Trial of CT38 for ME/CFS by Cortene Inc.: big claims being made...

[Denise]

In looking at changes in cerebral spinal fluid, Baraniuk found
"The changes in brain chemistry — observed in levels of miRNAs that turn protein production on or off — were seen 24 hours after riding a stationary bike for 25 minutes.

“We clearly see three different patterns in the brain’s production of these molecules in the CFS group and the two GWI phenotypes,” says Baraniuk."

 

[Forbin]

Dear Forbin
I do appreciate your detailed response. I saw another interview with Dr Klimas (can't find it anymore) where she is suggesting that there are enough similarities between Gulf War Illness and ME for her to consider using the GWI protocol on ME patients, at some point in a trial, if things work out in the present trial.

From earlier in this video, in her conversation with Dr. Nahle, I got the impression that, in the event that the Gulf War Illness trial showed good results, they would proceed with an ME/CFS trial relying entirely on computer simulations - as opposed to going through the lengthy process of developing an ME/CFS animal model. It's possible that those simulations would indicate the same procedure for ME/CFS as for GWI, but I don't know. The two diseases seem to manifest in opposite ways following exercise, but it might be that both of them can be addressed by "resetting" the same underlying system. There have been indications that Dr. Klimas was going to start an initial ME/CFS trial relatively soon, if it has not begun already.

 

[Perrier]

From earlier in this video, in her conversation with Dr. Nahle, I got the impression that, in the event that the Gulf War Illness trial showed good results, they would proceed with an ME/CFS trial relying entirely on computer simulations - as opposed to going through the lengthy process of developing an ME/CFS animal model. It's possible that those simulations would indicate the same procedure for ME/CFS as for GWI, but I don't know. The two diseases seem to manifest in opposite ways following exercise, but it might be that both of them can be addressed by "resetting" the same underlying system. There have been indications that Dr. Klimas was going to start an initial ME/CFS trial relatively soon, if it has not begun already.

What I can't find is any indication the GWI trial has begun. We've all seen these interviews where Dr Klimas says she has the cash and will start the trial, but nothing more has appeared.
Yes, she does say the diseases manifest differently after exercise, but she seemed to say the symptoms are very similar.

 

[Forbin]

This is what Dr. Klimas says in the video above, which was recorded in mid-October 2017.

Klimas: For our group, the fact that we were able to take an animal model that was the equivalent of ten years of chronically ill and flip it back into a normal pattern, and make these animals healthy, is so promising that I'm ready to do clinical trials right now, without an animal model. I don't need an animal model. Our "in silico" thing worked.

And so, if the Gulf War phase one study is also promising, I feel like the training wheels are off and let's just get going - you know? This is just so exciting.

Nahle: That's great.

Klimas: So I'm very enthusiastic about that. I dare say that this Gulf War trial that we're just launching right now - it will be done in about a year - will be our proving ground. So let's hope that it's as good as we hope it should be.

Nahle: Wonderful. And can ME/CFS arms be added to that trial...?

Klimas: Absolutely. In fact I have one private foundation research institute that's going to fund our first chronic fatigue [trial]. So I actually have that protocol in hand and we're hiring the clinical coordinator - she starts next Monday actually.

So I'm hoping to be in a chronic fatigue homeostatic reboot trial by early next year.

Early 2018 could be as late as the March/April time frame. From the above, it seems like the gating issue for pursuing an ME/CFS trial at this point would be whether or not the Gulf War phase one study was "promising." I would guess that any initial trial would involve relatively few patients and would be looking to see how well the procedure is tolerated as a first step.

 

[Perrier]

This is what Dr. Klimas says in the video above, which was recorded in mid-October 2017.


Early 2018 could be as late as the March/April time frame. From the above, it seems like the gating issue for pursuing an ME/CFS trial at this point would be whether or not the Gulf War phase one study was "promising." I would guess that any initial trial would involve relatively few patients and would be looking to see how well the procedure is tolerated as a first step.

Forbin,
Are you saying this GWI trial is beginning in March? I thought it was already begun in Dec 2017 (at least from her other video). Klimas' had a sister with ME who died, I'm not certain of what causes.

 

[Forbin]

Forbin,
Are you saying this GWI trial is beginning in March? I thought it was already begun in Dec 2017 (at least from her other video). Klimas' had a sister with ME who died, I'm not certain of what causes.

No, you are right. As far as I know, the GWI phase one trial began in Dec 2017. She says that, if the results of that trial are promising, then she hopes to be doing a ME/CFS trial in early 2018. I was just saying that a trial said to begin in "early 2018" could start as late as March/April 2018.

 

[Stuart]

Oy (facepalm), really? Again with this 'stress loop' nonsense. Been here, done that.

