Folic Acid vs. Methyl Folate Overview (PDF)

Q1) Why does Shaklee use folic acid, instead of the form of this B vitamin (B9) found in foods?

Answer 1) Folic acid is more bioavailable and stable than food folate, and most of the clinical studies tested folic acid, rather than food folate, for the effect on health benefits.

 

Folic acid is one of many forms of vitamin B9. On a gram-for-gram basis, folic acid delivers twice as much B9 when compared to food folate, according to the Dietary Reference Intake (DRI)* by Institute of Medicine (IOM). This recommendation is based upon many research results on bioavailability, indicating that folic acid is more bioavailable than food folate.1

(*Dietary folate equivalents: 1 µg food folate = 0.6 µg of folic acid from fortified food or as a supplement consumed with food = 0.5 µg of a supplement taken on an empty stomach.)

Linus Pauling Institute, one of the leading academic nutrition research institutes in the world, also indicated that bioavailability of food folate is limited and varies from one food matrix to another; further supporting folic acid is more bioavailable than food folate.2 We encourage consumers to consume foods such as beans, lentils, and dark green leafy vegetables, such as spinach that are good sources of folate;3 but for supplementation and fortification, folic acid is the primary choice.4

No dietary supplements that we are aware of use folate actually derived from food; some use synthetic methyl folate,2 i.e., L-5-Methyl-tetrahydrofolic acid, in the form of a calcium salt.

 

Q2) Are people with a MTHFR mutation required to take 5-methyl-tetrahydro folate (methyl folate) form rather than folic acid?

Answer 2) NO.

 

Methyl folate has been proposed as an alternative supplemental folate form, especially for people with MTHFR gene mutation.5 However, there is no clear evidence or recommendation by authorities that people with a MTHFR mutation should take methyl folate.

In fact, several human studies comparing the efficacy of methyl folate vs. folic acid showed that supplemental folic acid reduced homocysteine levels significantly in people with a MTHFR mutation while methyl folate DID NOT show significant reduction or showed no advantage over folic acid.6,7,8 (Elevated homocysteine levels can be caused by low vitamin B9 status.)

More research is necessary to recommend a new form of folate used in a supplement. Methyl folate has yet to be proven safe and effective, especially for women in childbearing age (who need folic acid to prevent neural tube defects9). Currently IOM and US FDA recommend the folic acid form for both supplement use and food fortification. 1,4

 

Q3) Can people with a MTHFR mutation absorb and utilize folic acid?

Answer 3) YES.

The enzyme MTHFR enables your body to use folate to lower homocysteine levels. Humans receive one copy of the MTHFR gene from each parent. About 10-12% of the population receives two copies of the altered genes (TT homozygous individuals); about 40% of the population receives one altered copy of the gene from one of the parents (CT heterozygous).10 Many human studies showed that people with an MTHFR mutation can benefit from folic acid supplements as much as people without the mutation, as determined by improved B9 status and reduced total homocysteine level in the blood.11,12 Elevated blood homocysteine is an indicator of poor B9 status and has been studied as one of the risk factors for heart disease and neural tube defects (NTD).13,14,15 The reason that folic acid fortification is widely practiced in many countries is to prevent NTD, a good example of the power of nutrition to address a serious public health concern.

Studies have shown that folic acid supplementation at the dose of 360 mcg – 4000 mcg significantly prevented neutral tube defects without showing any evidence of side effects.16 This conclusion is supported by the data compiled from five clinical trials involving 6105 women, among which 1949 women with their previous pregnancy affected with NTD.17 Folic acid supplementation was significantly effective in preventing NTD in these women despite the above noted widespread occurrence of the altered gene, which suggests that women affected by the altered genes are able to take advantage of folic acid supplements as well as unaffected women.

In fact, there is no difference in blood folate and homocysteine levels between CT heterozygous individuals and unaffected people.18 In TT homozygous individuals (the 10-12% of people described above receiving two affected MTHFR genes, one from each parent), MTHFR is still functional but with marginally reduced activity. Predisposition to increased blood homocysteine levels caused by the reduced enzyme activity can be corrected by the optimal blood folate level, which can be achieved by sufficient folate intake. The individuals with two affected genes require higher folate intake than the unaffected.19 Therefore, it is important for these individuals to ensure meeting folate requirements by adding more bioavailable form of folate, such as folic acid fortified foods or supplements, if they don’t consume enough folate from foods.

