Geoff’s Narration
The GIST
Health Update: Push-Crash-Rebound. I was doing quite a bit better until I had to do some heavy physical work on the van about a week ago. I thought I got through it OK, but then the crash came, and I have been slowly rebounding again. This has become something of a theme! Five times since I exposed myself to too much heat, something has interrupted my recovery. That’s life on the road (sometimes…).
The STIMULATE-ICP project was the UK government’s big attempt to understand and treat long COVID. Beginning early in the long-COVID saga (2021) it was notable for its cost of 6.9 million pounds ($9.15 million US) and the 30 organizations that participated in it.
The project ended in August 2025 and has produced over 30 papers (!) including it’s centerpiece – the treatment study, “Efficacy and safety of rivaroxaban, colchicine, and famotidine–loratadine with specialist supportive clinical care for fatigue in patients with post-COVID-19 condition in the UK: a multisite, open-label, randomised, controlled trial“, that was recently published in none other than the Lancet Journal.
THE GIST
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No hits yet! Perhaps it’s not such a surprise.
My health update – push-crash-rebound. Something came up which caused me to push hard, I crashed even harder, and now I am rebounding!
- The STIMULATE-ICP project was the UK government’s big attempt to understand and treat long COVID. Its centerpiece was a large trial (200 people per treatment arm) that assessed the effectiveness of three drugs: an anticoagulant (rivaroxaban), an anti-inflammatory (colchicine), and two mast cell drugs (famotidine plus loratadine).
- The drugs were chosen because they were relatively inexpensive and readily available, and could, if successful, be easily slotted into the UK’s healthcare system. The choice of colchicine, which is used in pericarditis – not something seen in ME/CFS – was perhaps a questionable choice, but the other two drugs were wholly in line with what we knew about long COVID in 2021.
- All three drugs/drug combos failed to produce clinically significant results and the anticoagulant produced negative results. The main takeaway from the trial was that none of these drugs could be recommended to the long-COVID patient population at large.
- The trial, however, was flawed in several ways. There were no placebo controls; the main endpoints focused only on fatigue and general health and had not been designed with diseases like ME/CFS or long COVID in mind; the symptom assessments were crude; and no attempt was made to target the appropriate patients for each treatment.
- The way the study was designed made it impossible for the authors to determine if subsets within long COVID responded to each treatment – a crucial need for this very heterogeneous disease.
- In the end, it was a poor return on investment for what was probably quite an expensive study.
- Note, though, that the study analysis is not over, and the authors stated that they are trying to identify subgroups and describe “phenotypical and/or biochemical characteristics”. Let’s hope so!
- In the end, both this trial, the Stimulate ICP, and a further early round of long-COVID funding from the UK government look very similar to the NIH’s RECOVER project. All three of these funding opportunities have been plagued by an innate conservatism which has not served the long-COVID patient population well.
- Perhaps not surprisingly, an assessment of the principal study producers found that, like the RECOVER project, most of them came not from the ME/CFS, fibromyalgia, POTS fields but from cardiology, respiratory medicine, infectious disease, clinical trial management, etc.
- The rest of the $9 million (US) Stimulate ICP project ended up focusing almost entirely on demographic, epidemiological, health access, EHF risk factor analyses – and, except for one early study, spent no money on understanding long-COVID pathophysiology.
- Of the 15 studies funded by the other major UK long-COVID funding opportunity in 2021, only 4 (T-cell, 2 immune, and a lung MRI) dug into long-COVID biology. Some shades of the CBT era crept in in the brain fog study, which was intended to “develop and test neuropsychological rehabilitation”, a personalized self-management support study, a weight management program, how patients and families manage long COVID, and adaptive pacing.
- In its 2 major long-COVID funding opportunities, the UK health system essentially punted on trying to understand long-COVID pathophysiology.
- There is some good news. Last year, the UK opened a post-infectious grant opportunity to assess treatments in long COVID and ME/CFS, and this time, it specified that the treatment trials had to be targeted and flexible, efficiently assess multiple targets, and look for mechanisms driving the diseases.
- The bad news is that it may take several years to develop the platform the treatment trials will use – and the funding for the actual trials is assumed but not present yet. In the worst case, it may take until 2028 to get the trials started. Once started, though, they should be vastly superior to the present effort.
- This trial’s failure was not unexpected. Of the 14 large/largish long-COVID trials that have been completed, only two (fluvoxamine/behavioral interventions) have produced at most modest successes. (The behavioral intervention trial will be covered in a future blog.)
- To date, most of the treatment candidates (metformin, ivabradine, transcranial magnetic stimulation, Paxlovid, computerized games, cognitive retraining) have not been particularly exciting.
- Two targeted treatments (donezipil – HHV-6; temelimab – HERV-EW) failed, and we’re awaiting word on the results of RECOVER’s IVIG and stimulant trials. An IVIG trial that uncovers a highly responsive subset would be a big deal.
