Among those who have not been able to tolerate the treatments, it appears that excitotoxicity has been one of the main problems. This leads to insomnia, anxiety, hypersensitivity of the senses, and a constantly "wired" feeling.
First, for the people who can tolerate the treatments but do not experience benefits from them, I suspect that the likely causes are that the methylation cycle and related pathways do not have all the nutrients they need to come back up to normal operation. These include amino acids (especially methionine, serine, glycine, glutamine, and cysteine), vitamins (especially the other B vitamins and vitamin C), and certain minerals (especially zinc, copper, magnesium, manganese, selenium and molybdenum). These deficiencies could be at least partly caused by dysfunction of the digestive system, and I think that there is a lot of potential in working to fix the gut problems.
If glutathione becomes more depleted, the mitochondria of the astrocytes will be less able to produce ATP at normal rates, because of the oxidative stress that will arise, partially blocking the Krebs cycle and the respiratory chain. So I think there is a good basis for suspecting that the temporary glutathione depletion that occurs when this treatment is used is what is responsible for the rise in excitotoxicity.
I have just heard from Lisa (slayadragon) that when she and another person have dealt with other issues, including mold toxins, they have then found that the methylation treatments have been much more effective in helping them to detox. Again, I think this suggests that other impediments to raising glutathione may need to be dealt with first.
Along this same line, the women who were treated in the study that Dr. Neil Nathan and I carried out had already been treated for a variety of other issues before starting the methylation treatments. These issues included mold illness, Lyme disease, and heavy metal toxicity.
...The point is that the adults (especially those who have been ill with CFS for many years) may have many more impediments to the success of these treatments than the young children with autism, and they may need more additional treatments to address them specifically.
I would be interested in your thoughts about these things. Does this seem to make sense in the light of your experiences?
Lots to think about (if only my brain was working)...
Just my two cents, but it seems to me that it is indeed probably multifactorial (is that a word?) and will be different for everyone. But I wouldn't be surprised that many of us are not getting enough of the trace minerals needed to support the conversion of glutamate to glutamine, nor the amino acids like glycine and taurine which have been reported to help lower/convert glutamate levels.
And the accumulation of heavy metals/pesticides/chemicals over one's lifetime makes a lot of sense Rich. Hardly anyone mentions pesticides these days, despite the increasing evidence of their involvement in many different diseases/syndromes.
Here's something perhaps to add to the mix -- salicylate intolerance:
10 years ago I had an amino acid profile done by Great Smokies, and am only now finally waking up to it's significance. I was very low in glycine (required to detoxify benzoates (described as excitotoxins by Usman) and salicylates), was also low in taurine, and the highest amino tested was...glutamate. The results way back then suggested "nitrogen insufficiency", "impaired xenobiotic detoxification" and an "increased susceptibility to occlusive arterial disease".
(Why my docs back then didn't take this more seriously is confounding, but since they didn't, I didn't. (Perhaps it's because the lab test results were printed in rainbow colors and the lab's name was "Great Smokies" instead of the more legit-sounding "Genova".)
The CFS - Autism connection is fascinating. A sub-group of autistic kids have been found to react to salicylates (found in artificial colors, and also at high levels in certain common vegetables, fruits, and spices, etc.). If we're all a part of a 'spectrum', then it might make sense that over time certain amino acids (esp glycine) become depleted as a result of trying to detoxify these salicylates or phenolic compounds. Sals can cause hyperactivity (to say the least), anxiety, tinnitus, difficulty concentrating/finding the right words(!), digestion problems, etc. I've definitely had an anxiety issue even before developing CFS, so am hoping there is a salicylate connection, and that might explain why my glycine was so low.
Do the digestive problems occur because they body is basically saying NO to any more of these compounds until amino acid levels increase?
Does correcting the methylation block using b12/folates expose other detoxification pathway problems -- sulfation, amino acid conjugation, acetylation, etc. -- or is one getting increased excitoxicity because now that methylation is working well, the other pathways become more imbalanced?
Just my two cents,
p.s. For those who can tolerate it, might SAM-e be a way to increase ATP levels?