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Folic Acid

Nutrient Name: Folic acid; folate, folinic acid.
Synonyms: Folacin; folate triglutamate, folicin, pteroyltriglutamate, pteroylglutamic acid, vitamin B9, vitamin Bc, vitamin M; 5-formyltetrahydrofolate (5-FTHF), 5-methyltetrahydrofolate (5-MTHF), 6(S) 5-MTHF,L-methylfolate; calcium folinate, calcium levofolinate, citrovorum factor, sodium folinate.

Summary Table
nutrient description

Chemistry and Forms

The Latin word for leaf, folium , was chosen to designate the nutrient present in green leafy vegetables and originally isolated from four tons of spinach leaves in 1946. The terms “folic acid” and “folate” are often used interchangeably for this water-soluble B-complex vitamin. However, folate is the preferred term for the mixture of related compounds occurring naturally in foods, whereas folic acid is the more stable form and is used in supplements and added to fortified foods, but rarely occurs in foods or the human body. Thus, forms are preferentially referred to on this basis in most usages within this monograph, with deference to nomenclature of original sources.

Folic acid may be more specifically identified as pteroylmonoglutamate or pteroylglutamic acid (PGA). Described chemically as N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid, it is comprised of para-aminobenzoic acid (PABA) linked at one end to a pteridine ring and at the other end to glutamic acid. Its molecular formula is C19H19N7O6, and its molecular weight is 441.40 daltons. Folic acid forms yellowish orange crystals. The color is imparted by the pteridine ring of folic acid. Pteridine also imparts color to the wings of certain butterflies.

Pteroylmonoglutamate (PGA) is the parent compound for many structurally related, derivative compounds that exhibit the biological activity of folic acid and are collectively referred to by the generic term folate . Most naturally occurring folates are pteroylpolyglutamate derivatives, containing two to seven glutamates joined in amide (peptide) linkages to the gamma-carboxyl of glutamate, with folylpoly-γ-glutamates being the predominant, naturally occurring form of dietary folates. Naturally occurring folates include 5-methyltetrahydrofolate (5-MTHF), 5-formyltetrahydrofolate (5-formyl-THF), 10-formyltetrahydrofolate (10-formyl-THF), 5,10-methylenetetrahydrofolate (5,10-methylene-THF), 5,10-methenyltetrahy-drofolate (5,10-methenyl-THF), 5-formiminotetrahydrofolate (5-formimino-THF), 5,6,7,8-tetrahydrofolate (THF), and dihydrofolate (DHF). The term folate is also used specifically to designate the anionic form of folic acid.

Physiology and Function

Folate, usually present as pteroylpolyglutamate derivatives in food, is hydrolyzed to pteroylmonoglutamate forms by folyl conjugase (also known as folate conjugase or γ-glutamylhydrolase) from the pancreas and mucosal conjugase from the intestinal wall before absorption from the small intestine. The monoglutamate forms of folate, including folic acid, are transported across the proximal small intestine, primarily the jejunum, by both active transport and diffusion. This is a saturable pH-dependent process, so absorption is decreased in an alkali medium and in the presence of added zinc. When ingested on an empty stomach, folic acid is generally twice as available as dietary sources of folate; folic acid consumed with food is 1.7 times as available as folate in food.

Following absorption of physiological amounts of folic acid into the enterocytes, a certain percentage undergoes reduction. Folic acid (PGA) is the inactive precursor of tetrahydrofolic acid (THFA) and methyltetrahydrofolate; it is converted to THFA, its biologically active form, with the participation of niacin and vitamin C, as well as several coenzymes and other nutrients. However, a functional methionine synthase deficiency can develop within the context of vitamin B12deficiency so that essentially all the folate becomes trapped as the N5-methyl THF derivative, thus preventing the synthesis of other THF derivatives required for the purine and thymidine nucleotide biosynthesis pathways. Reduced folate is transported to the liver via the portal circulation, where it is metabolized to polyglutamate derivatives by the action of folylpolyglutamate synthase. These pteroylpolyglutamate forms are the active cellular cofactor forms of folate.

The total body store of folate is about 12 to 28 mg. All tissue forms of folate are polyglutamates, with pteroylpentaglutamates being the principal type of intracellular folates. Approximately two thirds of folate in plasma is protein bound. Circulating forms of folate are monoglutamates, with pteroylmonoglutamates as the principal extracellular folates and 5-MTHF in its monoglutamate form being the principal folate in the plasma. The liver contains approximately 50% of the body stores of folate, or about 6 to 14 mg. Folate is excreted in the bile, and much of it is reabsorbed through the enterohepatic circulation. This enterohepatic recycling is important for modulating serum levels. Folate is also synthesized by the gut microflora, and as a result, some folates may be eliminated in the feces. However, the kidneys provide the predominant route for folate excretion. Folate enters the glomerulus intact and is reabsorbed into the proximal renal tubule. It is excreted in the urine primarily as folate cleavage products, with only a small amount of intact folate. The excretion of folates found through the breast milk represents a critical pathway for folate activity by providing availability for infant development.

The functions of folate in human physiology are relatively simple, but the implications of their activity (and dysfunction) can be profound and far-reaching. Through its coenzymes, folate plays an essential role in synthesis of nucleic acids, interconversion of amino acids, and single-carbon metabolism. Mediation of single-carbon transfer reactions is considered the primary and possibly exclusive function of folate coenzymes involved in a variety of reactions critical to the metabolism of nucleic acids and amino acids, especially the synthesis of purines and pyrimidines, glycine, and methionine. Thus, through its role in the synthesis of nucleotides from guanine, adenine/pyrimidine, and thymine, folate is required for the synthesis, methylation, and repair of deoxyribonucleic acid (DNA) and is involved in the synthesis of transfer ribonucleic acid (tRNA). This role in cell division is critical in cellular development and maturation, including tissue regeneration, but especially fetal growth and development in general and healthy formation of the nervous system in particular.

