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Mestinon moves the needle on ME/CFS in unusual one-shot exercise study

Mestinon idea

The goal was to demonstrate in a one-day test that Mestinon has the ability to improve blood flows and cardiac output in ME/CFS and pave the way for a bigger clinical trial

This is the most unusual clinical trial/study that I’ve come across. Too short to be a full-blown clinical trial, it was essentially a short-term test of the idea that problems with neurovascular regulation (i.e. blood vessel flows) are inhibiting energy production during exercise In ME/CFS and – drum roll … can be improved by a drug.

It tried to do two things: it tried to show that neurovascular problems were affecting energy production in ME/CFS and that a drug could help ameliorate those problems, increase blood flows to the heart, and improve one’s ability to exercise.

In a sense, it was an impossible task. Since the study, “Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine“, took place over one afternoon, there was no time for the full strength of the drug to show itself. Still, the authors hoped that a one-time shot of the drug would move the needle on blood flows and energy production – and thus lay the groundwork for a larger trial.

It did require finding 50 people willing to experience the joy of having a catheter inserted into their arteries and veins – engage in exhaustive exercise – rest for 50 minutes (catheters still in place, I imagine) – and repeat the exercise test! What a fun afternoon that sounds like. So a big shout out to the 50 people willing to go through some pain to support this study and this field. A big shout out to the Open Medicine Foundation Eliassen Fund that funded this study as well.

The authors explained two ways – both of which could be present – that may be impairing blood flows (e.g. hemodynamics) in ME/CFS. (Other ways of impairing blood flows may be present but were not germane to this paper.)

(1) Damage to the small nerve fibers (small nerve fiber polyneuropathy (SFPN)) found on the smooth muscles lining the blood vessels was one. (The smooth muscle cells lining the blood vessels are responsible for constricting or dilating the blood vessels).

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It’s an intriguing idea. Skin and eye studies have generally found reduced numbers of small nerve fibers as well as narrowed small nerve fibers in from 30-50% of people with fibromyalgia, ME/CFS, and/or long COVID.

Because the small nerves could affect so many organs and parts of the body, a small fiber polyneuropathy (SFPN) that interfered with blood flows could conceivably explain much of what is going on with these diseases. We don’t know what’s causing the SFPN, but an autoimmune process would certainly fit the bill – and so could, apparently, in what was a rather shocking recent discovery – natural killer cells.

Immune Cells May Be Killing the Small Nerve Fibers in Fibromyalgia

The role these damaged nerves may play, however, is not clear yet. An earlier study did not find that the amount of small nerve fiber damage found was associated with reduced blood flows during exercise; i.e. more small nerve fiber damage was not associated with worsened blood flows during exercise. That study, though, was not able to assess the deeper small nerve fibers that are more likely to play a role in this process. (A study to assess that is reportedly underway).

(2) Damage to the nerves found in the nerve ganglion (ganglionopathy) that impairs the release of two neurotransmitters acetylcholine and norepinephrine.

Pyridostigmine bromide, or Mestinon, potentially fits the bill for ME/CFS because it may be able to overcome the effects of a ganglionopathy by boosting the availability of acetylcholine and norepinephrine. Mestinon is a “reversible acetylcholinesterase inhibitor”; i.e. it blocks the acetylcholinesterase enzyme from breaking down acetylcholine in the synapse between the nerves. That immediately increases acetylcholine levels and norepinephrine levels further down the line.

Acetylcholine is the main neurotransmitter of the parasympathetic, or cholinergic, nervous system (PNS), or the “rest and digest” system. Studies suggest that the PNS – which regulates the sympathetic nervous system (or fight/flight) system –  is impaired in ME/CFS.

Mestinon - veins - ME/CFS

Note the smooth muscles lining the veins. Mestinon’s job was to help them tighten up the veins and send more blood back up to the heart – thus improving cardiac output and energy production. (Image by Kelvinsong,-CC-BY-SA-3; Wikimedia Commons)

By increasing acetylcholine levels at the nerve synapses in myasthenia gravis, Mestinon enhances the signal that tells a muscle to contract – thus reducing the muscle weakness found in that disease. Muscle weakness is not the primary problem in ME/CFS, though, and it wasn’t the acetylcholine angle that these researchers were interested in. It was norepinephrine (NE).

NE is a sympathetic nervous system neurotransmitter that constricts the blood vessels, and by doing so, potentially increases blood flows to the heart (improving preload), cardiac output, and aerobic capacity, particularly when standing. (All three of those are reduced in at least a subset of people with ME/CFS). Properly constricted blood vessels are needed to produce the pressure (vascular tone) needed to force blood back up to the heart and out to the muscles during standing and upright exercise.

