Scientific Backgrounders Folic Acid

Purpose

The purpose of this backgrounder is to present a summary of current scientific data and research regarding the use of folic acid as a dietary supplement. It is intended for educational use only and is not intended to be used as third-party literature.

Note: μg=mcg=microgram

Folic Acid
Derived from the term “foliage,” folate, is a member of the B vitamin family found primarily in dark leafy green vegetables, legumes, citrus fruits, beets, meat, and wheat germ.  Folic acid does not occur in nature and is rarely found in unfortified foods; it is not an active form of the B-vitamin. However, it is the most common form of folate used in supplements and in fortified food products because it is highly bioavailable and chemically stable and is readily reduced to tetrahydrofolate, the active coenzyme form of folate. Folic acid is water-soluble and absorbed from the small intestine and some is stored in the liver and other tissues. Water-soluble vitamins are predominately excreted through sweat and urine, thus additional loss may occur in active individuals.¹ Folates are absorbed in the proximal small intestine by a saturable, pH sensitive transporter that transports oxidized and reduced folates.² Most dietary folate, and folic acid in the diet, is metabolized to 5-methyltetrahydrofolate during its passage across the intestinal mucosa. When high doses of folic acid or other folate forms are consumed, a part is absorbed by passive diffusion, and appears in the circulation unchanged. The bioavailability of folic acid is close to 100% when it is consumed on an empty stomach. Although information on the bioavailability of food folate and folic acid taken with food is limited, the current best estimates are 50% (aggregate food folate) and 85% (folic acid).^{2, 3} Recent studies have indicated that supplements provide a more bioavailable form of folic acid than do fortified foods. A study comparing folic acid from orange juice and folic acid from a supplement showed that the supplement had better absorption rate than the fortified orange juice.⁴

Figure 1. Folic Acid Chemical Structure

Folate is used as a generic term for a family of chemically and functionally related compounds based on the folic acid structure (Fig. 1). Folic acid (molecular weight 441.4), also known as pteroylglutamate, is a chemically oxidized, synthetic form of the vitamin and consists of a pterin (2-amino-4-hydroxypteridine) ring linked to p-aminobenzoic acid, which is conjugated to a molecule of L-glutamic acid. Folic acid is readily reduced within the cell to the metabolically active 5,6,7,8-tetrahydrofolate form. Folates in tissues act as donors and acceptors of one-carbon units in metabolic reactions known as one-carbon metabolism. These units can be at the oxidation level of methanol (5-methyltetrahydrofolate), formaldehyde (5,10-methylenetetrahydrofolate), or formate (5- or 10-formyltetrahydrofolate or 5,10- methenyltetrahydrofolate). The predominant coenzyme forms are listed in Table 1. ²

Table 1.  Active Forms of Folate

Food Fortification and Supplementation to Prevent Deficiencies

In 1998, the United States Food and Nutrition Board of the National Academy of Sciences and a joint FAO/WHO Expert Consultation on Human Vitamin and Mineral Requirements reviewed their recommendations for folate intake.³ Since that time U.S. Food and Drug Administration and the U.S. Department of Agriculture have required grain products to be fortified with folic acid. Estimates conclude that fortification increases the daily intake by approximately 100 μg per day.⁴ The panel found that Individuals who do not routinely consume the suggested level of folate from foods should be encouraged to supplement their diets with folic acid. The Institute of Medicine’s recommendations on Folate intake, the recommended daily intake (RDI) can be found here: http://www.iom.edu/Object.File/Master/7/296/webtablevitamins.pdf

Prevention of Neural Tube Defects (NTD)

