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The GIST is in a bit different place…Scroll a bit down, and you will find it. 🙂
Another pulmonologist with an invasive testing machine (David Systrom was the first) enters the fray 🙂
There are a couple of reasons to celebrate seeing Inderjit Singh pump out long COVID studies: he’s a well-published Yale pulmonologist with an invasive exercise machine to play with. A leader in the invasive exercise field, Singh recently published an article, “The casting of invasive cardiopulmonary exercise testing: towards a common goal,” which, among other things, calls for increased use of iCPET to understand exercise intolerance.
Invasive exercise studies are so revealing because their ability to assess both arterial (oxygen rich blood coming from the heart) and venous (depleted blood after it has passed through the muscles) blood means they can tells what happened to the blood as it goes through the muscles during exercise. They can tell us if the muscles picking up sufficient amounts of oxygen or if blood is being lost during transit or is pumped out of the heart in sufficient amounts. Problems with all of these processes have been found in ME/CFS and long COVID.
In 2022, Singh teamed up with David Systrom, Aaron Waxman and others to show that the reduction in energy production found during exercise in long COVID was not due to heart issues but to “peripheral issues” such as blood flows and possible mitochondrial disruption and featured a hyperventilatory breathing pattern.
The gist is that people with ME/CFS and long COVID may be hyperventilating, i.e., breathing more rapid and deeper during exercise than normal in an attempt to get more oxygen into their muscles, and/or they might have autonomic nervous system problems.
The Gist
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Another pulmonologist with an invasive testing machine (David Systrom was the first) enters the fray 🙂
It’s great to see Yale researcher Inderjit Singh with his invasive exercise machine work in the long COVID field.
- The ability of invasive exercise studies to assess both arterial (oxygen rich blood coming from the heart) and venous (depleted blood after it has passed through the muscles) blood means they can tells what happened to the blood as it goes through the muscles during exercise.
- This is the first invasive exercise study to use metabolomics (the study of metabolism) in an invasive exercise study. Because metabolites power the Krebs cycle – which provides essential factors to the electron transport chain (which produces ATP) – a breakdown in metabolism could be behind the reduced energy production found in these diseases.
- The cardiovascular findings were as expected. They found that the muscles of long COVID patients were not getting normal amounts of oxygen (read energy). Because the muscles were not using up oxygen, the levels of oxygen found in the blood after it passed through the muscles was almost ten times higher than that normally found.
- Peak energy production was reduced and the long COVID patients began to rely on anaerobic energy production at an exercise level comparable to having to walk upstairs – far earlier than in healthy people. The pattern found suggested that mitochondrial problems were to blame.
- A “net extraction” of nine amino acids from the bloodstream suggested that the muscles of the long COVID patients had become depleted and were turning to the bloodstream to capture amino acids.
- A large increase in the consumption of purine inosine suggested, once again, that long COVID patients relied more on anaerobic metabolisms and suggested that it’s breakdown products were interfering with the mitochondria.
- A major takeaway from the study was its finding that both the aerobic and anaerobic energy production pathways in long COVID had been blunted.
- High levels of succinate suggested that a slowdown of the Krebs cycle might be causing succinate to accumulate in the mitochondria and subsequently get released into the bloodstream.
- The authors proposed that purine metabolism may serve as a potential novel treatment target but didn’t mention specific treatments.
- Asking several AI engines which purine inhibitors might be helpful in diseases with exercise intolerance/postexertional malaise uncovered a wide variety of drugs which might be helpful most of which I’d never heard of…Interestingly, the AI engines specifically mentioned ME/CFS, fibromyalgia and long COVID as diseases that might benefit from these drugs. See the blog for those drugs.
- Suramin – a drug which Dr. Naviaux has championed with regard to ME/CFS – was not among them because it’s a different kind of purine inhibitor. Suramin doesn’t block purine metabolism but blocks purine receptors from activating.
In 2023, in “Post-Acute Sequelae of SARS-CoV-2: More Than Deconditioning,” Singh and another Yale researcher put the brakes on the idea that long COVID was nothing more than deconditioning. Again, in 2023, Singh co-authored a paper comparing the exercise physiology of ME/CFS with long COVID.
Then, in November 2024, Singh’s invasive exercise study, “The metabolic and physiologic impairments underlying long COVID associated exercise intolerance,” employed metabolomics for the first time. Now Singh focuses on metabolism—a critical component of energy production. A lot of focus is on the mitochondria, but without metabolism, the mitochondria don’t have the resources they need to produce ATP.
Metabolic Slant
Before we get to the mitochondria, a long chain of metabolic events has to happen for the mitochondria to function properly. First, carbohydrates, fats, and proteins are metabolized or broken down into glucose, fatty acids, and amino acids, which are then broken down to produce ATP.
We often think of the mitochondria as the electron transport chain where ATP is produced, but it’s the Krebs or citric acid cycle that provides the electron donors the electron transport chain needs to produce ATP. Glucose, fatty acids, and amino acids feed the Krebs cycle, which takes place both in the cell’s cytosol and the mitochondria.
This problem with energy production in ME/CFS and long COVID could be due to metabolic problems that prevent the proper “feeding” of the Krebs cycle. A wonky Krebs cycle would not provide enough electron donors (FADH2, NADH) to the electron transport chain to produce the ATP needed for people with ME/CFS or long COVID to successfully in exercise.
