Thanks very much for the above summary of this thread, Iritu1021.
When you say "intracellular calcium release", I take you mean the release of calcium from its stores in the cell's endoplasmic reticulum into the cytosol of the cell (rather than release of calcium from the cell out into the extracellular spaces, by pumping calcium out of the cell via the calcium channels on the cellular membrane).
I don't know how this fits into your current discussion, but I've often wondered whether within the neurons in the brain of ME/CFS patients, intracellular calcium levels might be high, due to possibly elevated brain glutamate. Glutamate stimulation of neurons causes high levels of calcium ions to enter these cells — and this calcium influx to the neuron ultimately ends up with excitotoxicity if glutamate levels are very high.
It's been speculated that ME/CFS might involve high levels of extracellular glutamate in the brain, and that these high levels might cause the "wired but tired" hyperaroused feeling of ME/CFS. It has been shown that microglia are chronically activated in ME/CFS, and activated microglia pump out lots of glutamate, so that could be the source of the speculated high brain glutamate in ME/CFS. Though I have not seen any direct evidence for high extracellular glutamate in the brain in ME/CFS, so it's not clear whether or not there are high levels of this neurotransmitter.
But if there is high extracellular glutamate in the brain in ME/CFS, you might expect neurons to have high intracellular levels of calcium.
I have a decent amount of faith in this theory due to some personal observations.
Very early in my illness--when I was only slightly starting to be ill (I had an initial trigger of lyme but the onset was still slow -e.g. I did feel better after initial abx treatment and then symptoms slowly returned) I felt great on phenibut. At the time I didn't really think I was sick or just thought it would be a malaise that passed so I was using the phenibut more recreationally/for anxiety/etc. But incidentally it seemed to help the brain fog and give some kind of "cooling sensation" to the brain, that was hard to describe. I did a lot more productive stuff on it even tho it's a relaxant more than a stimulant. Later I got prescribed gabapentin, which didn't have such a dramatic effect, but felt somewhat similar, in a way more lowkey way.
When I was a little more sick--say about 3-4 months later/the next semester, I started to get hangovers from phenibut, which was new to me. But they weren't exactly like the typical alcohol hangover. They were really weird and hard to describe in normal clinical language. There was no direct headache, and the somatic/tactile aspect of the experience was very strong but if I had tried to describe it I felt like any doctor would consider it a psyschological symptom, not to mention I didn't want to bring up "recreational" drug use.
But the symptoms of this hangover were like a feeling that my brain was overheated, sort of. I mean i didn't have any fever or feeling of overall warmth but it just felt like my cognition was extremely, extremely under duress and had hit an error message or "cannot compute" thing, any and all stimuli would make everything worse.
I looked it up and GABAergics are known to sometimes cause glutamate excitotoxicity as a rebound phenomenon, GABA has the opposite effect but when the receptors "bounce back" from the inhibition, this can happen. Apparently this is the only way certain GABAergics are neurotoxic.
Later in the year, I did some GHB, partially for fun, partially for sleep. Felt actually very nice on it at the right dose, but the same thing--this awful "hangover". no headache, or whatever, but the feeling that my brain was on fire, and that I'd hit some kind of extreme limit (at the time I thought this was caused by permanent brain damage related to the drug, but I think it more exacerbated a tendency present in CFS)
I at times got this effect from stimulants, which I overall avoided after I got sick (my stimulant intolerance after illness is another thread), but took for a very short time for finishing my thesis. (Oddly enough, due to this effect and low tolerance for stims, opioids were the only thing I could use to be relaxed and focused enough to write).
Every time I got this effect, taking gabapentin was the only thing that really helped (well, I didn't want to try phenibut to take the edge off a phenibut hangover, b/c I had very strict rules about not using phenibut on consecutive days). And you may say "well that still sounds like hair of the dog, gabapentin is very similar to phenibut pharmacologically". Well yes, and that's probably part of why it worked , but also no... it doesn't have the gabaergic effects phenibut has, even if it shares the effect on ion channels.
Anyway this "cooling" feeling from gabapentin when I would get these hangovers was dramatic and very nice and beatific. I remember getting this feeling, and coffee didn't help, NAC didn't help, food didn't help, exercise didnt' help (I was more moderately sick so I was still trying dumb shit like that), and I had to go on a date with someone in an hour and thought I wouldn't be able to handle it, until I took a small gabapentin dose and I felt normal, was suddenly able to be talkative, etc. The hangover feeling was like a "storm" that was calmed by gabapentin.
