One of the things which has puzzled me for a long time is why some people with ME find that extra salt and fluids can make such a difference. There is the light-headedness, the problems with standing up, the feeling that your body is running on empty and the desperate need for a drink or something salty. Many people have been told that they have low blood volume, or hypovolaemia. Yet it is an area which has received remarkably little attention.
A number of studies have found that people with ME/CFS can have a significant reduction in circulating blood volume. This is not a minor issue. If there is less blood circulating there is less available to carry oxygen to the brain, muscles and other organs. It may help explain why being upright can be so difficult, why cognitive problems can become overwhelming and why some of us feel as though we have been physically knocked sideways by the most ordinary activity.
Professor Klaus Wirth’s February 2026 pre-print paper, In Search of Lost Volume: The Potential Causes of Hypovolemia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, looks at what may be causing this. He puts forward a detailed hypothesis in which problems in the energy metabolism of skeletal muscles lead to the release of chemicals which affect blood vessels and the kidneys. The result, he suggests, is that the body loses salt and water when it should be trying to retain them. In other words, it is another of the vicious circles which may be helping to keep people with ME ill.
The science in the paper is not easy going. I have therefore included some background on Professor Wirth and a glossary at the end. I apologise in advance for any misunderstandings on my behalf of his work. His paper is a hypothesis, not a completed clinical trial, and the mechanisms he proposes will need to be tested. But it does offer one possible answer to a long-standing and rather disturbing question: why does the body appear to accept low blood volume when it should be fighting to correct it?
During that time he was involved in around 70 patents and five clinical development projects. His work on bradykinin receptor antagonists led to the development of Firazyr™ (Icatibant), which is used for acute attacks of hereditary angioedema.
Professor Wirth became interested in ME/CFS in 2018 after watching a regional television documentary about the illness. He contacted Professor Carmen Scheibenbogen, who heads the Charité Fatigue Center in Berlin. Together they developed the Wirth-Scheibenbogen hypothesis, which was first published in 2020. It argues that ME/CFS involves problems with the autonomic nervous system, the small blood vessels, skeletal muscle and autoantibodies directed against adrenergic receptors.
In 2022 Professor Wirth co-founded Mitodicure GmbH. He is its Chief Scientific Officer and Managing Director. The company is developing oral treatments, including MDC002, aimed at the mitochondrial and ion-transport problems which may contribute to PEM and muscle damage in ME/CFS and Long COVID.
The strange thing in ME/CFS is that renin can be low, or not high enough, even when blood volume is depleted and it ought to be rising. You suggest that chemicals released from muscles which are struggling to produce energy, including bradykinin and prostaglandin E₂, may be making the kidneys lose sodium and water while also preventing the normal renin response. Could you explain in lay terms why the body seems to be working against itself, and what this might tell us about ME/CFS?
Klaus Wirth: From exercise physiology, it is well known that both the heart and skeletal muscle release vasoactive mediators to increase blood flow during periods of increased metabolic demand. In skeletal muscle, blood flow can increase by a factor of 20–30 during intense activity, a response mediated by a complex network of signaling molecules. Among the mediators involved are bradykinin, prostaglandin E2, prostacyclin, adenosine, and histamine.
My hypothesis is that the impaired energy metabolism of skeletal muscle in ME/CFS leads to excessive production of these vasoactive substances. Under normal physiological conditions, their effects are largely confined to the local tissue because of their short half-lives and rapid degradation. However, if produced in sufficiently large quantities, some of these mediators may escape local control, enter the systemic circulation, and reach distant organs. These mediators also cause pain and microvascular leakage. In the kidney, such circulating vasoactive mediators could increase renal perfusion and promote sodium loss. Renal hyperperfusion and salt loss would reduce blood volume. An increase in renal blood flow and an elevated sodium chloride concentration in the distal tubules eliminate the physiological signals that physiologically stimulate renin release so that renin remains low despite hypovolemia (renin-paradox).
The question of why the body appears to work against itself arises repeatedly in medicine. This self-perpetuating dysfunction is embedded within what are known as vicious circles. These are feedback loops in which pathological processes reinforce one another, sustaining and often amplifying diseases.
