Crashes - what does science tell us for practical use?

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My fear pwME on PR,

as some of you might know, I'm very engaged in advocating and feel a kind of responsibility to educate pwME who can't read/understand/handle all the science on PubMed and elsewhere and want to translate that into plain language.

Atm I'm dealing with a bad crash again and had the idea to do a post on IG about first aid in a crash.

I want to combine lifestyle methods like deep rest, meditation, vagus stimulation, stay away from media and do on with supplements and serious medical interventions (like good old benzos to stabilize everything a bit to prevent deeper PEM)

I want to link it to the most recent and/important science on PEM and would kindly ask you to see this thread as a collection dump for science on PEM and what we could POSSIBLY try to prevent or bust PEM.

I'm very aware of the fact that @Hip has already created some kind of this but I would love to summarize it in a scientific/theorotical way more than n=1/2/3/4 findings.

therefore I would politely ask the more scientific educated/understanding members here to just through out what they think science shows us and what we as a consequence could try.

many thanks 🙏

@Hip @Pyrrhus @nerd @sometexan84 @Learner1 @bread. i forget many due to brainfog pls feel free to tag more users!
Ps.: of course I will first rest myself!

This would be priceless to me and many others!
thanks again!
 
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Well what is a "crash"?
As far as i understood its excessive lactat Accumulation due to mito Fragmentation and impaired Krebs cycle.
And then the Problem becomes more drastic as it needs a lot of Energy (which is not their) to remove the lactat. In the mean while their is a lot of mitochondrial apoptosis on going. Increased Oxidative Stress .
Very unrealistic that in this state the impaired Immune System is working as in non crash state. So the viral Load increases more and more.
This explains the duration often from weeks to Months to no recovery.
 
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Well what is a "crash"?
As far as i understood its excessive lactat Accumulation due to mito Fragmentation and impaired Krebs cycle.
And then the Problem becomes more drastic as it needs a lot of Energy (which is not their) to remove the lactat. In the mean while their is a lot of mitochondrial apoptosis on going. Increased Oxidative Stress .
Very unrealistic that in this state the impaired Immune System is working as in non crash state. So the viral Load increases more and more.
This explains the duration often from weeks to Months to no recovery.
Or it is impaired metabolic output due to hypoxia.

Qs there are some PEM busters for some there must be Sth practical explainable by what we know.
 

Diwi9

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I ask respondents to be clear about which symptoms their suggested remedies are treating as we don't all have the same PEM symptoms. For example, amino acids don't help my extreme brain fog and hypersomnia, neither do they help joint and nerve pain. I have some treatment regimens that I have devised, but will not list my treatments because I can't explain the medical/biochemical reason why specific treatments help me.
 

Pyrrhus

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From my perspective, we know quite a bit about the physiological basis of exercise intolerance, but very little about the physiological basis of PEM.

So although we can discover techniques that may alleviate PEM, it might prove hard to put those techniques on a purely scientific footing.

Techniques that reduce exercise intolerance, and the tissue hypoxia that comes with it, may be easier to put on a scientific footing, but may not turn out to be relevant to reducing PEM.
 
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From my perspective, we know quite a bit about the physiological basis of exercise intolerance, but very little about the physiological basis of PEM.

So although we can discover techniques that may alleviate PEM, it might prove hard to put those techniques on a purely scientific footing.

Techniques that reduce exercise intolerance, and the tissue hypoxia that comes with it, may be easier to put on a scientific footing, but may not turn out to be relevant to reducing PEM.
That's very said especially hearing that from you bc then I know it's an accurate statement. I will investigate this further when I'm well enough and if sth turns out be be an explanatory model then I'll discuss that here.
Thanks
 

Irat

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There is an article where all studies and findings are shown during and before PEM (at baseline)

5.1 Gene expression
5.2 Immune activation
5.2.1 Oxidative stress
5.2.2 Complement C4a
5.2.3 Cytokines
5.3 Autonomic response
5.4 Sleep
5.5 Cognitive performance
5.6 Pain modulation
5.7 Other
5.7.1 The gut microbiome
5.7.2 Catecholaminergic hyporeactivity
5.7.3 Nitric oxide metabolites

https://me-pedia.org/wiki/Post-exertional_malaise


Why benzos might prevent a crash (it also did for me back than ) could might be that a benz o a)keeps your autonomic response stable b) prevents gen expression in the adrenergic and glucocorticoid pathway....but just guessing.

I read that Whitney uses visualization techniques to ask his response before doing something if he crashes or not,....

@Martin aka paused||M.E.
 
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There is an article where all studies and findungs are shown during and before PEM

5.1 Gene expression
5.2 Immune activation
5.2.1 Oxidative stress
5.2.2 Complement C4a
5.2.3 Cytokines
5.3 Autonomic response
5.4 Sleep
5.5 Cognitive performance
5.6 Pain modulation
5.7 Other
5.7.1 The gut microbiome
5.7.2 Catecholaminergic hyporeactivity
5.7.3 Nitric oxide metabolites

https://me-pedia.org/wiki/Post-exertional_malaise
Why benzos might prevent a crash (it also did for me back than ) could might be that a benz o a)keeps your autonomic response stable b) prevents gen expression in the adrenergic and glucocorticoid pathway.

