked high homocysteine levels to coronary heart disease, cerebral vascular disease (linked to strokes), and peripheral vascular disease (in the arms or legs).³ Studies have shown that folic acid, along with other B vitamins, may help prevent these diseases by lowering homocysteine levels.

Toxicity Topic header down arrow

Folic acid at high doses of 5 to 30 mg has demonstrated some increase in frequency of seizures in epileptics.
Adverse effects are unlikely with intakes of up to 1000 mcg.
Over 1000 mcg of folic acid may mask B12 deficiency symptoms.

Dietary Sources Topic header down arrow

Fortified foods such as breads and cereals are good dietary sources of folic acid. Other good sources are dark green leafy vegetables (such as asparagus and broccoli), brewer’s (nutritional) yeast, and liver. Orange juice, beets, dates and avocado are also good sources. Poor sources of folic acid are chicken, milk, most fruits and meats.

Populations w/ Special Needs Topic header down arrow

Anticonvulsant drug therapy in pregnant women has been associated with a higher risk of birth defects in their babies. Folic acid supplementation 400 mcg per day in pregnant women greatly reduces the risk of neural tube defects.
People with arthritis who regularly take aspirin may experience an increased loss of folic acid in the urine. In patients with rheumatoid arthritis, supplementation of 400 mcg of folic acid per day is sometimes recommended by physicians.
Smoking and chewing tobacco have been shown to deplete folic acid concentrations. Folic acid supplements are recommended for smokers to help increase plasma and red blood cell folate concentrations.
Intake of large quantities of alcoholic beverages can deplete stores of folic acid by interfering with absorption. Anyone who consumes excessive alcohol may benefit from supplementation with folic acid. Physicians may want to include supplements of folic acid for their alcoholic patients.
A number of conditions can lead to folate deficiency. Malabsorption syndromes, including Chron's disease, lymphoma or amyloidosis of the small intestine, diabetic enteropathy, tropical and non-tropical sprue can result in folate deficiency secondary to inadequate absorption. Other conditions such as chronic hemolytic anemias, chronic hemodialysis or peritoneal dialysis, and chronic exfoliative skin disorders increase the demand for folate.
Since homocysteine, one of the factors affecting cardiovascular disease and cognitive function, increases with age, folic acid supplementation or multivitamins are recommended in the elderly.
Increased blood homocysteine concentrations are associated with increased risk of cardiovascular disease incidence and mortality in general population and with even greater risk in persons with diabetes mellitus. Hyperhomocysteinemia in macrovascular and microvascular diabetes complications could be of importance in their prevention through dietary (folic acid and B12) and pharmacological modifications of blood homocysteine concentrations.

Drug-Vitamin Interaction Topic header down arrow

⁶ ⁷ ⁸

Anticonvulsant such as Carbamazepine [Tegretolâ], valproic acid [Depakeneâ], and phenytoin [Dilantinâ] have been reported to reduce folic acid absorption in humans.
Antibiotics such as Isomiazidâ, tetracycline, cycloserine and erythromycin therapy longer than 2 weeks may interfere with absorption and/or activity of folic acid.
Oral contraceptives use can cause folic acid depletion.
Sodium bicarbonate (an antacid) can decrease folate metabolism.
Long-term use of H2 blockers such as Famotidineâ and Nizatidineâ may promote a deficiency of folic acid due to decreased absorption, since folic acid requires the presence of stomach acid for optimal absorption.
Indomethacinâ, a non-steroidal anti-inflammatory drug (NSAID), has been reported to decrease absorption of folic acid.
Antidepressant agents such as fluoxetine [Prozacâ] can lower blood concentrations of folic acid. High blood concentrations of folic acid respond better to lithium, an antidepressant agent.
Folate antagonists such as Methotrexateâ (anticancer and antiarthritis agent) and Pyrimethiamineâ (antimalaria agent) can interact with folic acid metabolism, requiring more folic acid.
Salicylic acid (aspirin) used for reducing pain and incidences of heart attack and stroke decreases blood folic acid concentrations.
Long-term sulfonamide therapy, including Sulfamethoxazoleâ and Sulasalzineâ, of more than two weeks can interfere with the activity of folic acid.
Metforminâ, used to lower blood sugar concentrations in non-insulin-dependent diabetics, can lead to low serum folic acid and vitamin B12 concentrations.

Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary Topic header down arrow

Topic: Neural Tube Defects and Birth Defects

	Impaired folate status and or folate related genetic polymorphisms have been linked with risk for a number of birth defects, including neural tube defects. There is definite evidence that sufficient dietary folic acid, currently determined to be 400 mcg a day, before conception and very early in pregnancy, can decrease the risk of babies developing neural tube birth defects.

	• Folic acid and the outcome of pregnancy
	A number of studies have indicated that adequate folic acid status during pregnancy is important for optimal fetal growth and suggest that folic acid supplementation may help problems associated with it. Women with moderately elevated blood homocysteine concentrations may be at increased risk for habitual spontaneous abortion as well as placental abruption (detachment of the placenta from the uterine wall), which can lead to premature delivery and infant death.¹
	Read Abstract

	• Homocysteine induces congenital defects of the heart and neural tube: Effect of folic acid
	A study tested whether exogenous homocysteine would induce congenital defects in avian embryos in the absence of folate depletion. 27% of embryos were given either 200 mM D, L-homocysteine or 100 mM L-homocysteine thiolactone. Folate supplementation kept the rise in serum homocysteine concentration to ~45 nmol/ml, preventing a tertogenic effect in the embryos. Results suggest homocysteine may cause dysmorphogenisis of the heart and neural tube, as well as the ventral wall.¹⁰
	Read Abstract

Topic: Cardiovascular Diseases/Lowering Homocysteine

	Low folic acid concentrations are known to increase plasma homocysteine. Data have suggested that modest doses of folic acid(<1 mg/d) are sufficient to lower plasma homocysteine concentrations. Moderate hyperhomocysteinemia is, today, considered an established risk factor for cardiovascular disease.

	Lowering Homocysteine in Patients with Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death: The Vitamin Intervention for Stroke Prevention(VISP)Randomized Controlled Trial
	The VISP was a randomized controlled trial conducted on over 3600 survivors of non-disabling stroke evaluating whether high doses of folic acid (2.5 mg), B12 (0.4 mg), and B6 (25 mg) reduced the risk of recurrent stroke in adults over a 2 year period. In summary, modest reductions of total plasma homocysteine had no effect on vascular outcomes.¹⁶
	Read Abstract

	Vitamin Intervention for Stroke Prevention Trial: An Efficacy Analysis
	In an efficacy analysis of VISP, the researchers found a subgroup of ~2100 participants more likely to benefit from vitamin therapy. A 21% reduction in risk for events (ischemic stroke, coronary disease or death) was observed in the high-dose vitamin group (25 mg of vitamin B6, 0.4 mg of vitamin B12, 2.5 mg of folic acid), compared to the low-dose vitamin group (20 mcg folic acid, 200 mcg vitamin B6, 6 mcg vitamin B12).¹⁷
	Read Abstract

	Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous TIA
	In a randomized substudy of the VITATOPS trial, effect of B vitamin therapy vs. placebo on lowering tHcy (total homocysteine) was examined in 285 patients with recent TIA or stroke. Folic-acid based multivitamin therapy (2mg folic acid, 0.5mg vitamin B12, 25mg vitamin B6) did reduce tHcy, however, there was no significant difference in blood concentrations of markers of vascular inflammation (hs-CRP), endothelial dysfunction and hypercoagulability in patients receiving vitamin therapy.²⁷
	Read Abstract

	Randomized trial of folic acid supplementation and serum homocysteine levels.
	A study determined how different levels of folic acid supplementation affect serum homocysteine concentration on 151 patients with ischemic heart disease. Dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo were given over a 3 month period. Results indicated that supplementation of folic acid necessary to reduce serum homocysteine concentrations may be greater than the recommended dose (DRI 400 mcg) in ischemic heart disease patients.¹¹
	Read Abstract

	Effect of homocysteine-lowering treatment with folic acid plus vitamin B-6 on progression of subclinical atherosclerosis: a randomized, placebo-controlled trial.
	A trial among 158 healthy siblings of 167 patients with premature atherothrombotic disease, were given either 5 mg of folic acid and 250 mg of vitamin B6 or placebo for 2 years. The overall data suggested that vitamin treatment aimed at lowering concentrations of total blood homocysteine can favorably influence the course of atherosclerotic disease.¹²
	Read Abstract

