MTHFR, Folic Acid, and Folate

Folate, also known as Vitamin B9, plays a crucial role in methylation pathways, which are essential for proper bodily functions. It can be found in natural food sources like leafy greens, vegetables, corn, wheat, and beans. On the other hand, folic acid is a synthetic form of folate that can hinder the methylation process by competing with natural folate for absorption in the body. While folic acid can be converted to folate, certain genetic mutations can slow down the conversion process. Even without these mutations, folic acid can slow down methylation processes for everyone.

MTHFR gene mutations are genetic variations that affect the way the body processes folate, an essential nutrient for many bodily functions. MTHFR mutations can reduce the activity of the MTHFR enzyme, which can result in elevated levels of homocysteine in the blood and a decreased ability to produce methylfolate. These effects can lead to various health problems, including cardiovascular disease, neurological disorders, pregnancy complications, and other conditions. However, the severity of the symptoms can vary depending on the specific mutation, as well as other genetic and environmental factors. Treatment may involve supplementing with methylfolate and other B vitamins, and making dietary and lifestyle changes to support methylation and reduce homocysteine levels.  The MTHFR gene is an important part of the methylation process, but it's only a small part of the entire pathway.

For those with methylation mutations such as MTHFR, MTR, MTHFD1, SHMT1, and DHFR, folic acid is even more problematic. It is recommended to avoid folic acid and instead use natural folate or methylfolate, the methylated version of folate.

Folic acid is commonly found in our American diet because the FDA requires white flour to be enriched with it to restore vitamins lost in the refining process. However, manufacturers prefer folic acid over natural folate because of its longer shelf life, without considering the long-term effects of its competition with natural folate for absorption in the body.

Leclerc D, Sibani S, Rozen R. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from:

Kang SS, Wong PWK, Bock HGO. et al. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet. 1991;48:546–551.

Gabriela Nielsen M, Congiu C, Bortolomasi M, Bonvicini C, Bignotti S, Abate M, Milanesi E, Conca A, Cattane N, Tessari E, Gennarelli M, Minelli A. MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder. J Affect Disord. 2015 Sep 1;183:179-86. doi: 10.1016/j.jad.2015.05.003. Epub 2015 May 11. PMID: 26021967.

Cornet, Dominique et al. “High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome.” SAGE open medical case reports vol. 7 2050313X19850435. 17 May. 2019, doi:10.1177/2050313X19850435

Christensen KE, Mikael LG, Leung KY, Lévesque N, Deng L, Wu Q, Malysheva OV, Best A, Caudill MA, Greene ND, Rozen R. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015 Mar;101(3):646-58. doi: 10.3945/ajcn.114.086603. Epub 2015 Jan 7. PMID: 25733650; PMCID: PMC4340065.

Henry, Curtis J et al. “Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis.” Haematologica vol. 102,12 (2017): 1985-1994. doi:10.3324/haematol.2017.171074

Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011 Feb;34(1):75-81. doi: 10.1007/s10545-010-9177-4. Epub 2010 Sep 4. PMID: 20814827; PMCID: PMC3026708.

Barbosa, P R., et al. "Association Between Decreased Vitamin Levels and MTHFR, MTR and MTRR Gene Polymorphisms as Determinants for Elevated Total Homocysteine Concentrations in Pregnant Women." European Journal of Clinical Nutrition, vol. 62, no. 8, 2008, pp. 1010-21.

Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26. PMID: 18950248.

Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997 May;55(5):145-9. doi: 10.1111/j.1753-4887.1997.tb06468.x. PMID: 9212690.

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