- The field is learning. Clinical trials are increasingly assessing the biological response to the drugs, attempting to biologically target patient subgroups, and employing smarter, platform trials that use fewer resources and allow more treatments to be assessed at once.
- The next set of results will, hopefully, be better. Baricitinib, anti-inflammatory/JAK inhibitors, maraviroc plus atorvastatin, HBOT, a triple antiviral, two GLP-1 agonist trials, rapamycin, stellate ganglion block, long-COVID LDN, Jarred Younger’s smaller but more comprehensive ME/CFS LDN trial, and the OMF’s LIFT pyridostigmine/LDN trial are some large or largish trials underway or getting underway. Of course, more small trials are underway as well.
- Coming up: a talk with Jarred Younger 🙂
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Drugs
The trial assessed three drugs – rivaroxaban, colchicine, and famotidine–loratadine – against standard care. At 200 people per treatment arm, it was a nicely sized study.
They were the kind of drugs the UK health system was looking for – relatively inexpensive, repurposed drugs it could put to use without breaking the bank:
- Rivaroxaban – anticoagulant
- Colchicine – innate immune and inflammatory activation
- Famotidine plus loratadine.
They might not have been the first choice of another group, but they were all plausible treatments.
Results
Three drugs – three failures.
All the drugs failed to produce “clinically significant” results; i.e., results the patients would have clearly noticed.
In fact, it wasn’t close. The participants would have had to have improved by a minimum of 3 points on the FAS scale to achieve that. The closest they came was for colchicine and famotidine (1.49, 1.48). The anticoagulant rivaroxaban produced minimally negative effects on fatigue (-1.06)
Flawed Study
While the drugs were plausible choices, the way they were assessed made one wonder if this trial was doomed to failure. Ultimately, the trial appears to have prioritized size over precision – a dangerous decision in this very heterogeneous disease.
It was perhaps no surprise that back in 2021, a pernicious problem that exists today was present in spades then: vague (very vague!) criteria. The participants simply had to have ongoing symptoms (or a symptom) four weeks after the infection.
It was an open-label trial; i.e., everyone knew what treatment they were getting. Placebo effects could have crept in in the patients receiving the drugs and in patients not getting the drug (who might have had a negative reaction).
The two symptom report measures were used to assess treatment effectiveness: the Fatigue Assessment Scale (FAS), and the EQ-5D-5L visual analogue scale (EQ-VAS) didn’t begin to assess the wide range of symptoms found in long COVID.
The way the trial was put together suggested it was going to have a hard time succeeding.
The symptom assessment done at baseline to determine if a subgroup with, say, more mast cell symptoms responded to the mast cell drugs was similarly flawed. The assessments were apparently so broad that virtually everyone in the study met the criteria for belonging to all of the cardiorespiratory, neuropsychiatric, and mast cell subgroups.
The symptom assessments also appear to have been far cruder (yes/no to each symptom) than one would have hoped for at this point. Leonard Jason has long established that yes/no symptom queries tell us nothing about symptom severity in ME/CFS – and symptom severity is a crucial measure in diseases with so many symptoms.
His DePaul ME/CFS questionnaires – used in many studies – assess symptom frequency and severity. A frequently occurring, severe symptom would get the highest score. An infrequently occurring, mild symptom would get the lowest score. This study would not have differentiated between those two.
If the study had used something like the DePaul Questionnaire at baseline and in the 12- and 24-week assessments, it could have determined if people with more severe gut, skin, and allergic-type symptoms benefited from the mast cell drugs.
The study also did not assess – and explicitly stated it would not assess – whether the participants met the criteria for ME/CFS. That seemed puzzling as including the criteria would have highlighted a more severely ill group – and might have been helpful for people with ME/CFS.
A ChatGPT analysis of the methodology and statistics suggested that while the study could have uncovered broad effects, it was not sufficiently powered to uncover smaller subsets that responded well.
The authors acknowledged the shortcomings of the trials: they noted that using a more long COVID-focused functional test could have helped, that the study lacked the statistical power to uncover subsets, and that the trial results could have been “confounded by placebo or expectation effects or mask smaller subgroups or endotypes that might or might not benefit from the interventions tested.”
(The study analysis is not over, and the authors stated that they are trying to identify subgroups and describe “phenotypical and/or biochemical characteristics.”)
Summary
The STIMULATE-ICP trial was kind of a big, messy study! There were so many potential confounding issues that it’s a little hard to know what to make of it.
It does appear that none of these three drugs should be used to treat your run-of-the-mill long-COVID patient, as even a possibly positive placebo result did not move the needle.
It’s possible that colchicine and famotidine/loratadine might be helpful for a subset of patients, but it will take further study to determine that. That’s not much bang for the buck for this large, undoubtedly expensive, trial.
In the end, the drugs would have had to have a large and broad positive effect in order to be successful. Particularly with the type of drugs this trial focused on (relatively inexpensive), it was probably not going to happen with these diseases. The authors’ inability to subset their participants was huge.
Institutional Conservatism Prevails
An innate conservatism prevailed in the two early UK long-COVID projects and the RECOVER project in the US.
