Underuse of Pharmacologic Therapies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Before Specialist Evaluation, 2026, Grach et al

[forestglip]

Underuse of Pharmacologic Therapies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Before Specialist Evaluation

Stephanie L. Grach, Jaime Seltzer, Michael R. Mueller, Chris A. Aakre, Lasonya T. Natividad, Donna K. Lawson, Ravindra Ganesh, Ryan T. Hurt

PURPOSE
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem neurologic disease characterized by profound fatigue and decreased functional capacity, postexertional malaise, and unrefreshing sleep, along with cognitive impairment and/or orthostatic intolerance. Its prevalence has risen exponentially with the COVID-19 pandemic. Pharmacologic therapies have been used successfully by ME/CFS specialists but may be underused by the general medical field.

METHODS
To assess this potential practice gap, we retrospectively analyzed the records of 571 patients with an ME/CFS diagnosis referred to our ME/CFS specialty clinic in Minnesota during 2018-2022. We ascertained medications that had already been tried at the time of consultation and also ascertained supplement use.

RESULTS
With the exception of medications primarily used for pain and anxiety, use of pharmacotherapy for ME/CFS symptom management as proposed by specialists was limited. Overall, 68.3% of patients had had at least 1 medication potentially prescribed for ME/CFS; the most common were serotonin-norepinephrine reuptake inhibitors, gabapentin, and tricyclic antidepressants. A slightly larger share of patients, 72.2%, reported having taken at least 1 dietary supplement; the most common were vitamin D, vitamin B12 and B complex, and fish oil.

CONCLUSION
Our findings suggest that potentially helpful medications for ME/CFS are being underprescribed in the general medical field and that patients may resort to supplements to manage symptoms. Better education of clinicians about available treatment options and treatment guides may improve management of this debilitating disease.

Web | DOI | PDF | Annals of Family Medicine | Open Access

 

[Utsikt]

Pharmacologic therapies have been used successfully by ME/CFS specialists but may be underused by the general medical field.

This is what they say about medications:

ME/CFS experts have prescribed various medications for symptom management. Many are summarized in expert statements such as those developed by the US ME/CFS Clinician Coalition and the International Consensus Panel or discussed in review articles related to ME/CFS or long COVID.8,9,14-19

Recent studies have emerged in particular on the use of low-dose naltrexone, aripiprazole, and pyridostig- mine in ME/CFS.20-23 Knowledge about these options is not widespread, however. This is likely due to a combination of factors, including but not limited to little coverage of this topic in medical training pertaining to ME/CFS and comorbid conditions.24,25

Medication sensitivity also presents a common barrier to medications when they are tried, deterring both patients and clinicians from pursuing additional treatment. ME/CFS specialists generally recommend comparatively lower doses than standard followed by gradual titration, col- loquially referred to as the “start low, go slow” strategy.8

So they have no evidence of efficacy, but still claim that the medications are underused.

 

[Felis Catus]

Yeah, the abstract left me wondering what do they suggest. Table 2 (too big to screenshot) in the paper lists same old same old treatments...

 

[Hutan]

CONCLUSION
Our findings suggest that potentially helpful medications for ME/CFS are being underprescribed in the general medical field and that patients may resort to supplements to manage symptoms. Better education of clinicians about available treatment options and treatment guides may improve management of this debilitating disease.

It's a shame that the abstract conclusion calls for educating clinicians to use these unevidenced treatment options, but makes no mention of the need for trials to determine if in fact these medications are of any use.

 

[Holinger]

Dr. Chris Aakre is an internist at Mayo from the Integrative Medicine department. This and his promotion of central sensitization theory doesn’t fill me with evidence based confidence re medication. But is probably a better option than the psycho behavioural model at Mayo on offer.

 

[ahimsa]

... but makes no mention of the need for trials to determine if in fact these medications are of any use.

To be fair, I did see this in the "Need for Education" section (near the end):

There has been a rapid acceleration in ME/CFS and related research with the rise of long COVID, accompanied by increasing use of symptom-focused therapies as outlined in the expert resources and Table 2.

Research is beginning to support use of these clinical options in ME/CFS and/or long COVID, but additional real-world studies and randomized control trials in ME/CFS are greatly needed.

