Filling a Gaping Hole
ME/CFS orgs have been working recently to fill a gaping hole in the ME/CFS field – clinical trials.
ME/CFS organizations have been doing something different lately. Long focused purely on research, they’ve been putting more resources into treatment trials lately – suggesting they feel more confident about moving forward in that arena – a good sign. They’re doing their best to fill a gaping hole in the ME/CFS field – the lack of treatment trials – and they’re being quite innovative about it as they explore emerging treatment options that organizations like the NIH would never touch. (We learned that in spades when the RECOVER Initiative failed to fund an LDN trial).
Solve M.E. recently funded small trials on Enhanced External Counterpulsation (EECP), stellate ganglion block, repetitive transcranial magnetic stimulation, and inspiratory muscle training. One nice thing about these trials is that they tend to look a bit deeper than symptom improvement and get at the physiological changes that may have occurred.
Complex Diseases Deserve Complex Clinical Trials
“These two drugs have shown a lot of promise in the clinic” David Systrom
With its new “Life Improvement”, or LIFT trial, the Open Medicine Foundation (OMF) has created the first two-fer” – a clinical trial that combines two drugs – that I can remember – a very welcome development.
ME/CFS and its cousins are, after all, complex, chronic diseases that – at least for the time being – are going to do best when hit with complex treatment protocols.
Complex diseases will likely require complex solutions
Nobody is hiding the fact that these diseases are complex and are a bear to study and treat. Just look at the names of some of the major clinics: “The Center for Complex Diseases “(Kaufman/Chedda); the Complex Chronic Diseases Clinic at the BC Women’s Hospital in British Columbia; the Institute for Neuro-Immune Medicine (Klimas) helps people with “complex neuro-inflammatory illnesses“; and the Bateman Horne Center helps doctors care for patients with “multi-symptom Chronic, Complex Diseases“. We even have an acronym, msCCD (multi-symptom Chronic, Complex Diseases) that emphasizes just how complex these diseases are!
Given that, it’s not surprising that ME/CFS experts employ a very wide variety of supplements, drugs, and techniques to treat these diseases. Dr. Arseneau, for instance, has handouts on almost 50 treatments for ME/CFS on his website.
Until a magic bullet shows up – if it ever does – good treatment protocols for ME/CFS are going to involve a variety of treatments that hopefully work together to make things better. Dan Neuffer is a patient, not a doctor, but he’s interacted with hundreds of people who have recovered and his conclusion is that recovery usually requires a multi-faceted approach.
The OMF’s trial will determine if two drugs work better than one in ME/CFS
The First “Two-fer” ME/CFS Clinical Trial
So why not duplicate what works best in the real world and assess more than one treatment at once? That idea probably sends shudders down the spine of many researchers, but if you want to really move the treatment arena forward – which is what this disease really needs – it’s best to study things in tandem.
The Open Medicine Foundation’s LIFT trial is going to do that. In fact, it’s going to do both. It’s going to assess the two top medications from its treatment survey (to be released soon): low-dose naltrexone (LDN) and Mestinon (pyridostigmine bromide) – both separately and in combination.
Long Reach
You may have tried these drugs and you may have tried them together and, if so, good for you to have access to them – but this trial goes far beyond you and I. It’s designed to alert doctors, many of whom probably know little or nothing about ME/CFS, about new treatments for ME/CFS patients who are probably currently getting little or no help.
Since neither LDN nor Mestinon has been subjected to an ME/CFS treatment trial – let alone a good treatment trial – most primary care doctors won’t consider prescribing them. A successful trial should change that and finally give doctors good treatment options for their patients.
THE GIST
- With its new “Life Improvement”, or LIFT trial, the Open Medicine Foundation (OMF) has created the first two-fer” – a clinical trial that combines two drugs – a very welcome development.
- Most clinical trials involve one treatment but ME/CFS is a complex disease that is usually treated – when it’s treated successfully – in multiple ways. The LIFT trial is one of the first to assess treatments the way they are done in the doctors’ office – in tandem.
- It will assess the effects of two drugs (low-dose naltrexone (LDN) and Mestinon) separately and in combination. David Systrom and Jonas Bergquist will lead the trial which involves 160 participants and will begin shortly and last as long as two years. Neither of these drugs has been adequately tested in ME/CFS.
