Lotus97
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I see, so you're getting benefit from B12 alone which is why you're taking the dose you are? I assume you're taking the B12 sublingually? The only reason I ask is because you mentioned the part about the gut and also because I was surprised a COMT could tolerate that much methylcobalamin. BTW, the standard B12 tests aren't very accurate at least in determining how much B12 you need. I don't remember the reason why.Thanks. I started off taking B-12 because I was diagnosed with a B-12 deficiency in 2008 when I woke up one day and my feet and lower legs were numb, walking on them was like walking on clubs. It was very disturbing.
I increased the dosage as necessary (with the help of people on a B-12 forum) to offset the tingling, numbness and fatigue. So I've been at this dosage for at least a year, perhaps slightly less the year before that. It took a long time to get up to that level but each time I increased it, it was helpful. Gradually the problems like constant muscle pains and headaches disappeared as I increased.
Of course, perhaps the B-12 was compensating for folate issues?
My serum level was something like 150 when I was tested. There's only a small region of the intestine that can absorb it because it's such a large molecule, apparently, so the idea is that my gut got wiped out by antibiotics.
That is a tricky thing to answer since you're getting benefit from high doses of B12, but you're also COMT which means if you're taking a lot of B12 or even a low to moderate dose of B12 you're not going to be able to tolerate much folate. Maybe you can find some kind of balance where you still get benefit from B12, but are also able to take some folate because you need both. One reason Rich recommends the dosages and ratios is because he's concerned about overdriving the methylation cycle. I don't know much about SNPs, but COMT tend to be overmethylators. Have you tried lowering your dosage of methylcobalamin? Maybe try gradually lowering it until your symptoms return. Once you find the dosage of B12 you need then you can figure out how much folate you can tolerate.Maybe that's another strategy, that when I start the methylfolate again, to decrease the B-12 ahead of time.
The other reason why Rich recommends those specific starting dosages are because similar dosages were used in a study he and Dr. Neil Nathan conducted on CFS patients.Or perhaps the ratio doesn't actually matter and Rich proposed that because it seemed logical. I still do not fully understand the methyl trap.
http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf
Some people need higher doses which is why he gave instructions on increasing dosages (if necessary) when he revised his protocol last year.
According to Rich's theory of glutathione depletion, it seems that most people here who need methylation would be depleted of gluathione causing a B12 deficiency which would then cause a folate deficiency. I don't know what your situation is though so I can't answer whether you need methylation or not, but this is what he said. The first quote is a summary of Rich's Glutathione Depletion-Methylation Cycle Block theory. The second quote explains why the need for a high dose of B12 for the people here.Rich's protocol wouldn't necessarily be for someone with an actual deficiency, who gets almost no B-12 from diet.
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According to the GD-MCB hypothesis, if glutathione goes low enough, it provokes a functional B12 deficiency, which in turn leads to a partial block in methylation, followed by loss of folates and development of a stable vicious circle that makes ME/CFS chronic.Best regards,
Rich
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Why is the dosage of vitamin B12 so high for ME/CFS treatment?
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
Biochem Biophys Res Commun. 2011 Aug 26;412(2):360-5. Epub 2011 Jul 29.
Glutathione increases the binding affinity of a bovine B?? trafficking chaperone bCblC for vitamin B??.
Jeong J, Kim J.
School of Biotechnology, Yeungnam University, 214-1 Dae-dong, Gyeongsan-si, Gyeongsangbuk-do 712-749, Republic of Korea.
Abstract
Intracellular B(12) metabolism involves a B(12) trafficking chaperone CblC that is well conserved in mammals including human. The protein CblC is known to bind cyanocobalamin (CNCbl, vitamin B(12)) inducing the base-off transition and convert it into an intermediate that can be used in enzyme cofactor synthesis. The binding affinity of human CblC for CNCbl was determined to be K(d)=?6-16 ?M, which is relatively low considering sub-micromolar B(12) concentrations (0.03-0.7 ?M) in normal cells. In the current study, we discovered that the base-off transition of CNCbl upon binding to bCblC, a bovine homolog of human CblC, is facilitated in the presence of reduced form of glutathione (GSH). In addition, GSH dramatically increases the binding affinity for CNCbl lowering the K(d) from 27.1 0.2 to 0.24 0.09 ?M. The effect of GSH is due to conformational change of bCblC upon binding with GSH, which was indicated by limited proteolysis and urea-induced equilibrium denaturation of the protein. The results of this study suggest that GSH positively modulates bCblC by increasing the binding affinity for CNCbl, which would enhance functional efficiency of the protein.
Copyright 2011. Published by Elsevier Inc.
PMID: 21821010