Specifically, we suggest that CFS is caused by sustained arousal. Wyller

Brun Wyller has raised controversy in Norway for his drug/behavioral approach to chronic fatigue in service of a hypothesis asserting that ‘sustained arousal’ (increased sympathetic nervous system (fight or flight)) activity is the cause.

We suggest that sustained arousal can originate from different precipitating factors (infections, psychosocial challenges) interacting with predisposing factors (genetic traits, personality) and learned expectancies (classical and operant conditioning). Wyller

Wyller diagram

Wyller put personality up at the top of the perpetuating causes for ME/CFS

While Wyller cites ‘firm evidence’ that long’lasting infections are present in ME/CFS andcould  initiate the SNS arousal, his model of sustained arousal relies heavily on psychological factors  (illness perceptions, poor control over symptoms), ‘personality’ issues (strong focus on bodily symptoms, poor sense of personal control), and maladaptive cognitive processes’ (negative stimulus expectancies and ‘inappropriate learning processes’) to perpetuate the illness.

While psychological factors are embedded in Wyller’s theory, he also believed physiological factors could explain the fatigue, muscle and even some of  the ‘behavioral problems’ present, hence the Clonidine trial for ME/CFS adolescents. If his theory was correct, then Clonidine, a sympathetic nervous system inhibiting drug should clear up a variety of problems.

In this Clonidine study of adolescents with ME/CFS Wyller put his ‘sustained arousal’ hypothesis to the test.

Big Trial

Wyller has gotten a lot of support in Norway, and the study, containing 120 people with chronic fatigue syndrome and 69 controls, was a large one.As usual, Wyller used his own case definition of chronic fatigue – severe fatigue over the last three months – to delineate ‘chronic fatigue syndrome’ patients. Seventy-three percent ended up meeting the Fukuda criteria. Forty-one percent had ‘depressive symptoms’.

Because Clonidine can lower blood pressure, which could have negative effects on people with orthostatic intolerance, low doses designed not to affect blood pressure were used. To his credit Wyller used a fairly rigorous primary endpoint to measure effectiveness: the number of steps the adolescents took during the day. If that number increased significantly, the trial would be considered a success. Numerous secondary measures were also taken.

SNS Arousal Hypothesis …Not Sustained

“The results were both interesting and somewhat depressing” Wyller


Clonidines SNS antagonism,neuroprotective and anti-inflammatory properties suggested it might work in ME/CFS

Much seemed to line up for Clonidine. It inhibits SNS (fight/flight) activity and enhances PNS (rest/digest) activity and it has anti-inflammatory properties. The receptors it affects were identified in the Light gene expression studies as possibly contributing to ME/CFS. It is used to inhibit anxiety, treat ADHD, migraines and sleep disorders, and even reduce stress – a key component of Wyller’s understanding of chronic fatigue.

Arousal responses also include behavioral changes, which seem to be mediated – at least in part – by catecholaminergic neurotransmission to brain motor areas. Wyller

Given Wyller’s belief that some of the behaviors in ME/CFS are driven by catecholamines such as norepinephrine, Clonidine should have even changed the participants behaviors as well. Reducing sympathetic nervous system activity should also be able to enhance natural killer cell functioning, increase anti-inflammatory activity and reduce pro-inflammatory activity.

Unfortunately, not only did Clonidine not make the adolescents with ME/CFS better, it actually made them worse.

Reduced levels of norepinephrine in the ME/CFS patient’s blood stream indicated Clonidine was indeed reducing sympathetic nervous system activity,but instead of increasing activity levels and reducing fatigue, Clonidine significantly reduced physical activity and significantly increased fatigue scores. By the end of the trial the ‘CFS’ patients were significantly worse off, leaving Wyller’s hypothesis that increased ‘arousal’ caused ME/CFS in shambles.

tower falling down

Clonidine effects – increased fatigue and reduced activity – suggested the sustained arousal might be there for a reason.

