[Part II] A New Drug & A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)

Part 1 introduced how Cortene became involved in chronic fatigue syndrome (ME/CFS), and introduced its hypothesis that a maladaptation within the limbic system, which shapes our response to stress, may underlie ME/CFS.

The Cortene Way: New Drug to Be Trialed in Chronic Fatigue Syndrome (ME/CFS) Soon – Pt. I

In Part II Health Rising takes a deeper dive into nuts and bolts under girding Cortene’s hypothesis.(Given the long nature of this post you may want to print the blog out using the print/PDF buttons on the bottom left hand side of the post)


“Stress” is an unfortunate term. Usually we think of stress as emotional; in biology, though, stress means any threat that disrupts the balance (or homeostasis) of the body. The stress response or HPA axis, prepares the body to respond to the threat. Any threat then, whether infectious, emotional, physical, chemical, etc, will initiate the stress response.

Once triggered, the stress response suppresses non-critical functions such as growth and metabolism (i.e., hypothyroidism, long linked to ME/CFS) and reproduction (i.e., hypogonadism, also connected with ME/CFS). It also releases cortisol to make sure the brain, heart and muscles have sufficient glucose (at the expense of less critical functions like digestion). Cortisol also primes the immune system for action (and has a delayed proinflammatory effect).

As noted in Part 1, studies indicate that chronic stress causes a progression from high to low cortisol and can result in the development of cortisol sensitivity – a situation in which the body becomes more responsive to cortisol. (When cortisol sensitivity occurs low cortisol can have the same or greater effects than high cortisol does in healthy individuals.) This increased cortisol sensitivity cannot be measured by cortisol/synacthen tests (which measure level not effect) but it does results from epigenetic changes that can be shown.

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Cortene’s new hypothesis for ME/CFS will shortly be tested in a small exploratory drug trial

Studies indicate that ME/CFS patients show the same alterations in cortisol levels and cortisol sensitivity seen in chronic stress. These findings help to explain the overlap of immune and metabolic symptoms found in ME/CFS and chronic stress but they do not explain the neurological issues found in ME/CFS.

The stress response also involves brain neurotransmitters such as serotonin, norepinephrine, dopamine and GABA (gamma-aminobutyric acid), which focus on and deal with the stress in a ressor-specific way. These neurotransmitters – which may have been under-appreciated in ME/CFS research – are at the core of Pereira’s hypothesis.

Animal studies indicate that short, medium and long term responses to stress are governed by two factors, CRF (corticotropin-releasing factor) and UCN1, that affect the release of serotonin (and norepinephrine) in the brain and cortisol (and epinephrine) from the adrenal glands.

If these two factors do indeed govern the response to stress in humans, Pereira/Cortene believe that if they can get at the switch controlling them they can reset the stress response system. That can be achieved they believe by altering the receptors found on the neurons that govern the stress response.

Some background…

The Players

Corticotropin-releasing factor (CRF or CRH) is a hormone produced in response to stress that initiates and shapes the stress response. It has two receptors it can bind to on neurons: CRF1 and CRF2.

Receptors are proteins on the surface of a cell which make it possible for the cell to respond to its environment. When molecules lock onto receptors they trigger actions in the cells –such as the production of hormones, neurotransmitters, cytokines, etc.

Cells don’t just respond to their environment, however. By altering the kind and number of receptors on their surface they determine the kinds of response that are possible.

As we’ll see, cells often prime themselves for one type of action by loading their surface with one type of receptor. In the scenario below, different levels of stress; i.e. different levels of CRF, have very different effects on two receptors found on stress response neurons.

Depending on how much of the stress hormone CRF is present one or another receptor will dominate the surface of our stress response neurons. Each of those receptors, in turn, will have very different effects on how much serotonin those neurons will produce. Keep your eye on serotonin in the following scenario

Low Stress States (CRF1) – Low levels of stress (low CRF) activate CRF1 receptors on GABA-releasing neurons of the raphe nuclei and limbic system, triggering the release of GABA, which decreases serotonin release in the limbic system. During low levels of stress, then, CRF acts via CRF1 to inhibit serotonin. (The CRF1 receptor, then, inhibits serotonin.)

