I think that the experiences described in this thread add further evidence that M.E. is in part or in whole a neurological (NOT psychological) disease. Here are some facts that point in this direction:
-Both physical and mental effort produce a similar PEM response: This should immediately discard any mitochondrial hypothesis. The performance of neuronal mitochondria has no bearing on the mitochondria of the feet, yet pain after mental exercise is widespread.
-No clear, consistent mitochondrial damage or alterations in energy pathways: Non-replicable slight alterations in pathways are found, and while lactate is elevated in a subgroup, it is not related to symptom burden. Mitochondrial interventions don't show any promising long-term results, while in true mite-disease patients, even just Vit. C, Vit. E and CoQ10 have a noticeable and consistent benefit.
-Onset is sudden: Again, the mitochondria in the whole body don't suddenly stop working in a matter of hours, unless you are being poisoned by cyanide. Even immunological reactions have the acute onset measured in hours (see Steven-Johnsons Syndrome). Only the nervous system allows for a rapid change that affects the whole body. Consider also the people that experience sudden remission after a bee sting or after having general anaesthesia. Only the CNS works in such constrained timeframes.
-Interventions suddenly stop working: This only happens when there is a strong and very well regulated negative feedback mechanism, and the only system in the body that has this is the nervous system. Corticosteroids don't suddenly stop working in autoimmunity patients, hormones don't stop working in a matter of hours in endocrine deficiency, Dichloroacetate doesn't stop working in PDH deficiency (a true mitochondrial disease) etc..
-Lacklustre cytokine studies: Much wasted money, and no results in cytokines. Yes, TGF-b is slightly elevated, but this is more related to the TGF/NGF pain-axis. There is no clear evidence of elevated inflammatory markers that is in proportion to the disabling symptoms experienced by PwME. In fact ERS is lowered, and there is IgG deficiency.
-No T-cell clonal expansion and no clear autoantibodies: No results yet after many years of searching. Again, some studies find a slight change, but we have to keep in mind that the severity of the symptoms needs to be in proportion to the physiological aberration discovered if it is to be relevant.
-Nimodipine works for a subgroup and for some people even blocks PEM: Nimodipine blocks L-type calcium channels selectively in the brain. While this results in increased vasolidation, many other vasodilatory substances don't have any effect. L-type calcium channel blockade reduces excessive excitatory tone in CNS neurons.
-GABAergic medications provide temporary relief: For example Whitney with Atvian, or many people with gabapentin (or pregabalin etc..). However, tolerance quickly develops.
-Dopaminergic substances work: Goldstein elaborated on this, and he also predicted that the biggest obstacle would be tolerance development.
-Anti-epileptic/ substances work: There are many anecdotal reports of topiramate, lamotrigine etc... working, until tolerance develops. Again, Goldstein wrote extensively both about why they work, and why they stop working.
-Antidepressants sometimes work: This is a very controversial topic, but it is no coincidence that the antidepressants shown to help neuropathy also help with M.E. It has nothing to do with mood, but with biological mechanisms.
It is therefore imperative that the role of excessive Glutamate (the main thesis of Goldstein) be investigated, because as far as I know, he is the doctor with the best track record, and the only doctor that could consistently achieve symptomatic remission.
The root cause of M.E. may be somewhere else, maybe in the gut, maybe in immunologically derived exosomes... who knows. But the CLINICAL picture clearly points to the nervous system, and what we need is not a 20 year long crusade to find the primun moves of M.E., we need CLINICAL improvement of symptoms.
If not I wrote “decent period of time”. There have been countless individual reports of pretty much everything causing big improvements for a few days to weeks. But to me these are all background noise because none of them were ever reproducible.
