Geoff’s Translations
The GIST
“There are inherent uncertainties in the individual response, but at a group level, it should provide a solid base for interpretations” The authors
The Open Medicine’s TREATME survey assessed a wide variety of drugs and supplements.
The Open Medicine Foundation said it would focus more on treatments a year or so ago, and it has made good on that promise with the results from its massive TREATME survey. The study, “Patient Reported Treatment Outcomes in ME/CFS and long COVID” – led by Martha Eckey – recently published in none other than the august Proceedings of the National Academy of Sciences (PNAS) journal.
The TREATME survey is the most extensive attempt yet to assess the efficacy of most of the mainstream (and some not-so-mainstream) attempts to get well in people with ME/CFS and long COVID. Almost 4,000 people with ME/CFS and long COVID (split almost equally) answered questions about 150 drug, supplement, and non-pharmacological treatments. Brain retraining programs, brain stimulation, Lorazepam (Ativan), Klonopin (Clonazepam), cannabinoids, diet, and physical therapy were not assessed.
The Open Medicine’s TREATME survey assessed a wide variety of drugs and supplements.
THE GIST
- The results from the Open Medicine Foundation’s massive TREATME survey were recently released. The survey, which covered 150 drug, supplement, and non-pharmacological treatments, was filled out by almost 4,000 ME/CFS and long COVID patients. Brain retraining programs, brain stimulation, sleep drugs, and physical therapy were not assessed.
- The authors produced a figure called “net assessment score” (NAS), which was based on patients’ positive and negative responses to each treatment. Because any level of improvement or worsening is included in NAS, NAS, by itself, does not tell us much about the degree of effectiveness. This led some treatments that did not improve patients much, but were viewed positively by many patients, being included in the top 20 treatments.
- This blog focused more on an appendix, which isolated treatments that “moderately/much better” improved symptoms.
- Twenty-one treatments resulted in moderate to much better improvement over 30% of the time, while 41 other treatments resulted in moderate to much better improvement between 20% and 30% of the time.
- All told, 62 treatments were deemed by greater than 20% of patients to make them “moderately/much better”.
- See the blog for the list of top 21 efficacious treatments.
- IVIG was the big Surprise – IVIG is expensive and hard to get, but of the 91 people who tried it, almost 2/3rds reported moderate to much improvement. The NAS/symptom assessment suggested that IVIG can help fatigue (55.4%), PEM (46.7%), POTS (55.8%), and brain fog (50.8%) frequently (!). Additionally, the NAS graph of the top 20 treatments showed that IVIG was the treatment most often associated with a “much better” response. Check out Martha Eckey’s post on IVIG to learn more.
- Low-dose naltrexone’s high efficacy rate (60% and nearly 1,000 responses) suggests that targeting immune activity in the brain may be highly beneficial. The NAS calculation found LDN improved fatigue or low energy (41.5%), PEM (33.2%), and brain fog (42.3%). (LDN is often used for pain, but pain was not assessed in this study.)
- While being mindful that only 30 people had tried ketamine, its high efficacy (43%) also suggests that brain-targeting drugs may be helpful.
- One big surprise was how few people (20%) have tried pacing, given how often it was efficacious (37%) and how long it’s (supposedly) been a mainstay in managing ME/CFS. (Was this due to fewer long COVID patients embracing it?). According to NAS, pacing was found to help frequently with fatigue (82.7%), PEM (62.6%), brain fog (71.2%), and POTS.
- The good response rates from heparin, triple therapy, and nattokinase/lumbrokinase + serrapeptase suggested that clearing out blood clots can be very helpful. Check out lead researcher Martha Eckey’s post on nattokinase/lumbrokinase + serrapeptase to dig down into these inexpensive supplements’ results, including which brand might work best.
- Ivabradine’s success rate was not surprising given that it appears that it, more than other drugs, is helpful with POTS. The relatively good efficacy for Ivabradine, beta blockers, and propanolol indicates the important role these drugs can play in those with orthostatic intolerance/dysautonomia.
- Only 58 people had tried maraviroc, the drug Bruce Patterson introduced to the field, but the good response rate (41%) suggested he may be onto something.
- Thirty-two treatments were assessed by more than 300 people. In this list, the big losers were the supplements, 17 of which made this list, but which, unless they were paired with something, rarely made the top 62 most efficacious treatments.
- The fact that one type of antihistamine (H1RA) had been tried by about 40% of the patients indicates how far mast cell activation syndrome (MCAS) has penetrated the ME/CFS patient population. (The greatly increased efficacy rate (38%) of the H1RA+H2RA group suggested that patients taking H1RA only might want to add an H2RA antihistamine.)
- It was surprising how few people (20%) have tried pacing, given how often it was efficacious (37%) and how long it’s (supposedly) been a mainstay in managing ME/CFS. (Was this due to fewer long COVID patients embracing it?). According to NAS, pacing was found to help frequently with fatigue (82.7%), PEM (62.6%), brain fog (71.2%), and POTS.
- Many people had tried stimulants (n=457), which had one of the highest response rates (37% moderately-much better), but also produced some significant negative responses.
- MCAS treatments were among the more commonly effective treatments. Of the fifteen treatments assessed, ten were reported by at least 20% of the patients to moderately/much improve their symptoms.
- All of the antiherpesvirus drugs (famciclovir, valganciclovir, valaciclovir, aciclovir) were rated by between 20% and 30% of patients to moderately/much improve their symptoms.
- Except for buproprion (n=172; 30% moderate/much better),the antidepressants did not produce impressive (<20%) results. Two old standbys, Lyrica and gabapentin, both scored fairly well (26% moderate/much better improvement), and low-dose Abilify did well (32% reported moderate/much better improvement)
- None of the gut enhancers or antioxidants produced strong results. The mitochondrial enhancers, in general, did poorly. The big surprise was that only 18% of respondents reported that oxaloacetate produced moderate/much better improvement. If you’re trying CoQ10 or ECCG, higher doses appear to increase efficacy.
