Methylfolate, Folic Acid, Methylcobalamin, and Cyanocobalamin – What’s the Difference?

Vitamins B9 (Folate) and B12 (Cobalamin) are water-soluble vitamins that are essential to health. Because of these vitamin’s role in all stages of life, from fetus to adulthood, many foods are fortified with these vitamins and vitamins supplements contain them to help individuals avoid deficiency.

Over the last decade, methylated forms of vitamins B9 and B12 have become popular supplement alternatives to the traditional forms that have been well-researched and used for decades. Each of these vitamins has their own benefits and reasons for different forms being available. Read on to learn more.

Vitamin B9 (Folate)

Folate regulates cellular metabolism and cell division. Coupled with its role in DNA and RNA, it supports healthy tissue growth and the regeneration of red blood and immune cells. It’s essential for fetal development, so it’s critical for pregnant women and those who may become pregnant to get enough folate.

It is always better to get nutrients from a healthy diet, and no supplement replaces the overall benefit of a healthy and nutritious diet. Foods containing folate are generally very nutritious, but folates themselves are not always the most bioavailable. As a result, the average intake of folates in food are typically well below recommended levels.

Low folate levels are especially concerning among women of child-bearing age. This is the reason that foods have been fortified with folic acid in many countries, and folic acid supplementation has become so popular.

Folic acid is the form most commonly used in fortification and supplements because it is generally more bioavailable, more stable, and less complex than food folates. The appearance of methylfolate is largely due to developments in the science of human genetics, and the discovery of a particular gene (MTHFR) that influences the ability to metabolize this vitamin.

MTHFR Variants

The methylene tetrahydrofolate reductase (MTHFR) gene codes an enzyme that converts folic acid into a form that can be used by the human body, and is also responsible for converting homocysteine into methionine. One variant of the MTHFR gene (MTHFR C677T) results in a reduced capacity for metabolizing folic acid.

Your DNA contains two copies of the MTHFR gene, one from each of your parents. You could potentially have one or two copies of the MTHFR C677T gene variant. Having a single mutation of the MTHFR gene is rather common, and is typically medically irrelevant since one gene is still functioning normally.

Where you might have heard about more concern, is when the C677T variant is present on both copies of a person’s MTHFR genes (homozygous MTHFR C677T variant). Even in the case of a homozygous MTHFR C667T, research has shown that adequate dosages of regular folic acid, can be used safely and with good success (Moll S).

Statements like folic acid is ineffective in people with MTHFR “mutations”, it blocks methylation, can’t be absorbed, or is unsafe, are exaggerations and not entirely accurate. This variant merely lessens the efficiency of conversion.

What’s important when discussing folate (as folic acid, methylfolate, or any other form) is blood levels of folate. In other words, regardless of the form and differences in bioavailability, dosages, etc, the goal is to have adequate blood folate levels. Even with the MTHFR C677T variant, individuals can normalize their serum folate levels with consistent intake of adequate levels of folic acid. In fact, folic acid is the most researched type of folate shown to prevent neural tube defects (Crider, Crider, Wilcken, Tsang, Seyoum).

On the other hand, too much folic acid or unmetabolized folic acid (UMFA) is not entirely without issues either. So, you cannot take endless amounts to compensate for decreased absorption. Fortunately, the body is very resilient, and studies suggest that there are mechanisms by which the body adapts to higher folic acid intakes to limit exposure to unmetabolized folic acid (Tam).

Regardless of MTHFR variant, folic acid at levels of 600-1,000 mcg falls in a range that is both safe to consume and will typically increase blood-folate to an adequate level.

Vitamin B12 (Cobalamin)

Vitamin B12 is an extremely complex molecule. Humans rely on the bacteria in their gut to make much of the vitamin B12 in their body. The other source of vitamin B12 is animal products, where the animals also obtained this vitamin from bacteria in their gut.

While anyone can have low vitamin B12 levels, vegetarians and vegans are especially susceptible to vitamin B12 deficiency because they don’t eat meat products—the main source vitamin B12. Those who are low in vitamin B12 will likely need to turn to supplementation.

Vitamin B12 is the only vitamin that cannot be made entirely synthetically. It is produced via a complicated process referred to as biosynthesis, since we rely on micro-organisms to manufacture or “synthesize” the vitamin. It is manufactured in basically the same way nature makes it in the gut.

The most common biosynthesis uses a bacterium called pseudomonas dentrificans and takes over twenty separate chemical reactions. This is the way nearly all commercially available vitamin B12 is made and available. Different forms such as cyanocobalamin and methylcobalamin would be biosynthesized the same way, with a single substitution reaction at the end between the methyl group and cyanide group.

Cyanocobalamin is the most common supplemental form of vitamin B12, due to its increased stability over forms like methylcobalamin.

Studies show cyanocobalamin can be readily converted in the body to active vitamin B12. When comparing cyanocobalamin to methylcobalamin, overall dosage and frequency of supplementation play a more important role than form in ensuring adequate blood levels (Zugravu).

Methylfolate and Methylcobalamin as Methyl Group Donors

It is not necessary to take methylcobalamin or methylfolate to support normal methylation. They are already abundant in a mixed diet. Typical intake of choline provides about 1,000 times more methyl groups, than typical intake of folate. In addition to choline, other B vitamins and amino acids like methionine provide thousands of times more methyl groups than simply taking methylated folate and B12.

Crider KS, Devine O, Hao L, et al. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ. 2014;349:g4554.

Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: A review of molecular mechanisms and the evidence for folate’s role. Adv Nutr. 2012;3(1):21-38.

Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation. 2015;132(1):e6-9.

Seyoum E, Selhub J. Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action. J Nutr. 1998;128(11):1956-1960.

Tam C, O’Connor D, Koren G. Circulating unmetabolized folic Acid: relationship to folate status and effect of supplementation. Obstet Gynecol Int. 2012;2012:485179.

Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015;101(6):1286-1294.

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 world wide. J Med Genet. 2003;40(8):619-625.

Zugravu CA, Macri A, Belc N, Bohiltea R. Efficacy of supplementation with methylcobalamin and cyancobalamin in maintaining the level of serum holotranscobalamin in a group of plant-based diet (vegan) adults. Exp Ther Med. 2021;22(3):993.

Can’t find what you are looking for? Please try your search again or submit a question here