Hi, pea.
I can't speak for Dr. Yasko, but 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
Hi Rich,
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.
You need to consider that the experience piling up isn't at all reflective of this. Healing turns on with about 50mcg of mb12 and appears to typically require 1600-3200mcg of Metafolin in the absence of paradoxical folate deficiency.
With FMS, CFS, ME symptoms and healing response started (methylation startup), and no apparant paradoxical folate deficiency:
Potassium 1600-3000mg
at 50mcg of mb12/adb12 absorbed - 1600-3200mcg of metafolin
at 1mg of mb12/adb12 absorbed - 1600-3200mcg
at 5mg of mb12/adb12 absorbed - 1600-3200mcg of metafolin
at 40mg of mb12/adb12 absorbed 1600-3200 mcg of metafolin
Without FMS, CFS,ME symptoms and no healing response started, no paradoxical folate deficiency appararant, methylation was never broken:
Potassium 99mg
at 50mcg of mb12/adb12 absorbed - 800 mcg of metafolin
at 1mg of mb12/adb12 absorbed - 800 mcg
at 5mg of mb12/adb12 absorbed - 800 mcg of metafolin
at 20mg of mb12/adb12 absorbed 800 mcg of metafolin
With FMS, CFS, ME symptoms and healing response started (methylation startup), and apparant paradoxical folate deficiency - folic acid:
Potassium 1600-3000mg
at 50mcg of mb12/adb12 absorbed - 6000-8000 mcg of metafolin
at 1mg of mb12/adb12 absorbed - 6000-8000 mcg
at 5mg of mb12/adb12 absorbed - 6000-8000 mcg of metafolin
at 40mg of mb12/adb12 absorbed 6000-8000 mcg of metafolin
With FMS, CFS, ME symptoms and healing response started (methylation startup), and apparant paradoxical folate deficiency - folic acid and folinic acid:
Potassium 1600-3000mg
at 50mcg of mb12/adb12 absorbed - 12,000+ mcg of metafolin
at 1mg of mb12/adb12 absorbed - 12,000+ mcg
at 5mg of mb12/adb12 absorbed - 12,000+ mcg of metafolin
at 10mg of mb12/adb12 absorbed 12,000+ mcg of metafolin
You appear to be obsessed with mg of mb12. However, except for neurological healing 50mcg appears to work just as well for most people.
If I have observed this even approximately accurately it should be clear that quantity of mb12/adb12 beyond 50mcg makes no difference to the quantity of Metafolin or potassium in any kind of direct relationship. They don't have a feedback cycle where an increase in one requires an increase for the other. There are perhaps several quantum steps. There is the layer of epithelial healing set of by mb12, there is a layer of muscle healing set off by adb12-carnitine in addition to mb12, and there is a layer of neurological healing set off by both. The epithelial layer adds a large requirement for Metafolin. The muscle layer adds a need for Metafolin. The neurological layer which often requires the difference between 1mg of mb12 and 40mg of mb12 to have heal, doesn't increase the Metafolin need.
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.
By selecting the right group, and that right group is those who have had a lot of healing from adb12/mb12/metafolin which were also those who have a big response to these things, say 75% of the people here more or less, one can see the effect of glutathione on approximately 100% of persons, the same or similar enough response to glutathione that it is indistinguishable without lab tests. That doesn't sound rare at all. First they heal and then the healing can be reversed by glutathione with full predictablity. You can bet on it near 100%. This group of people have lots of symptoms because the the active b12s deficiency causes hundreds of symptoms and also can relieve hundreds of symptoms without any of this struggling to fit a camel through the eye of a needle. Rare should make it difficult to find. Maybe ME-FMS-CFS selects for such people and puts all us bad eggs in one basket. The results I get with glutathione can be matched by almost everybody here. Even the people saying it relieves some of their symptoms are having relief by getting rid of the discomfort caused by Metafolin and Mb12 becasue it of the exact same effects of glutathione. The people who find comfort are so deep in deficiency they are ultra sensitive to mb12-metafolin and don't have the return of symptoms becasue theirs have never left and so the relief is the relief of returning to deep deficiency and getting rid of that pesky startup.
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.
Rich, I can give you precise written directions on how to precisely reproduce the results I have gotten personally and in the N=10 trial, which had 100% results similar to mine. I've run into one person so far put into the hospital by glutathione "detox" response who is very dissimiler to me in all sorts of ways and a much more limited deficiency set and no paradoxical folate deficiency at all. The difference, in N=10 trial, was a difference in dose size and frequency, and how severe the response was. There was some variation in response. The several most severely neurologicall damaged people had the quickest furthering of neurological damage. Some of the people here are all frothed up about the theoretical possiblity of overmethylation (no known examples, but I am certainly looking) or mercury (highly uncertain, low probablity comparatively, and I am certainly looking for the clues), so severely that they won't even get methylation going in the first place and yet here you are ignoring that some percentage, perhaps a third or a quarter or half could have increased brain damage/cord damge in 6 weeks of gutathione or precursor usage.