Study Results
Cardiovascular Findings
Not enough oxygen being used by the muscles resulted in higher than normal levels of oxygen in the venous blood leading from the muscles.
Oxygen-Poor Muscles – Once again, we see a reduction in peak VO2 (peak energy production) caused by reduced peak EO2 or peak oxygen consumption; i.e., the mitochondria in the muscles were simply not using up enough oxygen. This is the oxygen extraction problem” that Systrom’s invasive exercise studies have found.
Oxygen-Rich Venous Blood – The reduced oxygen extraction in the muscles showed up as unusually high levels of oxygen in the venous blood. While this study did not have a healthy control group, the levels of oxygen found in the venous blood of the long COVID patients was almost ten times higher (26.5 ± 3.6%) than that normally found in healthy people.
When their peak VO2 plateaued, the muscles of the long COVID patients ran out of oxygen and started relying more on the less effective anaerobic energy production system to provide energy. The authors calculated that this turn to anaerobic energy production probably occurred at an exercise level comparable to having to walk upstairs. The pattern suggested that mitochondrial problems were to blame.
Metabolic Breakdown
Amino acids are usually pulled from the muscles. In the long COVID patients they were pulled from the blood stream as well – suggesting that the muscles have become exhausted.
Muscle Breakdown – The authors simply stated that a “net extraction” of nine amino acids was found and left it at that. A “net extraction” refers to more amino acids being taken from the bloodstream than released into it. Because amino acids are first taken from the muscles during exercise the net extraction suggested that the muscles of the long COVID patients had turned to the bloodstream in an attempt to renew themselves. If I’m reading it right, though, this finding appears to jive with another key finding in ME/CFS – that amino acids are being preferentially used in these diseases to feed the Krebs cycle.
Anaerobic Metabolism Emphasized—A global metabolic analysis indicating a large increase in the consumption of purine inosine suggested, once again, that long COVID patients relied more on anaerobic metabolism. Inosine is produced when ATP is rapidly broken down. The high consumption of inosine suggested that long COVID patients’ energy production systems maxed out early in the exercise session.
Inosine is catabolized ultimately into purines such as hypoxanthine and uric acid – suggesting that high hypoxanthine levels which have been associated with mitochondrial problems and reduced ATP levels – might be present.
Double Energy Hit – A major takeaway from the study was its finding that both the aerobic and anaerobic energy production pathways in long COVID had been blunted. The authors proposed that the findings “have important implications towards the development of potential pharmacotherapeutic interventions directed towards mitigating early reliance of anaerobic metabolism, which may include shifting, restoring, and/or enhancing mitochondrial oxidative phosphorylation capacity during exercise.
Succinate Sticks Out – A dramatic correlation between succinate in the venous blood and peak energy production was found (VO2 (r = 0.68; p= 0.0008). The authors suggested this could reflect post‐exercise glucose tolerance problems.
Succinate shows up! Look directly up to see where succinate enters the citric acid/Krebs cycle. (Image from Narayanese-Yassine, Mrabet_TotoBaggins; CC 3.0, Wikimedia Commons)
A familiar scenario may be playing out as well. While succinate can enhance ATP production in the electron transport chain, it also plays a role in the Krebs cycle. In hypoxic or low-oxygen conditions—the conditions this study suggests exist in the muscles during exercise—a slowdown of the Krebs cycle could cause succinate to accumulate in the mitochondria and subsequently get released into the bloodstream.
Itaconate Shunt Connection ????
The authors didn’t mention it, but the itaconate shunt inhibits succinate dehydrogenase (SDH), which breaks down succinate – resulting in increased succinate levels.
The two succinate elevations occur in different contexts: one results from metabolic activity during exercise, while the other results from inflammation. Could inflammation produced by exercise be propping up the succinate levels in ME/CFS patients and contributing to an itaconate shunt? I have no idea. 🙂
Purine Findings Suggest Treatment Options
In the end, the authors proposed that purine metabolism may serve as a potential novel treatment target but didn’t mention specific treatments.
High levels of ATP breakdown can have many consequences (Image from Jynto, CC0, via Wikimedia Commons)
The situation is complex given purines’ role in many processes and the variety of purine inhibitors found. However, purine inhibitors might be able to help situations where exercise intolerance is present and in conditions in which high levels of ATP are broken down. High ATP breakdown occurs when high levels of metabolic stress are present, causing the cell to break down more ATP than it synthesizes and can cause numerous problems.
Under these conditions, the muscle’s ability to relax and produce force is impaired. (Bob Naviaux, some time ago, stated that the low-energy state found in ME/CFS results in contracted, tense muscles.) Increased lactate and H⁺ ion production can cause intracellular acidosis. A predilection for protein misfolding can result in protein aggregations that gum up the works. All in all, high levels of ATP breakdown – which appeared to be happening in these long COVID patients – result in muscle fatigue, cellular stress, and metabolic imbalances.
We also might want to inhibit high levels of purine production because it can produce metabolites such as inosine and hypoxanthine that can be broken down into uric acid. Uric acid—which some ME/CFS/Long COVID doctors test for—enhances oxidative stress (the last thing anyone with these diseases wants more of) and muscle fatigue.
Purine Inhibitors
I asked ChatGPT AI and Perplexity AI about purine inhibitors and individuals with exercise intolerance or post-exertional malaise. ChatGPT AI suggested that the same kinds of purine inhibitors might be helpful for either condition.