@Martin aka paused||M.E.
Thank you!
 

Learner1

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There is an article where all studies and findings are shown during and before PEM (at baseline)

5.1 Gene expression
5.2 Immune activation
5.2.1 Oxidative stress
5.2.2 Complement C4a
5.2.3 Cytokines
5.3 Autonomic response
5.4 Sleep
5.5 Cognitive performance
5.6 Pain modulation
5.7 Other
5.7.1 The gut microbiome
5.7.2 Catecholaminergic hyporeactivity
5.7.3 Nitric oxide metabolites

https://me-pedia.org/wiki/Post-exertional_malaise
Why benzos might prevent a crash (it also did for me back than ) could might be that a benz o a)keeps your autonomic response stable b) prevents gen expression in the adrenergic and glucocorticoid pathway....but just guessing.

I read that Whitney uses visualization techniques to ask his response before doing something if he crashes or not,....

@Martin aka paused||M.E.
Excellent list. I think it helps explain why different people may experience different benefits from various PEM busters. Looking at the list, it might be summarized into:
  1. Immune activation - microbiome, cytokines, complement C4a, inflammation
  2. Nervous system - pain, cognitive performance, sensitivity to stimuli, sleep, autonomic dysfunction
  3. Oxidative and nitrosative stress
  4. Gene expression
The things that have been most effective for me are:
  • BCAAs - "As important metabolic substrates, branched-chain amino acids (BCAAs) and fatty acids (FAs) participate in many significant physiological processes, such as mitochondrial biogenesis, energy metabolism, and inflammation, along with intermediate metabolites generated in their catabolism. The increased levels of BCAAs and fatty acids can lead to mitochondrial dysfunction by altering mitochondrial biogenesis and adenosine triphosphate (ATP) production and interfering with glycolysis, fatty acid oxidation, the tricarboxylic acid cycle (TCA) cycle, and oxidative phosphorylation. BCAAs can directly activate the mammalian target of rapamycin (mTOR) signaling pathway to induce insulin resistance, or function together with fatty acids. In addition, elevated levels of BCAAs and fatty acids can activate the canonical nuclear factor-κB (NF-κB) signaling pathway and inflammasome and regulate mitochondrial dysfunction and metabolic disorders through upregulated inflammatory signals. " Source
  • The Pall protocol for reducing oxidative and nitrosative stress, as well as the antioxidant network. This includes folate, B12, BH4 and C, along with ALA, E, and glutathione.
I would think that things that calm the immune system, infections, and the nervous system might help too, as well as those that reduce lactic acid.
 

Hip

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When I looked into the possible mechanism of action of the supplements that members reported reduced PEM, I found a lot of them were athletic performance enhancers that worked by reducing lactic acid. See this post.

So if you are a patient who appears to generate a lot of lactic acid through exercise, perhaps those lactic acid-targeted PEM busters might be useful for you.

If the Myhill group's analysis of the metabolic subtypes of ME/CFS patients is accurate, it is the Group A ME/CFS patients who generate lots of lactic acid during exertion.

The Myhill group find it is what they call the Group A ME/CFS patients who during exertion rely on anaerobic glycolysis (the breakdown of glucose to lactic acid) to generate emergency energy, and so there is lactate build up.

If you look at the first three pages of this thread , and search for the word "group", you will see a lot of info on Group A and Group B patients.

Group B tend to be the more severe patients. According to the Myhill group, these may benefit from D-ribose supplementation to bolster their energy metabolism against PEM.

That said, I remember a published case study by very severe Dutch ME/CFS patient Mark Vink, who found that his 6 meter once daily walk to the bathroom produced more lactic acid in his blood than even a marathon runner! So even the severe patients can produce lactic acid, it seems.



The PEM busters thread first post is a bit of mess, it needs a complete re-write to make clearer. I will need to do that at some point.
 

Learner1

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When I looked into the possible mechanism of action of the supplements that members reported reduced PEM, I found a lot of them were athletic performance enhancers that worked by reducing lactic acid. See this post.

So if you are a patient who appears to generate a lot of lactic acid through exercise, perhaps those lactic acid-targeted PEM busters might be useful for you.
My lactic acid is usually low, even after exercise.

Thiamine deficiency seems to be fairly common in ME/CFS patients.

"Thiamine deficiency as a cause of lactic acidosis"
https://derangedphysiology.com/main...823/thiamine-deficiency-cause-lactic-acidosis

"Lack of thiamine can lead to potentially life-threatening events. Inadequate stores of thiamine result in the failure of pyruvate to enter the tricarboxylic acid cycle, thus preventing aerobic metabolism, which may lead to profound lactic acidosis through anaerobic metabolism."
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6260286/#__sec5title

"Severe lactic acidosis reversed by thiamine within 24 hours"
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3388689/
 

Hip

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"Severe lactic acidosis reversed by thiamine within 24 hours"
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3388689/
It would be interesting to see if high dose vitamin B1 could act as a PEM reducer, especially in patients who know they have lactic acid build up.



