Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine, 2022, Systrom et al

ABSTRACT
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.
Research Question
Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?
Methods
Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.
Results
Twenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.
Interpretation
Pyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.

https://journal.chestnet.org/article/S0012-3692(22)00890-X/fulltext

 

The note about downloading the PDF is confusing. I don't think this is open access.

 

If it's meant to be open access, then that download link is broken.

 

The site says you have to login or make a payment, so unfortunately it's not free to read.

 

WebMD
"Pyridostigmine is used to improve muscle strength in patients with a certain muscle disease (myasthenia gravis). It works by preventing the breakdown of a certain natural substance (acetylcholine) in your body. Acetylcholine is needed for normal muscle function."

 

Am I right in thinking that this study essentially builds on the following more anecdotal study done back in 2003:

https://pubmed.ncbi.nlm.nih.gov/14567934/

I wonder why the long (19 year) delay in further research in this area? Also, does anyone with more medical knowledge than me have a view on the safety/side effects profile of Pyridostigmine?

Thanks very much for flagging this study.

 

But it is equally important in neural regulation of other things. I have not looked at this in detail but I wonder if they have information on normal controls in terms of pyridostigmine affecting peak VO2. It would be quite odd if it did it seems to me, but we need to know.

I continue to be sceptical about liking these physiological changes to malaise, in the sense of feeling unwell. There is no obvious reason to link them.

 

My memory is that it is fairly unpleasant to take. The blurbs say: Nausea, vomiting, diarrhea, abdominal cramps, increased saliva/mucus, blurred vision, decreased pupil size, increased urination, or increased sweating may occur. I think it also interferes with sleep.

 

I appreciate this point very much. Weakness and "malaise" are completely distinct experiences. Researchers do not always seem to really get this about ME.

If I only suffered from muscle weakness and had to carry a heavy object, I could just push hard and try to get it done nonetheless. Exertion and/or orthostatic intolerance in itself is not the biggest problem. The whole life-ruining problem is feeling unwell for days afterwards.

 

I've been looking forward to this study! Eager to see full text if anyone can access?

Pyridostigmine has seen further limited trials over the years in the POTS/dysautonomia domains. It isn't a first line treatment and lacks the higher quality evidence we have for Ivabradine, for example, but is in the toolbox and prescribed by some specialists. This trial builds on related work by Systrom in those domains and he considers various syndromic conditions as overlapping (Fibro/POTS/ME etc.).

I've been prescribed it since 2018 and can only give n=1 experience but Jonathan's list of side effects are fairly accurate. They wore off over some weeks and I only experience benefits now, though it required some patience and a very slow titration to minimise the unpleasantness.

In terms of safety profile I'm not aware of any problems. Its been used for decades in Myasthenia Gravis and at much higher doses.

I really hope the research continues with a longitudinal study now. I couldn't personally detect an immediate, subjective improvement in stamina, for me it was more subtle and gradual - though I suppose this could be related to the tiny dose I started with. After some weeks & dose increases the first sign I had of improvement was that I could tolerate a late night for the first time since becoming ill (decades) and not suffer the next day, after that I noticed my threshold to trigger PEM increased and the duration of any PEM decreased massively. My energy levels/stamina for cognitive work are vastly improved.

 

Thanks so much for this - really interesting.

I also strongly second Chris's point above - namely that muscle "weakness and "malaise" are completely distinct experiences. I'm not sure I actually suffer from any underlying muscle weakness, once the impacts on muscles of general ME/CFS symptoms are taken into account. Put another way: if a magical cure for PEM and related symptoms became available, I'm confident I'd return instantly to pre-illness levels of muscle strength.

 

In my case I have always muscle weakness and lactate accumulation. If I push myself I still have muscle weakness, then very big lactate accumulation which start to be very unpleasant and I start to feel unwell. I think muscle weakness is part of being unwell. I have impression that muscle weakness is always there, feeling unwell come with PEM. But I can feel unwell also without PEM. Complicated :-(

 

As an aside I watched the bbc documentary about the novichok poisonings recently and this list of symptoms seemed very familiar! I suppose it's not surprising that the nerve agent sarin would give the same symptoms if they're both inhibiting acetylcholine breakdown

 

Unfortunately Mestinon never helped me all that much in the past. Maybe it’s worth another shot though

 

it's not open access; but some might be able to access it through 'Access through your institution'
here
https://www.sciencedirect.com/science/article/abs/pii/S001236922200890X

 

@Ryan31337

Do you take mestinon consistently or only as needed?

