Hip
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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:
Note that if you have an overstimulation mental state (like the overstimulation that can arise from overmethylation), rather than a mental tension mental state, then then taking vitamin B3 in the form of niacinamide 1000 mg can be very effective.
Sometimes it can be hard to distinguish between the overstimulation feeling and the mental tension anxiety feeling.
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:
Note that if you have an overstimulation mental state (like the overstimulation that can arise from overmethylation), rather than a mental tension mental state, then then taking vitamin B3 in the form of niacinamide 1000 mg can be very effective.
Sometimes it can be hard to distinguish between the overstimulation feeling and the mental tension anxiety feeling.
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