Do ME symptoms fit with the faulty energy metabolism hypothesis?

My PEM seems totally neurological: primarily lethargy and malaise. I don't suffer from physical problems. I'm sure my muscles could manage a 6-hr bike ride while I was suffering from PEM; it would just feel like horrible torture, and I might need someone with a whip to keep me from giving up. Thus I disagree with theories about energy metabolism, unless it's limited to brain cells involved in motivation and muscle signalling. I haven't suffered physically-induced PEM for quite a while (I use an effective PEM blocker), but IIRC, the severity and duration of my PEM didn't vary much with the strength of the trigger; a minute of washing windows caused similar severity and duration that a 40 km bike ride did.

I think PEM is a change in brain cell function. There's a trigger, and then some ratios of molecules changes, or there's a change in micropores in cell walls or whatever, which changes our perceptions and nerve signalling. That gradually returns to our ME baseline (rather than 'normal').
 
MeSci said:
What is the PEM blocker? I don't think I've heard of this.
Click to expand...
From a previous post by @Creekside
Creekside said:
.......Also, I can block my physically-induce PEM with cumin (Cuminum cyminum), but it doesn't work on cerebrally-induced PEM. I've recently discovered that cumin seems to work in my brain, rather than elsewhere, since it's effective if taken sublingually and not swallowed.
Click to expand...

It does nothing for me, but.......

...and I'm not sure it's internally consistent with @Creekside's own hypothesis - but whatever works ;)
 
 
Cumin works wonderfully for me. A level tsp of ground cumin blocks my physically-induced PEM completely for 3 days. I'm pretty sure I posted it on this forum long ago, and on PR and HR as well, but no one has reported that it works for them. It seems something unique to me. I keep hoping that it will work for someone else, so that researchers might follow up. It makes a huge difference in my quality of life (able to do physical activities again). Once in a while I start feeling unusually lousy, and realize that I'd forgotten to take my dose, so it's not placebo effect. FWIW, taking more cumin only increases the duration slightly: 3 full tsps lasted 6 days. I prefer the minimal dose every 3 days. I discovered cumin's effect by accident, when PEM expected after some physical exertion failed to show up.

I did some experimenting with other herbs and spices to try to identify the active chemical. I'm pretty sure that it's cuminaldehyde, but I don't have an alternate source to verify that with. Cuminaldehyde content varies with where it's grown. IIRC, the Turkish variety is high in cuminaldehyde, but cumin from some other countries (Egypt? India?) are low. The bulk bin seeds and non-name ground cumin have all worked for me, but some brands might not.

If it does work for someone else, please let me know.
 
@Creekside are you referring to black seeds aka black cumin? As in Nigella Sativa? Dr. Moreau mentioned thymoquinone, an active ingredient found in Nigella.

I took the Turkish formula oil for over a year but didn't notice anything helpful.
 
Mij said:
@Creekside are you referring to black seeds aka black cumin? As in Nigella Sativa? Dr. Moreau mentioned thymoquinone, an active ingredient found in Nigella.

I took the Turkish formula oil for over a year but didn't notice anything helpful.
Click to expand...
@Creekside referred to Cuminum cyminum earlier.
 
  • Like
Reactions: Mij
I've gotten into the habit of including the (Cuminum cyminum) whenever I mention cumin, because there is confusion. The black cumin is frequently mentioned as a health product, while regular cumin isn't. My guess is that it's the 'rare ingredient' marketing approach: sellers of fake treatments used rare ingredients because everyone already knew that the easily available ones didn't work. Rare ingredients have the 'I don't know for sure that it doesn't work' aspect.

As I said, I'm pretty sure that the active chemical is cuminaldehyde. I found one source saying that perilla had cuminaldehyde, but other sources say that it has perillaaldehyde. I didn't have a convenient source of that, so I didn't try it. I don't see a point in trying pure cuminaldehyde unless a researcher is going to follow up on why/how cumin is blocking my PEM.
 
Trish said:
Good point. Same for me.

Another example is I can no longer write much without my handwriting deteriorating. When I was teaching I really struggled with report time, when I had to hand write dozens of half page reports on students in limited time. When I was well I could write for hours without problems. Now when I write a cheque by the time I get to my signature it's barely legible. I'm not sure that fits with @Jonathan Edwards' idea.

And if it's like an infection, why would doing repeated activity in a day bring on PEM, when just doing it once or twice isn't a problem apart from the immediate effects? Surely if the biological process is bad enough to cause PEM, we would have PEM all the time. In an infection that is bad enough to put you to bed, the level of activity the day before is irrelevant.

I don't think I'm thinking or expressing myself clearly. I'd better stop.
Click to expand...
Maybe there is some medium-term cumulative effect going on. Supposing the failure (or partial failure) of one subsystem leads to overloading of another subsystem, the latter then being forced to undertake an abnormal role, and thereby itself maybe hitting its own secondary failure mode. This is a common failure scenario for many things. e.g. Laptop lid hinge goes stiff which then stresses the case over time. Or some injury leading to an abnormal gait, then putting abnormal stresses on other parts of the body.

