Supplements and Drugs That Reduce or Prevent PEM (Post-Exertional Malaise)

[frozenborderline]

A bit off topic, but are there Corticosteroids that cross Blood-Brain Barrier? Because if there is brain inflammation, it may be very helpful...

I assume just taking Corticosteroids as eye drops doesn't work, because to treat Temporal Arteritis they inject Corticosteroids into the eye, specifically: Triamcinolone intravitreal is injected into the eye to treat inflammation

(Temporal Arteritis is brain inflammation from what I understand)

This is confusing bc corticosteroids are well known for producing cognitive effects, including psychosis ... is that indirect, meaning they dont directly affect the brain? I didnt know that they didnt cross bbb

 

[Hip]

A small dose of lorazepam knocks me out cold for 4 hours. I wouldn't say it's a PEM buster.

Like most ME/CFS treatments, PEM busters which work for one patient may not work for the next.


This anti-PEM effect of benzos makes me wonder whether kava kava (Piper methysticum) might have anti-PEM effects, as kava has sensitizing effects on the GABA receptors: this herb it is thought will actually increase the number of GABA receptor binding sites over time (see this study).

Nearly all drugs or herbs which act on GABA tend to cause some degree of tolerance (receptor desensitization), but kava is one of the very few supplements or drugs acting on GABA which actually results in reverse tolerance, making the GABA receptor more sensitive the long you use it.

I sure wouldn't take it more often - It's addictive.

For some people, benzodiazepines are highly addictive, and can cause hellish withdrawal symptoms lasting for 6 months or more when people do decide to come of benzos. They have to taper incredibly slowly for many months to try to avoid the "cold turkey" symptoms, and even with this super-extended taper, they still have horrible withdrawal symptoms.

But other people can stop benzos abruptly, and experience no adverse effective at all. And some people are in-between these two extremes, Years ago, Cort ran a good survey on benzodiazepines, including withdrawal issues.

There is a new benzodiazepine called imidazenil, which @frozenborderline mentioned above, that creates only minimal tolerance and addiction. But is has not yet been licensed. The reason imidazenil does not result in tolerance and addiction is because it targets the alpha-5 subunit of the GABA-A receptor, rather than the alpha-1 subunit which both benzodiazepines and Z-drugs target.

 

[Learner1]

Cheney and levine regularly prescribe it for PEM. (Well, Cheney used to, when he was alive ). Levine still does. wouldn't argue about it being dependence forming , and maybe it doesnt work for you, but it's been known to help PEM , energy envelopes, sound sensitivity, and fatiguability , which are all related.

By what mechanisms? It'll definitely deaden sound sensitivity, but by what means does it increase ATP production, reduce fatiguability or PEM?

Seems to help whitney's PEM.

While that's exciting for Whitney, I'm pretty sure he has something different than a lot of us. I've had treatments help me that have failed him, do an not surprised something helps him that doesn't help me. Additionally, perhaps we need to define helping PEM. My version is not feeling like I've been hit by a truck, so I'm able to return to my usual normal function, which involves regular exercise.

 

[frozenborderline]

There is a new benzodiazepine called imidazenil, which @frozenborderline mentioned above, that creates only minimal tolerance and addiction. But is has not yet been licensed. The reason imidazenil does not result in tolerance and addiction is because it targets the alpha-5 subunit of the GABA-A receptor, rather than the alpha-1 subunit which both benzodiazepines and Z-drugs target

imidazenil seems to live up to its hype but idk if its properly a benzodiazepine... it targets different subtypes of receptors

For some people, benzodiazepines are highly addictive, and can cause hellish withdrawal symptoms lasting for 6 months or more when people do decide to come of benzos. They have to taper incredibly slowly for many months to try to avoid the "cold turkey" symptoms, and even with this super-extended taper, they still hav

dependence forming is a better term than addictive. They cause very little euphoria or typical reinforcement compared to opioids but they cause awful dependence.

But other people can stop benzos abruptly, and experience no adverse effective at all. And some people are in-between these two extremes, Years ago, Cort ran a good survey on benzodiazepines, including withdrawal issues.

I'd bet that peoppe with ME/CFS are more prone to bad benzos withdrawal symptoms than others bc of the excess brain glutamate. It's why they help so much but also why I'd caution against regular use. Again , this is like emergency thing. You need to get out of house to go to a funeral or a medical appointment once a month, or u need to fly without crashing to get to a medical appt other side of country. Benzos.

This anti-PEM effect of benzos makes me wonder whether kava kava (Piper methysticum) might have anti-PEM effects, as kava has sensitizing effects on the GABA receptors: this herb it is thought will actually increase the number of GABA receptor binding sites over time (see this study).

