Hydroxocobalamin Vs. Methylcobalamin for MTHFR: Which is Better? banner

Hydroxocobalamin Vs. Methylcobalamin for MTHFR: Which is Better?

Katie Stone - Naturopath

Written By:

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

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

February 11, 2025

Table of Contents

    What is Methylcobalamin?

    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 plasma2 and is also present naturally in foods. 


    Injectable methylcobalamin is no longer available in the US3. Oral forms are widely available as prescription or OTC. l


    Methylcobalamin is synthesized by probiotic bacteria4, 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 barrier5 without biotransformation. It is often preferred over cyanocobalamin6, 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.

    Benefits

    Vitamin B12 is essential for neuronal function7, 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 coenzyme8 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.

    What is Hydroxocobalamin?

    Hydroxocobalamin (also known as vitamin B12a) is a manufactured form of injectable vitamin B129. 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.

    Benefits

    Hydroxocobalamin is retained in the blood for longer10 than synthetic forms of B12 (cyanocobalamin) and binds more firmly to the TC II transport protein11 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 cyanocobalamin12. 


    Transcobalamins13 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.

    How Do They Work for People with MTHFR Gene Mutations?

    People with MTHFR mutation(s) have limited145-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 impaired15 without methylcobalamin and 5-MTHF, resulting in lower levels of SAMe and neurotransmitters16 and higher levels of homocysteine. 


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


    As the precursor to methylcobalamin and adenosylcobalamin, hydroxocobalamin is useful for the management and treatment of vitamin B12 deficiency17 and elevated homocysteine levels.


    Methylcobalamin accounts for 90% of the total cobalamin18 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 methylation19.

    Comparing Hydroxocobalamin and Methylcobalamin to L-Methylfolate

    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 result20 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 illness21. 


    MTHFR mutations are commonly associated with low levels of active folate and B1222 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 mutation23. 


    A 2015 comprehensive review of vitamin B1224 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 B1225 for treating B12 deficiency. Supplementing with methylcobalamin, hydroxocobalamin, and adenosylcobalamin means both coenzyme forms are obtained.

    Which is Best for You?

    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 B1226 in the body. 


    L-methylfolate is the only form of folate that can bypass the MTHFR mutation27 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 results28 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. 

    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 studies1 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.  

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    References

    1. 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://pmc.ncbi.nlm.nih.gov/articles/PMC5312744/

    2. Science Direct; "Methylcobalamin; 2025

      https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/methylcobalamin

    3. DailyMed; "Label: METHYLCOBALAMIN injection"; 2015

      https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24fd5ca6-b69e-3542-e054-00144ff88e88

    4. 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://pmc.ncbi.nlm.nih.gov/articles/PMC5312744/

    5. Gupta JK, Qureshi Shaiba Sana; "Potential Benefits of Methylcobalamin: A Review"; Austin Journal of Pharmacology and Therapeutics; 2015

      https://austinpublishinggroup.com/pharmacology-therapeutics/fulltext/ajpt-v3-id1076.php

    6. 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://pmc.ncbi.nlm.nih.gov/articles/PMC5312744/

    7. Carlos Alberto Calderón‐Ospina, Mauricio Orlando Nava‐Mesa; "B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin"; CNS Neuroscience & Therapeutics; 2019 Sep

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6930825/

    8. Science Direct; "Methylcobalamin; 2025

      https://www.sciencedirect.com/topics/nursing-and-health-professions/methylcobalamin#:~:text=Methylated%20vitamin%20B12%20(methylcobalamin,form%20proper%20myelin%20basic%20protein.