And though biology is mostly a mystery to me, from what I read here in S4ME it is has a lot in common with some pretty amazing and highly complex process control, which I do have some understanding of. Many of the transfer functions likely having time constants of some kind, meaning delays between cause and effect, some short and some not so short. These time delays often being due to an integral build-up effect, cumulative.
 
Barry said:
Supposing the failure (or partial failure) of one subsystem leads to overloading of another subsystem, the latter then being forced to undertake an abnormal role, and thereby itself maybe hitting its own secondary failure mode
Click to expand...
I have often thought of it this way. Some systems in the body can tolerate up to maybe an eighty percent failure. Like the heart circulation. Once that threshold is reached though you are in deep trouble, though minor symptoms occur earlier. With ME there is a small failure in many subsystems, with a few having larger failure. Each failure is within a compensatable range, but as you point out the compensation puts stress on other systems. ME is about partial failure in a great many interlocking systems, so that the overall failure is very high. For example, if you have a 10% failure in ten systems, the final result is an over 70% failure. Degradation in each subsystem has an impact on overall performance, and with enough sybsystems failing the total performance is bad.

With a computer analogy this might be partial CPU degradation, memory degradation, hard drive degradation, frayed wiring, a failing power supply, all at a low level of failure until you put them all together.

Whether or not this is some kind of cascading failure is not known. It is however possible that its not some kind of cascading failure effect, but many partial failures having a cumulative failure effect. Some knock on is still likely though even in this scenario.
 
Barry said:
If this is true then of course it would be good to establish. But then how do you go about clarifying that the neural inhibitory signals are not down to some mental condition that can be fixed by going round in circles and chanting stuff, but instead a real physical shortcoming, be it in the brain, body, whatever?
Click to expand...
The priority comes the other way down, given that there are:
  • sudden onsets after physiological impacts
  • outbreaks
  • some genetical predisposition as suggested by twin studies

It might be a big mistake to assume that there must be something which is by no any means linked to any any mental thing, just to rule out to get mistreated.

It is an unbelievable event that the PACE trial managed to sidestep these first (and strong) hints.
 
I like the concept of linked subsystems failing and affecting other subsystems. It could explain the gradual changes in my ME symptoms over the years. One subsystem weakens, and another gradually strengthens to 'take up the load'.
 
I dont see how their should be a problem explaining PEM as related to metabolic problems if the metabolic problems are downstream of the ultimate cause of the disease, and thus different from inherited metabolic disorders (although I think some inherited metabolic disorders can present like me/cfs, if we are to believe the NIH has ruled people out based on finding those disorders in thorough workup, and ron tompkins says something similar)

When naviaux compares the hypo metabolism in me/cfs to sauer, it makes me think of taking the analogy further. Dauer is caused by prolonged exposure to periods of starvation, so the hypo metabolism is protective. But clearly me/cfs patients aren't suffering from a lack of calories. So what else could make hypometabolism protective?

Well, the term "oxidative stress" may be overused and too broad, because oxidative reactions and free radicals are sometimes good and protective... but if there is some sort of xeno biotic situation in me/cfs that causes oxidative stress from various sources... either the immune reaction to the organism or directly from the organism, or toxicity...? Then it makes sense for energy production to down regulate in response. Even though cellular oxidative metabolism isn't the sole source of oxidative radicals it is a source, and so if the body has too much damage from these going on it may shut down energy production to compensate. Also I believe there are enzymes involved in reducing oxidative radicals as a step in cellular metabolism, if those enzymes are impaired in any way this may be more important than hypometabolism in general.

The delayed symptoms in exertion, unlike primary mitochondrial diseases, could be explained by all I'm saying... if the hypometabolism is secondary rather than primary ... increasing oxidative stress through a number of things that are known to do so, like exercise , or stimulant usage , could cause a crash and down regulation of metabolism later.

One really really interesting clue in me/cfs for me was that prior to developing me/cfs I had ADHD and stimulant medications for it were well tolerated and sometimes even made me relaxed. After the infection that triggered my slow decline into total me/cfs , I started experiencing only negative side effects of stimulants , with none of the beneficial effects like focus. Before me/cfs ritalin would make me feel somewhat calm and focused at the same time. After me/cfs, I would feel extremely uncomfortable, wired, brain on fire., etc. From stimulants. There are other drugs in which my reaction changed so starkly before and after me/cfs that I have to imagine they hold clues to the pathophysiology. Stimulants increase oxidative stress which may not be a problem in otherwise healthy people
 
This post has been copied and discussion moved from UK: Physios for ME

Trish said:
Thank you, @PhysiosforME. A very helpful article.
Click to expand...
Yes, it is. Thank you. @PhysiosforME :thumbup:

Some comments:

This helps to explain the main symptom of ME/CFS, post-exertional malaise (PEM). Any activity that uses energy can cause PEM. There can be over 30 symptoms of PEM and people with ME/CFS usually experience PEM up to 24 to 48 hours after the activity. Called a crash, they can last days, weeks or months; some people never recover.​

I am not convinced the 'energy' is the right framing for PEM. It suggests an understanding of underlying mechanisms (e.g. mitochondria) that just doesn't exist yet. Of the current imperfect options I prefer 'activity capacity' and variants.

