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

Discussion in 'Neurological/Neuro-sensory' started by Hip, Apr 27, 2016.

  1. Hip

    Hip Senior Member

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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:
     
    Last edited: Oct 18, 2017
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  2. aaron_c

    aaron_c Senior Member

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    Don't forget carnitine

    and CDP-choline aka Citicoline. One study found that:

    According to entrezgene: EAAT2 is "the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system."
     
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  3. Justin30

    Justin30 Senior Member

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    So would this mean that using L Glutamine for gut issues would essentially increase glutamate or should we not worry about this?
     
    Last edited: Apr 28, 2016
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  4. Valentijn

    Valentijn Senior Member

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    I found that NAC resolved my wired-but-tiredness.
     
  5. u&iraok

    u&iraok Senior Member

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    These work for me:

    l-theanine and Kavinace (Taurine, 4-amino-3-phenylbutyric acid, B6) and laying in the sun work the best for me.

    Also,
    St. John's wort
    Gaba
    Dr. Christopher's Relaxe-Eze (Black cohosh, capsicum, hops flowers, lobelia, skullcap, valerian, wood betony, mistletoe)
    Bach flower essences
    Lavender, chamomile essential oils
     
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  6. Hip

    Hip Senior Member

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    In general I don't think this is an issue. I have no problems taking L-glutamine, even in doses of 3 heaped teaspoons of power. If anything, I find this lowers my anxiety symptoms, probably through its anti-inflammatory effects.

    Some ME/CFS patients report problems with taking L-glutamine, but this may have nothing to do with the conversion to glutamate; L-glutamine has an immune boosting effect, and so adverse reactions to L-glutamine may possibly arise from that.


    (By the way, it may be in idea to edit out the very long quote in your above post, as very long quotes tend to look a bit unwieldy).
     
  7. Hip

    Hip Senior Member

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    Very interesting.

    It says here that:
    So that seems to explain how N-acetyl-cysteine can reduce glutaminergic activity.

    I can't say that I have noticed much effect from N-acetyl-cysteine myself, in the doses I have taken (400 mg once or twice daily). What sort of dosing of do you use?

    The half-life of NAC is 6 hours, so twice daily dosing is probably best (or time-release formulation).
     
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  8. Hip

    Hip Senior Member

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    That's an interesting one. Have you noticed a positive effect from L-carnitine, in terms of reducing the "wired" over-stimulation of ME/CFS?



    I included citicoline in this list of drugs and supplements which increase the function or expression of glutamate transporters in the brain. This list includes: amoxicillin, ceftriaxone (Rocephin), riluzole, valproic acid, alpha lipoic acid, citicoline and pyroglutamate.

    The study on amoxicillin though showed this antibiotic induced an impressive 500% increase in GLT-1 glutamate transporter expression within a matter of days.

    GLT-1 (aka: EAAT2) is indeed the main glutamate transporter in the brain, responsible for removing 90% of the glutamate from the extracellular spaces in the brain.
     
    Last edited: Apr 28, 2016
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  9. Valentijn

    Valentijn Senior Member

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    I do 600mg three times per day. Which is on par with the dose used in longer-term studies.

    I use Jarrow's NAC Sustain, and that seems to work pretty well. The dose before bed is the important one for getting to sleep, but I find a morning and early afternoon dose to generally be helpful as well.
     
    Last edited: Apr 28, 2016
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  10. aaron_c

    aaron_c Senior Member

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    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.

    I forgot to mention Manganese. It is a cofactor for glutamine synthetase, which converts glutamate to glutamine. I found I had to experiment to get the right dose--too much and I get angry easily or get insomnia, too little and I get insomnia. Also, I found that the more carnitine I took, the less manganese I needed.
     
  11. CCC

    CCC Senior Member

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    Another great post from @Hip - we have several of your posts bookmarked in the short list now.
     
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  12. Silence

    Silence

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    I wonder if there is a way to test for increased glutamate activity within the brain? Would an MRI show neuronal damage caused by ongoing exccess glutamate activity?
     
  13. Deltrus

    Deltrus Senior Member

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    Anxiety and impulsiveness are a good indicator of an increase in excitatory activity. Insomnia with low energy is also a sign. Responding very well to gaba drugs, phenibut, lavender, ashwagandha etc is also a sign you have more glutamate than gaba.
     
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  14. Sidereal

    Sidereal Senior Member

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    Alpha lipoic acid (on Cutler's dosing schedule) got rid of this symptom for me.
     
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  15. Deltrus

    Deltrus Senior Member

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    Hello everyone I used to have a very excitatory brain, close to the siezure threshold often. I even had several low movement seizures during the night. Trans-Resveratrol, and the stuff I posted in stage 1 in my thread greatly lowered my brain excitation/inhibition ratio.

    If you can get the full methylation cycle going then that is the best for excitatory/inhibitory balance.


    Once I got my methylation going I had several bursts of heavy metal detox symptoms, and I then dumped all my magnesium and became super tense again. Resveratrol seems to prevent this while curcumin/vitamin c/ALA does not.


    I have a hypothesis based on my experiences that taurine and b6 are very vulnerable to oxidation from oxidative stress, and by oxidation from heavy metals such as copper. Taurine is dependant on b6 to be synthesized and holds potassium/magnesium in cells.

    The problem is that b6 is the rate limitting cofactor in the synthesis of glutathione, the body's main antioxidant. So it prevents oxidation and is vulnerable to oxidation. Once I get b6 high and can manage to absorb a lot of magnesium, then I also get a huge response to glutathione cofactors such as vitamin e and selenium.

    The resveratrol initially helps lower oxidation so b6 can start working without getting damaged. It also chelates any copper that gets released.

    B6 is integral to the synthesis of GABA. High intracellular magnesium is also integral.

    I'm tired while writing this so forgive the poor sentence flow and lack of sources.
     
    Last edited: Apr 29, 2016
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  16. CCC

    CCC Senior Member

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    This:
    How do you know?

    It's the low energy I'm interested in.
     
  17. u&iraok

    u&iraok Senior Member

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    Interesting. I take resveratrol. It makes me feel better but I'll be paying attention as to why.
     
  18. Deltrus

    Deltrus Senior Member

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    Insomnia can also be from high energy availability (thyroid, cycadian rythym issues etc). You feel wide awake and restless in this case. You slowly eventually lose energy and fall asleep. I've experienced both types of insomnia.

    Insomnia from high glutamate/excitation is very uncomfortable, you are extremely tired and low energy but basically have to stay awake until you completely crash, which may be like 4 am.

    Remember excitation isn't the same as energetic and stimulated, something like phenibut gives massive inhibition but makes me more energetic and stimulated than anything. Perhaps my vagus nerve is overactive/damaged, which then strongly activates brain pathways involved with resting.
     
    Last edited: Apr 29, 2016
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  19. Christopher

    Christopher Senior Member

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    It is definitely anti inflammatory.
     
  20. Christopher

    Christopher Senior Member

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    Do you respond well to Alpha Lipoic Acid?
     

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