- If successful the trial should begin to open the door to widespread use of these drugs by primary care doctors.
- The trial will also, by digging deep into the patient’s physiology with proteomics, metabolomics, and other assessments, attempt to find biomarkers that can pluck out those who respond, and will help us learn more about ME/CFS. Researchers in other diseases commonly use treatments to perturb patient’s systems and learn what factors play a role in them. This is the first ME/CFS trial I remember that is actively trying to do this.
- These drugs may be able to work together better than used separately because both fight inflammation and enhance the production of feel-good chemicals like dopamine and endorphins.
- This trial is planned to begin soon and will take place in the Boston area. David Systrom will recruit patients from his practice and use patients who have signed up for the StudyME research project.
- Kudos to the Open Medicine Foundation for funding such an intriguing project.
Digging Deep to Learn More
Note that the trial is going to go way beyond the normal “did it help?” symptom assessment and dig deep into the participants’ physiology as well. Along with the symptom assessments, a new functional capacity survey (FUNCAP), and functional capacity test (a 3-minute step test that will assess aerobic capacity), the LIFT study will also assess metabolomics, proteomics, and immune assays.
This could do three things – provide validation, uncover biomarkers, help us understand ME/CFS better.
If the treatments work, having a physiological signature of success will provide validation for them – something this disease could always use more of (lol). The researchers will also attempt to uncover biomarkers that can be used – aka precision medicine – to identify which patients are likely to benefit from these treatments.
They will also attempt to learn more about ME/CFS. We haven’t, to my recollection, seen this in ME/CFS, but researchers often perturb a system with a treatment and then do deep physiological dives in order to better understand their diseases. If the treatment results in levels of certain metabolites or cytokines moving in one direction or the other, those factors are likely playing a role in the disease.
These more complete trials, then, are both treatment validating and learning experiences, and that’s why it was good to hear that the Open Medicine Foundation is planning to use this first study as a template for later studies.
Synergism?
We all want synergism! Synergism means doing better with less. When asked how these treatments might synergistically work together to prevent post-exertional malaise, Dr. Systrom had one answer – inflammation.
Studies have shown us that exertion produces an inflammatory state in ME/CFS. The latest example of that came from the Alaedini study which suggested that a hole in the immune system is allowing gut bacteria to persist in the blood longer – thus producing more inflammation – in people with ME/CFS following exercise.
Mestinon enhances the functioning of the vagus nerve and the parasympathetic nervous system. By stimulating vagus nerve activity, it may be able to do a nice two-fer itself; i.e. reduce the fight or flight response and increase the anti-inflammatory response at the same time. It also, interestingly enough, appears to enhance the production of dopamine – a feel-good neurotransmitter in the brain.
Low-dose naltrexone’s (LDN) anti-inflammatory properties appear to enable it to quiet agitated microglial cells in the brain and tamp down neuroinflammation. Plus, it also increases endorphin levels which themselves have an anti-inflammatory effect.
Note that both dopamine and endorphins are considered “happiness chemicals”; dopamine enhances the “reward center” of the brain, while endorphins provide relief from pain and can produce euphoria. Both the reward center and endorphin levels may be lacking in these diseases.
With their ability to impact both inflammation and endorphins, the two drugs seem ripe for a duo treatment trial.
The First Precision Medicine Breakthrough for ME/CFS?
Systrom and Bergstrom will also be on the hunt for biomarkers. If they can show that patients with biomarker “x” respond well to Mestinon and/or LDN, a simple lab test could identify who is likely to benefit.
LDN Pops Up Again
LDN is also interesting because it also popped up in a two-fer drug combination that a Biovista study produced about 20 years ago. In an innovative effort in the early 2000s, Suzanne Vernon and the Solve ME/CFS Initiative contracted with Biovista to do a kind of AI analysis where Biovista fed all the ME/CFS data it could find into a computer and asked it to come up with a drug combo that could help.
Biovista returned with a low-dose naltrexone-trazodone combination. Trazodone, which is used largely as a sleep aid in ME/CFS, has some fascinating properties. Not only is it able to able to reduce the activity of the alpha waves known to hamper sleep in fibromyalgia, but it also appears able to reduce neuroinflammation, and enhance lactate release (increase energy).