	Vitamin status and intake as primary determinants of homocysteinemia in an elderly population
	A study on 1160 surviving adults, aged 67 to 96, from the original Framingham Heart Study cohort were examined every 2 years. Overall, researchers found that there was a strong association between plasma homocysteine concentration and folate, vitamins B12 and B6 status, as well as age.¹³
	Read Abstract

	Homocysteine lowering and cardiovascular events after acute myocardial infarction
	The Norwegian Vitamin Trial (NORVIT) evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infarction (MI). 3,749 men and women were randomly assigned to receive folic acid (0.8 mg,) B12 (0.4 mg,) and B6 (40 mg); folic acid and B12; B6 alone; or placebo. Patients were seen at a 2 month follow-up visit and at a final visit after 2 to 3.5 years. Despite a substantial reduction in plasma total homocysteine, interevention with B vitamins did not lower the risk of recurrent cardiovascular disease or death after an acute MI. In the group receiving B vitamins, there was a trend toward an increased rate of events. Researchers conclude that B vitamin intervention not be recommended after acute MI.²⁹
	Read Abstract

	Homocysteine lowering with folic acid and B vitamins in vascular disease
	The Heart Outcomes Prevention Evaluation (HOPE) 2 researchers evaluated whether therapy with homocysteine-lowering B vitamins reduces the risk of major vascular events in a high risk population. The investigators randomly assigned 5,522 patients aged 55 years or older with vascular disease or diabetes to a daily treatment with a B vitamin combination (2.5 mg folic acid, 50 mg B6, 1 mg B12) or placebo for an average of 5 years. The results show daily administration of the B vitamin combination significantly lowered homocysteine but had no beneficial effects on major vascular events in a high risk population with vascular disease.³⁰
	Read Abstract

Topic: Bone Health

	Risk factors for osteoporosis include nutritional factors such as vitamin D deficiency and low calcium intake. Additionally, it has been noticed that those with homocystinuria are often diagnosed with osteoporosis and past studies have linked high homocysteine levels to fracture risks.

	Homocysteine as a predictive factor for hip fracture in older persons
	Researchers examined the association between the totol homocysteine concentration and the risk of hip fracture in 825 men and 1174 women enrolled in the Framingham Study. The results suggest that homocysteine concentration is an important risk factor for hip fracture in persons aged 59 to 91 years.³¹
	Read Abstract

	Homocysteine levels and the risk of osteoporotic fracture
	The association between circulating homocysteine levels and the risk of incident osteoporotic fracture was studied in 2406 subjects aged 55 years or older who participated in either the Rotterdam Study or the Longitudinal Aging Study Amersterdam. Findings suggest an association between homocysteine levels and fracture risk. An increased homocysteine level appears to be an independent risk factor for osteoporotic fractures in older men and women.³²
	Read Abstract

Topic: Breast Cancer

	Studies have indicated that folic acid may have a protective effect against certain types of cancer.

	• A prospective study of folate intake and the risk of breast cancer
	Researchers from Harvard analyzed data from the Nurses' Health Study. The analysis was separated according to alcohol intake (less than or more than 15 g/day), and found that increased consumption of folic acid (at least 300 mcg/day) was associated with a lower risk of breast cancer among women with higher alcohol intake but had no effect on risk among women with lower alcohol consumption.¹⁴
	Read Abstract

Topic: Colon Cancer

	Folic acid may have a supportive role in the prevention of certain types of adenoma, neoplasms associated with ulcerative colitis, and colon cancer. In patients with ulcerative colitis, folic acid has been shown to have a protective effect against neoplasia or abnormal tissue growth.

	• Multivitamin use, folate and colon cancer in women in the Nurses’ Health Study
	Data from the Nurses' Health Study was analyzed to see if multivitamins and folate were associated with risk of colon cancer. Women with a higher folate intake (>400 mcg/day vs.<200 mcg/day)as well as long-term use of multivitamins significantly reduced their relative risk of colon cancer.¹⁵
	Read Abstract

Topic: Diabetes

	There may be a relationship between homocysteine, folate and vitamin B12 concentrations, and urinary albumin excretion in patients with diabetes mellitus. Increased blood homocysteine concentrations are associated with increased risk of cardiovascular disease incidence and mortality in the general population and with even greater risk in persons with diabetes mellitus.

