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This blog asks if it’s possible to reduce the PEM period by doing things other than resting. It’s a long blog – you may want to print it out using the print button on the bottom left of the blog.  

Post exertional malaise chronic fatigue Syndrome

Small amounts of exertion (let alone getting on an exercise bike!) typically result in large increases in symptoms.

About 5 years ago, Health Rising did a post on possible post-exertional malaise (PEM) busters. Since then we’ve learned more about PEM, and people have tried more things, so it seemed like time for an update.

For those who don’t know, post-exertional malaise (PEM) is kind of like “it” in chronic fatigue syndrome (ME/CFS). PEM is so prevalent – and unusual – that the term didn’t even exist in the medical lexicon until the ME/CFS community spoke it into existence. PEM refers to a dramatic and unusual exacerbation of symptoms brought on by small amounts of exertion (potentially any kind of exertion, including physical, mental, emotional) that usually peaks a day or two after the exertion has occurred.

We don’t know what causes it, but thanks to some excellent recent work from the Hanson group, in particular – which has been assessing what happens before and after exercise at the molecular level – we’re learning a lot about it. The Hanson group’s recent proteomic and metabolomic findings jive with ME/CFS patients’ experiences: that is, while they found that some abnormalities crop up during the actual exercise session, the really big hit – the really large abnormalities – come after the exercise is over.

Could Core Issues in ME/CFS Be Cropping Up? Report from the IACFS/ME Conference #4

That points a big arrow at the recovery mechanisms that return the body to normality, or homeostasis. It also suggests that, if we want to reduce a PEM hit, while we certainly want to boost our ability to exercise, what we may really want to do is to boost our ability to recover from it.

Exertion – exercise, in particular – comes at a cost. As the muscles lengthen in response to the exercise, microtears are produced that the body must heal and “fill in” afterward. (It’s the filling-in process that creates larger muscles.) Along with the immense amount of energy produced comes greatly increased production of reactive oxygen and other species (free radicals) that the body must find a way to mop up. Many other factors most certainly also come into play. Studies of overtraining syndrome have found that hormones certainly do.

Layman’s Speculations

Uninformed with any real knowledge about what actually happens during the post-exertion period, I nevertheless offer some ideas. 🙂

repair chronic fatigue syndrome

Recent studies suggest that the repair processes that should kick in after exercise aren’t.

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Body doesn’t ramp down – there’s some evidence that the body has trouble turning itself off, thus possibly keeping the healing process from kicking in as quickly as it should and allowing the damage to spread. Perhaps a signal, or signals, that tell the body to come off its exertional state don’t get fully produced, or are not responded to, leaving the body in a kind of jacked up and ultimately exhausted state.

The usual repair mechanisms are simply broken – the repair mechanisms don’t kick in, allowing the inflammation produced as an inevitable result of exercise to feed on itself – producing more and more symptoms until the body finally brings it at least somewhat under control.

An exercise trigger is present – while not as many proteomic and metabolomic abnormalities show up during the exercise period as in the post-exercise period, it’s possible that something produced during the exercise period throws the repair system off balance or overwhelms the healing process. High levels of oxidative stress that start an inflammatory cascade would certainly fit the bill. A South African group recently proposed that a hypoxic situation that results in an ongoing ischemia-reperfusion injury may be present.

The NIH’s Exercise Initiative should tell us much about what’s going on during exercise and allow us eventually to target places where the exertion and repair processes have gone awry. Until then, we’re guessing and probably using hammers, whereas in the future we’ll be using scalpels.

Targeting the Post-Exertional Malaise Period With Treatments

“I think the overall story now is people with PEM should be exploring anti-inflammatory approaches in different ways, especially those agents demonstrated to cross the blood-brain barrier. On the research side, we should be running clinical trials on various anti-inflammatories for PEM, and ME/CFS more broadly.” Jarred Younger

There doesn’t seem to be much of an effort yet to develop treatments that specifically target the post-exertion phase. Right now we mostly have one treatment – rest.

The next part of this blog will use a recent, excellent video on PEM from Dr. Yelman at the Bateman Horne Center as a foundation to review what we know has gone wrong in the post-exercise period, and my speculations on potential treatments that could be initiated or more likely boosted during the PEM phase to reduce it. Your help is requested in coming up with more treatment possibilities.

After that will come reports of PEM reducers that have worked in ME/CFS/FM community – at least for some people – followed by further ideas from outside the ME/CFS/FM community.