Biovista never was able to get a trial funded and the effort died, but one wonders, given what Biovista found then and what Efthymios Kalatafis’s personal efforts produced recently, what gems might pop up in an AI-enhanced effort now.
The Trial
This trial will begin soon and will take place in the Boston area. David Systrom will be recruiting from his patients and from patients who have signed up for the StudyME research project.
Time will tell how long the trial will last, but it may last as long as two years. Kudos to the Open Medicine Foundation for producing such an innovative and potentially far-reaching trial.
- Find out more about the OMF’s Life Improvement Trial (LIFT) trial here.
- Find out more about the OMF’s StudyME project here.
Next up – the SImmaron Research Foundation’s Rapamycin Trial
I hope lots of patients in the Boston area sign up for the trial. They’ll be lucky to be part of Dr. Systrom’s study.
“David Systrom will recruit patients from his practice and use patients who have signed up for the StudyME research project.”
From the gist Waiting.
Thanks, Tracey. Yes, I read that.
I hope they get lots of sign-ups.
Yes, let’s hope so. Dr. David Systrom seemed fairly positive about ME/CFS patients getting involved in research, if they’re able to (if I remember correctly?!)
I took Mestinon for years. I knew it helped me but I was still quite disabled (bedbound). Now I take both Mestinoin and LDN, I have a far more active life.
Nice!
Hello Melanie, can I ask what Mestinon dosage you take? I take LDN at 4 mg and my quality of life has greatly improved. Thanks
I sure hope they find a biomarker. I think validation will help people talk about their condition. Also I really hope this combination works or at least improves our condition.
4,5 mg LDN did not help me.
I was on LDN twice and it didn’t work either. I wonder if the combination of drugs would work better.
I take two 60mg Mestinon daily (morning, night)
and one 4.5mg Naltrexone at night.
Thanks
One thing- Mestinon after food. Otherwise terrible nausea.
And, I’ve just remembered: Ondansetron was essential for nausea initially. I don’t get any nausea from Mestinon now.
Very curious about the dose(mg) and frequency of both meds that will be used in this study. Did I overlook this information or is it not yet known/public info since the study hasn’t started? I’ve been on both medications for a few years now, with pyridostigmine (aka mestinon) prescribed for off label use, at a much lower dose than it’s FDA approved diagnosis dose.
I am not looking to change my dose without instruction from my physician, of course. I am just super curious what dose and frequency will be used in the study, for both meds.
No thanks. I’ve tried both these meds and can’t tolerate either of them. LDN especially made my inflammation way worse, gave me bad flares of arthritis and made me suicidal. Personally I think the hypothesis in the LDN groups is inaccurate, and one could hypothesize that in some people it could induce or make autoimmunity worse. Mestinon just made me feel really sick and severe headaches and nausea/vomiting and other severe GI issues.
At what dose did you try LDN? Lots of people have terrible troubles with them unless they start quite low.
I started at 0.2mg and in five months have worked up to 0.45mg. I am noticing a real difference.
Others started much, much lower (0.01 or even less).
You may know all this, but I have noticed that many doctors think that starting at 1mg our 2mg is low enough, and for many people it absolutely isn’t.
I had a very successful response to LDN, starting at 0.25mg up to 0.75 now, but i cannot tolerate any antihistamines at all and benadryl nearly made me run out of oxygen. It really just goes to show that everyone’s body is different and what works for some is hell for others. Also it seems the golden rule in CFS treatment is low and slow starting at a tiny dose and slowly raising it
I also had a horrible reaction to LDN even at a tiny dose. I remember it would make me dizzy for hours to the extent I had to stay in. I never felt safe because of it.
From memory I think I tried it for at least 3 weeks maybe a month but symptoms never improved.
I have 2 copies of the slow version of COMT which means my body doesn’t clear neurotransmitters very well so if anything the last thing I need is more dopamine. I have plenty of get up and go, its just that my energy runs out so quickly so Mestinon wouldn’t be any good for me either though I was interested in that it helped the parasympathetic nervous system which I know I would benefit from.
