Hypothesis piece by Amy Proal, a microbiologist with ME/CFS

[TigerLilea]

How many drugs and supplements out of the following fairly standard list of medications known to help ME/CFS have you tried? Many of these are employed by leading ME/CFS doctors.

B12 methylcobalamin injections
Low-dose naltrexone
Oxymatrine (for enterovirus ME/CFS)
Valcyte (for herpesvirus ME/CFS)
Nimodipine
GcMAF injections
Tenofovir

Piracetam (for brain fog)
(for brain fog and fatigue)
Dichloroacetate (for brain fog, fatigue and pain)
Modafinil (for brain fog)
Moclobemide (for brain fog)

D-ribose (to speed up PEM recovery)

I have tried the B12 injections and d-ribose. As far as prescription drugs I have not yet met a doctor who will prescribe random drugs simply because I have ME/CFS. Neither would I be willing to try them without proof that they work for our condition. Many years ago before ME/CFS, I was put on Ritalin and became extremely hyper when I was on it. Forget sleeping. I was too wired.

There might be some doctors who are willing to prescribe these drugs, but I seriously doubt that it is the norm.

 

[Jonathan Edwards]

the morale-raising effect of pursing treatments is in itself a treatment of sorts.

That I entirely understand and you might even say that is the whole point of the forum until something actually turns up.

But doctors get a lot of stick for falsely claiming that treatment works. It seems to me there should be a level playing field. Nobody should be claiming ineffective treatments work - that is quite different from being enthusiastic about trying things.

Whether a trial is has 1 or 3 is not really the issue. PACE was sort of phase 3. What matters is whether it provides reasonably reliable evidence and as far as I know none of the studies so far provide that.

 

[NelliePledge]

The only supplement I can honestly say I’ve noticed when I ran out was magnesium. I hadn’t registered that I’d run out until i felt worse a few days later.

The only prescription stuff I’ve been given was amitryptiline - yuk hated due to sedative hangover. And very low dose pregabalin which does help get rid of neuropathic burning but I only take when I really have to as again I get sedative hangover.

I think it’s inaccurate to describe anything as a treatment that isn’t evidenced and it isn’t treating me effectively unless the symptom is almost entirely removed or a least significantly alleviated.
So a supplement that helps reduce symptoms somewhat isn’t a treatment it’s making things a bit less bad.

 

[Londinium]

Personally I try and avoid all treatments and supplements as I've not seen good evidence for any of them and I'm worried about making things worse. One of my main concerns with a lot of ME/CFS research is that some of the differences found between patients and HCs is down to the former often taking a cocktail of medicines and supplements - this is especially the case when such research has a small sample size.

 

[Snowdrop]

One of my main concerns with a lot of ME/CFS research is that some of the differences found between patients and HCs is down to the former often taking a cocktail of medicines and supplements - this is especially the case when such research has a small sample size.

That's something I never considered in the equation. Do research trials not control for this?

 

[Jonathan Edwards]

That's something I never considered in the equation. Do research trials not control for this?

It tends to be the first thing I consider if what is being measured might be affected by medicines etc.
Any biochemical or metabolic studies could easily be skewed, as would microbiome studies for sure.

Some more sophisticated trials may attempt to control for it but I suspect they are rare.
One option is to include a control disease cohort but that is not necessarily going to cover things like supplement usage - it might help for painkiller usage for instance, although that would be hard to guarantee.

 

[JES]

One of my main concerns with a lot of ME/CFS research is that some of the differences found between patients and HCs is down to the former often taking a cocktail of medicines and supplements - this is especially the case when such research has a small sample size.

It wouldn't make much difference anyhow. These days healthy persons pop supplement pills left, right and center, there's the superfood boom etc. For example probiotics are now the first thing people mention to me when I discuss about ME/CFS and the hypothetical gut connection, as if I didn't know about them. It seems every other person I know takes some probiotic these days without much consideration.

 

[pone]

In the Marshall Protocol, you are taking the drug Benicar which activates the vitamin D receptor (VDR), so as I understand it, even if your vitamin D levels are low, you will still have VDR activation from Benicar.

The overall idea of the Marshall Protocol is not to reduce VDR activation, but to increase it. Taking Benicar and avoiding vitamin D is supposed to serve that purpose of increasing VDR activation. Activating the VDR releases the anti-microbial peptides beta-defensins and cathelicidin.

I am not sure if I understand the mechanics, but Dr Marshall said something about the inactive form of vitamin D (called 25-D) being an antagonist to VDR, whereas the active form (called 1,25-D) is a VDR agonist, and that when too much 25-D binds to the VDR, it inactivates this receptor, and stops 1,25-D from binding to and switching on the VDR.

I am not going to attempt to review every part of the Marshall protocol, but what is most disheartening to me about the whole thing is Marshall clearly does not understand the difference between a hypothesis based on computer modeling and a tested drug therapy that is safe for real patients.

A key part of his hypothesis is that Benicar binds to the VDR and activates it. As a hypothesis that is novel. Now do searches in PubMed. I cannot find a single study in the history of science in which animals were administered Benicar and the VDR activity was measured. How can it be that Marshall did not see a need to test his hypothesis with an experiment in animals, to validate that his computer model was right? How can he think it is okay to start giving Benicar to humans and then to use hearsay testimony from patients - all of which could be placebo effect - to validate the computer model? You can believe Marshall is right on every point and still understand that everything about the way he implemented his ideas is wrong.

I am also very confused on Marshall's ideas on 25-D and 1,25-D. 25-D may inactivate the VDR, but that fact alone is meaningless because 25-D is converted by the body to 1,25-D, which activates the VDR. So if I remove 25-D, I may remove an antagonist to the VDR. But I also removed the metabolic byproduct 1,25-D which is an agonist. Shouldn't his ideas be tested in animals by measuring the amount of VDR activation under different levels and ratios of 25-D and 1,25-D? I think there may be an unstated hypothesis here that the pathogens that are deactivating the VDR somehow are able to defeat 1,25-D but not able to defeat Benicar, otherwise why the need to lower 1,25-D? His ideas are not really clearly stated, which makes the fact that he never tests his ideas in animals even scarier.

 

[Sing]

@Jonathan Edwards makes the point that there is no evidence that ME/CFS is an inflammatory disease. My own lack of any discernible benefit from drugs to treat my supposed Mast Cell Activation Syndrome as well as SIBO, and my theoretical neuroinflammaton by LDN, sure seem to bear out this idea.

Yet if some people do get benefit from these treatments for inflammation as well as leaky gut (SIBO), perhaps we have dissimilar illnesses with some overlapping symptoms?

in any case I don't see that my “version” of ME/CFS is inflammatory.