It is a rehash of the idea of heterogeneous chronic fatiguing illnesses caused not by a pathogen, but by a 'stress loop' inappropriate response. Regardless of physiological findings, this is a BPS favorite. 'Reset' ideas of the inappropriate 'stress loop' have been made before (by Cort as well, welcome to Groundhog Day).

Idiopathic chronic fatigue is not ME, ME is not a fatiguing illness, although they try to make it one. Conflating ME with the CDC whole cloth invention after the Tahoe outbreak of 'CFS' which is nothing more than idiopathic chronic fatigue disappears ME.

Creating a false illness lends itself to false illness models and treatments. We've been here before. I'm dubious and underwhelmed so far. A drug in search of a purpose and we are the wastebasket to drop it in.

 

[Forbin]

Of course, psychological stress is not the only kind of "stress" there is.

What if you get into some kind of stable "loop" or altered homeostasis due to the physical stress of a severe infection ("worst flu ever")? Or the physical stress of a bodily injury?

What if your body's response to physical stress can be exaggerated by overexertion, sleep deprivation, poor diet, toxic exposure or genetic susceptibility? None of these are psychological stresses.

It is also probably a mistake to conflate the possible effectiveness pharmacologically suppressing/blocking the HPA axis with the reduction of psychological "stress" through psychotherapy. If there is an altered homeostasis in place, one which can apparently remain stable for decades, I've seen no evidence that any amount of "calming" psychotherapy is enough to break that feedback loop. Once established, the part of the loop that could be nudged by "calming" influences might not even be a significant part of the loop, if it's part of the "loop" at all. It might well be like trying to put out a burning house by blowing on on it.

And all of this has absolutely nothing to do with the dominant psychological explanation for ME/CFS, which is that patients are deconditioned by lack of exercise due to the holding of false illness beliefs which can be addressed by CBT. None of that psychobabble is done on the theory that the effects of psychological "stress," let alone physical stress, are bumping a molecular signalling system into an altered, aberrant, yet stable state.

 

[Amw66]

Of course, psychological stress is not the only kind of "stress" there is.

What if you get into some kind of stable "loop" or altered homeostasis due to the physical stress of a severe infection ("worst flu ever")? Or the physical stress of a bodily injury?

What if your body's response to physical stress can be exaggerated by overexertion, sleep deprivation, poor diet, toxic exposure or genetic susceptibility? None of these are psychological stresses.

It is also probably a mistake to conflate the possible effectiveness pharmacologically suppressing/blocking the HPA axis with the reduction of psychological "stress" through psychotherapy. If there is an altered homeostasis in place, one which can apparently remain stable for decades, I've seen no evidence that any amount of "calming" psychotherapy is enough to break that feedback loop. Once established, the part of the loop that could be nudged by "calming" influences might not even be a significant part of the loop, if it's part of the "loop" at all. It might well be like trying to put out a burning house by blowing on on it.

And all of this has absolutely nothing to do with the dominant psychological explanation for ME/CFS, which is that patients are deconditioned by lack of exercise due to the holding of false illness beliefs which can be addressed by CBT. None of that psychobabble is done on the theory that the effects of psychological "stress," let alone physical stress, are bumping a molecular signalling system into an altered, aberrant, yet stable state.

Yes, but just watch it change.
The paradigm is already shifting- but the treatment remains the same.
Biomedical and stress are proving a bit like " sustainable"in the green context- sufficiently vague that it means all things to all people.

 

[hixxy]

A follow up article from Cort: Cortene II: A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)

 

[Sasha]

A follow up article from Cort: Cortene II: A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)

That's all way over my head and I can't tell whether it makes any sense but perhaps the proof of the pudding, etc.:

We should know if Cortene is safe and effective in a small number of patients in a couple of months. If Cortene passes its first test then determining if it is effective in ME/CFS overall could take as little as 1-2 years.

That's a very short timescale for a rapid indication. I don't know how well designed their test is likely to be.

 

[Alvin]

A follow up article from Cort: Cortene II: A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)

Cort has quite the talent for hyping anything...
Lets just say i am not planning for a post treatment future yet.

 

[Sasha]

Do you have a view on any of this, @Jonathan Edwards?

 

[Hoopoe]

Part 2 is out

https://www.healthrising.org/blog/2018/02/17/cortene-chronic-fatigue-syndrome-hypothesis/

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.

Ok.

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.

In my experience, cortisone improves symptoms, and insulin is low (without diabetes) suggesting insulin sensitivity (this might just be my subgroup).

In my opinion another inconsistency with this hypothesis is that stressors are not equally likely to lead to symptom aggravation. Exertion stands out. I don't view emotional stress as particular problem, but a repeated walk to the park can easily induce delayed symptom aggravation.

Who knows, maybe it will all work out in the end.

 

[dreampop]

So it seems this is proposed pathology?

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

I may be totally off, but from reading wikipedia this is how some antidepressants work.

