Excitotoxicity

judyinthesky

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Hello.

I've read about excessive glutamate release and I think it could fit the issue of my super heightened nervous system.

I wonder, can one somehow measure such a thing?
For those who have been trying to treat that, how?
I have found the thread on opiates in this regard, but I wonder as opiates make depressed whether this could be an issue.

It seems to me as Xanax helps me, that there is something like this going on.
Are there any other potential treatments apart from opiates and Xanax/benzos?
 

pattismith

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nerd

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This can be measured in a urinary neurotransmitter panel (example). Depending on the results, there will be options for GABA or glutamate antagonists/allosteric modulators. But the results of this test will depend on the time of the day. This test is normally done in the morning. But in the morning, CFS/ME pathology from the CAC isn't at its greatest, so the results might be more indicative in the evening, after exertion, when you feel the symptoms.

Taurine is a GABA agonist, which can exacerbate GABAergic excitotoxicity. In the context of glutamate hyperexcitation, this might help for a short duration, but it won't help with the succeeding GABA hyperexcitation. A typical CFS/ME pathology would hypersaturate the complete glutamate-GABA pathway, thereby causing excitotoxicity of both systems.

Magnesium deficiency would also exacerbate the problem, but excessive magnesium supplementation itself is no simple solution since it can be counterproductive given a high ADP to ATP ratio, which is normally the case with CFS/ME (pmid:2359406).

B6 can play a great role in whether the glutamate or GABA system is overactivated since the elevated demands for B6 have to be provided for. Given sufficient B6 and magnesium, I would stick with negative allosteric modulators on GABA and glutamate, depending on the symptomatic indicators.

L-Theanine is an NMDA-specific coactivator, which would be counterproductive in the presence of glutamate-mediated excitotoxicity (10.1021 / acschemneuro.7b00036).

I think Melatonin might be very helpful because vegetative dysregulation from poor sleep can also exacerbate the excitatory excitotoxicity.
 
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pattismith

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This can be measured in a urinary neurotransmitter panel (example). Depending on the results, there will be options for GABA or glutamate antagonists/allosteric modulators.

Taurine is a GABA agonist, which only exacerbates excitotoxicity. In the context of GABA hyperexcitation, this might help for a short duration, but it won't help with the succeeding GABA hyperexcitation.
Do you have source for this GABA excitation? I always thought GABA was an excitatory inhibitor ...

B6 can have toxic effect on small fibers, so Blood testing is necessary before supplementing.

Pyridoxine Toxicity Small Fiber Neuropathy With Dysautonomia: A Case Report - PubMed (nih.gov)
 

judyinthesky

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This can be measured in a urinary neurotransmitter panel (example). Depending on the results, there will be options for GABA or glutamate antagonists/allosteric modulators. But the results of this test will depend on the time of the day. This test is normally done in the morning. But in the morning, CFS/ME pathology from the CAC isn't at its greatest, so the results might be more indicative in the evening, after exertion, when you feel the symptoms.

Taurine is a GABA agonist, which can exacerbate GABAergic excitotoxicity. In the context of glutamate hyperexcitation, this might help for a short duration, but it won't help with the succeeding GABA hyperexcitation. A typical CFS/ME pathology would hypersaturate the complete glutamate-GABA pathway, thereby causing excitotoxicity of both systems.

Magnesium deficiency would also exacerbate the problem, but excessive magnesium supplementation itself is no simple solution since it can be counterproductive given a high ADP to ATP ratio, which is normally the case with CFS/ME (pmid:2359406).

B6 can play a great role in whether the glutamate or GABA system is overactivated since the elevated demands for B6 have to be provided for. Given sufficient B6 and magnesium, I would stick with negative allosteric modulators on GABA and glutamate, depending on the symptomatic indicators.

L-Theanine is an NMDA-specific coactivator, which would be counterproductive in the presence of glutamate-mediated excitotoxicity (10.1021 / acschemneuro.7b00036).

