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

[Wayne]

even the f*#*#*g tinnitus is gone.

Hallelujah! Congratulations on that awesome development. Could you share more about it? -- Thanks!

 

[Sundancer]

Hallelujah! Congratulations on that awesome development. Could you share more about it? -- Thanks!

well, I can tell you what steps I took, but whether it works for someone else I do not know Also I now have some idea about why and how, which I had not at the moment it happened. The fact the I'm very histamine intolerant I was unaware of.

So..the steps were as follows. First I quit the last little bit of gluten ( yes, also the cheap oatmeal) then I stopped all dairy. These steps gave some stress initially but after a few days..hem I think 2 weeks, i started to feel somewhat better and the loud ringing seemed to retreat just a tiny bit.
then started with DPPIV enzyme. The first effect was an enormous bout of laughing, i started with just a quarter of a capsule and my reaction was strong, as with the quitting gluten and dairy, the initial reaction was more stress, but then I started to feel better and the twired diminshed a bit. I slowly built up the amount of enzyme until I could tolerate one cap a day, that took a long long time. Brainfog went down some. I still take 1 cap a day.
https://exendo-epigenomics.com/product/dpp-iv-optimum-gold/

Then someone brought me to a therapist who adviced strict histaminfree diet, plus no gluten/soy/dairy/ any additives, whole hog. and as much organic as i can afford, especially eggs, ghee and meat.

GABA max 2 caps to help sleeping ( with added a small amount of B6 and some herbal extract)
https://exendo-epigenomics.com/product/sleep-optimum-60-caps/
I still use 1 cap but hope to start reducing the amount soon

he also advised theanine 2 caps daily
https://exendo-epigenomics.com/product/nmda-relief-45-capsules/
at the time I started these there was a small amount of 5HTP in these caps, this 5HTP was then removed from the mixture. The new recipe did not sit well, the effect was less good with me so I've consulted him and then added some 5HTP to the mix. This I do not take or need anymore and it is not an advisable supplement I think. I seem to remember that Ron Davis, or another scientist, warned the community not to take it, or maybe that was tryptophan, which I'm not sure is the same or a very close relative, not sure about it though, maybe someone else can chime in and tell about it.
It was a number 1 stress reliever for me and for many months I've used a small amount to help fall asleep.

this NMDArelief too I had to build up slowly as I got much more tired when taking it, but a better tired, a real relaxed tired, a not twired tired. that took me 6 weeks I think, I started with 1/6 of a capsule. But after taking these for 6 weeks the tinnitus ( and the twired state) were gone.
Later it returned somewhat, when I got a viral infection but receded again.

It has been gone for almost 2 years now I think, only when i inadvertently trigger histamine release it comes back, but as a very light sound that warns me, take care baby, you're either overdoing or eating something wrong.

I recently started on hydroxyinjections and that triggered my histamine release awfully, so a lot of shit came back, now I take a benadryl 10 minutes before I take a shot and found balance again, the hydroxy shots are doing me real good, better then the methyl/adenoyl lozenges that I used before. Would someone had started me on that one 6 years before though, doctors are real stupid... I'm on the verge of going back to 1 theanine capsule as I'm doing so well now.

so now I'm studying how to get a natural handle on the MCAS, I've already found out that ( for me) bifidobacterium infantis is very helpful. Then I found this supplement online
https://www.ergomax.nl/seeking-health-probiota-histaminx-60-capsules

which is a formulation from Ben lynch, I've heard him talking about it and he said about half of it is bif infantis, plus some more things, one of them Plantarum.
as i did have plantarum lying around I now take that too and see what the combi of these 2 does to my gut and the histamin release. If that works out well I might try the combination supplement when the current bottles are emptied.