Even though ME/CFS, fibromyalgia, and post-infectious diseases were the most commonly recommended diseases, I had not heard of most of these used to treat these disorders. All the drugs came with some cautions – but most seemed manageable.
Xanthine Oxidase Inhibitors (XOIs)
- Would work best in individuals with mitochondrial dysfunction or metabolic fatigue by reducing oxidative stress and improving energy efficiency
| Drug | How It Helps? | Who Might Benefit? |
|---|---|---|
| Allopurinol | Lowers uric acid and oxidative stress, improves nitric oxide bioavailability for better muscle oxygenation and endurance. | Individuals with mitochondrial dysfunction, chronic fatigue syndrome (CFS), fibromyalgia, or exercise-induced oxidative stress. |
| Febuxostat | Selectively blocks xanthine oxidase, reducing oxidative stress and ATP depletion without affecting other metabolic pathways. |
Purine Synthesis Inhibitors
- Best for people who need to manage chronic inflammation and immune overactivation, which can impair recovery and energy metabolism.
| Drug | How It Helps? | Who Might Benefit? |
|---|---|---|
| Methotrexate (low dose) | Reduces chronic inflammation and autoimmune responses that contribute to exercise intolerance. | Individuals with autoimmune disorders (RA, lupus, inflammatory myopathies) that impair exercise capacity. |
| Azathioprine | Suppresses excessive immune activation, preventing muscle and joint inflammation that limits exercise. | People with chronic fatigue, muscle inflammation, or post-viral syndromes (e.g., |
3. Adenosine Deaminase (ADA) Inhibitors
🔹 Best for: Boosting adenosine levels to enhance blood flow, ATP conservation, and reduce metabolic stress.
| Drug | How It Helps? | Who Might Benefit? |
|---|---|---|
| Pentostatin | Increases adenosine levels, leading to better vasodilation, oxygen delivery, and mitochondrial function. | Individuals with poor circulation, endothelial dysfunction, or metabolic fatigue (e.g., chronic fatigue syndrome, fibromyalgia, or long COVID). |
4. Purine Analog Nucleosides
🔹 Best for: Supporting mitochondrial function, ATP balance, and muscle recovery.
| Drug | How It Helps? | Who Might Benefit? |
|---|---|---|
| Ribavirin (purine analog) | Helps maintain nucleotide balance, preventing excessive ATP depletion. | Individuals with chronic fatigue, mitochondrial disorders, or viral-induced exercise intolerance. |
| Cladribine | Influences nucleotide turnover, possibly reducing exercise-related muscle degradation. | Endurance athletes or individuals with persistent muscle damage. |
Suramin?
Suramin (Image from Lanulos, Public domain, via Wikimedia Commons)
What about Suramin – the drug that Bob Naviaux has specifically targeted for ME/CFS and other post-infectious diseases?
Suramin is a different kind of purine-inhibitor. Instead of blocking purine metabolism, Suramin blocks purine receptors (P2X and P2Y) from signaling when signs of metabolic breakdown, such as ATP and ADP, are present. Bob Naviaux, if I remember correctly, believes that signals of metabolic stress, such as ATP and ADP, are causing the cells of ME/CFS patients to hunker down and exist in a low-energy state.
Suramin can also reduce the high levels of ATP breakdown (see above) found in ME/CFS, fibromyalgia, and long COVID-19. Overall, Suramin may be able to reduce high levels of ATP breakdown, improve energy efficiency, reduce inflammation, and protect neurons.
Great article Cort!!
What ever happened to Suramin? I vaguely remember the pharmaceutical company who manufactured it for African sleeping sickness, had purity issues. yet the WHO allowed it to be used in emergency situations for disease in Africa because the disease was worse than any side-effects from impurities. So it wasn’t pure enough to be allowed into clinical trials. Is that correct? And if so, surely they must have improved the purity by now?
I wonder if Bob Naviaux ever got a pure supply of it? or, if not did that hold up his studies? Because I remember he was wanting to use Suramin years ago in ME/CFS after a successful Autism trial.
An important point that people might not be aware of, is there is an overlap of multiple symptoms between autism and ME/CFS. (16 symptoms last time I looked) It’s almost like a ME/CFS type of illness is what triggered infant autism.
Imagine severe brain fog as an infant. It would be very difficult to form neuro pathways during that crucial developmental stage. Communication would be very difficult. Maybe the kids grow out of the ME/CFS stage so don’t display ‘Post Exertional Malaise’, but by then the damage is done to the brain due to the lost opportunity for early neural development.
And interestingly a percentage of autistic children do go onto develop ME/CFS as teenagers.
Also there is a higher number of autistic children (compared to the same number of healthy children) who developed long Covid. And psychiatrists in the UK wrongly assumed it was (yet again) behavioural, without realising there was already an overlap between ME/CFS and some forms of autism.
I asked him a couple of months ago I think it was about the trial – and did not get a response. I thought the trial was getting close when the pandemic started – and I wonder if it got thrown off. I don’t know what its status is right now.
Paxmedica.com is pursuing mfg of Suramin in USA, first for African Sleeping sickness that is quite rare, then perhaps later for ME/cfs, Autism etc. https://www.linkedin.com/company/paxmedica/posts/?feedView=all
I asked about this and it turns out it is a scam. As Intranasal suramin is not absorbed.
