Advifolate - L-5-Methyltetrahydrofolate calcium salt [L-5-MTHF-Ca] [USP]

  • L-Methyltetrahydrofolate, calcium salt; L-Methylfolate, calcium; L-5-MTHF-Ca; N-{4-[[((6S)-2-amino-3,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6-pteridinyl)methyl]amino]benzoyl}-L-glutamic acid, calcium salt
  • CAS Number: 151533-22-1
  • Chemical Formula: C20H23CaN7O6 (anhydrous form)
  • Molecular Weight: 497.5 g/ mol
Advifolate - L-5-Methyltetrahydrofolate calcium salt [L-5-MTHF-Ca] [USP]
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Advifolate Key Facts

  • Compliant to latest USP monograph; L Isomer: 95 to 102%; D isomer: NMT 1%
  • High purity product; Control on all impurities as per USP monograph
  • Realtime stability data - minimum 4 years of stability
  • EFSA recognises L-5-Methyltetrahydrofolate calcium salt as bioavailable source of folate and safe for use in infant and follow-on formula, babyfood and processed cereal-based food
  • Full technical support is available for method development and formulation development

  • Background

    L-5 Methyltetrahydrofolate Calcium is a source of folate and an alternative to folic acid. Folate (vitamin B9) is the term used to refer to a family of water-soluble B-vitamins which serve a vital role in reactions required for normal cell metabolism and regulation, and in the synthesis of DNA and RNA methionine regulation (Bailey & Gregory, 1999). Maintaining adequate folate levels vital at all stages of life however it is especially important during gestation and infancy, with folate deficiency being associated with an increased risk for neural tube defects, certain chronic diseases and cancer (Shrubsole et al., 2001; Robinson et al., 1998; Laurence et al., 1981). Folate is an essential vitamin, and cannot be synthesized by the body and must therefore be obtained through the diet or supplementation. Dietary folate naturally occurs in foods such as green leafy vegetables, legumes, egg yolk and liver, while folic acid is the synthetic form.

    Folic Acid Vs Folate

    To become metabolically active, folic acid must be converted to dihydrofolate and then tetrahydrofolate which is subsequently converted to the biologically active L-5-Methyltetrahydrofolate by an enzyme called methylenetetrahydrofolate reductase. However, many individuals have a genetic polymorphism in which their methylenetetrahydrofolate reductase enzyme is less active, meaning that they are unable to convert folic acid to L-5-Methyltetrahydrofolate (Greenberg et al., 2011). This poses as a problem for folic acid supplementation, as it has been found that in people with this type of polymorphism, folic acid is unable to raise plasma L-5-Methyltetrahydrofolate levels (Greenberg et al., 2011). Calcium salt of L-5 Methyltetrahydrofolate has a great stability profile and it has been shown to be a superior supplement to folic acid as it reduces the potential for masking haematological symptoms of vitamin B12 deficiency (Savage & Lindenbaum, 1994), reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism, as well as reducing the potential negative effects of folic acid in peripheral circulation (Scaglione & Panzavolta, 2014; Pietrzik et al., 2010).


    L-5 Methyltetrahydrofolate Calcium

    CAS – 151533-22-1
    Molecular Formula – C20H23CaN7O6.xH2O; C20H23CaN7O6 (anhydrous form)
    Molecular Weight – 497.5 g/mol
    IUPAC - N-[4-[[(2-Amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6-pteridinyl) methyl]amino]benzoyl]-L-glutamic acid

    Folate and Health

    Folate deficiency can be caused by many factors including dietary insufficiency, malabsorption, medication or an increase in requirements based on physiological conditions (for example, during pregnancy). This deficiency has been associated with an increased risk of several chronic diseases such as cardiovascular disease, cancer and cognitive dysfunction (Ebara, 2017). Folate deficiency has also led to other ailments such as ulcerations on the tongue, changes in skin, hair, or fingernail pigmentation, gastrointestinal symptoms, and elevated blood homocysteine concentrations (Bailey & Caudill, 2012; Carmel, 2005; Ho et al., 2011).