Activity capacity is a more general term that covers any active behaviour – physical, cognitive, emotional, and social, and to any degree, without presupposing where the underlying pathology may lie. I think is a useful practical distinction in everyday life for patients, and for helping non-patients understand the concept better.

It may turn out to be that the primary problem is with the biochemical energy production system itself, or it may be something downstream from that which blocks the normal use of that available energy, or it may that something else is demanding so much of the overall energy budget that many unrelated systems are having to operate in a compromised sub-par manner on a significantly reduced energy budget and functional capacity.

We just don't know the answers to these questions yet.

usually experience PEM up to 24 to 48 hours after the activity.​

I would phrase it as: ...usually experience the peak of PEM up to 24 to 48 hours after the activity.

Also, I draw a distinction between a single episode of PEM, and a full crash, which I regard more as the result of repeat episodes of PEM, with insufficient recovery time in between them (to the extent that is possible). A full crash is much more serious than a single episode of PEM.

I also think that PEM is probably a permanent underlying feature of ME/CFS, maybe even the, or at least a, defining feature. What differs is the degree of PEM, from practically non-existent, through to ongoing and extremely serious, debilitating, and disabling.

Lastly, planning, while relevant and useful, also needs to be accompanied by the equal recognition that one critical feature of ME/CFS is that there are large variability and unpredictability components to it, and they need to be allowed for in any planning.

That, of course, is particularly so for new inexperienced patients. Over time, mostly via lived experience and sheer necessity, patients will gain a better practical understanding of it, and find better ways to adapt and respond to, and where possible mitigate, the nature and limitations of the condition.

But even if it is possible (and I think it usually will be) to dampen down the variability and unpredictability – which is a substantial benefit in its own right, even just for quality of life independent of any practical gain in activity capacity – I think it will remain a significant feature require constant navigation and accommodation.

The real value, certainly at this stage, from clinicians like PhysiosforME is in being able to expedite that process for patients, to help minimise the difficulty, time, and cost of that early learning and adaption to often profoundly adverse changed health circumstances. The earlier in a patient's journey this can happen, the better the overall outcome is going to be.
 
Last edited by a moderator:
Jonathan Edwards said:
I agree. I think we can be pretty sure from both the clinical pattern and what science we have that PEM has nothing to do with having 'used energy'.
Click to expand...

The problem is that ‘energy’ in the general non scientific use of the word fits so well, that as @Sean says it is quite hard to find a more accurate replacement. Somehow ‘capacity for action’ or even ‘incapacity for action’ does not subjectively conjure the right feeling, though it might more accurately reflect current knowledge. In conversation I use the word ‘oomph’ but that is also most inadequate.
 
Peter T said:
The problem is that ‘energy’ in the general non scientific use of the word fits so well, that as @Sean says it is quite hard to find a more accurate replacement.
Click to expand...

Yes, I agree. I'd phrase the sentence like this:

This helps to explain the main symptom of ME/CFS, post-exertional malaise (PEM). Any activity that uses energy can cause PEM.
Click to expand...
 
Sean said:
Activity capacity is a more general term that covers any active behaviour – physical, cognitive, emotional, and social, and to any degree, without presupposing where the underlying pathology may lie.
Click to expand...
But energy availability is the core requirement for all these things, it's fundamental physics rather than understanding of pathology. We may not understand the pathology of why people with ME cannot convert energy as quickly as they need it, but there is no misunderstanding or doubt that reduced energy is the core issue. What is very well known is that ME limits a person's energy availability for just about anything; anything a person does requires energy available to do it.
 
Last edited:
I disagree strongly, @Barry.
Barry said:
But energy availability is the core requirement for all these things, it's fundamental physics rather than understanding of pathology.
Click to expand...
The activities Sean lists surely share elements at the biological level other than a need for energy (in the physics sense), which is shared by all biological processes. My car needs energy to transport me from A to B, but when I have a flat tire, the problem lies not with energy conversion.
Barry said:
We may not understand the pathology of why people with ME cannot convert energy as quickly as they need it, but there is no misunderstanding or doubt that reduced energy is the core issue,.
Click to expand...
A problem with energy conversion could be a plausible explanation for our illness, but I haven't seen strong research supporting this. I believe I have seen the absence of evidence for such claims mentioned on this forum.

A personal anecdote. In the first six months of my illness, I was terribly fatigued. The words 'I have limited energy' or 'my battery is empty' were accurate then. Nowadays, I am never fatigued, but I still get severe PEM (flu-like feeling and pains, in my case). In fact, I would say I'm relatively full of energy: I could go for a run if activity beyond my capacity didn't give me PEM. We don't know wether this limited capacity is caused by a problem with energy.

Statements involving the word "energy" are sensitive to the interpretation of the listener and lead to misunderstanding. I think it is fair to say we have seen some research projects that only make sense if you misunderstand patient's symptoms. The ambiguity of words like "energy" and "fatigue" play a big role in that.

@Sean's suggestion to use the word capacity is a big improvement.
 
You must log in or register to reply here.
Back
Top Bottom