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The OMF’s Severe ME/CFS Big Data Study
As of 2018, the Severely Ill Big Data study had collected more data than any other ME/CFS study.
Remember the Open Medicine Foundation’s Severe ME/CFS Big Data study? Initiated in 2015, it was one of three unusually large and expensive ME/CFS studies (Intramural Study NIH, CDC’s Multisite Study) begun in the 2010s.
THE GIST
- Remember the Open Medicine Foundation’s Severe ME/CFS Big Data study? Initiated in 2015, it was one of three unusually large and expensive ME/CFS studies (Intramural Study NIH, CDC’s Multisite Study) begun in the 2010s. By 2018, the study had gathered more data than any ME/CFS study before it but has largely faded from view.
- I asked, Wenzhong Xiao PhD., the big data guy leading the computational end of the study, what had happened with it? Was it a bust or did it uncover some findings we don’t know about? It turned out that the latter was true.
- A recent study that used whole genome sequencing (WGS) to assess one of the millions of base pairs that make up our genome resulted in the identification of 96 pathogenic genetic variants. These rare genetic variants pointed an arrow at the central nervous system and neurodegenerative diseases. Genes associated with the Epstein-Barr virus, estrogen, and connective tissues, among others, showed up as well.
- Many other metabolic and immune abnormalities were found. In fact, Ron Davis said they found almost too much, including many test results that were orders of magnitude altered in the severe ME/CFS patients.
- The findings have spurred background research that seeks to understand the molecular underpinnings of ME/CFS by exploring more extensive findings from better-funded diseases.
- Thus far, several drug possibilities have popped up that they’re exploring further.
- A whole genome sequencing effort identified almost 100 rare pathogenic genetic variants that may be contributing to ME/CFS. The central nervous system showed up in spades. The six potential neurodegenerative disease pathways that were identified suggested that the buck may end up stopping at the CNS in ME/CFS.
- Pathogenic genes associated with the Epstein-Barr virus (EBV) and antigen processing and presentation (how the immune system recognizes invaders) also showed up big-time.
- The treatment possibilities popping up from the Severe Big Data study – particularly molecules that modulate the nervous system – most excited Wenzhong now. Those are under wraps as they figure out how to test them and when and how to announce them or publish them.
The hope was that it would illuminate the core features of ME/CFS but disappeared from view for awhile. Thus far, the study has produced just two papers – a 2021 one, “A Comprehensive Examination of Severely Ill ME/CFS Patients“, that singled out low cortisol and focused on symptoms, and a 2024 study “A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study“, that illuminated some intriguing pathways.
As we’ll see, though, the short publication list to come out of the Severely Ill Big Data study thus far hardly reflects its potential impact: its story is far from over.
Talk with the Big Data Guy
Given it was a very “big data” study, it made sense to go to the big data guy who’s been making sense of it. Check out the Zoom interview and/or read the blog below, or do both!
An expert in computational analysis, Wenzhong Xiao PhD co-leads the Open Medicine Foundation’s Ronald G. Tompkins Harvard ME / CFS Collaboration
Dr. Wenzhong Xiao is the director of the Immunometabolic computational center at the General Hospital at Harvard Medical School, and leads the Computational Genomics group at Stanford Genome Technology Center (note all the computational stuff).
More to our purposes, Dr. Xiao is also a member of the OMF Scientific Advisory Board, is the Co-Director of the OMF-funded Ronald G. Tompkins Harvard ME / CFS Collaboration at the Harvard-Affiliated Hospitals, and is a longtime collaborator of Ron Davis.
In an era of billowing amounts of molecular data from genomics, metabolomics, proteomics, and immunology, finding ways to computationally integrate these enormous data sets is one of the hot areas in medicine right now – and that’s what he does.
The data, you might say, stops with him.
Findings
When asked what findings the study produced, Ron Davis stated they “almost found too much”. Many metabolic and immune abnormalities were found, including test results that were orders of magnitude different in the severe ME/CFS patients.
The low morning cortisol finding may seem like yesterday’s news, but Xiao sounded shocked by how significantly it popped out – it looked like a major driver. With Akiko Iwasaki’s similar finding in long COVID (it was the most significant finding there as well), we should see more interest in the HPA axis and the adrenal glands. Plus, Wenzhong stated that the low estrogen findings they found, in combination with the low cortisol finding, put even more attention on the adrenal glands.
The HPA axis – one of the two major stress response systems in the body – was a hot topic early in the history of ME/CFS and faded over time as a topic, but studies still regularly come out on it. Dr. Janet Mullington in an Open Medicine Foundation-funded study, for instance, is in the midst of a rare deep dive on cortisol and sleep in ME/CFS. (Blog coming up.)
Another thing that popped out was the brain-derived neurotrophic factor (BDNF). BDNF is a key neuroplasticity supporter in the central nervous system and here Xiao presented a kind of theme in their work – using other data sets to validate their findings.
An analysis of an NIH long-COVID muscle study suggested similar alterations in BDNF were occurring in the muscles. That’s an intriguing finding because BDNF helps the muscles use fatty acids to produce energy, and fatty acid metabolism seems pretty clearly disturbed in ME/CFS. Could BDNF be a surprise entry in the disturbed fatty acid metabolism sweepstakes?
