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This thread talks about overmethylation and some of the symptoms:Could someone translate for this newbie?
I have been doing the methylation supplements for 6 weeks are so, but what is 'overdriving'?
Thanks a bunch .
Rich and Freddd have different approaches to methylation. Rich tends to favor "low and slow" and only doing what you're comfortable with while Freddd prefers higher doses and more methyl donors and "pushing through" adverse symptoms. People have had success with both approaches. You'll have to find out what works best for you. I find that higher doses make my health worse so I don't have a choice in terms of whether or not I do "low and slow"And what is 'low and slow'?
So you think the 300 lb guy flipping burgers and spending his evening drinking beer and watching TV has a perfectly well running methylation cycle?Over-methylation is a big unknown. Some people have adverse reactions from methylation supplements. If someone can really over stimulate the methylation cycle, why can't a healthy person? Or can they? How about people who have recovered?
Healthy person = someone without me/CFS.
So you think the 300 lb guy flipping burgers and spending his evening drinking beer and watching TV has a perfectly well running methylation cycle?
I don't have a full understanding of it, but I think its about whether the chemical structures in your body accept methyls or not -- if you are already fully methylated, there is no space and need for any methyls to be added, hence, nothing changes, hence, no side effects or potassium sink or anything else. It's a chemical reaction that can happen, but doesn't happen if there is no room for CH3 to be added anywhere.
http://en.wikipedia.org/wiki/Methyl_group
But this is just my hazy understanding of it.
I've seen people eat mB12 like candy and have zero reaction no matter how much they take. They are regular people who get colds and have bad days, are overweight, etc.
I have seen lab test data (methylation pathways panel and plasma amino acids panel) from three people who had been on high-dose methylfolate together with high-dose methyl B12, and they showed what seems to me to be evidence of this. Namely, they had plenty of methionine and SAMe, low cystathionine and glutathione, low glycine and high sarcosine.
The rate-limiting enzyme in the methylation cycle is methionine synthase. It requires homocysteine and methylfolate as reactants and methyl B12 as a coenzyme. Normally the cells regulate the rate of the methionine synthase reaction by several feedback mechanisms. The amounts of methylfolate and methyl B12 are normally controlled. However, when large amounts of both are supplemented, the cells no longer have control over the rate of the methionine synthase reaction, and it speeds up, raising the rate of the methylation cycle. This has the effect of tending to raise the ratio of SAMe to SAH, which would raise the rates of the many methyltransferase reactions in general and would have major effects on gene expression and the biochemistry. However, the glycine N-methyl transferase reaction is there to limit the SAMe to SAH ratio. It does so by draining off methyl groups to convert glycine to sarcosine, which is why glycine goes down and sarcosine rises. Sarcosine delivers its methyl group to tetrahydrofolate, forming methylene tetrahydrofolate. This can then either go to form thymidine for new DNA formation, or it can be converted back to methylfolate by the MTHFR reaction. If the latter occurs, methylfolate delivers the methyl group back to the methionine synthase reaction, so this forms a sort of futile cycle. Meanwhile, the flow of homocysteine into the transsulfuration pathway is deficient, because homocysteine is being rapidly converted to methionine. Thus, the synthesis of cysteine is deficient, and therefore glutathione synthesis is, as well.
Best regards,
Rich
As you know, I have suggested a somewhat different approach to treating the methylation cycle partial block than Freddd has suggested.
When high dosages of methylfolate and methyl B12 are taken together, the cells are no longer able to control the rate of the methylation cycle, and it becomes overdriven.
One result of this is a rapid buildup of folates in the cells, because of the rapid production of tetrahydrofolate by the methionine synthase reaction.
Tetrahydrofolate is readily converted to the forms of folate needed to support DNA and RNA synthesis, and this releases cells from a block at the S phase of the cell cycle.
They rapidly start dividing, and this produces a strong demand for potassium.
