L-5-Methyl Tetrahydrofolate

L-5-Methyl Tetrahydrofolate

L-5-methyl tetrahydrofolate (L-5-MTHF) is the metabolically active form of folate utilized by the body. Many people are familiar with the benefits of incorporating folic acid supplements into their daily lives. Folic acid, also called folate or vitamin B9, is critical to many body processes, including the health of the nervous system, blood, and cells. Folic acid may also protect against heart disease, birth defects, osteoporosis, and certain cancers. Many of the benefits derived from folic acid are a result of its role in methylation, which is necessary for healthy homocysteine metabolism, proper DNA function, neurotransmitter synthesis, detoxification of unwanted compounds, and many other functions.

Despite all of this information, many people are unaware that up to 40% of the population may not receive the vital benefits expected from their form of folate supplementation due to a certain genetic variation, called a single nucleotide polymorphism (SNP). Unfortunately, if a particular SNP is present in one's DNA, the activity of the folic acid metabolizing enzyme methylenetetrahydrofolate (MTHFR) may be disrupted. Through MTHFR disruption, the conversion of folic acid to its functional and beneficial form, L-5-MTHF, may be greatly compromised. Thus, by simply taking folic acid supplements, patients who carry the SNP may be unable to complete all of the necessary steps required to convert folic acid to L-5-MTHF.

However, with direct introduction of L-5-MTHF, several steps including the crucial MTHFR enzymatic step, are bypassed. Ultimately, this makes L-5-MTHF the preferred form of folate for those individuals who are unable to convert folic acid to its most active and beneficial form.


  • Provides the metabolically active form of folate, helping to ensure that all of the critical benefits of folate nutrition are realized.
  • Helps promote optimal methylation and homocysteine levels. High homocysteine levels have been linked with increased risk of heart disease and stroke. Thus, L-5-MTHF supports cardiovascular and overall health.
  • Supports neurotransmitter synthesis, such as dopamine and serotonin, thus promoting healthy mental function. L-5-MTHF helps regulate mood, sleep, and appetite.
  • Helps support the metabolism and detoxification of estrogen.
  • Helps prevents birth defects such as spina bifida and other neural tube defects. Half of all neural tube defects are believed to be preventable if women of childbearing age supplement their diets with L-5-MTHF (folate). Studies suggest that the amount of L-5-MTHF (folate) needed to prevent neural tube defects is more easily reached with supplements than from dietary sources alone.
  • Helps maintain healthy DNA synthesis, replication, and repair. These are all important factors in maintaining healthy genetic expression and the integrity of tissues throughout the body.

Dietary Sources

While folic acid is found in many foods, such as liver, lentils, rice germ, brewer's yeast, soy flour, black-eyed peas, beans, peanuts, spinach, turnip greens, whole wheat, and asparagus, adequate amounts of L-5-MTHF for those who may be unable to fully metabolize folic acid is best received through direct nutritional supplementation.

Other Forms

L-5-MTHF is available in tablet form.

How To Take It

The Recommended Daily Intake (RDI) for L-5-MTHF (folate) depends on your age and sex, but ranges from 65 to 400 mcg. Check with your healthcare provider before you start taking L-5-MTHF supplements and before giving L-5-MTHF supplements to a child.


L-5-MTHF toxicity is rare. High doses (above 15 mg) can cause stomach problems, sleep problems, skin reactions, and seizures. L-5-MTHF supplementation can mask vitamin B12 deficiency, which can cause permanent damage to your nervous system. Thus, L-5-MTHF supplementation should always include vitamin B12.

Possible Interactions

  • Birth control medications, anticonvulsants (such as phenytoin), and cholesterol-lowering medications, may reduce the levels of L-5-MTHF (folate) in the blood as well as the body's ability to use this vitamin.
  • Sulfasalazine, a medication used for ulcerative colitis and Crohn's disease, may reduce the absorption of L-5-MTHF (folate), leading to lower levels in the blood.
  • L-5-MTHF (folate) should not be taken at the same time as tetracycline, an antibiotic, because it interferes with the absorption and effectiveness of this medication. L-5-MTHF (folate) alone or as part of a vitamin B complex supplement should be taken at different times from tetracycline.
  • When taken for long periods of time, aspirin, ibuprofen, acetaminophen, and other anti-inflammatory medications can also increase the body's need for L-5-MTHF (folate).

For more information about L-5-MTHF, consult your healthcare provider.

Supporting Research

Bailey LB, Gregory JF. Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 1999;129(5):919-22.

Choi S-W, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr 2000;130(2):129-32.

Deloughery TG, Evans A, Sadeghi A, et al. Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease. Circulation 1996;94(12):3074-78.

Jacob RA. Folate, DNA methylation, and gene expression: factors of nature and nurture. Am J Clin Nutr 2000;72(4):903-04.

Kim YI. Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutr Rev 2000;58(7):205-17.

Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 1996;94(10):2410-16.

Miyao M, Morita H, Hosoi T, et al. Association of methylenetetrahydrofolate reductase (MTHFR) polymorphism with bone mineral density in postmenopausal Japanese women. Calcif Tissue Int 2000;66(3):190-94.

Nelen WL, Blom HJ, Thomas CMG, et al. Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J Nutr 1998;128(8):1336-41.

Rampersaud GC, Kauwell GPA, Hutson AD, et al. Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am J Clin Nutr 2000;72(4):998-1003.

Yager JD, Liehr JG. Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 1996;36:203-32.

Advanced Nutrition Publications 2002

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