Seated yoga helps me to feel better and calmer every time and we work a lot on that.
I’ve taken Mestinon for years for what seems like myasthenia gravis symptoms, even though my single fiber EMG didn’t indicate myasthenia. (Dr. Jaradeh at Stanford who ran the EMG said the results weren’t normal, but not diagnostic for MG.) I take 45mg twice a day, and I do much better on it.
I tried LDN many years ago before I went on Mestinon. It really didn’t do anything for me other than give me strange weird dreams, which many drugs in the past have done (Effexor gave me horrific nightmares), so I stopped taking it. If it weren’t for the vivid bizarre dreams, I’d probably try it again.
is the lift trial and the the omf’s study ME the same?I signed up under the 2 nd one??Olease let me know if I should do it again or if it is all the same.Thankyou!!
Signing up for StudyME gives you potential access to the LIFT study as some of the participants will come out of it. I think once you’ve done that you’ve done all you can do regarding LIFT. They will either contact you or not. Congrats on signing up! 🙂
“One man’s balm is another man’s poison.”
I have only tried LDN and it did not work. Because LDN is an opioid agonist, I could not take any opioids for my Ehlers-Danlos pain durning my LDN trial–and opioids are the only drug I have found effective. Since I still suffered horribly from pain during my LDN trial, I started using kratom which hits some of the opioid receptors but not the same ones as Norco and similar–so no interactions. Kratom was moderately successful in quelling the pain.
In reading about Mestinon (and the generic pyridostigmine bromide) I have run across articles that think P.Gs use is one of the causal factors in Gulf War Illness. I’m no expert in biochemistry, so I don’t know if they are one and the same. I suspect that the Mestinon dose that will be used in this trial will be way, way lower than the dose used to counteract nerve agents in war. Regardless, it does make me wonder.
Betty I Mekdeci., if you are reading this, what are your thoughts?
Does anyone know where I can get more information for my doctor in regards to what dosages and for how long of each of these medication’s.
I believe my doctor may offer them to me if she can find more information.
Check out Health Rising for the LDN Resources page – lots of information there. I think its cited in this blog. If you actually want a study go to PubMED and look up fibromyalgia and low dose naltrexone. HR also has a nice page on Mestinon – https://www.healthrising.org/treating-chronic-fatigue-syndrome/drugs/mestinon-for-chronic-fatigue-syndrome-me-cfs-fibromyalgia-pots-and-long-covid/ – but it does not contain dosage. You should be able to get it in this study – https://pubmed.ncbi.nlm.nih.gov/18240245/ and this blog mentions 30 mg and links to an ME/CFS study.
Cort, as an aside, I had a little laugh because the graphic of a hole, pile of dirt and shovel really looked like digging around in a sh@t hole. I think that sometimes us frustrated patients think that all these studies seem to be like digging in the sh@t because none seem to leading to a successful treatment.
I know this this isn’t the case but sometimes it just feels like it.
I give up hope.i recall when omf first came on the scene. I believe their statement was
“Well have answers in about a year”
Well, here we are years later, still nothing.
Here are my thoughts.
I think infection or virus gets in our system and wreaks havoc. Once the damage is done to our immune system many of our other organs become out of synch with all the other organs.
ASK YOURSELF THIS…
AM I HUNGRY?
I think there is a supplement – Huperzine A – with similar mechanism of action as Mestinon and allegedly less occurence of side effects. Some Myasthenia Gravis patients take it. Has anyone tried this?
I did. Twice. It made me so sick I had to stop. All my symptoms were made much worse. Sorry.
All these awful drugs! May the gods protect us!
The post-Covid snake oil revival is absolutely soul destroying
Hope enhancing placebo?
ME conflated with CFS is a dustbin diagnosis = MUS FND BDS and all the other mind body confabulations
We need 21st century criteria, definitions and treatment
I had severe ME from MAY 2013 through JUN 2020. I have been taking LDN 9mg AM and 3mg in PM since Feb20.
LDN was the second medication that made significant improvements to my daily chronic spine, bone & muscle pain.
I am currently able to be up and about half of the day, 3 days a week.