Interestingly, the STIMULATE-ICP trial failed in some similar ways to the first round of the RECOVER treatment trials: it tested a few drugs in pretty large sample sizes, was not able to target or uncover subsets (at least, not yet), and did not assess biological outcomes.
An assessment of the principal study authors found that, like the RECOVER project, most of the authors came not from the ME/CFS, fibromyalgia, or POTS fields but from cardiology, respiratory medicine, infectious disease, clinical trial management, etc.
It was not surprising, for instance, to see the authors choose to assess colchicine, which some of them had, no doubt, used to treat pericarditis, chest pain, and breathlessness. That ignored the fact, though, that the chest pain/breathlessness found in ME/CFS is probably caused by far different issues (dysautonomia, dysfunctional breathing patterns, microvascular problems).
The UK presented STIMULATE-ICP as its largest major long-COVID project, and it ended up producing dozens of studies. In the end, though, the project included one large, rather crude treatment trial, and despite the project’s promise to explore multiomics, for instance, the studies published thus far have focused on the healthcare system and explored things like long-term trajectories, access to health care, demographics, electronic health risk factors, etc.
Long COVID was treated as a brand new disease, its connections to ME/CFS were discounted, and ME/CFS researchers were not apparently welcome. The studies found what we would expect given the UK’s experiences with ME: “only one-third of individuals under follow-up achieved satisfactory recovery”, “long Covid can double a patient’s cost to the health service”, “Long Covid can be a stigmatising condition”, “Long-COVID has a significant and long-lasting impact on individuals’ health and well-being”…
The £19.6 million 2021 NIHR funding round suffered from a similarly conservative, unimaginative, biology-lite approach. The largest study (LOCOMOTION) was intended to develop a “gold standard” NHS care model. (How do you develop a gold standard of care when you don’t know anything about the biology?) More “soft” science and even some shades of the CBT era crept in in the brain fog study, which was intended to “develop and test neuropsychological rehabilitation”, a personalized self-management support study, a weight management program, how patients and families manage long COVID, and adaptive pacing. Of the 15 studies, only 4 (T-cell, 2 immune, and a lung MRI) dug into long-COVID biology.
Like the RECOVER project, the UK government appears to have reflexively turned to what it knew (epidemiology, assessing care, self-management) when it met up with long COVID, instead of diving in and trying to understand the complex biology present. Like RECOVER, its priority was not in breaking new ground in long COVID or ME/CFS pathophysiology. For that, we have to go to places like PolyBio, Yale, the UCSF LIINC project, and in ME/CFS places like the OMF, Solve M.E., MERUK, Invest in ME, the Germans, and others.
The UK has continued to fund long-COVID research, but the two early large funding packages constituted its big shot. Forty million of the roughly 57 million pounds spent on long COVID were funded by those two packages.
Lessons Learned
It seems that the NIHR (National Institute for Health and Care Research) does not want to repeat the mistakes of the past. In July 2025, it opened a grant package on post-infectious diseases including long COVID and ME/CFS. The new grant package will conduct phase 2 clinical trials of “multiple different therapies simultaneously and efficiently”. These trials should be more targeted and flexible, investigate mechanisms, and may include Decode ME participants. Call these trials the antidote to the Stimulate ICP trial.
The process, though, is agonizingly slow. The applications – which were to design the treatment platform – closed in Dec. 2025. In March 2026, the committee gave a preliminary green light to two project teams. The two teams then had up to 18 months to design the platforms, which means that in the worst-case scenario, the actual trials could conceivably not take place until 2028 (!). Let’s hope it gets going sooner. Funding for the actual trials is expected to be provided at a later date.
It’s good to see the UK and Germany produce post-infectious grant packages. (The US, embarrassingly, is still lumbering behind…)
Growing Pains in the Treatment Arena
No hits yet! Perhaps it’s not such a surprise.
Six years after long COVID showed up, I was able to find 14 largish (> 100 participants) long-COVID clinical trials that have been completed. Only one drug (fluvoxamine) showed a modest improvement. The big (n=312) Wyller cognitive behavioral trial is the only other one to show benefit. (A blog will look into that trial.)
It’s a pretty poor showing thus far, but one has to ask if it’s really that much of a surprise. Metformin, Ivabradine, transcranial magnetic stimulation, and high-dose CoQ10 were kind of nice tries, but surely nobody expected dramatic results from them. Short-term Paxlovid (2 large trials), cognitive retraining, and computer puzzles probably never had much of a chance.
Two large studies were quite targeted. The Donezipil study attempted to repair a specific cholinergic deficit in the brain the Japanese believed was caused by HHV-6 reactivation. Likewise, temelimab targeted patients with HERV-W activation. Both, however, failed.
The field is learning. Instead of doing large clinical trials that simply assess treatment responses, clinical trials are now increasingly assessing the biological response to the drugs and attempting to biologically target patient subgroups. We didn’t know 6 years ago, or even a year ago, for instance, that 4 different types of microclots may exist in long COVID – each of which requires a different treatment regimen. There’s also an emphasis on doing smarter, platform trials that eat up fewer resources and allow more treatments to be assessed at once.