- Some of the newer treatments (rapamycin, GLP-1 agonists, plasmapheresis, fecal transplants, stellate ganglion patch, psychedelic drugs) were not assessed. Not many people had tried HBOT (n=37), but almost 30% reported that it moderately/much improved their symptoms. Not many people had tried nicotine patches (n=25) either, and 24% reported that it moderately/much improved their symptoms.
- The study didn’t assess brain retraining, which is open to anyone. The fact that most of the better treatment options involve drugs indicates, though, that this is not a do-it-yourself illness, and that a doctor who is willing to take the time and trouble to trying different approaches is essential.
- Looking to the future, one wonders if the promising showing by immunomodulators (IVIG, maraviroc), brain-impacting drugs (ketamine, guanfacine + NAC), mast cell-impacting drugs, and anticoagulants will play a larger role. Note that several large immunomodulatory drug trials are underway in long COVID.
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This was a massive study—and it’s a massive blog. This blog turned out as blogs often do – it got bigger and bigger as time went on, and I found more and more to dig into. This blog, which produces lengthy posts that delve into the details of the subject, ultimately focused most of its attention not on the paper’s text but on one of its appendices. If you want that kind of detailed attention we’re the blog for you.
The Study Approach
To encourage more accurate results, patients were asked to review treatments only if they had a good idea of their effects. The participants were asked, “How were your symptoms affected by the following treatments?” and given a series of options from approximately February 2023 to February 2024 (with a 3-month break in the middle).
Five core symptoms (fatigue or low energy, postexertional malaise, POTS, brain fog, unrefreshing sleep) associated with the IOM’s core diagnostic criteria for ME/CFS were included in the primary assessment. (The treatment’s impact on pain was not included.)
- Much better
- Moderately better
- Slightly better
- Unchanged or unsure
- Slightly worse
- Moderately worse
- Much worse
To evaluate the patient-reported effects of treatments, the authors produced a figure called “net assessment score” (NAS) which was based on patients’ positive and negative responses to each treatment. The NAS score for each treatment was then compared to a reference treatment (patient reports for a Vitamin C supplement) and the results were analyzed using a two proportion Z test.
If I’m reading it right, because any level of improvement or worsening is included in NAS, NAS, by itself, does not tell us much about the degree of effectiveness; e.g., NAS does not give a treatment extra points for producing “much better” results. Instead, it tells us which treatments received the most positive and the least negative responses in the most people.
Results
The study found that people with long COVID and ME/CFS were similar symptomatically and responded to the treatments similarly.
The way NAS was produced resulted in treatments like CoQ10, PEA, curcumin, and melatonin, which rarely produced moderate or much better effects but were reported to have positive effects by many people, ending up on the list. Some treatments in this group (IV saline, ivabradine, IgG, heparin (UFH and LMWH), and maraviroc) did, however, produce a significant percentage of moderately/much better results. (See the orange/yellow bars on the left for moderately/much better results).
As the paper pointed out, most of the top 20 treatments with the highest NAS are well known.
Treatments That Moved the Needle
Twenty-one treatments were reported by at least 30% of the patients who tried them to result in moderate to much better improvements.
It was encouraging to see that, of the 150 or so treatments assessed, at least 30% of patients reported some positive effect in 120 of them. I was most interested, though, in treatments that moved the needle; i.e., treatments that were more likely to produce “moderately and much better responses”. These were found in an appendix. (A separate list of “much better responses” was not included for all the treatments. Note that this analysis did not assess the probability statistics.)
The appendix indicated that patients reported that twenty-one treatments resulted in moderate to much better improvement over 30% of the time. It also reported that between 20% and 30% of the time, 41 other treatments resulted in moderate to much better improvement.
All told, 62 treatments were deemed by greater than 20% of patients to make them “moderately/much better”. While patients clearly had searching to do, the study suggested that a wide variety of treatments have the potential to at least moderately improve the symptoms of ME/CFS patients.
- Check out Table 3 in the “Supporting Information”, which lists the responses of all the treatments. Table 3 is found about six or 7 pages down from the top. The column I used (% moderate/much better response) is outlined in blue. The percentage of negative responses is beside it to the right.
The Top 21 Treatments (>30% of patients reported moderate/much better improvement)
- IVIG (64%)
- Low dose naltrexone (60%)
- IV saline (52%)
- Ketamine (43%)
- Ivabradine (44%)
- Maraviroc (41%)
- Ketotifen + H2RA (40%); (Ketotifen w/out H2RA – 29%)
- Enoxaparin or unfractionated heparin (40.1%)
- Guanfacine + NAC (39%…guanfacine w/out NAC – 12%!)
- Cardioselective beta blocker (38%)
- Corticosteroids (37%)
- Pacing (37%)
- Stimulants (35%)
- Triple therapy (anticoagulants) (33%)
- Tollovid > 15 days (36%)
- Mestinon (32%)
- Abilify <2 mg (32%) (Less is generally more with Abilify. Abilify > 2mg dropped to 9%)
- Vedicinals (31%)
- Nattokinase (NK) or Lumbrokinase + serrapeptase (31%)
- Propanolol (31%)
- Buproprion (30%)
Assessment
IVIG – The Big Surprise
IVIG is expensive and hard to get, but of the 91 people who got a hold of it, almost 2/3rds reported moderate to much improvement. The NAS/symptom assessment suggested that IVIG is able to help fatigue (55.4%), PEM (46.7%), POTS (55.8%), and brain fog (50.8%) frequently (!). Additionally, the NAS graph of the top 20 treatments showed that IVIG was easily the treatment most often associated with a “much better” response.
Nothing in the ME/CFS literature made me suspect IVIG’s efficacy would be so high. Both Dr. Ruhoy and Dr. Kaufman, however, like it and Dr. Klimas has said that pooling of IVIG from a large population gives it such a “tremendous advantage” that if an infection is the problem, protection provided by the product can be so complete that you don’t need to know what virus is present – you just need to boost your immune functioning.