I think Melatonin might be very helpful because vegetative dysregulation from poor sleep can also exacerbate the excitatory excitotoxicity.
Help me out again, the "negative allosteric modulators" you would stick to are?
 

nerd

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Do you have source for this GABA excitation? I always thought GABA was an excitatory inhibitor ...
Sorry, this was a typo I've corrected in the meantime. The sentence didn't make sense having "GABA hyperexcitation" two times in it. Please check the updated version.

B6 can have toxic effect on small fibers, so Blood testing is necessary before supplementing.
But in which doses? Shouldn't excessive B6 be excreted before it comes to this point, since it's water-soluble? This might only be relevant for patients with CKD or with dysregulated kidney function. The case in this report took excessive amounts of B6 from multiple sources, including an energy drink. Energy drinks usually contain multiple potentially neurotoxic ingredients and also ingredients that affect filtration rate.
 

judyinthesky

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I think there's a neurotransmitter panel that measures GABA from urine in my lab. But last time it was fine, hm, but I haven't been as severe then. What would it have to show?
 
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@nerd:
You wrote :
Taurine is a GABA agonist, which can exacerbate GABAergic excitotoxicity
Do you have a quote for it? I think GABA has a calming impact and is not excitoxic. Maybe you wanted to say it and mixed just things up.
wiki Gamma-Aminobutyric-acid
Aminobutyric acid
, or γ-aminobutyric acid /ˈɡæmə əˈmiːnoʊbjuːˈtɪrɪk ˈæsɪd/, or GABA /ˈɡæbə/, is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.
 

nerd

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I think there's a neurotransmitter panel that measures GABA from urine in my lab. But last time it was fine, hm, but I haven't been as severe then.
You'd need glutamate and GABA at least. Glutamine would be preferable as well. Urine shows buffered values. This is why they often tell you to take the second-morning urine, so as to reflect refreshed values after buffer depletion. However, blood also serves as a buffer. Buffers make test results more prone to bias by long-term baseline vs. short-term deviations.

Morever, it's not untypical for CFS/ME patients to have creatininuria (not proteinuria!). Creatininuria basically makes all creatinine-ratio-based urine tests worthless. Some pathologists and medical doctors aren't aware of this. The hyperfiltration in this case from selective kidney overfunction adds a currently unpredictable ratio to the results. This ratio isn't studied well enough to calculate it and add it to the test results. All you have left then is 24-hour urine because this testing method doesn't rely on creatinine ratios. However, 24-hour urine adds a lot of buffer from the night which is a bias of its own kind.

What would it have to show?
Some of the measurements would have to be elevated.

Also, would antidepressants help that in any way?
Not that I know. The mechanisms of action of antidepressives are different.

I think GABA has a calming impact and is not excitoxic.
There is no consistent definition for excitotoxicity. Some authors (Choi, Lai, et al.) delimit it on excessive activation of the excitatory nervous system only, which would not include GABA activation. But other authors (Nesterova et al.) define it as "neuronal cell damage or death due to excessive stimulation by neurotransmitters" (10.1016/B978-0-12-817086-1.00005-1), which seems to be more complete from my perspective because there wouldn't be an equivalent term for GABAergic neurotoxic effects, except for symptomatic descriptors such as "coma".

GABA has a calming impact and is not excitatory. It can still be neurotoxic.
 

hapl808

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The only natural one I can think of is Kudzu. There are other ones mentioned in the literature (10.1016/bs.irn.2017.02.013), but they aren't available outside of China as far as I could check.
So would kudzu be able to reduce glutamate levels without other negative effects?

And those TCM herbs for addiction look pretty standard I think? I'm not super familiar with TCM, but I've ordered various things from 1stChineseHerbs in the past and they have a pretty extensive collection. Although arguably using TCM herbs in isolation doesn't have the same effects as combined formulas.
 

nerd

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So would kudzu be able to reduce glutamate levels without other negative effects?
Given the limited evidence that is available, since it interacts with the [3H]flunitrazepam binding site of the GABA receptor, I think the effect on glutamate is mediated by the GABA-mediated glutamate synthesis. GABA agonists and their receptor activation aren't affected by Kudzu after all. It's only ethanol and other drugs that are affected by the interaction with GABA receptors. I can not tell if it is without side effects or if it even if it makes any difference for CFS/ME patients in particular.