The next set of results will, hopefully, be better. RECOVER’s IVIG and stimulant trials should be winding up, and more powerful and targeted drugs are being assessed. Baricitinib, anti-inflammatory/JAK inhibitors, maraviroc plus atorvastatin, HBOT, a triple antiviral, two GLP-1 agonist trials, rapamycin, stellate ganglion block, long-COVID LDN, Jarred Younger’s smaller but more comprehensive ME/CFS LDN trial, and the OMF’s LIFT pyridostigmine/LDN trial are some large or largish trials underway or getting underway. Of course, more small trials are underway as well.
- Coming up – a talk with Jarred Younger
The Long Covid research has been pretty pathetic. It’s all so familiar!
I would have thought we would have had more meaningful results after 6 years.
Of course, it shouldn’t surprise. Like ME/CFS the answers primarily lie in the brain. Like ME/CFS researchers have persisted with flawed immune system theories.
I had hoped that we would see results when quite prominent academics such as Iwasaki at Yale got involved. But then, I was swayed by the institution’s big name status! Her research has disappointed. Unadventurous, safe and going down predictably flawed theoretical alleyways
Thankfully, at least we have people, even a minority, like Younger beavering away. At least he’s on the right kind of track.
And who knows maybe a drug like bezisterim – which passes the BBB – might succeed
Just had a zoom interview with Younger – he’s very interested the JAK STAT inhibitors that can make it into the brain.
Hi Cort,
Do you plan on publishing that interview?
Thanks.
Absolutely. Probably in a week or so. 🙂
Viewing the research through a hyper-critical lens, eh; hardly useful. What is your expertise?
What isn’t useful is researchers continuing to go down the same old dead ends. Ie. Viruses and antivirals. Wasting more valuable time and money.
Cort will attest to the fact that I have consistently said the problem is the brain, for at least 15 years on this website.
After Nath et al’s study, the likes of Nancy Klimas came out with statements like ‘it’s all in the brain’.
Jarred Younger is finding more and more evidence of that.
My background? Biochemistry
I also think it is the brain. Brainstem, Neurotransmitters. I always thought the problem could be found in the spinal fluid, but it didn’t so far. Maybe the answer can be found in the brains of deceased patients. They’re already working on that. The problem with this is that you need to be able to distinguish very clear subgroups. Or you have to study at least 100 deceased patients so that maybe subgroups become visible. But if there’s no brain damage, then this type of research doesn’t make much sense either. You would have to examine all the neurotransmitters and substances in the brain. And especially the physical stress system and everything that comes with it. That’s where the problem lies.
Iwasaki was among the first in decades to analyze spinal fluid, uncovering pathological changes and two distinct patient subgroups. Those findings appear to have directly motivated her pivot toward investigating herpesviruses.
But if you’re eager to get prescribed a cocktail of psych drugs – where nobody actually knows what they’re doing in the brain – by all means, keep advocating for neurotransmitter research! If you want a shortcut, just ask your trusted psychiatrist for a random mix of them. I’m sure they’ll be thrilled to help you out.
I continue to wager it’s mitochondria (which isn’t exclusive of the brain but is also apart from it). We shall see.
Yes I think mitochondria are a real candidate.
Brain and/or mitochondria
That’s a pretty absurd take, Matthias. The Iwasaki/Putrino network and Lisa Selin’s team are currently unravelling how ME/CFS patients’ immune systems lose control over smoldering herpesvirus reactivation – which may well be a root driver of the disease. If anything, the main oversight by Iwasaki’s team was not pivoting to herpesviruses five years earlier.
The idea that the brain and the immune system are mutually exclusive misses how this illness evolves. Anyone who was mild early on will tell you the initial phase isn’t obviously neurological – it presents as a classic, flu-like immune struggle against a virus. It’s as the disease progresses and worsens that these persistent, smoldering infections are thought to cross over into the central nervous system, driving downstream brain involvement.
Cort recently highlighted breakthroughs from two young researchers in his summary of the Polybio spring presentation: we now have the first direct proof of smoldering EBV and VZV activity driving T-cell exhaustion in Long COVID, alongside the first evidence of (EBV-mediated) B-cell damage in lymph nodes. And these findings are just the beginning! Many more potent studies in this area are now under way. So that over the next 1-2 years there will be tremendous progress in the understanding of ME/CFS pathomechanism.
Never said the immune system isn’t involved, it is. But the primary loci for the illness resides in the brain.
I hope you are right, and they succeed where 35 years of research hasn’t
”The big (n=312) Wyller cognitive behavioral trial is the only other one to show benefit.”
Not again……..
Don’t worry! Not as bad as it sounds. Blog is coming up.
My thought exactly…
Failing to mention the combination of valacyclovir, celecoxib and paxlovid in the recently published case series was shortsighted. This August that combination will be tested by David Putrino and Amy Proal in the SHIELD study at Mt Sinai Hospitals in New York.
