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Plenary speakers provide critical information that the conference organizers believe everyone needs to hear. This presentation from the 2025 IACFS/ME conference certainly fit that bill.
The Catechaholic
David Goldstein is a highly published “scientist emeritus” in the NIH’s autonomic nervous system division. He gave the plenary lecture at the 2025 IACFS/ME conference.
David Goldstein, MD, PhD, is not your ordinary researcher. An NIH National Institute of Neurological Disorders and Stroke (NINDS) researcher, the winner of several awards, and co-author of more than 600 research articles as well as several books (“Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine,” “Dysautonomias: A Handbook for Patients”, “Stress, Catecholamines, and Cardiovascular Disease”, “The Autonomic Nervous System in Health and Disease”, “Principles of Autonomic Medicine”, and “The Dysautonomia Project“), the man has clearly gotten around.
Officially retired from the NIH (he’s listed as a “scientist emeritus”), he’s still actively involved in research and working in a non-salary or limited-salary capacity. Clearly, a highly productive individual, Goldstein is spending his “retirement years” doing what he’s always done – research. Now he and his post-doc, Lilian Aregawi, are working on ME/CFS.
Acknowledging that he’s not an expert in ME/CFS, Goldstein stated he is an expert in catecholamines – the hormones/neurotransmitters the brain produces – and called himself a “catecholaholic”. He’s been studying catecholamine systems for 50 years.
THE GIST
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In this scenario, the sympathetic nervous system is not dominating, it’s struggling.
David Goldstein, MD, PhD, an NIH National Institute of Neurological Disorders and Stroke (NINDS) researcher and co-author of more than 600 papers and several books, gave the plenary lecture at the 2025 IACFS/ME conference.
- Calling himself a “catechaholic”, Goldstein focused on the role that brain neurotransmitters called catecholamines (dopamine, norepinephrine, and epinephrine) play in ME/CFS and long COVID.
- These brain chemicals are involved in the stress or fight/flight response, the autonomic nervous system, movement, mood, pleasure, reward, memory, and more.
- Lilian Aregawi, a post-doc, assessed catecholamine pathway strength by measuring catecholamine levels in the cerebrospinal fluid of ME/CFS, long COVID, and Parkinson’s patients.
- She found greatly reduced levels of norepinephrine products in ME/CFS and reduced levels in long COVID.
- Among these three catecholamines, only norepinephrine requires ATP production; the study suggested that low ATP production may be present.
- That was a bit of a shock as norepinephrine is the main neurotransmitter of the sympathetic nervous system (SNS); i.e., the fight-or-flight system we’ve believed is overactivated. This finding, though, suggested the fight/flight system is actually flailing about.
- This is because low NE vesicle levels require more signal to reach them in order for the neuron to respond and emit NE, the LC neurons in ME/CFS and long COVID appear to demonstrate what’s called “impaired drive”. Instead of being a true adrenergic hyperactivity disorder, these diseases appear to have what’s called a “pre-synaptic vesicle energy problem“.
- The SNS is activated, all right – but it’s also quickly pooping out – a common theme in these diseases. The brain is trying very hard to produce more norepinephrine (high LC firing rate) but is failing because the vesicles are too low in dopamine.
- That constant compensatory effort results in high levels of sympathetic noise but low levels of sympathetic gain.
- In this scenario, the SNS is not dominating – it’s struggling. Recognizing that SNS is trying to get things going, the parasympathetic nervous system is not broken – it’s lying low.
- This pattern of high LC neuron firing but low production could produce classic ME/CFS/long-COVID symptoms that leave one overstimulated, overwhelmed, and anxious, wired and tired, and particularly low in energy in the morning.
- Most of the norepinephrine produced in the brain is produced in the locus coeruleus (LC). Heavily involved in the stress response, the LC is connected to many parts of the brain, including the limbic system and the prefrontal cortex, and plays a role in many issues in post-infectious diseases like ME/CFS and long COVID, such as arousal, the sleep-wake cycle, attention, memory, and neuroplasticity.