Folate plays a fundamental role in synthesis and interconversion of amino acids and the formation and utilization of formate. Folate is involved in the synthesis of glutamic acid, norepinephrine, and serotonin and the detoxification of homocysteine (Hcy) to methionine. Notably, several genetic mutations, including the 677CT polymorphism, influence Hcy metabolism by their effect on the activity of 5,10-methylenetetrahydrofolate reductase, the gene that provides instructions for making methylenetetrahydrofolate reductase (MTHFR), a critical enzyme (requiring flavin adenine dinucleotide [FAD] as a cofactor) that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is required for the conversion of Hcy to methionine. Consequently, individuals who are homozygous (TT) for the abnormal gene have lower levels of the MTHFR enzyme and a marked tendency to hyperhomocysteinemia. Improved folate nutriture appears to stabilize the MTHFR enzyme, as does adequate riboflavin nutriture (the source of FAD), resulting in improved enzyme levels and lower Hcy levels. Methionine synthase (another enzyme requiring folate and B12as cofactors) combines Hcy with the 5-MTHF produced in the reaction catalyzed by MTHFR so that the Hcy becomes methionine and the 5-MTHF becomes MTHF. Thus, this folate coenzyme plays a critical role in the synthesis of methionine, which is required for the synthesis of S-adenosylmethionine (SAMe), the universal methyl donor essential to many biological methylation reactions.

Folate is also essential for the formation and maturation of red blood cells (RBCs) and white blood cells (WBCs). Folic acid is required for nucleoprotein synthesis and maintenance in erythropoiesis and is the single carbon carrier in the formation of heme; it also stimulates WBC and platelet production. Folate deficiency anemia is one of the megaloblastic anemias and is clinically and pathologically indistinguishable from vitamin B12deficiency anemia (pernicious anemia).

Impairment of any of these activities of folate, whether caused by genetic mutations, dietary deficiency, or drug-induced depletion, can produce a cascade of adverse effects directly influencing fetal development, DNA replication, healthy cellular and system function, and development of atherosclerosis, heart disease, and cancer.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Within conventional practice, supplemental folic acid and dietary folate are used exclusively for the prevention of neural tube defects (NTDs; e.g., spina bifida, anencephaly) during in utero development and the treatment of demonstrated folate deficiency, primarily manifesting as megaloblastic and macrocytic anemias. However, epidemiological and clinical evidence continues to emerge regarding the preventive and therapeutic efficacy of enhanced folate intake in reducing atherogenic Hcy levels and improving endothelial function to modify cardiovascular risks, supporting neurotransmitter levels in relation to mood disorders and neurodegenerative processes, and preventing cancers, particularly breast, pancreatic, and colon cancers.

Broad efforts at preventing NTDs through dietary fortification have produced mixed benefits. Thus, although largely successful, these programs have exhibited varied penetration of key susceptible populations, and controversy as to their adequacy continues regarding both NTDs and other epidemiological patterns. 1-9For example, a 2006 survey showed that, even after mandatory fortification of U.S. cereals and grains with folic acid in 1998, women in racial and ethnic minority groups had lower serum folate levels than non-Hispanic white women. 10 Thus, pregnant women who do not regularly take folic acid–containing supplements are eight times more likely to have low serum folate values, despite eating folate-fortified foods. 11 Additionally, expanding knowledge of the multiple polymorphisms affecting folate metabolism is providing a working understanding of susceptibilities to folate-related pathologies and is highlighting the influence of individual genomic variability in the effectiveness of preventive measures and therapeutic applications.

Historical/Ethnomedicine Precedent

The long-standing adages declaring the value of leafy green vegetables in health maintenance and disease prevention may be a result, at least in part, of their being rich in folates.

Possible Uses

Acquired immunodeficiency syndrome and human immunodeficiency virus (AIDS/HIV) support, age-related hearing loss (reduction), Alzheimer's disease, anemia (thalassemia, if deficient), anger (hyperhomocysteinemia associated with MTHFR mutations), atherosclerosis, bipolar disorder, breast cancer prevention (risk reduction in women who consume alcohol), canker sores (with deficiency), cardiac events and death (risk reduction after first stroke), celiac disease (deficiency only), cervical cancer prevention, cervical dysplasia (abnormal Pap test), Crohn's disease, colon cancer prevention, depression, dermatitis herpetiformis (deficiency), diarrhea, Down syndrome, epilepsy, folate metabolism polymorphisms, gingivitis (as rinse), gout, hemorrhagic stroke (risk reduction), hypercholesterolemia, hyperhomocysteinemia, hypertension (risk reduction), laryngeal leukoplakia (risk reduction), lung cancer (risk reduction), malabsorption and gastrointestinal inflammation, megaloblastic anemia, migraine headaches, myocardial infarction, neural tube defect (prevention), osteoarthritis (with vitamin B12), osteoporosis, periodontal disease, peripheral vascular disease, postpartum support, preeclampsia, pregnancy (potential or known), psoriasis, restless legs syndrome, rheumatoid arthritis, schizophrenia (deficiency or hyperhomocysteinemia associated with MTHFR mutations), seborrheic dermatitis, second stroke (risk reduction), seizure disorders, sickle cell anemia (hyperhomocysteinemia), skin ulcers, ulcerative colitis, vitiligo.

Deficiency Symptoms

Folate deficiency results in reduction of DNA synthesis and thus in reduction of cell division. Because the main metabolic consequences of folic acid deficiency are changes in cellular nuclear morphology, rapidly multiplying cells are most affected, such as fetal tissue, erythrocytes, and the epithelial cells of the stomach, intestines, vagina, and cervix. Thus, folate deficiencies result in neural tube and other birth defects, impaired infant development, poor growth, megaloblastic (macrocytic) anemia and other blood disorders, fatigue, weakness, frequent infections, insomnia, irritability, paranoid behavior, mental confusion, hostility, forgetfulness, depression, syncope, headache, palpitations, elevated Hcy level, atherosclerosis, dyspnea, anorexia, glossitis, nausea, dyspepsia, constipation, diarrhea, cervical dysplasia, and hair loss. Gastrointestinal (GI) disturbances are common, resulting from atrophy of digestive tract epithelium. Reduced production of platelets can increase risk of abnormal bleeding. Likewise, impairments in WBC development reduce immune response and increase susceptibility to infections.