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

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

    10. C A Hall, J A Begley, P D Green-Colligan; "The availability of therapeutic hydroxocobalamin to cells"; Blood; 1984

      https://pubmed.ncbi.nlm.nih.gov/6692038/

    11. Bionity.com; "Hydroxocobalamin"; 2025

      https://www.bionity.com/en/encyclopedia/Hydroxocobalamin.html

    12. Keith Boddy, Priscilla King, L. Mervyn, J.F. Adams; “RETENTION OF CYANOCOBALAMIN, HYDROXOCOBALAMIN, AND COENZYME B12 AFTER PARENTERAL ADMINISTRATION“; The Lancet, Vol. 292 Iss. 7570 Pg. 710-712; 1968 Sep

      https://www.sciencedirect.com/science/article/abs/pii/S0140673668907526

    13. Valery Teplitsky, David Huminer, Joseph Zoldan, Silvio Pitlik, Mordechai Shohat, Moshe Mittelman; "Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults"; The Israel Medical Association Journal; 2003 Dec

      https://pubmed.ncbi.nlm.nih.gov/14689755/

    14. Maša Vidmar Golja, Alenka Šmid, Nataša Karas Kuželički, Jurij Trontelj, Ksenija Geršak, Irena Mlinarič-Raščan; "Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate"; Journal of Clinical Medicine; 2020 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

    15. John M. Scott; "Folate and vitamin B12"; Proceedings of the Nutrition Society, Vol. 58, Iss. 2; 1999 May

      https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/folate-and-vitamin-b12/93748DEBFA8ADFA72FAAE2DAF7C34AAA

    16. Alan L Miller; "The methylation, neurotransmitter, and antioxidant connections between folate and depression"; Alternative Medicine Review: A Journal of Clinical Therapeutic; 2008 Sep

      https://pubmed.ncbi.nlm.nih.gov/18950248/

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

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

    18. Amrita Sil, Hrishikesh Kumar, Rahul Deb Mondal, Sidharth Sankar Anand, Anirban Ghosal, Ashis Datta, Sandesh V Sawant, Vaibhavi Kapatkar, Ganesh Kadhe, and Sameer Rao; "A randomized, open labeled study comparing the serum levels of cobalamin after three doses of 500 mcg vs. a single dose methylcobalamin of 1500 mcg in patients with peripheral neuropathy"; Korean J Pain; 2018

      https://www.epain.org/journal/view.html?doi=10.3344/kjp.2018.31.3.183

    19. Shanna Anderson, Jacob Panka, Robin Rakobitsch, Kaitlin Tyre, Kerry Pulliam; "Anxiety and Methylenetetrahydrofolate Reductase Mutation Treated With S-Adenosyl Methionine and Methylated B Vitamins"; Integrative Medicine: A Clinician's Journal; 2016 Apr

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4898281/

    20. Jacob Selhub, Martha Savaria Morris, Paul F Jacques, Irwin H Rosenberg; "Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency"; The American Journal of Clinic Nutrition; 2009 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC2647758/

    21. B R Hutto; "Folate and cobalamin in psychiatric illness"; Comprehensive Psychiatry; 1997 Nov-Dec

      https://pubmed.ncbi.nlm.nih.gov/9406735/

    22. Katie Stone; "MTHFR Mutations and Vitamin B12 Deficiencies"; Methyl-Life®; 2021 Jul

      https://methyl-life.com/blogs/mthfr/mthfr-b12

    23. "How To Choose The Right Methylfolate For You"; Types of Methylfolate; 2025

      https://methyl-life.com/blogs/mthfr/methylfolate-vs-folic-acid

    24. Rima Obeid, Sergey N Fedosov, Ebba Nexo; "Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency"; Molecular Nutrition & Food Research; 2015 Jul

      https://pubmed.ncbi.nlm.nih.gov/25820384/

    25. K Thakkar, G Billa; "Treatment of vitamin B12 deficiency–Methylcobalamine? Cyancobalamine? Hydroxocobalamin?—clearing the confusion"; European Journal of Clinical Nutrition; 2015

      https://www.nature.com/articles/ejcn2014165

    26. 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 (Encinitas, Calif.); 2017 Feb

      https://pubmed.ncbi.nlm.nih.gov/28223907/

    27. "How To Choose The Right Methylfolate For You"; Types of Methylfolate; 2025

      https://methyl-life.com/blogs/mthfr/methylfolate-vs-folic-acid

    28. 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/

    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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