- The brain’s “immune sentinel”, the LC, coeruleus, is hit early and hard during an infection. Because the brain needs lots of norepinephrine to produce a fever, activate the immune cells and, in general, to produce “sickness behavior”, the LC gets pushed into overdrive.
- Flushed with mitochondrial cells that produce many free radicals during energy production, the LC is considered a “metabolically fragile” organ. Plenty of study evidence has implicated the LC in ME/CFS.
- Because a chronically stimulated locus coeruleus stops the glymphatic system from detoxifying the brain during sleep, unrefreshing sleep and a toxin-laden brain could result.
- Microglial and/or mast cell activation is all that’s needed to produce a state of chronic, self-reinforcing illness.
- Given the poor brain cleansing and toxin buildup, it only makes sense that intracranial hypertension – high cerebral spinal fluid pressure – could result.
- Hyperadrenergic POTS (HPOTS), which is characterized by high blood NE levels, would seem at first glance not to fit this scenario but it may fit it perfectly. In HPOTS, NE levels in the vesicles are still low, but the neurons – in an attempt to compensate – are firing so rapidly that NE spills out of the nerve synapses and into the blood.
- The paradox. There is a paradox here. Low NE vesicle levels should make the neurons inert because they require more signal to become activated. When the brain senses more NE is needed, though, it punches the gas, working the neurons harder and harder. Instead of precisely delivering NE, they try to pump it out all the time. They’re like a panicked machine gunner who sprays the bushes every time a twig gets snapped.
- Next up – Pt. II – treatment options.
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It’s good to have outside experts who are drenched in the minutiae of their fields – but not in these diseases – bring their attention to diseases like ME/CFS and long COVID. For one, the fact that these diseases have caught their eye says something. For another, they should bring objective, well-seasoned analyses of complex subjects to the field.
Produced by the brain, the nerves, and the adrenal glands, catecholamines like dopamine, epinephrine, and norepinephrine are particularly intriguing in ME/CFS and long COVID because they are involved in the stress or fight/flight response, the autonomic nervous system, movement, mood, pleasure, reward, memory, and more.
Simple Study – Potentially Profound Results
Aregawi’s study has not been published yet. She did a surprisingly simple but potentially profound thing that hasn’t been done in ME/CFS before. She assessed the activity of the dopamine, norepinephrine, and epinephrine pathways in the brain by measuring the levels of their products in cerebrospinal fluid.
Aregawi used Parkinson’s patients as a “positive control,” i.e., because low dopamine and norepinephrine levels are present in Parkinson’s disease, the Parkinson’s patients demonstrated what low levels of these catecholamines looked like.
Role Reversal
For all the talk of dopamine in ME/CFS, the dopamine pathway levels were fine. The low levels of the products of the norepinephrine (NE) pathway suggested that norepinephrine was in freefall in ME/CFS. The NE pathway is not as low in long COVID but was still significantly reduced.
That was a bit of a shock. Norepinephrine is the main neurotransmitter of the sympathetic nervous system (SNS) — the fight-or-flight system we’ve believed is overactivated. What’s needed is to calm it down by increasing the function of its regulator — the parasympathetic nervous system, or rest/digest, system. In other words, a wimpy PNS is simply failing to regulate the SNS.
This scenario, though, has been punctured a bit by the success of several drugs (Mestinon, Survovexant) that increase NE activity. If this study findings hold up, it blows the overactive/underactive SNS/PNS scenario to smithereens. A weak PNS is not the problem, a weak SNS is.
Interestingly, it all comes down to ATP. Catecholamine metabolism proceeds like this: Tyrosine → L-DOPA → Dopamine → Norepinephrine → Epinephrine)
The findings suggested low ATP levels may play a key role.
The only part of this chain that requires ATP is the conversion of dopamine to norepinephrine. Because NE is metabolized in vesicles of the locus coeruleus, a proton pump is needed to move dopamine into those vesicles. It takes about 1 ATP molecule to transport 1 molecule of dopamine into the vesicles.