Folate deficiency is common, and folate activity is subject to many stressors. Intake of dietary folate and supplemental folic acid is inadequate for a significant proportion of the population, and mild folic acid deficiencies are often undetected. Populations particularly at risk for compromised folate nutriture include alcoholics, the elderly, impoverished people, women using birth control pills, and individuals with malabsorption disorders. Some conditions, such as chronic alcohol consumption and celiac disease, are associated with both low dietary intake and diminished absorption. Tobacco decreases the absorption of folic acid. Certain conditions, such as pregnancy, lactation, hemolytic anemia, leukemia, and other cancers, result in increased rates of cell division and metabolism, leading to an increase in the body's demand for folate. In 1975, folate deficiency during pregnancy was estimated as high as 60%; programs of folate fortification of grains have not been consistently effective in eliminating this significant risk factor. Finally, numerous medications can interfere with folate metabolism, deplete folate (especially with long-term use), or exacerbate folate deficiency in those with other factors adversely influencing folate status.

Several genetic mutations may directly impair folate activity, with profound implications only beginning to be understood. Most prominently, the C677T MTHFR polymorphism, a common variation involving the gene for methylenetetrahydrofolate reductase (MTHFR), can adversely affect folate metabolism and function, particularly the conversion of 5,10-methylene-THF to 5-methyl-THF. Elevated Hcy levels and increased risk for vascular disease are strongly associated with these MTHFR mutations because methyl-THF is the predominant circulatory form of folate and the main carbon donor for the remethylation of homocysteine to methionine. A mutation in the MTHFR gene leading to mild to moderate hyperhomocysteinemia has been found in 15% of patients with premature cerebrovascular disease. Individuals with severe MTHFR deficiency (0%-20% residual activity) present in infancy or adolescence with developmental delay, motor and gait dysfunction, seizures, schizophrenic disturbances, and other neurological abnormalities; they are also at risk of vascular complications.

Homocysteic acid, the oxidation product of Hcy, exerts potent excitatory effects and may be associated with anger, hostility, schizophrenia-like psychosis, depression, and bipolar disorder, particularly in individuals with the homozygous TT genotype of the thermolabile C677T MTHFR polymorphism. The risk of elevated serum levels of total homocysteine (tHcy) is increased in individuals with the combination of the MTHFR 677TT and RFC1 80GG genotypes. Devlin et al. 12 conducted a study of interactions among polymorphisms in folate-metabolizing genes and serum tHcy concentrations in a healthy elderly population. They found that folate and tHcy concentrations were not affected individually by the MTHFR 1298AC, RFC1 80GA, or GCPII 1561CT polymorphisms or by combinations of the MTHFR 677CT and MTHFR 1298AC genotypes. However, individuals with the combination of MTHFR 677TT and RFC1 80GG genotypes exhibited higher serum tHcy.

Inherited defects in methionine synthase, dihydrofolate reductase, and glutamate formiminotransferase, as well as congenital conditions affecting folate absorption and membrane transport, can also influence vascular and mental health through their impact on folate metabolism.

Administration of folic acid will produce marked alleviation of pernicious anemia (the megaloblastic anemia related to vitamin B12deficiency), but the GI signs and symptoms and the neurological lesions continue to progress. For this reason, supplements of 1000 µg (1 mg) or greater of folic acid require a prescription in the United States and some other Western countries. Combining 1 mg or more of oral vitamin B12with 1 mg or more of folic acid would obviate this problem; 1 mg or more of vitamin B12will reliably correct B12deficiency, even in the presence of pernicious anemia, atrophic gastritis, chronic proton pump inhibitor therapy, or other B12malabsorption syndromes.

Dietary Sources

Foods rich in folates include dark-green leafy vegetables (spinach, kale, mustard greens, turnip greens, escarole, chard, arugula, beet greens, bok choy, dandelion green, mache, radicchio, rapini or broccoli de rabe, Swiss chard), liver (beef or chicken) and other organ meats, egg yolk, and brewer's yeast. Folylpoly-γ-glutamates are the predominant form of folates occurring naturally in foods. Other good sources are beets, broccoli, brussel sprouts, cabbage, cauliflower, asparagus, orange juice, cantaloupe, kidney and lima beans, pinto beans, garbanzo beans, black-eyed peas, lentils, soybeans, soy flour, potato, wheat germ, and whole-grain cereals and breads. Fortified cereals made from processed grains can also serve as sources of folic acid. The symbiotic flora comprising the intestinal microbiota, if intact, also synthesize a significant amount of folate.

Folic acid is water soluble, with some forms stable to heat and others heat sensitive. Some forms are stable to acid and others destroyed. Vegetables stored at room temperature undergo considerable loss of folic acid. Virtually all the folate in dried milk has been destroyed.

The absorption efficiency of natural folates is approximately 50% that of folic acid in supplements or fortified foods. The model of dietary folate equivalents (DFEs) has been introduced to account for the difference in absorption efficiency between natural food folate and folic acid. Thus, DFEs can be calculated as follows: 1 microgram (µg) of DFEs = 1µg food folate = 0 .5 µg folic acid taken on empty stomach = 0 .6 µg folic acid taken with meals

Nutrient Preparations Available

The principal form of supplemental folate is folic acid, as a single ingredient or in combination products such as B-complex formulations. Folate triglutamate (pteroyltriglutamate) is also used. 5-Methyl folate and 5-formyl folate are commercially available reduced folates.

5-formyltetrahydrofolate (5-FTHF) and 5-methyltetrahydrofolate (5-MTHF) are the reduced and metabolically active forms of folic acid. Folinic acid, the free acid of calcium folinate, is the more frequently used form and is also known as calcium folinate (Leucovorin Calcium, Leukovorin, Wellcovorin), calcium levofolinate (Isovorin), citrovorum factor (Citrovorum), and sodium folinate (Sodiofolin). Folinic acid is a racemic mixture of levorotatory and dextrorotatory isomers. The levo-isomer is the metabolically active moiety. These calcium or sodium salts are used for parenteral or oral administration.

