Hydroxocobalamin vs. Methylcobalamin (B12) for MTHFR

Hydroxocobalamin vs. Methylcobalamin (B12) for MTHFR

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - BSN, RN

Edited By:

Kari Asadorian - BSN, RN

Updated On:

February 11, 2025

What is methylcobalamin?

Methylcobalamin (MeCbl) is a metabolically active, bioidentical form of vitamin B12. It is the form naturally present in the human body and in animal products. It is required for numerous biological processes, including red blood cell formation, homocysteine metabolism and the methylation of myelin, which forms the protective sheath surrounding nerves. Methylcobalamin is essential for converting homocysteine to methionine (alongside methylfolate) which is vital for nucleotide synthesis and normal cell division.

Benefits of methylcobalamin

  • Supports nerve function
    B12 is essential for maintaining myelin, the protective sheath surrounding nerve fibers. Myelin supports nerve conduction, signal transmission and overall nerve health and regeneration. Deficiency can lead to myelin degeneration, which disrupts nerve signaling. This can lead to memory loss, motor dysfunction and dementia.1
    Recent studies show that methylcobalamin can alleviate pain in neuropathic pain disorders, and is an approved neuropathic pain medication in several countries.2

  • Red blood cell production
    Methylcobalamin is required for erythropoiesis, the formation of red blood cells. Deficiency can lead to malformed red blood cells (megaloblastic anemia) and impaired DNA synthesis in bone marrow cells.

  • Cognitive function
    Methylcobalmin treatment has been found to reduce both cognitive impairment and neuronal cell death (apoptosis) in people affected by fine particulate matter (PM2.5). Researchers suggest that this may be due to B12’s role in regulating mitochondrial pathways.3

  • Mood regulation
    Vitamin B12 is essential for the synthesis of neurotransmitters that regulate mood. One study found that early supplementation of B12 may help to delay the onset of depression and improve the effect of anti-depressants.4

  • Homocysteine regulation
    Methylcobalamin works with methylfolate to convert homocysteine to methionine, which is essential for preventing damage to the cardiovascular and neural systems. Methionine is then required for producing S-adenosylmethionine and neurotransmitters.

What is Hydroxocobalamin?

Hydroxocobalamin is another active form of vitamin B12 and the precursor of methylcobalamin and adenosylcobalamin. Hydroxocobalamin  is often used by clinicians to treat B12 deficiency as it is retained in the body for longer than other forms. It is usually given as an injection to people affected by conditions that impair the absorption of vitamin B12 from the GI tract, including malabsorption and pernicious anemia.5

Benefits of Hydroxocobalamin: Restoring B12 levels

Hydroxocobalamin is effective in treating macrocytic anemia associated with vitamin B12 deficiency, particularly in conditions such as pernicious anemia and malabsorption syndromes.6

It is taken up by cells in larger amounts per unit time and is better retained in the body than cyanocobalamin.

Intramuscular injections of hydroxocobalamin every three months after initial treatment is shown to maintain serum cobalamin levels within normal range for several years.7

MTHFR and B12 deficiency

People with MTHFR mutations may experience impaired B12 utilization, even if B12 levels appear normal. This is because active folate (methylfolate) is required for B12-dependent reactions, and MTHFR variants can reduce folate availability.8

While the MTHFR mutation does not directly cause B12 deficiency, it can impact the methylation cycle. B12 requires active folate (5-methyltetrahydrofolate) to function properly in the methionine synthase reaction, but folate levels are often low in people with MTHFR variants.

Homocysteine levels are often elevated in people with MTHFR variants, especially the homozygous MTHFR C677T. The risk of elevated homocysteine is even higher in those with low B12.9 Supplementation with methylated forms of folate and B12 is often recommended to support methylation and help reduce homocysteine levels.10

Hydroxocobalamin, Methylcobalamin and L-Methylfolate for MTHFR

Methylcobalamin is the most readily available and intracellularly active form of B12, and is relatively easy to find in supplements. Several leading nutraceutical brands use methylcobalamin instead of cyanocobalamin. 

Hydroxocobalamin is generally only available in the form of B12 injections. Methyl-Life® is one of the few brands that use a combination of all three bioidentical forms (methylcobalamin, adenosylcobalamin, and hydroxocobalamin) in our B12 supplement for most optimally and naturally increasing B12 status.11

Hydroxocobalamin injections are often recommended for those with B12 deficiency as it is retained in the blood for longer and binds more firmly to the TC II transport protein than other forms of B12.  Studies have shown that hydroxocobalamin reaches a higher peak concentration in the liver than cyanocobalamin 28 days after treatment.12

People with MTHFR genetic variants are often low in both folate and B12 due to impaired methylation. It is highly recommended that those with MTHFR take supplements that contain one or more of the active forms of B12 (methylcobalamin, hydroxocobalamin and/or adenosylcobalamin) along with the active folate form, methylfolate. These bioidentical forms of B12 and folate require no further conversion in the body and are immediately available to be used in many essential biological processes.

Hydroxocobalamin vs. Methylcobalamin (B12) for MTHFR

Key takeaways

  • Icon Methylcobalamin and hydroxocobalamin are two of the three active forms of B12. Both are readily available for use in the body upon ingestion.
  • Icon Methylcobalamin supports nerve health, red blood cell formation, cognitive function and homocysteine regulation.
  • Icon Supplementation with active forms of B12 is often recommended to those with MTHFR mutations.