Neural tube defects (NTDs) are major birth defects of a baby’s brain or spine. They happen when the neural tube (that latter turns into the brain and spine) doesn’t form right, and the baby’s brain or spine is damaged. The two most common NTDs are spina bifida and anencephaly. About 3,000 pregnancies in the United States are affected by spina bifida or anencephaly each year.  These birth defects can cause lifelong disability or death. The US Public Health service (http://www.cdc.gov/ncbddd/folicacid/), along with the March of Dimes recommends that all women of childbearing age take 400 μg as a supplement every day in order to reduce the risk of these NTDs caused by folic acid deficiency.[i] This evidence is so convincing that the FDA has authorized a disease risk reduction health claim for folic acid supplements in regards to birth defect risk reduction. Because the neural tube closes during the 4th week of embryonic life, before many women realize they are pregnant, and the population at risk of this condition cannot be identified, it is recommended that all women planning a pregnancy or who of child-bearing age take 400 μg folic acid/daily, either as a supplement or through fortified foods.^{3, 5} In addition, women with a family history of NTDs or who have had a previous NTD affected pregnancy should be encouraged to take a daily supplement containing 40005000 μg folic acid during the periconceptional period. Some argue that increased fortification is required to further decrease NTD rates and point to the 70% reduction observed in the initial intervention trials. However, others maintain that NTD rates had been falling prior to fortification, and the underlying rate in the United States was low in comparison to that observed in some other countries. Folate intervention studies in China demonstrated a 70% drop in NTD rates in areas of high prevalence and a much smaller drop in areas of lower prevalence.⁶

A 2004 study by the Lewin Group found that if 10.5 million women of childbearing age began taking 400 μg of folic acid daily, approximately 600 fewer babies would be born with neural tube defects per year, which would provide significant relief in national health care costs. This study compared the low cost of the supplement versus the costs in direct medical expenses, varying types of therapy, equipment and special education costs. The study concluded that an estimated $1.3 billion in lifetime medical costs could potentially be saved over a five year period at the time of publication.⁷

Although research is preliminary, folic acid, taken either alone or as part of a multivitamin, may also provide critical support for both mother and fetus and ensure a healthy pregnancy. Most recently, the link between folic acid and healthy blood pressure during pregnancy has been studied, as well as folic acid’s possible beneficial effect on full term pregnancy.^8-15

Heart Healthy

Folic acid is not just for expectant mothers. Extensive research indicates it also maintains heart and blood vessel health by controlling a substance called homocysteine. Homocysteine is a byproduct of the breakdown of protein, and excess blood levels of homocysteine have been linked to increased risk of cardiovascular disease, stroke and Alzheimer’s disease.^16-18 Folic acid assists in keeping balanced blood levels of homocysteine, as well as providing antioxidant protection.^19-21 Folic acid and certain other B vitamins function as coenzymes to either recycle homocysteine or break it down for excretion in the urine. ¹⁹

Although it cannot be conclusively stated that high concentration homocysteine is a cause of vascular disease, a compelling body of observational studies over the past two decades strongly implicates modest elevations in plasma homocysteine with an increased risk.

In healthy ambulatory populations, low dietary intake and low blood levels of folic acid, B12, and B6 are the primary determinants of blood homocysteine levels.²² It is clear that daily administration of these three vitamins reduces blood homocysteine levels to those associated with considerably lower cardiovascular risk. Provision of supplementation with folic acid often suffices, with two notable exceptions. If hyperhomocysteinemia is due to a deficiency of B12 or B6, folate supplementation will not help. Secondly, the hyperhomocysteinemia that commonly develops in individuals with chronic renal insufficiency and in post-renal-transplant recipients is particularly resistant to low doses of folic acid supplementation.²³

Cognitive Effects

The role of folate in nucleic acid synthesis and methylation reactions is essential for normal brain function. Over the past decade several investigators have described associations between decreased folate levels and cognitive impairment in the elderly.²⁴ A large cross-sectional study of elderly Canadians found that those individuals with low folate levels were more likely to have dementia, be institutionalized, and be depressed. However, these findings could reflect the poorer nutritional status of institutionalized elderly and individuals with dementia. In the same study, low folate levels were associated with an increased likelihood of short-term memory problems in elderly individuals who did not show signs of dementia. ^{25, 26} In a recent study of 30 elderly nuns, who lived in the same convent, ate the same diet, and had similar lifestyles, researchers found a strong association between decreased blood folate levels and the severity of brain atrophy related to Alzheimer's disease after their deaths.²⁷  Moderately increased homocysteine levels, as well as decreased folate and vitamin B12 levels have also been associated with Alzheimer's disease and vascular dementia. Low serum vitamin B12 (< 150 pmol/L) or folate (< 10 nmol/L) levels were associated with a doubling of the risk of developing Alzheimer's disease in 370 elderly men and women followed over 3 years.²⁸