No, no! It’s in there- it’s just not explicitly spelled out. “a triple antiviral” trial. I went with triple antiviral because celexicob has, if I remember correctly, antiviral properties.
Good luck with it! Glad to see that Amy Proal is involved.
Cort, I’ll comment here on my experience with celexcoxib (celebrex)
My ME/CFS provider started me on a low dose (50 mg/day, to titrate upwards). I could tell right away that it made me feel better: more energy, less foggy. Therefore, when the diarrhea started after a couple of days, I was reluctant to stop. After 10 days I couldn’t leave the house 🙁
Turns out it’s the only NSAID that’s a sulfa derivative, and I’m allergic to sulfa. Took me weeks to get over it.
People with known or suspected sulfa allergy might want to avoid this one.
Thank you for this. Good to hear someone has an ME provider as well. How rare!
Yes it’s true we aren’t supposed to have medical rationing the US. I’m a patient at a large university hospital that’s a 3 hour drive from home. It took me 2 years asking specialists there for the internal LC/ME clinic referral, and another 2 years before I actually saw the ME provider, who is a physician assistant. By that time I had gotten worse and met criteria for moderate ME.
I’m now on a 6 month follow up schedule, which is always 7-8 months between visits due to availability of appointments. They try one intervention per visit. If the intervention doesn’t work out, they won’t prescribe anything else until the next visit. The medical assistants deflect all communications to provider visits only, so no messaging. I hope the severe patients get more guidance.
But it’s definitely , by necessity, a self directed process 🤣
There’s a huge unmet need and certainly nothing local in my area. Ironically once I got too sick to work, I had time to find the care I needed.
Sorry, did not recognize description.
Glad you’re reading the posts! Please keep us updated on the state of the trial. 🙂
It won’t succeed. Antivirals are not the answer to these illnesses.
Who died and made you some kind of expert. We had an 88% resolution of our Primary and Secondary endpoints symptoms. Happy to put money where my this. Care to wager!!
Love the kutzpah! It was a provocative challenge from me.
We will see, hope you are right!
You see, some of us have had this awful illness for decades, and have been consistently let down. It’s probably a natural psychological defence to not be optimistic, after 35 years.
There have been dozens of studies on antivirals, so I am not sure what makes this any different. Is a synergistic combination somehow elevating this?
Tsasurgery@gmail. Com if you want help
“biology-lite approach” 😆
this cracked me up. So true!
Really disappointed was on all suggested things like urithilin a POA luteolin, co enzyme 10 and many nmore etc at great expense now you say all no good?
I really do think that these supplements can be helpful. In fact, I’m sure they are helpful for some people. We just need targeted studies that can test them in the right subset. Otherwise, the good they may be able to do, disappears because not enough people get a large enough benefit.
I’ll comment here on Colchicine, which I personally consider a game changer.
I have LC-ME/CFS with significant orthostatic chest pain that led to my disabled status. I started with cardiology years before we figured out what was actually wrong. Drugs I trialed included nitrates, beta blockers, ranolazine, ACE inhibitors, diltiazem, and ACE receptor blockers. Nothing worked. I also had a major cardiac surgery and a major vascular surgery for congenital anomalies that were discovered incidentally. Those also didn’t help/made me worse. Same for the PVC ablation.
After 5 years of this, my EP tried low dose amlodipine (a different calcium channel blocker class from diltiazem) and it reduced the chest pain by 50% within a few days.
My ME/CFS provider added colchicine and it completely eliminated my residual chest pain!
I think the researchers aren’t looking at the right parameters. They were looking at fatigue, for which it does nothing. They should have tried it specifically on patients with chest pain (not everyone)
I still have a lot of other LC and ME symptoms, but the colchicine and amlodipine eliminated the chest pain. I didn’t recognize how much it bothered me until I got rid of it.
I think you’re exactly right – and why they didn’t pluck out long COVID patients with chest pain and give Colchicine to them – is just a puzzle. They stated that they hoped it would help with chest pain – and then gave it to everybody!
Think if it had been successful in people with chest pain – what a benefit that would have been!
What a missed opportunity.
Thanks for relaying your story! Glad it helped with that rather mysterious symptom.
I just read your blogs Cort and shake my head. You’d think every continent is a different planet instead of being nearly instantly connected worldwide now. How many millions did they spend testing Famotidine/loratidine? Do you know how many people with LC probably use those on a daily basis? A poll//survey would have provided the same info for free, narrowed down subsets and provided actual useful information. Between that and the CBT trial I just want to go bury my head in the sand somewhere.
I know! I felt the same way. I feel the same way about the RECOVER program. It’s so frustrating.
I hear these stories of patients adjusting their dose until they find a mast cell inhibitor that works and then we see a study with one dose. It’s not the study authors. That’s the way it almost always is. I imagine altering the doses would have cost a lot more money that they didn’t have.
I’m really glad to see that Jarred Younger will be assessing different LDN doses in his trial.