In JUN 2021 I began a Mestinon trial. I titrated up from about 15-30 Meg’s, twice a day. I tolerate 60mg’s 2-3 times a day. I’ve tried several times to go up on each dosage’s mg’s, but haven’t been able to. I am going to try again, this winter.
During an iCPET test, it showed that I had low right atrial pressure, probably compensated by my athletic body habits 🙂
I was relieved that “something” showed up “wrong”. As we all know, the medical gaslighting and disbelief is Soul-crushing!!!!
Every singe day, throughout the day, I would get sharp, chest pain. My cardiology cardiac work up was negative.
My ties and feet would turn dark pinkish-red and DARK, dusky feet while taking a shower, especially the left toes and foot.
From the first day of taking Mestinon, I FELT BETTER. Now, the only time I get chest pain is when I haven’t taken my next dose (60 mg’s) on-time! My toes and feet continue to turn a darkish, pink-red colour, but nothing compared to before my taking Mestinon.
I can vouch that I need BOTH medications. I get reminded every time I don’t fill my LDN or Mestinon RX’s on-time.
Be patient.
Be well.
Katie
Katie, have you been checked for May Thurner? It is a compression of the iliac veins on the left side. It could possibly be the cause of the issues in your foot. It is very common with Ehler’s Danlos if you have that
Oh Crystal, Thank you for educating me about May Thurner! I never heard of that. Very interesting. Thankfully I don’t have ED. What an horrific process.
Be well, Katie
LDN had no negative side effects for me. I had tests done to measure the number of Natural Killer Cells and the function of NK cells, and LDN proved effective in increasing those to a low but normal acceptable number and function. Additionally, after nine months on LDN, my adrenal function improved enough to stop taking adrenal supplements and has remained improved for a few years now.
I am sorry there are so many negative comments based on an individual adverse experience. Please don’t let it discourage you if you are trying to learn how to manage your own situation.
I agree, Janet. I take 6mg of LDN each bedtime and I wouldn’t be without it. I had to start with .01mg for weeks before I could increase it. Sure, I get wild dreams, but to be honest I like them. It’s a real adventure and since I only leave the house once a week because I need to avoid Covid-19, those nightly adventures are a real treat.
I’ve recently started taking Serrapeptase and I have noticed improvement in my EDS symptoms. It’s a proteolytic enzyme and it seems to be helping my joints and circulation. The first time I took it I forgot that I had taken it and hours later I began to feel warm all over. Then I started panicking because I thought I was numb, “I can’t feel anything, I’m going numb!” After touching my arms and face I realized what I thought was numbness was actually I’M NOT HURTING ANYMORE! I have become so used to constant pain that when it went away I thought I was numb. Weird. And yes, the effect has continued.
Thank you for sharing your experiences. Wow, 0.01mg is really low and kudos for hanging in there for weeks – I find it always difficult to stick with something that does not help right away – did you find LDN helped right from the start or were these weeks spent waiting out initial side effects?
And may I ask about your serrapeptase dosage? Thank you 🙂
JR, no the LDN did not help right away, I had to take it for about six months before I noticed any relief, because I was increasing the dose so slowly. Once I increased it too fast and got really sick so I had to back off and go even more slowly.
Serrapeptase strength is measured in units and the bottle says 120,000 SU. It also says 60mg. The brand is Enerex, but other companies also make this. At first, I tried nattokinase, but got terrible diarrhea probably because it is made from soy and is fermented, both of which are not good for MCAS.
You have to take serrapeptase on an empty stomach, so taking it when I get up in the morning, half an our before breakfast is good.
There is also lumbrokinase, but it is pretty spendy, so I’ll stick with serrapeptase. I felt better even after just the first dose, so give it a try. Also, you don’t have to taper off if you don’t like it, just stop taking it, no problem.
Very helpful, thank you Ann1!
After reading this article a few months ago I asked my doctor to prescribe mestinon and to test me for MG. I began a small 30mg dose TID and immediately (within 20 minutes) felt better. I could breathe deeper and easier, my trunk muscles/stabilizers felt stronger and had much less pain, my digestion improved, my energy improved. I’m interested to find out how this study goes.
Here’s the listing on the clinical trials website:
https://clinicaltrials.gov/study/NCT06366724