The Post-Exertional Malaise Hits in ME/CFS – and the Treatment Targets They Present

Light- exercise - 20111

The most famous graph in ME/CFS history. Check out the huge difference in the metabolic/immune gene expression in the post-exercise period between the healthy controls top and the ME/CFS patients (second from top).

Massive Upregulation in Adrenergic and Metabolic Receptors – Yelman referred to still one of the most startling graphs and studies I’ve ever seen regarding ME/CFS. It concerned the massive upregulation in the gene expression of adrenergic and metabolic receptors that Alan Light found after exercise in ME/CFS in 2011.

The finding suggested that exercise was hitting the two sides of the stress response – the autonomic nervous system and HPA axis – hard, and producing high levels of metabolites associated with muscle injury. Follow-up studies highlighted the role of alpha 2 adrenergic receptors – which affect blood flows through the blood vessels – and a glucocorticoid receptor – which could affect cortisol sensitivity – during the post-exercise period.

(These findings foreshadow what we’re seeing in long COVID – problems with blood flows and cortisol. With regard to cortisol, it appears that the normal cortisol response is also lost in overtraining syndrome as well.)

  • Possible Treatment Approach – boost cortisol, enhance blood vessel functioning via blood volume enhancers, and anticoagulants, change breathing patterns to support the parasympathetic side of the autonomic nervous system, take drugs that normalize ANS functioning such as Mestinon, propanolol etc., when appropriate pre and post-exercise???

Cognitive Issues – Gelman also referred to Dane Cook’s exercise study which showed that, in contrast to healthy controls – who got “smarter” after exercise, ME/CFS patients’ cognitive problems worsened and were accompanied by changes in brain activity not seen in the healthy controls. Gelman suggested that an uptick in microglial activation and neuroinflammation could be causing these problems.

  • Possible Treatment Approach – emphasize knocking down neuroinflammation with increased use of anti-inflammatories including supplements and drugs like etanercept, antioxidants such as intranasal glutathione, turmeric, etc. Try nootropics?

Lactate Accumulations – High levels of lactate (a very unusual finding, Gelman noted) were found in a part of the brain called the anterior cingulate cortex (ACC) in ME/CFS. The ACC has been intimately tied to the sickness response (flu-like symptoms, fatigue, etc.) that the brain produces during an infection. PET scans and ME-spectroscopy studies also suggest neuroinflammation is present in ME/CFS. Plus, BOLD studies suggest reduced blood flows to the brain as well as elevated activity in the prefrontal cortex.

  • Possible Treatment Response – focus on reducing lactate levels with supplements, breathing techniques, stretching, increase blood flows to the brain, knock down neuroinflammation.

Activation of the dorsal midbrain after exercise could be affecting things like attention, mood (ever feel depressed while in a PEM state?), threat (hypervigilance), pain, sensory processing (problems with light, sound, smell), cognition, sleep, autonomic nervous system functioning and others.

  • Treatment Approach – ???

Some other findings not mentioned by Yellman include:

Leaky guts spark inflammation

  • Possible Treatment Approach – increase probiotics, prebiotics, and butyrate enhancers including fermented foods if you can handle them, mop up toxins with charcoal.

An inhibition or even loss of the normal metabolic response to exercise linked with peroxisome and fatty acid metabolism problems

  • Possible Treatment Approach – mitochondrial enhancers (CoQ10, acetyl-carnitine, D-ribose, oxaloacetate, etc., muscle repair supplements and herbs, stay away from long chain fatty acid foods and focus on medium chain fatty acid foods such as MCT oil.

Viral Reactivation – Epstein-Barr virus reactivation has been found in several long COVID studies.

  • Possible Treatment Response – increase antivirals, herbs, and supplements ( Ashwagandha, licorice, St. John’s wort, lemon balm, ginseng, and holy basil, Monolaurin: 1800 mg twice daily; Olive Leaf: 1000-1500 mg twice daily, L-Lysine: 1000-1500 mg twice daily; Cat’s Claw tincture: 30-60 drops twice daily).

Known PEM Busters For ME/CFS

Return to normal

Some people have found things that allowed them to return to normal; i.e. their ME/CFS baseline, more quickly.