High Stress States (CRF2) – High levels of stress (high CRF), cause the CRF1 receptors to leave the surface (or internalize) on GABA-releasing neurons and bring CRF2 receptors to the surface of serotonin-releasing neurons. During intense stress, CRF acts via CRF2 to pound out serotonin. (CRF2, then, increases serotonin.)

Urocortin 1 (UCN1) – UCN1 is a peptide that interacts with CRF1 and CRF2. When the stress dissipates, UCN1 causes the CRF2 receptors to internalize in the serotonin-releasing neurons, and the system returns to baseline. UCN1, then, normalizes the stress response.

A Dysfunctional System Appears

Step I: Serotonin Release


Serotonin producing neurons and serotonin play key roles in Peireira’s hypothesis.

Serotonin is the bogeyman in this hypothesis. In the brain, serotonin is produced by the raphe nuclei in the brain stem, and serotonin neurons extend throughout the limbic system (including the hypothalamus) and the prefrontal cortex, affecting all the other neurotransmitters and coordinating the response to stress.

Step II: Desensitization

The raphe nuclei and limbic system shape the stress response (by incorporating assessments of risk, reward, history, etc), but under intense stress they can desensitize the 5HT1A autoreceptors that normally halt the stress response – allowing it to run amok. Pereira/Cortene believe this is what is happening in ME/CFS.

No stimulatory part of the body is ever designed to be “on” all the time. Because stimulating any system for too long will cause it to break down, any stimulating response comes equipped with brakes. The brakes on an out-of-control serotonin response in the brain are the 5HT1A serotonin autoreceptors. (“Auto” meaning that when these receptors sense serotonin around a particular neuron, they reduce that neuron’s release of serotonin).

Studies in both animals and ME/CFS patients suggest that riding the serotonin stress-response system for too long causes the 5HT1A “brake” to fail and the 5HT1A autoreceptors become desensitized.

With that the foundation of this hypothesis is complete.

Step III: Chronic Fatigue Syndrome (ME/CFS) Begins

In situations of intense stress (e.g., infection, trauma, emotional distress), high levels of CRF in the raphe nuclei (and limbic system) propel serotonin promoting CRF2 receptors to the surface of serotonin producing neurons. The high levels of serotonin produced cause the 5HT1A “brake” to fail. Once that happens, high serotonin levels prevent the release of UCN1 and the re-establishment of homeostasis.

UCN1, remember, causes the serotonin promoting CRF2 receptors to disappear back into the neuron. With UCN1 unable to return the system to normality, the CRF2 receptors remain on the neuron’s surface – telling it to keep pumping out serotonin.

With the neurons (in the raphe nuclei and limbic system) now packed with serotonin-producing receptors (CRF2), and the brakes on serotonin release gone (desensitized 5HT1A autoreceptors), the HPA axis has become sensitized. Now even minor stressors, like exercise or emotional stress, or even stimulation (light, sound, conversation) can initiate a major stress response. This is what Pereira/Cortene believe is happening in ME/CFS (and probably in related diseases such as fibromyalgia).

bombs in path

Peireira’s hypothesis proposes a way even minor stressors can produced major stress reactions in the body in ME/CFS

Animal studies demonstrate how this progression occurs. Intense or prolonged stress (particularly early in life) causes CRF2 receptors to remain on the surface of the neurons long after the triggering stress has gone causing 5HT1A desensitization and behavioral issues (impaired memory and learning ability, anxiety, PTSD-like behavior).

There is hope for these animals, however. Removing the serotonin promoting CRF2 receptors (via sophisticated experimental techniques) eliminates the 5HT1A desensitization and the behavioral issues.

Consequences of Excess Serotonin

If ME/CFS patients’ brains have been turned into serotonin pumping machines, what causes the immense fatigue and post-exertional malaise found in this disease?

It turns out that serotonin plays a vital role in the motor cortex and spinal cord as well. At low levels, it increases motor neuron excitability, making the muscles more responsive. As activity increases, serotonin levels increase, and the motor neurons/muscles become even more responsive.

