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MTHFR polymorphism– folic acid or 5MTHFR which is best? (Part 2)

Yvonne Gattung B.Soc.Sci, DipMedHerb, MNZAMH, Natural Fertility Specialist

Continuing the discussion from part 1, folic acid or 5MTHFR which is the best form to take?baby-on-tummy-smiling-in-wh

4. Folic Acid Blocks Natural Folates and Causes Pseudo MTHFR?

A study working on gene-nutrient interaction found that high folic acid consumption through diet leads to pseudo MTHFR deficiency when it was fed to mice for 6 months due to the fact that high folic acid in the diet reduces MTHFR protein and its activity levels.12, 13

It results in hepatocyte degeneration because mutated hepatocytes lose their ability to accommodate lipid disturbance resulting in changes in phospholipid / lipid metabolism and altered membrane integrity. The researchers mentioned that this results may have clinical implications for people consuming higher dose of folic acid particularly populations with MTHFR deficiency.

5. Folic Acid Induces Higher Risk of Cancer

The first report linking folic acid with cancer can be tracked back to 1947 when a study administered folic acid to treat leukaemia children and found with surprise that it actually accelerated leukaemia progression.14

A recent big-scale clinical trial in the U.S. and Canada administrated 1 mg / day of folic acid as supplement to test its impact on recurrence of colorectal adenomas, and found no effect on recurrence when it was the first follow-up at year 3 in 987 patients; but at the second follow-up of year 3-5 in 607 patients, there was a 67% of increased risk of advanced lesion or invasive colorectal adenomas, > 2 folds of increased risk of having at least 3 colorectal adenomas, and increased risk of non-colorectal cancers mostly of prostate cancer.15

The mechanism that over-dose folic acid induces higher risk of cancer is currently unknown, but some molecular epidemiologic studies inidcate that genetic polymorphism in folate metabolic processes, such as MTHFR, directly modify cancer risk, or indirectly modify cancer risk,16

This emphasizes the consideration of use of folic acid in MTHFR mutations because MTHFR deficiency may amplify cancer risk.

Note: there are also many studies indicating folic acid has a protective role in cancer progression.

6. 5-MTHF Is More Effective than Folic Acid

To test the differences of treatment effect of 5-MTHF and folic acid on MTHFR, healthy females with homozygous MTHFR mutation received one single dose of 5-MTHF (416 microgram) or folic acid (400 microgram), and plasma folate indexes were measured 8 hours after supplementation. Results show that 5-MTHF induces significantly higher plasma folate concentration vs. time and maximum concentration, and shorter time-to-reach maximum compared to folic acid in both genotypes. Furthermore, unmetabolised folic acid in plasma appears regularly after folic acid supplementation but rarely after 5-MTHF supplementation. The report suggests that 5-MTHF increases plasma folate more effectively than folic acid irrespective of mutations of MTHFR.17

As historically used, folic acid is the reference folate in clinical trial studies to assess relative bio-availability of dietary folate however, some reports suggests that folic acid should not be used as the reference folate in longer term human studies.18


The use of folic acid in general populations without MTHFR or DHFR mutation is most likely of limited concern; but even for them, it is considered safe only when the dose is 400 mcg. For those people having fortified flour or cereal, energy drinks, protein bars and supplement, the dose of folic acid is exceeding the limit easily and considerably.

Folic-Acid15-MTHF has some important advantages compared to synthetic folic acid. It is well absorbed even when gastrointestinal pH changes, it is bioavailable and is not affected by metabolic defects. The use of 5-MTHF to replace folic acid in treating MTHFR reduces potential of masking haematological symptoms of vitamin B12 deficiency, reduces interactions with medications inhibiting dihydrofolate reductase, prevents formation of unmetabolised folic acid in blood circulation, and overcomes metabolic defects caused by MTHFR polymorphism.

Clearly, folic acid suits some people and not others. However, it is unwise to make blanket statements with research continuing to shed more light on this subject. There does seem sufficient research to indicate caution (if not total avoidance) of folic acid with those who have the MTHFR polymorphism.


Bibliography – all accessed 19th January 2016.

1. Morales DR, Greenberg DM. Purification and properties of dihydrofolate reductase of sheep liver. Biochim Biophys Acta. 1964; 85: 360–376. PMID: 14194852

2. Jarabak J, Bachur NR. A soluble dihydrofolate reductase from human placenta: Purification and properties. Arch Biochem Biophys. 1971; 142: 417–425. PMID: 4396284



5. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci U S A. 2009; 106(36): 15424-9. PMID: 19706381

6., Norwich BioScience Institutes. Scientists Question Folic Acid Fortification. ScienceDaily. ScienceDaily, 2007


8. Sweeney MR, McPartlin J, Scott J. Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health. 2007; 7: 41. PMID: 17378936.

9. Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E, Potter JD, Ulrich CM. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006; 136(1): 189-94. PMID: 16365081



12. 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; 101(3): 646-58. PMID: 25733650


14. Farber S, Cutler EC, Hawkins JW, Harrison JH, Peirce EC 2nd, Lenz GG. The Action of Pteroylglutamic Conjugates on Man. Science. 1947; 106(2764): 619-21. PMID: 17831847

15. Kim YI. Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev. 2008; 17(9): 2220-5. PMID: 18768486

16. Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol. 2004; 159(5): 423-43. PMID: 14977639

17. Prinz-Langenohl R, Brämswig S, Tobolski O, Smulders YM, Smith DE, Finglas PM, Pietrzik K. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C–>T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009; 158(8): 2014-21. PMID: 19917061

18. Wright AJ, King MJ, Wolfe CA, Powers HJ, Finglas PM. Comparison of (6 S)-5-methyltetrahydrofolic acid v. folic acid as the reference folate in longer-term human dietary intervention studies assessing the relative bioavailability of natural food folates: comparative changes in folate status following a 16-week placebo-controlled study in healthy adults. Br J Nutr. 2010; 103(5): 724-9. PMID: 19852872


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