The low NE pathways in ME/CFS and COVID suggest that reduced ATP levels were failing to deliver sufficient dopamine into vesicles to produce normal amounts of NE.
Locus coeruleus neurons with poorly filled vesicles can still fire, but require a much stronger signal to do so; i.e., they demonstrate what’s called “impaired drive”. This is the exact opposite of what happens in a true adrenergic hyperactivity disorder, which is characterized by an overproductive SNS. Instead, this is called a “pre-synaptic vesicle energy problem“.
The SNS is activated, all right – but it’s also quickly pooping out – a common theme in these diseases. The brain is trying very hard to produce more norepinephrine (high LC firing rate) but is failing because the vesicles are too low in dopamine. That constant compensatory effort results in high levels of sympathetic noise but low levels of sympathetic gain.
In this scenario, the sympathetic nervous system is not dominating: it’s struggling.
In this scenario, the SNS is not dominating- it’s struggling. Recognizing that SNS is trying to get things going, the parasympathetic nervous system is not broken – it’s lying low. This may be why trying to increase parasympathetic/vagal tone through breathwork, HRV training, or vagus stimulation often only goes so far. Both the PNS and the SNS need to be revived.
That means you don’t want to suppress the SNS or increase NE synthesis using tyrosine or stimulants. Instead you want to reduce the noise, increase ATP levels, get dopamine into the vesicles, and increase NE production that way. When SNS begins to respond normally, parasympathetic nervous system activity naturally returns to a normal level.
Symptoms
This pattern of the high LC neuron firing but low production could produce classic ME/CFS/long-COVID symptoms that leave one overstimulated, overwhelmed, and anxious and tense, but without the energy to do anything. It would naturally result in the ubiquitous “wired but tired” symptoms (high levels of stimulation but no response because of low NE vesicle levels), orthostatic intolerance (reduced blood vessel tone), early mental or physical fatigue (norepinephrine levels in the vesicles quickly fade and fail to refill).
Unrefreshing sleep and rough mornings are other possible outcomes of NE depletion in the LC vesicles.
Feeling stuck, unrefreshed, etc., in the morning (due to poor vesicle filling overnight) is another logical outcome. Exposure to light, getting up, and resuming a normal breathing pattern should immediately tell the locus coeruleus to boost NE levels in the vesicles and get the body and brain moving in the morning. That includes having our system driving blood to the tissues to get them rolling. Having low NE vesicle levels in the morning puts the brakes on all that.
Low NE vesicle levels could also explain why stimulants either do not work or do not work for long in some patients: stimulants increase firing in the locus coeruleus but do not help to refill the vesicles; i.e., the gas pedal is pushed, but the car does not move.
A Focus on Post-Exertional Malaise (PEM)
Aregawi did an interesting thing in this study when she separated out long-COVID patients with and without post-exertional malaise (PEM) and found that the low NE levels were confined to the LC patients with PEM.
That made sense with the pathophysiology she uncovered. NE levels in the LC vesicle are quickly depleted with exertion, resulting in a longer recovery period. During that time, sympathetic “noise” (sensitivity to stimuli, sleep issues), and the ability to exert oneself (low NE vesicle levels) is down.
That should bring a clear warning to LC researchers to subset their participants by the existence of PEM. It’s also a reminder that five years into LC, we still don’t a biological biomarker, or even agreed upon criteria to separate out the ME/CFS subset of LC from the rest. Why it’s taken this long for the field to recognize that all long-COVID patients are not alike, and that willy-nilly herding them into research studies and clinical trials is a recipe for slow progress, is beyond me. Distinguishing the subsets should, IMO, have been the first task of this field, and, of course, we looked to RECOVER to take the lead in this … which it hasn’t. (Rant over.)
That finding suggested that the NE levels in the ME/CFS subset of LC patients were probably as low as the NE levels of the ME/CFS patients.
Next, Aregawi assessed a large number of neurobehavioral measures to determine whether she could identify significant correlations with the pathway findings. She found that fatigue, general fatigue, mental fatigue; general health and vitality, the ability to sustain handgrip were correlated with low NE pathway levels.