- Check out lead researcher Martha Eckey’s take on the surprise IVIG finding here. She noted that it took ten IVIG sessions to produce the result in about a third of patients. A remarkable 80% reported benefits lasting for at least 6 months, with over 50% enjoying benefits for over a year. Discontinuing IVIG, however, resulted in some or all of their symptoms returning. Find out more in her report.
Its high efficacy in this survey may, in part, be due to the doctors who use it knowing which patients it is most likely to help. It suggests that immunomodulators may play a key role in treating ME/CFS over time.
Others
Low-dose naltrexone’s high efficacy rate (60% and nearly 1,000 responses) suggests that targeting immune activity in the brain may be highly beneficial. The NAS calculation found LDN improved fatigue or low energy (41.5%), PEM (33.2%), and brain fog (42.3%). (LDN is often used for pain, but pain was not assessed in this study.)
While being mindful that only 30 people had tried ketamine, its high efficacy (43%) also suggests that brain-targeting drugs may be helpful.
Ivabradine’s success rate was not surprising given that it appears that it, more than other drugs, is helpful with POTS. The relatively good efficacy for Ivabradine, beta blockers, and propanolol indicates what the important role these drugs can play in those with orthostatic intolerance/dysautonomia.
Only 58 people had tried maraviroc, the drug Bruce Patterson introduced to the field, but the good response rate (41%) suggested he may be onto something.
The good response rates from heparin, triple therapy, and nattokinase/lumbrokinase + serrapeptase suggested that clearing out blood clots can be very helpful.
- Check out lead author Martha Eckey’s complete take on nattokinase/lumbrokinase + serrapeptase including brands that might be helpful here.
While supplements did not do well as a group, two drugs suggested that adding them can be very helpful. Adding ketotifen to an H2RA boosted its efficacy dramatically (40-29%). Similarly, adding NAC to guanfacine more than tripled the number of people who reported that it moderately/much better improved their symptoms (39%…guanfacine w/out NAC – 12%!)
Some of the most commonly tried treatments in ME/CFS did well while others did not.
The Tried (and True?) Treatments
It was interesting to see which treatments had been tried the most. With an average duration of illness of around 13 years, this group has been around long enough to let us know what has worked over time and what kinds of treatments have become widely adopted among patients.
Check out the most tried treatments (n<300) (top to bottom) and the percentage of people who reported they produced moderate-to-much better results for them. Thirty-two treatments were assessed by more than 300 people.
The big losers were supplements, 17 of which made this list, but which, unless they were paired with something, rarely made the top 62 most efficacious treatments. (Note, though, that a compound treatment called Vedicinals, which consists of various mast cell reducers, anti-inflammatory and antioxidant herbs, and natural compounds, did pretty well in long COVID (n=58, 31% moderate/much better improvement).
The Top 32 Most Tried Treatments (in descending order)
- Fluids/electrolytes – n=2860; 26% reported moderate/much better improvement.
- Antihistamines – H1RA (2nd/3rd generation) – n=1474; 22% reported moderate/much better improvement (Check out below to see how combining H1RA+H2RA antihistamines seems to work better (below) than using H1RA antihistamines alone, and how adding ketotifen to H2RAs may work even better (n=48; 40%).
- B-complex – n=961; 8% reported moderate/much better improvement.
- Compression stockings – n=952; 24%. Compression stockings positively help 66% of people but moderately help 24%.
- Low dose naltrexone – n=951; 29%. LDN has been well tried (951 responses) and has one of the highest “moderate to much better” effectiveness.
- Omega-3 complex (DHA + EPA) – n= 818; 7.6%.
- Pacing n=803; 37% reported moderate/much better improvement. Only 803 people reported that they’ve tried pacing yet pacing’s 37% “moderate to much better effect” on symptoms suggested it’s one of the most effective things to do.
- B-12 injection – n=760; 20% reported moderate/much better improvement. B-12 injections may be the oldest treatment on this list – and at 20% of people reporting that it produced moderate to much better effectiveness, it’s still hanging in there.
- SSRI antidepressants (minus fluvoxamine) – n=731; 16% reported moderate/much better improvement. The different kinds of antidepressants all clocked at about 15-20% (moderate to much better effectiveness) except for Bupropion (n=172; 30%)
- Aspirin n= 636; 11% reported moderate/much better improvement..
- Omega-3-6 or Omega 3-6 9 – n=573; 6.3% reported moderate/much better improvement.
Coenzyme Q10 – many people have tried CoQ10, and more does indeed seem to be better, although the percentage of people reporting moderate to significant improvements even at the highest dose was relatively small (14%).
- Coenzyme Q10 – 100 to 200 mg/day – n=566, 6%.
- Coenzyme Q10 – 50-100 mg/day – n=382; 8%.
- Coenzyme Q10 – >200 mg/day – n=377; 14%.
NAC – as with CoQ10 ,notice the jump in NAC’s effectiveness at the higher doses. (NAC ≤600 mg/day 562; 8% reported moderate/much better improvement; NAC >600 mg/day n=352; 20% reported moderate/much better improvement. Also that while guanfacine + NAC has been less tried, adding NAC to guanfacine appeared to boost its effectiveness dramatically.
- H2RA (Famotidine) – n=551; 21% reported moderate/much better improvement.
- D-ribose – n=548; 10% reported moderate/much better improvement. D-ribose was a big hit a decade or two ago, but according to this survey, it has not stood the test of time.
- Amytriptyline and other TCA antidepressants – n=529; 15% reported moderate/much better improvement.
- Green tea/Matcha/EGCG – n=485; 4% reported moderate/much better improvement.
- Curcumin – n=480; 11% reported moderate/much better improvement.
- Nattokinase/Lumbrokinase – n=475; 27% reported moderate/much better improvement.
- Nattokinase/Lumbrokinase + serrapeptase – n= 430; 30% reported moderate/much better improvement. These are anti-clotting supplements, and with a 27% moderate to much better improvement rate, they were one of the most effective supplements.
