Tracking in at somewhere around $350 million, the Congressionally Directed Medical Research Program (CDMRP) is not a small program. It was created in 1992 to fund novel approaches to “biomedical research in response to the needs … of the American public, the military, and Congress”.
Another win for ME/CFS advocacy at the legislative level leads to a new pot of money being available for research
That “needs of the American public” inclusion is intriguing given the decades-long buildup of pent-up needs that have not been addressed in ME/CFS. Might the CDMRP program be more receptive to ME/CFS than the NIH?
We couldn’t know because we haven’t been allowed in the program for almost a decade. Back in 2017, though, Emily Taylor and Solve M.E. first pushed to get ME/CFS back in the program. Then, Solve M.E. and ME Action pushed again for inclusion in 2018. Finally, in December of last year, Solve M.E. and ME/CFS advocates (sending over 12,000 messages via Solve M.E.’s message center) brought the effort across the finish line – and a new basket of potential funding opened up for ME/CFS.
That wasn’t the end of the story. We needed ME/CFS researchers – a group not exactly known for pumping grant applications into the NIH – to respond. This time they did – and in spades. ME/CFS researchers – many of them associated with the Open Medicine Foundation (OMF) – leapt at the opportunity and sent in approximately 25 grant applications – an unprecedented number for this community.
Now we have the results: two of the 25 grant applications were funded, adding about 1/2 million dollars in new research funding for ME/CFS over the next two years.
The Harvard Hub and the Grants
The decision for the Open Medicine Foundation to establish an ME/CFS collaborative research center at Harvard appears to be paying off. The two ME/CFS CDMRP “Discovery Awards” were given to young investigators working with Open Medicine Foundation-funded researchers at the Harvard ME/CFS Center. Getting young researchers involved is a distinct plus, as everyone agrees that it’s critical to get more young investigators into this field.
ME/CFS Muscles Get Worked Up
Dan Wilkinson of the University of Nottingham will be using new proteomic analytical techniques to “better understand molecular basis for post-exertional malaise in skeletal muscle”. Anything that assesses the skeletal muscle floats my boat.
Wilkinson’s been collaborating with Ron Tompkins and Wenzhong Xiao of the Harvard Collaborative Center. We learned last year that Tompkins was working with U.K. researchers to dig into the “omics” (genomics, proteomics, etc.) of skeletal muscle biopsies of ME/CFS patients. Wilkinson is apparently part of this group.
What is happening with the poor muscles in ME/CFS? Dan Wilkinson and Ron Tompkins hope to find out
The muscles are one area that Ron Tompkins, a co-leader of the Harvard effort, has said he’s particularly excited about. Given all the evidence of exercise intolerance, one would think that something MUST be going on with those skeletal muscles.
Tompkins has proposed that exercise may doing lasting damage to the small myofibrills which make up our muscle fibers. Stress to the muscles does, in fact, damage those myofibrills even in healthy people, but the damage is quickly resolved. Tompkins believes the muscle repair processes may be broken in ME/CFS. While we don’t have much information on this new study, it’s possible that it may be assessing this or some other aspect of the muscles.
Find out more about that:
Mestinon Clinical Trial
Health Rising broke the news on Mestinon and ME/CFS when it reported that a long-term ME/CFS patient was able to exercise after Dr. Systrom prescribed the drug. Since then we’ve heard of patients who have done very well on it, and others it hasn’t helped. This new grant aims to find out who will respond to this drug.
Systrom believes Mestinon may improve blood flows to the muscles in some people with ME/CFS. He’s doing a rare placebo-controlled, double-blinded trial in ME/CFS to test that.
This study enlarges a fascinating David Systrom trial, “The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, that was slated to begin earlier this year at Brigham and Women’s Hospital. In the clinicaltrials.gov report on the trial, Systrom states what he believes is happening in a subset of ME/CFS/FM patients.
If I understand it correctly, Systrom has found an anomaly in one set of ME/CFS patients. During exercise, the heart is pumping out more blood than it is receiving; i.e. blood, at some point, disappears into the body. That could explain why an exercise session could start off somewhat OK and then get worse and worse over time as less and less blood makes it to the muscles. So, where does the missing blood go?