However, when serotonin levels become too high, they inhibit motor neuron signals, preventing muscle contraction (to avoid muscle damage). Several studies suggest that reduced motor cortex excitability, motor preparation, motor performance and central activation during exercise may be present in ME/CFS.

Pereira/Cortene believe that the hypersensitive serotonin response in ME/CFS patients causes them to reach this threshold very quickly. Intriguingly, their hypothesis also may illuminate an unusual experience that many people with ME/CFS may feel: that their muscles feel more like they’re stuck or paralyzed than that they’ve have run out of energy – and that any stimulation can make the situation worse.

Increases in serotonin have been directly implicated in increased pain sensations, cognitive dysfunction, migraine, sensitivities (light, sound, etc.), sleep dysfunction and depersonalization. Indirectly, by stimulating other neurotransmitters such as dopamine and norepinephrine, serotonin regulates everything from behavior (e.g., mood, perception, reward, anger, aggression, attention, appetite, memory, sexuality) to physiology (e.g., gastrointestinal functioning, blood coagulation, blood pressure, heart rate).

But why have these postulated CRF2/CRF1 maladaptations not shown up in the ME/CFS research to date? Tests of blood and other bodily fluids will not pick up a problem existing only on specific neurons in the brain. Nor can the serotonin output of these specific neurons be measured. While cerebrospinal fluid can get close, it lacks the precision to identify a problem involving a tiny subset of neurons in the brain. Biopsies of specific neurons in the raphe nuclei and limbic system in the brain are needed.

Some indirect evidence does suggest that this hypothesis may be correct. The limbic system neurons postulated by Pereira/Cortene to be problematic are, in fact, the same brain regions that light up in Nakatomi’s ME/CFS work. Cleare’s 2005 pet scan study indicates 5HT1A autoreceptors are desensitized across the entire limbic system in ME/CFS; and Maes has found antibodies to serotonin in ME/CFS patients’ blood.

Of course, there’s more to ME/CFS than altered brain chemicals.

How does this hypothesis account for the hypometabolism seen by Naviaux, Armstrong, Fluge and Mella and Davis?

The Pereira/Cortene hypothesis proposes that a sensitized HPA axis causes even small stresses (including the disease itself) to release cortisol into a system with increased cortisol sensitivity. The resulting excess of cortisol stimulation creates insulin resistance, a situation where the normal insulin-directed uptake of glucose by cells is inhibited by cortisol.


Peireira believes his hypothesis could account for the low energy states studies have found.

The result is increased blood levels of both insulin and glucose, shown to be present in ME/CFS patients (Armstrong/McGregor). Elevations in insulin and glucose in ME/CFS serum could also explain Ron Davis’s work, in which healthy cells become abnormal in ME/CFS serum but remain normal with the addition of pyruvate (which reduces insulin resistance in animals). The resulting lack of glucose in ME/CFS cells could also explain why these cells appear to be using non-glucose substrates (Naviaux, Fluge and Mella).

What about the Immune System?

The notion of a sensitized HPA axis could also help explain the immune dysfunction found in ME/CFS. Cortisol has both an initial anti-inflammatory effect and a delayed pro-inflammatory effect which is intended to deal with any injury arising from the stress. In chronic stress, however, excessive cortisol stimulation suppresses Th1 (cellular immunity) and promotes Th2 (humoral immunity), with attendant changes in cytokines. This could explain why ME/CFS patients are prone to both allergies (driven by increased Th2) and opportunistic infections (driven by decreased Th1). Note also, that under certain circumstances, a corticosteroid (which is essentially a cortisol mimic) could worsen an ongoing stress response and worsen ME/CFS.

Other Symptoms?

A sensitized HPA axis would also result in excess norepinephrine (NE) release potentially explaining many of the autonomic symptoms found in ME/CFS, such as a high resting heart rate, low heart rate variability, low blood pressure and orthostatic intolerance, and abnormalities of the gastrointestinal system (potentially leading to leaky gut) and urinary system.

