Hi Rich,
Two modifications of of information to reconsider. First, why the pronounced folate antagonist appearance? The b12 deficiencies are not as pronounced as the folate deficiency, or perhaps the folate deficiency symptoms merelyu appear sooner. That begs the question of what could be the cause of the very pronounced folate deficiency? This appears to happen regardless of the dosage level of the active vitamins and they are not actually a required component. They merely allow the observation of the already gained benefits turning off suddenly and then turning back on suddenly. This can be easily duplicated over and over. It is independent of actual doses taken before hand. Some were taking a lot less b12 than others and almost nobody was taking anything ohter than a single 800mcg methylfolate beforehand. I'm sure I could assemble a panel that will produce those results to perform that experiment if you can provide the funding for before and after tests. Now that we know that it can be recovered from as quickly as it is induced it isn't so scary. The problem is money. If I had it I would fund it myself. The other group of people afflicted have nothing to do with active b12 and folate. They are generally the ones that widely report it as glutathione detox reaction. This class of people doesn't see this happen suddenly as the active effects turn off suddenly since they don't have this benefit in the first place. Not being aware of this they experience the appearance of this new class of symptoms and worsening of existing symptoms and can't assign it to the specific cause of returning deficiency since they had never relieved them in the first place. However, I have communincated with several folks who formerly have had glutathione detox reaction by their own description and then had it relieved by taking relatively large doses of methylfolate, adb12 and mb12. The name not withstanding that too is induced folate and active b12s deficiencies. While I had a severe long lasting instance, it isn't at all unique.
I will however, after the lab is back up and running, do the draw and have the methylation test panel and send the results to you for interpretation. I do have curiosity. At the gross symptoms level, what would be symptomatic of overdriven methylation in theory? Only 200mg of SAM-e makes any noticable difference at my present dose of 30mg/day sc injected of methylb12. That is completely unchanged from 5mg/day sc injected or even 5mg/day sublingual (1mg sc injected) . The only apparant difference of that large dose is of certain CNS neurological effects.
Hi, freddd.
I'm not sure I totally understand what you have written (above), but I think you mean that it appears that when the people with the conditions you are dealing with supplement with glutathione precursors, the effect is to counter their folate function and cause it to appear that they are deficient in folate, because their resulting symptoms can be reversed by taking more folate. Is that right?
And I think you also mean that supplementing with glutathione precursors in these people can also counter the active B12 coenzymes, and cause it to appear that they are deficient in B12. Is that right?
I'll make some comments, though I'm not sure that they will be responsive, because I'm not sure I understand what you are saying.
In CFS, as it appears to me, anything that brings about a partial block in the methionine synthase enzyme in a genomically susceptible person will bring about a vicious circle interaction between this block and depletion of glutathione, so that both remain present chronically. I think this most often occurs by the initial depletion of glutathione by various causes, which leaves B12 unprotected in the cells and allows it to react with toxins. There is then insufficient production of methylcobalamin, and that causes the partial block of methionine synthase.
When methionine synthase becomes partially blocked, 5-methyl THF initially builds up in the cells, because the methionine synthase reaction, which normally converts it to THF, is partially blocked. Because 5-methyl THF does not have a glutamate tail, as do other folate forms, it is able to leak out of the cells, into the blood plasma. That is called the "methyl trap" mechanism. The result of it is that the cells become depleted in all forms of folate, as other forms are channeled into producing 5-methyl THF, and it leaves the cells.
So the combination of low methyl B12 and low 5-methyl THF in the cells is the reason that both B12 and folate must be supplied to overcome the partial block. It is observed that when this is done, glutathione rises back up to normal automatically, which verifies that there is a vicious circle mechanism that links the partial methylation cycle block to the depletion of glutathione.
Before I learned about the partial methylation cycle block from the autism researchers in late 2004, I used to encourage people to try to raise their glutathione by direct methods, such as supplying glutathione precursors. Some PWCs (perhaps most) reported that this gave them some benefit temporarily, but they had to keep doing it or they would return to their initial state. A few people could not tolerate direct boosting of glutathione. Perhaps they correspond to the people you have described.