	• Plasma homocysteine and folate are related to arterial blood pressure in type 2 diabetes mellitus
	A study on NIDDM patients and healthy volunteer's fasting and postmethionine load plasma homocysteine concentrations were assessed with folate, B12 and urinary albumin excretion concentrations. NIDDM patients with higher urinary albumin excretion values had enhanced concentrations of systolic/diastolic blood pressures and mean arterial blood pressure. Furthermore, correlations were seen between folate and mean arterial pressure, systolic blood pressure, vitamin B12, and homocysteine.¹⁶
	Read Abstract

	• Reduced total plasma homocyst(e)ine in children and adolescents with type 1 diabetes
	A study investigated total plasma homocysteine (tHcy), methyltetrahydrofolate reductase (MTHFR) genotype, and the contribution of diet to plasma homocysteine concentration among adolescents with Type 1 diabetes and a control group. Total plasma homocysteine (tHcy) concentrations were lower in children and adolescents with type 1 diabetes.¹⁷
	Read Abstract

	• Is pregnancy in diabetic women associate with folate deficiency?
	A study on pregnant diabetic and non-diabetic women's dietary folate intake, serum folate, red blood cell folate, urinary folate and homocysteine were measured and compared. Diabetic women, who had a higher incidence of vitamin supplementation than non-diabetic women, showed significantly higher concentrations of serum and red blood cell folate and ratio of urinary folate to urinary creatinine. Overall, abnormal folate metabolism did not appear to occur in pregnant diabetic women.¹⁸
	Read Abstract

Topic: Psychiatric Disorders



	Nutrition and depression: the role of folate.
	An increase in mental disorders associated with reduced folate status. Folate deficiency appears to be tightly associated with depressive disorders. Epidemiological studies found that 15 to 38% of depressed patients had red blood cell folate deficiency. This may be because folic acid deficiency affects central monoamine metabolism.¹⁹
	Read Abstract

Topic: Cognitive Function



	Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment of improving memory deficits.
	In reviews on more than 10 papers, folic acid supplementation has proven to be effective in improving memory deficit. The degree of cognitive improvement by folate is related to the severity of folate deficiency. However, the severity of initial cognitive function was not correlated to the degree of folate deficiency.²⁰

Topic: Depression

	A low folate status or folate deficiency has been linked to depression and poor antidepressant response, however, these relationships have not been recognized in the general population.

	Depression and folate status in the US Population.
	Researchers from the Human Nutrition Research Center on Aging at Tufts University looked at an ethically diverse sample of healthy subjects with major depression or dysthymia (despondency or mild depression). Low folate status was detected in depressed individuals in the U.S. population. Supplementation with folic acid may be indicated for those suffering from depression.²⁸
	Read Abstract

Topic: Hearing loss



	Age-related hearing loss, vitamin B-12, and folate in elderly women.
	In study of age-related hearing loss in 55 women 60-71 years old of age, poor vitamin B status was associated with hearing impairment. Women with impaired hearing had 31% lower red blood cell folate concentrations than women without impairment.²²
	Read Abstract

Topic: Folic Acid Absorption from Food and Supplements

	Since January 1, 1998, cereal grains sold in U.S. are fortified with 140 mcg of folic acid per 100 g of grain. Despite this level of fortification, however, many experts estimate that total folic acid intake of most women will remain below the recommended concentration.

	• Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease.
	Researchers gave three different concentrations of folic acid (127mcg, 499 mcg, 655 mcg) in cereal and measured plasma folic acid concentration and homocysteine concentrations. Cereal fortified with higher folic acid (499 and 655 mcg) showed larger increases in plasma folic acid concentrations, and a greater decrease in plasma homocysteine concentrations than 127 mcg folic acid. The levels which foods are fortified with folic acid today may not be sufficient to reduce plasma homocysteine.²³
	Read Abstract

Topic: Alzheimers Disease

	Increased plasma homocysteine and decreased serum folate concentrations may be associated with Alzheimer's disease (AD) and dementia of Alzheimer type.

	• Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease
	Researchers at Oxford University in England examined the association between blood homocysteine concentration and the development and progression of AD. The study concluded that elevated blood homocysteine concentrations and low concentrations of folic acid and vitamin B12 may be fairly common among persons with AD.²¹

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The dietary supplement information contained on this site has been compiled from published sources thought to be reliable, but it cannot be guaranteed. Efforts have been made to assure this information is accurate and current. However, some of this information may be purported or outdated due to ongoing research or discoveries. The authors, editors and publishers cannot accept responsibility for errors or omissions or for any consequences from applications of the information in this site and make no warranty, expressed or implied, with respect to the contents herein.