Kava may work but I felt it caused worse liver symptoms or something post ME/CFS than it did pre ME/CFS, it definitely produces moderate gabaergic relaxation though. Watch out for nausea. It can taste downright awful.

 

[Hip]

To put things in perspective, a 30 min walk or equivalent will certainly cause me to crash, and sans piracetam that's me done for the day. With piracetam, I'm actually somewhat restored after a few hours' rest.

Very interesting. What dose of piracetam do you take?

Would you consider piracetam to be a PEM shielder, rather than a PEM reliever? A PEM shielder means if you take the substance before exertion, it stops PEM from manifesting afterwards, or reduces the severity or duration of the PEM which does manifest.

A PEM reliever is something which you take after PEM has appeared, and it helps to reduce the PEM severity or shorten its duration.



I take piracetam sometimes to improve brain fog and increase cognitive clarity. It always works for that purpose, but I have never tried it as a PEM buster.

The only downside I find with piracetam is that when you come down from it (which occurs after around 8 hours or so), you tend to get blunted, weakened emotions. This is a common complaint I have seen among ME/CFS patients taking piracetam (not surprising, given that blunted emotions is a common symptom of ME/CFS). And it even occurs in healthy people.

But I find if I keep to a lowish dose of 800 mg, that still provides good cognitive clarity, and minimizes the emotional flatness comedown.

 

[Hip]

Kava may work but I felt it caused worse liver symptoms or something post ME/CFS than it did pre ME/CFS, it definitely produces moderate gabaergic relaxation though. Watch out for nausea. It can taste downright awful.

You definitely want to be on the lookout for any liver symptoms, since very rarely, kava can cause liver failure and death (I think there have been a total of three such cases in the world), which is why kava is banned in Europe, but it can be obtained in the US.

 

[frozenborderline]

By what mechanisms? It'll definitely deaden sound sensitivity, but by what means does it increase ATP

I'm going by their clinical experience, not trying to get into a scientific debate. We dont even know what the mechanism of PEM is. I know that susan levine writes benzos specifically for PEM. I hope people wont misuse this info and report her or something as I am only trying to show her clinical expert judgment, but there are some heated debates on here ... I'm unsure if I should even leave this up or anonymize it.

Anyway, it was their clinical judgment, they found this helped.

However if I was to merely guess why it helped ... glutamate in the brain. It's that simple. I dont think excitotoxicity is the single mechanism behind PEM but it's a plausible one. For many reasons. Ivs gone into more detail about this elsewhere. Excess Glutamate is present in me/cfs brains, shown by spectroscopy I believe. Orinferred due to activated glial cells on PET scans.

Glutamate is produced by neural stretch injury or toxin injury , such as classic cyanotoxin or mold toxin injuries--one example being penitrem a... it's a pretty generic brain. Response to a number of insults, sort of like extracellular ATP is for issues throughout the body.

And gaba is protective against this. When cyanobacteria toxins poison dolphins, diazepam helps them live.

 

[frozenborderline]

You definitely want to be on the lookout for any liver symptoms, since very rarely, kava can cause liver failure and death (I think there have been a total of three such cases in the world), which is why kava is banned in Europe, but it can be obtained in the US.

I didnt have any really serious symptoms but it wasnt tolerate well post me/cfs , whereas I had it sometimes pre ME/CFS

 

[frozenborderline]

While that's exciting for Whitney, I'm pretty sure he has something different than a lot of us. I've had treatments help me that have failed him, do an not surprised something helps him that doesn't help me. Additionally, perhaps we need to define helping PEM. My version is not feeling like I've been hit by a truck, so I'm able to return to my usual normal function, which involves regular exercise.

If so, I'm confused why the OMF obtained such homogeneous results among the severely Ill patient study . They were impressively uniform results. I say this, with everyone knowing full well I have many criticisms of the omf, but they seem to have obtained a very statistically meaningful result there ... and I fail to see why it would be likely that whitney has a totally different disease. Although it's an interesting question.

I'm a lumper not a splitter and I think it's more likely most me/cfs people share the same core issues and then there are a certain percentage with more divergent issues and only small venn diagram overlap. Maybe 15 or 20 percent. But I dont think of whitney as being particularly divergent... to me despite him not having severe cci , many of his other symptoms seem like how I've experienced severe ME and are closer to my experience than most people with moderate or mild cfs. I dont know...

 

[Hip]

By what mechanisms? It'll definitely deaden sound sensitivity, but by what means does it increase ATP production, reduce fatiguability or PEM?