Mestinon is also particularly effective at enhancing blood flows to the slow-twitch muscles that we rely on for activities requiring endurance and which use aerobic energy production to power them. A recent long-COVID study and an earlier ME/CFS study suggested that a wholesale conversion of slow-twitch to fast-twitch muscles may be occurring in these diseases.

Long-COVID Exercise Study Points to Mitochondrial Dysfunction and Twitchy Muscles

Marrying POTS and ME/CFS

In a recent interview with the Open Medicine Foundation, Systrom said he was, with his colleague Peter Novak, trying to “marry” the results between the different stress tests done in ME/CFS and POTS; i.e. between his invasive exercise studies in ME/CFS and the tilt table studies done in POTS. Indeed, Mestinon popped up in ME/CFS largely because of its prior use in POTS.

The Gist

  • David Systrom’s Mestinon trial in ME/CFS was an unusual one. It was a one-shot, one-day duo invasive exercise trial that tracked the ability of Mestinon to attack one of the exercise-related problems Systrom has found: the inability of the veins in a substantial subset of ME/CFS patients to firm up enough to send normal amounts of blood back to the heart.
  • Those low blood flows back to the heart (low preload) result in reduced cardiac output and ultimately less blood flows to the muscles and less energy production.
  • This problem, which is also found in postural orthostatic tachycardia syndrome (POTS), is apparently caused by nerve damage to the smooth muscles lining the blood vessels which inhibits the veins from contracting enough when we stand and during exercise.
  • Mestinon blocks the activity of an enzyme that breaks down acetylcholine in the nerve synapses. By doing so, it increases both acetylcholine and norepinephrine levels. It’s the norepinephrine’s ability to tighten up the blood vessels that Systrom and his team were after.
  • After the 50 patients in the study did an invasive exercise test, half were given Mestinon and half a placebo. They rested for 50 minutes and then redid the exercise test.
  • The patients who were not given the drug exhibited an increased amount of energy production during the resting period – suggesting that their sympathetic nervous systems remained active. During the second test, their ability to produce peak amounts of energy dropped.
  • Mestinon reversed both these trends. It stopped the energy drain during the post-exercise period – allowing their systems to rest – and improved their ability to produce energy during the second test. Mestinon did not improve oxygen extraction or the ventilatory inefficiency (hyperventilation) present in the group.
  • Clinically (eg symptomatically) the changes were not significant and fatigue was not helped. Mestinon may not, however, have been expected to produce significant clinical changes in this one-shot trial, as its effects usually show up over weeks to months.
  • With evidence in hand that Mestinon has the ability to move the needle on ME/CFS patients biologically, the authors called for more extensive and longer-term Mestinon trials in ME/CFS to be funded.
  • With several processes (lax veins, mitochondrial problems, left-right shunt of blood away from the muscles, hyperventilation) potentially affecting energy production in ME/CFS, Mestinon provides the opportunity to improve one of them (lax veins that prevent proper blood returns to the heart). Systrom is in the midst of a clinical trial of a mitochondrial enhancer that may affect another.
“Loose” or not correctly constricted blood vessels have been documented, particularly in the lower body and legs, in a subset of people with postural orthostatic tachycardia syndrome (POTS) over 30 years ago. POTS is a common comorbid condition in ME/CFS – and one which produces almost identical symptoms.

When those POTS patients stand, their veins fail to constrict enough to overcome the gravitational flows of blood downward. This causes blood to pool in the lower body, thus reducing blood flows to the brain, and causing symptoms very similar to those seen in ME/CFS. These blood vessel failures appear to be the result of nerve damage in the lower bodies of POTS patients. This blood pooling is why compression stockings can be helpful in POTS.

A 2005 Vanderbilt study found that Mestinon (30 mg) significantly reduced the standing heart rates and symptom burden of POTS patients 2 and 4 hours later. The authors speculated that Mestinon helped the parasympathetic nervous system rein in the increased heart rates, while improved sympathetic nervous system functioning helped improve the blood flows in the lower body.

Systrom’s finding that only upright exercise tests reveal the problems present in ME/CFS suggests that something similar may be happening in this disease.

Study Goal

The goal of this study was to determine if a drug designed to improve nerve functioning and increase blood flows would work in ME/CFS. If the drug improved matters during an exercise test, it would show that problems with the nerve-blood vessel interface that’s responsible for moving blood back up to the heart is contributing to the exercise intolerance in ME/CFS. Plus, it provided data on the effects of exercise on blood flows, cardiac output, oxygen use by the muscles, etc.

