Correct Dose of B12 for ME/CFS Treatment

For those of us taking Vitamin B12 as part of their ME/CFS treatment, it's always difficult determining the exact right dose (not to mention the right combination of forms of B12).  I recently stumbled on Dr. Rich VanK's explanation of why the dose needs to be at least 2000 to 2500 mcgs to see results. Quoted here in full:

Hi, all. 

The above question has been around for quite a few years, and we haven't had a good answer for it. I think it is now possible to answer it, based on some recent research in Korea. 

Here's some background: In the 1990's, Drs. Charles Lapp and Paul Cheney initiated treatment of their CFS patients by injection of vitamin B12, after observing that many patients had elevated homocysteine or methylmalonate in urine testing. They found that there was a threshold of response at between 2,000 and 2,500 micrograms per injection to produce an improvement in energy, stamina or wellbeing that lasted for two or three days. Lower dosages did not appear to produce improvements. This was puzzling, because the recommended daily allowance (RDA) for vitamin B12 in adults is only 2.4 micrograms per day. Why did the dosage need to be so high to produce improvement in symptoms?
As many of you know, the sublingual hydroxocobalamin dosage in the Simplified Methylation Protocol today is comparable to the injected dosages that Drs. Lapp and Cheney found to be necessary, still very high compared to the RDA dosage, and this question has remained. (I note that high dosages of B12 are also used in autism, which shares much of the same pathophysiology with ME/CFS.) 

O.K., in 2011 a paper was published by two researchers in Korea, Jeong and Kim. The abstract is pasted below. 

The research they report was actually done on a bovine (cow) B12-processing complementation group and cyanocobalamin. However, the human complementation group is very similar, and I suspect that the results will also be similar for other forms of B12 than cyanocobalamin. 

They studied the CblC complementation group. This is part of the B12 processing pathway that is found inside all cells. When a form of B12 comes into a cell from the blood by the usual transcobalamin route, it is bound to CblC, and its beta ligand (cyano-, methyl-, or adenosyl-) is removed. Then it is sent on to be converted back to methylcobalamin or adenosylcobalamin as needed by the cell.

In order for this processing to happen, the CblC complementation group must first bind the B12 form. The strength of binding is called the affinity (Kd), and it is measured in concentration units. The higher the affinity, the lower the Kd. It turns out that the bare CblC complex has a relatively low affinity for B12, compared to the concentration of B12 in the cells, and this would be unfavorable for the necessary binding, and would tend to lower the reaction rate. 

What these researchers found is that normally glutathione binds to CblC, and in doing so, it increases the affinity of CblC for B12. And it does so by a whopping amount--over a factor of a hundred!! 

Turning this around, if glutathione becomes depleted, as in ME/CFS and autism, the affinity of CblC for B12 is going to drop substantially. I suggest that the glutathione depletion, combined with its major effect on this affinity, is the reason the B12 dosage must be so high in treating ME/CFS and autism.

Best regards,
Rich

[Citations omitted]

Back when I tried a methylation protocol for the first time, I was taking about that amount (if not more at times), but never really showed much improvement over 8 or 9 months.  In fact, the only thing I experienced was symptoms of overmethylation.  But I think that was because I had the wrong combination of forms, focusing too much on methylcobalamin.  Now that I have genetic testing results showing CBS and BHMT mutations, I know that I probably have trouble with excess methyl donors. While I haven't yet reached the stage of Yasko's protocol where B12 is added in, this time I'm going to work on taking a good mix of hydoxy- methyl-, and adenosyl- cobalamin.