“Network Medicine” Produces Drug Possibilities
The cortisol and the recent pathways finding highlighted a distinct way the Stanford team works. They’ve put past ME/CFS molecular findings in ME/CFS into a large database they can analyze all at once. If the data indicates that a metabolite might be off, they will look to see if other data indicates that the gene that regulates that metabolite is off as well. If both show up, they will start to look for a drug that might affect both.
Then because ME/CFS is so understudied, they’re also going outside the disease to gather molecular data on better-studied diseases to: a) help them understand what might be going on in ME/CFS; b) uncover diseases that look most like it; and c) determine whether drugs used in these diseases might be helpful in ME/CFS. They call this molecular bootstrapping approach “network medicine”.
The process has worked – they’ve come up with several potential drugs for ME/CFS and are exploring them further.
If I’ve understood it correctly, they’ve also downloaded around 1,000 papers in an attempt to use artificial intelligence to answer questions about ME/CFS and have been exploring that with Efthymios Kalafatis – who used AI to recover from ME/CFS.
Rare Pathogenic Genes…
Rare gene mutations may be contributing to ME/CFS.
Decode ME, a joint UK/NIH-funded study that got started in 2021, is the most recent mega-ME/CFS study to get going. (DecodeME says it’s the largest ME/CFS study ever :)). Wenzhong thought this genome-wide association study, or GWAS study, will help determine if common genetic variants created genetic weaknesses that allowed this disease to get started. Note that a 2011 ME/CFS heritability study suggested that genetic weaknesses to these diseases are present.
(DecodeME recently published a study which found that people whose ME/CFS was triggered by an infection had a different pattern of symptoms, that women with ME/CFS tend to have more comorbidities (other conditions), that being female and having ME/CFS for more than 10 years increased one’s risk of having more severe ME/CFS.)
Ron Davis and Wenzhong Xiao and the Stanford group are looking at a very different possibility, though. They are using whole genome and/or exome sequencing (WGS/WES) to determine if very rare genetic variants are contributing to ME/CFS. The GWAS studies, for instance, as big as they are, examine hundreds of thousands to a million of the 3 billion genetic bases, i.e. about one in 3,000. WGS, which is quite a bit more expensive, looks at all of them.
The whole genome sequencing approach highlighted 96 possibly pathogenic mutations in the Severe ME/CFS Big Data project. The central nervous system showed up in spades – suggesting that the buck may end up stopping at the CNS in ME/CFS.
While many of the genes were different in different patients, as a group they were distinguished by their ability to alter neurological functioning. Six potential neurodegenerative disease pathways were identified in the severely ill patients. This paper comes on the heels of a Ron Davis and Michael Jensen paper from Stanford suggesting that antibodies found in multiple sclerosis may be attacking the myelin sheaths of the nerves in ME/CFS.
Interestingly, none of the pathways identified were associated with depression. In fact, the analysis suggested that ME/CFS was about as far away from depression as could be.
Epstein-Barr Virus (EBV) on the Prowl Again
Are pathogenic gene mutations impairing some people’s ability to fight off EBV?
Pathogenic genes associated with the Epstein-Barr virus (EBV), and antigen processing and presentation (how the immune system recognizes invaders), also showed up big time. That’s an encouraging finding at a time when EBV is also showing up in spades in long COVID. It’s yet another finding suggesting that EBV could be a core driver of severity in ME/CFS.
Wenzhong said they’re still trying to figure out what the EBV findings mean and is involved in several studies that will attempt to determine if EBV reactivation in ME/CFS is sparking an inflammatory or autoimmune reaction.
He noted that Rob Phair’s Itaconate Shunt hypothesis proposes that the body shuts down metabolism (energy production) to shut off the inflammatory response to a virus. On the autoimmune side, Health Rising recently reported that Akiko Iwasaki’s Yale group recently produced a long-COVID-like state in mice by transferring IgG antibodies from long-COVID patients into them.
If that was happening with EBV in ME/CFS (or long COVID), that would mean that in its effort to attack EBV, the immune system had misfired and ended up attacking our own tissues. Finding the antigen – the part of the virus the immune system had aimed at – is apparently not a trivial matter. The search, however, is on.
An NIH Interlude
Always the careful researcher, Xiao stated, “I think we have to basically validate this rigorously” with larger studies – a seemingly constant theme in ME/CFS. While we don’t have them or the funding to do them, the good news is that ME/CFS research is not lacking for findings or possibilities – it’s simply lacking in money – and to a large extent that means National Institutes of Health (money).
That brings to mind #MEAction’s Petition to the new NIH Director, Monica Bertagnolli, who has shown interest in both ME/CFS and long COVID – to provide funding for the Roadmap Initiative. The NIH created the Roadmap Initiative to guide it in its ME/CFS research – with the understanding – at least in the patient community – that funding would follow.
The same was true with Nath’s Intramural Study. The Intramural study was designed, then-director Francis Collins said, to provide clear research avenues the NIH would follow up on. So far, though, it’s been business as usual for the NIH regarding ME/CFS. Please help to change that and sign the petition.