I'm on that combi now for a few days and it does seem to be a hopeful start, I also use some daosin on the days that I do not do benadryl.

for me, the culprit is ( and was) a severe histamine reaction, that culminated in the fucked up glutamate/GABA balance , in my case the tinnitus and the twired state ( which btw, led to anxiety, in that way feeding itself ) was caused by months-long severe histamine overload ( which I was totally unaware of btw, would that a doctor had realized it, much suffering and damage to my body would not have happened if someone had realized that, told me to take histamin free food and some benadryl....)

so the way to sort of reverse that is to try to ' tame' my mastcells and let them behave as normal as possible.
that is the next chapter, from bedbound gone up to homebound and dressed in the daytime, lately I'm able to venture out of the house for small walks or even to the village to buy my own groceries ( someone needs to bring me there, I do not trust myself i a car yet, but hopeful in that department too)

 

[Lee88]

The excitoxicity seems to be my biggest problem right now, at times when I’m lying down, I feel what I assume is adrenaline surging across the stomach/abdominal area. Is this tied to the same thing?

 

[HABS93]

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:

@ Hip I know we've discussed transmitters downregulating on my post. Which I've found very helpful. I found this article and felt this has already of information for what I'm going through. I believe my NMDA was negatively affected from Drug use. I was wondering if the brain fog I felt after I quit was from Brain inflammation?

 

[judyinthesky]

@HABS93 this is interesting. I find it interesting that some of the medications used to ease drug withdrawal would also work for fatigue... like NAC... I wonder whether similar processes could take place when something the body is used to is abruptly taken away. Like in my case thyroid hormones - was hyper, then hypo... maybe if it is for a long time it is too much for the body. I experienced extreme brain inflammation like feeling (more wired than tired though) before my body crashed at some point.

 

[JoeyJo]

I just wanted to say a MASSIVE thank you for this thread!!!!

I've had severe insomnia for the past 3 years and felt like I'd tried almost everything. I was completely wired during the day too and so unable to nap even after being awake all night. It's been absolute torture and it was getting to the point when I didn't know how much longer I'd be able to take it. It'd either take me hours and hours to get to sleep ( even after taking multiple sleep meds), or I'd wake 5-7 times a night. There was no respite.

However, after reading this thread I decided to give NAC a go.

Well, for the past 3 nights, I've seen a ginormous improvement! I don't want to get my hopes up, but honestly cannot tell you what relief it has brought me. The first night I only woke twice, the second I woke once, and last night I didn't wake at all ( although my Fitbit registered three 'awake' spells).

I've been taking 600mg one hour before bed and it's not time-release, so I'm aware that I might see further improvements if I switch to a time-release tablet or take it twice a day. I just wanted to start low and go slow having learned that lesson the hard way before.

The only side-effect I've noticed is that yesterday I felt super fatigued/ anemic, and the fatigue side of CFS is something which I fortunately haven't had to deal with for many years. It could just be because I've had a stressful and exhasuting week moving house, I'm not sure. I took an iron tablet and feel much better for it today ( but usually they like B12, make the insomnia unbearable), so I'm just praying that I'll be able to take them to feel normal in the day and still be able to sleep at night now that I have the NAC.

On that point, I almost didn't try NAC because pretty much everything else I've tried has made it 10x worse and left me feeling overstimulated. So I'm just putting this out there incase anyone else is feeling the same way and unsure whether to give it a go.

EDIT (21/10/2020) Warning!

I take back what I said. NAC didn't work for me. I ended up having a huge flare-up and could barely move from the fatigue. I'm pretty sure it was a side-effect of the NAC as nothing else had changed for me, and I read that other people have had similar reactions to it. I'm starting to feel better now that I've stopped it too. I'm still really grateful for this thread and glad that I tried it, as having a few nights of drastically improved sleep was absolute bliss.

 

[AliMac64]

The NAG, turmeric and flaxseed oil. Does it need to be taken in the evening. And is linseed oil the same as flaxseed? I can tell you how helpful it is that members of this community have put so much effort into understanding and then explaining things here

 

[Donsboig]

And is linseed oil the same as flaxseed?

