Five ways to reduce your ME/CFS "wired but tired" hyperaroused brain state

Deltrus

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Interesting. I take resveratrol. It makes me feel better but I'll be paying attention as to why.
https://selfhacked.com/2016/03/12/top-15-scientific-health-benefits-of-resveratrol-with-references/

#2 point says that resveratrol increases glutamate intake by astrocytes, which then use it to make glutamine, which is then used as an energy source and also it is then used to synthesize BOTH gaba and glutamate in neurons.

Glutamine synthase is very similar to GAD67 in that it balances glutamate and GABA.

I just realized GAD67 uses PLP as a cofactor, I guess that is another reason why high b6 is extremely important for excitatory/inhibatory balance. It is speculation of mine that resveratrol can reach deep into cells and prevent oxidation of b6.

B6 seems to be very important in excitatory/inhibatory balance, through enabling taurine synthesis and enabling gaba synthesis through GAD67.
 
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Hip

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#2 point says that resveratrol increases glutamate intake by astrocytes,
Glutamate transporters are found mainly on astrocytes and microglia, so I imagine resveratrol may be another supplement/drug that increases glutamate transporter function (the resveratrol study in question says resveratrol increases glutamate uptake, and glutamate uptake is primarily performed by the glutamate transporter GLT-1 / EAAT2 — 90% of all glutamate uptake is facilitated by GLT-1).

It's possible that resveratrol increases glutamate uptake via its ability to scavenge for reactive oxygen species, since hydrogen peroxide and peroxynitrite impair glutamate uptake. 1



As an aide, a very potent booster of glutamate transport and uptake is the injectable antibiotic Rocephin (ceftriaxone), which one forum member found made her "almost totally well" around 48 hours after her Rocephin injection. My theory of that remarkable (but temporary) remission is that Rocephin potently boosted glutamate transport gene expression (which a study showed takes around 48 hours to occur), leading to reduced levels of glutamate the brain, which then ameliorated ME/CFS symptoms.

However, I could not replicate this result when I injected 1000 mg of Rocephin subcutaneously; but I did notice some mild improvements in my "wired" state from oral amoxicillin 2000 mg twice daily, which from what I can work out, has a potency comparable to Rocephin in terms of boosting glutamate uptake.
 
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Hip

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Do you respond well to Alpha Lipoic Acid?
You wouldn't expect too much from alpha lipoic acid, as the study showed it only produced a 20% increase in glutamate uptake.

This is small in comparison to the 3 to 4-fold increase glutamate transporter GLT-1 gene expression (see this study) that is achieved with amoxicillin, Rocephin and other beta-lactam antibiotics (I assume an increase in GLT-1 gene expression is accompanied by a comparable increase in glutamate uptake).
 

Wayne

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So benzodiazepines like Klonopin come with a risk of possible tolerance, and possible severe withdrawal symptoms.
Hi @Hip,

Thanks for the great writeup on addressing the wired but tired phenomenon. I recently discovered transdermal magnesium oil and niacin were very effective for calming down my own brain and neurological wiredness. The niacin in particular felt like I had taken a benzodiazapine (I've had many years experience taking both clonazepam and valium).

The following article gives a pretty in-depth description of various supplements that can be used to ease benzodiazapine withdrawal, most of which I assume can be used to calm the tired but wired feeling that results in benzodiazapine use to begin with. The article particularly focuses on niacin, but includes other supplements as well.

Supplements Accelerate Benzodiazepine Withdrawal
 

dannybex

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Glutamic acid lowers ammonia levels (I think during the process of converting glutamate to glutamine) so it could actually help with overstimulation and sleep issues if one has elevated ammonia.

Will try to find the study I saw on this, but undenatured whey (which is high in glutamic acid) is actually helping me sleep, plus finally helping stop muscle loss...
 

dannybex

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Hi @Hip,

Thanks for the great writeup on addressing the wired but tired phenomenon. I recently discovered transdermal magnesium oil and niacin were very effective for calming down my own brain and neurological wiredness. The niacin in particular felt like I had taken a benzodiazapine (I've had many years experience taking both clonazepam and valium).
Hey @Wayne,

Another reason niacin may help is because it helps to lower and/or prevent the rise in quinolinic acid -- a nasty neurotoxin that is implicated in many things, but especially alzheimers. Here's a screen cap from a study:
 

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Hip

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quinolinic acid -- a nasty neurotoxin that is implicated in many things, but especially alzheimers.
It's not clear to me from that study whether niacin can help prevent neurotoxicity from quinolinic acid, but I just posted a comprehensive list of drugs and supplements that have been shown reduce quinolinic acid neurotoxicity in this post.