Plus the website has been taken down. with 404 alerts
I know you meant well as I initially believed it too
Fingers crossed. This somehow sounds right: mechanism for the damage and possible treatments.
The measurements from exercise are all/mostly known results – and make sense with the lived experience of the diseases.
Without starting from zero.
I’m concerned about seeing a reliance on information from AI from a science-based publication. As we are all no doubt aware, generative AI is not intelligent. It’s simply a very fancy averaging machine. It can often return accurate information, but it can also very easily return inaccurate information and there will be no way to tell the difference. I am unsurprised to see laypeople asking AI for medical information, though I always warn them when I see them doing so. But for a scientifically minded organization to be depending on AI—and then *publishing* that AI-derived “information”—is incredibly worrying to me, and makes me trust the rest of the information I see here less. I hope you will address this in the future, because I and many others in the ME/CFS and Long Covid communities depend on your information! Which is why I hope you will ensure it is reliable moving forward by removing AI from your process or at the least having a verification process (with reliable, human-made information) for anything you get from AI. Please understand I mean this with all respect, this publication has been one of my primary sources of information since not long after I got Long Covid, and I hold you in the highest respect. That’s why this caught me so off guard.
Thanks JS for your nice words! I appreciate them.
This is quite an issue because I am finding AI VERY helpful. I really am.
I’m mostly using Pro Perplexity AI which provides citations and the questions I’m asking tend to be very technical as well. I would find it hard to drop it now.
For instance – a question “what does it mean when a net extraction of amino acids is seen during an exercise test?” brought up an answer which derived from dozens of published papers, a couple of books and two websites.
A question “what do high succinate levels during an invasive exercise test indicate?” used 28 scientific journals and one UCLA website.
A question “Could high succinate levels found during an invasive exercise study contribute to an itaconate shunt?” told me that it’s possible but no direct link has been established in the literature. That answer came from an assessment of over 20 published papers plus Health Rising. (I didn’t particularly like seeing Health Rising in there actually.)
I do sometimes see general websites including Health Rising and MEAction show up but the questions I
ask has Perplexity turn almost entirely to scientific papers.
The list of purine inhibiting drugs from ChatGPT Plus. That’s bit of an anomaly as I’ve mostly moved over to Perplexity AI Pro in part because it gives citations.
If you have any suggestions how I can make the best use of AI without compromising the integrity of the information please let me know either here or via email. One thing I can promise is to use AI generated information that’s derive from scientific papers – or a few select websites.
Thanks!
I feel a lot better about it knowing there are citations (and I’m assuming you’re checking those citations to make sure they’re actually saying what the AI summary says they’re saying). The most important thing with AI is verifying, so as long as you’re using those citations to confirm the info you’re being given, I feel much better about the information quality. Thanks again for the great work you’re doing!
Please, please check the references to verify that they actually support what AI is saying. AI does not always correctly synthesize or summarize information; it’s just really good at wording things in a way that it sounds like it knows what it’s talking about. Thanks for being upfront about what information is from AI so we can do our own research, but I also saw that and thought, “Oh! I had kind of hoped this was a responsible organization with accurate information.” I only recently signed up for the mailing list and, after reading an AI summary with no indication of medical review or oversight, lost some faith in the articles. (Again, though, being upfront about it is much better than posting potentially inaccurate information without any kind of disclaimer.)
Based on what you said, there may be too many websites to check, but a quick search to find medical articles related to the specific topic/assertion that was produced could help verify it, or if the AI makes it clear which references support specific assertions, you could click on those to confirm.
Are those links checked out? AI tools often make up credible sounding links that lead to a death end or link to existing papers that have completly different content then what the AI claims it has.
Even With citations you have to be careful cort. Watched a piece on this very issue where the citations either didn’t exist ir were fac smilies of ball park similar ideas.
Literally non of the citations but one were correct.
So better to double down in ang citations at this point
From the little I have read about AI, there are many incidents of confabulation — for example, journal articles and legal briefs written with AI turn out to list and analyze totally fictitious references.
So please, please don’t rely upon AI-generated references without reading the purported reference and ascertaining that it actually does exist and does say what the AI summary claims. Recently I found the Google AI confidently asserted that a study had found exactly the opposite of what it claimed. Fortunately, the subject was simple enough that I could recognize that error. But much of the research you discuss is pretty technical, so it would be difficult for us to verify on our own.
Thanks for all that you do, Cort!
Thanks for the warning. While I can’t read all the references (sometimes dozens of them) I can certainly check out the major ones. Here’s a video of a guy who’s using Perplexity AI for research.
https://www.bing.com/videos/riverview/relatedvideo?&q=using+perplexity+ai+for+research&&mid=0C27972F8D3068CC73D80C27972F8D3068CC73D8&&FORM=VRDGAR
Thanks for your reply, Cort.
I like Jim Young’s suggestion about sharing the Perplexity link. That way we can choose to check out the references and rabbit hole, if it seems necessary for our situation. 😊
I’ve been using Perplexity Pro, especially in research mode, and it’s been a game-changer for me. It’s like having a super-smart assistant that can answer our questions without me having to spend hours digging through research papers and all that jazz. The mental energy it saves is priceless! Plus, it helps to avoid those endless rabbit holes that can be so draining.
