There is a lot of conversation around folate, folic acid and methylfolate. Which form is better? What is the gene mutation? What if I have gene mutation? Nutrition advisor Will Jordan reviews the research and explains why it’s important to understand the difference between the different types of folate and how it can impact your health.
What is folate?
The terms folate, folic acid and methylfolate are commonly used interchangeably, so it’s important to start with our first question: what is folate?
Folates are a group of water-soluble compounds found naturally in non-fermented foods with similar biological properties in the human body. Folate has many names which has led to confusion as vitamin B9, folate, folic acid, methylfolate, and methyl tetrahydrofolate are often used interchangeably by news sites, blogs and articles. [1] Folic acid is the most used form of folate in food supplements and does not occur in foods naturally but is used in food fortification and supplements all over the world as it is more stable and less likely to degrade over time. [2] To be biologically active in the body, folic acid needs to be methylated via several enzymic reactions, including methylenetetrahydrofolate reductase (MTHFR). [3] [4] Methylfolate in food supplements is already methylated and thus does not need to be converted to be biologically active. This form is less stable than folic acid in food supplements.
How common is the MTHFR gene variant?
However, recently there has been controversy around the metabolism of folic acid. This stems from the methylenetetrahydrofolate reductase single-nucleotide polymorphisms (MTHFR-SNP). A polymorphism is a common gene mutation that affects more than 1% of the total population. These generally don’t cause issues and are nothing to worry about. Specific polymorphisms may increase susceptibility to disease in some cases. [5]
So how do we get a polymorphism?
We inherent one set of genes from our mother, and the other set from our father. There are two specific variants of MTHFR-SNPs, with the 677C>T SNP affecting an estimated 38% of individuals, [6] and 1298A>C SNP thought to affect approximately 40% of individuals. So, an estimated 70% of the population globally may have at least one of these polymorphisms. [7] If one or both parents have one of the MTHFR-SNPs there is a chance to get one copy, known as being heterozygous which affects up to 40% of the population , or two copies, known as homozygous, which affects approximately 8.5% of the population. If you have one copy of both SNPs, this is called compound heterozygous, which affects approximately 2.25% of the population. If you have two copies of both, it is called compound homozygous. [7] Compound homozygous is extremely rare and not well documented but is recognised as a genetic possibility but estimated to affect 0.0003% of the population. [8]
Breaking the misconception
The common misconception is that these polymorphisms cause a complete inability to methylate folic acid which isn’t true. These polymorphisms only reduce the production of the enzyme methylenetetrahydrofolate reductase but not completely stop it. Severe deficiency of MTHFR enzyme can occur and leads to serious health conditions. This will present in early life and is not caused by the MTHFR-SNPs and will be picked up by healthcare professionals in infancy. [9]
So how do we know if we have a polymorphism?
Generally, you won’t notice if you only have one copy of either the 677C>T or 1298A>C as there are no associated health risks. However, the more copies of the polymorphisms you have, you may have greater chance at experiencing health conditions or risks, such as high homocysteine levels, increased risk to coronary heart disease, dementia, and neural tube defects. [10] However, you may not experience any health conditions at all, it is a very individual experience. If you have concerns, you can get private genetic testing which can tell you if you have a polymorphism or not. The general recommendation to manage the polymorphism is to supplement with folic acid, or methylfolate.
What the scientific evidence show
Both folic acid and methylfolate have been investigated using human research. Folic acid has a wealth of large-scale and long-term randomised clinical trials (RCTs), and review papers of these human studies have been conducted for decades. Results from these studies consistently show benefits of folic acid supplementation in different areas of health including stroke prevention and cardiovascular health, [11] [12] [13] improving blood sugar control, [14] and well known for reducing the risk of neural tube defects during pregnancy. [15] [16] Research into methylfolate supplementation has grown significantly in recent years, but to nowhere near the scale of folic acid. A lot of the RCTs investigating methylfolate revolve around homocysteine support, [17] and mental health, including schizophrenia, [18] and SSRI-major depressive disorder. [19]
Conclusion
The safety and effectiveness of folic acid is well established. Folic acid has been repeatedly found to improve folate status in the body, and support and prevent serious illness, regardless of MTHFR polymorphisms. [20] Methylfolate has its place as supplement as an immediately biologically available form of folate. It may help support folate deficiency in those with or without genetic polymorphisms and high-quality safety data is beginning to emerge for its use in pregnancy and children. [21] [22] Both folic acid and methylfolate have been found to improve folate status in humans, however folic acid remains the only form that is currently recommended for the prevention of neural tube defects. [23] So if you are planning to use for conception and during pregnancy this is the form we would recommend. But otherwise, it seems most of us don’t need to worry and either folic acid or methylfolate would be perfectly fine to take.
When choosing supplements, we recommend opting for clean formulations which are free of additives, binders and fillers to ensure it is fully beneficial to your health.
Author: Will Jordan, BSc (Hons) MSc, is a Nutrition Advisor at Viridian Nutrition. He holds a Master’s degree in Sports and Exercise Nutrition, BSc in Food and Nutrition.
References
1 Bailey LB, & Caudill MA. Folate. Present Knowledge in Nutrition. 10th Edition. 2012; 321-342. Washington DC. Wiley-Blackwell.