    Low folate status has been associated with numerous cancers such as colorectal, breast and prostate cancer (Chen et al., 2009). Folate intake has also been associated with a protective effect for some cancers including cancers of the bladder (He & Shui, 2014), pancreatic (Lin et al., 2013), oesophageal (Tio et al., 2014) and pharyngeal (Galeone et al., 2015).

    Autism Spectrum Disorder

    There is evidence that suggests increasing folate intake periconceptionally may reduce the risk of Autism Spectrum Disorder (ASD) from prenatal exposure to certain drugs and toxic chemicals (Roffman, 2018; DeVilbiss et al., 2015).

    Cardiovascular Disease

    While increased levels of folate do not directly decrease the risk of cardiovascular disease, elevated homocysteine levels have been associated with an increased risk of cardiovascular disease (Bailey & Caudill, 2012) and folate, along with other B vitamins have been shown to be involved in homocysteine metabolism, decreasing homocysteine levels and therefore could indirectly reduce cardiovascular disease risk.

    Cognitive Decline, Dementia and Alzheimer’s disease

    Elevated homocysteine levels have also been observed to correlated to an increased incidence of Alzheimer’s disease as well as dementia (Ho et al., 2011). There have also been numerous observational studies that have found correlations between low serum folate concentrations and a higher risk of dementia and Alzheimer’s disease, as well as poor cognitive function (Kim et al., 2018; Hooshmand et al., 2011; Smith & Refsum, 2016).


    Studies have found a link between low folate status and depression and a poor response to antidepressants (Huang et al., 2018; Gougeon et al., 2015).

    Neural tube defects

    Neural tube defects result in the malformation of the spine (spina bifida), skill, and brain. Folate is especially important during phases of rapid cell growth due to it playing a role in the synthesis of DNA and other critical cell components (Lamers, 2011), with numerous clinical trials demonstrating the importance of supplementation periconceptionally to help prevent neural tube defects (Wilson et al., 2007; Pitkin, 2007; Scott, 2001).

    Interactions with Medications

    Methotrexate is used to treat rheumatoid arthritis. However, Methotrexate directly inhibits target enzymes of the folate pathway, reducing plasma folate levels (Liu et al., 2018). Therefore, not only is increasing folate levels through supplementation in individuals being treated with Methotrexate very important for general health, but it has also been shown to reduce the incidence of hepatoxicity, gastrointestinal side-effects and patient withdrawal in these individuals (Liu et al., 2018).

    EFSA Approved Health Claims

    • Folate contributes to normal psychological function (2010;8(10): 1760).
    • Folate contributes to the normal function of the immune function (2009;7(9): 1213).
    • Folate contributes to the reduction of tiredness and fatigue (2010;8(10);1760).
    • Folate has a role in the process of cell division (2009;7(0): 1213; 2010;8(10):1760)
    • Folate contributes to normal homocysteine metabolism (2009;7(9):1213).
    • Folate contributes to normal blood formation (2009;7(9):1213).
    • Folate contributes to normal amino acid synthesis (2010;8(10):1760).
    • Folate contributes to material tissue growth during pregnancy (2009; 7(9):1213).


    Advifolate is a trademark of Vita Actives, EU trademark number 018526656.