In Shaklee’s Landmark Study, a group of 278 people taking multiple supplements from Shaklee, including a folic acid supplement, for more than 20 years showed significant reduction in homocysteine level as compared to people without supplements, implying that people in general, regardless of MTHFR mutation, can benefit from folic acid supplements.20 Judging by the standard clinical definition of elevated homocysteine, not one of the Shaklee subjects in this study had high homocysteine [data on file].

In conclusion, (1) folic acid is more bioavailable than food folate, (2) people with a MTHFR mutation are not required to take methyl folate, and (3) people with a MTHFR mutation can benefit from folic acid supplements in increasing folate level and reducing homocysteine level in the blood as much as people without mutation. Therefore, Shaklee’s choice of folic acid is very well justified for people with a MTHFR mutation as well as the general population, and helps people meet their B9 requirements and healthy blood levels for folate and homocysteine as one step in improving their health.

  1. Institute of Medicine. Food and Nutrition Board (1998). Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington DC, National Academy Press.
  2. Delage B. Linus Pauling Institute. Oregon State University. Folate in Vitamins. Updated in June 2014.
  3. US Department of Agriculture Agricultural Research Service (2012), USDA National Nutrient Database for Standard Reference.
  4. US Food and Drug Administration (1996). Food standards; amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register 61(44).
  5. Greenberg JA, Bell SJ. Multivitamin Supplementation During Pregnancy: Emphasis on Folic Acid and l-Methylfolate. Rev Obstet Gynecol. 2011;4(3-4):126-7. PMID: 22229066
  6. Fohr IP, Prinz-Langenohl R, Brönstrup A, 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 Feb;75(2):275-82. PMID: 11815318.
  7. Venn BJ, Green TJ, Moser R, et. al. Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid. J Nutr. 2002 Nov;132(11):3353-5. PMID: 12421850.
  8. Lamers Y, Prinz-Langenohl R, Moser R, Pietrzik K. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr. 2004 Mar;79(3):473-8. PMID: 14985224.
  9. Toriello V. Folic acid and neural tube defects.” Genetics in Medicine 7, no. 4 (2005): 283-284.
  10. Wilcken B, Bamforth F, Li Z, et. al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide. J Med Genet. 2003 Aug;40(8):619-25. Erratum in: J Med Genet. 2004 May;41(5):400. Redlund, M [corrected to Renlund, M]. PMID: 12920077.
  11. de Bree A, Verschuren WM, Bjørke-Monsen AL, et. al. Effect of the methylenetetrahydrofolate reductase 677C–>T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample. Am J Clin Nutr. 2003 Mar;77(3):687-93. PMID: 12600862.
  12. Ashfield-Watt PA, Pullin CH, Whiting JM, et. al. Methylenetetrahydrofolate reductase 677C–>T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial. Am J Clin Nutr. 2002 Jul;76(1):180-6. PMID: 12081832.
  13. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113
  14. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA. 1993 Mar 10;269(10):1257-61. PMID: 8437302.
  15. Wilcken DEL (1997)MTHFR 677C-T mutation, folate intake, neural-tube defect and risk of cardiovascular disease. Lancet 350:603–604
  16. Bortolus R, Blom F, Filippini F, et. al; Italian and Dutch folic acid trial study groups. Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid: community-based randomized clinical trial in Italy and the Netherlands. BMC Pregnancy Childbirth. 2014 May 13;14:166. PMID: 24884885.
  17. De-Regil LM, Fernández-Gaxiola AC, Dowswell T, Peña-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev. 2010 Oct 6;(10):CD007950. PMID: 20927767.
  18. Pullin CH, Ashfield-Watt PA, Burr ML, et. al. Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype. J Am Coll Cardiol. 2001 Dec;38(7):1799-805. PMID: 11738277.
  19. Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998 May;62(5):1258-60.PMID: 9545406.
  20. Block G, Jensen CD, Norkus EP, et. al. Usage patterns, health, and nutritional status of long-term multiple dietary supplement users: a cross-sectional study. Nutr J. 2007 Oct 24;6:30. PMID: 17958896.