You describe how a problem with these receptors may affect a sodium transporter called NHE3, make the small blood vessels more likely to leak fluid, and make the energy problems in skeletal muscle worse. β₂AdR dysfunction seems to come up in many different aspects of ME/CFS. Do you think it could be one of the early drivers of the illness, perhaps through autoantibodies or some other event, or is it more likely to be a consequence of something else which has already gone wrong?
Klaus Wirth: Apart from activating NHE3 to increase sodium absorption, β2-adrenergic receptors also reduce microvascular leakage, thereby limiting the loss of plasma volume into the surrounding tissue. Dysfunction of β2-adrenergic receptors may itself be a primary driver of the disease, for example through autoantibodies targeting these receptors or through severe stress that downregulates and desensitizes these receptors so that become inactive. Once the disease is fully established, β2-adrenergic receptor dysfunction may worsen further, particularly because of chronically elevated sympathetic tone for which orthostatic stress could be the most important stressor. Persistent sympathetic activation can desensitize these receptors to the point where they can no longer be adequately stimulated, even though their activation would be important during exercise.
There is increasing evidence that sympathetic tone is abnormally elevated at rest, yet may become exhausted during exercise, resulting in levels that are lower than normal and insufficient to meet physiological demands. Consider a person with autoantibodies against β2-adrenergic receptors whose receptors are already desensitized, and who then experiences reduced receptor stimulation during exercise due to exhaustion of the sympathetic nervous system. In this situation, receptor function may become profoundly impaired due to the combined effects of autoantibodies, receptor desensitization, and inadequate sympathetic stimulation during exertion.
PEM is the symptom which distinguishes ME from many other illnesses. It is extraordinary, therefore, that blood volume and cardiac preload, the amount of blood returning to the heart, do not appear to have been measured during PEM itself. How important is it to fill this gap in the research, and what would a study need to do to find out whether this is happening?
Klaus Wirth: From a theoretical perspective, I hypothesize that hypovolemia worsens during PEM and represents one of several pathophysiological mechanisms driving it. Patients’ reports are consistent with this assumption. However, the hypothesis can only be confirmed or disproven through controlled investigations comparing plasma volume and body fluid distribution, RAAS-activity and vasopressin and renal excretion at rest with measurements obtained after exercise that reliably induces PEM.
Designing such a study would be challenging. Either patients would need to undergo exercise protocols that intentionally provoke PEM, or volumetric measurements would have to be obtained during spontaneous PEM episodes, which would be logistically difficult to organize.
If robust evidence could be established, it might become possible to develop new therapeutic strategies aimed at mitigating hypovolemia during PEM. Such approaches could potentially reduce the severity of PEM itself or shorten its duration.
You point out that low vasopressin in the face of low blood volume looks rather like diabetes insipidus. But unlike diabetes insipidus it does not respond to desmopressin, a synthetic form of vasopressin. You suggest that problems with serotonin, noradrenaline and possibly angiotensin II, all of which are involved in stimulating vasopressin release, may be part of the picture. Has this possible link between neurotransmitters and fluid control been overlooked in ME/CFS research? Could it lead to any useful treatments?
Klaus Wirth: Serotonin, noradrenaline and also Angiotensin II are involved as transmitters in the secretion of vasopressin. There is some evidence that the three transmitters are disturbed. The typical causes of diabetes insipidus for low vasopressin seem excluded in ME/CFS so it makes sense to consider the involvement of these three mediators. If these transmitters were disturbed their correction must be seen in the whole context of other disturbances where they could be involved. I cannot see these neurotransmitters as isolated targets for correcting hypovolemia only.
Your paper describes impaired sodium retention, low blood volume and a failure of the normal systems which should put this right. Does it make physiological sense that taking electrolytes at night might partly compensate for some of these problems? It would be useful to know whether this is something which should be investigated properly rather than left to patients trying to work it out for themselves.