It really is remarkable! Being able to get a quick answer to technical questions that could have taken me hours otherwise is really something :).
Hello Cort, which of these medications would you most recommend for MECFs triggered by Covid? I’m severely affected myself and am wondering whether I should try one of these medications?
Perplexity Pro used in research mode is an energy saving super assistant, it gets to the essence of a question and saves hours of work. It keeps you out of the rabbit holes which is a huge waste of mental energy.
If people are concerned you could provide the link to your query on Perplexity and others can see what you’re looking at.
Long may your excellent mind last, Cort! I know how you are always looking for ways to help us, and am glad you have learned to use AI for its possibilities in assistance in too. Good hunting!
Thanks! 🙂
All well and good. How do I treat/try for my wife in the Akron Ohio with these novel pharmaceutical treatments?
Her gp is not up to date with your research. Two year long Covid. Nothing works.
Thank you
Joe juska
joejuska@gmail.com
Following, I have a similar question. The science is moving forward, but what do we, as patients, do to try to apply this?
Following as well…🤞🏼
Great Cort, thanks.
I remember your 2022 article, “A Gas Exchange Disease?” (https://www.healthrising.org/blog/2022/06/25/chronic-fatigue-syndrome-gas-exchange-disease/), and it came to mind recently.
A friend’s husband was admitted to the hospital in Feb. 2024 and diagnosed with elevated oxidant output (metabolic alkalosis). His PO₂ was 81.9 mmHg and SO₂ was 97.2% — but the test was reported as a venous blood sample. Whether it was venous or arterial wasn’t clarified, but if it was venous, those readings might indicate an issue with oxygen utilization at the tissue level.
He was prescribed allopurinol for hyperuricemia, but the treatment had an overall negative effect, likely due to his underlying Von Willebrand Factor issue (VWF 8 / Hemophilia A).
In my own case, I initially had a positive experience with methotrexate in 2022— I noticed improved muscle function and significant relief from lupus symptoms, to the point I thought it might be a breakthrough. However, after three weeks of using metex® PEN 17.5 mg once per week, I had to stop due to serious side effects: excessive bleeding (blood in both stool and urine), likely related to VWF types 2 and 5, and Antiphospholipid Syndrome (APS), along with sudden and excessive hair loss.
Based on this, I strongly recommend that patients ask for a VWF test before accepting certain medications, especially those with bleeding or thrombosis risk profiles.
I totally agree with the metabolic derangement theory Cort. I also think that there is a genetic component where our bodies compensate for years untill a high metabolic demand( infection, stress, trauma, inflammation, toxin) break this ability to compensate. I have recently discovered that I have a mutation in a gene causing PDH ( pyruvate dehydrogenase) deficiency. This would explain the inability to feed the Krebs cycle, the build up of lactic acid, the low oxygen extraction ( if the Krebs cycle is not functioning as it should) it would also explain the exercise intolerance, the immune disregulation due to perhaps lactic acidosis, the autonomic nervous system malfunction etc. If our bodies run on glycolysis we will produce only 2 net ATP instead of 36 from cell respiration. If pyruvate is not feeding the Krebs cycle then amino acids and fatty acids would need to fuel it. I do also have another genetic mutation which leads to reduced beta oxidation of fatty acids so for me it’s the amino acids that are left. Or at least this is my theory. For others it could be high insulin. If the insulin is elevated then the body is unable to use fats for energy so again it’s the amino acids that remain as fuel. My recent blood tests show elevated uric acid but I also see alot of this in a Facebook group about insulin resistance. I don’t still know how to overcome this block. I am still reading and researching. Sadly the increase in lactic and uric acid carry damaging effect for our vascular health. I now have small vessel damage which I don’t know how to repair. The issue with my theory is that these genetic mutations are very rare where ME/CFS is not. Do you have an idea when the biggest UK genetic study is due to report?
Hi Cort, thank you!
Your write: “The two succinate elevations occur in different contexts: one results from metabolic activity during exercise, while the other results from inflammation. Could inflammation produced by exercise be propping up the succinate levels in ME/CFS patients and contributing to an itaconate shunt? I have no idea. 🙂”
Yours is a good question – and we´d be closer to answering it if CPET measurements would be repeated in the subsequent PEM phase as the latter certainly has a different pathobiological underpinning as the trial phase. Don´t get me wrong: of course studying the immediate reaction to exercise is of great interest and value – but so is what happens in the body thereafter when it transitions into this highly specific clinical state of PEM.
Looking at 99.9 percent of ME/CFS research I sometimes wonder: is there a kind of phobia among researchers to collect data from patients during PEM? We´d be far better off in our understanding of ME/CFS if we had more comparative work on what the hell is different in these bodies when they are in their normal baseline – and when they are in the hell of PEM.
Great comment! I’ve wondered the same thing: why aren’t measurements being done in those later days, after the trial is over and patients are in full-blown PEM? I know my body is in a very strange state during PEM, very hard to describe, and then it dissipates on its own over the course of some days (or weeks) of rest.
Agreed. In my experience it’s during the PEM phase that my symptoms really go kablooey – not during the exertion itself.