I agree that this statement may not be strong enough but at least they do say that more evidence is needed. (unless I'm completely misinterpreting this?)

 

[Hutan]

I agree that this statement may not be strong enough but at least they do say that more evidence is needed.

I think it matters what makes it to the abstract. The single most important thing to say about current medication use in ME/CFS is that research is needed to clarify whether commonly prescribed medications are useful.

The medications and supplements identified in our study and the above discussion represent options for ME/CFS symptom reduction; more research is needed to identify disease-modifying treatments and, ultimately, curative therapies.

That statement in the Ongoing Research section makes it sound as though the medications and supplements they list in their tables are reasonable options for symptom reduction.


This is what they say about CoQ10 in Table 3.

Most studied supplement in ME/CFS; supplementation increases levels and improves symptoms, especially cognitive fatigue, sleep disturbances, and impaired quality of life.74,76-78

See the review of CoQ10 that I did here. It is certainly true that there are quite a few studies of CoQ10 for ME/CFS and related conditions. But, it is not true to claim that the body of evidence suggests that it improves ME/CFS symptoms. It is just not reasonable to make those claims - an unbiased review of the literature does not support it. It seems that the authors of this paper take claims in abstracts at face value. Edit to add - the references are only to papers that made positive claims. The papers with null results are not referenced.

There are some good things in this paper, such as the recognition that ME/CFS can be a consequence of Covid-19 infections, and some implied concern about the high rate of anti-depressant prescriptions. But, people with ME/CFS deserve better than this paper and the unevidenced medical care that it sounds like this Mayo Clinic is providing.

The observed pattern of medication use does not align with our specialty clinic’s initial approach to ME/CFS, which typically focuses first on fatigue, brain fog, and postexertional malaise, but is as expected based on the average knowledge of ME/CFS treatment in the general medical field.27-29 Our findings are also consistent with patient reports of clinicians being more likely to target mood concerns, as symptoms may often be labeled psychological before the actual diagnosis of ME/CFS is determined.30,31 In contrast, supplement use was more targeted toward improving energy and reducing inflammation, which better aligns with the medication strategies used in our clinic.

 

[Hutan]

A minor annoyance of mine is papers that report detail of their participants marital status when that status has no relevance to the subject of the paper.

Marital status

Married 326 (57.1)
Single 190 (33.3)
Divorced 35 (6.1)
Life partnership 8 (1.4)
Widowed 3 (0.5)
Separated 2 (0.4)
Chose not to disclose 1 (0.2)
Unknown 6 (1.1)

That report is from Table 1. There is no analysis in the paper of whether being married makes someone more likely to be using a particular medication than someone who is single. And, I think that absence of analysis is for a good reason. The marital status of the participants is just not relevant. There is no good reason to clutter up the paper with this information.

Similarly, there is highly detailed information on ethnicity/race - nine categories are reported. Perhaps the Mayo Clinic wanted this information for its clinic marketing plan, but this information, certainly at the level of detail presented, has essentially no relevance to the subject of the paper.

 

[Hutan]

First author is Dr Stephanie Grach, a doctor at Mayo Clinic. Clearly she is trying to help. But she needs to understand that blind acceptance of everything she has been told is definitely not helpful. People with ME/CFS will be going to extraordinary lengths in terms of effort and expense to get to see her, and they deserve a doctor who carefully scrutinises the evidence for interventions and is honest about the level of help that can be provided.

Dr. Grach received her M.D. degree from the University of Illinois College of Medicine in Rockford, IL, and completed her Internal Medicine residency at the Mayo Clinic in Rochester, MN. She obtained additional training at the Bateman Horne Center of Excellence for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia. Her primary interests include improving clinical, research, and educational aspects surrounding ME/CFS and related complex chronic diseases; additional interests include sexual health, general medical education, and diversity, equity, and inclusion in medicine.

This paper probably functions mostly as a marketing exercise for Mayo, aiming to pull in new clients with its claim of superior knowledge.

The observed pattern of medication use does not align with our specialty clinic’s initial approach to ME/CFS, which typically focuses first on fatigue, brain fog, and postexertional malaise, but is as expected based on the average knowledge of ME/CFS treatment in the general medical field.27-29 Our findings are also consistent with patient reports of clinicians being more likely to target mood concerns, as symptoms may often be labeled psychological before the actual diagnosis of ME/CFS is determined.30,31 In contrast, supplement use was more targeted toward improving energy and reducing inflammation, which better aligns with the medication strategies used in our clinic.