A Post-Infectious Failure Point?
The NE issue implicated the locus coeruleus, a brain region that has been implicated many times in these diseases. (Image by Diego69 from at Wikimedia Commons)
Most of the norepinephrine produced in the brain is produced in the locus coeruleus (LC). Found near the bottom of the brain, the LC is located in a part of the brainstem called the pons. Heavily involved in the stress response, the LC is connected to many parts of the brain, including the limbic system and the prefrontal cortex, and plays a role in many issues in post-infectious diseases such as arousal, the sleep-wake cycle, attention, memory, and neuroplasticity.
The brain’s “immune sentinel”, the LC, coeruleus, is hit early and hard during an infection. Because the brain needs lots of norepinephrine to produce a fever, activate the immune cells and, in general, to produce “sickness behavior”, the LC gets pushed into overdrive.
All that activity means the LC are loaded with mitochondria which need to fire continuously. Their high energy needs and the high stress state they’re put in leave the LC neurons in a “metabolically fragile” state. Basically, everything has to go right. If strong antioxidant systems can’t cope with the free radicals produced during high levels of energy production, mitochondrial damage results, and ATP production drops, and so does dopamine into the vesicles where norepinephrine is made.
Studies indicate that the antioxidant systems in these diseases have been hit hard, resulting, if these study findings are correct, in a chronically activated AND depleted locus coeruleus. Reduced NE causes the brain to chronically activate these neurons in an attempt to get them back up to speed. The chronic activation prevents the glymphatic system from engaging and clearing the brain of the bad stuff (lactate, glutamate byproducts, lipid peroxides, microglial inflammatory signals it’s been accumulating in its hyperactivated and depleted state).
Could the locus coeruleus be the weak link in the brain?
If autoantibodies to various receptors (𝛼1 and β2-adrenergic receptors, M3/M4 cholinergic receptors, NMDA / AMPA synaptic receptors) block those receptors, as is thought in ME/CFS, the LC responds by increasing its firing, thus exacerbating the problem.
The locus coeruleus is a small nucleus in the brain stem. Direct imaging of the LC is difficult, but studies have implicated the LC/brainstem in ME/CFS, FM, and chronic pain. MRI studies suggest that neuroinflammation/microglial activation has occurred in that area, and that brain circuits leading to the LC have become abnormally activated in ME/CFS.
The “flattened sleep architecture”, reduced slow wave sleep, and increased nighttime sympathetic nervous system activation fit perfectly the idea that chronic LC activation is preventing the glymphatic system from opening and flushing the brain of toxins (see below).
Because the LC regulates blood pressure + heart rate upon standing, a chronically activated LC could result in increased heart rate during standing, reduced vascular tone, and sympathetic overdrive.
A Vicious Circle
Microglial activation is all that’s needed to produce a state of chronic, self-reinforcing illness. (The microglia are the immune cells of the brain.) The cytokines activated microglia emit all increase locus coeruleus firing.
The reactive oxygen and nitrogen species (free radicals) that activated microglia produce can take a hammer to the mitochondria, reducing ATP production and preventing the vesicles from filling with enough norepinephrine. Those free radicals can also disrupt glymphatic detoxification by impairing astrocyte functioning. The high levels of the excitatory amino acid glutamate produced create a hyperexcited state that results in sensory overload.
Rest does not cure ME/CFS because the activated microglia do not rest. Because two mast cell products, histamine and tryptase, increase LC firing and disrupt the blood-brain barrier, respectively, they only add to the stuckness.
That’s a lot, but we’re not at all done with the possible consequences of an NE filling problem in the locus coeruleus. It could also produce toxic brains.
Toxic Brains
Dr. Perrin proposed that the NE depletion in the vesicles could disrupt the glymphatic system, resulting in a toxin-ridden brain.
Noting that norepinephrine produced by the locus coeruleus controls cerebrospinal fluid flows, Dr. Perrin asked whether the NE problem could lead to a dysfunctional glymphatic system. (He proposed this problem could be at the heart of many neurological disorders.)