Why benzos might prevent a crash (it also did for me back than ) could might be that a benz o a)keeps your autonomic response stable b) prevents gen expression in the adrenergic and glucocorticoid pathway....but just guessing.
Benzodiazepines directly activate a receptor on the mitochondria called TSPO, which might explain how these drugs can reduce PEM. See this post.
 

hapl808

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I'm very interested that at this point for me mental or physical exertion causes very similar (or the same) PEM crashes. That implies that at least for my subset it's not solely a muscular result but potentially related to neurotransmitter function or some process that supports mental exertion (the brain uses lots of energy so I'm not sure what other cycles could be impaired as muscular exertion does the same).

There also seems to be a strong gut-brain axis involvement, as many of my gut symptoms only appear during PEM crashes - particularly very bad reflux that basically disappears when I'm not experiencing PEM. If I don't exert for a week, then I get no symptoms.

Obviously the delay between activity and PEM seems like it must be a critical element as that's one of the hallmarks distinguishing fatigue from PEM. I've noticed that some activities seem to have longer delays before the crash, but I have no idea why.

And as others have also described, my PEM symptoms and triggers have changed (and worsened) over the years, so I would have described it differently even five years ago.

Not sure if any of that is helpful, though. I can make guesses on excess or improperly metabolized glutamate or dopamine or inadequate GABA (hence the benefit of benzos?) but I don't really have any evidence or any way of effectively controlling that function.
 
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I'm very interested that at this point for me mental or physical exertion causes very similar (or the same) PEM crashes.
similar

so odd to lay down, and merely do some more intense thinking/reading/pondering, my throat gets more and more sore. And I"m not speaking. (daily run down symptom, not a PEM symptom).

The gut running out of energy, resulting in increased permeability, may be tied to the delayed PEM response we more typically see the day later. I figure the BBB is doing the same thing, more permeable.

Feeling poisoned by substances going drip drip inside our bodies seems to be PEM.

Instead of flu-like, try poisoned.
 

sometexan84

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This is just an idea. And it's quite rough...

But, it would be interesting to see if taking antimicrobial peptides helped w/ PEM. The reason for why this might work is described below.

Again, this idea is pretty rough, and not as organized as I could have made it. But it's basically about PEM being "sickness behavior" from prolonged pro-inflammatory cytokines, possibly exacerbated by bacterial translocation, and changes in gut bacteria. And the damaged cells that fail to fix this.

-----------------------------------------

Post Exertional Malaise (PEM)

  • Sickness Behavior - An adaptive behavioral response aiming to conserve energy and to redirect energy to immune cells to combat the pathogens. Adaptive response to counteract negative energy balance
    • Production of proinflammatory cytokines induces sickness behavior
    • Gastrointestinal symptoms are one the few symptoms seen in ME/CFS, but NOT in sickness behavior
  • PEM shows increases in both pro-inflammatory and anti-inflammatory cytokines post exercise, they remain high
  • Increase in bacteria in blood of ME/CFS post-exercise. High levels of bacteria maintained at 72 hours post-exercise. Altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients
  • IL-17Fduring exercise, increases in controls, but not in ME/CFS
    • IL-17F is produced from Th 17 cells, also innate immune cells and epithelial cells
    • If epithelial cells are infected (as well as the innate immune cells in the lamina propria), IL-17 production may no longer be operational here
    • And If Th17 cells are dysfunctional, then it would explain the lack of IL-17F production. If healthy controls produce IL-17F during exercise, it must be protective.
    • “IL-17A” is sometimes called “IL-17”
    • IL-17F has the ability to produce defensins and other antimicrobial peptides
    • Defensins and microbial peptides might help w/ PEM
    • Defensins are produced by cells of the innate immune system and epithelial cells. Enterovirus infection of epithelial cells and innate immune cells in lamina propria won’t produce microbial peptides like they’re supposed to
  • Th17 - major dysfunction of Th17 cells in ME/CFS patients
    • Th17 cells are a subpopulation of CD4 T lymphocytes
    • Th17 regulates viral or bacterial infections and the microbiota
    • Th17 helps maintain mucosal barriers and with pathogen clearance at mucosal surfaces
    • Also been implicated in autoimmune and inflammatory disorders. The loss of Th17 cell populations at mucosal surfaces has been linked to chronic inflammation and microbial translocation
    • Th17 promotes integrity of mucosal epithelial barriers. And play a role in induction of autoimmune disease
    • This could explain the increased bacterial translocation following exercise, which would explain pro-inflammatory situation, which would explain increased sickness behavior.
    • The Th17 immune response protects hosts from pathogens at epithelial and mucosal tissues including the skin, lung, and intestine
  • If a virus is tropic for intestinal epithelial cells (Enterovirus, SARS), it causes cell damage and loosens the normally impermeable barrier that keeps bacteria in the intestinal lumen