It's disappointing to see Jaime Seltzer of ME Action associated with a paper like this. We need our patient charities to be a lot more discerning about what they promote.

 

[Mij]

"Medications for core ME/CFS symptoms, as recommended by ME/CFS specialists, are underutilized in general practice despite being overall easy to prescribe.
Our paper highlights common therapies recommended and/or researched in ME/CFS - check out the tables to learn more!"

 

[rvallee]

the most common were serotonin-norepinephrine reuptake inhibitors, gabapentin, and tricyclic antidepressants

There is no evidence for the use or SSRIs and other psychotropic drugs in ME/CFS. Evidence-based medicine is a lie, evidence is entirely irrelevant to modern clinical practices. This is just as bad as psychobehavioral woo having no evidence and still being widely advised. Outside of key areas and basic biology, modern medicine is stalling, even regressing in many areas.

It's not credible to argue against the use of some medication lacking evidence when many drugs where efficacy has been proven to be nil are common. Expert systems need to be consistent and coherent, and we aren't seeing this anywhere. It's all just arbitrary.

 

[ahimsa]

Edit to add - the references are only to papers that made positive claims. The papers with null results are not referenced.

Thanks - for this note in particular (on CoQ10 research) but also for all the rest of your thoughts on this paper. I always appreciate your analysis.

This is a skill that I simply don't have.

 

[Hutan]

That's kind of you @ahimsa. I do have mixed feelings when I do this, because I know that the authors believe that they are helping, and also, contrary to what some people think, I don't enjoy criticising people. I know that some people have written me off as too critical. I post because I feel so frustrated that we have people of influence inadvertently making things worse and not taking care to thoroughly check the things they say and the things they recommend.

It's extremely difficult for me, as an unemployed online commentator with no qualifications in medicine, or even all of us collectively on this forum, to compete with the authority of the Mayo Clinic. These people are supposed to be on the side of the ME/CFS community, they make good money from providing services, and yet they are causing the many harms that flow from promoting drugs that aren't useful.

For some of the medications, it's not just that we don't have evidence to support their use, we actually have some reasonable evidence that they don't help. And still, they are recommended. For example, these authors have had to both cherry-pick and read uncritically in order to suggest that evidence supports the use of CoQ10 for ME/CFS.

One thing I forgot to mention, is that these authors don't seem to understand the problems of open label trials in a disease that is fluctuating and where it is often possible to believe something is helping for a while. The paper cites a substantial number of open-label trials that report small benefits as useful evidence. There are several calls for more research, but no significant discussion of the problems with the existing research base (e.g. selection bias, small trial size, lack of controls, lack of objective outcomes).

The closest the paper comes to calling for better research is this:

Research is beginning to support use of these clinical options in ME/CFS and/or long COVID, but additional real-world studies and randomized control trials in ME/CFS are greatly needed.

That's really inadequate in a paper promoting more medication use in ME/CFS.

I don't know if any of our members personally know these authors? If so, perhaps they could tell them that undiscerning promotion of medications does not help people with ME/CFS.

 

[Hutan]

I've alerted Stephanie Grach, the corresponding author, to the thread and have invited her to respond.

 

[Concentric_Spiral]

I know that some people have written me off as too critical.

If the criticisms are valid what's the problem? Engaging with research is the highest compliment one can pay.

 

[Jonathan Edwards]

That's really inadequate in a paper promoting more medication use in ME/CFS.

I agree. 'Real world studies' is a tired trope for inadequate methodology - like 'pragmatic'. Randomisating and controlling are important but yet again blinding gets missed out.

It is not as if these issues have not been very high profile in ME/CFS debate for a decade now. The authors know this.

 

[Hutan]

Stephanie has kindly replied very quickly to my email (see paragraph breaks added for readability)


"Thank you for your concerns. For our patients, the norm experience is that patients have not been provided any options outside of antidepressants for their symptoms; for the vast majority, there is lack of validation of diagnosis (or existence of ME/CFS as an entity) and similarly patients are told that there is nothing to do for it, or worse, CBT/GET.

