Methylcobalamin (Vitamin B12)

The methylation of homocysteine by L-methylfolate with methionine synthase requires vitamin B12 as coenzyme. In conjugation with supplemented folate (0.5-5 mg) the addition of vitamin B12 (500 µg) has been shown to maintain more efficiently homocysteine than folic acid alone (Clarke 2000). In combination with folate 0.4 mg vitamin B12 are reported to maintain best the homocysteine level (Homocysteine Lowering Trialists’ Collaboration 2005). B-vitamins (B12, B6, B2) are essential for the reduction of homocysteine in particular depending on the Methylenetetrahydrofolate Reductase (MTHFR) genotype. In a randomized, placebo controlled study over 7 years with 5202 individuals with pre-existing cardiovascular diseases (CVD) vitamin B12 intake of 1000 µg together with folic acid and vitamin B6 reduced the risk of AMD (Christen et al. 2009). Hence, an upper limit of 1000 µg vitamin B12 given as cyanocobalamin over 7 years without reported adverse effects can be considered as safe (Christen et al. 2009). In another study with 214 individuals with type 2 diabetes mellitus L-methylfolate (3 mg), methylcobalamin (2 mg) and pyridoxal-5’-phosphate (35 mg) have been administered over 24 weeks without observable adverse effect level (Fonseca et al. 2013). 

Because of the controversy and discussion of high doses of synthetic cyanocobalamin in the literature, the activated vitamin B12, methylcobalamin (active compound in homocysteine metabolism), has been selected (Zhang et al. 2013) for the formulation. In vitamin B12 replacement therapy oral dosages between 1-5 mg vitamin B12 are used, with no supportive evidence of adverse effects (European Food Safety Authority (EFSA) 2008). A toxicologically upper level of vitamin B12 is not defined, yet.

The association between vitamin B12 and folate intake and 10 year incidence for AMD indicated an intake of ≥ 6.67 µg vitamin B12 (Gopinath et al. 2013). The Scientific Committee on Food has issued an opinion on the Tolerable Upper Intake level of Vitamin B12 and concluded that it is not possible to derive an Upper Level, mainly because no clearly defined adverse effect could be identified. The Panel also noted that the proposed levels of use amounting up to 500 μg vitamin B12/day are below the guidance value of 2000 μg/day defined by Expert Group on Vitamins and Minerals (EVM) (Aguilar et al. 2008).

Conclusion: The effective dosage of methylcobalamin of 500 µg as a cofactor reduces homocysteine effectively also in individuals with attenuated MTHFR genotype and there is no evidence of adverse effects when used in this dosage. There is no maximum upper limit defined.