Metafolin, Merck's patented synthetic form of 6(S) 5-MTHF, orL-methylfolate, is the only form available (for the duration of Merck's patent) of the levorotatory (L) chiral isomer of 5-MTHF, which is the chiral isomer made by human metabolism from folic acid, and also the chiral form found in foods which contain 5-MTHF. It is derived from commercially available B-complex vitamin folic acid, which is reduced to tetrahydrofolate in a process that leads to the formation of a new chiral center and two diastereoisomers in an equimolar ratio. TheLisomer (6S-isomer) of methylfolate is then isolated by selective crystallization. Metafolin is promoted as a form of folate that requires no reduction steps once absorbed and that is immediately bioavailable and thus unaffected by the MTHFR C→T polymorphism. 14L-Methylfolate also bypasses most folate-interfering compounds, such as those that inhibit dihydrofolate reductase (e.g., methotrexate, pemetrexed, EGCG).

Dosage Forms Available

  • Oral:   Capsule, liposomal spray, liquid, tablet, tablet (effervescent).
  • Injection:   Deep intramuscular, subcutaneous, or intravenous; sodium folate solution (0.1 mg folic acid per 1 mL), usually 5 mg/mL (10 mL), contains benzyl alcohol.

Source of Materials for Nutrient Preparations

Folic acid used in supplements, prescriptions, and food fortification (e.g., wheat flour) is synthesized from guanidine and glutamic acid as starting materials. The chemical synthesis ofL-5-MTHF (Metafolin) starts from the commercially available vitamin folic acid, which is chemically reduced to tetrahydrofolate (THF). This reduction step leads to the formation of a new chiral center and two diastereoisomers in an equimolar ratio. In nature, reduced folates consist only of the pure levo (L) isomer (corresponding to the 6S isomer for methylfolate); thus, processes were developed allowing the isolation of the naturalLform by selective crystallization. 13

Dosage Range

Adult

Dietary: 300 µg folic acid daily for adults. In United Kingdom, average adult daily diet for women provides 224 µg, and for men, 322 µg.

  • Supplemental/Maintenance:   400 µg daily for adults.

The U.S. Food and Drug Administration (FDA) recommends 600 µg folic acid for pregnant women and 500 µg for nursing women. Based on survey data published in 1996, Lawrence et al. 10 recommend, “Until the optimal folate level is identified that confers maximum protection against neural tube defects, health care providers and women's health advocates should continue to encourage women who can become pregnant to take a vitamin containing 400 micrograms of folic acid every day.” Women who could become pregnant are advised to take 400 to 800 µg of folic acid per day in anticipation of the possibility of conceiving because folic acid deficiency is most critical during the initial stages of pregnancy, when many women are not yet aware of their being pregnant.

The folic acid dose in over-the-counter (OTC) nutritional supplements is limited to 900 µg. Doses of 1 mg or greater require a prescription. Folic acid is best taken between or with meals, preferably with the dose divided throughout the day.

Pharmacological/Therapeutic:

  • 500 to 800 µg/day is common.
  • Pregnant and lactating women: 0.8 mg/day
  • Pharmacological dosages in scientific literature: 400 to 4000 µg

Administration of 5 to 10 mg daily may occur in research or other specialized settings, including treatment of severe deficiency. Men show a smaller increase in folate and decrease in Hcy to a given dose of folic acid than women. 15

  • Toxic:   Folic acid is essentially nontoxic, even at very high doses. The tolerable upper intake level (UL) established by the U.S. Institute of Medicine's Food and Nutrition Board is 1000 µg/day (based on synthetic folic acid). This UL is based on folic acid doses of 1 mg or more masking an undiagnosed vitamin B12deficiency (by correcting the anemia that occurs with B12deficiency, which is often the sole sign that alerts health care providers to the presence of an underlying B12deficiency).

Pediatric (<18 Years)

Dietary:

  • Infants, birth to 6 months: 25 µg/day
  • Infants, 7 to 12 months: 35 µg/day
  • Children, 1 to 3 years: 150 µg/day
  • Children, 4 to 8 years: 200 µg/day
  • Children, 9 to 13 years: 300 µg/day
  • Adolescents, 14 to 18 years: 300 µg/day

Supplemental/Maintenance:

  • Infants, birth to 12 months: 0.1 mg/day
  • Children, 1 to 3 years: up to 0.3 mg/day
  • Children, 4 years and older: 0.4 mg/day

  • Pharmacological/Therapeutic:   None specifically established at this time.

  • Toxic:   None specifically established at this time.

Laboratory Values

Serum Folate

Serum folate reflects recent dietary intake and is most useful when combined with assays of vitamin B12and red blood cell (RBC) folic acid. However, serum folate and serum vitamin B12can be normal in mild folate and vitamin B12deficiencies. Homocysteine (folate and B12) and methylmalonic acid (B12only) are more sensitive indicators of mild folate and vitamin B12deficiencies.

  • Normal levels: 4.5 to 30 nmol/L or 5.4 to 24 µg/mL.

Red Blood Cell Folate (Erythrocyte Folate)

The RBC folate levels reflect body folate stores. RBCs are generally macrocytic when folate and/or B12deficiency states are present except in combined deficiencies of both folate and iron, common in malnourished individuals.

  • Normal levels: 280 to 790 ng/mL RBCs.
  • Levels < 312 nmol/L can indicate deficiency.
  • Note:   Different laboratories use different reference ranges for serum folate and RBC folate because their analytical assays vary. Many antibiotics may interfere with the microbiological assay for serum and erythrocyte folic acid and can produce falsely low results.

Neutrophilic Hypersegmentation Index (NHI)

The neutrophilic hypersegmentation index (NHI) can identify the earliest stages of folate insufficiency. Deficiency indicated when the ratio of neutrophils with five or more lobes to those with four or fewer lobes is greater than 30%. Hypersegmentation can also result from vitamin B12deficiency and is not reliable during pregnancy.

