Folic acid v.s Methyl folate



Folic acid v.s Methylfolate

By Yolandi Rademeyer R.D(S.A)


Plain text summary:

50% of people have a genetic mutation that causes folate deficiency.  Many are completely unaware of this and the issue goes overlooked or unnoticed even though it causes health problems and fertility issues.

Active folate is needed for healthy cardiovascular health, preventing anaemia, detoxification and fertility. It is the main nutrient in a mother’s body responsible for preventing neural tube defect (NTD) in newborns.

Taking folic acid supplementation may not be enough to overcome this problem since it is not being activated in the body, therefore taking an already active folate source (methylfolate) is a more reliable way to overcome this deficiency and prevent blood clots(heart attacks, strokes, even miscarriage can be due to blood clots), and improve detoxification systems in the body. And Especially ensuring you have activated folate in your body around conception to prevent NTD.


Folate and folic acid are both forms of vitamin B9. Folate being the natural form occurring in foods and folic acid being the synthetic form in supplementation and fortified cereals.

Folic acid is a common recommendations prior to conception and during pregnancy because of its crucial role in cell division and the development of the spinal cord and brain in the fetus during the first few weeks immediately after conception; preventing malformation (neural tube defect).

The reason why it is suggested to supplement with methyl folate rather than folic acid is the following:

Methyl folate(L-5-MTHF) is the active form of the B9 vitamin in the body. Both folate from food and folic acid from supplements and fortified foods need to be converted to methyl folate in the body to be able to be used.

Conversion happens through a methylation process with the help of an enzyme made by the  MTFHR gene [1][2][3].

One in every 2 or 3 people in society have a mutation to their MTFHR gene and do not convert folate and folic acid to active methyl-folate to some degree, depending on the degree of mutation. Some have a mutation that decreases the enzyme activity by 35% where others have a 75% decrease [4]

A disruption in this methylation pathway due to MTFHR mutation poses two important consequences:

Firstly. Where natural folate from food  is a soluble organic compound; when it is not converted to methyl folate it simply washes out of the body. Folic acid on the other hand is a synthetic compound without enzymatic acitivity and when not converted into methyl folate  it builds up in the blood stream and may cause health problems.

Circulating unmetabolised folic acid is now being linked with increasing incidence of food allergies, neurological disorders and other conditions

Secondly, when the MTHFR gene is mutated to a larger degree, a very small amount of folate and folic acid are being converted to methyl folate, causing a deficiency since the body simply does not have enough active folate to perform its functions.[5]

Supplementing with methyl folate instead of synthetic folic acid or relying on food folate sources is a way of bypassing the MHFHR mutation problem. Methyl folate is already active and does not need the MTHFR gene.

Women trying to conceive know how important folic acid supplementation is. Active folate is crucial for brain  development of the fetus and and preventing NTD. One study showed that periconceptional supplementation with 360-800mg  folic acid continued through the first trimester decreased the incidense of NTD by 33%[6].

Another study showed a 70% decrease in NTD incidense in women who had previous  pregnancies with NTD complications [7]

Another reliable study showed that women who supplement  with prenatal vitamins containing 800mcg/d decreases the risk of malformations in the baby by 90%[8].

Other than its role in the development of the spinal cord and the neural tube in the fetus, another  function of active B9 is metabolising harmful homocystein (a stress marker for increased cardiovascular risks due to blood clots[9]) to beneficial methionine(DNA synthesis, protein synthesis). Elevated levels of homocystein and decreased levels of methionine results in inflammation and risk of diabetes[10], Impaired healing and a decreased immunity, extreme fatigue, and an increased risk for cancer [11](due to reduced production of glutathione ;the body’s most important intracellular antioxidant) and reduced detoxification (of chemicals, heavy metals and hormones via the liver).

Folate also plays a role in zinc production and with zinc being a key micro nutrient for optimal fertility in both men and women, folic acid supplementation prior to conception increases the chances of conception.

Couples who are MHFHR deficient may have more trouble conceiving [12]. This is due to the role that methyl folate plays in

  • Spermatogenisis [13] and embryogenisis [14][m]
  • zinc production
  • detoxifying heavy metals out of the system
  • Antinflammatory responses
  • Cell energy for rapid cell division

Active folate also plays a role in the production in healthy red blood cells, preventing anaemia. Folate is so important in this funtion that clinical treatments  recommend supplementing iron and folate simultaneously for treatment of anaemia.

Whether we are consuming natural folate or supplementing with folic acid, if our MTFHR genes are at all mutated, we are simply not activating much, or any, of these molecules into their active methyl folate forms and therefore we are still folate deficient and possibly also just building up synthetic folic acid in the blood stream.