Also what dosage?

Thanks

 

I’ve only read the abstract, but this paper appears to be relevant:

“Effect of acetylcholinesterase inhibition with pyridostigmine on cardiac parasympathetic function in sedentary adults and trained athletes”: https://pubmed.ncbi.nlm.nih.gov/17322413/:

“Abstract
Heart rate variability and postexercise heart rate recovery are used to assess cardiac parasympathetic tone in human studies, but in some cases these indexes appear to yield discordant information. We utilized pyridostigmine, an acetylcholinesterase inhibitor that selectively augments the parasympathetic efferent signal, to further characterize parasympathetic regulation of rest and postexercise heart rate. We measured time- and frequency-domain indexes of resting heart rate variability and postexercise heart rate recovery in 10 sedentary adults and 10 aerobically trained athletes after a single oral dose of pyridostigmine (30 mg) and matching placebo in randomized, double-blind, crossover trial. In sedentary adults, pyridostigmine decreased resting heart rate [from 66.7 (SD 12.6) to 58.1 beats/min (SD 7.6), P = 0.005 vs. placebo] and increased postexercise heart rate recovery at 1 min [from 40.7 (SD 10.9) to 45.1 beats/min (SD 8.8), P = 0.02 vs. placebo]. In trained athletes, pyridostigmine did not change resting heart rate or postexercise heart rate recovery when compared with placebo. Time- and frequency-domain indexes of resting heart rate variability did not differ after pyridostigmine versus placebo in either cohort and were not significantly associated with postexercise heart rate recovery in either cohort. The divergent effects of pyridostigmine on resting and postexercise measures of cardiac parasympathetic function in sedentary subjects confirm that these measures characterize distinct aspects of cardiac parasympathetic regulation. The lesser effect of pyridostigmine on either measure of cardiac parasympathetic tone in the trained athletes indicates that the enhanced parasympathetic tone associated with exercise training is at least partially attributable to adaptations in the efferent parasympathetic pathway.”

 

A couple of experiences with Meniston.

Scroll down:

https://twitter.com/user/status/1522538838425546754

 

I took Mestinon for about half a year. Started at a low dose of 15mg & worked up to 60mg x3/day. I'm typically sensitive to medications but going slowly Mestinon resulted in only minor temporary side effects. I noticed an almost immediate improvement in energy level and remember thinking that I'd finally found something that worked and started to fantasize about going hiking.

In reality I only increased my energy output marginally, stood up a bit more and visited a next door neighbour in a wheelchair. After about 10 days I used an eraser to remove some markings in a children's book, something I definitely couldn't have done pre Mestinon, but which then resulted in several days of PEM. I continued to take it for several months and then started to forget doses and didn't notice a difference so went off it with no discernible effect except possibly sleeping better.

My observation from social media is many people with ME have tried it in Canada. Some can't tolerate it and people who can often report slight improvements. And then there are a few who report major improvements.

 

Hi,

I take it every day. The protocol used in POTS is usually 3x 60mg per day, starting with 30mg once per day and titrating very slowly over weeks/months. I started at 15mg as I'm usually sensitive to meds.

The side effects for me were temporary, returning with dose increases but then fading again. They sound bad but for me were more a nuisance than anything seriously unpleasant. Interestingly I had problems before with the opposite of some listed side effects, e.g. dry eye/mouth, pupil dilation and reduced urge to pee, presumably as part of my dysautonomia. These and my general digestive problems have all improved since starting mestinon.

My cardiologist wasn't comfortable going beyond 180mg per day but I've since seen a professor of clinical pharmacology in a tertiary clinic who was happy for me to increase it to 540mg per day and to play with dose and timing, e.g. more in the morning, less at night, as required. I've been at 300mg per day for a while now and that's sufficient for me to be mentally active all day without running out of energy or needing rests. Physical exertion/orthostasis is another matter entirely but being able to think clearly and be at my desk all day is a wonderful improvement.