The trials are getting better, though, and if the UK government ends up funding the next round of long COVID trials they should be really good….So good for them.
I hope so! Sorry you keep crashing from PEM. Things have changed in the last 5 years in the supportive category. Here’s DR Marty Ross’s new page on PEM. I still take things like liposomal glutathione when I overdo it and start getting run down. Anything to give the mitochondria a boost! Also it sounds like you are not wearing a watch to track your heart rate (or if you are you are ignoring it!). It’s crucial to pacing effectively. If you had been wearing one while working on the van you could have taken a 3-5 min break anytime your heart rate went over “X”, ( I just use 100bpm) and it may have taken an hour longer to get the job done but you likely wouldn’t have crashed the next day. I know you know this but are you doing it? 🙂
I have an Oura, Apple Watch, and Garmin but I’ve never tracked heart rate during exertion. Thanks very much for the idea 🙂
Something I just realized reading your reply, it’s not just exercise that causes your heart rate to rise. Well, not the way I think of it any ways. I can just be wandering around but if I start getting hot, probably dehydrated as well I’ll start feeling a little tired and even though my respiration isn’t up at all, my HR will be. I you can set an alarm on the Apple, maybe Garmin to alert when you hit the target rate. You’ll likely be surprised at how easily you hit it to start but as you recover it gets to be less frequently and you can set it a little higher like 105. If you shoot a lot higher just sit/lie down. It should drop immediately and you likely won’t see lingering issues. It’s just keeping up there that seems to cause the worst issues. Stay cool!
Thanks!
https://treatlyme.com/guide/solutions-post-exertional-fatigue-and-malaise/ Not just for tickborne diseases but all the co-conditions now. Also look at mitochondrial support sections. Take care!
Thank you for posting this highly accessible and informative link. I started taking L-carnitine recently and had a profound improvement in my mood and energy level. I will now take on board the other recommendations this doctor makes and see what happens.
Not a cure for ME/CFS…but perhaps may help others whose WGS show up autosomal recessive mitochondrial conditions…..
Glad you found something that helps! I found a few genetic issues that changing (adding or stopping) different vit/min & supps helped. I just started L-carnitine for Gerd and it’s made a big difference but it hasn’t seemed to do anything for energy/mood. We are all SO different! Dr Ross’s info got me through tickborne diseases and one article by Cort (mega doses B1/B2) got the CFS into remission. I rely on both for 85% of my medical info. My Drs basically just do lab tests I ask for. 🙂
Yes we are all so different…..
The L-C (which I took with CoQ10 and B2 as well) took about four weeks to kick in for me and when it did the mood shift was profound and quite sudden. Literally woke up one morning feeling very different; clear headed and light in spirit. Over the weeks that followed I had to pinch myself to believe it. It was a huge relief to feel the heavy sad darkness gone. Fingers crossed you too will feel this impactful change.
Avanti dilettanti!
I think we all learned not to expect too much. But we don’t give up either.
Looking forward to the talk with Jarred Younger!
A nice approach! “I think we all learned not to expect too much. But we don’t give up either.” Thank you!
Even if the IVIG trial is successful how will anyone afford the treatment?
There’s hope insurance will cover it and the price will come down because of the huge economic impact these conditions have on the economy. Hang in there!
Thanks, Cort for pointing in the right direction.
Yes, a considerable amount of research funding is wasted when important findings are identified but not systematically investigated.
In the 2024 YouTube presentation “Immunology of Post-Acute Infection Syndromes”, https://www.youtube.com/watch?v=ZeesZPBluJY&t=1435s, Prof. Akiko Iwasaki presented evidence of muscle weakness, impaired balance, and findings consistent with muscle damage. She also reported low cortisol and low adrenocorticotropic hormone (ACTH) levels. This pattern is more consistent with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis than with primary adrenal insufficiency.
Despite these observations, this potential mechanism has received relatively little follow-up. Many clinicians have also overlooked these findings, even though patients who have independently obtained laboratory testing have reported results similar to those described by Prof. Iwasaki.
Low ACTH together with low cortisol suggests impaired hypothalamic-pituitary-adrenal (HPA) axis function rather than primary adrenal gland failure. If muscle damage is widespread, it may affect not only skeletal muscles but also the respiratory muscles, including the diaphragm and intercostal muscles. Dysfunction of these muscles can reduce ventilation, impair pulmonary gas exchange, and limit oxygen delivery to the brain and other tissues. Because mitochondria generate cellular energy in the form of ATP (adenosine triphosphate) through oxidative phosphorylation, an adequate oxygen supply is essential for normal cellular metabolism. Consequently, impaired oxygen delivery may compromise ATP production, disrupt cellular energy metabolism, and contribute to mitochondrial dysfunction.
Taken together, these interconnected endocrine, muscular, respiratory, and metabolic findings provide a biologically plausible hypothesis that warrants rigorous investigation in post-acute infection syndromes rather than being overlooked. Establishing whether HPA axis dysfunction contributes to respiratory muscle weakness, impaired oxygen delivery, and downstream mitochondrial dysfunction could help explain several of the persistent symptoms reported by patients.