Klaus Wirth: Even under physiological conditions, there is a nocturnal fluid shift from the peripheral circulation toward the central and upper parts of the body. In ME/CFS, this redistribution may be substantially more pronounced because of orthostatic dysfunction, which can lead to excessive fluid accumulation in the lower extremities during daytime upright activity. In addition, ME/CFS specific pathological fluid shifts into the interstitial and intracellular compartments may be partially reversed during sleep.
As a consequence, cardiac filling and cardiac output in the supine position during sleep could transiently become excessively elevated. In the context of reduced RAAS activity, lower vasopressin levels, and atrial distension leading to the release of atrial natriuretic factor (ANF), this may promote renal hyperperfusion with increased renal excretion of salt and water. Pure acute volume expansion in a healthy person usually suppresses sympathetic nerve activity, but relatively sudden increases in cardiac filling can also activate the sympathetic nervous system under certain conditions. Increased sympathetic nervous system activation could cause nocturnal awakenings and increased arousal. While transient hypervolemia is likely in the beginning of sleep in ME/CFS it is unclear what the effect on the sympathetic nervous system is. Subsequently, this transient state of relative “hypervolemia” could evolve into hypovolemia later on during sleep after the excess fluid has been excreted, which then will then certainly elevate sympathetic tone to disturb sleep.
These mechanisms clearly require further investigation, both to improve our understanding of the disease and to develop more effective therapeutic strategies. Improvements in sleep quality and circulating blood volume could potentially have significant effects on ME/CFS symptomatology.
From this perspective, it appears reasonable that, following excessive nocturnal losses of water and salt, fluid replacement should include appropriate electrolytes rather than water alone, similar to recommendations after excessive sweating or diarrhea where drinking water alone can even be harmful due to imbalances of electrolytes.
If you had to pick one experiment or clinical study which could seriously support, or seriously challenge, the main argument in the paper, what would it be? And if the result were positive, what might it mean in practical terms for people with ME?
Klaus Wirth: From the beginning of my work in ME/CFS, drawing on my experience as a drug researcher who has worked across numerous diseases and organ systems, I was convinced that there ultimately must be a central mechanism that can be therapeutically targeted. The key question for me was: what is the core pathomechanism of the disease?
ME/CFS is highly heterogeneous with respect to symptoms, risk factors, and triggers. It is impossible to treat this variety of symptoms and pathomechanisms with a single drug. At the same time, ME/CFS is remarkably homogeneous in its defining features—exercise intolerance and post-exertional malaise (PEM). I therefore focused primarily on these hallmark characteristics and asked two central questions:
Which pathomechanisms are primarily responsible for the symptoms of PEM?
Why does this disease become chronic, with such a low rate of spontaneous recovery, despite the absence of major organ damage, severe genetic defects, or autoimmunity, which appears to be present in fewer than half of patients?
My conclusion is that ME/CFS is both caused and sustained by a large vicious cycle involving multiple interacting dysfunctions. This leads to the next critical question: which disturbance lies at the core of this system's stability? In other words, what is the key mechanism that maintains the vicious cycle, and whose elimination would destabilize it, allowing the body's recovery processes to proceed spontaneously?
How can such a hypothesis be tested? Demonstrating or refuting complex biological concepts through basic research alone often requires many years of investigation. Indeed, it is difficult to identify a single basic research study that can definitively prove or disprove a hypothesis of this complexity. This is where drug development becomes particularly valuable. A pharmacological agent derived from the pathophysiological concept provides a direct opportunity to test the hypothesis in patients. If the agent demonstrates clinical efficacy, it proves that the proposed mechanism plays a central role in the disease process. If, in addition, the agent is shown to be safe, it ultimately becomes an effective treatment.
At a certain stage, therefore, drug development becomes one of the most powerful tools of basic research. By translating a concept into a testable intervention, it enables hypotheses to be evaluated directly in the human disease for which they were conceived. In this way, drug research and development not only seeks new treatments but also serves as a critical instrument for advancing our understanding of disease mechanisms.
Summary: What Professor Wirth is proposing
What I find interesting about Professor Wirth’s model is that it tries to join up findings which have too often been treated as separate problems. He suggests that muscles which are unable to produce energy properly release too much of certain vasoactive chemicals, including bradykinin and prostaglandin E₂. Normally these chemicals act locally, helping a working muscle get more blood. In his model, too much of them gets into the general circulation and reaches the kidneys.