    1. Bailey LB, Caudill MA (2012). Folate. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Washington, DC: Wiley-Blackwell; pp 321-42.
    2. Bailey, L. and Gregory, J., 1999. Folate Metabolism and Requirements. The Journal of Nutrition, 129(4), pp.779-782.
    3. Carmel R (2005). Folic acid. In: Shils M, Shike M, Ross A, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, MD: Lippincott Williams & Wilkins; pp 470-81.
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    5. DeVilbiss, E., Gardner, R., Newschaffer, C. and Lee, B., 2015. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. British Journal of Nutrition, 114(5), pp.663-672.
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    8. Gougeon, L., Payette, H., Morais, J., Gaudreau, P., Shatenstein, B. and Gray-Donald, K., 2015. Intakes of folate, vitamin B6 and B12 and risk of depression in community-dwelling older adults: the Quebec Longitudinal Study on Nutrition and Aging. European Journal of Clinical Nutrition, 70(3), pp.380-385.
    9. Greenberg, J., Bell, S. and Guan, Y., 2011. Folic Acid Supplementation and Pregnancy: More Than Just Neural Tube Defect Prevention. Rev. Obstet. Gynecol, 4(2), pp.52-59.
    10. He, H. and Shui, B., 2013. Folate intake and risk of bladder cancer: a meta-analysis of epidemiological studies. International Journal of Food Sciences and Nutrition, 65(3), pp.286-292.
    11. Ho, R., Cheung, M., Fu, E., Win, H., Zaw, M., Ng, A. and Mak, A., 2011. Is High Homocysteine Level a Risk Factor for Cognitive Decline in Elderly? A Systematic Review, Meta-Analysis, and Meta-Regression. The American Journal of Geriatric Psychiatry, 19(7), pp.607-617.
    12. Hooshmand, B., Solomon, A., Kåreholt, I., Rusanen, M., Hänninen, T., Leiviskä, J., Winblad, B., Laatikainen, T., Soininen, H. and Kivipelto, M., 2011. Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. Journal of Internal Medicine, 271(2), pp.204-212.
    13. Huang, X., Fan, Y., Han, X., Huang, Z., Yu, M., Zhang, Y., Xu, Q., Li, X., Wang, X., Lu, C. and Xia, Y., 2018. Association between Serum Vitamin Levels and Depression in U.S. Adults 20 Years or Older Based on National Health and Nutrition Examination Survey 2005–2006. International Journal of Environmental Research and Public Health, 15(6), p.1215.
    14. Kim, S., Choi, B., Nam, J., Kim, M., Oh, D. and Yang, Y., 2018. Cognitive impairment is associated with elevated serum homocysteine levels among older adults. European Journal of Nutrition, 58(1), pp.399-408.
    15. Lamers, Y., 2011. Folate Recommendations for Pregnancy, Lactation, and Infancy. Annals of Nutrition and Metabolism, 59(1), pp.32-37.
    16. Laurence, K., James, N., Miller, M., Tennant, G. and Campbell, H., 1981. Double-Blind Randomised Controlled Trial of Folate Treatment before Conception to Prevent Recurrence of Neural-Tube Defects. Obstetrical & Gynecological Survey, 36(11), p.626.
    17. Lin, H., An, Q., Wang, Q. and Liu, C., 2013. Folate intake and pancreatic cancer risk: an overall and dose–response meta-analysis. Public Health, 127(7), pp.607-613.
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    19. Pietrzik, K., Bailey, L. and Shane, B., 2010. Folic Acid and L-5-Methyltetrahydrofolate. Clinical Pharmacokinetics, 49(8), pp.535-548.
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    22. Roffman, J., 2018. Neuroprotective Effects of Prenatal Folic Acid Supplementation. JAMA Psychiatry, 75(7), p.747.
    23. Savage DG, Lindenbaum J. (1994). Folate–cobalamin interactions. In: Bailey LB, ed. Folate in health and disease. New York: Marcel Dekker; pp 237–85.
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    26. Shrubsole, M., Din, F., Dai, Q., Shu, X., Potter, J., Herbert, J., Gao, Y. and Zheng, W., 2001. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res., 61(19), pp.7136-7141.
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    29. Turck, D., Castenmiller, J., De Henauw, S., Hirsch‐Ernst, K., Kearney, J., Maciuk, A., Mangelsdorf, I., McArdle, H., Naska, A., Pelaez, C., Pentieva, K., Siani, A., Thies, F., Tsabouri, S., Vinceti, M., Cubadda, F., Engel, K., Frenzel, T., Heinonen, M., Marchelli, R., Neuhäuser‐Berthold, M., Poulsen, M., Sanz, Y., Schlatter, J., van Loveren, H., Bernasconi, G., Germini, A. and Knutsen, H., 2020. Calcium l‐methylfolate as a source of folate added for nutritional purposes to infant and follow‐on formula, baby food and processed cereal‐based food. EFSA Journal, 18(1).
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