Cort-keep using AI please. This was a solid article with a good addition about possible medications.. My son just used ChatGPT to review his mother’s medications. She had just seen a cardiologist who was not her own because she was in a very complicated medical crisis. ChatGPT said the medication this doctor had just prescribed was contraindicated (as it doubled a heart medication she was already on) plus some other issues. The pharmacy had filled the prescription. This gave him confidence to contact her own cardiologist’s office on an emergency basis. He was perfectly aware that AI could be wrong but in this instance it was spot on.
Wow…This is a nice example – your son used AI and then checked with a doctor to see if it made sense.
I don’t see any way to turn away from AI – and I will use the AI engines that focus on academic papers. When treatment options show up I’ll identify when they are AI generated.
Hi Cort, Good blog. What you write gets to the core of our problem in the most objective way. I would like to note that the medication you mention such as Methotrexate and Azathioprine can have serious side effects and are not ideal. I know this from the experience of some people in my environment who have tried this. Even a low dose gave adverse effects such as becoming hypersensitive to infections.
That is the question..what did happen to suramin? It was my great hope and this is like 10 year old ideas….breaks my heart we just retread old groubd without truly establishing whether these things work
Yes…over the many decades I’ve been ill, I’ve witnessed different researchers thinking they are doing research that they think is new but if they would look back,they would see many of the research has already been gone through….big waste of sick peoples valuable time.
While many of us have nothing but time,we’d love to get on with our lives…what little bit we have left in many cases
I totally agree. I’m starting to think some of these findings are too radical for the stars quo because they’re literally showing its the environment that’s raking people out. Or rather big money toxins
It makes no sense to me that after naviaux completed the stage 2 surMin trial which was successful, that he just left it.
Similarly, the university of Bristol ( I think) had a professor trialling this similar purine therapies fir b.p. meds.
Then he and his work just disappeared
Bob naviaux, I belueve is working for nasa now. I’m hoping that the similar issues astronauts face with mitochondria etc that he gets backing and can extrapolate any therapies out to the general public maybe ggsts hus plan?
What I dont understand is layman like you and I have managed to dial in on these therapies years ago and have been urging scientists to look at these ideas
Then nea scientists show up thinking they’ve found the holy tail.
Don’t grt me wrong, I’m appreciative but also flabbergasted by the inertia
So… does this make hyperbaric oxygen therapy a good or bad idea?
“This is the first invasive exercise study to use metabolomics (the study of metabolism) in an invasive exercise study.” – Wasn’t Maureen Hanson first with the urine metabolomics 2-day CPET study? Or does “invasive exercise” mean something different (what does invasive exercise mean?) Thanks as always Cort!
Maybe you could add a brief explanation to the Gist…? Thank you very much!
I quickly ran the drugs through a German online apothecary and Wikipedia for prices and primary uses, with the following results (no guarantee for mistakes):
The first 4 drugs on the list are cheap (without looking further into their primary uses or side effects).
Pentostatin is an anticancer chemotherapeutic drug with – according to German Wikipedia – severe side effects.
Ribavirin is an expensive (3 digits) antiviral.
Cladribin is an expensive (4-digit) Multiple Sclerosis treatment, and is also a cancer chemotherapeutic.
Vaguely reminds me of an ME/CFS patient who reported online that she got better after (of all things) cancer chemotherapy.
☝️that’s why I decided to try fenbendozole
( anti-cancer) …and I can report my lymph lumps are shrinking.i don’t have cancer that I know of.
I took one single dose of ivermectin and had surprisingly good result. I’ve been around animals all my life so put my betting money on parasites
There is a book that has just appeared, ‘the parasites’ by Pr Philippe Humbert. For the moment, the book is only in French. The Professor says to keep all his blood tests, even those of 20 years old, see more, because, if at some point, there was an increase in the number of white eosinophilic blood cells, there is a strong chance that there are parasites in the body.
Parasites can be the cause of cystitis, eczema, psoriasis, herpes, parkinson virus, certain cancers, depression, sibo, Crohn’s disease, sama … and why not EM/SFC?
The PF Humbert uses the ivermectin to kill the larvae of certain parasites. It is very difficult to find which parasites are in the body, because there are many, and the treatment will not be the same.
Yes, and while there are many different visual parasites that can be seen, there ,apparently, are thousands of microscopic parasites that cannot be seen, so I’m learning
Note: I do NOT support self treating with horse dewormer in any single way. Doctor’s prescription and follow up is always necessary. Still, this is interesting information, potentially revealing underlying mechanisms:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10209955/
“Ivermectin Protects Against Experimental Autoimmune Encephalomyelitis in Mice by Modulating the Th17/Treg Balance Involved in the IL-2/STAT5 Pathway”
“However, to date, there are no in-depth studies on the effect of ivermectin on the function effector of T cells in murine experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we conducted in vitro experiments and found that ivermectin inhibited the proliferation of total T cells (CD3+) and their subsets (CD4+ and CD8+ T cells) as well as T cells secreting the pro-inflammatory cytokines IFN-γ and IL-17A; ivermectin also increased IL-2 production and IL-2Rα (CD25) expression, which was accompanied by an increase in the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg). Importantly, ivermectin administration reduced the clinical symptoms of EAE mice by preventing the infiltration of inflammatory cells into the CNS. Additional mechanisms showed that ivermectin promoted Treg cells while inhibiting pro-inflammatory Th1 and Th17 cells and their IFN-γ and IL-17 secretion; ivermectin also upregulated IL-2 production from MOG35–55-stimulated peripheral lymphocytes. Finally, ivermectin decreased IFN-γ and IL-17A production and increased IL-2 level, CD25 expression, and STAT5 phosphorylation in the CNS.”