Yep, linseed and flaxseed oil is the same thing

 

[AliMac64]

Thanks

 

[Hip]

The NAG, turmeric and flaxseed oil. Does it need to be taken in the evening.

You can take it any time you feel that wired feeling, to see if it might help. The effects of these supplements will kick in after an hour or two.

 

[overtheedge]

@Hip
You mentioned in the first post of this thread that gaba supplements can lead to tolerance and withdrawal, which ones should be watched out for?

In the near future I'm planning to test out the following supplements for their ability to induce relaxation, are any of them problematic?: theanine, california poppy seed, passionflower, american skullcap, lemon balm, valerian, english lavender

Its been a while since ive done my reading on them but i remember many of them had part of their effects attributed to GABA action of some form on examine and other sites.

 

[Hip]

You mentioned in the first post of this thread that gaba supplements can lead to tolerance and withdrawal, which ones should be watched out for?

Here's how various GABA system-targeting supplements work:

GABA neurotransmitter level upregulation:
Passion flower (Passiflora) †
L-theanine †
Lemon balm (Melissa officinalis) †

GABA receptor agonists:
Taurine
Phenibut
Ashwagandha (Withania somnifera) †
Passion flower (Passiflora) — may be a GABA agonist †

GABA receptor positive allosteric modulators:
Valerian (Valeriana officinalis) †
Skullcap (Scutellaria lateriflora) †
L-Arginine †

I think all of these would be subject to some degree of tolerance build-up. In most cases, nothing to worry about, as I don't think you will get withdrawal symptoms from these supplements. The exception is phenibut, a supplement which people report can have withdrawal symptoms as bad as benzodiazepines.


One potent GABA system-targeting supplement which is not subject to tolerance is kava kava. In fact, rather than desensitizing the GABA system over time, there is evidence that kava kava actually makes it more sensitive. So you get this beneficial reverse tolerance effect.



You can often observe yourself when a GABA-targeting supplement starts to build up tolerance, as it effects get weaker.

I use high-dose taurine (4 grams daily) as an anti-anxiety supplement. This works on both GABA and NMDA. But after taking it for around 3 days in a row, I notice its anti-anxiety effects getting weaker. That I believe is the tolerance build-up. So I only use taurine for short periods of a few days, usually on days when my anxiety is higher than normal.

 

[overtheedge]

Thanks for that @Hip

Open medicine foundation linked to this a few weeks ago in one of their email updates and i thought it might be of interest to you since it contains a list of possible conditions that can resemble CFS, https://www.omf.ngo/2019/09/01/new-guidelines-for-diagnosing-and-treating-me-cfs/ you might already have seen it or know about all the involved conditions but in case you haven't and it contains something that might be of aid to your treatment roadmap i figured I'd post it

 

[Hip]

Open medicine foundation linked to this a few weeks ago in one of their email updates and i thought it might be of interest to you since it contains a list of possible conditions that can resemble CFS, https://www.omf.ngo/2019/09/01/new-guidelines-for-diagnosing-and-treating-me-cfs/ you might already have seen it or know about all the involved conditions but in case you haven't and it contains something that might be of aid to your treatment roadmap i figured I'd post it

Thanks for that link, I've just added it to the roadmap.

 

[Hoosierfans]

@Hip
You mentioned in the first post of this thread that gaba supplements can lead to tolerance and withdrawal, which ones should be watched out for?

In the near future I'm planning to test out the following supplements for their ability to induce relaxation, are any of them problematic?: theanine, california poppy seed, passionflower, american skullcap, lemon balm, valerian, english lavender

Its been a while since ive done my reading on them but i remember many of them had part of their effects attributed to GABA action of some form on examine and other sites.

Curious how these worked for you as I am looking at an alternative for benzos! I just ordered some tinctures of lemon balm, skullcap and Valerian.