Once there, he suggests, they increase blood flow through the kidneys and make the kidneys excrete sodium. The kidneys then receive signals which falsely suggest there is enough fluid and sodium in the body. Renin is not released, even though the rest of the body has low blood volume. That is a bleak thought when you consider how many people with ME spend their lives trying to manage the consequences of low volume with salt, fluids, compression garments and a great deal of pacing.
Of course, this is still a hypothesis. It needs to be tested properly. But blood-volume problems, the renin-aldosterone paradox, reduced blood flow to the brain and the symptoms people report when upright have been sitting in plain sight for years. Professor Wirth’s paper gives researchers something concrete to investigate. It would be good if they did. People with ME have had enough of being told to manage individual symptoms while the underlying biology is left on the sidelines.
I would like to thank my friend Manny for help with this interview and for providing the glossary of terms below:
A number of studies have found that people with ME/CFS can have a significant reduction in circulating blood volume. This is not a minor issue. If there is less blood circulating there is less available to carry oxygen to the brain, muscles and other organs. It may help explain why being upright can be so difficult, why cognitive problems can become overwhelming and why some of us feel as though we have been physically knocked sideways by the most ordinary activity.
Professor Klaus Wirth’s February 2026 pre-print paper, In Search of Lost Volume: The Potential Causes of Hypovolemia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, looks at what may be causing this. He puts forward a detailed hypothesis in which problems in the energy metabolism of skeletal muscles lead to the release of chemicals which affect blood vessels and the kidneys. The result, he suggests, is that the body loses salt and water when it should be trying to retain them. In other words, it is another of the vicious circles which may be helping to keep people with ME ill.
The science in the paper is not easy going. I have therefore included some background on Professor Wirth and a glossary at the end. I apologise in advance for any misunderstandings on my behalf of his work. His paper is a hypothesis, not a completed clinical trial, and the mechanisms he proposes will need to be tested. But it does offer one possible answer to a long-standing and rather disturbing question: why does the body appear to accept low blood volume when it should be fighting to correct it?
Professor Klaus Wirth
Professor Klaus Josef Wirth is a medical doctor and pharmacologist. He is an Adjunct Professor at the Institute of Pharmacology at Goethe University Frankfurt in Germany. Between 1984 and 2022 he worked as a Senior Researcher at Sanofi, where his areas of work included cardiovascular pharmacology, cerebral blood flow, stroke, heart failure, cardiac arrhythmias and endocrinology.During that time he was involved in around 70 patents and five clinical development projects. His work on bradykinin receptor antagonists led to the development of Firazyr™ (Icatibant), which is used for acute attacks of hereditary angioedema.
Professor Wirth became interested in ME/CFS in 2018 after watching a regional television documentary about the illness. He contacted Professor Carmen Scheibenbogen, who heads the Charité Fatigue Center in Berlin. Together they developed the Wirth-Scheibenbogen hypothesis, which was first published in 2020. It argues that ME/CFS involves problems with the autonomic nervous system, the small blood vessels, skeletal muscle and autoantibodies directed against adrenergic receptors.
In 2022 Professor Wirth co-founded Mitodicure GmbH. He is its Chief Scientific Officer and Managing Director. The company is developing oral treatments, including MDC002, aimed at the mitochondrial and ion-transport problems which may contribute to PEM and muscle damage in ME/CFS and Long COVID.
The interview
1. Why does the body fail to respond to low blood volume?
One of the ideas in your paper is what you call the “renin paradox”. Renin is an enzyme made by the kidneys. It starts a chain of hormonal events called the renin-angiotensin-aldosterone system, or RAAS. Normally, when blood volume falls, the system should help the body hold onto sodium and water so that blood volume can be restored.The strange thing in ME/CFS is that renin can be low, or not high enough, even when blood volume is depleted and it ought to be rising. You suggest that chemicals released from muscles which are struggling to produce energy, including bradykinin and prostaglandin E₂, may be making the kidneys lose sodium and water while also preventing the normal renin response. Could you explain in lay terms why the body seems to be working against itself, and what this might tell us about ME/CFS?