In a sample of 1,092 men and women without dementia followed for an average for 10 years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia.^{16, 29} Those with plasma homocysteine levels greater than 14 micromoles/liter had nearly double the risk of developing Alzheimer's disease. A recent study which followed the diets of 965 seniors for six years, found that those who had the highest intake of the nutrient from both food sources and supplements were least likely to develop the disease.³⁰ As part of the FACIT trial to assess the effect of folic acid on markers of atherosclerosis in men and women aged 5070 years with raised plasma total homocysteine and normal serum vitamin B12 at screening, 818 participants were given either 800 μg daily oral folic acid or placebo for 3 years.³¹  Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.³¹

Some evidence links low levels of folate with depression There is emerging evidence from randomized controlled trials that using folic acid in addition to antidepressant medication may have benefits.^32-34 However, the evidence is probably too limited at present for this to be a routine recommendation.^35-37

Supplemental Folic Acid for Pharmacotherapeutic Induced Deficiencies

Many physicians prescribe methotrexate (7.515 mg per week) for the treatment of rheumatoid arthritis, asthma, and ulcerative colitis. The side effects of this treatment, including alopecia, stomatitis, pancytopenia, and interstitial pulmonary fibrositis, are thought to be inversely related to serum folate levels at the start of treatment.³⁸ Daily administration of 1 mg of folic acid to people who take methotrexate appears to significantly reduce the development of side effects, and does not interfere with the efficacy of treatment.^{39, 40} Long-term use of sulfasalazine, an anti inflammatory that is often administered for the treatment of inflammatory bowel disease and rheumatoid arthritis, is often associated with folate deficiency.⁴¹ Therefore, prophylactic co-administration of folic acid at 4001000 μg per day is indicated.³⁸ Phenytoin, and Phenobarbital have repeatedly been associated with either low serum folate levels or frank folate deficiency.⁴² Therefore, chronic administration of these drugs should also prompt prophylactic administration of 4001000 μg of folic acid per day. ³⁸

Chronic alcoholism is associated with a considerable risk of folate deficiency.^{43, 44} A large part of this effect can be explained by the fact that the diet of a chronic alcoholic is often folate poor. However, other mechanisms have also been described, including impaired intestinal deconjugation of polyglutamated food folates, increased metabolic turnover or urinary excretion, and cleavage of the folate molecule by acetaldehyde.^{43, 44} Since deficiencies of other B-vitamins commonly accompany folate deficiency in this setting, administration of a multivitamin preparation containing 400 μg of folic acid is probably the best approach to avoid development of deficiency.²

Safety

Although folic acid is not generally associated with side effects, there have been individual clinical reports that high levels of folic acid may mask a deficiency of vitamin B12. However, a deficiency of B12 is uncommon, and the Institute of Medicine has determined that only amounts above 1000 μg per day of folic acid may have this masking effect, which can be eliminated by supplementing with a few mcg of B-12.³

NOTICE

By furnishing this backgrounder, the Natural Products Association does not provide any opinion as to:

-The safety of any product containing this ingredient;

-The efficacy of any product containing this ingredient;

-The use of any specific brand of product; or

-The level of substantiation for either the safety or efficacy of any such product.

Neither this backgrounder nor any portion of this backgrounder may be used in advertising or promotional materials. In addition, this backgrounder does not constitute, and is not to be used as, "third party literature" as that term is used in connection with section 5 of the Dietary Supplement Health and Education Act (DSHEA).

References

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