- Beta blockers or Ivabradine – n=458; 38% reported moderate/much better improvement.
- Quercetin – n=422; 13.3% reported moderate/much better improvement.
- SNRIs – n=407; 21%reported moderate/much better improvement.
- Melatonin 1-3mg; n=407;16% reported moderate/much better improvement.
- Stimulants (Vyvanse, Adderall, Ritalin, Focalin, Dexedrine, others) – n=427; 35% reported moderate/much better improvement. The survey suggests that, while they can have more negative side effects, stimulants are more effective at enhancing energy than mitochondrial supplements.
- Antihistamines – H1RA + H2RA (combo) – n=352 – 38%. Among all the MCAS medications, combining H1RA (diphenhydramine, hydroxyzine, etc.) and H2RA (Cetirizine, fexofenadine, loratadine, etc.) antihistamines were the most effective.
- Vitamin C (oral, liposomal) – n=330; 8% reported moderate/much better improvement..
Assessment
The fact that fluid/electrolytes and compression stockings rank high on the list indicates that, at least in this (knowledgeable) patient population, the word on POTS/orthostatic intolerance has been received.
Similarly, the fact that one type of antihistamine (H1RA) had been tried by about 40% of the patients indicates how far mast cell activation syndrome (MCAS) has penetrated the ME/CFS patient population. (The greatly increased efficacy rate (38%) of the H1RA+H2RA group suggested that patients taking H1RA only might want to add an H2RA antihistamine.)
The big surprise for me was how few people (20%) have tried pacing, given how often it was efficacious (37%) and how long it’s (supposedly) been a mainstay in managing ME/CFS. (Was this due to fewer long COVID patients embracing it?). According to NAS, pacing was found to help frequently with fatigue (82.7%), PEM (62.6%), brain fog (71.2%), and POTS.
The word has clearly gotten out about blood clots. I was surprised by how many people (mostly long COVID patients?) had tried nattokinase/lumbrokinase (475) and impressed by the relatively good response rate (w/+ serrapeptase 30%). (Note that by itself, serrapeptase had a low moderate/much better response rate (11%).
I was also surprised that so many people had tried stimulants (n=457), which had one of the highest response rates (37% moderately-much better), but also produced some significant negative responses.
Types of Treatments
MCAS Treatments
Mast cell inhibitors, in general, seemed to do better when combined together.
MCAS treatments were among the more commonly effective treatments. Of the 15 MCAS treatments assessed, only two were rated as moderate/much better by less than 10% of patients, four by between 10% and 20% of patients, and eight by between 20% and 30% of patients. Two were reported by over 30% of patients (ketotifen + H2RA (40%) and H1RA + H2RA (combo) (38%)) to moderately/much improve their symptoms.
Antivirals/antibacterials
All of the antiherpesvirus drugs (famciclovir, valganciclovir, valaciclovir, aciclovir) were rated by between 20% and 30% of patients to moderately/much improve their symptoms.
Of the antibiotics, doxycycline (<50 mg; > 100 mg) was rated by between 20-30% of patients to moderately/much improve their symptoms. Patients should stay away from sulfamethoxazole drugs which had low efficacy and high rates of side effects.
Neuropsychiatric drugs
Except for bupropion (n=172; 30% moderate/much better), with less than 20% of patients reporting significant improvement, SNRIs (Cymbalta, Savella) or SSRIs (Paxil, Zoloft, Lexapro, Prozac) antidepressants produced impressive results. Two old standbys, Lyrica and gabapentin, both scored fairly well (26% moderate/much better improvement). Low-dose Abilify (32%) also appears here to stay and shows how one doctor (Dr. Hector Bonilla at Stanford) can make an impact. Twenty to thirty percent of respondents reported, though, that several of these drugs produced negative effects.
Blood Clot Removers
With three anti-clotting treatments in the top 21 (heparin, triple therapy, nattokinase/lumbrokinase + serrapeptase) the blood clot removers did well.
Lead author, Martha Eckey, reported that nattokinase/lumbrokinase + serrapeptase worked better in long COVID than ME/CFS, but still was often helpful in ME/CFS. The symptoms most commonly improved included fatigue (56%), brain fog (55%), memory problems (47%), feeling of weakness (46.5%), PEM (46%), shortness of breath (40%), chest pain (36.5%), and fast/fluttering/pounding heart (33%). Most people (3/4) knew whether the supplement was working or not within two weeks. Note that nattokinase/lumbrokinase + serrapeptase is not an expensive supplement. More (8,000 FU) was better, and Eckey found that Solaray’s NK-SP seemed to work best. Check out her report here.
Gut enhancers
None of the gut enhancers (colostrum, lactoferrin, various kinds of probiotics, butyrate) were reported by more than 20% of patients to moderately/much improve their symptoms.
Mitochondrial Enhancers – go high with them (if you go at all)
While the mitochondrial enhancers had middling results, several times it appeared that more was better when it came to them.
In general the mitochondrial enhancers did not do well. Most surprising (and disappointing) was the fact that only 18% of the 77 responders reported that oxaloacetate made them moderately or much better. (Did they not take enough of it?). Over 500 people tried D-ribose, but only 10% reported that this formerly very popular supplement made them moderately or mostly better.
In general, the survey suggested that if you’re going to try a mitochondrial supplement, go high (ECCG <400 mg = 7%; >400 mg 20%; CoQ 10 <50 mg/day – 8%; 50-100 mg/day – 8%; 100-200 mg/day – 6%; >200 mg/day 14%). CoQ10 has been well-tried with hundreds of people providing responses for each dose.
Mitoquinol, a form of CoQ10, on the other hand, did better with 22% of the 49 responders reporting it moderately/much better improved their symptoms.
If you want to up your energy, though, stimulants might be a riskier but more promising shot.
Vasodilators
Few patients (10-16%) reported moderate to much better improvements using vasodilators such as Sildenafil, L-arginine, and/or citrulline.