Now that all this speculation has occurred, let’s see what the ME/CFS community reports helps to reduce PEM. Note that since we don’t know how to treat it well – Yelman stated there is nothing that definitively speeds up recovery from PEM – the first and best PEM buster is simply to avoid getting into it. Pacing is key. The turtle is the Bateman Horne Center’s mascot. More on avoiding PEM – and whether you’re doing all you can do to keep it to a minimum – later.

Yelman reported two things the Bateman Horne Center has found that can help with PEM in some patients.

Low dose naltrexone (4.5 mg or less) – It’s well known that LDN suppresses microglial activation and that is what the BHC believes is happening.

Low Dose Naltrexone (LDN) Fibromyalgia and Chronic Fatigue Syndrome Resource Center

Dextromethorphan (cough syrup! – standard dose) – Dextromethorphan is an NMDA receptor antagonist that Gelman stated may also assist with the autonomic nervous system. It’s used directly before or right after an exertional event.

Several years ago, Jarred Younger reported that several studies have shown that dextromethorphan affects microglial cells in a different way than LDN does and proposed that it might work for those who didn’t get relief from LDN. Younger warned that taking it at 200 mg or higher could have dissociative and even hallucinogenic effects, and indeed, a 2006 FM study that used over that amount reported positive results in 35% of patients but negative ones in 40%.

Younger’s 15-week 2021 pilot clinical trial used a small dose (10 mg at morning and night) that would not affect central nervous system functioning but which, he hoped, would calm the microglial cells that he believes are causing neuroinflammation in a small study of fibromyalgia patients. General pain and maximal pain were reduced over the entire study period, but analyses indicated this was true only in the first part of the study – bringing up the specter of the placebo effect.

Dr. Bateman and Yelman are finding that it helps. It’s not unusual for a study to fail but for some people to benefit from the treatment that didn’t in the broadest sense hold up.

Tylenol as a PEM Buster – Christyne’s Experience

Tylenol may shorten PEM duration via TRPV1 reducing neuroinflammation from microglia

Priming the pain receptors in fibromyalgia

TRPV1 and ASICs prime the pain receptors for action in a mouse model of FM (Wikimedia Commons: Chen et. al 2014 Molecular Pain)

I watched Dr. Jarred Younger’s video describing inflammation and increased temperature in ME brains, Dr. Jarred Younger Presents: How We Can See ME/CFS Inflammation In the Brain – YouTube . As a result, I had a new experience with post-exertional malaise.

I have had PEM episodes monthly or so for years, and they’ve always lasted 5-10 (miserable) days. So I thought I would try taking a maximum dose of Tylenol (acetaminophen) anytime I had a low-grade fever, especially during PEMs. I was shocked to find my monthly PEMs shortened to 1 to 2 days for the first time in 14 years! and I had much less brain fog.

I wasn’t sure that the fever reduction would account for such a big effect, so I searched for a connection between brain inflammation and Tylenol in the literature. Recently it has been found that rather than impacting COX, acetaminophen impacts TRPV1, and TRPV1 impacts neuroinflammation from the microglia!

Dr. Renz-Polster et, al. describe the impact of neuroinflammation and microglial reactivity in ME/CFS and post-exertional malaise in their recent hypothesis paper, The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. They propose that “PEM may reflect a stress-induced aggravation of CNS inflammation or neuroglial dysfunction”, (in addition to endothelial cell and mitochondrial dysfunction). Dr. Renz-Polster pointed out a paper Differences in Metabolite-Detecting, Adrenergic, and Immune… : Psychosomatic Medicine (lww.com), where TRPV1 mRNA was shown to increase more in ME/CFS patients than in controls after an exercise challenge.

That suggested that trying to reduce inflammation could be helpful. In a note to me, Dr. Younger agreed, stating:

“I think the overall story now is people with PEM should be exploring anti-inflammatory approaches in different ways, especially those agents demonstrated to cross the blood-brain barrier. On the research side, we should be running clinical trials on various anti-inflammatories for PEM, and ME/CFS more broadly.”

That provided some possible scientific justification for my experiences with Tylenol preventing and/or shortening the duration of my PEM. The question is, have other people used Tylenol for pain relief, unknowingly preventing or shortening PEMs?

Because PEMs happen the next day or more after exertion, it can be tricky recognizing cause and effect. I wonder, though, if others have found that Tylenol prevents or shortens PEMs in their experience. At the moment, I’m a sample of 1.