Both quinolinic acid and glutamate are secreted by activated microglia in brain inflammation, and both quinolinic acid and glutamate are agonists of the NMDA receptor, and thus by the hypothesis presented in this thread, both potentially can cause the "wired" hyperaroused mental state.

However, according to this study, the amount of quinolinic acid produced by activated microglia in neuroinflammation remains far below the concentrations of quinolinic acid that are necessary for excessive NMDA receptor activation.

So in general, it's probably more glutamate than quinolinic acid that is responsible for the high levels of NMDA receptor activation assumed to be behind the the "wired" hyperaroused mental state.


Though in the case of Lyme disease, quinolinic acid may be more implicated in the "wired" hyperarousal (as well as neurotoxic processes in general), because quinolinic acid has been found to be significantly elevated in Borrelia infection, with dramatically high levels of quinolinic acid found in Lyme patients with CNS inflammation.


When quinolinic acid was injected into the striatum area of a rat brain, it was found to severely impair energy metabolism through activation of NMDA receptors.
 

pspa123

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I have seen suggestions of 2-3x600 mg. daily for anxiety/OCD. I could be wrong but I assume you get a pretty quick sense of whether it is going to work for you or not.
 

Valentijn

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I have seen suggestions of 2-3x600 mg. daily for anxiety/OCD. I could be wrong but I assume you get a pretty quick sense of whether it is going to work for you or not.
No idea if it helps for anxiety or OCD. I don't have either. It's also been used in HIV patients, which is where I was able to see it's pretty safe at high doses in the long term.
 

Jimbo39

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Brand new so excuse my ignorance. Has anyone tried oxaloaloate?

In experiments in rats with traumatic brain injury, a natural compound called oxaloacetate, which reacts with the blood enzyme glutamate-oxaloacetate transaminase, was used to scavenge blood glutamate. Rats with brain injury treated by this method regained normal body function and recovered faster and more fully than rats with the same brain injury that received no medication to lower glutamate levels.3

I've been supplementing with it for about 4 months. I've felt a great improvement but I'm also taking resveratrol, NAC and ALA so it may not be doing anything.
 

Jimbo39

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Note that you should take calcium (orally) if you are taking high doses of magnesium for extended periods.
Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell.[1][2] Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.

I'm sure you all know this but I've heard this quote "if glutamate is the gun then calcium is the bullet" so many times I'm afraid to take anything with calcium in it. I guess I'm looking for assurance that a little is OK.
 

Hip

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I once went on a very high dose transdermal magnesium protocol (for anti-anxiety purposes, as high dose magnesium blocks the NMDA receptors)

I was perhaps taking 3 or 4 grams of transdermal magnesium daily for several weeks; and I forgot about the need for balanced calcium supplementation. A bizarre thing then happened: I suddenly developed an adoration for drinking milk. I had never been particularly fond of drinking milk, it's OK, but normally for me the taste is nothing special. But all of a sudden, my taste buds just went totally wild for milk. Milk just suddenly tasted delicious to me!

Eventually, I figured out that my body was just desperate for the calcium in milk, because with all that magnesium I was administering, my minerals were out of balance. And so amazingly enough, it seems that the body is intelligent enough to make you love the foods or drinks that contain the minerals you need.

Calcium receptors on the tongue were discovered not so long ago, and I imagine that these calcium receptors detected the calcium in the milk, and then my brain picked up on this, and made me start really enjoying the flavor of milk. Thus is seems the brain can control whether you like or dislike the taste of any food or drink, according to your current nutritional needs.

Once I stopped the high dose magnesium, my absolute love of the taste of milk soon disappeared.
 
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Jimbo39

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A few of the supplements I've order including calcium. 5-HPT for example. I guess it's necessary for certain reactions to take place. (I quit ordering from Amazon because it's hard to read the ingredients.)