Again, if I understand it right, Systrom believes that damage to the small nerve fibers (e.g. a small fiber neuropathy/polyneuropathy) is failing to constrict the blood vessels, allowing blood to escape into the interstitial spaces.
The Gist
- It took three years of steady advocacy (12,000 messages to Congress (!)) from Solve MECFS (with an assist from ME Action one year) but finally ME/CFS got in – and became eligible to apply for the $350 million in funding offered from the Congressionally Directed Medical Research Program or CDMRP.
- ME/CFS researchers jumped at the opportunity putting in about 25 grant applications – most of them from Open Medicine Foundation affiliated researchers.
- Only seven of the 25 fit the requirements but of those 2 were funded – a high success rate. They will add about $500,000 to ME/CFS funding over the next two years.
- One team from the U.K. will team up with Ron Tompkins at the Harvard Collaborative ME/CFS center to do proteomic analyses of muscle biopsies. Tompkins has suggested in the past that it may be that muscle repair processes are not working well in ME/CFS.
- The other study will piggyback on an ongoing study on Mestinon with Harvard pulmonologist David Systrom. Anecdotal reports suggest that Mestinon works very well in some people with ME/CFS but not so well in others.
- The study references findings indicating that blood is lost somewhere in the body during exercise in ME/CFS. This apparently results in less and less blood being delivered to the muscles as exercise continues.
- The invasive exercise study will determine if Mestinon can enhance the constriction of the veins thus propelling more blood to the heart and eventually the muscles.
- The placebo controlled, double-blinded study hopes to identify which ME/CFS patients the drug works in.
- If the study is successful it’s conceivable that Mestinon could, if follow up studies are also successful, become the first FDA approved drug for a subset of patients with ME/CFS.
No studies, though, have used the more powerful invasive exercise tests Systrom employs to assess the effects of the drug. Nor have placebo-controlled, double-blinded studies been done.
Systrom is doing both: in a study funded by the Brigham and Women’s Hospital, Systrom is putting 50 ME/CFS patients through a double-blinded, placebo-controlled invasive exercise trial that’s assessing the effects of Mestinon on a wide variety of cardiovascular factors. For instance, Systrom will be determining if Mestinon alters lactate levels, oxygen uptake by the muscles, output from the heart, heart rate, carbon dioxide production and 7 more cardiovascular factors.
Now, that study is being extended in an important way by the CDMRP grant to Dr. Rosa Maria Pari Ñaña. Dr. Nana reported that the study will help them identify which patients will likely benefit from Mestinon from those who won’t. (Hopefully that won’t require an invasive exercise test. Since very few people do invasive exercise tests, I imagine that it won’t,)
Think of the possibilities here. Identifying a subset of patients who respond to Mestinon could – after more studies – ultimately lead to the first FDA-approved drug for ME/CFS. Even publication of a successful placebo-controlled, double-blinded trial could open the door for physicians across the U.S. and the world to prescribe it. It would take more studies to get insurance companies to pay for it, but a successful study would open the door to those studies.
Systrom has also, it should be noted, received funding (via a donor) from the Solve ME/CFS Initiative to continue his invasive exercise work on ME/CFS. Plus, in an OMF-funded effort, Tompkins has already apparently been analyzing blood samples from Systrom’s invasive exercise studies.
Systrom’s work has potentially opened a big window in ME/CFS. It’s good to see his work be rewarded by the two major private ME/CFS research funders in the U.S. – and now by the CDMRP.
Wrap-Up
The the Congressionally Directed Medical Research Program (CDMRP) money is not a huge amount of money – it’s not going to solve this big, nasty, complex disease by itself. That task is going to take lots of funding and efforts by many researchers.
These grants should provide some more pieces to fit into the larger ME/CFS puzzle.
Every bit of funding is precious, though. Take the new pledge for Dutch ME/CFS funding. If I remember correctly, it’s $30 million over 10 years. That’s $3 million a year – not an immense amount of money for medical research – but still a nice chunk. That $3 million dollars could fund six large new studies a year. (After what Visser et al. have done in the Netherlands, who knows what could happen if they get their hands on more money.)