This was also the first duo invasive exercise study ever done in ME/CFS that I’m aware of. When 2-day non-invasive exercise (CPET) studies are done, they’re usually done a day apart. These invasive CPET tests were done, though, 50 minutes apart – potentially giving us an interesting assessment of what happens very quickly to people with ME/CFS after exercise.

Results

Effects of Exercise

The study found that exercise caused the systems of the ME/CFS participants who had received the placebo to remain activated after exercise – causing a further energy drain. This showed up in increased resting oxygen consumption (energy usage) and cardiac output during the 50-minute rest period before the second exercise bout. Peak VO2 was also decreased in the patients given the placebo.

The authors proposed that an inflammatory response triggered by the exercise had, among other things, jacked up the production of reactive oxygen and nitrogen species (free radicals). They also suggested, as past studies have shown, that exercise produces prolonged activation of the fight/flight or sympathetic nervous system.

Effects of the Drug

Mestinon

Mestinon’s proposed mechanism (taken from the paper). Notice how Mestinon affects “post-ganglionic” nerve transmission; i.e. it attempts to compensate for low levels of acetylcholine due to nerve damage by stopping an enzyme from degrading acetylcholine in the nerve synapse.

A key finding was that peak VO2 – the maximum amount of energy produced at a point during the exercise test – decreased in the patients given the placebo but increased in the patients given Mestinon. With this finding, two hypotheses were confirmed – problems with blood flow do contribute to the energy problems during exercise in ME/CFS – and they can be ameliorated at least somewhat with Mestinon.

How much, we don’t know. The “effect size” of this single-dose experiment was small; that is, while Mestinon did improve the ability to generate peak amounts of exercise, the effects were not “clinically significant”; i.e. it did not improve fatigue. Smaller amounts of Mestinon were able to quickly improve both fatigue and reduce standing heart rates in POTS patients, but Mestinon was given a much more difficult task in this trial.

Instead of testing Mestinon’s ability to improve standing for ten minutes, this study asked the drug to improve the ability to exercise in a second maximal exercise test taken 50 minutes after a first exercise stressor – a far more demanding task. Indeed, Systrom noted that the exercise test appears to be picking up more problems with preload and dysautonomia than the tilt table test.

Mestinon - energy drain stopped

Mestinon appeared to stop the strange post-exercise energy drain found, allowing the ME/CFS patients to return to a normal resting state more quickly.

Mestinon also stopped the after-exercise energy drain; i.e. the increased oxygen consumption (peak resting VO2) that showed up during the resting period in the patients who didn’t get the drug. In fact, instead of increasing their oxygen consumption, the people receiving Mestinon actually significantly decreased their peak oxygen consumption during the rest period. Similarly, the decreased resting right arterial pressure (RAP) in these patients also suggested that Mestinon helped the systems of people with ME/CFS return more quickly to normal after exercise.

Mestinon did not improve systemic oxygen extraction or energy production at the anaerobic threshold, or a number of other measures. This was probably anticipated, as Systrom noted in his recent talk that it often takes weeks or a month for Mestinon to take effect. Two conference reports indicated that long-term Mestinon use (> a year in some cases) in people with the kind of preload failure found in ME/CFS can indeed increase aerobic capacity. In those studies, it did not increase peak oxygen extraction or help with the problems with breathing found during exercise.

Mestinon for Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, POTS, and Long COVID

Breathing Issues

Possible breathing issues that occur during exercise have only recently received much attention in ME/CFS but seem to be gathering more attention. Systrom, for instance, has been mentioning hyperventilation for a while. Hyperventilation – also called over-breathing – refers to overly rapid or deep breathing.

This study found that a “ventilatory inefficiency” probably caused by hyperventilation (rather than “dead space” in the lungs) was present. Ventilatory inefficiency (VI) appears to occur, if I have it right, when our lungs move more air than is necessary to remove the carbon dioxide produced by the body when it produces energy aerobically. The “inefficiency” comes to play in high amounts of air moved relative to the body’s need to remove carbon dioxide. (It’s the need to remove the carbon dioxide produced during energy production that primarily triggers our need to breathe more deeply during exercise.)

Ventilatory inefficiency appears to be mostly found in chronic obstructive pulmonary disease (COPD) where it’s associated with dead space in the lungs, poor breathing regulation and early lactic acidosis, and is associated with difficulty exercising.

