Dispelling Myths Surrounding Methylfolate And Folic Acid

Introduction Folate, also known as vitamin B9, is a crucial nutrient for DNA replication and various essential processes in our bodies [1] (1). It plays a role in converting homocysteine to an essential amino acid, methionine. Without sufficient folate, homocysteine would become elevated, potentially leading to a myriad of health issues including infertility and recurrent miscarriages [2]. Folate is also vital to produce red and white blood cells and heme, and its deficiency can lead to megaloblastic anemia (a type of anemia characterized by very large red blood cells) [3].
The total body content of folate is estimated to be 15 to 30 mg; about half of this amount is stored in the liver, and the remainder in blood and body tissues [4]. Our bodies can’t produce folate, so we need to get it from our diet.  Certain groups, like women of childbearing age, are at risk of not getting enough folate from diet alone (NIH). This deficiency is a common nutritional issue, and supplementing with folic acid has been proven to reduce the risk of neural tube defects and to help maintain proper homocysteine levels [5, 6].
Beyond the Basics: Exploring the Forms of Folate There are different forms of folate, with folic acid being the one commonly used in fortified foods and supplements. Another form is 5-methyltetrahydrofolate (MTHF or methylfolate), which is a biologically active alternative to folic acid. It’s worth noting that people with a specific genetic variation might have a reduced ability to convert folate to its active form, but scientific data suggests they can still process various folate types, including folic acid, effectively [7].
The main form of folate in plasma is MTHF, which accounts for approximately 98% of folate in human plasma. People with a genetic polymorphism, 677C>T in the methylenetetrahydrofolate reductase (MTHFR) gene, have a reduced ability to convert folate to one of its active forms because the MTHFR enzyme needed for this conversion is less active. This is because the mutation results in an amino acid change from alanine to valine at a site critical for enzyme stability. There is a misconception that this might lead to elevated homocysteine levels (vitamin deficiency) and an increased risk of neural tube defects. Actually, people with MTHFR polymorphism can safely and effectively process all types of folates, including folic acid.
Based on Clinical Studies, MTHF is Equivalent to Folic Acid Clinical studies comparing folic acid and MTHF show no significant differences in their effectiveness. While there’s nothing wrong with using MTHF, there’s no clear advantage over folic acid. Both forms have similar scientific support, and the choice may come down to affordability.
Prinz-Langenohl and colleagues [7]  conducted a clinical study of twenty-one healthy women who were given single oral doses of folic acid (400 mcg) and equimolar amounts of MTHF. Plasma folate concentrations were determined using an immunoassay, which measured all folate forms. The concentration of folates did not differ significantly between folic acid and MTHF, regardless of whether the subjects were preloaded with folic acid. In another study [5] , researchers treated 160 young women with 400 mcg of folic acid or equimolar amounts of MTHF. After 8 weeks of treatment, the increase in red blood cell folate in both treatment groups was comparable (69% and 66%, respectively).
The Crucial Link: Folic Acid’s Role in a Healthy Pregnancy Based on recent studies, folic acid is the only type of folate shown in published clinical studies to help prevent neural tube defects (severe birth defects of the brain or spine) [1, 8] (. The Centers for Disease Control and Prevention (CDC) recommends 400 mcg/day of folic acid (not MTHF) for women who could become pregnant, even if they have a 677C>T MTHFR polymorphism.
Further, the American College of Obstetricians and Gynecologists (ACOG) recommends 600 micrograms of folic acid daily, including food sources and supplements. The recommendation includes taking a prenatal vitamin of at least 400 mcg at least one month before and throughout the initial 12 weeks of pregnancy. For women who previously had a child with a neural tube defect, ACOG recommends a separate 400 mg folic acid supplement daily, beginning three months before conception and continuing through the first trimester. Similarly, the National Academy of Medicine (formerly the Institute of Medicine) recommends that all women who can become pregnant get 400 mcg of folic acid each day, in addition to consuming food with folate from a varied diet, to reduce the risk of neural tube defects.
Summary Ensuring an adequate intake of folate, especially during pregnancy, is crucial. The MTHFR C677T variant affects how the body processes folate but research has shown that people with the MTHFR genetic variant can safely and effectively process all types of folates including folic acid.  Folic acid supplements are widely recommended by medical experts, and while other forms like MTHF are an option, there’s currently no proven need, or additional benefit to use methylfolate.
Author: Maciej Chichlowski PhD, PMP
Crider, K.S., et al., Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv Nutr, 2012. 3(1): p. 21-38. D’Uva, M., et al., Hyperhomocysteinemia in women with unexplained sterility or recurrent early pregnancy loss from Southern Italy: a preliminary report. Thromb J, 2007. 5: p. 10. Sayar, E.H., et al., The frequency of vitamin B12, iron, and folic acid deficiency in the neonatal period and infancy, and the relationship with maternal levels. Turk Pediatri Ars, 2020. 55(2): p. 139-148. Bailey, L.B. and M.A. Caudill, Folate, in Present Knowledge in Nutrition. 2012. p. 321-342. Fohr, I.P., et al., 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr, 2002. 75(2): p. 275-82. Venn, B.J., et al., 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, 2003. 77(3): p. 658-62. Prinz-Langenohl, R., Lamers, Y., Moser, R. et al., Effect of folic acid preload on the bioequivalence of [6S]-5-methyltetrahydrofolate and folic acid in healthy volunteers [abstract no. 169-P]. J Inherit Metab Dis, 2003(26 ): p. 124. Tsang, B.L., et al., Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr, 2015. 101(6): p. 1286-94.

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