While neither of the CDMRP grants will provide the answer for ME/CFS, could they provide important insights into this disease?
Absolutely. Finding altered proteins in the skeletal muscles could give us a ground-level view of what’s happening there. Identifying a subset of patients who respond to Mestinon could not only be helpful for many, but could alter how this disease is viewed.
As Sadie Whittaker of the Solve ME/CFS Initiative pointed out, making progress in ME/CFS is going to take doing a lot of things – including many smaller things – right. Over time, it comes together.
Congratulations to Solve M.E. for persisting with its three year effort to get ME/CFS back into the the Congressionally Directed Medical Research Program (CDMRP), and to the Open Medicine Foundation-associated researchers for getting their grants funded.
Correction: After being told the number of grant applications that made it through to the final stages was incorrect, it was removed.
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Fascinating, and this sounds like one of the more promising leads. I went to the links and there are more autoimmune linkages, that is where ultimately I believe the answer will lie for us. But if mestinon helps address PEM in a significant number of patients, that would be a significant game changer. Speaking of autoimmunity, does anyone know where Carmen S’s research in Germany is headed?
Note that an autoimmune process could be what’s knocking out those small nerve fibers. We don’t know that – why they are disappearing is a mystery – but it’s certainly a possibility.
Carmen and Klaus Wirth are due for part two of their autoimmune-vasodilator-energy production hypothesis next year. Expect a study coming out which shows that symptoms track with the autoantibodies they’ve found as well.
I find Systrom’s work fascinating; I guess because it seems to actually offer an explanation. I tried the Mestinon, though, two years ago — and my CFS doc made me start very very slowly at a very low dose. Even so, I couldn’t get to the dose he was recommending because of the adverse side effects.
If his theory is correct, I hope mestinon won’t be the only way to address the problem.
Systrom has potentially identified a couple of ME/CFS subsets – one of which would be helped by Mestinon while others would not I don’t think.
Even if mestinon could help, the side effects seem like it would be too hard to for the gut unless it could be rubbed on as a cream. My dr had me take follistatin when it was available-it is not right now. I found that was the most helpful thing for my muscles. I was able to maintain exercise a little better. I haven’t heard of other me/cfsers who have used it-of course it is compounded, injected. Apparently a bill went thru congress preventing drs from selling it which left me up a creek.
Some people don’t have any gut problems.
Hi Cort,
I have written before. I got my Dr in New zealand to prescribe Mestinon 3 months ago, it has been amazing,
I got up to 69 mg TDS but have settled at 60 mg BD.
I have so much more muscle ability and life in my muscles on exertion.
So excited about this new study.
Robyn Smith NZ
I finally convinced my doctor to prescribe Mestinon after providing all the research articles I could get my hands on. Amazing results for me in capacity to exercise and management of fatigue. It’s been a year now of gains on Mestinon. No help though with brain fog.
How about that! It sounds like it’s helping get blood to your muscles but not to your brain yet!
Still – a very nice gain – and if you can exercise – that’s so much better for your health overall.
Nice job advocating for it with your doctor as well and good for him/her to let you try it.
PS What is CDRMP? Some of us can’t keep up with all the initials. Thanks.
Congressionally Directed Medical Research Program. I did reference it in the first line of the blog but should have put it elsewhere – which I have just done. Thanks for the reminder. 🙂
Does anyone know what percentage of the patients Systrom sees benefit from Mestinon. I know several patients with severe ME and they tried this drug beginning slowly but not one of these 5 people could tolerate this drug, nor did it help with the small amounts they took. I will also be interesting to see how they can test for the subsets. Thanks again Cort.
I have classic ME/CFS with mild / moderate orthostatic intolerance I tried Mestinon for a month. The drug was well tolerated but I received no benefit. Although my GP said he would prescribe for me because he saw a bed-bound patient return to near normal activity using the drug. So you never know.