What about the four facets of the disease (mentioned in Part 1)?

Diverse triggers: Any stress, e.g., infection, emotional distress, physical trauma, chemicals, could result in the postulated CRF2/CRF1 maladaptations. A sudden outbreak of ME/CFS would likely be due to a single pathogen sweeping an area. Plus, Hickie found in the Dubbo studies that different infectious triggers cause post-viral fatigue in ~11% of cases. The fact that those with the most intense immune response (i.e., greatest symptoms) tended to come down with ME/CFS, suggests that for the known infectious triggers, an underlying natural, likely genetic, proclivity to the development of ME/CFS exists (see below).

Sudden/gradual onset: Over time accumulated CRF2/CRF1 maladaptations could result in a sensitized HPA axis. This could happen via an intense stress sufficient to produce maladaptation (sudden onset), or the accumulation of sub-threshold stresses over time (gradual onset).

Gender bias: The female stress response releases more CRF than does the male, has more CRF1 and CRF2 receptors overall, has greater concentrations of CRF1 and CRF2 in certain parts of the limbic system, and shows reduced rates of CRF1 and CRF2 internalization. Other differences exist as well, but all point in a direction that heightens the female response to stress. Importantly, many of these differences emerge at puberty, which explains why the gender bias in ME/CFS is only evident post-puberty (i.e., no gender difference pre-puberty).

Symptom range and variability: Animal work has shown that stress-based adaptations are stressor-specific and result in different maladaptations in the limbic system. This suggests that the symptom presentation of a given ME/CFS patient depends on that patient’s cumulative stress history. This could explain how some patients can present with primarily physical symptoms while others have primarily cognitive symptoms. The symptoms vary over time because the level of the HPA axis response is affected by whatever stress the patient might be under at the time of measurement. This explains why some patients are able to reduce their symptoms with meditation and other calming techniques while some are not. It also explains why putting patients under stress (e.g., via CPET or cardiopulmonary exercise testing) improves the consistency of study results in ME/CFS.

Other Evidence

The risks of developing ME/CFS, and increased symptom severity after one has ME/CFS, have been associated with a wide range of genes involved in the HPA axis and serotonin. That list includes CRF2, CRF1, TPH2 (involved in serotonin synthesis), 5HTT (the serotonin transporter), NR3C1 (the cortisol receptor), POMC (a precursor for ACTH, which triggers the release of cortisol under stress), and TH and COMT (both involved in dopamine, epinephrine and norepinephrine synthesis/breakdown).

Note that all of these genes are involved in the stress response. Defects in them could either make it difficult to unwind or tamp down an ongoing stress response or result in a hypersensitive stress response. Either of those situations could lead to the loss of the 5HT1A “brake” described in Pereira’s hypothesis, and potentially explain the Dubbo findings.

Genetic studies suggest Cortene may be looking in the right area

Finally, Peireira’s hypothesis has something to say regarding the mixed effects SSRI antidepressants have on people with ME/CFS. Neurons communicate via neurotransmitters (such as serotonin) jumping the gap between them. SSRIs work by blocking the serotonin transporter (a channel in the neuron that recycles serotonin in the gap). This was proposed to solve depression by increasing what was thought to be low serotonin.

In fact, depression is caused by high serotonin releases from specific neurons. Blocking the serotonin transporter, causes serotonin to build up outside these neurons until, 2-8 weeks later, it triggers 5HT1A auto-regulation which reduces these neurons’ release of serotonin.

The trouble is that SSRIs block the serotonin transporters on all neurons. This means SSRI will eventually reduce serotonin from neurons releasing excess serotonin (via auto-regulation), but it will also increase serotonin release everywhere else (just not to a level that triggers auto-regulation). This is what causes the many side-effects of the SSRIs—and, notably, these are the symptoms of ME/CFS.

This long overview suggests that Pereira/Cortene’s hypothesis could explain much of what’s happening in ME/CFS. But is there evidence that turning down CRF2 receptor activity as they propose could work?

In Part 3 we’ll dig into that question and describe the upcoming clinical trial.

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