- Sign the petition here.
The Severely Ill Patients – Not Different – Just Worse Off!
One train of thought has been that the severely ill are different – that something extra must be going on to make them so ill. The other train of thought is that they’re the same as other ME/CFS – just worse off.
It’s an important question. If the severely ill are in some core biological ways different from the rest of us, they are in a world of hurt given how hard it is to get them into research studies. If, on the other hand, they are similar but worse off, they should be able to benefit from all the other ME/CFS studies (and long-COVID ones as well.)
When I asked Wenzhong about this, he said the study suggested it was door number 2: biologically, the severely ill appear to be the same as other ME/CFS patients but just worse off.
Connective Tissue Breakdown?
One potentially important gene variant (ADAMTSL2 RS 35767802) was found in 45% of the severely affected patients, but – and here was the kicker – it’s not found in the general population in such a high degree. This variant appears to play a role in the degradation of the extracellular matrix and that means connective tissues, which potentially means spinal issues, blood vessel and gut problems, tweaked nerves, and more.
These kinds of amino acid changes can completely disable a protein but since this mutation only affects one amino acid in the protein it’s not clear if that’s happening in ME/CFS. Nevertheless, seeing it pop up in such high amounts in severe patients was startling.
New treatment possibilities, including molecules to modulate nervous system activity, most excited Wengzhong now.
What’s Exciting Wengzhong Right Now
The treatment possibilities popping up from the Severe Big Data study – particularly molecules that modulate the nervous system – most excited Wengzhong now. Those are under wraps as they figure out how to test them and when and how to announce them or publish them. Their concern is patients trying strong drugs before it’s clear they can be safely used in ME/CFS.
Note that the Stanford OMF team recently published a study suggesting that an amino acid combination called LOLA might be helpful. The authors proposed that using the L-ornithine plus L-aspartate (LOLA) supplement regimen “could potentially rescue the metabolic changes observed in ME/CFS patients” (!). LOLA is a supplement combination that is readily available and has been used for decades to reduce ammonia levels in people with liver problems. That’s intriguing given that some researchers believe the liver is involved in ME/CFS.
Wengzhong was also intrigued by the possibility that the neurological pathways found in some neurodegenerative diseases will shed light on what’s happening in ME/CFS – and that was it for our talk! Thanks so much to Wengzhong for taking the time to talk about his and the Open Medicine Foundation’s work.
I find it interesting that Wengzhong is looking at ADAMTSL2 gene as that is one of genes often found on the Ehlers-Danlos diagnostic gene panels.. EDS patients, especially hypermobile, have high levels of fatigue and often carry both the Dx of hEDS and ME/CFS. He then identifies the central nervous system being an area of great interest–think POTS! and other dysautonomias also common in ME/CFS and EDS. He has recommendations to find drugs that are gentle enough for the ME/CFS population, but I might add that EDS as well as ME/CFS patients are often VERY drug sensitive.
I personally have wonky cortisol fluctuations and know my circadian rhythm highly affects (overly affects) my energy levels. This is all very interesting and I can’t wait until the rest of your blog comes out, Cort.
Now, I see that I am one of the first to post this time as I have been in shock at the results of our recent election (USA), and suppose others are as well. With the announcement that Kennedy will become the “Health Czar” of all the big agencies, NIH, CDC etc., I wanted to know more about his health philosophy and not just anti-vaxx or against big pharma.
Listened to a 3 hour conference which featured him and others talk on this topic and basically they placed a lot of the blame on highly processed food, poorly tested additives in food and farming, a deficient diet of the wrong kinds of foods, lack of exercise and the overuse of medications for problems that could be cured by natural means and fragmented health care. Many of the presenters stressed an organic ketogenic diet.
Of course with Trump elected, and his past efforts to dismantle the US health care, primarily the ACA, his win has distressed me greatly. It is my belief that many illnesses are quite complex and the causes and treatment of chronic afflictions like ME/CFS are not so easily cured with just lifestyle changes. Diet? I’ll bet so many Long Covid and ME/CFS folks have tried a plethora of diets and supplements–all to no avail. I’m not even going to entertain the thought of insurance companies being able to turn down people with pre-existing conditions–or charge them at an exorbitant rate. It’s all a bit much. I hope this gloomy view is just a product of my over active imagination…
I take LOLA and the effect is–mildly helpful. Poco a poco. I want something better than that!
I personally have zero confidence in Trump doing anything of value. I believe he wont allow RFK do anthing at all, even if he is appointed
A great pity as I think RFK has his heart in the right place and his ideas, as outlined below are good
https://carnivorecampus.com/how-robert-f-kennedy-jr-could-revolutionize-food-policy-and-public-health/
I know he can come off as pretty kooky at times, especially with media spin, but I too think Kennedy could do some good things if allowed. He does talk a lot about processed and chemical-laden food and regenerative agriculture (awesome), but i think in his long career as a very successful environmental lawyer he has also seen the horrid effects environmental factors, toxic chemicals and pollution has wrought on the country’s health, and he defends those victims and wins bigly against some of the largest and most powerful corporations in the world as well as some of the very depts of gov that he may be tasked with overseeing. He knows their games and has beat them at it, and claims to know the problems and the specific corrupt players that need to be fixed/fired.