What was going on in the people who could not tolerate this treatment? I'm not sure. Perhaps they were mobilizing toxins, in which case it would properly be called a detox effect. Perhaps cysteine was being boosted too high, since cysteine is known to be a neurotoxin if it goes too high. For the people who were using NAC as one of the glutathione precursors, perhaps they were moving mercury into their brains, since according to the work of Aposhian et al. in rats, NAC can move mercury into the brain. Perhaps this supplementation was causing the generation of too much sulfite, and the sulfite oxidase enzyme was overloaded, allowing sulfite to rise to toxic levels.
Perhaps these people had sulfate-reducing enzymes in their gut, and this supplementation was eventually leading to too much hydrogen sulfide production by these bacteria. I think there are many possibilities, and it may have been different for different people.
In your particular case, as I wrote before, I think that supplementing glutathione may have caused the conversion of methyl B12 and adenosyl B12 to glutathionylcobalamin, and your body was not able to convert it back, for genetic reasons. When you went low in methyl B12, the methyl trap mechanism then would have drained folate metabolites from your cells into the blood, which would have rendered the cells deficient in folate, as well as being deficient in active B12. Under these conditions, supplementation with active folate and active B12 would have restored the methionine synthase back to normal operation.
As I also wrote before, in other people, who do not have genetic issues with the B12 processing enzymes, it may be that the glutathionylcobalamin could not be utilized because it was not associated with a chaperone molecule, as in the normal processing of B12 in the cells.
As I understand it, you associate certain symptoms with low folate and other symptoms with low B12. I'm not sure how this works, because both are needed for the methionine synthase operation. It is true, though, that folates have a small number of other functions, the most notable being the synthesis of purines and thymidine, which are needed to make new RNA and DNA for new cells. The most rapidly proliferating cells would likely be the most sensitive to a folate depletion, such as those lining the gut and the blood cells, including both red and white cells. This is believed to be the origin of the macrocytic anemia that results when folate is low. Low B12 can also do this, because of the methyl trap mechanism, which produces low folate availability in the cells.
And B12 does have the separate function of adenosyl B12, which assists in feeding certain substrates into the Krebs cycle to produce energy in the form of ATP.
So I can sort of see how some symptoms might be associated with deficiency of one or the other, but it would seem that there would be a big overlap, because a lot of the symptoms would result from a partially blocked methylation cycle, and either low folate or low B12 can cause that.
With regard to funding, I'm in the same boat you are. Our clinical study was funded by an anonymous donor, but this donor doesn't seem to be interested in doing it again. I'm hopeful that eventually someone who is properly connected and can obtain funding will get interested in the methylation block.
There's no money in it for the drug companies, except perhaps the "medical food" supplier, because patented drugs are not involved, so the usual sources of biomedical research funding are just not there.
I'm happy to hear that you are going to run a Vitamin Diagnostics methylation pathways panel on yourself. I think the results will be very interesting.
I think that the fact that taking 200 mg of SAMe has a noticeable effect on you suggests that your methylation capacity is still below normal, even with the heavy supplementation of methyl B12. Again, I realize that I seem to keep harping on this, but I think this may be a result of the genetic issue. Those are very large dosages of B12, and ordinarily, I think they would give generous support to the methylation cycle, so that taking 200 mg of SAME would not produce a noticeable effect. So I'm guessing that your methylation cycle is still not overdriven. However, I can't be sure that this would be the case in people who don't have genetic issues with their B12 processing enzymes, but are supplementing at the same high levels you are.
You asked what would be the symptoms of an overdriven methylation cycle.
I can only try to project them theoretically from the biochemistry and my hypothesis, so I could be off the mark. However, if flow down the transsulfuration pathway is diminished because of fast conversion of homocysteine back to methionine, then I think that all the symptoms that flow from depleted glutathione, as well as depleted cysteine and taurine, would follow. These include most of the symptoms of chronic fatigue syndrome, according to my hypothesis.
Best regards,
Rich