Klaus Wirth: From exercise physiology, it is well known that both the heart and skeletal muscle release vasoactive mediators to increase blood flow during periods of increased metabolic demand. In skeletal muscle, blood flow can increase by a factor of 20–30 during intense activity, a response mediated by a complex network of signaling molecules. Among the mediators involved are bradykinin, prostaglandin E2, prostacyclin, adenosine, and histamine.
My hypothesis is that the impaired energy metabolism of skeletal muscle in ME/CFS leads to excessive production of these vasoactive substances. Under normal physiological conditions, their effects are largely confined to the local tissue because of their short half-lives and rapid degradation. However, if produced in sufficiently large quantities, some of these mediators may escape local control, enter the systemic circulation, and reach distant organs. These mediators also cause pain and microvascular leakage. In the kidney, such circulating vasoactive mediators could increase renal perfusion and promote sodium loss. Renal hyperperfusion and salt loss would reduce blood volume. An increase in renal blood flow and an elevated sodium chloride concentration in the distal tubules eliminate the physiological signals that physiologically stimulate renin release so that renin remains low despite hypovolemia (renin-paradox).
The question of why the body appears to work against itself arises repeatedly in medicine. This self-perpetuating dysfunction is embedded within what are known as vicious circles. These are feedback loops in which pathological processes reinforce one another, sustaining and often amplifying diseases.
2. Is β₂-adrenergic receptor dysfunction a cause of ME, or a consequence of it?
Your paper repeatedly comes back to the β₂-adrenergic receptor, or β₂AdR. These receptors are found on many different cells, including cells in blood vessels, muscles, the kidneys and the gut. They respond to adrenaline-like signals and are involved in blood flow, sodium absorption and keeping fluid inside blood vessels.You describe how a problem with these receptors may affect a sodium transporter called NHE3, make the small blood vessels more likely to leak fluid, and make the energy problems in skeletal muscle worse. β₂AdR dysfunction seems to come up in many different aspects of ME/CFS. Do you think it could be one of the early drivers of the illness, perhaps through autoantibodies or some other event, or is it more likely to be a consequence of something else which has already gone wrong?
Klaus Wirth: Apart from activating NHE3 to increase sodium absorption, β2-adrenergic receptors also reduce microvascular leakage, thereby limiting the loss of plasma volume into the surrounding tissue. Dysfunction of β2-adrenergic receptors may itself be a primary driver of the disease, for example through autoantibodies targeting these receptors or through severe stress that downregulates and desensitizes these receptors so that become inactive. Once the disease is fully established, β2-adrenergic receptor dysfunction may worsen further, particularly because of chronically elevated sympathetic tone for which orthostatic stress could be the most important stressor. Persistent sympathetic activation can desensitize these receptors to the point where they can no longer be adequately stimulated, even though their activation would be important during exercise.
There is increasing evidence that sympathetic tone is abnormally elevated at rest, yet may become exhausted during exercise, resulting in levels that are lower than normal and insufficient to meet physiological demands. Consider a person with autoantibodies against β2-adrenergic receptors whose receptors are already desensitized, and who then experiences reduced receptor stimulation during exercise due to exhaustion of the sympathetic nervous system. In this situation, receptor function may become profoundly impaired due to the combined effects of autoantibodies, receptor desensitization, and inadequate sympathetic stimulation during exertion.
3. Does blood volume fall further during PEM?
You describe a series of events following exertion in ME/CFS. Fluid may move into muscle cells, fluid may leak out through blood-vessel walls into the surrounding tissue, and the systems which are supposed to restore blood volume may not switch on properly. You argue that worsening hypovolaemia during and after activity may be one of the things driving post-exertional malaise.PEM is the symptom which distinguishes ME from many other illnesses. It is extraordinary, therefore, that blood volume and cardiac preload, the amount of blood returning to the heart, do not appear to have been measured during PEM itself. How important is it to fill this gap in the research, and what would a study need to do to find out whether this is happening?