I have heard him speak a LOT on helping chronic diseases, even naming things like Lyme and LC. I think he will be very supportive of research, and he could be a great ally to us if we make ourselves known to him. If you listen to him without preconceptions in long form interviews, he seems to be a rational and reasonable person whose opinions are largely based on deep research – but he will listen and isnt afraid to change his position on something if he learns new information. I know his vax positions are controversial, but I also think they are misrepresented, and yes he has many personal failings but who doesn’t – and that bar is pretty low these days anyway. Regardless, there are other things that also matter, like truly helping chronic sufferers.
Now, my bigger concern is actually that he wants to clean house at these departments and change their focus to chronic disease prevention and treatment, but Trump and the rest say they want to just eliminate everything. That concerns me that RFK will be hobbled by resistance and lack of funding from his own team. I hope I am right about him and wrong about how they handle him!
Cleaning up out food process from farm to table can only have a positive effect on the health of our nation. We should move into the future with hope and optimism.
I’m glad he has good dietary recommendations! That was good to hear! My main concern with Mr. Trump regarding ME/CFS is my main concern with everyone really – will they continue to fund the NIH and can anyone get the NIH to pay attention to ME/CFS?
It’s important to note that while Republicans are hesitant to tell the NIH what to do (like fund ME/CFS more) funding health research is one of the few bipartisan topics that both sides agree on – so hopefully NIH and CDC funding will be safe.
Cort,
I think your concerns are way too low… I hope you are right but in my opinion, I guess he could easily scew up NIH and CDC funding with a sudden decree written on a napkin one morning.
Do not forget that this guy is the one who wanted to inject javel water into the people’s arm to cure the Covid-19 pandemic. He is the hell of a public hazard. He knows as much in medicine as a donkey.
:)….Mr. Trump can be very changeable, that’s for sure. He did actually try to slash the NIH’s budget the first time around.
Bertagnolli may be gone – which could be a huge hit for us and long COVID.
“Onlookers do expect a change in NIH leadership. Current Director Monica Bertagnolli, a cancer researcher, will be expected, like many other presidential appointees, to submit a resignation letter to the president in late January when Trump takes office. (Her long-serving predecessor, geneticist Francis Collins, was retained by Trump, but there is no reason to expect that for Bertagnolli, who has been in the position for just a year.)”
The NIH is undoubtedly due for reform – look how its done with ME/CFS and with long COVID = it’s badly in need of reform: the question is what kind of reform it will get.
So fascinating – thank you! The Stanford team’s work excites me and gives me so much hope. (Their findings are like a really great TV series… as soon as an episode has ended I just want more!)
Did Wengzhong say what any of the six neurodegenerative disease pathways they found were at all Cort?
And do you know if the Stanford team are looking for more severe participants for the whole genome sequencing? I’m severe and could manage a saliva sample so would love to take part if they’re recruiting.
I think these findings are interesting and for me at least, reflect my own experience; severe ME, POTS, hEDS, sleep disorders (DSPD, hypersomnia/possible narcolepsy since I get cataplexy), amongst other things. The worse my ME has become, the more severe and intense the connective tissue, vascular, CNS and HPA axis issues have become. I had mild autoimmune conditions as a teen (pre-ME) and have wondered if they’re linked or not.
I wonder if they found any crossover with the recent big finding in hEDS about the involvement of the kallikrein genes – they’re involved in so much of what you and Wengzhong talked about.
https://cortneygensemer.substack.com/p/heds-and-the-kallikrein-gene-family?utm_campaign=posts-open-in-app&triedRedirect=true
The six neurodegenerative disease pathways involved a pretty nasty list – but then again not too many neurodegenerative diseases are anything other than nasty. They included Prion disease, Parkinson’s Disease, Alzheimer’s disease, Huntington’s disease, Spinocerebellar ataxia, and ALS).
Yikes, that’s a pretty scary list indeed – especially as none have a cure.
I remember a comment about ME and related chronic disease research that said something like: ‘cure one and you’ll cure them all’ so if that’s the case then perhaps developments in ME and any of the other 6 diseases could help each other move forward (I hope!)
Just to add to that… the seriousness of the diseases listed does give some much needed validation as to how serious ME is though. Might help people outside of the ME community understand it better if they realised that.
Ann1, Our organization has worked with Gulf War veterans and researchers involved with the issue of Gulf War Syndrome (GWS) since the early 1990’s. Nearly one third (100,000) of the veterans who served have GWS which is almost identical to ME/CFS. Subtle differences are probably due to the preponderance of GWS in male veterans whereas ME/CFS is more common in females.
What can we learn from this? Genetic factors are unlikely to be a major contributing factor. But if 100,000 veterans did have the same genetic profile, it would suggest an enormous vulnerability to toxic chemical exposures (particularly pesticides) in the general population. Keep in mind, however, that we have a volunteer army of only the heathiest physical specimens.
