Folic acid vs Methylfolate - what are the main differences?
Note
4 minutes
difficulty level Advanced
Matthew Messer

Matthew Messer

Editor-in-chief

Folic acid supplementation has long been used successfully to prevent pregnancy complications. (1) However, folic acid is only  a synthetically produced form of vitamin B9. The natural forms of vitamin B9 are various folates, which can be found in organic food. Folates, similarly to folic acid, are eventually transformed into methylfolate. Many foods contain methylfolate originally, but there can be major disparities between consuming dietary methylfolate, folic acid  or methylfolate only. 

What are the downsides of folic acid intake? 

The main downside of folic acid supplementation is that people with certain genetic mutations can have problems transforming it into methylfolate. (1) Folic acid is first transformed into folate, then methylfolate; the enzyme MTHFR is responsible for the latter, but its function is impaired in many people.  

Higher doses of riboflavin can compensate for this genetic defect, but if one’s unsure whether they have the mutation, it’s advised to take more riboflavin and supplement vitamin B9 in the form of methylfolate (2,3). Moreover they should take higher doses of choline and betaine.  

If folic acid is supplemented in large doses, it can be detectable in the blood undigested, which is a clear sign that the body can no longer utilize it. This issue starts over doses of 200-250 mcg and also depends on how much folate one ingests from other sources, and how efficiently they can transform it. It’s very likely that a maximum of 200 mcg of folic acid is safe to intake daily and should cause no problems if it’s taken alongside vitamins B2, B6 and B12, as well as choline, betaine, creatine and glycine. 

Folates found in food are not absorbed well 

The transformation of folates found in food can also decrease  in the case of the above-mentioned genetic mutations, and the solution is the same as for folic acid intake. The main issue with folates found in food is absorption, as due to vegetal fibers and other ingredients only a portion  of the ingested folate is  absorbed. This is well illustrated by a study where folic acid and methylfolate supplementation was compared to the intake of folates from food. The same amount of methylfolate and folic acid resulted in higher folate levels by the end of the study than extra folate ingested  from food. (4) This is why folate equivalents are taken into account for vitamin B9 supplementation: 0.5 mcg or less of folic acid or methylfolate provides as much folate as 1 mcg dietary folate.  

Methylfolate versus folic acid supplementation  

In a randomised controlled trial conducted in 2014, methylfolate supplementation resulted in far higher folate levels which were utilized faster than the same dose of folic acid. The latter is slower to get utilized in general, and even more slow for people with MTHFR mutation. Researchers believe that methylfolate would be more useful than folic acid in treatment. (5) 

In a comparative study, women who were given vitamin supplements containing methylfolate and large doses of vitamin B12 during their pregnancy demonstrated fewer cases of prenatal anaemia  than women who were given the traditional treatment of folic acid and low doses of vitamin B12. (6) 

In a 2004 clinical trial two different doses of methylfolate, a daily dose of 200 mcg or 400 mcg were compared to a daily dose of 400 mcg folic acid to test their respective effectiveness in lowering homocysteine. Both doses of methylfolate were just as effective in lowering homocysteine as 400 mcg of folic acid. (7) 

In a randomised, controlled study in 2019 methylfolate supplementation resulted in significantly higher levels of folate compared to similar doses of folic acid. Methylfolate was marginally better at lowering homocysteine levels as well. (8) 

In a clinical trial conducted in 2012, high dose methylfolate supplementation  proved to be an effective supplementary therapy in the treatment of depression. Folic acid was not tested in the study, but in other studies folic acid supplementation did not have substantial results. (12,13) 

In conclusion, methylfolate supplementation can be more effective than folic acid supplementation for a number of reasons, but it’s highly likely that proper dosage of folic acid in synergy with the supplementation of other micronutrients would not cause any issues.  

  1. Rozen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis. 1996;19(5):589-94. doi: 10.1007/BF01799831. PMID: 8892013. 

  2. McNulty H, Dowey le RC, Strain JJ, Dunne A, Ward M, Molloy AM, McAnena LB, Hughes JP, Hannon-Fletcher M, Scott JM. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation. 2006 Jan 3;113(1):74-80. doi: 10.1161/CIRCULATIONAHA.105.580332. Epub 2005 Dec 27. PMID: 16380544. 

  3. García-Minguillán CJ, Fernandez-Ballart JD, Ceruelo S, Ríos L, Bueno O, Berrocal-Zaragoza MI, Molloy AM, Ueland PM, Meyer K, Murphy MM. Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine. Genes Nutr. 2014 Nov;9(6):435. doi: 10.1007/s12263-014-0435-1. Epub 2014 Oct 17. PMID: 25322900; PMCID: PMC4235830. 

  4. 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 Mar;103(5):724-9. doi: 10.1017/S0007114509992339. Epub 2009 Oct 26. PMID: 19852872. 

  5. 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 Dec;158(8):2014-21. doi: 10.1111/j.1476-5381.2009.00492.x. PMID: 19917061; PMCID: PMC2807663. 

  6. Bentley S, Hermes A, Phillips D, Daoud YA, Hanna S. Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis. Clin Ther. 2011 Feb;33(2):204-10. doi: 10.1016/j.clinthera.2011.02.010. Epub 2011 Mar 25. PMID: 21440300. 

  7. 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. doi: 10.1093/ajcn/79.3.473. PMID: 14985224. 

  8. Henderson AM, Aleliunas RE, Loh SP, Khor GL, Harvey-Leeson S, Glier MB, Kitts DD, Green TJ, Devlin AM. l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women. J Nutr. 2018 Jun 1;148(6):885-890. doi: 10.1093/jn/nxy057. PMID: 29878267. 

  9. 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 Dec;158(8):2014-21. doi: 10.1111/j.1476-5381.2009.00492.x. PMID: 19917061; PMCID: PMC2807663. 

  10. Fohr IP, Prinz-Langenohl R, Brönstrup A, Bohlmann AM, Nau H, Berthold HK, Pietrzik K. 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. doi: 10.1093/ajcn/75.2.275. PMID: 11815318. 

  11. Venn BJ, Green TJ, Moser R, Mann JI. 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 Mar;77(3):658-62. doi: 10.1093/ajcn/77.3.658. PMID: 12600857. 

  12. Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012 Dec;169(12):1267-74. doi: 10.1176/appi.ajp.2012.11071114. PMID: 23212058. 

  13. Bedson E, Bell D, Carr D, Carter B, Hughes D, Jorgensen A, Lewis H, Lloyd K, McCaddon A, Moat S, Pink J, Pirmohamed M, Roberts S, Russell I, Sylvestre Y, Tranter R, Whitaker R, Wilkinson C, Williams N. Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation. Health Technol Assess. 2014 Jul;18(48):vii-viii, 1-159. doi: 10.3310/hta18480. PMID: 25052890; PMCID: PMC4780991. 

Related contents:

Should food be enriched with folic acid

Note
3 minutes
difficulty level Advanced
I want to read it

The B Vitamins can slow the progression of cognitive decline

News
1 minutes
difficulty level Easy
I want to read it