Serum Methylmalonic Acid

Methylmalonic acid (MMA) is useful in differentiating folate and cobalamin deficiency.L-Methylmalonyl coenzyme A (CoA mutase is a vitamin B12–dependent enzyme; therefore a B12deficiency, but not a folate deficiency, will lead to an increase in MMA.

Total Homocysteine

Total homocysteine (tHcy) concentration indicates folate and/or cobalamin deficiency and serves as predictor of risk for arterial stiffness, ischemic stroke, and myocardial infarction. Homocysteine levels can also be elevated by genetic polymorphisms that result in greater requirements of pyridoxine (vitamin B6), as well as deficiencies of pyridoxine and methyl donor nutrients in general.

A plasma tHcy concentration exceeding 15 µmol/L indicates hyperhomocysteinemia, although many investigators propose that achieving much lower levels (7-10 µmol/L) is necessary for decreasing vascular disease risk.

If anticoagulated blood tubes are allowed to sit longer than 10 minutes before spinning, the tHcy level can be falsely elevated. Pharmacological doses of niacin also falsely elevate tHcy levels and should be held for 24 hours before drawing blood to determine tHcy levels.

Serum Homocysteine

Serum Hcy indicates folate or cobalamin deficiency and serves as predictor of risk for ischemic stroke and myocardial infarction. It is used to assess homocystinuria.

  • Normal levels: Male: 4.3-11.4 micromol/L
  • Female: 3.3-10.4 micromol/L

Emerging and Related Tests

  • Tetrahydrofolate (THF) concentrations.
  • Whole-blood folate may also be valuable in some settings, but standards have only recently been established.
  • Fluorescence polarization immunoassay (FPIA) can be performed for the quantitation of total human L-homocysteine in serum or plasma.
  • Methylene-THFR identifies normal, heterozygous, and homozygous genotypes.
  • 5,10-Methylene-THFR C677T polymorphism identifies the mutation and provides preliminary evaluation of associated increased thrombotic risk and obstetrical risk.

Emerging research indicates the need to test for MTHFR 1298AC, RFC1 80GA, and GCPII 1561CT polymorphisms in establishing cardiovascular risk. 12

Analysis of both the C677T mutation and the A1298C mutation is recommended for evaluation of obstetrical risk in patients with recurrent fetal loss. Patients who are heterozygous for the C677T mutation are reflex-tested for the A1298C mutation. Only C677T homozygotes and C677T/A1298C compound heterozygotes are at increased risk for thrombotic events.

  • Note:   S-adenosylmethionine (SAMe) has a similar molecular form to S-adenosylhomocysteine, and exogenous intake, at therapeutic levels, may interfere with this assay.

safety profile

Overview

Supplemental folic acid is essentially nontoxic, even at high doses, and extremely safe at nutritional doses. Folic acid doses up to 1 mg daily are well tolerated. Substantive and consistent evidence of adverse effects attributable to folic acid supplementation is lacking. Adverse effects attributed to folic acid primarily derive from issues of diagnosis and clinical management.

Health care professionals are advised to counsel patients to avoid supplementing with 800 µg or more of folic acid daily unless they have been evaluated for vitamin B12deficiency or they coadminister 1 mg or more of B12. Inappropriate use of folic acid in large doses could precipitate neuropathy in individuals with undiagnosed B12deficiency (usually from pernicious anemia). More than 100 cases have been reported in which vitamin B12–deficient subjects receiving oral folic acid at 5 mg or more daily experienced progression of neurological symptoms and signs. Reports are rare of such complications in individuals receiving doses of folic acid less than 5 mg daily. Consequently, the U.S. Food and Nutrition Board advises that all adults limit their intake of folic acid to 1000 µg daily. The concerns regarding safety underlying dose restrictions are limited to synthetic folic acid intake through supplements and fortification. Folate from food sources is generally considered highly unlikely to mask vitamin B12deficiency.

Aggravations of seizure disorders have been reported in patients who initiated folic acid supplementation while undergoing anticonvulsant therapy. Such reactions may result from folic acid interfering with the activity of antiepileptic drugs.

Nutrient Adverse Effects

General Adverse Effects

Sleep disturbances, mental changes, and GI effects have been associated with high-dose folic acid intake, greater than 10 mg daily. Doses greater than 5 mg (5000 µg) daily may cause digestive upset in some individuals. Wheezing, dyspnea, fever, erythema, skin rash, itching, and other symptoms of allergic reactions have been reported on rare occasions.

Some secondary sources suggest that extended intake of high doses may cause uricosuria or produce folacin crystals in the kidney. Dialysis patients have increased requirements for folic acid and vitamin B6, needing at least 800 µg to 1 mg or more of folic acid and 10 mg or more of B6each day.

Adverse Effects Among Specific Populations

Folic acid supplementation, without vitamin B12, is contraindicated in patients with B12deficiency, especially pernicious anemia.

The effects of folate on cognitive function have generally been considered salubrious, particularly in elderly persons. However, a single study in 2005 produced the unexpected finding that high folate intake was associated with more rapid cognitive decline in older adults, particularly men and women taking supplemental folic acid at levels greater than 400 µg/day. Subjects in the top quintile of folate intake (> 700 µg/day) exhibited twice the rate of mental decline over 6 years as those who with the lowest folate intake. Although suggesting caution in routine use of folic acid supplements (without vitamin B12), the authors emphasized that evidence was lacking to confirm that folate itself caused the cognitive deterioration seen in some study participants and noted that high folate intake might be masking a vitamin B12deficiency in some individuals. 16 No other research has pointed to similar patterns. An intervention trial administering folate supplements, B12supplements (in equivalent doses to the folate), and both folate and B12together, with single and double placebo control groups, to elderly subjects over 5 years would be required to address the issues conclusively. Notably, in the subsequent Veterans Affairs Normative Aging Study, Tucker et al. 17 found that high Hcy and low B-vitamin plasma levels predicted cognitive decline in aging men. Moreover, folate (plasma and dietary) “remained independently protective against a decline in spatial copying score after adjustment for other vitamins and for plasma homocysteine.”