The VA and military researchers attribute GWS to chemical exposures during service, primarily pesticides and possibly low levels of nerve gas agents which have the same effects of pesticides.
How were the veterans exposed? Their uniforms were pretreated with permethrin; they were also given aerosol cans of pesticides to use and their blankets, tents and base perimeters were sprayed with pesticides.
We actually have a uniform, a can of aerosol pesticides and a package of pyridostigmine that veterans sent our organization.
I have not opened the uniform because we have had reports of families who opened boxes of things sent back from the Gulf also getting sick.
Some pesticides can lower your immunity allowing endogenous viruses, bacteria, fungi and mycoplasma to reactivate and cause symptoms.
A study found that Gulf War Illness (GWI) patients had significantly higher levels of antibodies to HHV-6 and VZV dUTPases than controls.
I can’t imagine why the ME/CFS and Long Covid researchers haven’t studied Gulf War Syndrome or collaborated with the DOD and VA which have plenty of money for studies.
I’m about to try low dose Aciclovir for potential underlying EBV. A long shot, but this blog and my integrative GPs success with it on others has me hoping I’m finally on the right path.
We have a blog coming up featuring a doctor who uses antivirals to treat ME/CFS. He said results take 3 months to show up at a minimum – so its probably best to give it some time. I have never taken antivirals for that long…
Thanks Cort, that’s interesting and very different from my doc’s belief that improvement comes quickly if it’s working. Looking forward to reading the blog.
PolyBio are starting a clinical trial with an antiviral
Found no benefit from Lola!
Did anyone else see Jarred Younger’s Youtube video on the Stanford symposium a few weeks back? He seemed very excited about a few things mentioned at the symposium, but he couldn’t talk about them. It certainly piqued my curiosity. I wonder if drug trials alluded to by Wengzhong was one of the things
Regarding comments on Lola above could poor quality supplements be giving a false impression I wonder? Dr. Theoharides recently said in a podcast that a study showed around 60% of supplements have non of the marketed substance in them!
I dread to think how much money I have wasted and continue to waste on these supplements 🙁
If you’re concerned about the quality of your supplements, you can look them up at https://www.consumerlab.com/. I can’t make any promises, but I’ve heard good things about them. I’m not affiliated with them in any way. They test supplements from different brands and report on what they actually contain.
Looks like it might not be so useful for the UK but I’ll definitely delve a bit deeper. Thanks for the tip Lisa
What an important study! Let me comment on this finding:
“Another thing that popped out was the brain-derived neurotrophic factor (BDNF).”
This could be an important hub. We all know that a few drugs can work (short-lived) wonders in ME/CFS, especially benzodiazepines like Ativan etc. We also heard of freak improvements from Ketamin, Propofol etc.
The kicker is: they all seem to work by increasing BDNF levels ((https://pdf.sciencedirectassets.com/271928/1-s2.0-S0753332223X00122/1-s2.0-S0753332223017481/main.pdf))
So possibly, a non-addicting drug acting on BDNF may be a therapeutic option for the future.
… btw, psychedelics also act through BDNF – they bind directly to the BDNF receptor TrkB
https://www.nature.com/articles/s41593-023-01316-5
Interesting! Jarred Younger has a psychedelic fibromyalgia (FM) trial underway and if I remember correctly another is underway in FM.
Help Herbert, thanks for the info! I asked Chat GPT if there were any supplements you could buy to help BDNF and it came up with this:
7,8-Dihydroxyflavone (7,8-DHF) is a small-molecule TrkB agonist available as a supplement. It’s thought to mimic BDNF by binding to the TrkB receptor and activating similar signaling pathways. However, evidence on its effectiveness in humans is still limited, and its safety profile is not fully established for long-term use.
There seems to be one company producing it that sells in the US only so far as I can tell:
https://www.amazon.com/8-Dihydroxyflavone-Capsules-Nootropic-Supports-Cognitive/dp/B07HNH4PT5#aw-udpv3-customer-reviews_feature_div
Do you think this could be worth a go or does it seem too good to be true? Thank very much for any help (and in general for your research for our community!)
Thank you for this piece of research! I mean we are all searching for the needle in the haystack, and AI is more and more part of this. As to the compound itself: I have no idea, would need a thorough review of all published data… a brief search mentioned that there may be some controversies about it being an agonist for TrkB (https://elifesciences.org/reviewed-preprints/93094/reviews) – so: more work needed, but certainly a good lead!
Magic mushrooms to the rescue.
I’ve been micro dosing shrooms….they work everytime but I don’t like being on them steady
And…if you’re really having a bad time do a full dose and the magic happens everytime you close your eyes
Roonie, I microdose psilocybin every day at 125mg and I wouldn’t be without it. I can get the capsules easily in Canada.
👍yes, I see in the city where I live even cannabis outlets will sell them if you ask discretely…and they have very high quality as well.
125 MG…wow…I don’t do that much everyday. I do just a very small micro dose
Paul stametts(spelling)(?)is the mushroom king here in 🇨🇦
He’s written several books.id like to go out and find my own someday
buckey, Paul Stamets lives in Washington state and sells products through his website:
fungi.com
He also sells his books there. I have two of them and they are very well written.