The only alternative would be taurine, but then you'd have to be sure it's glutamatergic excitotoxicity and not GABAergic excitotoxicity that you want to treat.
 

Hip

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For those who have been trying to treat that, how?
ME/CFS doctors have speculated that excessive glutamate release may be behind some of the symptoms of ME/CFS, especially the "wired but tired" symptoms. Glutamate acts as a sort of volume or gain control on neurons, amplifying their sensitivity.

The source of the glutamate in ME/CFS may be from brain inflammation, since the activated microglia in neuroinflammation release copious amounts of glutamate.



In this thread, I looked at 5 ways to reduce your glutamate levels, methods such as reducing inflammation using N-acetyl glucosamine (thus addressing the possible root cause of high glutamate), or increasing GABA binding site density with kava kava.



Note that excitotoxicity (where glutamate actually kills neurons) does not occur until glutamate levels are very high, and there is no evidence of excitotoxicity in ME/CFS.
 

judyinthesky

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ME/CFS doctors have speculated that excessive glutamate release may be behind some of the symptoms of ME/CFS, especially the "wired but tired" symptoms. Glutamate acts as a sort of volume or gain control on neurons, amplifying their sensitivity.

The source of the glutamate in ME/CFS may be from brain inflammation, since the activated microglia in neuroinflammation release copious amounts of glutamate.



In this thread, I looked at 5 ways to reduce your glutamate levels, methods such as reducing inflammation using N-acetyl glucosamine (thus addressing the possible root cause of high glutamate), or increasing GABA binding site density with kava kava.



Note that excitotoxicity (where glutamate actually kills neurons) does not occur until glutamate levels are very high, and there is no evidence of excitotoxicity in ME/CFS.
That's the best explanation so far I've heard. Thank you very much.

One issue I have with what I am experiencing is that this can switch very much. Like, I would have a very good evening brain wise, but awake with painful wiredness in my nervous system still.
Do you have any potential theory on why this is? I have been martyring my brain about this (in addition to the torture it already has to endure).
 

judyinthesky

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@Hip and also, the bigger mystery, why a fucking (excuse me) vaccine would bring this on so much. I am guessing as it's parallel to the body losing energy, but still don't understand why I have so much of the wired state. I understand we are all on a continuum, but my ME even started with this (and pancreas illness). Hey body I see your survival mechanism, but it's really not useful!!

Ah and I even see sharp with this. Wondering whether any other mechanism could be overwhelmed or -excited. Greetings from the normal evening - it will not last long!
 

Hip

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Do you have any potential theory on why this is? I have been martyring my brain about this (in addition to the torture it already has to endure).
If you are OK one day, and wake up worse the next, possibly the food you ate the evening before might have an effect, if the food promotes gut inflammation.

There is well-characterized link from gut to brain along the vagus nerve: when this nerve senses increased inflammation in the gut, it signals that information to the brain, and the brain in turn will respond by ramping up its own internal neuroinflammation levels.

So by this mechanism, and increase in gut inflammation may worsen brain inflammation. If you already have a degree of chronic brain inflammation going on (perhaps because of a smoldering viral brain infection, which have been detected in ME/CFS), then this brain inflammation can be worsened by gut inflammation.

Gut inflammation may be caused for example by SIBO, or gut dysbiosis (overpopulation of bad bacteria in the colon). Things that can help reduce gut inflammation include probiotics and especially prebiotics as well.
 

judyinthesky

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@Hip well yeah I have severe pancreas insufficiency so that means my gut is always off. I will pay attention to the food thing but don't think it's that. Because I have severe issues with eating so timing is always the same.