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

Jimbo39

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I don't know how my first post got there. Please disregard.

So to recap, NAG, turmeric, and flaxseed oil, are your top 3 choices? Why turmeric instead of curcumin? I read that NAG helps with gut inflammation so I'm definitely taking it. What brand worked best for you? In another post you mentioned sesame oil instead of flaxseed. Was this for something else?
 

Sidereal

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I noticed your comment regarding alpha lipoic acid, in what form did you take this, i have heard itmworks well for neuropathy which i have.
I took regular ALA (not R-LA) by Kirkman Labs, small dose, every three hours around the clock. I tried a couple of other brands and they were not as effective. I started with just 6.25 mg and worked my way up to 100 mg every three hours slowly over the course of a year. I currently don't take it because I don't perceive a need for it anymore.
 
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(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
Another herb that supposedly increases GABA receptors is zizyphus seed, which is the main sedative herb used in Chinese herbalism.

http://www.shaman-australis.com/for...-active-plants/&do=findComment&comment=390099
 

Hip

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Another herb that supposedly increases GABA receptors is zizyphus seed, which is the main sedative herb used in Chinese herbalism.

http://www.shaman-australis.com/for...-active-plants/&do=findComment&comment=390099
Thanks for posting that.

I think the studies your link may be refering to are these: 1 2 3

But briefly looking at those studies (the full papers are on Sci Hub), I don't think the sanjoinine A from Ziziphus spinosa seeds actually increase the number of GABA-A receptors, but rather it increases the gamma subunit on the GABA-A receptors.

The gamma subunit of the GABA receptor responds to benzodiazepines, whereas the alpha and beta subunits provide the binding site for the GABA molecule. So this appears to be why sanjoinine A can increase the potency and effects of benzodiazepines.

The α and β subunits provide the binding site for the GABA molecule, while the α and γ subunits are sensitive to benzodiazepine binding (Whiting, 1999; Bateson, 2004). We found that sanjoinine A increased the abundance of the GABAA receptor α-subunit and γ-subunit but had no effect on the abundance of the β-subunit. This indicates that sanjoinine A might increase responses of GABA receptor to benzodiazepine by influence GABA receptor subunits compositions.
Source: 1

But sanjoinine A may have other possible GABAergic and anti-anxiety mechanisms:
Our results suggested that sanjoinine A might exert its sleeping potentiating effects by three pathways; 1st, increase GABA synthesis by GAD activation; 2nd, increase sensitivity of GABA receptor to pentobarbital or GABA by influence GABA receptor subunit compositions, especially by increasing subunit expression; 3rd, it is also possible that sanjoinine A activate GABA receptors directly.
...
ZSS might be another good candidate for use in psychiatric illnesses such as sleeping disorders.
Source: 1
It is interesting that these seeds are a traditional treatment for insomnia. The seeds might be helpful for ME/CFS insomnia and sleep issues.

Names of these seeds:
jujuba seeds
Semen Ziziphi spinosae
Suan Zao Ren

Google search: here.

Species name: Ziziphus jujuba (botanical synonym: Ziziphus spinosa)

Good article: Ziziphus jujuba - Scientific Review | Examine.com
 
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I found that NAC resolved my wired-but-tiredness.
I'm experimenting with NAC after seeing the positive abstract about it from the Florida conference. Almost all of the time I'm tired but wired ratherthan sleepy tired. since starting NAC a couple of days ago I'm so sleepy I'm struggling to keep my eyes open. It is quite a cosy type of feeling, compared to my normal state but I can't really do anything!

The half-life of NAC is 6 hours, so twice daily dosing is probably best (or time-release formulation).
I'm wondering if I'm misattributing the effect though. I didn't take it today and still very sleepy. Would it have completely worn off if NAC?

Have you noticed a positive effect from L-carnitine, in terms of reducing the "wired" over-stimulation of ME/CFS?
I haven't noticed this. I'm trying to combine the mitochondria related supplements. I have d-ribose, b vitamins, l-carnitine.

Absolutely. If you look at the thread that I quoted myself from, it is titled "Carnitine = More Fatigue," although for myself (and I argue for others as well) I think this is just what happens when you help bring glutamate levels back where they should be--you get tired for a few days, then you feel roughly the same as before but less wired. I could tell the difference specifically because it helped with insomnia.
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I wonder about this idea for NAC as well. Somewhere else on PR I saw people saying about sleepiness as a side effect. I wonder if we need to be sleepy for a bit. is it a healing thing? Are general ME symptoms improving as a consequence of being less wired?
 

Valentijn

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I'm wondering if I'm misattributing the effect though. I didn't take it today and still very sleepy. Would it have completely worn off if NAC?
Yes, it wears off pretty quickly. It has a half-life of 5.6 hours, so a dose from yesterday wouldn't have any effect today.

I've never felt sleepy from it. It just lets me sleep when I'm tired, and turns down my brain a bit when I'm feeling too wired.
 
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Almost too sleepy to write...

I still think it is NAC that is making me sleepy, partly cos it seems to have completely resolved tired-but-wired state for me (at least for the time being). Perhaps sleepiness may be slightly indirect and so the halflife not so relevant?

My ME is generally inclined towards tired but wired and under sleeping. Most of you probably know that this is very unpleasant as a form of fatigue. Tortuous.

Could NAC be resolving this and leaving me with a less severe form of fatigue which is sleepiness? It isn't as unpleasant in fact i quite like it but I can do less, which is a conundrum.

I've noticed on here people mention NAC causing a crash. I wonder if this is what they mean? I wouldn't describe as a crash.