125mg isn’t a very high dose of psilocybin. I take it on a schedule of six days on, one off. Cheers.
I think BDNF is very important in combintion with stress and infections, toxins there is a possible loop 🙂 The drugs you describes could help a lot.
Especially with the GABA connection, i forgot to say
Bingo! Couldn’t agree more based on firsthand experience. Benzodiazepines have given me a marked improvement overall in symptoms and quality of life. Better energy too. In addition, I’ve always told family and friends how I feel so much better for one to three months after anesthesia (which contains Propofol).
Not just a firm believer but living proof.
I’ve noticed that I always have a bigger spring in my step after dental anesthesia :). and benzo’s can be good for dysautonomia. How often do you take them?
Every night for 4.5 years. I cut my dose in half (reduced) early this year to see what would happen. It’s been many months and I think I’m going to go back up to where I was. It’s worth it to me.
For me the same it helps a lot low dose, i stay on it till the end. The only thing that works for me
wow me the same 🙂
I don’t think benzodiazepines give me much benefit, personally.
Regarding hypnotics, I had an accidental temporary partly remission event last year, when during a) a bad stomach bug, I b) took first dimenhydrinate, then diphenhydramine and kind of got “high” on it 😉 while not exceeding normal doses, and c) may have inadvertently have had drug interactions with anti-histamines that I was taking at the same time. I had a good & relaxed feeling like I last felt when I was 10 years old and basking in the sun besides a mountain brook (endorphines? serotonine?) – it felt as if something was healing inside my body, and I could suddenly deeply meditate and lost the wish to consume media. Over the days that I was taking diphenhydramine or dimenhydrinate, it unfortunately morphed into sedation. I could not maintain or reproduce the positive effect. I think I must have overloaded my H1 receptor or something, as it took rather long for me to tolerate antihistamines again after this event.
I can to this day not say to what extent it were the medications or immune effects produced by the gut infection that produced the remission event.
The drugs that give me short-lived wonders (with bad crashes and systemic overactivation for days afterwards) are coffeine related (tea, coffee, cocoa). Possibly alcoholic beverages, too. But they only work if there is a certain “reserve” for them to burn (my guess is that they are adrenal stimulants, and only work if there’s enough adrenal reserves to bur”; possibly also that they temporarily remove that central fatigue mechanism discovered in the Nath study which I assume to possibly be a protective mechanism against PEM). Could also be their effects on dopamine etc. and circulation though.
… another comment on the finding of deranged cortisol and estrogen levels that popped up in this study:
we should always keep in mind that the steroid synthesis pathway is easily “hijacked” from viruses.
So the mess-up in diverse steroid hormones often seen in ME/CFS may not necessarily come from the HPA-axis – but may be a marker for ongoing reactivation of endogenous viruses.
That’s a great thought. As some will know I have been a skeptic of the virus reactivation theory. However, while not totally convinced, I am starting to change my mind…. At least open to the theory
Did you read about the recent University of Colorado study that found low levels of cortisol? Iwasaki found it too, although the cortisol collection methodology was criticised by one party
sure i read these papers. Imho, viral reactivation is well supported by evidence. What we do not know, is if it´s the abundance of the species reactivated, or the “mix” thereof, or the kind(s) of species, or if there is a common denominator (like torque teno virus).
We definitely should get better in developing methods that can pick up viral reactivation in tissues…
Because just imagine: we are always talking about endothelial dysfunction – well, the endothelium is where HHVs like EBV and some endoviruses replicate. Could endothelial dysfunction/inflammation reflect ongling viral reactivation? Theoretically, yes,but we don´t know.
Because nobody ever looked at it 😉
“We definitely should get better in developing methods that can pick up viral reactivation in tissues…”. Thankfully this is starting to happen a bit with Long COVID I believe.
Cort, you featured the work of the team at Griffiths University in Australia in a post in August of this year, called “Could a Widespread Ion Channelopathy be Causing ME/CFS, Long COVID and Gulf War Illness?”
https://www.healthrising.org/blog/2024/08/20/channelopathy-chronic-fatigue-long-covid-gulf-war-illness/
In this post, you highlighted the result that in ME/CFS the TRPMC ion channels are not allowing ions to pass into cells, including into mitochondria. As noted in the study and in your blog post, naltrexone can reverse this block in the ion channels.
The work of the Griffiths group notes that this block often occurs post infection among genetically susceptible individuals.
In the comments on your post, Sue Edwards asked whether or not increased dosing of naltrexone could help. No one responded.
I have since then searched far and wide for evidence that naltrexone can be taken more than once a day. I was surprised at what I found.
I already knew that there were some instances noted in comments on presentations at the LDN Research Trust conferences every year that some people took “low dose naltrexone” in the morning instead of at night, and that some people took LDN in the morning and at night. I also knew that some peope took LDN at doses up to 25mg and found relief.
