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

iwillwin1day

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the "wired" state.

Anti-inflammatory supplements that I have found calming, both for the "wired" state and for my anxiety symptoms, are N-acetyl-glucosamine (NAG) 700 mg, turmeric 1000 mg and flaxseed oil 15 ml daily. NAG has also been shown to reduce excitatory states in the brain. Other supplements that can reduce brain inflammation are found in this post and this post.
Turmeric is stimulatory and not calming. Also it will increase anxiety and not decrease it.
 

Hip

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Turmeric is stimulatory and not calming. Also it will increase anxiety and not decrease it.
When you say that, are you referring to your own experience, or are you quoting something you have read?

For me around 1 gram of turmeric once or twice a day has anti-anxiety effects, which I suspect may come from the ar-turmerone component of turmeric, which is thought to reduce microglial activation. Microglial activation (which occurs during neuroinflammation) releases lots of the stimulatory neurotransmitter glutamate into the brain.

Ar-turmerone also has other anti-neuroinflammation effects.
 

ljimbo423

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Turmeric is stimulatory and not calming. Also it will increase anxiety and not decrease it.
I found curcumin from turmeric, makes me feel wired and increases my anxiety for a few days.

Then it seems to have somewhat of a calming effect but also seems to give me a little bit of an increase in energy. I think it's a great anti-inflammatory if you can tolerate it.

Like all supplements though, what works for one person doesn't always work for someone else. I had to start at only 50-100mg a day, because it was so stimulating at first.

I have been taking 500 mg a day of curcumin for months and the inflammation in my body has improved noticeably.

Jim
 

Hip

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In terns of anti-anxiety effects, I found stronger effects from turmeric (which is only 3 curcumin) than I did pure curcumin. Which suggests it is not the curcumin in turmeric which has the main anti-anxiety effect.
 

iwillwin1day

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When you say that, are you referring to your own experience, or are you quoting something you have read?

For me around 1 gram of turmeric once or twice a day has anti-anxiety effects, which I suspect may come from the ar-turmerone component of turmeric, which is thought to reduce microglial activation. Microglial activation (which occurs during neuroinflammation) releases lots of the stimulatory neurotransmitter glutamate into the brain.

Ar-turmerone also has other anti-neuroinflammation effects.
Personal experience. I tried for few days then stop it. Maybe long term it would help with anxiety.
 
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The Longvida form of curcumin has a mild sedating affect on me. My nutritionist said that's fairly common with this form. Over time, it's helped me quite a bit with short-term memory.
 
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hum i was thinking glutamate was my worst enemy but Xanax is also anticholinergic and antihistaminic. I react very badly to any choline supplements or foods (makes me super depressed, dead inside and completely spaced out, derealization). Recently found that Fish oil omega 3 boosts acetylcholine. I have ultra bad reaction to that.

Am starting to think i might have high acetylcholine depression. I'll try a common antihistaminic which is also a potent anticholinergic to see if my symptoms alleviate a bit.

If not, it could be my 5HT2A receptor which is overstimulated. This receptor is just plain bad. I don't see how taking SSRI without a 5HT2A antagonist is a good idea. The more i read about SSRI the more they make no sense at all.
 
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This post details five approaches for reducing the over-stimulated, over-exited, hyperaroused "wired but tired" mental state that is often found in ME/CFS.

This feeling of "wired but tired" is specifically mentioned in the ICC definition of ME/CFS (see page 17), in the context of associated symptoms such as restless sleep, unrefreshing sleep, and the inability to go back to sleep (insomnia). The fact that being "wired" is being linked with these sleep problems suggests that calming the "wired" state may improve the quality of sleep.

A similar sort of "wired" hyperarousal is also found in post-traumatic stress disorder (PTSD), where this "on edge" feeling can lead to insomnia, anger and irritability. 1

I think this hyperaroused "wired" mental state most likely arises from elevated levels of glutamate in the brain. Dr Cheney has proposed similar ideas, as has @Marco in his blog here.

Glutamate is a stimulatory neurotransmitter, too much of which over-excites neurons. Glutamate activates the NMDA receptor on neurons, and activating the NMDA receptor is analogous to turning up the volume control of the neuron, amplifying the signals the neuron receives.

The counterpart to the neurotransmitter glutamate is another neurotransmitter called GABA, which activates a neuronal receptor of the same name, the GABA receptor. As the GABA neurotransmitter activates the GABA receptors, this relaxes the neuron, and turns down the volume.

