Key Benefits of Metafolin®

A Readily Bioavailable Folate Vitamer

Metafolin - Click to view larger image
Click image to enlarge.

Metafolin® is L-methylfolate, the active form of folate that predominantly occurs in foods and is directly bioavailable. Folic acid, in comparison, needs to be activated before it can be used by the body. The efficacy of these metabolic processes shows high individual fluctuations, which means it is possible that folic acid will not be adequately converted into metabolically active folate forms by some individuals. Metafolin® can be directly used by the body – independent of the underlying genotype of specific folate dependent enzymes (e.g., MTHFR: methylenetetrahydrofolate reductase).


  • A readily bioavailable folate vitamer (folic acid is a provitamin and needs to be activated)

    Metafolin® is the naturally-occurring predominant form of folate. Taking a Metafolin®-containing food supplement provides the same folate benefit as enriching your diet with a natural folate vitamer.

  • Directly usable by the body, independent of genetic variants of folate dependent enzymes

    Metafolin® is identical to the main circulating form of folate in the body. It can be directly used by the body – independent of the underlying genotype of specific folate dependent enzymes. In contrast, the activation of folic acid into an active folate requires several enzymatic steps. Individuals with polymorphisms in the enzymes involved (e.g., MTHFR), may not benefit sufficiently from folic acid supplements.

  • Directly involved in lowering homocysteine blood levels

    Metafolin® is directly involved in decreasing homocysteine blood levels, which are associated with cardiovascular diseases.

  • The only form of folate able to cross the blood-brain barrier

    Experiments with labeled folate forms suggest that the transport into the central nervous system (CNS) is specific for L-methylfolate (as Metafolin®). Other folate forms need to be transformed into the biologically prevalent form, L-methylfolate, before they can be transported into the CNS.

  • Does not mask vitamin B12 -deficiency

    Elderly people are at an increased risk for vitamin B12-deficiency. A fast diagnosis is critical to prevent irreparable neurological damages caused by this disease.

    The symptoms of vitamin B12-deficiency include both hematological and neurological effects. While the hematological effects are reversible, the associated neurological effects may be irreversible depending on how far they have progressed before detection and treatment. High intakes of folic acid are said to mask the anemia associated with a vitamin B12-deficiency. This may delay diagnosis and prompt treatment while neurological damage progresses.

    It has been suggested, that Metafolin® lacks the ability of masking symptoms of B12 deficiency. The rational explanation behind this is called the “methyl-trap hypothesis”: The reaction from L-methylfolate to tetrahydrofolate is B12 dependent. This means that in the case of B12 deficiency, L-methylfolate becomes “trapped” as it cannot be further biochemically processed. See references for a more detailed description of the “methyl-trap hypothesis”.

  • No risk of accumulation of unmodified folate in the body

    Today, folic acid is added to a wide variety of foods (e.g., fruit juice, cereals, chocolate milk). In some countries there is a mandatory folic acid food-fortification of specific foods (e.g., grain products in the U.S., Canada and Chile). In addition, some parts of the population take folic acid-containing multivitamins. Consequently, the individual amount of daily folic acid intake differs considerably. Given that some individuals cannot sufficiently metabolize folic acid into L-methylfolate due to an enzyme polymorphism, this may lead to unmetabolized folic acid circulating in the human organism. Although folic acid has been consumed for decades, it does not occur in nature and our body is not used to handling it.

  • Extensive toxicological tests deem Metafolin® as safe

    Numerous toxicological studies have been conducted on this product. Based on this data, the U.S. FDA accepted our new dietary ingredient notification.

    Additionally, JECFA (Joint FAO/WHO Expert Committee on Food Additives) considered Metafolin® as safe for the use in dietary supplements, foods for special dietary use, and other foods.

Meeting regulatory requirements

In 2001, the U.S. FDA accepted our new dietary ingredient notification. Metafolin® is approved in key regions and for product categories. Metafolin® is also known as L-methylfolate; L-5-MTHF-Ca; L-methylfolate calcium; L-5-Methyltetrahydrofolic acid, calcium salt; [6S]-5-Methyltetrahydrofolic acid, calcium salt.

Patent information

Metafolin® is protected by a comprehensive set of patents and patent applications on the substance, key intermediates, production processes and its use in specific fields. Therefore Metafolin® can be licensed to selected companies in clearly-defined market segments.

For more information regarding Metafolin®, please contact us.


Boilson A, et al. (2012). Unmetabolized folic acid prevalence is widespread in the older Irish population despite the lack of a mandatory fortification program. Am J Clin Nutr. 96(3):613-21.

Botto L & Yang Q. (2000). 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE Review. Am J Epidemiol. 151(9):862-77.

Gutstein S, et al. (1973). Failure of response to N5-methyltetrahydrofolate in combined folate and B12 deficiency. Evidence in support of the “folate trap” hypothesis. Am J Dig Dis. 18(2):142-6.

Hasselwander O, et al. (2000): 5-Methyltetrahydrofolate: The active form of folic acid. Functional foods 2000, Conference proceedings.

Herbert V & Zalusky R. (1962). Interrelations of vitamin B12 and folic acid metabolism: folic acid clearance studies. J Clin Invest. 41:1263-76.

Kelly P, et al. (1997). Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 65(6):1790-5.

Kirke P, et al. (2004). Impact of the MTHFR C677T polymorphism on risk of neutral tube defects: case-control study. BMJ. 328(7455):1535-6.

Lamers Y, et al. (2004). Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr. 79(3):473-8.

Levitt M, et al. (1971). Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate. J Clin Invest. 50(6):1301-8

Lucock M. (2004). Is folic acid the ultimate functional food component for disease prevention? BMJ. 328(7433):211-4.

Noronha JM & Silverman M. (1962) On folic acid, vitamin B12, methionine and forminoglutamic acid metabolism. In: Vitamin B12 and Intrinsic Factor ( H.C.Heinrich), pp. 728–736. Enke, Stuttgart.

Obeid R, et al. (2011). Concentrations of unmetabolized folic acid and primary folate forms in plasma after folic acid treatment in older adults. Metabolism. 60(5):673-80.

Patanwala I, et al. (2014). Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr. 100(2):593-599.

Scott J. (2001). Methyltetrahydrofolate: The Superior Alternative to Folic acid. Nutraceuticals in health and disease prevention, 75-90 [Krämer K, Hoppe PP and Packer L, editors]. New York: Marcel Dekker Inc.

Spector R & Lorenzo AV. (1975). Folate transport in the central nervous system. Am J Physiol. 229(3):777-82.

Sweeney M et al. (2005). Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants. Br J Nutr. 94(5):727-30.

Troen A, et al. (2006). Unmetabolized folic acid is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr.136(1):189-94.

Venn BJ, et al. (2003). Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr. 77(3): 658-62.