What I also found out in my search was that there are a lot of people who take naltrexone numerous times a day at different doses. I searched the web in general, Reddit, YouTube, and various patient forums. I found people whose “sweet spot” was 0.0002mg once a week. I found people who took it every other day. Some take it twice a day, and some take it three or even four times a day. One YouTube video consists of a social science researcher in Norway interviewing the two main authors of the work at Griffiths University. He takes naltrexone when he feels that he needs it and some days that is four times a day. He asked the researchers whether or not they recommended this. They refused to answer “because we have not completed clinical trials on this.”
Responses to these dosing regimes range from “I’m going to try that” to “You can’t do that! That’s not low dose naltrexone anymore!” to “When you take it so often, there’s no rebound effect for the release of endorphins, so you’re defeating the whole purpose!” But there are so many people doing so many different things with naltrexone and finding relief, that there just cannot be one way of doing it.
Naltrexone does many things. It’s an anti-inflammatory, an antioxidant, a binder of mu-opioid receptors, an endorphin enhancer, and an opener of ion channels. Maybe people have different conditions that respond to the different actions of naltrexone. Everyone is different, everyone responds differently. People take naltrexone for alcohol addiction at doses of 50mg or 100mg every night, so we know it’s safe even long term.
I do not doubt that people taking natrexone in novel ways are finding efficacy. I cannot be otherwise.
I started taking naltrexone four years ago and veeerrrry slowly ramped my way to 6mg per night where I found that it helped me a lot. So I’ve been there for 3 years now. After looking deeply into the experience of others, I began taking 6mg the mornings, as well.
The first two days were rough, I felt like I’d been hit by a truck or had the flu plus anxiety and depression. The third day was wonderful: the nauseating poisonous ache in my right hip was gone, the swelling in my legs was gone, the anxiety and depression were gone, but I still had some fatigue and PEM.
I upped it to three and then four times a day over the next week. I’m telling you now, this has been life changing for me. Clearly the ion channels in my cells and mitochondria were blocked. When I first take it, I feel warm all over as if blood is getting to places it hasn’t been in a long time. I am not 100% recovered, I’m 76 years old and though I used to be extremely active, I have lost conditioning. I can’t jump back into activity I haven’t done in a long time. I must pace.
Having said all this, I feel better than I have in years. My hairbrush tells me my hair is not falling out at the rate it was. I have no idea if my fingerprints will come back, but at this point I don’t care about that.
This works for me. It will not work for everyone, it can’t possibly do that. I started and stopped naltrexone in the beginning. I went up and I went down in dosage. But I kept trying different ways, different times, different methods (capsules, skin lotion, and finally, dissolved in distilled water). But every time, when I stopped doing it, I got worse again, so I knew it was doing something good. Now I’m glad I kept it up. I’m rather stubborn that way.
I will do anything to keep up my supply of this now. I will tell any prescriber that I’m an alcoholic and I need 100mg tablets of this, one every night, in order for the province (I live in British Columbia) to pay for it – they like to feel they are helping alcoholic addictions anyway.
My hunch is that there is a genetic component to this, plus a precipitating event or series of events. I hope this comment can help other people who are sitting on the fence about trying naltrexone.
For me what convinced me that reactivation in tissues could play a role was when I saw the recent research results how viruses can interact with and influence cells without even replicating in the blood (like Prusty’s research, but there’s more). I think in one study Prusty even showed that very few infected cells can influence cells around them by emitting certain molecules. It was found that there are stages/states of viral reactivation that are not replication in the bloodstream. Also, the big multiple sclerosis study that found EBV infection to be a necessary condition for developing MS, the fact that some viruses like HHV6 can even be inherited with germ cells..
So from me it’s likely a no to viral reactivation in the classical sense (replication in the blood), but a yes to “stationary” reactivation & interference of viruses as co-inhabitants of cells.
Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons
https://pmc.ncbi.nlm.nih.gov/articles/PMC5469259/
Relation between psychoneuroendocrine profile in stressful conditions and antibodies to herpesvirus 6 and 7
https://pubmed.ncbi.nlm.nih.gov/19036226/
This was such a fascinating interview, Cort. For a more in-depth look at the role viruses may play in autoimmunity, here is an excellent technical presentation at the NIH. The first two speakers cover the role of EBV in lupus and MS. The last speaker presents the role of enterovirus and adenovirus in Type 1 diabetes. Each virus has its own unique pathway to develop T1D, which corresponds to which autoantibody develops first, and which MHC haplotype (system the body uses to recognize foreign substances) is present in the child.
https://videocast.nih.gov/watch=54970
Thank you Cort.
I left a message on: https://www.youtube.com/watch?v=LkNb0JlVJK8&t=3593s
Great article with promising news! Looking forward to hearing more about the specific genes they found and the results of cortisol testing. I have taken all of the products below for 3+ years at least.
PEA and luteolin (Mirica) increases BDNF https://selfhacked.com/blog/palmitoylethanolamide-pea/ https://www.amazon.com/Mirica%C2%AE-Palmitoylethanolamide-Netherlands-Anti-Inflammatory-Supplement/dp/B07365MZLY
Cytozyme A/D (Biotics Research) raises cortisol levels. Testing: DiagnosTechs https://www.diagnostechs.com/our-tests/adrenal-stress-index-asi/ It is a 24 hour saliva test. Both need Drs orders.