Preschool children administered folic acid (and iron) may be at higher risk of severe illness and death in a high-malaria-transmission setting. Routine prophylactic supplementation should be avoided pending further research. However, within the context of an active program “to detect and treat malaria and other infections, iron-deficient and [anemic] children can benefit from supplementation.” 18

Haggarty et al. 19 reported that high levels of serum folate appear to increase the risk of a dizygotic twin birth after women are impregnated through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). In particular, the rate of twins was associated with elevated levels of plasma and RBC folate (odds ratio [OR] 1.27 for each 100-g change in folate intake). However, the authors noted that “there was no significant association between folate and vitamin B12intake, or blood levels, and pregnancy or rate of live births or pregnancy loss after IVF.”

Pregnancy and Nursing

Enhancement of dietary folates and supplemental folic acid is recommended for any woman of childbearing age who might become pregnant, and this is specifically required during pregnancy. Folate enters breast milk and is beneficial. Folic acid and folate are specifically recommended to prevent developmental birth defects, particularly neural tube defects. Specific maximum safe dosages have not been established for pregnant or nursing women. (See, however, previous discussion on possible effects of high folate levels in relation to assisted reproduction.)

Infants and Children

No adverse effects have been reported in children or would be predicted.

Contraindications

Folic acid at doses greater than 800 µg/day is contraindicated when vitamin B12status is uncertain. Doses greater than 1 mg/day may obscure pernicious anemia, with irreversible progression of neuropathy, unless the B12deficiency is corrected with high-dose (1-2 mg/day) oral or parenteral B12.

Prophylactic folic acid (and iron) may be contraindicated for children in malarial environments. 18

Some clinicians have suggested that individuals with elevated blood levels of histamine (i.e., histadelia) should avoid supplemental folic acid because it can produce further histamine excess and aggravate a tendency to depression, schizophrenia, or other adverse effects purported to be associated with elevated histamine levels.

Precautions and Warnings

Self-administration of folic acid at levels greater than 400 µg/day is inadvisable in individuals being treated with anticonvulsants, antifolates, and other medications with a mechanism of action based on interfering with folate activity.

interactions review

Strategic Considerations

Folate is a vital nutrient for everyone, as evidenced by universal recommendation to eat bountiful amounts of dark-green leafy vegetables and other folate-rich foods. Overwhelming evidence indicates that folate deficiency is widespread, even among those presumed to have adequate diets, but particularly among the elderly population, malnourished individuals, tobacco smokers, and those who excessively consume alcohol or processed foods. Furthermore, the folate that is consumed in the diet, produced endogenously, and ingested as a supplement is fragile, or at least vulnerable to a wide range of stressors, most notably pharmacological agents.

Healthy levels of folate in the blood and target tissues enable many key physiological functions, such as normal DNA synthesis and healthy cell division, homocysteine regulation, and endothelial function, and thus play a key role in preventing many pathological processes, including carcinogenesis and atherogenesis. However, polymorphisms in the genes coding for key folate metabolism enzymes, such as MTHFR, thiopurine methyltransferase (TPMT), and inosine triphosphate pyrophosphatase (ITPase), play a key role in folate status, susceptibility to folate-related pathologies, response to folate administration, and tolerance of and therapeutic response to medications affecting folate.

Conventional medicine does not generally employ laboratory tests adequately sensitive for detecting compromised folate status, particularly depletion patterns and deficiency states at the tissue and mitochondrial level, before they reach pathological proportions at a system-wide level. Unless specifically contraindicated, folic acid supplementation could reasonably be recommended for everyone as basic nutritional support for health maintenance and prevention of many pathological and degenerative processes, especially if the person is taking one of the medications discussed later. The supervising caregiver then focuses on carefully monitoring the patient in specific situations requiring closer clinical management. The implications of folate deficiency can be profound and severe, from teratogenesis during pregnancy to stroke later in life, and constitute the primary clinically significant influence of drug interactions involving folate and folic acid for both short-term medical management and long-term strategies of wellness and prevention.

The main caution against folic acid administration is that vitamin B12deficiency, especially severe deficiencies such as those associated with pernicious anemia, might be masked. This warning, however, seems misplaced or at least uninformed because almost every folic acid product on the market is formulated with vitamin B12, at a minimum, or a comprehensive range of synergistic nutrients, as in a multivitamin or B-complex formulation. All health care providers experienced in nutritional therapeutics routinely coadminister folic acid and vitamin B12as a matter of safety, synergy, and efficacy. The more significant (and sometimes controversial) question centers on appropriate dosage levels, and emerging evidence is clarifying this clinical picture. Generous quantities of B12may be critical to effectiveness much more often than previously thought, especially in older people. Generally, conventional nutritional education has framed folate dosing in hundreds of micrograms and B12in single-digit micrograms because of the difference in quantity that prevents serious deficiency states. However, a pivotal clinical trial by Eussen et al. 20 showed that once deficient (by MMA levels), at least 500 to 600 µg of oral vitamin B12is required to correct an established pattern of “mild” depletion. Thus it is advisable always to give equivalent amounts of B12with folate.

Folic acid interacts with and is depleted by a wide range of medications. Some agents incidentally impair folate absorption and transport, but others rely on competitive inhibition and other means of directly interfering with folate activation and folate-dependent enzymes as central to their mechanism of action. In most cases, coadministration of folic acid offers a safe, easy, and inexpensive means of preventing, reducing, or reversing drug-induced adverse reactions, particularly folate deficiency at blood, tissue, and cellular levels, and interference with physiological activities of folate and related enzymes. Folate coadministration is contraindicated only in patients being treated with antifolate medications for tumors, and then primarily in doses greater than 1000 µg/day. Moreover, when the toxic effects of these medications exceed tolerance or safety limits, folic acid, or more often folinic acid, the activated form, is applied “to pull the situation back from the brink” (so-called rescue). Such contraindications are generally not applicable when the same medications, particularly methotrexate, are used for reasons other than antineoplastic activity.