Antioxidants
Despite clear evidence that reactive oxygen species are increased in ME/CFS, the antioxidants did not fare well.Only about 10% reported moderate to much better improvement with oral or liposomal glutathione, and alpha-lipoic acid, with its 5% significant response rate, was similarly disappointing.
The Newbies
Some of the newer treatments (rapamycin, GLP-1 agonists, plasmapheresis, fecal transplants, stellate ganglion patch, psychedelic drugs) were not assessed.
Hyperbaric oxygen therapy (HBOT) was, though. Not many people had tried HBOT (n=37), but almost 30% reported that it moderately/much improved their symptoms. Not many people had tried nicotine patches (n=25) either, and 24% reported it moderately/much improved their symptoms.
The Disappointments
Supplements, gut enhancers, vagus nerve stimulation, and metformin mostly appeared to miss the target.
With the acknowledgement that the vagus nerve stimulation field is still emerging and significant questions remain about dosing and the type of machine to use, it was still disappointing to find that only 14% of the 132 people reported receiving moderately to much better results from it.
Despite the fact that butyrate levels are low, butyrate-producing probiotics (n=27) did not fare well (7%) (but had not been tried much). Metformin has been much discussed, and 140 people had tried it, but only 14% reported that it moderately/much improved their symptoms.
Symptom Trends
When it came to which of the top 20 treatments produced the best outcomes for specific symptoms according to the NAS calculation, some interesting trends emerged. NAS – which measures positive results but does not assess higher degrees of efficacy – suggested that if you want to treat:
- Fatigue – pacing (83%), stimulants (72%), IVIG (55%), nattokinase/Lumbrokinase (50%), manual lymphatic drainage (45%)
- PEM – pacing (63%), IVIG (47%) – not many treatments for PEM.
- Brain fog – stimulants (77%), pacing (71%), Mestinon (57%), IVIG (56%), nattokinase/lumbrokinase (50%), low dose naltrexone (42%), PEA (35%), Rx anticoagulants and/or Rx antiplatelets (35%), Vit B12 (33%).
- POTS – Fluids/electrolytes (72%), beta blockers/Ivabradine (66%), compression stockings (64%), mestinon (57%), IVIG (56%)….many treatments for POTS.
- Brain fog – ADHD stimulants (77%!), pacing (71%), IVIG (51%), nattokinase/Lumbrokinase (50%).
- Unrefreshing sleep – melatonin (34%) – the survey did not assess many sleep drugs.
Overview
IVIG and Maraviroc’s success suggests that immunomodulators may ending up being key. Several are in long COVID clinical trials.
This is the most extensive survey of treatment results for ME/CFS and long COVID we’re likely to see for quite a while.
How happy you are with the results may depend on how deeply you want to dig. A 20% response rate (moderate/much better) indicates that for every five people who tried a treatment, one received at least a moderate effect, suggesting that extensive investigation is required. On the other hand, the fact that 62 treatments had a one in five chance of producing moderate results means plenty of options do exist.
The study didn’t assess brain retraining, which is open to anyone and has produced the majority of recovery stories on the internet. The fact that most of the better treatment options assessed in this survey involve drugs suggests that a doctor willing to take the time and trouble to try those approaches is essential.
Looking to the future, one wonders if the promising showing by immunomodulators (IVIG, maraviroc), brain-impacting drugs (ketamine, guanfacine + NAC), mast cell-impacting drugs, and anticoagulants will play a larger role. With IVIG and maraviroc, producing relatively high percentages of patients who reported feeling “much better” and with few side effects reported, immunomodulatory drugs may be the drugs of the future. Note that several large studies are currently assessing IVIG, maraviroc, and other immunomodulators in long-standing COVD.
Ketamine’s ability to increase neuroplasticity suggests that psychedelic drugs (currently being assessed) might be helpful, and makes one wonder again about the focused ultrasound machine Jarred Younger is testing. Given their decent showing, one has to wonder what improved antivirals might do.
Supplements pretty much bombed – unless they were paired with drugs, in which case a few proved helpful, indeed. Despite the obvious gut dysregulation, the short list of gut enhancers assessed did not appear to move the needle much.
The poor showing by most of the mitochondrial enhancers suggested, as several recent papers suggest, that there’s either more to ME/CFS than mitochondrial disruption (or that the wrong treatments were tried). It’s too bad, though, that rapamycin did not make the list.
The study, which began in 2023 and 2024, highlighted the rapid evolution of treatment options as a range of new therapies (rapamycin, GLP-1 agonists, plasmapheresis, fecal transplants, and psychedelic drugs) emerged, many of which had not been previously assessed.
Let’s hope the Open Medicine Foundation makes these surveys a regular occurrence. Lastly, check out lead researcher Martha Eckey’s substack for more information on the survey and long COVID treatments.
Health Rising’s Quick Summer Drive Update
What are the most effective treatments for ME/CFS and long COVID? We dug into the appendices to try and find out.
Thanks to everyone who has helped Health Rising reach 56% of its goal in its quickie summer drive.
This was a massive study—and it’s a massive blog. This blog turned out as blogs often do – it got bigger and bigger as time went on, and I found more and more to dig into. This blog, which produces lengthy posts that delve into the details of the subject, ultimately focused most of its attention not on the paper’s text but on one of its appendices. If you want that kind of detailed attention we’re the blog for you.
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I must say, I am surprised very high dose vitamin B1 was not on the list (unless I missed it), given Jeffrey Lubell’s survey results which you reported on. Something like 2/3 of respondents benefited significantly. It is the most helpful treatment I personally have tried.
👍 definitely
Actually, thiamine was assessed and they assessed it quite well (you have to go to the supplemental data – https://www.healthrising.org/wp-content/uploads/2025/07/Appendices_.Marked_Up.sapp_.pdf ) to find it, though.
With B1 more was better.