T Allen, I agree. I take PEA and lyposomal luteolin every day and they help. I would be most interested in seeing whether these mutations overlap with the known mutations found in MCAS.
Is there any research that confirms Cytozyme raises cortisol?
I don’t know about research but I know from my own experience that changing doses, the timing of doses and repeated testing over several years that it sure changes mine! Even my MD admitted that it obviously worked. (I get it from an ND). That’s why I suggest testing first for a baseline and seeing if it really is an issue. You wouldn’t want to take it if you don’t need it because it really would mess things up!
I was surprised to learn that viral reactivation is common in astronauts. Astronauts also need support to recover from POTS (postural orthostatic tachycardia) when they return to Earth. These are both significant factors for people with ME.
Learning what triggers viral reactivation in healthy people working in zero gravity, who also are experiencing dysautonomia may provide some clues to what is happening in ME.
Interesting!
From own experience of becoming severe, I suggest that one reason of becoming severe may simply be “energy mechanical”, i.e. what I call the “Pacing Watershed”:
Once, following a major crash, daily energy availability/exertion capability plunges below the level required for barest minimum tasks of daily living, a situation results where it becomes very difficult to achieve an energy balance via Pacing and thus regeneration of energy capacity and recovery from crash becomes impossible. People will then be forced to constantly overexert, enter a state of “rolling PEM” and not be able to recover from the major crash anymore. (A spiral of further deterioration can result from the constant overexertion in this state.)
I am not sure to which extent that severe state then “chronifies” or rather is being maintained by the constant overexertion resulting from minimum daily tasks or even just the energy required by the body in “stand-by”-modus (like e.g. for thinking and other bodily processes).
I call it the Pacing “Watershed”, because on one side of this watershed a degree of regeneration via Pacing is possible, while on the other side of it regeneration becomes very difficult.
While above the Pacing Watershed, achieving an energy balance (and thus stabilisation of state of functionality with ME/CFS and a degree of improvement) via Pacing are still possible, below the Pacing Watershed it becomes difficult or physically impossible for the system with ME/CFS to achieve an energy balance (or also psychologically untenable to endure the degree of activity deprivation – i.e. doing nothing – that would be necessary to achieve an energy balance in this state). So, ME/CFS can become kind of self-perpetuating below the Pacing Watershed.
JR this is an important factor that I don’t often see discussed.
My daughter and I made a good recovery after the first 10 years using a simple pacing method we found in a book to help young people with ME (Somebody Help Me by Jill Moss)
It gave a simple way to identify what level of activity would trigger a crash. By keeping under that level, with a little ‘recovery energy’ factored in we both clawed our way out of that danger zone back to functioning again.
Relapse following unavoidable events (Lyme disease, Typhoid, Vaccine reaction, medication reaction) meant the journey back up had to start all over again, repeatedly.
Living alone now, I have no extra pair of hands to help me pace my energy use. Very basic daily activity always takes me well into the danger zone.
So I am older, but the severity of my symptoms I do not put down to age, but to living without the support that would allow me to effectively pace myself back to good health.
Thank you for your reply! I’m in a similar situation (with the additional complication that due to ME/CFS I am very fragrance intolerant – another factor that I’d like to see discussed more often – which further complicates access to help). I am lucky to have a volunteer helper (a lady I knew before) since a couple of months – would that maybe be an option for you too, e.g. via a volunteering organisation? Have you already implemented stuff like a vacuum robot, and so on? Wishing you all the best, and sometimes I think we should have a group just for exchanging practical energy saving tipps :-).
Practical tips sound good. The things I found that have made the biggest difference are not medical interventions, but practical advice from others. Long-handled soft sweeping brush to clean the bath! That was a good one!
Yes, the severity seen in older people is not biological, it’s neglect. Perhaps that realisation would prise out more research funding.
Age does play a role in worse mitochondrial functioning that declines as we age. To what degree it happens may vary from person to person, but it is part of the aging process. https://pmc.ncbi.nlm.nih.gov/articles/PMC4003832/
Personally I wouldn’t believe anything written by
Gov
I learned decades ago, there not your friend
If gov.was your friend, this would have been solve decades ago instead of being told we are all crazy or, it’s all in your head
I’m very interested in the comment about cortisol and feeling awful in the morning, when I can’t get up until very late and if I’m going to improve at all that day improvement starts at about 5 pm. I’m always better in the evening. A morning and evening cortisol (saliva test) showed my cortisol does indeed increase in the evening (9pm test). I’d like to see more confirmation of this. It is also easily accessed evidence of our ‘abnormal’ state.
Me also. I’ve been a night owl my entire life. Takes me all morning just to think about how I’m going to begin my day.
Cort, your articles are always so informative and helpful to our ME/CFS community. Have you ever written about your backstory and passion for helping others understand these difficult illnesses? I think knowing your background and journey would help others cope with ME/CFS and its comorbidities.
Thanks for the interest 🙂 I put my story upon Phoenix Rising years ago but lost track of it I was asked to provide an oral story as part of a project – which I will do at some point 🙂