Now, I monitor my temperature and take Tylenol for a fever over 99F, which happens about every other day. If I plan to do something that I know is over my exertion threshold, I take a maximum dose beforehand and a maximum dose after. I follow the dosing limits, spacing them out over the recommended times on the bottle because Tylenol can be dangerous for your liver if you take too much. If I develop a fever after these doses, I’ll take another at the appropriate time.

I had a really long doctor’s appointment (3 hours in their office), that would normally put me into a bad PEM. But with the Tylenol, I didn’t get one at all! I was just a little more tired for a day, but no tachycardias, brain fog, memory loss, difficulty speaking, staggering, full body pain, diarrhea, etc.

I was so relieved! I have been able to stay upright longer than my typical 15 minutes per 1 ½ hours since I started this approach. But, of course, I got excited and pushed it by staying upright after my back and neck were getting tired. I managed to trigger a post-exertional malaise.

So I started Tylenol as soon as it started, and the tachycardia and brain symptoms only lasted a half day! Again, so relieved! Only a day in bed instead of a week. Now I’m being more careful with increasing my upright time, but it is increasing. I can’t walk very far, but my walking distance has doubled so far, with Tylenol. I haven’t had any PEMs since.

I will continue taking the Tylenol when I need it, but I have also started Mestinon (pyridostigmine) after hearing Dr. Systrom’s talk about its use for preventing PEMs to the point that patients can tolerate reclined graded exercise therapy.

My rheumatologist agreed to try it with me when I brought him Dr. Systrom’s recent paper on Mestinon. Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine – PubMed (nih.gov). I hope the two treatments together are going to make a big difference for me. This is the first time in a long time that I have some real hope for improving this disease.

Reducing Lactate Accumulations After Exertion

“Hip” came up with the following protocol he devised after assessing athletic performance studies:

    • Creatine hydrochloride (2 grams) This study shows that the supplement creatine reduces blood levels of lactate from exercise. And this study found creatine increases muscle recovery after injury.
    • Citrulline (1000 mg) – This study found citrulline reduces lactate levels produced by exercise.
    • Branched-chain amino acids (BCAA) (5 grams) – This study found that BCAA reduces lactate levels produced by exercise (and this study found that by inhibiting the L-system transporter, BCAA suppressed the uptake of tryptophan, thereby alleviating fatigue).
  • CoQ10 (800 mg) – This study found that co-enzyme Q10 reduces lactate levels produced by exercise (in myotonic dystrophy). And this study found Q10 improves muscle endurance. Hip finds taking 500 mg before an activity really helps.
  • Sodium bicarbonate (¼ teaspoon (1.5 grams)) – This study suggests that sodium bicarbonate (bicarbonate of soda) can help neutralize lactate circulating in the blood.
  • Catalase – 600 mg (taken after exercise)
  • D-ribose – (5 grams three times daily) – One person reported: I gave the d ribose a go and I am now on 10-30g a day. This seemed to drop the severity of the episodes for me. Before taking it I would be laid up for around 3 – 4 days. Now it’s 12 – 24 hrs recovery time when I overdo it.
Ativan for relief in ME/CFS

Some people find that short-term use of Ativan can get them through difficult situations

Ativan (Lorazepam)

Some people find that short-term use of Ativan can work wonders when they need to get through a difficult situation. Ativan is a benzodiazepine-based sedative-hypnotic that one book stated has a “relatively clean side effect profile”. Primarily used to treat anxiety it calms the central nervous system down by enhancing GABA activity.  Dr. Paul Cheney once famously said something to the effect that if he could just put ME/CFS patients in a coma state to calm their central nervous systems down he thought that would work wonders. That’s what Ativan appears to do – for short periods of time. (It can only be taken for short periods of time.)

Mental Exertion

  • Prednisone – at a dose of 20 mg or so taken 4 hours before the event. Some ME/CFS patients have vouched this works very effectively and reliably (though others report ill effects from this corticosteroid drug). See this thread. But also see the warning in this post (which cautions against using prednisone for any extended period of time, and warns that the PEM protective effects do not work for the whole day, they seem to wear off after about 6 to 8 hours).

Brendan’s PEM Buster

Brendan says the below regime drastically reduces his chances of getting PEM. He takes this combination only within a 48 hour window of exertion.

      • Anti-inflammatories taken before and after exertion plus an antihistamine, and curcumin (taken together and repeated every 4 hours for a day or two).
      • Also a teaspoon of baking soda in a glass of water morning and night.

