MTHFR: What is the Best Form of B12?


When supplementing the methylation cycle, it is important to consider which form of B12 is right for you.

Sounds easy, right?

Unfortunately, we’ve found that doctors do not necessarily have all the information about what the different forms of B12 are, which genes and genetic mutations benefit most from which forms, and how B12 gets converted within the body.

As part of our commitment to bringing you up-to-date information regarding MTHFR, we’re here to help you understand which form of B12 you may tolerate best.

The Different Types of B12: Methylocalamin, Hydroxocobalamin, Adenosylcobalamin, and Cyanocobalamin

There are 3 types of B12 that are considered extremely beneficial to the body:

methylcobalamin, hydroxocobalamin, and adenosylcobalamin

Yet, the most common form of B12 is actually a form called cyanocobalamin, which it is not very active or beneficial to the body because of its cyanide content and low absorption rate. The reason it doesn’t absorb well is that the body first has to convert it into hydroxocobalamin, which itself has to then be converted into both adenosylcobalamin and methylcobalamin. Especially if the body has genetic mutations, these conversions don’t happen well. As a result, the body cannot absorb or use the nutrient as effectively.

MTHFR: Choosing the best form of B12 based on your genetics

Because of their difficulty converting cyanocobalamin all the way through this process, it is often assumed that people with an MTHFR deficiency require supplementation of the methylcobalamin type of B12. But it’s actually a bit more complicated.

Your MTHFR status does not determine the type of B12 that’s best for you.

Here’s a well-known fact: methylfolate and methylcobalamin work together synergistically along the methylation cycle pathway. So, most doctors and nutritionists are currently saying that a methylcobalamin supplement would be beneficial for individuals with MTHFR deficiency. However, it doesn’t necessarily follow that if you tolerate methylfolate well you’ll tolerate methylcobalamin well.

What does determine the best type of B12 for your body is the status of genes like COMT, MTR, MTRR, VDR Taq.



So, what does this mean for you?

If you have your 23andme genetic test results, you can use those to guide you as you try the different B12 forms and see how well they do for you. For example, since our founder, Jamie, has a number of mutations in all of the B12 absorption genes (COMT, MTR, MTRR, VDR Taq), she actually needs all 3 types of B12. 

The table below, developed by Dr. Amy Yasko, helps folks determine their potential B12 needs based on their particular mutation status for COMT & VDR Taq:


COMT V158MVDR TaqB12 Types That Should Be Tolerated
– –+ + (TT)All 3 types of B12
– –+ – (Tt)All 3 types of B12 with less Methylcobalamin
– –– – (tt)Hydroxocobalamin and Adenosylcobalamin
+ –+ +All 3 types of B12 with less Methylcobalamin
+ –+ –Hydroxocobalamin and Adenosylcobalamin
+ –– –Hydroxocobalamin and Adenosylcobalamin
+ ++ +Hydroxocobalamin and Adenosylcobalamin
+ ++ –Hydroxocobalamin and Adenosylcobalamin
+ +– –Mostly Hydroxocobalamin

The Benefits of B12

Vitamin B12 deficiency is one of the most common ailments in adults today, affecting nearly 40 percent of people in the US.  


Why is this a problem?


Vitamin B12 is crucial for many of the body’s most important functions. It’s required for the synthesis of DNA and RNA, hemoglobin production, energy production, and the maintenance of the nervous system. It also works with L-methylfolate to lower homocysteine in the methylation cycle.

The Benefits of Folate (B9)

Folate (vitamin B9) is most useful to the body in its active form, L-methylfolate. L-methylfolate is essential for energy production and healthy red blood cell production. Folate enhances brain health, protects against birth defects, lowers homocysteine, and supports healthy pregnancy outcomes.

The Benefits of B6

Vitamin B6 is an enzymatic co-factor required for more than 140 biochemical reactions in the body. It’s especially important for breaking down amino acids into neurotransmitters including serotonin, dopamine, and γ-aminobutyric acid (GABA)

The Benefits of L-Methylfolate, Vitamin B6, and B12

Together, these three nutrients are essential for breaking down homocysteine. Homocysteine is a naturally-occurring amino acid created when your body metabolizes the amino acid methionine. Methionine is what your body needs: it’s involved in building proteins and producing the antioxidant glutathione (your body’s greatest antioxidant), as well as the molecule SAMe.


But if the body is lacking in B12, B6, or folate, homocysteine won’t be recycled’ back into methionine. Over time, excess homocysteine levels can lead to cardiovascular disease.


Methylfolate b12, L-methylfolate B6 and methylcobalamin (B12) are the active forms of these nutrients that your body can use immediately. Methylfolate and methylcobalamin work together along the methylation cycle pathway to convert homocysteine and produce the compounds your body needs. 


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