In ME/CFS, though, it appears to be associated with “poor breathing regulation”; i.e. hyperventilation during exercise, as well as early lactic acidosis and difficulty exercising. Hyperventilation has a disturbing knock-on effect: by reducing CO2 levels, it alkalinizes the blood, making it more difficult for red blood cells to lock onto oxygen molecules. Since it’s the red blood cells that carry oxygen to the mitochondria to be “burned”, this impacts energy production.

The hyperventilation may be another reason why Mestinon did not immediately improve shortness of breath scores, as it’s not clear that Mestinon has the ability to affect the breathing. (The authors noted, though, that this finding may be the result of a “false negative”, or Type II, statistical error that would be cleared up in larger studies.)

Mestinon has done very well for some people, but it was never expected to be a cure-all. As Systrom noted in his Open Medicine Foundation talk, multiple exercise issues have been found in ME/CFS. A drug that increases blood flows to the heart, and improves cardiac output by firming up the veins, may not be able to help with a right/left shunt in the peripheral blood vessels that drives blood away from the muscles, a mitochondrial problem, or hyperventilation.

Systrom reported that a mitochondrial problem could produce the same results in ME/CFS patients – and require a totally different treatment regimen. Calling the mitochondrial issue “relatively uncharted territory”, Systrom noted that some evidence suggests that viruses may be able to hack the mitochondrial genes (turning them off – a nice strategy if applied to the immune cells), or that infection-triggered oxidative stress could debilitate the mitochondria as well, and might even hit the small nerve fibers.

Systrom – keeping his eye on every possible factor – is also in the midst of an $8 million 40-person ME/CFS mitochondrial trial funded by the Estrellas corporation. So far, 27 people have enrolled.

Systrom, who is now the co-director of the OMF’s Ronald G. Tompkins Harvard ME/CFS Collaboration saluted Ron Tompkins’ efforts to break down silos and build multidisciplinary teams to attack ME/CFS. That, he said, was Ron Tompkins’ vision, and that was how this disease is going to get defeated. Systrom also recently joined the OMF’s Scientific Advisory Board

Conclusion

The first exercise test resulted in increased energy consumption during the rest period, and reduced energy production (peak VO2, cardiac output) during the second exercise test. All the patients also demonstrated “ventilatory inefficiency”; i.e. a potentially harmful reduction in CO2 levels caused by hyperventilation.

The trial succeeded in demonstrating that blood vessel issues affecting the veins are impairing energy production in ME/CFS, and can be improved with a drug. While the effect size was not large (i.e. the improvements did not meet “clinical significance”), this unusual one-shot drug trial didn’t appear to be designed to do that.

Instead, the study showed that the drug has the potential to move the needle biologically in people with ME/CFS; it turned off the “energy drain” seen during the rest period, and improved peak energy production and cardiac output during the second test. Conference reports suggest that long-term use of Mestinon may be able to actually increase aerobic capacity in ME/CFS.

Mestinon was never expected to be a cure-all drug. It may not be able to affect other problems such as the shunting of blood away from the muscles, mitochondrial problems, and hyperventilation that appear to be spread across the ME/CFS population. It may be most helpful in a large subset of the ME/CFS population who have problems constricting the veins in their legs, and thus have reduced blood flows to the heart and the reduction in energy production that goes along with that.

We’ll see what happens from here. The authors called for larger, more extensive studies. Their demonstration that Mestinon can move the needle biologically in an area of great concern in ME/CFS seems to be exactly the kind of evidence that the National Institutes of Health purports to require to fund a clinical trial.

Biological evidence, after all, is apparently what carried the day for Shungu’s rare, successful application for an ME/CFS clinical trial. Dr. Rosa Maria Pari Ñaña’s recent Department of Defense grant to identify the subset of ME/CFS patients that are likely to benefit from Mestinon. Success could be very helpful in this regard.

CDMRP Grants Power New Muscle and Mestinon Studies in ME/CFS

If Systrom goes for an NIH grant, he’ll have to go outside the NIH’s ME/CFS program as it still does not allow for clinical trials. Still, he’ll have some good evidence to back him up.

Systrom alluded to the possibility of repurposing FDA-approved drugs for ME/CFS in his interview. In that vein, Mestinon would be a great “starter” drug for this disease. It’s not a mystery, it’s been around forever and doctors presumably would have no problem prescribing it. Having a drug like Mestinon associated with ME/CFS would certainly change the face of this disease, could help a large subset of ME/CFS patients, and prompt further investigations into one of the hottest areas of ME/CFS and long COVID – the blood vessels and energy production.

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