Ivermectin is actually an organism that was discovered in the soil on a golf coarse in Japan.
Does this make ivermectin some kind of probiotic?
It’s one of the safest “drugs” with millions of doses given in underdeveloped countries anually
Anon….know that me/cfs, fibromyalgia
Etc are all names made up by people at the very top of the medical industry which,we have known for decades to be highly influenced by big pharma.
It’s the sole reason why we are all being held hostage.
There are people like joe tippins that had over 90 cancerous tumors that were told nothing can be done and given a death sentence.
On the advice of his friend a veterinarian he took it upon himself to go purchase ivermectin.His over 90 cancer tumors are completely gone!
There are now cases of people including some with pancreatic cancer that are alive today due to a one man, joe tippins
A simple search on youtube will show countless stories much the same as joe tippins.
If you want some more real life cures go watch prof Thomas Seyfried from boston university. He holds a tenured position so he cannot be stiffled.
You will learn from him how the cancer “industry ” is turning a blind eye to his press pulse thearapy for cancer that is now a new revolutionary cure for many cancers.
After decades of being outright lied to and belittled by the medical mafia, I decided to take my health into my own hands.it was the best decision I ever made.
I have ankylosing spondylitis from infection that got left due to medical ignorance.Three fused vertabrea.when I search ankylosing spondylitis one treatment calls for JAK STAT
Thanks for decades of abuse medical mafia
I have seen about 8 cases of long covid patients getting better with chemotherapy. Some significantly better at that.
I have been collecting records of each. Do you think you could find this women again? Or maybe just remember what site she reported this on.
I think I found it in my favourites: It was this Norwegian article https://www.tv2.no/nyheter/innenriks/la-bortgjemt-og-hjelpelos-reddet-av-kreftbehandling/15157897/ , English Google translate link: https://www-tv2-no.translate.goog/nyheter/innenriks/la-bortgjemt-og-hjelpelos-reddet-av-kreftbehandling/15157897/?_x_tr_sl=no&_x_tr_tl=en&_x_tr_hl=en . The article seems to have been withdrawn because the journalist also had a ME fundraiser, but the lady seems to be called Christine Moen https://www.facebook.com/Millionsmissingstavanger/posts/me-syk-reddet-av-krefbehandlingartikkel-om-nyhetsinnslaget-p%C3%A5-tv2-i-kveld-christ/3376271552695929/ , and maybe you could get in contact via the journalist mentioned in the tv2.no link (find his email here: https://www.tv2.no/nyheter/innenriks/la-bortgjemt-og-hjelpelos-reddet-av-kreftbehandling/15157897/ ), or via the Millions Missing Stavanger facebook. I think the article mentioned more than one patient.
Also, if you have not done so already, enter into Google sth like “ME/CFS I got better after chemotherapy”, and more links will come up, e.g.: https://meassociation.org.uk/2024/07/research-six-year-follow-up-data-on-cyclophosphamide-study/ , https://pmc.ncbi.nlm.nih.gov/articles/PMC7201056/ , https://www.sciencenorway.no/chemotherapy-chronic-fatigue-syndrome/cancer-drug-helped-patients-with-chronic-fatigue-syndrome-cfsme/1689388 .
Also enter “Cyclophosphamide” into the Health Rising search field to see if there are past blogs mentioning this like https://www.healthrising.org/blog/2021/09/16/autoimmune-options-chronic-fatigue-syndrome-scheibenbogen/ , also to see if there are patients speaking up about their experiences in the comments.
A German ME/CFS research review mentions “In the uncontrolled study by Rekeland et al. from Norway, the effects of treating ME/CFS with cyclophosphamide, which is used in cancer therapy and induces immunosuppression, were investigated. Patients (diagnosed according to the CCC) who were positive for the HLA-C∗07:04 and/or HLA-DQB1∗03:03 alleles (n = 12) reported greater improvements in fatigue and physical function during follow-up and had a statistically significantly higher response rate to treatment than patients who were negative for both alleles (n = 28) [Rekeland IG, Fossa A, Lande A et al. Intravenous Cyclophosphamide in Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study. Front Med
(Lausanne) 2020; 7: 162. https://dx.doi.org/10.3389/fmed.2020.00162%5D
Viel Erfolg! (German for “wishing you ‘much success'” :-))
Hey JR,
Thank you so much for the extensive detail and taking the time to pull it up.
I did some sleuthing to figure out what she was treated with. I couldn’t get access to the article because you need a subscription. I was able to see rituximab labeled with Christine Moen on her transfusion bag.
Rituximab is a B cell depleting MAB. So it gets rid of antibodies. That study with cyclosporamide also tested rituximab as well.
I would like to contact her and see if she knows of other cases like her. I have seen the cyclosporamide trial. It is interesting to say the least. There’s a newer 6 year update paper on that trail too I believe. I wish they would try other chemotherapies now. They act like it’s too dangerous. Yet, suffering for decades is totally viable…
I am trying to compile enough instances to make a case in front of some of the scientists researching LC. Many are focusing on viral persistence while not looking much into autoimmunity. I am a scientist myself and I think this needs to change.
I wouldn’t mind blogging this; but some of these people were really weary of opening up about it. So I would like to present it to researchers without identifying info and go from there.