This drug has been used for some subsets of POTS. (My having HyperPOTS and already too high NE levels with standing, was not a good experiment for me. Made me feel I would jump out of my skin by creating a hyper response. I seemed to have less blood flow and more trouble breathing. (Maybe because I do better vasodiliting rather than constricting.) And it affected my mood adversely. Was a no go.)
It is also used in Myasthenia Gravis, affects acetylcholine. (Please be aware of potential side affects.)
I had some links and it wouldn’t let me post them. You can do a search to find how this drug works (or doesn’t) for these two illnesses.
Hi issie you are right about blood flow and vasoconstrition and vasodilation as l see it. Having an active virus which enters the cells through ACE 2 receptors which are expressed on the Endothelial cells which are the inner lining of blood vessels activates an immune response which first immune response is to send cytokines to the area of infection causing inflammation and showing the second immune responders which are T cell antibodies to fight the infection. The inflammation causes vasoconstrition and possibly affecting red blood cells deformability problems. Also antibodies makes blood sticky further adding to problems with blood flow. No better place to be where most organs have a huge blood flow especially the heart and lungs and liver for a virus. With blood flow especially in the microcirculation affected the blood and nutrients and oxygen not being able to supply the heart and lungs and other tissue with a full supply of oxygen and nutrients from the red blood cells and also problems with oxidative stress waste returning no wonder we have CFS. I have noticed after having a hot shower I feel a bit better as the hot water helps with vasodilation also after one beer as alcohol in moderation is a vasodilator but too much will vasoconstrict. Have thought about vasodilation medications but must be careful as one has to know side affects such as expressing the ACE 2 receptors with some of them .
I use enzymes to thin my blood. Look at blog before this one, I added to it and gave names of some things I use. I try to do things more “natural” rather than prescriptions. Less side effects. But, even “natural/supplements”, are concentrated and become a medicine. So you have to know what you are doing and possible interactions with what you combine. Also know if they interfere with medicines you are on. And with us, less is more. We tend to be super sensitive and low and slow is better.
But, issues with vasoconstricting too much seems to be my issues rather than the other way around.
Would you also happen to have low body temperature?
Well said Dennis. I wonder why a low dose of Viagra doesn’t work for the bloodflow problems.
@Gijis, they have tried Viagra for ME/CFS. I know a woman who tried it. She didn’t stick with it. But a well known ME/CFS doctor in Utah, gave it to her to try.
For me, using enzymes is for more than just thinning the blood. It also helps with issues IN the blood.
And, you want to be careful with an instant boost of more blood flow, as you could cause repurfusion issues. Don’t want that. Then you have created more problems. Needs to be more sustained and less surge like.
@Gijs:
I agree with Issie here. Years or decades of poor to very poor blood flow in many parts of the body is a great risk for those areas to be in a state of frequent severe lack of oxygen or hypoxia.
It is often said that (when surviving hypoxia that is) that the following reoxygenation often causes more damage then the original lack of oxygen itself. That very inflammatory effect is know as reperfusion injury. It is sort of a massive imune response starting when oxygenation gets quickly better to try and clean up all the potential damage the hypoxia caused. Such massive imune response can be very damaging in healthy people, let alone in people with our types of disease.
Both Issie and I have poor to very poor experiences (of the inflamatory or MCAS type) when trying to “improve” or restore blood flow too fast and sudden. On the other hand we have some modest success by *very* slowly trying to “optimise” (as in not blindly increasing but allowing our bodies to find more adapted settings according to needs) blood flow over many many months in a low and more gradual way.
issie Yes I do have low temperatures also blood pressure on the low side and heart rate sometimes around 55 bmp. Was just researching micro circulation and found article from Health Rising dated December 2018 about micro circulation which is what I previously spoke about in my reply so sorry to bore people about articles already posted. After reading the 2018 article and agreeing with the article find it hard to understand why more has not been done in that direction and we keep going off in different directions confusing the issue. Still say the main reason for problems is reactivated viruses not detected by normal serology tests causing inflammation and vasoconstrition and very poor micro circulation.
Gijs I’m sure it would straighten one thing out, but not sure on any side effects.