2 Jennings IW. Chapter 5 – The Vitamin B Complex. Vitamins in Endocrine Metabolism. 1970; 58-77
3 Bailey SW, and Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106 (36) 15424-15429
4 Tjong E, Dimri M, & Mohiuddin S. Biochemistry, Tetrahydrofolate. StatPearls. 2023; available online: [https://www.ncbi.nlm.nih.gov/books/NBK539712] [accessed 24/02/2025]
5 Koonin EV, & Novozhilov AS. Origin and Evolution of the Universal Genetic Code. Annual Review of Genetics. 2017; 51, 45-62
6 Chita DS, Tudor A, Christodorscu R, Buleu FN, Sosdean R, Deme SM, Mercea S, Moldovan AP, Pah AM, Axelerad AD, Axelerad DD, & Dragan SR. MTHFR Gene Polymorphism Prevalence and Cardiovascular Risk Factors Involved in Cardiometabolic Stroke Type and Severity. Brain Sciences. 2020; 10 (8) 476
7 Long S, & Goldblatt J. MTHFR genetic testing: Controversy and Clinical Implications. Australian Family Physician. 2016; 45 (4) 237-240
8 Brown NM, Pratt VM, Buller A, Pike-Buchanan L, Redman JB, Sun W, Chen R, Crossley B, McGinniss MJ, Quan F, & Storm CM. Detection of 677CT/1298AC “double variant” chromosomes: Implications for interpretation on MTHFR genotyping results. Genetics in Medicine. 2005; 7 (4) 278-282
9 Burda P, Schafer A, Suormala T, Rummel Till, Burer C, Heuberger D, Frapolli M, Giunta C, Sokolova J, Vlaskova H, Kozich V, Koch HG, Fowler B, Froese SD, & Baumgartner MR. Insights into Severe 5, 10-Methylenetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients. Human Mutation. 2015; 36 (6) 611-621
10 Graydon JS, Claudio K, Baker S, Kocherla M, Ferreira M, Roche-Lima A, Rodríguez-Maldonado J, Duconge J, & Ruaño G. Ethnogeographic prevalence and implications of the 677C>T and 1298A>C MTHFR polymorphisms in US primary care populations. Biomarkers in Medicine. 2019; 13 (8) 649-661
12 Zhang N, Zhou Z, Chi X, Fan F, Li S, Song Y, Zhang Y, Qin X, Sun N, Wang X, Huo Y, & Li J. Folic acid supplementation for stroke prevention: A systematic review and meta-analysis of 21 randomized clinical trials worldwide. Clinical Nutrition. 2024; 43 (7) 1706-1716
12 Huo Y, Qin J, Wang J, Sun N, Zeng Q, Xu X, Liu L, Xu X, & Wang X. Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. International Journal of Clinical Practice. 2012; 66 (6) 544-551
13 Li Y, Huang T, Zheng Y, Muka T, Troup J, & Hu FB. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomised Controlled Trials. Journal of the American Heart Association. 2016; 5 (8) 27528407
14 Asbaghi O, Ashtary-Larky D, Bagheri R, Moosavian SP, Olyaei HP, Nazarian B, Kelishadi MR, Wong A, Candow DG, Dutheil F, Suzuki K, & Naeini AA. Folic Acid Supplementation Improves Glycemic Control for Diabetes Prevention and Management: A Systematic Review and Dose-Response Meta-Analysis of Randomised Clinical Trials. Nutrients. 2021; 13 (7) 2355
15 Toivonen KI, Lacroix E, Flynn M, Ronksley PE, Oinonen KA, Metcalfe A, & Campbell TS. Folic acid supplement during the preconception period: A systematic review and meta-analysis. Preventive Medicine. 2018; 114, 1-17
16 Imbard A, Benoist JF, & Blom HJ. Neural Tube Defects, Folic Acid and Methylation. International Journal of Environmental Research and Public Health. 2013; 10 (9) 4352-4389
17 Schmidl D, Howorka K, Szegedi S, Stjepanek K, Puchner S, Bata A, Scheschy U, Aschinger G, Wekmeister RM, Schmetterer L, & Garhofer G. A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systematic homocysteine plasma concentrations and retinal blood flow in patients with diabetes. Molecular Vision. 2020; 26, 326-333
18 Roffman JL, Petruzzi LJ, Tanner AS, Brown HE, Eryilmaz H, Ho NF, Giegold M, Silverstein NJ, Bottiglieri T, Manoach DS, Smoller JW, Henderson DC, & Goff DC. Biochemical, physiological and clinical effects of L-methylfolate in schizophrenia: a randomised controlled trial. 2018; 23, 316-322
19 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 Randomised, Double-Blind, Parallel-Sequential Trials. The American Journal of Psychiatry. 2012; 169 (12) 1267-1274
20 Hiraoka M, & Kagawa. Genetic polymorphisms and folate status. Congenital Anomalies: Clinical and Laboratory Research. 2017; 57 (5) Special Issue: Folic Acid and Neural Tube Defects. 142-149
21 Houghton LA, Sherwood KL, Pawlosky R, Ito S, & O’Connor. [6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. American Journal of Clinical Nutrition. 2006; 83 (4) 842-850
22 Troesch B, Demmelmair J, Gimpfl M, Hecht C, Lakovic G, Roehle R, Sipka L, Trisic B, Vusurovic M, Schoop R, Zdjelar S, Koletzko B, & MEFOLIN Study Group. Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomised-controlled trial. PLoS One. 2019; 14 (8) e0216790
23 Wald NJ, Morris JK, & Blakemore C. Urgent need for folic acid fortification of flour and grains: response to the 2019 UK Government’s public consultation. Archives of Disease in Childhood. 2020; 105 (1) 6-9
The information contained in this article is not intended to treat, diagnose or replace the advice of a health practitioner. Please consult a qualified health practitioner if you have a pre-existing health condition or are currently taking medication. Food supplements should not be used as a substitute for a varied and balanced diet.
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