Thiamine < 100 mg = 11% said it moderately/much better improved their symptoms Thiamine >100 mg = 19% said it moderately/much better improved their symptoms
Thiamine – dose unknow – 5% said it moderately/much better improved their symptoms
Thanks Cort. I ramped up slowly and only noticed any effect at 600mg/day. Now I take 1g/day with a very significant improvement. I owe it to your posting of Jeffrey’s survey! I took the chance of being the first commenter to evangelize a bit. As far as I am concerned (severe ME/CFS), thiamine is the real deal!
A case where more is indeed much better! This is the kind of fine-tuned stuff that I wish we had more of. I wonder how often we’re just off on the dose (???). Thanks for the reminder to try it at higher levels.
I agree Cort. I’ve tried a lot of supplements that seemed to help at first but diminished greatly later. I tended to think it was just the giant CFS mystery, but now I wonder if it was a dosage problem. It’s also expensive trying so many things.
Just want to point out that this survey didn’t originate with the OMF. It was the lead author’s (Martha Eckey @organichemusic) initiative. I assume she went to OMF to get help with analysis and writing it up.
There’s some detail on her initial analyses on her substack:
https://pharmd.substack.com/
Thanks! I missed her analysis! I am incorporating some of it in the blog.
Right! Martha Eckey, PharmD, is an extraordinary person. She persevered through thick and thin to be the sole creator of her deeply detailed survey, then she disseminate it far and wide and then she analyzed the results on many different levels. It was wonderful that she next teamed up with OMF and Wenzhong Xiao, PhD, and others to bring it to the conclusion of this very helpful paper. Thank to this team for bringing us this important information.
My experience with Maraviroc. My physician agreed to let me try Maraviroc at half doses (because of my sensitivity to chemicals) for six weeks. We decided to wait to see if adding a statin would enhance the effectiveness.
Maraviroc made me slightly dizzy and tired. I also gained three pounds of what I assume was water weight in a week to the point where I couldn’t button my jeans. I also developed an ear infection during this week. (Edema and ear infections have been reported as side effects of Maraviroc.)
When I researched the potential side effects of Maraviroc I found these and many more serious possibilities, especially regarding the liver.
Since I had not seen any improvement in symptoms and considering the new University of Edinburgh research listing blood markers for liver disease in their large study of 1455 ME/CFS patients, I decided to stop taking the drug.
Maraviroc may work great for patients without chemical sensitivity, but if you have this, I would be very cautious about trying this drug. In fact, I would wait for more published data on this protocol. I had been feeling worse and was anxious for some boost in health, but Maraviroc wasn’t it.
The chart in this blog didn’t mention clonazepam or Nexavir which were treatments Dr. Cheney found the most helpful in his patients over the years. These treatments and B-12 shots helped me the most over time.
There are some Gulf War researchers who believe that pyridostigmine (mestinon) can trigger ME/CFS so I have never understood using it is a treatment.
It’s quite interesting to have such overview at our disposal, for both patients and doctors seeking to evaluate treatment options. The full color bars give a good estimate of the chance of success versus the chances of it ending badly, be it temporarily or very hard to recover from.
What I noticed is that you (Cort) cut off the graph excluding the last treatment option: GET. That line states:
Graded Exercise Theraphy (299 | 1.0000 | -72.2%)
In plain words: that says 299 patients responded they had Graded Exercise Theraphy, there is a P chance of 1.0000 for the outcome or a 100.00% (yes, those decimals are correct before rounding) chance for GET *on average* to yield worse (as measured by patient reported experience) patient health and a score of -72.2% indicating much more patients got worse then better.
Actually, there is only ONE theraphy that gets as high as score in absolute value but positive, and that is Pacing, at a score of +75.2%.
Combined: both extremes (-72.2% and +75.2%) say that one theraphy has, on average, far more NEGATIVE then positive outcomes, the other on average far more positive then negative outcomes.
Curiously, some “research” was able to combine both in a single “research study” by hijacking the common name for it. The “study” was called “PACE”, and found GET to be very effective / curative and found that patients doing less made themselve ill by avoiding exercise out of an irrational fear (patients would call this method pacing).
To call pacing (on average!) as safe and effective as GET isn’t safe nor effective (on average!) based on these numbers would even be a big stretch too far. The typical amount of improvement for pacing is much less outspoken then the typical amount of getting worse (both as reported by patients’ experience) with GET: An overwhelmingly 50% reports to be MUCH WORSE after GET versus (hard to read on the graph) while only a paltry 1 to 2% reports to be much better.
=> from analyzing patients’ reporting included in this study, as done by the authors, GET can be called the exact opposite of a “piece of safe and benign theraphy”. Granted, patients reporting isn’t a double blind study. But the PACE “study” did have a lot of objective criteria in its design and ditched them all but one halfway the study to depend nearly completely on patient reporting too.
=> I feel this is essential information for both existing patients still having to shake of the guild from chosing to pace, for new patients being unaware of the average and very often extreme outcomes of GET (while it stil is at times recommended as a safe must do theraphy even up to today by health care and insurrance professionals) and health care professionals chosing to guide and help patients.
=> Any reason why this piece of information did not make it to the blog? To not stir up controversy?
I could imagine that choise. The paper just shows it in the graph and never mentions it either. I imagine that stirring up controversy was expected and chosen to be avoided by the authors. As a victim of PACE-type “research” and “theraphy” myself, I do however find good information on how things can have negative outcomes up to permanent devastating ones is as valluable or even more then emphasing what helps some. At ten years and counting, I am fighting with very much effort and dedication (plus quite an amount of skill, knowledge and plenty of plain luck) against the train wreck / “my year of hell on Earth” that followed in the wake of that “safe and benign piece of GET / CBT”.
It took me finding ways to try as safe and possible many of the positive things in the paper, learn to better evaluate outcomes, finding optimal doses and decision points to revert course PLUS quite a number of things not in that graph yet and I still am barely as “good” as I was before that round of GET / CBT. Therefore I say that even that one line is as important and valuable as the rest of the lines in that graph above it. Having the full table in that graph would be even better. I do understand the risk of the authors publishing that, but I hope one day that will become a reality.