Going back to sleep!
 

Hip

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Yes, I find NAC helpful by itself.
I've now included N-acetyl-cysteine in the original post of this thread, as one of the ways to reduce brain glutamate levels (and I change the title of this thread from "Four Ways To Reduce Your Wired But Tired State" to "Five Ways To Reduce Your Wired But Tired State").

I also found in this paper NAC's likely mechanism of action in reducing glutamate, and detailed this mechanism in the first post.

Thanks for pointing out the efficacy of NAC for reducing glutamate, Valentijn.
 
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I'm now about 72 hours not taking NAC and tired but wired is back. I've had two good for me ME days in between (neither too sleepy nor tired but wired). I've taken a NAC now for the tired but wired to help sleep. perhaps I need some sort of rhythm like that? We'll see, if I'm not back to sleepy tomorrow might not have been NAC.
 
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Ah well I seem to be coming down with my partner's virus so no conclusion re NAC atm. Possibly my good days were pre-virus respite. Do any of you get that? Much better cognitive clarity or even no brainfog just before (ie incubation of) new virus. Early on the whole virus was a general improvement, I felt better with cold/flu than without, but in recent years it's just beforehand. Post viral repercussions are a nightmare though, feeling :nervous:
At least I have NAC and bromelain to help with congestion
 
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Ah well I seem to be coming down with my partner's virus so no conclusion re NAC atm. Possibly my good days were pre-virus respite. Do any of you get that? Much better cognitive clarity or even no brainfog just before (ie incubation of) new virus. Early on the whole virus was a general improvement, I felt better with cold/flu than without, but in recent years it's just beforehand. Post viral repercussions are a nightmare though, feeling :nervous:
At least I have NAC and bromelain to help with congestion
 
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@Hip Thanks for the great post hip. I've bookmaked it and come back to it often.

Iseem to be in a state of ecxitotoxicity currently. I'm quite worried about the clonazepam I'm taking. I tried reducing the dosage but I'm still working on.

You have some great ideas listed. I'm already on nac, Taurine and L-theanine.. Dunno if it's helping me. I tried the amoxicillin but stopped midway because of some other issues. But plan to try it out a little later.. I'm also trying ancient mineral ultra Pure magnesium oil.. I'm trying to get off or reduce the clonazepam km thing.

I was just inquisitive as to why alcohol is not listed as something that might help. I understand most of us are intolerant. But for the few that are tolerant do you think it can help?

Thanks.
 
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@ArunP have you tried meditation? I don't think Alcohol is any better of a long term solution than Klonopin.
Yes I tried it a couple of times. It just makes me ponder on things I don't want to think about.. And I have autonomic dysfunction. Me being more aware of breathing making it even more out of sync. I can't explain it. It's like my heart beat and breathing are out of sync. It's a terrible feeling.
So meditation actually was counter productive. Maybe there is something other form of it I can look into. Thanks for your post.
 

Hip

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I was just inquisitive as to why alcohol is not listed as something that might help. I understand most of us are intolerant. But for the few that are tolerant do you think it can help?
Alcohol might help temporarily, provided you consume it in moderate amounts. Alcohol (ethanol) works on the GABA system, so has calming effects. However, you have to watch out for the glutamate rebound when drinking alcohol, because as the alcohol leaves your body several hours after drinking, and you return to sobriety, you start to produce higher than normal levels of glutamate. Some info on the alcohol glutamate rebound here.

So alcohol will tend to reduce neuronal excitation for some hours, but then increase neuronal excitation as the alcohol leavers the body and you get higher than normal levels of glutamate.


I think kava root (Piper methysticum) may be one of the best ways of boosting the GABA system. Kava is non-addictive, it does not produce a rebound, and you get no tolerance build-up with kava. In fact, kava has a reverse tolerance profile: over time, kava will increase the sensitivity of the GABA system (by increasing GABA receptor density), so it will shift your brain to a calmer state. 1

For this reason, kava may be a better option than benzodiazepines, because of kava's beneficial reverse tolerance effect. By contrast, benzodiazepines tend to make the GABA system less sensitive over time, which is the origin of the horrible withdrawal symptoms that a certain percentage of people experience when they try to stop taking benzodiazepines.

Note that you'd want to avoid kava leaves and stem: these have been associated with very rare but severe liver damage. But I read that kava root is safe. I often use 300 mg of kava root powder taken 2 hours before going out socially; I find this nicely calms and buffers my mind against the over-exciting stimuli of social interaction (and kava does not make you sleepy, or make you feel that you have been "drugged"; you are alert, but calm). Kava is the traditional drink on Polynesian islands such as Hawaii: kava is their version of alcohol, and they consume kava as social drink, analogous to the way other cultures use alcohol as a social lubricant.

Other useful GABA system activating supplements that have this beneficial reverse tolerance action are: Magnolia officinalis bark, 1 Bacopa monnieri, 1 and fasoracetam (NS-105). 1

These reverse tolerance supplements are uncommon; most GABAergic supplements and drugs usually tend to have the problem of causing GABA system desensitization over time, leading to tolerance build-up.



Generally, though, I think it is a good idea to try to treat the hyperaroused brain state of ME/CFS at its very source, and I think the source may be the high levels of glutamate produce by chronic brain inflammation, which activates the NMDA receptors. That's why I think the anti-brain inflammation approach detailed in section (1) of the first post in this thread is well worth trying. But you can combine these various approaches (the approaches that work on NMDA and approaches that work of GABA) in order to get a stronger overall effect.