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  • Methylcobalamin B12, Hydroxy B12 & Adenosylcobalamin
  • 3rd-Party Tested for Purity, Potency & Safety
  • 90 Vegan, Non-GMO, Chewable Mint Tablets

Frequently Asked Questions about MTHFR and B12

Is folate deficiency the same as B12 deficiency?

No. Although folate deficiency and B12 deficiency can have similar symptoms, they are different vitamins and deficiencies must be treated differently.
Folate is vitamin B9, and has its own role in supporting methylation processes, homocysteine metabolism and neurotransmitter production.
B12 is also involved in many of these processes, but it works alongside folate as a coenzyme in these processes: both vitamins are required for normal function.

Can MTHFR cause B12 deficiency?

Although MTHFR does not directly cause B12 deficiency, research suggests that people with the MTFHR C677T mutation have a significantly higher risk of deficiency.
MTHFR mutations can mean less active folate available to donate a methyl group to vitamin B12, which needs folate for the homocysteine-methionine conversion process. A lack of methylfolate means this conversion can’t happen as it should.
This functional deficiency disrupts methylation and homocysteine metabolism, leading to symptoms resembling B12 or folate deficiency.

Can MTHFR cause high B12?

No. High B12 is uncommon as it is a water-soluble vitamin and any excess is flushed out of the body in urine. High B12 may result from excess supplementation or medical conditions in which the liver cannot process it properly.
Essentially, high serum B12 can mean that your body is unable to absorb, metabolize, and/or utilize B12 properly, so it remains in your bloodstream. This has been referred to as a ‘paradoxical vitamin B12 deficiency’, because the B12 is functionally unavailable.
Paradoxical B12 deficiency may occur as a result of MTHFR because methionine synthase requires methylcobalamin to metabolize homocysteine. When MTHFR enzyme function is deficient, B12 remains inactive.

References

  1. Milind Umekar, Tanvi Premchandani, Amol Tatode, Mohammad Qutub, Neha Raut, Jayshree Taksande, Ujban Md. Hussain; "Vitamin B12 deficiency and cognitive impairment: A comprehensive review of neurological impact"; Brain Disorders; 2025 Jun

    https://www.sciencedirect.com/science/article/pii/S266645932500040X

  2. Amilia Ramadhani, Indwiani Astuti, Maria Goreti Widiastuti, Nunuk Purwanti; "Methylcobalamin as a candidate for chronic peripheral neuropathic pain therapy: review of molecular pharmacology action"; The Korean Journal of Pain; 2024

    https://www.epain.org/journal/view.html?uid=1854&vmd=Full

  3. Xintong Ji, Chenxia Li, Xiaozheng Zhu, Wenlei Yu, Yanyu Cai, Xinyi Zhu, Linjie Lu, Qiwei Qian, Yu Hu, Xuan Zhu, Huanhuan Wang; "Methylcobalamin Alleviates Neuronal Apoptosis and Cognitive Decline Induced by PM2.5 Exposure in Mice"; Journal of Alzheimer's disease; 2022

    https://pubmed.ncbi.nlm.nih.gov/35253753/

  4. Prerna Sangle, Osama Sandhu, Zarmeena Aftab, Adarsh Thomas Anthony, Safeera Khan, Alexander Muacevic, John R Adler; "Vitamin B12 Supplementation: Preventing Onset and Improving Prognosis of Depression"; Cureus; 2020 Oct

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7688056/

  5. Edris Ramezanpour Ahangar, Pavan Annamaraju; "Hydroxocobalamin"; StatPearls [Internet]; 2023 May

    https://www.ncbi.nlm.nih.gov/books/NBK557632/

  6. Edris Ramezanpour Ahangar, Pavan Annamaraju; "Hydroxocobalamin"; StatPearls [Internet]; 2023 May

    https://www.ncbi.nlm.nih.gov/books/NBK557632/

  7. Bruce HR Wolffenbuttel, Hanneke JCM Wouters, M Rebecca Heiner-Fokkema, Melanie M van der Klauw; "The Many Faces of Cobalamin (Vitamin B12) Deficiency"; Mayo Clinic proceedings. Innovations, quality & outcomes; 2019 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6543499/

  8. Khalid M Al-Batayneh, Mazhar Salim Al Zoubi, Murad Shehab, Bahaa Al-Trad, Khaldon Bodoor, Wesam Al Khateeb, Alaa A A Aljabali, Mohammad Al Hamad, Greg Eaton; "Association between MTHFR 677C>T Polymorphism and Vitamin B12 Deficiency: A Case-control Study"; Journal of medical biochemistry; 2018 Apr

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6294092/

  9. E. Zittan, M. Preis, I. Asmir, A. Cassel, N. Lindenfeld, S. Alroy, D. A. Halon, B. S. Lewis, A. Shiran, J. E. Schliamser, M. Y. Flugelman; "High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia"; American Journal of Physiology-Heart and Circulatory Physiology; 2007

    https://journals.physiology.org/doi/full/10.1152/ajpheart.01189.2006

  10. Andrew McCaddon, Joshua W Miller; "Homocysteine—a retrospective and prospective appraisal"; Frontiers in nutrition; 2023 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10294675

  11. Cristiana Paul, David M Brady; "Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms"; Integrative Medicine: A Clinician's Journal; 2017 Feb

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/

  12. Paula A Gonzalez‐Rivas, Michael Chambers, Jerry Liu; "A pilot study comparing the pharmacokinetics of injectable cyanocobalamin and hydroxocobalamin associated with a trace mineral injection in cattle"; Journal of veterinary pharmacology and therapeutics; 2021 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8252089

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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