People with chronic fatigue syndrome (ME/CFS) are not alone. Nor are people with fibromyalgia (FM) or dysautonomia or migraine. We all exist in a swirl of allied illnesses. ME/CFS experts recognize that, but researchers who typically get trapped in disease silos – not so much. People with all these diseases – chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, orthostatic intolerance (OI), mast cell activation syndrome (MCAS), joint hypermobility – the list goes on and on – badly need research that breaks the mold and explores the linkages between them.

Why? For one – they do seem to be linked together and those linkages could tell us much about each.  Despite David Kaufman’s initial focus on ME/CFS, his and Dr. Ruhoy’s Unraveled podcast series is not on ME/CFS – it’s on “Understanding Complex Illnesses“.  Bela Chheda and David Kaufman are most known for their work on ME/CFS, but they created “the Center for Complex Diseases“.

Similarly, when #MEAction chose to put their resources into a survey, they created a “Chronic Ilness Survey” featuring ME/CFS but also POTS, long COVID, hEDS, and MCAS, and planned to include more illnesses in the future.

There’s power in numbers. These diseases tend to affect a lot of people, but most get lousy funding. The more groups we have working together, therefore, the better chance we have to get more funding for all of them. The Long COVID Alliance the Solve ME/CFS Initiative cofounded contained illness groups from the ME/CFS, long COVID, dysautonomia, fibromyalgia, autoimmune, migraine, pain and neurological disorders communities. They all recognized they can do more together than apart.

Lastly, the Solve ME/CFS Initiative and others are working to create a post-infectious disease institute at the NIH. The more we can demonstrate the need to study these diseases together, the better chance we’ll have to produce that. We thought that long COVID would lift all boats – and it has – but not at the National Institutes of Health. Lyme disease funding remains strong, but ME/CFS and fibromyalgia funding has either fallen (ME/CFS) or remained flat (FM).

It was very good, therefore, to see two German researchers, Klaus Wirth and Mathias Lohn, back with a hypothesis paper that shows how these diseases may be linked together.

Dog digging a hole

Like a dog with a bone, Klaus Wirth has been digging away at ME/CFS and related diseases. The more he’s looked, the more he’s found.

A Dog With a Bone

Klaus Wirth, it seems, just cannot be stopped (not that anyone is trying). A pulmonologist by training, he’s dug into ME/CFS like a dog with a bone. Over the past 3 years, Wirth has published 5 hypothesis papers that extend what he and Carmen Scheibenbogen proposed is happening in ME/CFS in 2019.

The deeper and wider he looks, the more he seems to find. A hypothesis that originally focused mostly on ME/CFS has, over time, been potentially extended to fibromyalgia (FM), idiopathic intracranial hypertension (IIH), mast cell activation syndrome (MCS), endometriosis, postural orthostatic tachycardia syndrome (POTS) and small fiber neuropathy (SFN).

Hypothesis Predicts Major Failure Point in Chronic Fatigue Syndrome (ME/CFS)

The Oxygen Crunch

Wirth’s latest paper, “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?“, co-authored by Mathew Lohn, asserts that problems with the blood vessels could underlie all these diseases.

The basic idea goes something like this: damaged mitochondria stop the muscles (or brain or other tissues) from rising to the challenge. Since energy is, after all, the currency of the realm – our bodies, above all, need it –  the muscles or other tissues put out all the stops to get more energy; i.e. to bring more oxygen in. The way to do that is to increase blood flow to them.

There’s a problem, though. At the same time the mitochondria have pooped out, Wirth and Scheibenbogen posited that an ongoing sympathetic nervous system (“fight or flight”) hyperactivation has clamped down hard on those blood vessels – preventing blood to freely in them. Recent studies suggest that they’re correct.

Narrowed Small Blood Vessels Linked to Fatigue in ME/CFS

A process called stagnant hypoxia that may exist in ME/CFS and POTS provides another way by which oxygen delivery may be impaired in these diseases. Stagnant hypoxia occurs when the oxygen content of the blood is normal, but the blood is moving too slowly to deliver sufficient amounts of blood to the tissues.

Stagnant Hypoxia – Where Chronic Fatigue Syndrome and Hyperadrenergic POTS Meet?

The idea that oxygen-starved tissues are causing pain and fatigue in ME/CFS and fibromyalgia goes back at least ten years.

Are Oxygen Starved Tissues Causing Pain and Fatigue in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)?

David Systrom’s findings of impaired oxygen extraction at the level of the muscles would seem to cement this issue.

