Hydroxocobalamin Vs. Methylcobalamin for MTHFR: Which is Better?

Those with an MTHFR genetic mutation are often at a higher risk of B12 deficiency and need to supplement.

Hydroxocobalamin and methylcobalamin are two natural forms of B12 shown in clinical studies to improve vitamin B12 status. These forms are bioidentical to those that occur naturally in the human body and in animal foods.

This article will compare hydroxocobalamin and methylcobalamin and discuss how each may benefit those with an MTHFR genetic mutation. We will also explain which form of B12 may be suitable for someone with MTHFR.  

Methylcobalamin is one of the two natural and bioactive coenzyme forms of vitamin B12 (the other is adenosylcobalamin). It is the most abundant form in human plasma and is also present naturally in foods. 

Injectable methylcobalamin is no longer available in the US. Oral forms are widely available as prescription or OTC. l

Methylcobalamin is synthesized by probiotic bacteria, including Propionibacterium freudenreichii sbsp shermanii, or certain strains of lactobacilli, such as Lactobacillus lechmanii.

Methylcobalamin is the principal form of circulating vitamin B12 and can cross the blood-brain barrier without biotransformation. It is often preferred over cyanocobalamin, a synthetic B12 compound which occurs only in trace amounts in the body due to cyanide from smoking or other sources.

Methylcobalamin is essential for the normal metabolism of folate. Without methylcobalamin, folate cannot be used effectively by the body, which can lead to B12 deficiency, anemia, nerve damage, disruptions in cell division, and more.

Vitamin B12 is essential for neuronal function, red blood cell formation, DNA synthesis, and myelin integrity. It is also primarily involved along with folate in hematopoiesis and the development of the brain during childhood.

Methylcobalamin is an essential coenzyme in the homocysteine-methionine conversion process, which is often compromised in those with MTHFR mutations. It is the cofactor for the enzyme methionine synthase, which is required for the remethylation of homocysteine to methionine. 

Methionine is a precursor of S-adenosylmethionine (SAM), an important methyl group donor. SAMe provides methyl groups for over 100 methylation reactions, making it essential for detoxification, the regulation of enzymes and genes, protecting nerves, and synthesizing neurotransmitters.

Hydroxocobalamin (also known as vitamin B12a) is a manufactured form of injectable vitamin B12. In clinical settings, hydroxocobalamin is and used to prevent and treat macrocytic anemia associated with vitamin B12 deficiency. 

Hydroxocobalamin is a precursor of methylcobalamin and adenosylcobalamin, the two bioactive coenzyme forms of vitamin B12. To be used by the body, hydroxocobalamin is converted to either methylcobalamin or 5-deoxyadenosyl cobalamin.

Hydroxocobalamin is retained in the blood for longer than synthetic forms of B12 (cyanocobalamin) and binds more firmly to the TC II transport protein than cyanocobalamin or 5-deoxyadenosylcobalamin. One study found that the mean amount of hydroxocobalamin retained in the body 28 days aftertreatment was greater than that of cyanocobalamin. 

Transcobalamins are the main serum transport protein that delivers hydroxocobalamin to the tissues, ensuring the body’s stores are optimally replenished after deficiency. 

In the UK, hydroxocobalamin is the main treatment for vitamin B12 deficiency. It is also used to treat cyanide poisoning as it reacts with cyanide to form cyanocobalamin.

People with MTHFR mutation(s) have limited 5-methyltetrahydrofolate (5-MTHF) activity, which is required for the remethylation of homocysteine to create methionine. Vitamin B12 is also required as a cofactor in this process. Methylation is impaired without methylcobalamin and 5-MTHF, resulting in lower levels of SAMe and neurotransmitters and higher levels of homocysteine. 

Both hydroxocobalamin and methylcobalamin have benefits for those with MTHFR genetic mutations. 

B12 injections are no longer available in the US. 

As the precursor to methylcobalamin and adenosylcobalamin, hydroxocobalamin is useful for the management and treatment of vitamin B12 deficiency and elevated homocysteine levels.

Methylcobalamin accounts for 90% of the total cobalamin level in the cerebrospinal fluid (CSF), which indicates its pivotal role in the nervous system. It works alongside methylfolate to produce SAMe and ensure adequate methylation.

Both folate (vitamin B9) and B12 serve as coenzymes in one-carbon metabolism. Folic acid/vitamin B9 is not a substitute for methylcobalamin.

A folate deficiency can result if methionine is left inactive due to a lack of vitamin B12. A lack of methionine may then lead to hyperhomocysteinemia and low SAMe, the main methyl donor for the central nervous system. Folate deficiency and vitamin B-12 deficiency have been linked to cognitive impairment and mental illness. 

MTHFR mutations are commonly associated with low levels of active folate and B12 within the body, which converts homocysteine to methionine and numerous other methylation processes. People with an MTHFR mutation are advised to supplement with both nutrients in their active, methylated forms to ensure optimal uptake. 

L-methylfolate is the active form of folate which can bypass the MTHFR mutation. 

A 2015 comprehensive review of vitamin B12 metabolism stated that no advantage was demonstrated in using one of the B12 forms over another, except one related to cost.

Several studies have recommended a combination of all three active forms of B12 for treating B12 deficiency. Supplementing with methylcobalamin, hydroxocobalamin, and adenosylcobalamin means both coenzyme forms are obtained.

Vitamin B12 and folate are both crucial for proper methylation in the body and its many downstream processes.  For this reason, Vitamin B12 and folate should be taken together, especially in the case of an MTHFR mutation.

Hydroxocobalamin and methylcobalamin are both natural and active forms of B12 that are commercially available as supplements. Clinical studies show that these forms are successful in restoring B12 in the body. 

L-methylfolate is the only form of folate that can bypass the MTHFR mutation and be used alongside B12 for methylation processes. 

Methyl-Life’s® B12 Complete is one of the few OTC supplements that contains all three active forms of B12: methylcobalamin, adenosylcobalamin, and hydroxocobalamin.  This combination has been recommended for achieving faster clinical results following a B12 deficiency. It may also offset genetic polymorphisms involving B12 metabolism and related pathways.

Methyl-Life® also offers a comprehensive Methylfolate range with dosages of 2.5mg, 5mg, 7.5mg, and 15mg. For ultimate convenience, the unique B-Methylated-II contains both L-Methylfolate (3mg) and Methylcobalamin (3.75mg) to support daily Vitamin B12 and folate needs.