Research and clinical experience increasingly indicate significant clinical benefits from use of 5-FTHF (folinic acid) and 5-MTHF as sources of activated folate in light of impaired enzyme activity, especially MTHFR, as a result of drug interference and genetic polymorphisms. For many years the use of folinic acid (5-FTHF) has largely been restricted to rescue use with methotrexate and other antifolate medications. The therapeutic significance of this and other forms of folate administration that bypass enzymatic inhibition (e.g., 5-MTHF) becomes more apparent, with growing awareness of the potential adverse implications of unintended decreases in functional folate levels.

Along with the major risk of neural tube defects from folate deficiency during early gestation, homocysteine (Hcy) regulation appears as the most recurrent theme in reviewing the strategic significance of drug interactions with dietary folate and supplemental folic acid. The pervasive and destructive effects of elevated Hcy levels are well documented and widely known. Methionine synthase, the enzyme that metabolizes Hcy to methionine, uses 5-MTHF and vitamin B12as cofactors. Folic acid may have antiatherogenic mechanisms independent of lowering Hcy levels. Besides effects on the vascular system, plasma tHcy level and low serum folate concentrations are independent risk factors for dementia as well as low bone mineral density, particularly among women. 17,21-26In a randomized, placebo-controlled trial involving 46 Taiwanese subjects (42 men, average age 73), Lin et al. 27 demonstrated that low-dose folic acid (400 µg daily) supplementation reduces Hcy concentration in hyperhomocysteinemic coronary artery disease (CAD) patients and could also reduce CAD risk. Compliance was assessed over 8 weeks by 24-hour diet recalls at week 0 and week 8. Notably, although the low-dose folic acid supplements had no significant effect on Hcy concentrations in the general study population, levels did significantly decrease in hyperhomocysteinemic subjects, by 1.8 µmol/L, especially for carriers of the T-allele.

The evolving debate as to whether Hcy represents a causal or coincident factor in heart disease, cerebrovascular accident (stroke), and related conditions shifted to a new level with publication of the Vitamin Intervention for Stroke Prevention (VISP) trial. When the VISP intention-to-treat analysis failed to show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke, Spence et al. 27a conducted an “efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated.” After excluding “patients with low and very high B12levels at baseline,” they found “a 21% reduction in the risk of events in the high-dose group compared with the low-dose group.” Also, “patients with a baseline B12level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12less than the median assigned to low-dose vitamin had the worst.” They concluded: “In the era of folate fortification, B12plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine, may be needed for some patients.”

Subsequently, the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), NORVIT, and HOPE-2 trials supported research demonstrating that these nutrients help lower Hcy levels. However, these trials failed to support the hypothesis that lowering Hcy levels alone will provide protection against a future cardiovascular event in high-risk patients with established cardiovascular disease. For example, in the Norwegian study of post–myocardial infarction (MI) patients randomized to a folate-B12-B6formulation or placebo, Bønaa et al. 28,29observed a pattern of increased risk of a second MI in the intervention group, despite a lowering of Hcy. Although relevant to certain patient populations, the findings from these trials suggest that such a study of secondary prevention (patients with previous MI) have limited applicability to primary prevention (individuals without previous vascular events) in healthy individuals and in those with elevated risk. Notably, the HOPE-2 study demonstrated a statistically significant 25% reduction in nonfatal strokes. 30

Nevertheless, the current data are incomplete because all patients were taking standard post-MI medications (e.g., beta blockers, ACE inhibitors, aspirin). Also, investigators did not monitor drug levels to see if the B vitamins were depleted by the medications or, conversely, if the medications were impaired or levels lowered by the nutrients, as may occur if the nutrients (e.g., vitamin E) induce the pregnane X receptor (PXR). Such potentially significant variables, which were not assessed or factored in, might explain the unexpected “increased risk” associated with the B vitamins, which would actually be analogous to poor compliance with medication. Research into PXR is in preliminary stages, and a focus on its relevance to B vitamins may be warranted and could clarify these and other findings. More broadly, such findings do not detract from other potential benefits derived from lowering Hcy levels, or at least reversing processes associated with elevated Hcy.

An ongoing dialectic between reviews and meta-analyses continues and is unlikely to produce definitive conclusions and more precise recommendations until large-scale, long-term, and well-designed prospective interventional clinical trials are conducted. In reviewing the data from numerous cohort studies, Wald et al. 31 (2006) determined that despite controversy and apparently conflicting evidence in reports of the benefits of folate consumption on cardiovascular disease risk, the weight of evidence supports recommending folic acid for cardiovascular health. Their meta-analysis showed that a 3-µmol/L decrease in serum Hcy levels, considered achievable with a daily folic acid intake with 0.8 mg, lowers the risk of heart attack and stroke by 15% and 24%, respectively. Furthermore, in studies focusing on MTHFR genotypes, the investigators reported that high Hcy levels were associated as “causal” for the risk of stroke and that the “dose-response relation in the genetic studies is particularly relevant in suggesting a causal effect.” Overall, the estimate from the trials was consistent with a short-term protective effect of 12% on ischemic heart disease episodes and 22% on stroke, or a greater long-term effect. The degree that folic acid reduces Hcy concentration depends on background folate levels, so increasing folic acid consumption should reduce the risk of heart attack and stroke to a degree related to the Hcy reduction. The authors concluded “that the evidence is now sufficient to justify action on lowering homocysteine concentrations, although the position should be reviewed as evidence from ongoing trials emerges.” 31

Conversely, in a meta-analysis, Bazzano et al. 32 evaluated the effects of folic acid supplementation on risk of cardiovascular diseases and mortality in randomized controlled trials among persons with preexisting cardiovascular or renal disease. They concluded that folic acid supplementation “has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease,” but noted that “ongoing trials with large sample sizes might provide a definitive answer to this important clinical and public health question.”