The NMDA receptors and GABA receptors on a neuron thus have opposite effects, and are like the two sides of a seesaw: if you push the seesaw down on the NMDA side, you increase neuronal excitation, and if you push the seesaw down on the GABA side, you decrease neuronal excitation and increase neuronal relaxation.



So now we detail five approaches for easing the hyperaroused "wired" mental state often found in ME/CFS. These approaches reduce neuronal excitability in various ways: by reducing brain glutamate levels, by reducing NMDA receptor activation, and by increasing GABA receptor activation.

(1) Brain inflammation pumps out lots of glutamate. This glutamate comes from microglia that are activated as part of the inflammatory response. 1 One study on neuroinflammation in ME/CFS found that microglia are chronically activated in ME/CFS patients, so are likely constantly secreting glutamate. 1 This chronic brain inflammation in ME/CFS may be due to an ongoing low-level brain infection (and three brain autopsies have found enteroviral infections in the brain in ME/CFS patients).

By taking anti-inflammatories that target brain inflammation, you may be able to reduce your brain extracellular glutamate levels, which in turn may calm down the "wired" state.

Anti-inflammatory supplements that I have found calming, both for the "wired" state and for my anxiety symptoms, are N-acetyl-glucosamine (NAG) 700 mg, turmeric 1000 mg and flaxseed oil 15 ml daily. NAG has also been shown to reduce excitatory states in the brain. Other supplements that can reduce brain inflammation are found in this post and this post.

Inflammation in the intestines is now known to ramp up brain inflammation, via the vagus nerve and other signaling routes. 1 2 So by reducing inflammation in the gut, it may lower brain inflammation and decrease brain glutamate levels, which in turn may reduce the "wired" feeling. Many ME/CFS patients have gut symptoms, perhaps due to chronic viral infections in the digestive tract.

I found a combination of probiotics and prebiotics, along with Saccharomyces boulardii, help reduce my physical gut symptoms (I have IBS-D), and also noticeably reduce both my anxiety levels and "wired" state.


(2) As well as reducing glutamate levels, we can also reduce the effects of glutamate by blocking the NMDA receptors that glutamate normally activates. NMDA receptor blocking can be achieved with an NMDA antagonist such as high dose transdermal magnesium sulfate, applied to the body skin once or twice daily using the method described in this post.

Magnesium in high doses is a good NMDA receptor blocker, preventing glutamate from activating the NMDA receptor. Oral magnesium will not really help much, because of bowel tolerance issues: many people will find oral doses higher than around 500 mg of elemental magnesium daily will cause diarrhea. But applying magnesium transdermally does not have this problem, so you can achieve higher doses by the transdermal route. Note that you should take calcium (orally) if you are taking high doses of magnesium for extended periods.

I found that the calming effect of transdermal magnesium kicks in around 3 hours after application.

As an alternative to transdermal magnesium sulfate, there are also some drugs that block NMDA receptors, such as memantine.


(3) This third approach is more experimental, but high brain levels of glutamate can also be caused by a down-regulation of the activity of the GLT-1 glutamate transporter, which is responsible for removing most (90%) of the excess glutamate from the brain.

Indeed, one study found that as activated microglia start pumping out glutamate into the brain, unexpectedly, glutamate transporter functioning is simultaneously down-regulated, which only further exacerbates the glutamate build up in the brain. 1

So if the aim is to reduce brain glutamate levels, it may be a good strategy to ramp up the glutamate transporters, which pump glutamate out of the extracellular spaces of the brain.

To boost glutamate transporter function, the antibiotic amoxicillin at a dose of 2000 mg twice daily is very effective. Amoxicillin can increase glutamate transporter expression by over 500% in a matter of days — see this post about amoxicillin and glutamate uptake for more details.

A list of glutamate transporter boosters is given here.

I found amoxicillin 2000 mg twice daily had a noticeable calming effect on the mind, though it takes two or three days before these calming effects manifest (because it takes a little while for amoxicillin to increase the number of glutamate transporters in your brain).