Reasons to take methyl folate

  • Trying to conceive or at risk of falling pregnant
  • Are on contraceptives
  • stress
  • consume excessive amounts of alcohol/ smoking [15]
  • have a high metabolism
  • suffer from conditions such as hypothyroidism
  • taking antacids
  • some blood pressure medications
  • metformin (for type 2 diabetes)                 
  • antibiotic use
  • high coffee intake          

Availability of folates from food is limited and difficult to assess on an individual basis with a mean availability of around 50% in a mixed diet [16][17], although it can be as high as 60-90% from some fruit and vegetables[18]. Studies have even shown that a folate-rich diet can match the homocysteine-lowering effects of either a regular folic acid or 5-MTHF supplement.

FOODS high in natural folate?

  • Organic, grass-fed beef liver (pan fried) 80g  = 211 mcg (yes you can have liver during pregnancy 🙂
  • Lentils 1 cup = 180 mcg
  • Spinach 1 cup = 109 mcg
  • Broccoli 1 cup = 104 mcg
  • Avocado 1 cup = 90 mcg
  • Sunflower seeds 1 ounce = 82 mcg  
  • Asparagus 1 cup = 79 mcg
  • Orange 1 large = 55 mcg
  • Tomato juice 1 cup = 48 mcg


Other names for methyl folate supplements:

  • Methylfolate
  • L-Methylfolate calcium (refers to the calcium salt molecule it is attached to)
  • Metafolin and Deplin
  • 5-MTHF and L-5-MTHF (in this article 5-MTHF refers to L-5-MTHF)
  • Levomefolic acid
  • 5-methyltetrahydrofolate
  • (6S)-5-methyltetrahydrofolate and Quatrefolic.

How much to take?

The German Nutrition Society recommends that pregnant woman and women who wish to become pregnant consume at least 0.55 mg of a folic acid equivalent daily, which is rarely achieved without supplementary synthetic folic acid, even when adhering to a folate-rich diet [17]

more common recommendations are around 800 mcg (0.8mg/day)


Note that there are numerous genetic mutations that can

potentially hinder methylation. An MTHFR mutation is just one of many, but it’s the most well-researched and likely most important.

Methyl folate may have side effects if there is unresolved inflammation and is best introduced slowly, as slowly as need be.

If you want to get tested for the MTFHR mutation:




[1]Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S, et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet. 2002;10: 433–443. [PubMed]
[2]Stevenson RE, Schwartz CE, Du YZ, Adams MJ Jr. Differences in methylenetetrahydrofolate reductase genotype frequencies, between Whites and Blacks. Am J Hum Genet. 1997;60: 229–230.
[3] Ströhle A, Wolters M, Willers J et al. Mikronährstoffe in den verschiedenen Lebensphasen der Frau (Teil 3) – Schwangerschaft: Nahrung für einen optimalen Start ins Leben. Gyne 2014; 5: 33–39
[4]Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10: 111–113.
[5] Lucock M. Is folic acid the ultimate functional food component for disease prevention? British Medical Journal. 2004;328(7433):211–214. [PubMed] [Ref list]
[6] Goh YI, Bollano E, Einarson TR et al. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 2006; 28: 680–689
[7]Blencowe H, Cousens S, Modell B et al. Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol 2010; 39 (Suppl. 1): i110-i121
[8] Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. New England Journal of Medicine. 1992;327(26):1832–1835. [PubMed] [Ref list]
[9] Huang T, Ren J, Huang J, Li D. Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach. BMC Genomics. 2013;14: 867 doi: 10.1186/1471-2164-14-867 [PMC free article] [PubMed]
[10] Mehlig K, Leander K, de Faire U, Nyberg F, Berg C, Rosengren A, et al. The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism. Heart. 2013;99: 1761–1765. doi: 10.1136/heartjnl-2013-304460 [PubMed]
[11] Teng Z, Wang L, Cai S, Yu P, Wang J, Gong J, et al. The 677C>T (rs1801133) polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies. PLoS One. 2013;8: e55332 doi: 10.1371/journal.pone.0055332 [PMC free article] [PubMed]
[12]Quéré I, Mercier E, Bellet H et al. Vitamin supplementation and pregnancy outcome in women with recurrent early pregnancy loss and hyperhomocysteinemia. Fertil Steril 2001; 75: 823–825
[13] Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998;62: 1258–1260.
[14] Boxmeer JC, Macklon NS, Lindemans J et al. IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Hum Reprod 2009; 24: 1059–1066
[15] Lee HC, Jeong YM, Lee SH, Cha KY, Song SH, Kim NK, et al. Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Hum Reprod. 2006;21: 3162–3170.
[16]Sauberlich HE, Kretsch MJ, Skala JH et al. Folate requirement and metabolism in nonpregnant women. Am J Clin Nutr 1987; 46: 1016–1028
[17] Deutsche Gesellschaft für Ernährung e. V. Referenzwerte für die Nährstoffzufuhr: Folat. Online:; last access: 23.07.2014
[18] Gregory JF., 3rd Case study: folate bioavailability. Journal of Nutrition. 2001;131(supplement 4):1376S–1382S. [PubMed] [Ref list]

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