There is a mitochondrial benzodiazepine receptor, also called the peripheral benzodiazepine receptor, and now usually referred to as the 18 kDa translocator protein (TSPO).

This receptor for benzodiazepines is located on the outer membrane of mitochondria. According to this study, substances which bind to TSPO affect mitochondrial respiration.

So this might well explain the anti-PEM effects that @frozenborderline has noticed from benzodiazepines.


I guess other drugs which bind to TSPO may also have anti-PEM benefits.

I have been thinking about buying an anti-anxiety drug called etifoxine, which is on the Wikipedia list of TSPO agonists. Etifoxine is cheap and available at some of the Russian online pharmacies, like RUPharma and ExtraPharmacy.

This study says:

Accumulating evidence implicate that synthetic TSPO ligands are neuroprotective in various CNS disorders and thereby, TSPO is regarded as a therapeutic target for neurologic disorders. Along these lines, Etifoxine, a TSPO ligand and clinically approved drug for the treatment of anxiety disorders, promoted axonal regeneration and functional recovery in an animal model of peripheral nerve freeze injury.

TSPO is also found in high abundance on the mitochondria of activated microglia, which is why brain scans to detect TSPO have been used to demonstrate neuroinflammation in ME/CFS patients.

 

[SpiralOut]

Very interesting. What dose of piracetam do you take?

Would you consider piracetam to be a PEM shielder, rather than a PEM reliever? A PEM shielder means if you take the substance before exertion, it stops PEM from manifesting afterwards, or reduces the severity or duration of the PEM which does manifest.

A PEM reliever is something which you take after PEM has appeared, and it helps to reduce the PEM severity or shorten its duration.



I take piracetam sometimes to improve brain fog and increase cognitive clarity. It always works for that purpose, but I have never tried it as a PEM buster.

The only downside I find with piracetam is that when you come down from it (which occurs after around 8 hours or so), you tend to get blunted, weakened emotions. This is a common complaint I have seen among ME/CFS patients taking piracetam (not surprising, given that blunted emotions is a common symptom of ME/CFS). And it even occurs in healthy people.

But I find if I keep to a lowish dose of 800 mg, that still provides good cognitive clarity, and minimizes the emotional flatness comedown.

My dosing schedule is 4.8g, followed by 2.4g 4.5 hrs later and a possible third dose depending how late I got up. (As you can imagine this requires buying bulk powder.) I base that dosage on a bunch of studies from back in the day, f.e.
https://pubmed.ncbi.nlm.nih.gov/10555876/
https://pubmed.ncbi.nlm.nih.gov/9527146/
https://pubmed.ncbi.nlm.nih.gov/8272204/
Don't know if they're outdated but I've always got along well with that dose/staying on it throughout the day.

I would say it's mainly a PEM reliever, but arguably does some shielding as well. I can still induce a crash just as easily/reliably, but I'd say being 'down there' is a bit less unpleasant; plus there's the ability to 'rest out of it' at least to some extent.

 

[frozenborderline]

There is a mitochondrial benzodiazepine receptor, also called the peripheral benzodiazepine receptor, and now usually referred to as the 18 kDa translocator protein (TSPO).

This receptor for benzodiazepines is located on the outer membrane of mitochondria. According to this study, substances which bind to TSPO affect mitochondrial respiration.

So this might well explain the anti-PEM effects that @frozenborderline has noticed from benzodiazepines.


I guess other drugs which bind to TSPO may also have anti-PEM benefits.

I have been thinking about buying an anti-anxiety drug called etifoxine, which is on the Wikipedia list of TSPO agonists. Etifoxine is cheap and available at some of the Russian online pharmacies, like RUPharma and ExtraPharmacy.

This study says:



TSPO is also found in high abundance on the mitochondria of activated microglia, which is why brain scans to detect TSPO have been used to demonstrate neuroinflammation in ME/CFS patients.

Interesting... I've been curious about etifoxine for a bit.

But I'd always assumed much of the reason benzos help w PEM is that cognitive PEM at least has something to do with glutamate

 

[Hip]

But I'd always assumed much of the reason benzos help w PEM is that cognitive PEM at least has something to do with glutamate

Yes, mental PEM may be a different beast to physical PEM, and have different mechanisms, and I would not be surprised if glutamate was involved in mental exertion PEM.

 

[hapl808]

I think there's a distinction between mental exertion triggering PEM, and the mental and physical symptoms of a PEM crash. I have tachycardia most of the time when I'm just sitting at my desk, and the more 'flow-state' that I get in when I'm working, the worse the crash. It's a shame because I think there's crossover between the ME/CFS wired/tired feeling and a good flow-state of work, but the better my concentration, the worse the subsequent crash.

