“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 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“, was 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, sleep drugs, and physical therapy were not assessed.

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

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.

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 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 like it and Dr. Klimas has said that  that the pooling of IVIG from a large population gives it such a “tremendous advantage” that if an infection is the problem, then 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.

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.

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%!)

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 

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 buproprion (n=172; 30% moderate/much better), with less than 20% of patients reporting they helped significantly, antidepressants did not produce 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.

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)

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 better 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

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

How happy you are with the survey 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. 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. 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.

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