@Dennis, it seems many of us with virus or pathogens have low body temperature. If you do a search, appears that trying to up body temperature may kill off some of these things. Colder temperatures will make them go more dormant, but not necessarily destroy them. So us having such low temperature with them in our body may be keeping them down, but not destroying them. With us feeling better with more heat, it does help to vasodilate, but could aid in eliminating some of our pathogens too. (Then you have herxing to deal with.)
In an study reviewed in the Military times, an estimated one-quarter of the 700,000 U.S. troops who deployed to the Persian Gulf to liberate Kuwait have medical symptoms related to service in the region, including muscle and joint pain, fatigue, headache, gastrointestinal problems, memory issues, rashes and respiratory illnesses.
The exact cause of the symptoms has not been determined, although previous research has indicated that PB pills, pesticides, a contaminated batch of the anthrax vaccine and/or chemical agents may play a role.
Scientists involved with the study found that veterans with a gene variant that complicates their bodies’ efforts to metabolize chemicals in anti-nerve agent pills — pyridostigmine bromide, or PB — were up to 40 times more likely to have Gulf War illness symptoms than those who took the pills or were exposed but had a different gene variant.
Perhaps this is why pyridostigmine has good effect in some, but not all ME/CFS patients.
Betty, What is the genetic variant that made the veterans much more likely to get GWI?
I’m not Betty, but I wanted to know this too. Here is what I found.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(16)30481-9/fulltext
HLA genetic subsets of those who developed GWS.
(Side note: With CIRS, they also test HLA genetics and based on what yours shows and certain combinations, they can tell if you can throw off mold and biotoxins. There are articles talking of the genetic connections wit CIRS — Chronic Inflammatory Response Syndrome.)
https://link.springer.com/article/10.1007/s00221-017-5010-8#ref-CR28
Brain atrophy in GWS and partly attributed to not only toxin exposure but taking Mestinin to try to protect against nerve agents.
https://www.ncbi.nlm.nih.gov/books/NBK222848/
Very long and detailed article why Mestinin was given to GW soldiers and side effects of it and what was thought to contribute to GWS.
(potential duplicate, WordPress block)
@Gijs:
I agree with Issie here. Years or decades of poor to very poor blood flow in many parts of the body is a great risk for those areas to be in a state of frequent severe lack of oxygen or hypoxia.
It is often said that (when surviving hypoxia that is) that the following reoxygenation often causes more damage then the original lack of oxygen itself. That very inflammatory effect is know as reperfusion injury. It is sort of a massive imune response starting when oxygenation gets quickly better to try and clean up all the potential damage the hypoxia caused. Such massive imune response can be very damaging in healthy people, let alone in people with our types of disease.
Both Issie and I have poor to very poor experiences (of the inflamatory or MCAS type) when trying to “improve” or restore blood flow too fast and sudden. On the other hand we have some modest success by *very* slowly trying to “optimise” (as in not blindly increasing but allowing our bodies to find more adapted settings according to needs) blood flow over many many months in a low and more gradual way.
I understood that a genetic variant in the BCHE gene makes PB/mestinon toxic. There’s not much in the
Medical literature about this, but my Dr. found info. in the Chemistry literature.
Hi Cort, when is the Mestinon trial due to be out? How soon could I have this in hand to get my doc on board w a trial? Thanks!
I don’t know. The problem is the pandemic! It seems to have stopped treatment trials in their tracks 🙁
I asked OMF about Systrom’s study and they said the trial is done, now they need to work on the results and publish an article. I hope it won’t take too long! 🙂
Hi from france,
I have severe pots & ME.
If Mestinon releases norepinephrine, is it not contraindicated in POTS combined with ME where the adrenaline levels are already high?
Has anyone with asthma tried Mestinon?
I would like to try it, but I read it’s not recommended for people who have asthma (Extreme caution is required when administering Mestinon to patients with obstructive respiratory diseases like bronchial asthma and chronic obstructive pulmonary disease (COPD).
– although I found a small (and old) study where they tested Mestinon in mild asthma sufferers and they didn’t see any problems at a 30 mg dose: https://pubmed.ncbi.nlm.nih.gov/1757243/