Methyl B12 & Methylfolate

Methyl B12 and methylfolate are two of the most important drivers of one-carbon metabolism, the process that regulates methylation reactions.

Both methyl B12 and methylfolate play crucial roles in generating methyl groups for use in DNA synthesis and repair, amino acid maintenance, antioxidant generation, and epigenetics [1].

Methylfolate alone is required for numerous functions of the brain and nervous system, including proper methylation [2], the metabolism of homocysteine to methionine [3], neurotransmitter production [4], nervous system maintenance [5], normal fetal growth and development [6], immune system maintenance [7], and formation of myelin [8].

Methyl B12 (methylcobalamin) is essential for red blood cell production [9], re-methylation to methionine [10], cognitive function, and nervous system maintenance [11], along with many other roles in healthy fetal development, immune function, and more.

Deficiencies in one or both of these nutrients can result in developmental defects, impaired cognitive function, or abnormal blood production [12].

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L-Methylfolate 15+ mg - front bottle - Enhance Mood - filler-FREE w/active B12 + inositol - 30 ct - Methyl-Life
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Methylfolate 7.5 mg bottle front (Purest L-Methylfolate) + Active B12s - 3 month supply - Chewables - Methyl-Life

What’s the Difference Between Methylfolate and Methyl B12?

Methylfolate and Methyl B12 are both B-vitamins. However, they are distinctly different nutrients with specific roles and responsibilities in one-carbon metabolism.

Methylfolate and methyl B12 are the metabolically active forms of B vitamins and are significantly more bioavailable than non-methylated nutrients. They also act as “methyl donors,” which means they carry and transfer methyl groups from one compound to another. This process - called methylation - is crucial for normal daily function.

Methyl donors act as critical cofactors in one-carbon metabolism, including DNA synthesis and homocysteine metabolism. In the brain, methyl-donor nutrients are involved in creating neurotransmitters, epigenetic processes, and cellular membrane structures [13].

Unlike methylfolate, folate and folic acid must be reduced (metabolized) before they can be used in the body. Methylfolate is the main form of active folate that circulates in the blood and is involved in biological processes [14].

Methyl B12 (methylcobalamin) is the methylated and active form of vitamin B12. Cyanocobalamin (the synthetic B12 used in most supplements) contains a cyanide molecule to facilitate its complicated conversion to active B12. Methylcobalamin is the natural form of B12 and provides a methyl group required for the re-methylation of homocysteine to methionine [15]. 

Benefits of Combining Methylfolate and Methylcobalamin

Folate and vitamin B12 are involved in hundreds of biological processes in the human body. However, both folate and cobalamin can be affected by intestinal disorders and mutations that play important roles in their uptake and usage [16]

Combining methylfolate and methylcobalamin can have numerous benefits for the body and mind. 


Methylated nutrients are at their most important during fetal development and can improve the chance of pregnancy success

Lack of methyl-donor nutrients in the developing fetus has been linked to a higher risk of complications in pregnancy and congenital abnormalities. Supplementing with L-methylfolate rather than folic acid can prevent folate-related complications and health issues during pregnancy. Vitamin B12 works alongside folate in red blood cell formation and the development of the brain during childhood. Methylcobalamin is one of three naturally-occurring forms of B12 shown to be superior in absorption to cyanocobalamin. 

Neuronal Function and Mood

Supplementation with L-methylfolate has been shown to improve response to antidepressants in people with treatment-resistant depression, with many patients showing improvement within 2-4 weeks.

Sufficient vitamin B12 is required for the production of serotonin as well as other monoamine neurotransmitters and catecholamines.

Nutritional Status

Naturally occurring methylfolate is shown to be superior to synthetic folic acid because it is well absorbed in the body, even when gastrointestinal pH is insufficient for proper digestion. The bioavailability of methylfolate is not affected by metabolic defects or genetic mutations.

Clinical studies show that methylcobalamin is successful in restoring B12 in the body and lacks the cyanide molecule which is present in cynacobalamin. It is also worth noting that cyanocobalamin is a synthetic form of vitamin B12 used most often in supplements, while methylcobalamin is the natural form of B12.

Homocysteine Metabolism

Homocysteine is converted to methionine via the remethylation pathway in which both folate and vitamin B12 are required as cofactors. Both methylfolate and methylated B12 are required to initiate the methylation pathway and provide the necessary methyl groups for this reaction. 

Deficiency in either folate or vitamin B12 can lead to elevated homocysteine and subsequent cardiovascular health issues.

MTHFR, Methylfolate, and Methyl B12

Both methylfolate and methyl B12 are essential for bypassing the malfunctioning conversion process and ensuring the methylation cycle functions optimally. The bioavailability of methylfolate is not affected by metabolic defects, and it eliminates the risk of harmful unconverted folic acid in the peripheral circulation. In addition, methylfolate does not mask symptoms of vitamin B12 deficiency, nor does it interact with medications that inhibit dihydrofolate reductase (the enzyme required for reducing dihydrofolic acid to tetrahydrofolic acid). This is especially important for people with MTHFR mutations. 

Synthetic folic acid cannot be fully processed in those with MTHFR mutations. As a result, it may accumulate as unmetabolized folic acid, which can be hazardous. In addition, the build-up of homocysteine may damage blood vessels and increase the risk of complications in pregnancy [17]

Vitamin B12 deficiency is shown to be more prevalent in those with MTHFR mutations [18]

A lack of methylcobalamin is believed to impair cell multiplication and may also lead to accumulated homocysteine [19]

Those with MTHFR mutations are urged to take methylated forms of folate in order to bypass the MTHFR insufficiency. Taking methyl B12 alongside methylfolate ensures optimal uptake and utilization in the body.

What Dosage is Right For Me?

As with any nutritional supplement, it is important to first consult your health professional about the appropriate dosage for you. 

If you have an MTHFR mutation, it is also advisable to read our dosage guidelines on taking methylfolate and also our guidelines on taking vitamin B12



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