Hey Jacob, I am not not sure but believe the article you can’t access was about cyclophosphamide as I made a note about it on my bookmark. To my understanding, I think that the article is not behind a paywall, but that it was withdrawn due to journalistic ethics conflict of interest stuff, because the journalist who wrote it also had a ME/CFS fundraiser at the same time (oh well…). So I’d recommend that you send an email to the journalist Pal Sorum Schaathun asking for a copy of the article, his email is public if you click on the journalist’s name on the article page: pal.schaathun(at)tv2.no. If he’s done an ME fundraiser, he might be open to your inquiry too; maybe he can help you make contact with the lady. Or you try to make contact via the Millions Missing Stavanger facebook page https://www.facebook.com/Millionsmissingstavanger/posts/me-syk-reddet-av-krefbehandlingartikkel-om-nyhetsinnslaget-p%C3%A5-tv2-i-kveld-christ/3376271552695929/ .
Here is another article on Christine Moen https://www-nettavisen-no.translate.goog/nyheter/apnet-opp-om-me-diagnosen-na-har-christine-samlet-inn-700-000-kroner-til-sykdommen/s/5-95-838420?_x_tr_sl=auto&_x_tr_tl=de&_x_tr_hl=de&_x_tr_pto=wapp , also mentioning a fundraiser she did for ME,
and here is the homepage of the her fundraiser https://www.spleis.no/project/240979 .
She seems to be on facebook and has commented under this article under the name “Christine Moen – Titti” : https://www.facebook.com/story.php?story_fbid=716434633236663&id=100046103986775&_rdr
Rituximab has been dangerous to some patients I think; there is German athlete, Olaf Bodden, who got permanently wheelchair-bound following his rituximab trial, and said it wrecked his immune system.
Maybe compiling a short interview questionnaire might help with weary patients?
Good luck!
**Correction- It’s supposed to say Cyclophosphamide. My autocorrect is off the rails.
I replied with links but the comment is “under moderation”. I hope it shows up in the next days, if not let me know. You might write this up for blog later 🙂
I am also concerned about the use of AI in this article. I have often found that AI summarizes a research study incorrectly. It also cites some studies, which themselves are deeply flawed.
I sympathize with the energy limitations that make gathering all this information yourself impossible, but would rather not have the information, than have potentially faulty information. It is confusing enough for me to try to keep track of things that are actually known about my illnesses, without dealing with misinformation.
I do appreciate you letting us know that you did use AI. I would request that you use AI only to find potentially relevant studies, and then look at the studies yourself before including them in your article. Even if that means you would be able to give us fewer articles per year.
I am hugely appreciative of your site, and use it so much to help manage my illnesses. I would like to be able to continue to trust it.
Hello Cort, which of these medications would you most recommend for MECFs triggered by Covid? I’m severely affected myself and am wondering whether I should try one of these medications?
If anyone can identify supplements or herbs that work at Purine Inhibitors, that would be helpful
I ran a search on “natural purine inhibitors” and got a long list, too many to try to copy and paste here. I suggest if you haven’t already, try doing a search with the same keywords as I tried.
Also, for my own trial I landed on allopurinol. Mitochondrial dysfunction is a major part of my CFS, and immune over-activation seems less of an issue, which makes allopurinol look like a good fit. Allopurinol has been around since the 1960s, has a good safety profile and is one of the most frequently prescribed of all drugs. I will begin a trial as soon as possible.
And, btw, I recently began taking metformin (750 mg/day, started in January) and low dose naltrexone (started about ten days ago; I’ve titrated to 1.5 mg/day so far). I started the metformin first and it seemed promising, with periods of remarkable improvement lasting a few hours, but these were very transitory/hit-or-miss. After a few days on the low dose naltrexone, the improvement became much more consistent. If this persists, it will be a huge improvement in my quality of life. (I’ve lived with ME/CFS for over 30 years.)
It seems metformin and low dose naltrexone may be synergistic. This brings to mind the work Dr. Systrom is doing at Brigham and Women’s Hospital with LDN and pyridostigmine on the basis of his clinical experience that it appears the combination may be synergistic.
https://www.clinicaltrials.gov/study/NCT06366724?term=Life%20Improvement%20Trial%20(LIFT)&rank=1#study-plan
Congratulations! Thanks for sharing 🙂
According to what I’ve been able to read online, allopurinol reduces extracellular ATP (in addition to lowering uric acid). That might be significant because according to Dr. Naviaux, extracellular ATP is the key trigger in the Cell Danger Response, which he suggests is likely a key underlying factor in ME/CFS.
I can’t find any research on extracellular ATP in ME/CFS patients. Does anyone know if there’s any data on whether extracellular ATP in ME/CFS patients tends to be elevated, normal or low?
Thanks again Cort for keeping us all up to date with the latest research. From what I can gather this is a bit like a snowball effect . The initial issue be it viral or otherwise causing the first defect in energy production then the by products of the dysfunction causing further issues and so on .
My situation is severe energy deficit with high blood succinate ,muscles burning after walking around the house etc so for sure I am in anaerobic energy production all the time.
What I was wondering if anyone knows there other tests that could be done to find if purines are the culprit for the high succinate levels. I know you mentioned uric acid as one further test but are there others which could show high purine levels if uric acid levels are normal?