Note: he recommends the anti-inflammatory always be taken with food.

Breathing Better

Breathing techniques for chronic fatigue syndrome

Calming breathing techniques can also help.

We also have evidence that the breathing is off during exercise, and generally, and that people with ME/CFS are bringing in too much air either by hyperventilating or breathing too deeply. That reduces CO2 levels which, in turn, can constrict the blood vessels, thus impairing blood flows to the brain and muscles, as well as other things.

  • Possible treatment approaches – Better breathing patterns during and after exertion to bring up CO2 levels and increase blood flows to the tissues and brain; practice nose-breathing, watch breath holding, emphasize exhalations, try Buteyko breathing, Wim Hoff, ???

Blood Volume Enhancement 

Making extra efforts to increase blood volume before and after exercise makes sense given the low blood volume found in ME/CFS. Several people reported in the last survey that enhancing blood volume, whether by adding salt, drinking electrolyte drinks, or increasing water intake, helped with their PEM. Check out one person who improved her ability to exercise by using saline IVs.

Enhancing Blood Volume in Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia

 

Stretching 

Stretching has helped me recently in the PEM period, and I have a blog on this coming up. Because stretching increases blood flows to the muscles, reduces lactic acid, and relieves painful, contracted muscles, stretching during the PEM period, in particular, seems like a no-brainer for most of us. Several people reported in reply to the last blog that stretching/yoga was helpful.

Other reports from the ME/CFS/FM community

Other PEM inhibitors reported in the last blog:

  • Mitochondrial supplementation – pre-dosing with NAC, AMP, NADH and B Complex and glutathione intramuscular (self) injection, and creatine, D-Ribose, acetyl-l-carnitine and COQ10 as oral supplements.
  • Staying calm.
  • Oxygen therapy.

Other Ideas From Outside the ME/CFS Community

Enhancing Muscle Repair

How about enhancing muscle repair? Various websites tout supplements and herbs, often different supplements, as a way to increase muscle repair – in healthy people. ME/CFS patients are, of course, a different bag, but people with ME/CFS have found that some of these can help.

Frogfuel suggests

      • Tumeric to reduce inflammation.
      • Tart cherry extract to reduce inflammation and uric acid buildup.
      • Medium-chain triglycerides (MCT) fatty acids to reduce lactic acid buildup.
      • Collagen peptides to construct new connective tissues.

Muscle and Fitness suggests

      • Creatinine monohydrate to boost ATP production in the muscles and help them regenerate.
      • Whey protein powder “to provide the basic building blocks needed to repair and rebuild damaged muscle mass.”
      • Branched-chain amino acids (BCAAs) that are “important for muscle growth and recovery because they help reduce exercise-induced muscle damage.”
      • Formula XI, which contains creatine monohydrate, beta-alanine, betaine, L-Ornithine, D-Ribose.

Rootbabes.com recommends these herbs:

      • Tumeric – to fight inflammation.
      • Green tea – helps to process carbs and may be able to increase muscle mass. Possible Rapamycin analogue.
      • Ashwaganda – may be able to increase oxygen consumption and build muscle mass and strength.
      • Boswellia – is used in Ayurvedic medicine to increase blood flows to the connective tissues.
      • Eleuthero (Siberian ginseng) – may increase oxygen uptake and decrease lactic acid.
      • MACA – muscle-building properties.
      • Rhodiola – increased endurance.
      • American Ginseng – improve oxygen uptake, reduce lactic acid, reduce inflammation.

Cold Immersion

Wim Hoff has made putting yourself in cold, sometimes very cold, temperature a hot … err … topic. Brief periods of cold immersion, whether in the shower, the bath (ice baths!), in a cryotherapy chamber, or by plunging into the nearest freezing body of water, is often combined with breath training, meditation, and yoga to increase blood flows, improve oxygenation, kick in the parasympathetic nervous system and produce, believe it or not, a calming effect. One small fibromyalgia cryotherapy study found that it improved quality of life.

Andrew Huberman Ph.d. reported that A meta-analysis of cold-water immersion effects on recovery after exercise found that it “can be a highly effective recovery tool” and recommends that it be done 6-8 hours after exertion.

Question

What have you found helped during the post-exercise period to get that nasty period of PEM over with as quickly as possible? Please let us know in the comments.

Did the blog spark any new ideas? If so, please support Health Rising and keep the information coming.

 

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