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ALS Worldwide
April 12, 2018

Methylcobalamin for ALS

Methyl-cobalamin (Me-B12) is a natural product analogue of vitamin B12 (aka cobalamin) that has become popular as a parenteral (intramuscular (IM), intravenous (IV)) supplement for patients with amyotrophic lateral sclerosis (ALS). In ALS it has been used as 25-50 mg/day chronically, with no reports to date of any adverse effects. This lack of side effects from repeated B12 injections is consistent with the recognized safety of B12 injections, but it is important to realize that no controlled study (with inherent safety monitoring) of high B12 daily dosing has been reported.

Might there be a scientific rationale for its use? Vitamin B12 has been known in Western medicine as an essential nutrient for humans and other mammals for almost 100 years. Mammals, including humans, cannot synthesize B12 and depend on nutritional sources. B12 is readily synthesized by prokaryotes (cells that do not possess an organized nucleus, such as bacteria and Archea). Very few eukaryotes (cells that do possess an organized nucleus) can synthesize B12. Animals that are nutritional sources of B12 for humans derive this from bacteria in their GI system and if carnivorous, from eating other animals.
In humans, bacteria in the lower GI tract, the so-called microbiome, can synthesize B12, but humans absorb B12 in the upper GI tract, not the lower GI tract where the bacteria are located.  Dietary B12 from animal muscle or liver, certain plants or chemical supplements bind to a protein known as intrinsic factor that is essential for B12 absorption from the upper intestine. Intrinsic factor is made by specific cells in the stomach, so surgical removal of that portion of the stomach, or antibodies directed against the cells making intrinsic factor or against intrinsic factor itself can lead to B12 deficiency states. IM or IV B12 injections bypass the complexities of its absorption from the intestine.
As is the case for other vitamins, deficiency states were the first to be recognized, and current “therapeutic levels” of B12 are determined based on prevention of deficiency. This is not the same as potential benefits that might accrue from very high levels of B12 or other vitamins.
What might these benefits be? The major action of B12 in the body is to promote dozens of “methylation reactions”, where a methyl group (-CH3) is added to entities such as small molecules, protein or DNA.  These methylation reactions are essential for normal physiology and include the chemical detoxification of the neurotoxin homocysteine that is normally synthesized and chemically removed. Elevated levels of homocysteine cause vascular disease, can kill neurons and appear to be associated with decreased cognition. In ALS patients, blood homocysteine levels correlate with level of ALS disability. Working with folic acid and its metabolites, B12 changes homocysteine into the non-toxic amino acid methionine. Thus, high B12 dosing may serve to drive down homocysteine levels in blood and nervous system.
Another important methylation reaction is addition of methyl groups to DNA, specifically to cytosine (C) in so-called “CpG islands” where many cytosines in a row get methylated. These methylation reactions can control how our genes are expressed and made into proteins. This DNA methylation ultimately derives from B12, although it does use other intermediates. It is not yet known whether high B12 dosing alters the “methylome” of DNA.
So here are two methylation properties of B12 that are experimentally testable. First, it is possible to measure blood (and potentially spinal fluid) levels of homocysteine, to see if popular B12 doses lower homocysteine levels. Second, using modern molecular genetic tools, one can now quantitate the DNA stretches that are methylated. With this tool, it would be possible to determine if high B12 dosing alters DNA methylation and subsequent gene expression.
There may be other biochemical explanations of how B12 treatment might be helping ALS patients. I’ve listed only two of many possible mechanisms.
It is of interest to me as a pharmacologist that 25 mg of Me-B12 corresponds to 18.6 micromoles. If this amount quickly distributes after injection into total body water of a 70 kg person (water~60% by weight), this would correspond to a Me-B12 level of ~440 nanomolar (picomoles/liter). This is a “therapeutic” B12 level in blood, so this level of dosing is certainly within the physiological range of B12.

James P. Bennett, Jr., M.D., Ph.D.
President and Chief Scientific Officer
Neurodegeneration Therapeutics, Inc
3050A Berkmar Drive
Charlottesville, VA 22901