You talk about overmethylating the cells. But is there any risk of over methylation if one has an elevated MMA? IN teh 10 and above range?
How do you square your concerns with the large doses of methyl the DAN docs are giving the autistic kids?
This is tricky. I obviously need methyl, just not sure how to supplement.
It seems the low doses I can tolerate are completely inadequate for neurological healing.
Hi, AQ, freddd, and the group.
As has already been noted, an elevated MMA usually indicates that the cells do not have enough adenosylcobalamin. If a person takes dosages of methylcobalamin in the milligrams range either sublingually or by injection, significant amounts of it are apparently able to diffuse into the cells of the body in general, and are thus available directly to support methionine synthase. However, if this is the only form of B12 that is taken, there may still be a shortage of adenosylcobalamin in the cells, because some of the methylcobalamin would need to be converted to adenosylcobalamin in order to lower the MMA. This pathway depends on having enough glutathione in the cells to protect the cobalamin at an intermediate stage in the pathway to make adenosylcobalamin. In CFS, glutathione is depleted, so that can be a problem.
freddd's protocol overcomes this problem by including supplemental adenosylcobalamin at milligrams dosages, also.
In freddd's case, combined high-dose methyl- and adenosylcobalamin is apparently the only option that will work in a really good way, because he has an inherited defect in his B12 processing enzymes. Based on his disastrous experience with supplementing glutathione, I think we can narrow this down to an enzyme that normally acts beyond the step of formation of glutathionylcobalamin in the cells. Normally, this can be converted respectively to both methylcobalamin and adenosylcobalamin. However, in freddd's case, his cells are apparently not able to convert glutathionylcobalamin to methylcobalamin and adenosylcobalamin, so that when he built up glutathione in his cells, this trapped the B12 in a form that his cells could not access.
It is my view that this type of metabolic defect is not present in the vast majority of PWCs. Their basic problem is that their glutathione is depleted, so that their B12 is not protected from toxins. We have lab test data that shows that glutathione is depleted in PWCs, and also that it is increased as a result of treating the partial methylation cycle block. In PWCs, glutathione is not an enemy, it is a friend. It's a fundamentally different problem at the genetic and biochemical levels between freddd and the vast majority of PWCs. It happens that freddds' treatment protocol also works for many PWCs, because it bypasses the problem of insufficient glutathione, while it also helps him because it bypasses his problem of glutathione binding B12 in a form his cells cannot use. So I think his protocol works for him and for the PWCs for different biochemical reasons.
My concerns about overdriving the methylation cycle are first that if methionine synthase is driven too fast by high levels of 5-methyl THF and methylcobalamin, too much of the homocysteine is converted rapidly back to methionine, so that not enough is available to go down the transsulfuration pathway to form glutathione. I've seen results of organic acids and amino acids testing on people who were taking high dosages of methylcobalamin, and I think this concern was born out. I think this will slow the progress of recovery, and slow the detox of stored toxins. Second, I'm concerned about the possible effects of overmethylating the DNA. I don't know what the effects of this might be. DNA methylation controls gene expression, and the methylation capacity is normally tightly controlled in the body. Taking high dosages of methylcobalamin might override this normal control, and I think we should be cautious about doing that.
Though freddd has discounted the possibility that high methylcobalamin will methylate inorganic mercury, I still remember the people who reported serious neurological symptoms right after getting high-dose I.V. methylcobalamin. I realize that freddd does not advocate I.V. methylcobalamin.
The DAN! doctors give methylcobalamin subcutaneously. I think this limits the rate of release of methylcobalamin to the blood stream, from the subcutaneous fat layer, especially prominent in babies.
All I can suggest is to come up slowly on the dosage, if you find that you need methylcobalamin. As you know, Amy Yasko recommends methylcobalamin for people whose genetics indicates that they do not have enough methyl groups to do the conversion from hydroxocobalamin. Other ways of dealing with this might be to supplements some SAMe directly, or to boost the alternative BHMT pathway to make SAMe with betaine (trimethylglycine), making sure that there is also enough methionine to feed this pathway, so that more SAMe can be produced.
freddd has argued that the ability of the body to utilize hydroxocobalamin is limited to microgram levels per day. I think that is only true if the hydroxocobalamin is taken orally, so that its absorption is limited by the intrinsic factor mechanism. If it is taken sublingually or by injection in milligram quantities, I don't think this limit applies, because it is capable of diffusing into the cells of the body in general in the same way that methylcobalamin and adenosylcobalamin do in his treatment protocol. Once the hydroxocobalamin gets inside the cells, I think that the normal B12 processing pathways have a greater capacity than the limit posed by the intrinsic factor absorption pathway in the gut. Of course, if there is an inborn error of metabolism in these B12 processing enzymes, which freddd has reported having, and which is also evidenced by his negative response to building up glutathione, then I agree with him that hydroxocobalamin would not be very effective. But again, I don't think that's an issue in the vast majority of PWCs, and I think that the widespread positive response to hydroxocobalamin treatment in the CFS population is evidence of that. For documentation of this, see the reports on our clinical study at www.cfsresearch.org
. We have measured data that shows that hydroxocobalamin works well in a cohort that is documented to actually have CFS by the international definition. When freddd speaks of his 1,000 people, I continue to wonder how many of them actually had CFS, as opposed to B12 deficiencies from a variety of possible causes, including the one he has, as well as those with pernicious anemia, poor B12 absorption because of gastrectomy or gut disorders, transcobalamin deficiency, etc. freddd's treatment protocol will work for a wide variety of B12-related problems, but for different reasons in each cohort, and I object to applying his personal results directly to explaining what goes on in everyone who has CFS. I don't doubt that it will also work for many PWCs, but I think that some caution should be used, for the reasons I have given. And to tell people with CFS that they should avoid glutathione because it produced problems for freddd just does not make sense, in my opinion, based on the documented lab evidence. I would love to see some measurements run on freddd so that we could better understand these differences. The methylation pathways panel, together with urine organic acids (a Genova MAP panel) and plasma and urine amino acids tests would be very instructive, I think. Handwaving arguments can be interesting, but there is nothing like some hard data to figure out what is actually going on.