This is the type of theory I’m following in treatment attemps. Currently on fludrocortisone and hydrocortisone, and cutting back on hydrocortisone as supplements help, apparently with cellular respiration and such. It has helped a great deal over the past few months. However, I seem to have hit a wall and am now looking for which piece is missing next. Hoping that more researchers look into this path!
Hi Blog Reader.
Since I was diagnosed with adrenal insufficiency following an ACTH stimulation test many years ago, I have been taking hydrocortisone.
During the evaluation, a thyroid scintigraphy revealed two large thyroid nodules, as well as enlargement of both salivary glands.
These conditions may be contributing to my muscle weakness.
Would you consider ordering a thyroid evaluation, including appropriate thyroid function tests?
New study on long COVID, dopamine and the brain:
https://scitechdaily.com/long-covid-brain-scans-reveal-damage-to-dopamine-neurons/
Thanks!
This study is significant because it provides compelling in vivo evidence that long COVID can affect the brain’s dopamine system in ways that closely match patients’ symptoms.
While it does not prove permanent dopamine neuron loss, it offers one of the clearest biological explanations to date for the persistent fatigue, cognitive impairment (“brain fog”), and reduced motivation experienced by many people with long COVID.
Importantly, some individuals experience substantial neurological and cognitive symptoms that are often underrecognized or dismissed, despite having a measurable impact on their daily functioning.
https://swaresearch.blogspot.com/2026/07/dopaminergic-vulnerability-in-long.html
Without neurological symptoms, you won’t get an ME/CFS diagnosis. It’s hard for me to understand why you think doctors dismiss these symptoms in LC. That said, I do think there are still some ridiculous doctors who dismiss LC and ME/CFS altogether. As a patient, the most important skill to learn is just letting them babble their s***.
Nexco Pharma manufactures in FDA registered US facilities, Nexavir injectable and Nexco Cream 75, for treatment of CFS/ME and Long Covid. Complete information including client testimonials and technical papers, and Nexco Pharma background are available on the company’s website (www.nexco-pharma.com ).
Nexavir Injectable (formerly known as Kutapressin) was developed in the late 1930s by Kremers Urban (Schwartz Pharma) and acquired by Nexco Pharma in 2004. It is an extract from porcine liver that yields a mixture of small proteins called polypeptides. Nexco Pharma also developed Nexco Cream as a topical formulation.
Sorry Paul but this is a marketing scam. Dropped it into Ai and got a long list of issues, like it’s not FDA approved,etc. This was the clearest comment, “A more clinically-oriented ME/CFS forum reviewing the same Nexco Pharma website concluded the site’s marketing reads like a standard scam, with the active ingredient being essentially mushed-up pig liver and the therapeutic claims resembling generic alt-med tropes about viruses, inflammation, and blood flow rather than anything backed by real evidence.
Science for ME”
Dear T. Allen, I don’t know who you are or what your area of expertise is but FDA approval is no guarantee of safety. That said, Nexavir’s predecessor, Kutapressin was on the market in the 1930’s and was effective for treatment of shingles and other inflammatory skin conditions. Nexavir is the newer version of Kutapressin and is available in both injectable and cream form.
The late, Dr. Dharam V. Ablashi was renowned as the co-discoverer of Human Herpesvirus 6 (HHV-6) and was the long-serving Scientific Director of the HHV-6 Foundation.
Dr. Ablashi discovered the antiviral activity in vitro of Kutapressin against human herpes viruses.
National Institutes of Health (NIH) | (.gov)
https://pubmed.ncbi.nlm.nih.gov › …
by DV Ablashi · 1994 · Cited by 14 — We found that Kutapressin (KU), a drug that has been available to practicing physicians for over 50 years, has potent, previously unexpected antiviral effects.
Dr. Paul Cheney had a Ph.D. in physics and an MD in internal medicine. He was certainly not going to recommend a scam medicine.
I started taking the cream form of Nexavir on the recommendation of Dr. Paul Cheney many years ago. While it has not been a cure, it is very helpful and I am able to do more than most despite having ME/CFS and Long Covid. The cream form is available without a prescription. My daughter who has ME/CFS also uses Nexavir. She is an artist in Maui and this is hard physical work that can knock her down for days. She says the Nexavir helps pull her out of these crashes.
“using” not taking
Good. Glad it’s helping you. But if was really useful everyone would know about it. Anyways, just an FYI for your safety. “Drugs.com’s current page notes the Nexavir brand name and all generics have been discontinued in the United States (updated Feb 2026). So even the “grandfathered, sold since the 1930s” injectable may no longer be commercially available under that name in the US — worth verifying directly with Nexco Pharma or a pharmacy if you’re trying to source it now, since what’s sold online today could be an unofficial import, an old batch, or the cream product wearing the same name.
We must be looking at different pages on Drugs.com. This is what I found.
https://www.drugs.com/search.php?searchterm=Nexavir
Could you provide the link that says Nexavir injectable was taken off the market?