Klaus Wirth: From a theoretical perspective, I hypothesize that hypovolemia worsens during PEM and represents one of several pathophysiological mechanisms driving it. Patients’ reports are consistent with this assumption. However, the hypothesis can only be confirmed or disproven through controlled investigations comparing plasma volume and body fluid distribution, RAAS-activity and vasopressin and renal excretion at rest with measurements obtained after exercise that reliably induces PEM.
Designing such a study would be challenging. Either patients would need to undergo exercise protocols that intentionally provoke PEM, or volumetric measurements would have to be obtained during spontaneous PEM episodes, which would be logistically difficult to organize.
If robust evidence could be established, it might become possible to develop new therapeutic strategies aimed at mitigating hypovolemia during PEM. Such approaches could potentially reduce the severity of PEM itself or shorten its duration.
4. What is the connection between brain signalling and fluid regulation?
Two of the main systems which help the body control its fluid balance appear to be impaired in ME/CFS. One is vasopressin, sometimes called the antidiuretic hormone. It is made in the brain and tells the kidneys to retain water. The other is the RAAS, which should tell the kidneys to retain both sodium and water.You point out that low vasopressin in the face of low blood volume looks rather like diabetes insipidus. But unlike diabetes insipidus it does not respond to desmopressin, a synthetic form of vasopressin. You suggest that problems with serotonin, noradrenaline and possibly angiotensin II, all of which are involved in stimulating vasopressin release, may be part of the picture. Has this possible link between neurotransmitters and fluid control been overlooked in ME/CFS research? Could it lead to any useful treatments?
Klaus Wirth: Serotonin, noradrenaline and also Angiotensin II are involved as transmitters in the secretion of vasopressin. There is some evidence that the three transmitters are disturbed. The typical causes of diabetes insipidus for low vasopressin seem excluded in ME/CFS so it makes sense to consider the involvement of these three mediators. If these transmitters were disturbed their correction must be seen in the whole context of other disturbances where they could be involved. I cannot see these neurotransmitters as isolated targets for correcting hypovolemia only.
5. Could electrolytes during the night help some people with ME?
Many people with ME, including myself, have found that having an electrolyte drink containing sodium, potassium and magnesium can sometimes improve sleep or reduce the number of times they wake in the night. Sodium is particularly important because it helps the body retain water in the bloodstream.Your paper describes impaired sodium retention, low blood volume and a failure of the normal systems which should put this right. Does it make physiological sense that taking electrolytes at night might partly compensate for some of these problems? It would be useful to know whether this is something which should be investigated properly rather than left to patients trying to work it out for themselves.
Klaus Wirth: Even under physiological conditions, there is a nocturnal fluid shift from the peripheral circulation toward the central and upper parts of the body. In ME/CFS, this redistribution may be substantially more pronounced because of orthostatic dysfunction, which can lead to excessive fluid accumulation in the lower extremities during daytime upright activity. In addition, ME/CFS specific pathological fluid shifts into the interstitial and intracellular compartments may be partially reversed during sleep.
As a consequence, cardiac filling and cardiac output in the supine position during sleep could transiently become excessively elevated. In the context of reduced RAAS activity, lower vasopressin levels, and atrial distension leading to the release of atrial natriuretic factor (ANF), this may promote renal hyperperfusion with increased renal excretion of salt and water. Pure acute volume expansion in a healthy person usually suppresses sympathetic nerve activity, but relatively sudden increases in cardiac filling can also activate the sympathetic nervous system under certain conditions. Increased sympathetic nervous system activation could cause nocturnal awakenings and increased arousal. While transient hypervolemia is likely in the beginning of sleep in ME/CFS it is unclear what the effect on the sympathetic nervous system is. Subsequently, this transient state of relative “hypervolemia” could evolve into hypovolemia later on during sleep after the excess fluid has been excreted, which then will then certainly elevate sympathetic tone to disturb sleep.
These mechanisms clearly require further investigation, both to improve our understanding of the disease and to develop more effective therapeutic strategies. Improvements in sleep quality and circulating blood volume could potentially have significant effects on ME/CFS symptomatology.
