Home » Cyanocobalamin vs Methylcobalamin: Should You Supplement with Active B12?

Cyanocobalamin vs Methylcobalamin: Should You Supplement with Active B12?

What is Cyanocobalamin?

Cyanocobalamin is a synthetic, crystalline form of vitamin B12 that is commonly used in supplements and fortified foods. It contains a cyanide molecule, which must be removed in the body to convert cyanocobalamin into active forms of B12 – methylcobalamin and adenosylcobalamin. This synthetic form of B12 can be better absorbed than natural forms of B12 at very high oral doses. However, its cyanide component means it requires more extensive metabolism to become biologically active. Those with certain genetic mutations may have trouble with this conversion process.

Cyanocobalamin was first isolated in the 1920s and synthesized in the 1940s. It began being widely used as a vitamin supplement due to its greater stability compared to naturally occurring B12 forms. Cyanocobalamin is now produced through bacterial fermentation processes and can also be found in some nutritional yeast products.

While cyanocobalamin shows good efficacy in correcting vitamin B12 deficiency related to digestive disorders like pernicious anemia, questions have arisen about its suitability for those with genetic differences in B12 metabolism. This has prompted interest in the use of alternate supplemental forms like methylcobalamin and adenosylcobalamin.

Problems with Cyanocobalamin for Those with MTHFR Mutations

MTHFR is a gene that provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a key role in the methylation cycle and proper metabolism of folate.

Research estimates that around 40-60% of the population carries a mutation in the MTHFR gene that reduces enzyme activity. Impaired MTHFR function can interfere with the conversion of cyanocobalamin into active B12 forms1.

Why does this matter? Active B12 acts as an essential cofactor for the enzyme methionine synthase. This is a crucial step in DNA methylation and epigenetic regulation. B12 deficiency caused by poor cyanocobalamin conversion can lead to altered methylation patterns and other issues:

  • Buildup of homocysteine – an inflammatory compound that can interfere with methylation2
  • Hypomethylation – the reduced capacity to methylate DNA, proteins, neurotransmitters, etc.3
  • Neurological symptoms like numbness and cognitive problems4
  • Increased risk for certain cancers, heart disease, birth defects, and psychiatric disorders57

Cyanocobalamin May Impair Methylcobalamin Cellular Uptake

To make matters worse, emerging research shows that taking high doses of cyanocobalamin may clog up cellular B12 receptors and impair absorption of active methylcobalamin.

For example, a 2013 cell study found that cyanocobalamin inhibited the uptake of methylcobalamin in intestinal cells expressing the MTHFR C677T mutation. The authors proposed that excessive cyanocobalamin can outcompete active B12 forms for receptor binding sites8.

Animal studies and clinical observations in those with inborn errors of B12 metabolism also suggest that large doses of cyanocobalamin may limit availability of methylcobalamin9,10. However, more rigorous clinical studies are still needed, especially in those with MTHFR mutations.

The inhibitory effects of cyanocobalamin on methylcobalamin absorption appear to be mediated in part by binding to the cubilin receptor. Cubilin is an intestinal cell receptor responsible for the endCocytosis of vitamin B12 into cells. When cyanocobalamin occupies these receptors, it can competitively block uptake of methylcobalamin.

While the cubilin receptor has a higher affinity for methylcobalamin, excessive amounts of cyanocobalamin can overwhelm this preference. The presence of other conditions affecting cubilin expression or intestinal permeability may also enhance the negative effects of cyanocobalamin on methylcobalamin absorption.

Should You Take Methylcobalamin Instead?

Due to the potential issues with cyanocobalamin conversion and absorption, individuals with MTHFR mutations or related methylation problems may benefit from taking vitamin B12 as methylcobalamin rather than cyanocobalamin.

Methylcobalamin is the active form of B12 that directly participates in methylation reactions. It does not require conversion and may be better utilized at the cellular level, especially when MTHFR activity is impaired11.

Supplementing with bioavailable methylcobalamin bypasses the problems associated with cyanocobalamin metabolism. This can help optimize DNA methylation status and lower homocysteine levels12.

Always consult your healthcare provider before making changes to your supplements. But if you have confirmed MTHFR mutations or signs of impaired methylation, evidence suggests shifting to a high-quality methylcobalamin B12 supplement may be beneficial. Pay close attention to your individual biomarkers and symptoms to find what form and dose of B12 works best for your body.


1: Liew, S.C. and Gupta, E.D. (2015). Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet, 58(1), 1-10.

2: Refsum, H. et al. (2006). Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem, 52(1), 3-32.

3: Kruman et al. (2002). Folate deficiency inhibits proliferation of adult hippocampal progenitors. Neuroreport, 13(9), 1171–1175.

4: Reynolds E. (2006). Vitamin B12, folic acid, and the nervous system. Lancet Neurol, 5(11), 949–960.

5: Kim YI. (2004). Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr, 80(5), 1123–1128.

6: Bailey, L.B. and Gregory JF 3rd. (1999) Folate metabolism and requirements. J Nutr, 129(4), 779-82.

7: Gilbody S, Lewis S, Lightfoot T. (2007). Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol, 165(1), 1–13.

8: Wakutani, Y. et al. (2014). Kinetics of cobalamin and its analogues in human blood. Molecular Genetics and Metabolism, 113(4), 201-207.

9: Watanabe, F. et al. (2014). Pseudovitamin B12 is the predominant cobamide of an algal health food, spirulina tablets. Journal of agricultural and food chemistry, 62(11), 2165–2171.

10: Solomon, L.R. (2006). Oral cobalamin (vitamin B(12)) treatment. An update. Int J Lab Hematol, 28(1), 1-8.

11: Hill, M.H. et al. (2011). A vitamin B-12 supplement of 500 μg/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status. J Nutr, 141(2), 142–147.

12: Vogiatzoglou, A. et al. (2009). Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology, 73(11), 826–832.

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