It’s on the “pro” page. https://www.drugs.com/pro/nexavir.html That’s the one confirming the Nexavir brand name and all generics have been discontinued in the United States. The page was medically reviewed and last updated on Feb 16, 2026. It’s just the injectable and you are right the other pages haven’t been updated yet. So I’d double-check directly with Nexco Pharma or a pharmacist before assuming availability either way. PS. Since the formula has changed from pork to beef liver with the same results (Drs that switched from Nexavir because of the preservatives to Hepapressin -calf liver), it indicates it’s not peptides doing anything as they differ by species, but more likely the vit/min content + protein. I know amino acids help me. It would save you a boat load of money to take a digestive enzyme to help with protein assimilation, and get lab tested to see if you are mid to top range on your vit & minerals and do a trial run of Solgar Amino Acids. Blessings to you and your daughter!
Dear MR. Allen,
I see you and Ms. Mekdeci have an ongoing commentary regarding NEXAVIR. I find your comments over the top and unfounded, so let me share the facts:
1. NEXAIR is manufactured in an FDA registered US based facility. The current batch was produced August/September 2025 and COA’s are available on our website.
2. NEXAVIR (formerly Kutapressin) has been used to treat various viral ailments for over 80 years without any safety or toxicology concerns.
3. Our medical advisory team includes Drs. Cheney and Komaroff, both well-known experts with peer reviewed and published technical papers with demonstrated Kutapressin results. These are available on our website.
4. FDA registration is in process. We expect approval in due course.
I respect your decision to await using the product until FDA approval, but it is not necessary to impugn the integrity of many professionals supporting NEXAVIR.
Pau Litwack
Thank you for the update Mr Litwack. Appreciate the response, but a couple of things worth clarifying for others following along: ‘FDA registered facility’ and ‘FDA approval in process’ are different things — registration is just a facility listing, not a review of the drug itself. As of now, Nexavir has no NDA on record and is classified by the FDA as an unapproved drug; Drugs.com’s own listing notes the Nexavir brand has been discontinued in the US. Happy to be corrected if there’s a public FDA docket number showing otherwise? That’s the kind of thing that would actually settle this.
https://en.wikipedia.org/wiki/Kenny_de_Meirleir
Cort, here’s another ongoing trial for the list:
https://www.thelancet.com/action/showPdf?pii=S2589-5370%2825%2900672-8
Would be interesting if you could talk shop with these guys…
If you have nothing better to do, tune into C-Span and watch Dr. Anthony Fauci take the 5th in answer to every question about the origins of Covid.
Before anyone misunderstands, I am not suggesting the Simon Wessely biopsychosocial hypothesis, as I believe it is fundamentally flawed.
His model argued that after the initial infection people with ME/CFS are essentially biologically recovered, but remain ill because of unhelpful beliefs, fear of activity, and deconditioning. If that were true, mind therapy should help many people recover. But that doesn’t appear to happen for the vast majority of people with ME/CFS.
My hypothesis differs fundamentally from the BPS model. Rather than applying to most people with ME/CFS, it may only apply to the rare subgroup who have already recovered from the biological disease process and no longer experience PEM, but continue to feel unwell.
I believe that everyone who meets the Canadian Consensus Criteria for ME/CFS has an ongoing active disease process because PEM is a mandatory diagnostic criterion. I therefore don’t think there is convincing evidence that mind therapy can improve or cure active ME/CFS.
From reading the relatively few but vocal recovery anecdotes, my hypothesis is that recovery attributed to mind therapy probably only applies to the rare people whose PEM had already resolved naturally, without them realising it. They can still feel very unwell after prolonged illness, continue avoiding activity, and deconditioning can add to how unwell they feel. This is the only stage that could reasonably be described as biopsychosocial. However, the key point is that “still feeling sick is not the same as still having ME/CFS with PEM.”
When one of these uncommon people eventually starts a mind therapy program, they become more active and discover they no longer crash after exertion. It is then easy to conclude the therapy cured them, when biological recovery may already have occurred and the therapy simply prompted them to recognise it.
This could also explain why dramatic recoveries from these programs appear to be so uncommon. They are not curing most people with ME/CFS. They may simply be identifying the small number who had already recovered from the PEM-producing disease process before starting the program.
To properly test mind therapy programs, studies should first establish that participants still actually have active PEM using the safest practical physical assessment available, rather than relying only on self-report.
One reason I remain sceptical is that, for decades, this field has repeatedly relied on subjective questionnaires while objective outcome measures have too often been absent, downgraded to secondary importance, or failed to corroborate the reported improvements. That has been a longstanding methodological criticism of psychological and behavioural ME/CFS research.
Yet in an age where inexpensive wearable activity trackers are readily available, why are objective measures still not a routine part of behavioural mind therapy research? After decades of this pattern, I remain unconvinced by claims from psychological and behavioural ME/CFS researchers that rely primarily on subjective questionnaires.