5-HT1A autoreceptor desensitization and increased 5-HT1A receptor postsynaptic activation via general increases in serotonin levels by serotonin precursor supplementation, serotonin reuptake inhibition, or monoamine oxidase inhibition has been shown to be a major mediator in the therapeutic benefits of most mainstream antidepressant supplements and pharmaceuticals

Except for that second part.

One thought is that would a 5-HTA1 agonist specific to the ralphe nucleus be effect - there are 2, but i also read

While a 5-HT1A receptor agonist will acutely suppress 5-HT neuron firing in the dorsal raphe nucleus (DRN) and thereby reduce the release of 5-HT in terminal areas (e.g., mPFC and vHIP), repeated dosing of a 5-HT1A receptor agonist will lead to desensitization of somatodendritic but not post-synaptic 5-HT1A receptors

In any case I remain heavily on the fence about all this.

 

[Londinium]

A few initial, unfocussed thoughts:

• It's an interesting hypothesis. Overall I'm sceptical, for reasons set out below, but it's worth noting one item that isn't driving said scepticism: it is true that were this to pan out, the BPS crew would almost certainly claim it as a vindication of their theories. However that is to do with the fact that the BPS model is almost entirely unfalsifiable - as facts emerge, just dial up or down the B, the P or the S accordingly and one can still claim any illness meets the BPS criteria. This hypothesis may be proposing a model that colloquially could be described as 'in the head not in the blood' but what it *isn't* proposing is the false illness beliefs model that underpins ineffective and potentially harmful CBT/GET approaches. So any criticism that follows is not because I'm unwilling to look favourably on any model that involves ME/CFS primarily arising in the brain rather than body (given the paucity of conclusive evidence, I don't think I could rule out either with any scientific certainty).

• That rather long disclaimer out of the way, I do have a fairly major issue with the hypothesis as written up: there are far too many references to 'studies say' without references - I'm going to try and find links for these as I'm always suspicious the Fox News 'some people say' approach when it comes to 'studies say':

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.

Studies indicate that ME/CFS patients show the same alterations in cortisol levels and cortisol sensitivity seen in chronic stress.

I'm aware of studies measuring cortisol levels but this seems to be arguing cortisol levels fall but cortisol sensitivity increases? Is there much evidence for the latter?

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.

That seems to be a reference to this study, which did at least exclude comorbid psychiatric illness, but which is small.

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 afterthe triggering stress has gone causing 5HT1A desensitization and behavioral issues (impaired memory and learning ability, anxiety, PTSD-like behavior).

Need citations for this one. We should be wary of the 'early in life' claims as they have a number of issues: dubious Conversion Disorder diagnoses where the practitioner can skirt the fact that a patient doesn't have any such early trauma with the catch-all 'ah, but your traumatic memory is supressed'; also, early-life adversity claims in ME/CFS patients have often been based on studies with dubious selection criteria in which the patient group is likely to include people suffering anxiety or depression. Also, this bit doesn't tie with the later parts of the article that seem to suggest that excess serotonin is impeding the ability to use muscles, whereas this bit seems to be viewing the 5HT1A desensitisation as leading to an anxiety-related disorder.

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).

Again, it would be good to have links here. I have two concerns: the impacts described above don't seem to tie in with what one might see in Serotonin Syndrome - and to an uneducated layman such as myself I would have expected some overlap. Similarly, as somebody who his spent his teens/early twenties out clubbing, I have *ahem* some insight into what elevated serotonin levels feel like - and sadly ME/CFS feels nothing like that...



(Right, I've run out of time so I'll keep going through the rest of the article later and edit this post accordingly...)

 

[Hoopoe]

Similarly, as somebody who his spent his teens/early twenties out clubbing, I have *ahem* some insight into what elevated serotonin levels feel like - and sadly ME/CFS feels nothing like that...

What does it feel like?

 

[Alvin]

it is true that were this to pan out, the BPS crew would almost certainly claim it as a vindication of their theories.

But then antidepressants would significantly affect and even treat ME/CFS

This is snake oil, they are preying on our desperation and their own greed. That said they can try and prove themselves and if they do i will change my mind but so far this has my BS detector going overtime and i can't spare the energy to let it keep running.

 

[Dr Carrot]

What does it feel like?

It's funny - my only reference point as to how bad ME/CFS could feel when I was healthy was actually how it felt the day after taking amphetamines quite a few times in my youth and dancing all night.

You feel like there's nothing left in the tank, stuff is difficult to achieve cognitively, everything feels "off" and you have to drag yourself around a lot. You just feel very empty and given the fact that you're experiencing a comedown from frazzling all your serotonin levels, very depressed too.

As my only reference point, I would say it is probably as bad or maybe slightly better than my current level of health, which is severe ME (again, a fluid term, but for me means housebound apart from doctors appointments, spending all day lying down on a bed with meals needing to be made for me, and very little ability to use distractions like Netflix etc).

 

[madone]

No they would not treat it.

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.