Poor Oxygen Extraction is Contributing to Exercise Intolerance in Chronic Fatigue Syndrome (ME/CFS)

The Vasodilator Dump

While it’s apparently impossible to test for these substances (they disappear too quickly), Wirth, Scheibenbogen, and Lohn appear to have a solid basis for their hypothesis proposing that the body must be dumping massive amounts of vasodilators to open up those blood vessels and restore oxygen flows to the mitochondria in ME/CFS.

That might be all to the good in acute situations, but in chronic situations like ME/CFS, the vasodilators spill over into the bloodstream, causing pain and all sorts of symptoms.

Constricted and dilated blood vessels

The authors believe energy-starved tissues release massive amounts of vasodilators in an attempt to open constricted blood vessels in ME/CFS and related diseases.

That process – where tissues deprived of oxygen fight back by releasing vasodilators is known to happen in the heart. In ischemic (low oxygen) heart disease, our hearts pump out a variety of mediators (prostaglandins, prostacyclin, ATP, adenosine, and particularly bradykinin) to get the blood flowing again. The downside is the tissue acidosis, pain (angina), blood vessel leakage) they cause as well.

The Gynecological Connection

The gynecological connection to ME/CFS has received surprisingly little attention in a disease that’s dominated by women. Several studies, though, have found higher-than-normal rates of gynecological diseases in ME/CFS. Indeed, they suggest that as many as a third of all women with ME/CFS may suffer from endometriosis and resulting comorbidities.

Nobody, though, has potentially connected the blood flow issues in ME/CFS to the gynecological issues until now. The authors propose that a muscle/blood flow problem is either contributing to dysmenorrhea/endometriosis in ME/CFS or, interestingly, is perhaps causing ME/CFS in those diseases.


In dysmenorrhea (painful menstrual periods), we see a familiar situation; hypercontractile muscles lock down blood flows, causing an oxygen deficit (ischemia). That, the authors believe, triggers a massive production of vasodilators like bradykinin and prostaglandins to open the blood vessels back up and restore the blood flow. (The authors suggest the process may be akin to having an “intravenous infusion” of a vasodilatory “cocktail”.)

Once again, the authors propose that these powerful, pain, muscle spasm, blood vessel leak-producing compounds are spilling into the bloodstream and causing pain and other symptoms.


In endometriosis, tissue grows outside the uterus.


Endometriosis is a different case. Endometriosis (EM) occurs when endometrial tissue grows outside the uterus, triggering a “chronic inflammatory, estrogen-dependent gynecological disease”. Endometriotic tissue can be found in quite a few areas outside the uterus (peritoneal cavity, ovaries, bladder, or ureters); the effects can be widespread and quite complex.


  • People with chronic fatigue syndrome (ME/CFS) are not alone. Nor are people with fibromyalgia (FM) or dysautonomia or migraine. We all exist in a swirl of allied illnesses. Doctors recognize that, but researchers who typically get trapped in silos generally have not.
  • Recognizing the connections between these diseases and studying them will help us understand all of them, and importantly, should increase funding for these typically greatly underfunded diseases.
  • Given that, it was great to see two German researchers, Klaus With and Matthias Lohn, band together to produce a hypothesis paper potentially linking ME/CFS, endometriosis and MCAS together.
  • They propose that massive outflows of vasodilating substances that are spilling over into the bloodstream are producing the symptoms in these diseases.
  • In ME/CFS, mitochondrial problems are limiting energy production, causing the body to find ways of delivering their “food” – oxygen to them. This requires opening the blood vessels to allow more blood through. The problem, though, is that the blood vessels in ME/CFS are already tightened down – requiring massive levels of vasodilating compounds to open them.
  • Too high levels of these compounds (bradykinin, PGE2, and others), though, can produce pain, fatigue, other flu-like symptoms, and sleep disturbances; i.e., most of the symptoms in ME/CFS.
  • The problem is exacerbated by the inability of adrenoreceptors (β2AdR) to open the blood vessels and support mitochondrial health.
  • Wirth and Lohn propose that a similar process occurs in the gynecological disorders associated with ME/CFS (painful menstrual periods, endometriosis); they believe that contracted muscles lock down blood flows, causing an oxygen deficit (ischemia) which results in the production of massive amounts of vasodilators that produce the painful menstrual symptoms.
  • In endometriosis, they propose that a vasodilator called prostaglandin E2 (PGE2) causes the blood vessels to dilate; it’s also causing the uterine tissues to contract – thus imperiling blood flows and producing a kind of contraction/dilation back and forth. Instead of this process causing endometriosis, they believe it’s causing women with endometriosis to become diagnosed with ME/CFS.
  • Finally, in mast cell activation syndrome (MCAS), they believe an overabundance of vasodilators like histamine is producing similar symptoms to those found in ME/CFS, endometriosis, and dysmenorrhea.
  • Next up – a further look at the connections underlying these conditions as we tackle a paper and NINDS webinar produced by Beth Pollack.