It turns out that norepinephrine determines whether the glymphatic system is in an “open (cleaning) vs closed (not cleaning)” state. A drop in locus coeruleus (LC) NE release at night allows the glymphatic system to shift into cleaning mode.
A chronically activated LC, though, prevents the glymphatic system from engaging, leaving the ME/CFS/long-COVID patients not just wired but tired, but with a toxin-laden brain. The failure of that nightly neural housekeeping results in the accumulation of nasty metabolic byproducts (lactate, glutamate, lipid fragments). Unrefreshing sleep, neuroinflammation, worse brain fog in the morning, feelings of pressure/fullness in the head, and sensory overload are logical outcomes.
Toxic Brains, Frozen Spines and the Perrin Point: Ray Perrin, ME/CFS and Fibromyalgia
Intracranial Hypertension
Given the poor brain cleansing and toxin buildup, it only makes sense that intracranial hypertension – high cerebral spinal fluid pressure – could result. As waste products accumulate, the brain retains more fluid. If the astrocytes don’t “relax,” the CSF won’t get flushed out of the brain. Too much CSF retention will increase CSF pressure.
Possible symptoms include feelings of head pressure/fullness, feeling worse when lying down, feeling better after sleeping with your head slightly elevated, brain fog, pulsatile tinnitus (pulsing tinnitus sounds), neck or occipital tightness arising from a compensatory tension that tries to increase cerebral spinal fluid.
Under Pressure: Large Spinal Study Finds Intracranial Hypertension Common in ME/CFS
Hyperadrenergic POTS
What about the form of POTS – called hyperadrenergic POTS – which is characterized by high levels of norepinephrine in the bloodstream. At first glance, it doesn’t fit this low NE in the vesicles of the LC scenario.
In fact, it may fit it perfectly. Hyperadrenergic POTS is simply a slightly different compensatory approach to the same problem. Once again, low NE levels in the vesicles trigger neurons in the locus coeruleus to fire excessively. In hyperadrenergic POTS, the firing is so rapid that the normal reuptake system, which is designed to keep NE in the nerve synapse (which requires ATP), fails, and NE spills out into the blood, where it’s not helpful.
Instead of responding precisely, they’re firing indiscriminately and inefficiently. They’re like panicked machine gunners who spray the bushes every time a twig snaps. Instead of being too strong, the SNS is actually too weak.
The Paradox
There’s a paradox here, though. If low NE vesicular content requires a higher signal for activation, why are the neurons firing excessively? They should be inert, and they would be if they weren’t wrapped up in a network.
When the ever watchful brain senses more NE is needed, it puts its foot on the NE gas pedal, telling those neurons to produce. The neurons’ inability to respond to the signals causes the brain to push the NE gas pedal even more. That causes the neurons to fire continuously.
Their flailing about introduces “noise” into the system, which makes things worse. The brain interprets the instability and lack of precision present as a threat and calls for even more firing to resolve it, and, sensing danger, turns the microglia on to boot.. The inflammatory cytokines and oxidative stress they produce further strain the LC neurons and damage the mitochondria.
This “high noise”, low signal situation could explain why many people are so sensitive to lights, odors, and sounds. The core problem in the brain isn’t that it’s overstimulated; it’s that it’s not stable enough.
Even here in the central nervous system, in the end, we get back to a very common theme – a lack of power/energy – that’s shown up in the muscles, the immune system, etc. The nervous system is over-reactive because it is under-powered. The brain circuits that filter out and process sensory stimuli simply aren’t getting the energy they need to work properly. This reminded me of Bob Naviaux’s report that low-energy situations result in tension, not relaxation.
- Next Up: Pt. 2: Treatment Implications
Resources
- Check out the excellent Dysautonomia Project website – which is a companion to Goldstein’s 2015 Dysautonomia Project Book, which has gotten very positive reviews. As Sieglende pointed out, the 2nd edition of the book is just coming out. Order before 11/15/25 and you can get $10 off the price ($15 instead of $25).
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