The issue of whether the potential benefits of folic acid and related nutrients that affect Hcy derive from other functions and effects, beyond lowering Hcy, appears increasingly important given the controversial findings and disappointed expectations of Hcy-centered interventional trials and meta-analyses. The role of folic acid in reversing endothelial dysfunction may be central to these protective effects. In a small but potentially pivotal study involving 128 patients with CAD, Moat et al. 33 found that high-dose folic acid (5 mg/day) for 6 weeks significantly improved endothelial function, independent of its effect on lowering plasma Hcy levels. Notably, these investigators observed that subjects administered folate at either 400 µg/day or 5 mg/day had significant increases in plasma folate and significant decreases in plasma Hcy, whereas only subjects who received 5 mg/day exhibited significant improvements in flow-mediated dilation. Another subgroup of subjects, administered betaine (3 g twice daily), showed significant impairment in flow-mediated dilation, despite a reduction in plasma Hcy. The authors’ conclusion that their findings suggest that folic acid “dose-dependently improves endothelial function in CAD via a mechanism independently of Hcy lowering” may portend a significant evolution in this body of research.

In a related experiment focused on the mechanism(s) underlying such observed phenomena, Moat et al. 34 demonstrated that folic acid can reverse “both the endothelial dysfunction and increased production of superoxide following depletion of rabbit aortic ring tetrahydrobiopterin (BH4) levels with 2,4-diamino-6-hydroxy-pyrimidine (DAHP) and N-acetyl-5-hydroxy-tryptamine (NAS).” Thus, they concluded that “folic acid reverses the endothelial dysfunction induced by BH4 depletion independently of either the regeneration or stabilization of BH4 or an antioxidant effect.”

Emerging evidence indicates that the influence of elevated Hcy levels extends beyond risk of stroke and heart disease, and that folate and other B vitamins have an important role in preventing or reducing other degenerative processes, especially those associated with aging. The literature associating hyperhomocysteinemia with dementia is well known and suggests a broader focus for future research and preventive nutritional support. For example, in a 3-year, randomized, placebo-controlled trial involving 728 subjects age 50 to 72, Durga et al. 35 found that folate (800 µg/day) may reduce age-associated hearing loss, particularly in individuals with elevated Hcy levels. The interconnections between Hcy, folate nutriture, and degenerative processes will undoubtedly be the subject of continued investigation.

The causes of hyperhomocysteinemia are broadly categorized as “inherited” and “acquired.” Many causes involve folate nutriture, metabolism, and function. The inherited causes include MTHFR deficiency or defect, methionine synthase defect, vitamin B12transport defect, vitamin B12coenzyme synthesis defect, and cystathionine-β-synthase deficiency. The acquired causes can be grouped as vitamin deficiencies, chronic diseases, and medication effects. Nutritional deficits of folic acid, vitamin B12, and vitamin B6can usually be remedied by ensuring adequate dietary sources and administering supplements that provide these synergistic nutrients. Enhanced folate intake may be of direct and indirect benefit for patients with chronic renal failure, hypothyroidism, psoriasis, and malignancies (including acute lymphoblastic leukemia). Notably, conventional treatment of these conditions often involves drug therapies that deplete or interfere with folate. Also, medications that adversely affect folate status and function constitute one of the primary risk factors for hyperhomocysteinemia. Fortunately, this last factor may be the most amenable to clinician intervention, with this monograph being a tool in providing safe and effective medical management by employing an evidence-based, integrative approach to health care delivery.

nutrient-drug interactions
Acetylsalicylic Acid (Aspirin) and Salsalate
Antacids
Antacids

  • Evidence:

    Aluminum hydroxide (Alternagel, Amphojel).

Extrapolated, based on similar properties: Aluminum carbonate gel (Basajel), aluminum hydroxide combination drugs: aluminum hydroxide, magnesium carbonate, alginic acid, and sodium bicarbonate (Gaviscon Extra Strength Tablets, Gaviscon Regular Strength Liquid, Gaviscon Extra Strength Liquid); aluminum hydroxide and magnesium hydroxide (Advanced Formula Di-Gel Tablets, Co-Magaldrox, Di-Gel, Gelusil, Maalox, Maalox Plus, Mylanta, Wingel); aluminum hydroxide, magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets), calcium carbonate (Titralac, Tums); magnesium hydroxide (Phillips’ Milk of Magnesia MOM); combination drugs: magnesium hydroxide and calcium carbonate (Calcium Rich Rolaids); magnesium hydroxide, aluminum hydroxide, calcium carbonate, and simethicone (Tempo Tablets); magnesium trisilicate and aluminum hydroxide (Adcomag trisil, Foamicon); magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets); combination drug: sodium bicarbonate, aspirin, and citric acid (Alka-Seltzer).

Cimetidine and Related Histamine (H 2 ) Receptor Antagonists
Proton Pump Inhibitors
Anticonvulsant Medications, Including Phenobarbital, Phenytoin, and Valproic Acid
Antifolates and Related Antimetabolites, Including Lometrexol, Methotrexate, Pemetrexed
Bile Acid Sequestrants
Chloramphenicol
Colchicine
Fenofibrate, Bezafibrate, and Related Fibrates
Fluoxetine and Related Selective Serotonin Reuptake Inhibitor and Serotonin-Norepinephrine Reuptake Inhibitor (SSRI and SSRI/SNRI) Antidepressants
Isoniazid, Rifampin, and Related Antitubercular Agents
Levodopa and Related Antiparkinsonian Agents
Lithium Carbonate
Mercaptopurine, Azathioprine, and Thioguanine (Thiopurines)
Metformin and Related Biguanides
Neomycin
Nitroglycerin and Related Nitrates
Nitrous Oxide
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Pancreatic Enzymes, Pancreatin, and Related Proteolytic Enzymes
Pyrimethamine
Sulfasalazine and Related Sulfonamide Antibiotics (Systemic)
Tetracycline Antibiotics (Systemic)
Triamterene and Related Potassium-Sparing Diuretics
Trimethoprim-Sulfamethoxazole
Zidovudine/AZT
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Acyclovir
Antibiotics
Beta-Adrenergic Blocking Agents and Calcium Channel Blockers (Systemic)
Corticosteroids, Oral, Including Prednisone
Cycloserine
Fluorouracil
Furosemide and Related Loop Diuretics
Medroxyprogesterone
Raltitrexed
Thiazide Diuretics
nutrient-nutrient interactions
B Vitamins
Pancreatin and Proteolytic Enzymes
Vitamin C
Zinc
herb-nutrient interaction
Coffee
Citations and Reference Literature
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