From this perspective, it appears reasonable that, following excessive nocturnal losses of water and salt, fluid replacement should include appropriate electrolytes rather than water alone, similar to recommendations after excessive sweating or diarrhea where drinking water alone can even be harmful due to imbalances of electrolytes.
6. What is the most important way to test the hypothesis?
Your paper is clear that this is a framework of interacting hypotheses, not a report of new experimental data. It involves skeletal muscle metabolism, the autonomic nervous system, the behaviour of small blood vessels and kidney physiology. It is a lot to bring together.If you had to pick one experiment or clinical study which could seriously support, or seriously challenge, the main argument in the paper, what would it be? And if the result were positive, what might it mean in practical terms for people with ME?
Klaus Wirth: From the beginning of my work in ME/CFS, drawing on my experience as a drug researcher who has worked across numerous diseases and organ systems, I was convinced that there ultimately must be a central mechanism that can be therapeutically targeted. The key question for me was: what is the core pathomechanism of the disease?
ME/CFS is highly heterogeneous with respect to symptoms, risk factors, and triggers. It is impossible to treat this variety of symptoms and pathomechanisms with a single drug. At the same time, ME/CFS is remarkably homogeneous in its defining features—exercise intolerance and post-exertional malaise (PEM). I therefore focused primarily on these hallmark characteristics and asked two central questions:
Which pathomechanisms are primarily responsible for the symptoms of PEM?
Why does this disease become chronic, with such a low rate of spontaneous recovery, despite the absence of major organ damage, severe genetic defects, or autoimmunity, which appears to be present in fewer than half of patients?
My conclusion is that ME/CFS is both caused and sustained by a large vicious cycle involving multiple interacting dysfunctions. This leads to the next critical question: which disturbance lies at the core of this system's stability? In other words, what is the key mechanism that maintains the vicious cycle, and whose elimination would destabilize it, allowing the body's recovery processes to proceed spontaneously?
How can such a hypothesis be tested? Demonstrating or refuting complex biological concepts through basic research alone often requires many years of investigation. Indeed, it is difficult to identify a single basic research study that can definitively prove or disprove a hypothesis of this complexity. This is where drug development becomes particularly valuable. A pharmacological agent derived from the pathophysiological concept provides a direct opportunity to test the hypothesis in patients. If the agent demonstrates clinical efficacy, it proves that the proposed mechanism plays a central role in the disease process. If, in addition, the agent is shown to be safe, it ultimately becomes an effective treatment.
At a certain stage, therefore, drug development becomes one of the most powerful tools of basic research. By translating a concept into a testable intervention, it enables hypotheses to be evaluated directly in the human disease for which they were conceived. In this way, drug research and development not only seeks new treatments but also serves as a critical instrument for advancing our understanding of disease mechanisms.
Summary: What Professor Wirth is proposing
What I find interesting about Professor Wirth’s model is that it tries to join up findings which have too often been treated as separate problems. He suggests that muscles which are unable to produce energy properly release too much of certain vasoactive chemicals, including bradykinin and prostaglandin E₂. Normally these chemicals act locally, helping a working muscle get more blood. In his model, too much of them gets into the general circulation and reaches the kidneys.
Once there, he suggests, they increase blood flow through the kidneys and make the kidneys excrete sodium. The kidneys then receive signals which falsely suggest there is enough fluid and sodium in the body. Renin is not released, even though the rest of the body has low blood volume. That is a bleak thought when you consider how many people with ME spend their lives trying to manage the consequences of low volume with salt, fluids, compression garments and a great deal of pacing.
Of course, this is still a hypothesis. It needs to be tested properly. But blood-volume problems, the renin-aldosterone paradox, reduced blood flow to the brain and the symptoms people report when upright have been sitting in plain sight for years. Professor Wirth’s paper gives researchers something concrete to investigate. It would be good if they did. People with ME have had enough of being told to manage individual symptoms while the underlying biology is left on the sidelines.
I would like to thank my friend Manny for help with this interview and for providing the glossary of terms below:
![ME/CFS lecture | Dr Nancy Klimas | 2011 [Chronic Fatigue Syndrome / SEID / New Zealand] - YouTube](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