For me, any physical or mental exertion triggers similar PEM that is always both physical and mental in symptoms. Brain fog, blurry vision, even more exhaustion, nausea, acid reflux, balance issues, etc. Still haven't found anything that's a great shielder or reliever for me, although some things work slightly: BCAA, skullcap, CoQ10, ibuprofen, etc.

 

[Learner1]

So this might well explain the anti-PEM effects that @frozenborderline has noticed from benzodiazepines.


I guess other drugs which bind to TSPO may also have anti-PEM benefits.

I have been thinking about buying an anti-anxiety drug called etifoxine, which is on the Wikipedia list of TSPO agonists. Etifoxine is cheap and available at some of the Russian online pharmacies, like RUPharma and ExtraPharmacy.

This might be worth considering:

https://medicalxpress.com/news/2021-09-common-medications-accumulate-gut-bacteria.html

And this:

https://www.nibib.nih.gov/news-events/newsroom/making-microbiome-more-amenable-cancer-immunotherapy

 

[Hip]

I think there's a distinction between mental exertion triggering PEM, and the mental and physical symptoms of a PEM crash.
...
For me, any physical or mental exertion triggers similar PEM that is always both physical and mental in symptoms.

Yes, I think when patients get PEM, it tends to have both mental and physical manifestations (for example, getting worsened brain fog and feeling mentally tired, as well as feeling physically tired and weak in body and limbs).


When I refer to "mental PEM", that's just shorthand for "mental exertion-triggered PEM'.

And likewise by "physical PEM" I mean "physical exertion-triggered PEM".

To be clear, it should really be written out in full each time.

 

[frozenborderline]

Yes, mental PEM may be a different beast to physical PEM, and have different mechanisms, and I would not be surprised if glutamate was involved in mental exertion PEM.

Well, honestly I think that glutamate in brain may be part of physical PEM too, it's just that it couldn't explain ALL of it, so maybe it's like glutamate in brain but also lactate throughout the body. Something like that

 

[frozenborderline]

I will say, in the past before I got cci, and became more severe , heres what was the most impressive and most noticeable for either preventing or helping with PEM after the fact. Strong chaga tea (maybe an immune element to PEM), gabapentin , cyproheptadine maybe, bcaas,

Like most ME/CFS treatments, PEM busters which work for one patient may not work for the next.


This anti-PEM effect of benzos makes me wonder whether kava kava (Piper methysticum) might have anti-PEM effects, as kava has sensitizing effects on the GABA receptors: this herb it is thought will actually increase the number of GABA receptor binding sites over time (see this study).

Nearly all drugs or herbs which act on GABA tend to cause some degree of tolerance (receptor desensitization), but kava is one of the very few supplements or drugs acting on GABA which actually results in reverse tolerance, making the GABA receptor more sensitive the long you use it.





For some people, benzodiazepines are highly addictive, and can cause hellish withdrawal symptoms lasting for 6 months or more when people do decide to come of benzos. They have to taper incredibly slowly for many months to try to avoid the "cold turkey" symptoms, and even with this super-extended taper, they still have horrible withdrawal symptoms.

But other people can stop benzos abruptly, and experience no adverse effective at all. And some people are in-between these two extremes, Years ago, Cort ran a good survey on benzodiazepines, including withdrawal issues.

There is a new benzodiazepine called imidazenil, which @frozenborderline mentioned above, that creates only minimal tolerance and addiction. But is has not yet been licensed. The reason imidazenil does not result in tolerance and addiction is because it targets the alpha-5 subunit of the GABA-A receptor, rather than the alpha-1 subunit which both benzodiazepines and Z-drugs target.

https://www.reddit.com/r/researchchemicals/comments/gihbao

Very positive review w info

 

[frozenborderline]

@Hip incredibly interesting and strange thing about imidazenil--its useful in schizophrenia and in organophosphate poisoning. Is that bc organophosphates cause some kind of excitotoxicity? Either way , far out stuff. This just from the wikipedia

 

[Rvanson]

My insomnia is only controlled by a benzodiazapine. Once that is cut off, and it will be one day, things ain't going to be very pretty. I use a standard, but high dose Rx'ed by a doctor. The government doesn't like people on them,
since they are abused by DRUGGIES (no apologies will ever be given to my use of that term) They crush them up and snort it up their noses to get a high.

So now, we who don't have highs on them, have to pay for their crimes. Due to TOS I can't say what I am going to do about this, but I certainly is not going to be very pretty indeed. I've had enough of these criminals, and lucky enough not to be bedbound. I like my sleep time. That's all I can say due to terms of service.