As conventional healthcare says: it is far better and more effective to prevent then to have to cure. Having and showing the table with negative to deeply negative outcomes is of great value here.
I didn’t “cut off” the graded exercise therapy portion of the graph. If you look you can see that it was separated from the rest of the graph – and I could not fit it into the image when I copied it. That’s why its not there. Thanks for providing the information on it.
I just added the image separately into the blog.
My apologies Cort. I first half read your blog, then read the paper. I saw the graph in the paper and scanned it for any word on it and failed to find it in the analysis or discussion. Maybe I didn’t search well enough, but it is a rather sore point to me.
Before that round of CBT / GET that was so strongly claimed to be safe and effective (I would have settled for safe all on its own) I already had ME/CFS plus FM, yet still couldn’t understand why some studies called it one of the worst conditions to live with well before many other bad conditions. That “theraphy” made me very well and intimately acquainted with the depths and desparation of bad ME/CFS. At worst it is for people suffering it purified agony without reprieve, and now I know too. Just getting through even a single of a series of bad days was a mental challenge beyond words or comprehension to those who never experienced it. Even now I can no longer grasp the true depths of that agony thanks to getting a measure of health and life back.
Trying to halt the further gradual decline from even those depths back then and fighting bit by bit my way back was a challenge unlike anything I ever experienced in my life and never ever hope to experience again.
So I admit I was blind to what was below the end of that graph and scanned the text for any words on it, in a mental tunnel formed by the very pain this CBT /GET thing brought in and wrecked my life as it did with so many others.
From my experience and the experience of many others I heared and read about, it looks like the damage of this one “piece of benigne and safe theraphy” has caused more damage then all the good the theraphies on top of it combined have done for hordes of patients. And while those other theraphies can require taking risk for temporary or permanent setback, costing energy and effort we can’t muster or money we don’t have, avoiding the negatives of this CBT / GET combo requires no effort of us at all but rather the opposite: not doing the effort to further ruin our health. All we need is more information and studies making the very risk more clear and scientifically quantified.
In this case: we have a P equal to 100.00% that on average the outcomes of GET are negative. This paper / study even uses close to the same methodology as the PACE “study” does: mainly relying on patients’ self grading their symptoms before and after the GET “theraphy”. Remarkable how different the outcomes are given the modest differences in study protocol isn’t it?
So, sorry again Cort. I got blinded by spotting a very sore point for me.
No worries at all and thanks for explaining about your experience. I remember that it was very bad.
A note on d-ribose: I was lucky enough to be evaluated by a competent metabolism specialist (Dr Julian Ambrus, previously highlighted in a HealthRising blog) and was diagnosed with myoadenylate deaminase deficiency… among other things. Dr Ambrus recommended d-ribose for that condition and it basically allows me to live independently where otherwise I don’t think I could. I still have pretty significant “ME/CFS”. The deficiency is found in a small subset of the population and is exacerbated by infections/etc.
it’s worth trying as it is cheap and essentially side effect free and could change the lives of some individuals. However it makes sense that it’s not more widely effective.
Also I have to shout out creatine. Super helpful!!! I can’t believe more people don’t use it.
I also have MTHFR issues and methyl-folate and adenosylcobalamin (B12) are helpful for that.
At the end of the day, Dr Ambrus believes we each have a metabolism that is somehow messed up. The treatment for each situation depends on what is messed up. So it’s worth trying even the less well received from the list, if you can’t find relief elsewhere
Thank u , Ryan, for ur tips.
May I ask is the test for myoadenylate deaminase, covered by medicare or any insurance.? Thx Wendy
We saw that mitochondrial supplements taken in combination with guanfacine, for instance, can be very helpful and that more, in general was better. I wonder the study just didn’t capture how helpful they can be taken in combination with each other and other treatments.
Any you are right! I think 62 drugs and supplements were found to be moderately/very helpful by 20% of patients and many more by 10-20% of the patients.
Why did you cut off the extremely harmful “Graded Exercise Therapy” segment? See original post here: https://pharmd.substack.com/p/preprint-release-and-supplementary. Also, please stop (everyone) saying that pacing is “treatment” of anything. It’s a method of trying to avoid worsening symptoms while we’re waiting for real research. If that allows the body to heal a bit, that’s great. But to claim it as a valid treatment lets medical establishment off the hook for decades of neglect and mistreatment, in the literal origins of that word. It’s really only saying not to cause damage by overexertion while have nothing else by standard research due to decades of misconduct by mouthpieces spreading misinformation. Words matter. Don’t start statements with repeating their misinformation. Start always with correct information.
As I noted, GET was at the bottom of the graph and separated from it and it simply didn’t fit into the image I copied. (I just included it). I didn’t cover graded exercise therapy in general because it’s so clear to this community that it doesn’t work (we’ve been covering it for decades now) that I thought it wasn’t necessary.
Pacing was included in the treatment category because that was the category the authors put it in.
The misinformation I was referring to was being spread by the PACE cabal. And when I said please don’t repeat misinformation (from them), as I mentioned, it was a general plea to anyone writing about this topic. Example, not leading with “Chronic Fatigue” or “not all in your head” ( of course, it’s not) etc… again, it was a general comment to anyone writing about it anywhere. Separately, in your case, I do find it odd that you cut off just one item from the list and now you’re saying it’s because it’s been discussed here before. I think all of those things have been discussed here before, but it’s a new context which is why you wrote about it, right? It’s your blog and your choice.I was just asking the question. That’s all. It felt important to show how extremely harmful it had been to so many people since this is a source of information about treatment results.
Thanks, P – but please note that I did not cut the GET line off from the image. It was separated from the rest of the image, and when I copy an image, there are times I just can’t fit all of it into the copy.
As I said, thanks to yours and DeJurgen’s comments, I went back in, copied it separately, and added it to the blog.
Oh, then I wasn’t mistaken it wasn’t in the original blog. Yes, I understand the (probably) screen grab problem. Been there, done that :-).