One of the authors’ chief vasodilatory suspects – prostaglandin E2 (PGE2) – could be at play in a big way in endometriosis.

PGE2 causes the uterine tissues to contract and vasodilates (opens up) the blood vessels. That muscle contraction stops enough blood from getting through – which leads the tissues to produce more PGE2 production to open the blood vessels – but which also causes the tissues to contract more.

PGE2, interestingly, is not just a pain producer. It’s also been linked to the familiar flu-like symptoms, fatigue, and sleep disturbance found in ME/CFS. The authors proposed that it’s the PGE2 production in endometriosis that’s causing so many women with that condition to become diagnosed with ME/CFS. Overly high levels of PGE2 production, in other words, may be jumpstarting these conditions.

Mast Cell Activation Syndrome (MCAS)

The authors propose that a similar but different process occurs in MCAS. In the MCAS scenario, hyper-sensitive mast cells blast damaging mediators (histamine, heparin, prostaglandins, leukotrienes, and different proteases (tryptase, chymase), and more than 30 cytokines and chemokines) into the blood.

Here, histamine probably plays the same role in MCAS that prostaglandin E2 does in ME/CFS and endometriosis. It’s spilling into the bloodstream, causing pain, fatigue, flu-like symptoms, sleep issues, etc.

In each of these cases, high levels of vasodilators cause blood vessels to leak, produce spasms, and affect the sensory nerves – causing pain, fatigue, flu-like symptoms, etc.

The B2ADR Connection

Problems with the beta-2 adrenoceptor (β2AdR) figured strongly in Wirth’s and Scheibenbogen’s original hypothesis. In some ways, the β2AdR is the perfect receptor for ME/CFS. (Receptors dot the surface of cells; when they get turned on, they tell the cell how to act.)

Not only does the β2AdR play an important role in regulating blood flows to the skeletal muscles, the heart, and the brain, but in a nice twofer, it also affects cellular energy production.

This is because the β2AdR receptor stimulates the Na+/K+-ATPase enzyme that controls sodium levels in the cells. A failure of the β2AdR to trigger Na+/K+-ATPase can cause sodium buildup in the cells, which causes the sodium-calcium-exchanger (NCX) to switch sides, so to speak, and start importing rather than exporting calcium.

Not only does this calcium buildup damage the mitochondria but it can also injure the endothelial cells lining the blood vessels. Therefore it offers a potential double whammy: messed up energy production and malfunctioning blood vessels – both of which can be found in ME/CFS.

With that, we’re back to square one – we have energy-depleted muscles and a broken vasculature. The next step is now a familiar one with oxygen-depleted tissues. It involves flooding the muscles with vasodilators which then spill over into the blood – and potentially symptoms of pain, fatigue, flu-like symptoms, problems with sleep, etc.

Because β2AdR just happens to play an important role in uterus relaxation, dysfunctional β2AdRs could contribute to increased levels of uterine contractions which inhibit blood flows, thus starting the vasodilation process off.

Lastly, some evidence suggests that the β2AdR helps stabilize mast cells – suggesting that balky β2AdRs in ME/CFS could trigger MCAS.

Drug Effort

Wirth has found a drug that he believes could help clear up the muscle/blood vessel mess and has formed a company called Mitodicure to promote it. Mitodicure is currently looking for funding.

ME/CFS Muscle Study Results in Drug Company Startup

Klaus Wirth

Klaus Wirth reported that recent findings highlight the muscle/mitochondrial connection in ME/CFS. A blog is coming up on that.


Wirth and Lohn have added another addendum to their 2019 Wirth/Scheibenbogen hypothesis. Time will tell, of course, whether they’re on the right track or not. Simply by making us aware of the possible connections between ME/CFS and the comorbid conditions it is allied with, though, they’ve done us a service.

Wirth also reported that recent findings highlight the muscle/mitochondrial connection in ME/CFS. A blog is coming up on those, plus Health Rising is going to continue to explore the connections between all these “complex illnesses”. Coming up shortly, Beth Pollack explores the reproductive and connective connections between ME/CFS, POTS, connective tissue disorders like Ehlers-Danlos Syndrome (EDS), and endometriosis in a review paper, and leads a NINDS webinar exploring those connections.


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