 

[Hoosierfans]

One potent GABA system-targeting supplement which is not subject to tolerance is kava kava. In fact, rather than desensitizing the GABA system over time, there is evidence that kava kava actually makes it more sensitive. So you get this beneficial reverse tolerance effect.
.

Hey @Hip can you tell us more about Kava Kava?

After doctor after doctor throwing all sorts of meds at me over the years and treating all sorts of “wee beasties”, nothing which improved my symptoms, my doc gave me a baby dose of Klonopin the other day and it was unreal — got me out of bed, doing some short chores, etc.

I am well educated on benzos and the benefits / drawbacks, so before I jump in and start taking it and (probably) committing myself to a life on it, I want to look at GABA alternatives.

So Kava Kava makes your receptors MORE sensitive without downregulating them? What a win that would be!!!

 

[Hip]

So Kava Kava makes your receptors MORE sensitive without downregulating them? What a win that would be!!!

Yes, there is a study which suggests that is the case. This I think is why some people only start to experience the anti-anxiety relaxing effects of kava after about 2 weeks of daily dosing. But other people (like me) find kava usually has immediate relaxing effects, that appear within an hour or two of taking it.

My post here gives some more details. And if you search my posts for the word kava, you'll find more info and tidbits.


Are you considering benzos for anxiety or sleep? If the former, then this thread details a very viable alternative anti-anxiety treatment.

 

[Hoosierfans]

Yes, there is a study which suggests that is the case. This I think is why some people only start to experience the anti-anxiety relaxing effects of kava after about 2 weeks of daily dosing. But other people (like me) find kava usually has immediate relaxing effects, that appear within an hour or two of taking it.

My post here gives some more details. And if you search my posts for the word kava, you'll find more info and tidbits.


Are you considering benzos for anxiety or sleep. If the former, then this thread details a very viable alternative anti-anxiety treatment.

Hey Hip, thanks for answering. Yes I tried that cocktail and it didn’t help me but I appreciate so much your write up as it gave me something to try.
So my illness presents in an odd way — I am dizzy 24/7, lightheaded, have this feeling of cement in my brain and, most importantly, I have constant racing thoughts (like a 24/7 panic on my symtpms) and an all over burning sensation in my legs, arms, face and brain.

So when I tried a benzo the other day, it almost stopped my mind (I could stand watching tv, and could sit at a meal), my brain cement lightened, I was much less lightheaded and the burning went WAY down. So that’s all to say it’s for “anxiety” but way much more. It’s like my nerves are constantly over firing and the Klonopin really slowed that.

it’s the first thing that has worked in any way in many years.

I will definetly look up the posts on kava, thank you so much!

 

[Hip]

I have constant racing thoughts

You might also look into high dose inositol (search my posts for info), as this can have a calming effect by raising serotonin.

 

[Hoosierfans]

You might also look into high dose inositol (search my posts for info), as this can have a calming effect by raising serotonin.

Thank you, yes wrote that down and am going to try it. My health issues went from bad to worse after many years on an SNRI (Effexor) and then we went down the whole rabbit hole of lyme, mold, EBV etc etc. while I tapered the Effexor.

I have a new doc who is convinced (and so am I now) that this is some combo of Mito dysfunction and low serotonin. And maybe low dopamine and GABA too. So instead of chasing bugs, we are doing a few more tests and then plan on trying to get my neurotransmitters stabilized. (As an aside as a last ditch test we just tried a course of prednisone, 60 mg for two weeks and I got suicidal and it did nada for my symptoms— more evidence that serotonin is a problem for me and that this isn’t an inflammatory process).

We’ve trialed and tried so much that my neurologist and my internist are actually arranging a lumbar puncture for me in about a month to examine my neurotransmitter levels. I have an OATs test that shows low serotonin and dopamine, but we know those aren’t quite accurate when it comes to chemistry in the brain.

I sincerely appreciate your help. May message you with a few kava questions.