The glutamate transporter boosting effects of beta-lactam antibiotics such as amoxicillin and ceftriaxone are being investigated for the treatment of amyotrophic lateral sclerosis (ALS) and alcohol dependence, both of which involve glutamate. 1 2


(4) Another approach to easing the hyperaroused "wired" mental state is by increasing the GABA system activation, as GABA relaxes the neuron. The classic approach to this involves taking benzodiazepines such as clonazepam (Klonopin). Benzodiazepines are GABA receptor positive allosteric modulators, which means they make the GABA receptor more responsive to the GABA neurotransmitter, and in this way, boost the GABA system.

However, the problem with treatments such as benzodiazepines that work on the GABA system is the issue of tolerance and withdrawal symptoms. Tolerance means the loss of effect of the drug over time. And withdrawal symptoms to benzodiazepines can sometimes be quite nasty. One survey of ME/CFS patients taking Klonopin found that 36% experienced no withdrawal symptoms; 32% experienced minor or moderate withdrawal symptoms; but 32% experienced severe or very severe withdrawal symptoms.

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

Tolerance and withdrawal symptoms are in fact found with many supplements and drugs that work on the GABA system. That is why in general I think the best to approach to reducing brain over-stimulation and hyperarousal is by working on the glutamate / NMDA side of the seesaw, using the above approaches (1), (2) and possibly (3). This is because there are no tolerance and withdrawal problems with glutamate / NMDA treatments. It's only with GABA treatments that tolerance and withdrawal issues can occur.

However, there are some effective GABA treatments that do not suffer from tolerance and withdrawal problems: kava kava root (Piper methysticum) 300 mg once ot twice daily is one such GABA treatment that works well, and does not appear to be subject to tolerance and withdrawal.

Kava kava seems to increase the GABAergic response by increasing the number of GABA binding sites. 1 So rather than producing a loss of effect over time (tolerance), conceivably kava may actually nicely increase GABA system sensitivity over time.

I find the relaxing effects of 300 mg of kava kava root kick in after around 2 hours.

Note that kava has on rare occasions has been associated with liver damage, but the WHO suggest that liver toxicity may only come from kava plant leaves and stem. Kava root appears safe. Acetone or ethanol extracts of the active ingredient are also questionable, but water extracts appear safe. 1


(5) A fifth approach to reducing glutamate levels is by the supplement N-acetyl-cysteine (NAC), at a dose of around 600 mg taken three times daily (thanks to @Valentijn for suggesting this NAC approach). A sustained release NAC formulation may work best, such as Jarrow N-A-C Sustain.

NAC's mechanism of action of reducing brain glutamate levels appears to be the following:
I cannot seem to achieve great effects with even high quality kava kava. I was thinking that it may help with hyperacusis since Ativan does , and mitigate benzo and gabapentin tolerance.

Do you see any issues with taking expired amoxicillin? I know that expired tetracyclines have a toxic byproduct but was wondering if amoxicillin specifically does too even though it’s a different class of antibiotics.
 

Hip

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Do you see any issues with taking expired amoxicillin?
I am not aware of any problems amoxicillin might cause being out of date. I think it should be OK.

(By the way, in case you want to know how to quote a specific paragraph of another member's post, rather than the whole post, there is a new video I made showing how to do it. Lots of people don't know how to do this).
 
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Do you see any issues with taking expired amoxicillin? I know that expired tetracyclines have a toxic byproduct but was wondering if amoxicillin specifically does too even though it’s a different class of antibiotics.
I ordered a huge box of amoxicillin from an online pharmacy 10 years ago, and even though they're way past expiration, they still work fine.
 

Mel9

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I am not aware of any problems amoxicillin might cause being out of date. I think it should be OK.

(By the way, in case you want to know how to quote a specific paragraph of another member's post, rather than the whole post, there is a new video I made showing how to do it. Lots of people don't know how to do this).
 

Shoshana

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Will need to keep practising!
I cant see videos, but all I do, is select the part of a post, that I want, and when I let up on it, then there is a small pop-up near/below it, with 2 choices.
I click on the one that says "reply" and my selected portion is in this reply box.

You can do it, Mel9. Try it again! :)
 

prioris

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I ordered a huge box of amoxicillin from an online pharmacy 10 years ago, and even though they're way past expiration, they still work fine.
amoxicillin can be bought from calvet supply for 1/10th the cost of a pharmacy
outside of minocycline which has 1 year expiration ... rest of general antibiotics have at least 5+ years expiration
 

prioris

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wired and tired translates to anxiety problem
taurine, magnesium threonate, lithium orotate ... research and experiment with these