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, Dan p.s. For those who can tolerate it, might SAM-e be a way to increase ATP levels?