As Alex has noted, it has been shown that the intracellular potassium levels are low in CFS (likely because of an ATP deficit at the membrane ion pumps, due to mito dysfunction, in turn due to primarily to glutathione depletion), so there is no reserve there.
The result is that the plasma level of potassium drops
Note that another effect of overdriving the methylation cycle is a further drop in glutathione, as less homocysteine is available to go toward cysteine synthesis.
There seem to be more and more people who are exhibiting effects of overdriving the methylation cycle from taking high dosages of methylfolate and methyl B12 together. I do not recommend this approach.
Best regards,
Rich
The reason I don't recommend going much higher on methylfolate when it is combined with several milligrams of methyl B12 is that this combination takes control of the rate of the methionine synthase enzyme away from the cells and drives it too fast. The result is that too much of the homocysteine is converted to methionine, and there is not enough left to flow into the transsulfuration pathway to support synthesis of glutathione and other sulfur-containing substances that the cells need.
The result is that the methylation cycle gets going well, but glutathione does not come up, as it needs to do for full recovery. There are excess methyl groups produced because of overdriving the methylation cycle. These are shunted off to the folate metabolism by sarcosine, which is produced by the glycine N-methyltransferase reaction, and then they come back to the methylation cycle via methylfolate. It's sort of like a futile cycle, like a squirrel in a rotating cage.
This is not just based on biochemical theory, though it is supported by that. It is based on lab tests that people who have been on this regimen have sent me.
For most PWMEs, this does not work very well in the long run. In Freddd's own case, because of the genetic variations that he apparently has in the CblC complementation group and in MTHFS (not to be confused with MTHFR), it is necessary for him to use a high dosage of methyl B12 to overcome the CblC problem, and it is necessary for him to use a high dosage of methylfolate to feed his folate metabolism, since he cannot use folinic acid or folic acid. (I'm not sure why he cannot use folic acid. Perhaps he has a polymorphism in the DHFR enzyme, also). Freddd cannot tolerate raising glutathione, because it binds cobalamin to form glutathionylcobalamin, and his version of the CblC complementation group is not able to retrieve cobalamin from glutathionylcobalamin. As far as I can tell, this is a rare genetic variation. Most PWMEs are depleted in glutathione, and this is responsible for a large number of the symptoms.
There may be other PWMEs who have one or more of these genetic issues as well, since Freddd reports that there are some others who respond to these supplements in the same way he does, but most do not seem to have them, based on our clinical study and anecdotal reports from quite a few PWMEs.
Best regards,
Rich
Clearly B2 is very dose proportional in it’s effect and is a most limiting factor at times and appears to be able to drive certain processes beyond useful limits as has been hypothesized about other things like B12 and folate. This appears to be the “throttle” that at least some of us have been looking for.
I've heard of the case of one guy (I think this was at Ben Lynch's forum but don't quote me on that). Anyway, this guy was healthy, but found out he had MTHFR, so he started taking supps for it as a preventative. He ran into overmethylation problems and had to discontinue. Even after he discontinued, it took awhile for things to clear out.
This thread talks about overmethylation and some of the symptoms:
http://forums.phoenixrising.me/index.php?threads/what-does-overmethylation-feel-like.22229/
I don't think the symptoms from taking too high of a dose are necessarily from "overdriving the methylation cycle", but maybe some of the time they are.
Rich and Freddd have different approaches to methylation. Rich tends to favor "low and slow" and only doing what you're comfortable with while Freddd prefers higher doses and more methyl donors and "pushing through" adverse symptoms. People have had success with both approaches. You'll have to find out what works best for you. I find that higher doses make my health worse so I don't have a choice in terms of whether or not I do "low and slow"
Freddd has been doing methylation for several years and says he's "cured of CFS/ME", but he ran into major overmethylation problems a few months ago:
http://forums.phoenixrising.me/inde...kalemia-and-methylfolate-insufficiency.22968/