Synthetic vs Natural B12 

By Cliff Harvey

B12 is an essential vitamin, collectively known as cobalamin. Cobalamin contributes significantly to haematopoiesis (creation of blood cells), myelin synthesis and synthesis of epithelial tissue. As a coenzyme, it is also a principal component of fatty acid, carbohydrate and nucleic acid metabolism. Vitamin B12 and/or folic acid deficiency is one of the most common causes of hyperhomocysteinaemia (high homocysteine levels – a marker of cardiometabolic dysfunction).

Anaemia is usually the first sign of a B12 deficiency, but not always as a high intakes of folates can mask B12 deficiency for some time. Of note is that the neural (brain and central nervous system) damage induced by a B12 deficiency is not reduced by folate and so it is imperative for vegans to take a B12 supplement.
Early in the 20th century doctors coined the term "pernicious anaemia" for the form of anaemia that did not respond to iron supplementation. Pernicious anaemia occurs when the body doesn’t produce intrinsic factor in the stomach, necessary of absorption of B12. In 1948, vitamin B12 was identified as the cure for pernicious anaemia and a reliable form of B12 for supplementation was sought.
There is a common misunderstanding that oral Vitamin B12 administration is ineffective. However evidence suggests that oral use of Vitamin B12 is perfectly suitable to support health and reduce deficiency. The oral dosage required depends on the cause of deficiency and the severity of the disease. Dose of 10–100 µg/day generally lead to normalization of levels. However, higher dosages are needed in cases of malabsorption, intestinal disease, or disorders affecting the utilization of Vitamin B12. Randomized double-blind dosage determination studies with daily administration of 2.5, 100, 250, 500 and 1000µg of cyanocobalamin have shown that to normalize the levels doses of >500–1000µg/day may be required (1) and to normalize mild vitamin B12 deficiency more than 200 times greater than the recommended dietary allowance (which is approximately 3μg daily) may be required (2).
The common form added to supplements cyanocobalamin is a synthetic form not found in foods in nature. The metabolism of cyanocobalamin leaves behind a cyanide residue that the body must then excrete. This is unlikely to cause problems for most people as the amount of cyanide left is extremely small, however it has been suggested that those with pre-existing kidney problems may have trouble excreting even these small amounts and that a methylcobalamin form is preferred (3) and it has been suggested for decades that cyanocobalamin should be replaced with a non-cyanide form of B12 (4) for general safety.
An alternative to synthetic vitamin B12 is a natural co-factor of B12 methylcobalamin. Vitamin B12 regulates, together with 5-methyl-tetrahydrofolic acid (folate), the remethylation of homocysteine to l-methionine and the subsequent formation of S-adenosylmethionine (SAMe). SAMe is essential to most biological methylation reactions including the methylation of myelin, neurotransmitters, and phospholipids (e.g., phosphatidylcholine). Methylcobalamin, having a methyl group is able to act as a methyl donor for these reactions (5), whereas the synthetic forms need to themselves be methylated in order to do this. This step may be limited in some people and even in healthy people taxes methylation pathways unnecessarily.
Naturally occurring cobalamins (like methylcobalamin) in food appear to be absorbed at a better rate than synthetic B12 (cyanocobalamin) (6). In dialysis patients a ‘remarkable’ homocysteine reducing effect was observed when methylcobalamin was added to high-dose folic acid supplementation (7). Although it has been suggested that there is an extremely rare genetic disorder for which cyanocobalamin may be effective (8) for almost all others for prudence it appears that methylcobalamin is a better, more effective and safer supplemental choice. 

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References
1. Gröber, U., K. Kisters, and J. Schmidt, Neuroenhancement with Vitamin B12—Underestimated Neurological Significance. Nutrients, 2013. 5(12): p. 5031-5045.
2. Eussen, S.M., et al., Oral cyanocobalamin supplementation in older people with vitamin b12 deficiency: A dose-finding trial. Archives of Internal Medicine, 2005. 165(10): p. 1167-1172.
3. Vitamin B12 Deficiency. New England Journal of Medicine, 2013. 368(21): p. 2040-2042.
4. Freeman, A.G., Cyanocobalamin--a case for withdrawal: discussion paper. Journal of the Royal Society of Medicine, 1992. 85(11): p. 686-687.
5. Pfohl-Leszkowicz, A., G. Keith, and G. Dirheimer, Effect of cobalamin derivatives on in vitro enzymic DNA methylation: methylcobalamin can act as a methyl donor. Biochemistry, 1991. 30(32): p. 8045-8051.
6. Matte, J.J., F. Guay, and C.L. Girard, Bioavailability of vitamin B12 in cows' milk. British Journal of Nutrition, 2012. 107(01): p. 61-66.
7.Koyama, K., et al., Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high‐dose folic acid supplementation. Nephrology Dialysis Transplantation, 2002. 17(5): p. 916-922.
8.Gherasim, C., et al., Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling. Journal of Biological Chemistry, 2015. 290(18): p. 11393-11402.