I think what P is trying to say just as I do that there are four opportunities here:
A) Having a repeat from time to time how devastating bad treaments can be, as a way to tell people (patients, doctors, care-givers) who only recently started to read up on the topic. They are often new to ME/CFS, and those are the people that are still vulnerable to this piece of @#§$ theraphy still pushed by more then a few professionals.
B) Understanding that the methodology of this paper is in essence not that much different from the methodology (after they halfway the study ditched near all objective outcomes) from the PACE trial.
C) Understanding what a P = 1.0000 means: it is statistically extremely unlikely that the outcome is not negative. Actually the P for the average outcome for GET being negative according to the methodology use in the paper would be P < 0.0001 which is a very strong statistical indicator the hypothesis (outcome of GET is getting worse) is correct.
D) It takes a lot of "courage" for any scientist to claim the outcome of PACE is not obliterated (P < 0.0001 in study with fairly similar methodology) or at least very much under scrunity given point C).
I suspect that the reason for the low numbers of oxaloacetate is the cost for anyone to actually take the amount that previous study showed helpful.
I also suspect that the reason supplements paired so poorly, esp mitochondrial enhancers is that they need to be taken in combination &/or higher doses. There are so many things that impact mitochondrial function that taking one or two supplements for it, but leavign out other vital ones would prevent the ones being taken from working. FWIW, I am one for whom they have helped some, esp D Ribose, though my overall ME has worsened over the 21 yrs I’ve been sick. However, there are a lot of other reasons for that. Re D-ribose, I still notice a big difference when I take it, even though “big” is very relative, given how sick I am.
I have a lot more thoughts about this, but that’s all I can handle writing rt now.
oops that was supposed to say supplements fared so poorly, not paired….also while I only really explained re mito supps, what I said could hold true for a lot of other supps as well
“supplements paired so poorly, esp mitochondrial enhancers is that they need to be taken in combination &/or higher doses.”
I would not be surprised. I’ve been planning to take a bunch of them together and see what happens.
how did the authors define “pacing”?
Thanks for this excellent report, Cort.
The results suggest that, next time, we should be divided into groups: ME or LC alone; with POTS; with MCAS; with both POTS and MCAS.
Do you think adding this question would result in more informative data? (Or are too many patients still unaware of POTS & MCAS?)
Also, it would be good if we were questioned about allergies: eg I didn’t improve with nattokinase because I have MCAS and am allergic or sensitive to soy. But gingko biloba and aspirin cause a big improvement.
I’m bedbound with severe ME/CFS. I tried IVIG for 9 months (every other week), but it didn’t help. After each infusion, I’d crash for hours — too weak to open my eyes, sometimes short of breath. When I switched to subcutaneous IVIG, the crashes got worse and never really stopped.
It has now been 8 months since I stopped IVIG treatments, but I’m still having these episodes almost daily. They don’t feel like my usual ME/CFS crashes, but I don’t know what else to call them. My doctor has no idea what could cause this. Has anyone else had this reaction to IVIG? Any thoughts on what might be happening?
I’m curious about the reasoning behind this quote, Cort: “The study didn’t assess brain retraining, which is open to anyone. The fact that most of the better treatment options involve drugs indicates, though, that this is not a do-it-yourself illness, and that a doctor who is willing to take the time and trouble to trying different approaches is essential.”
What from this study indicates that this is not an illness that can be healed by an individual on their own? It didn’t look at any of the central strategies that people who have done just that typically use.
I tried about half the things this study mentions and the only things I still do/take now that I’m almost entirely healed are nervous system regulation work (similar to “brain retraining, but more holistic) and CBD. They both moved the needle for me much more than anything else this study included.
No surprise the brain meds worked best. All “brain retraining” does is help us re-establish frontal cortex control over the injured brain mechanisms that cause our symptoms, just as CBD helps calm their over-activation and inflammation. Most of us with these conditions are neurodivergent (ADHD, autism, or both) or have childhood trauma that structurally affected our nervous systems. Brain meds can help with that (I benefitted from both Guanfacine and Bupropion at times), though it seems to me that true healing is something more robustly achieved by ourselves, by doing a variety of internal work that heals our nervous systems.
‘No surprise that brain meds worked best’
Exactly, because the primary issue is in the brain, not immune system, viruses etc….
You’re Aaron. I meant to infer that but didn’t do a good job. I was very disappointed they didn’t assess brain retraining. It was a great opportunity to assess a controversial option that is of great interest in the community. I tried to find out why but didn’t have any success.
I changed the sentence to
“The study didn’t assess brain retraining, which is open to anyone and has produced the majority of recovery stories on the internet. The fact that most of the better treatment options assessed in this survey involve drugs suggests that a doctor willing to take the time and trouble to try those approaches is essential.”
Although useful to some extent, this study has a number of limitations:
– it is unlikely to have surveyed many recovered patients. This could distort (ie. downgrade) the results of some treatments / medications/ supplements
– for supplements, it lumps them together in a rather crude way. For example, curcumin. Some curcumin products are much more bioavailable than others. If most of those surveyed took poorer quality curcumin, and /or insufficient dosage, this might be downgrading the success rate for curcumin. The same goes for creatine. I have heard of many people only taking 1-2 grams per day. Research indicates it should be at least 5-10g
Many thanks for putting this all together, Cort. I’m pretty surprised that pain assessment/treatments were not part of the study as they appear, to some degree, in most chronic ailments. The utility of this study for folks with a primarily pain disorder like fibromyalgia is thus limited. Another chance missed for poor old FM pts, with repurposed old meds or “pacing” until death the usual treatment.
The paper was a bit confusing about that – at least to me. Martha Eckey’s Substack indicated a wide range of symptoms were assessed, but the primary analysis focused on those five.
I, too, wish pain had been part of the primary assessment, as pain plays a big role in my more fibroey ME/CFS.
I don’t know why FM keeps getting sidelined in these ME/CFS/ long COVID surveys and studies. Everything I see about FM – including its designation as a nociplastic disorder – suggests it should be in there.