Some basic characteristics of Wyller’s model (the SNS arousal, the parasympathetic nervous system inhibition, and the state of low-grade inflammation were validated, but the study results suggest these factors  may be an attempt by the body to improve health.

Stating that he still believes his ‘sustained arousal’ theory is sound Wyller wouldn’t go that far, but it’s hard to know how else to interpret this study. If Clonidine had had no effect that would have been one thing, but making chronically fatigued patients significantly worse is another.

The findings suggest, at least to me, a laymen, that the ‘arousal’ and activation of the fight/flight system, the increased heart rates during rest, the inability to relax, even maybe those rushing thoughts – are there for a reason. Far from causing ME/CFS, the fact that Wyller’s patients got worse when the arousal was tamped down, suggested it was actually helping.

Which leaves  the question what an aroused fight or flight system is trying to fix? We know continuous SNS activation is not good. It doesn’t give the body any time to ‘rest and digest’ or relax and repair itself. It’s going to blow some fuses over time. It also accentuates the Th2 side of the immune system while reducing the Th1 (antiviral) part of the immune system that fights pathogens in cells.

This study, though, suggests it’s better than the alternative, which is what? What worse fate is the ‘arousal’ keeping ME/CFS and probably FM patients from?

Any answers? Answers will need to come from an expert. We do know several things Clonidine does. Because it decreases vascular resistance (opens blood vessels) it should increase blood flows, which  would seem like a good thing.  Blood vessels may be constricted, however, to raise blood pressure. (Do people with ME/CFS have both low blood volume and low blood pressure?).  Clonidine also decreases gut motility and inhibits insulin release.  Insulin carries glucose to the cells. (Did clonidine interfere with energy metabolism?)

Deconditioning – Not ‘It’ in ME/CFS

As the results undermined Wyller’s hypothesis they also demolished the idea that deconditioning is a factor in ME/CFS. Some researchers have believed that the higher heart rates and the SNS activation indicated by increased norepinephrine (NE) levels found in ME/CFS could reflect deconditioning, but Wyller’s inability to find a link between blood NE and activity levels suggested the increased SNS activity was not being driven by deconditioning.

Inflammation – Not ‘It’ Either?

The fact that both NE and C-reactive protein (CRP) levels fell together suggested that SNS activation was indeed driving inflammation. (The sympathetic nervous system is an important immune regulator.)

Inflammation has long been proposed as a key factor in ME/CFS, and inflammation was present in Wyller’s patients, but Clonidine’s reduction of a broad inflammation factor (CRP) had no effect on symptoms or physical functioning. That was surprising.

The Autoimmune Connection

One blog listed autoimmunity as an alternate theory to Wyller’s stress response hypothesis, but my understanding is that the stress response issues could help prepare the ground for it. Chronic activation of the sympathetic nervous system and low cortisol levels from the HPA axis both upregulate the humoral (antibody driven) side of the immune response. Since cortisol is an anti-inflammatory, the low cortisol levels in ME/CFS should increase inflammation. Both would seem to help set the stage for autoimmunity.


We still believe that it’s about a sustained stress response in the patient. We have much evidence of this phenomenon in those who are chronically fatigued. But there is no direct correlation between the stress response and the patient’s ailments. Wyller

thinking-ladyThe study findings were a blow to Wyller’s hypothesis and must also be causing other researchers to scratch their heads a bit. While Wyller did emphasize behavioral modifications, studies have found evidence of ‘sustained arousal’ or an over-active sympathetic nervous system activation.

Looking very broadly we may be able to find ‘sustained arousal’ in a variety of situations; in the muscle contractions that don’t cease, in the brain’s stubborn energy draining attention to innocuous stimuli it should ignore,and in the natural killer cell ‘burn out’ that may be occurring.

Something is keeping ME/CFS patients systems on edge. At least in this case, removing that edge didn’t work. Finding out what’s putting them on edge sounds like the next step.

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