This paper does not state that the medications discussed are expected to be the appropriate therapy for all patients, but that there are symptom-directed options that have been used by ME/CFS specialists for quite awhile, as per the expert consensus papers referenced. For example, all medications listed in our table were ones used by clinicians at the Bateman Horne Center when I was there in 2021.

There is both initial data and hopefully soon upcoming data on % patients finding benefit in Long COVID, data from Wenzhong Xiao's team, among others showing that there are groups of patients that find benefit with the different therapies. It is important also to note that it is true across medical conditions in general (autoimmune diseases, neurologic diseases, cardiovascular diseases, and so on) that there is no one-size fits all therapies, that a portion may benefit and a portion may have side effects. That does not invalidate the positive experiences of those who benefitted, but should push us to find alternatives for those who didn't.

I appreciate that people would like more evidence - we would too. Unfortunately, it is difficult to get formal studies funded especially without preliminary studies. These types of studies and expert consensus are how are able to fields advance to the point of those better studies and truly evidence-based guidelines. In the meantime, we will do the best we can to validate patients and their experiences while working towards that gold standard."

 

[Holinger]

That is a pretty good response in that she has got back to you (Hutan) and some questions about why non antidepressant options are used. Obviously there is a large dearth of evidence for the use otherwise of these medications and supplements. Hopefully patients are told about the lacking evidence at least. No one is going to spend money on for example a blinded CoQ10 trial as the anecdotal evidence isn’t there.

Edit: the concerns about evidence base are not addressed.

 

[Hutan]

Unfortunately, I don't think Stephanie has understood the concerns.

This paper does not state that the medications discussed are expected to be the appropriate therapy for all patients, but that there are symptom-directed options that have been used by ME/CFS specialists for quite awhile, as per the expert consensus papers referenced.

I think that slides away from acknowledging that this paper is saying that the medications listed are in fact offered by the Mayo clinic, and it is these that they are saying doctors should be educated about. The paper does not just say 'these are medications that others are recommending'. The title of the paper includes the word 'underuse' - the aim of the paper is to increase the use of the medications, and specifically those listed in the tables.

Our study’s results support the need for increased education around available management strategies for ME/CFS. Treatment guides developed by ME/CFS and long COVID specialists detail potential therapies that can be used for vari-ous symptoms.14-16,19,33 Medications that we commonly discuss with patients in our clinic, as considerations for use, are listed in Table 2. Our clinic also supports the use of carefully selected supplements for symptom management, especially if medications are poorly tolerated

The tables listing the drugs and supplements include inaccurate representations of the evidence base for the various medications. For example, for Aripiprazole, Table 2 says "Improved fatigue, brain fog, and/or postexertional malaise in 74% of patients at 0.2 to 2 mg
daily, as shown in a Stanford retrospective study." We looked at that study - it is simply not good enough to be reliable evidence or to justify giving people a drug with significant side effects.

that there is no one-size fits all therapies, that a portion may benefit and a portion may have side effects. That does not invalidate the positive experiences of those who benefitted, but should push us to find alternatives for those who didn't.

Stephanie mentions that it is bad when patients are told that CBT and GET are suitable treatments. But, we can find patients who say that CBT and GET helped them, just as we can find patients who are certain that all of the drugs and supplements in those tables have helped them. The point is, we can't say that these things are useful for ME/CFS unless there are good quality trials. If you accept bad quality trials, as this paper does, then you have to acknowledge that there is similar levels of evidence supporting CBT and GET.

For example, all medications listed in our table were ones used by clinicians at the Bateman Horne Center when I was there in 2021.

Just because another clinic is using a drug, it doesn't make it right. Stephanie's response illustrates the problem. We need ME/CFS clinicians to be more scientifically literate. They have to take the time to actually read the studies that they say are evidence, to understand how flawed they are.

I appreciate that people would like more evidence - we would too.

Yeah, the problem is not that we are naively asking for the currently unattainable. It's not a matter of clinicians just doing the best they can in an imperfect world.

CoQ10 is a case in point - there is sufficient evidence to be pretty certain that CoQ10 is not the answer to ME/CFS, or even specific symptoms of ME/CFS. And yet, there it is listed in Table 3, with the suggestion that there is good evidence for it being useful.

And there's a world of difference between accommodating patients who have decided, rightly or wrongly, that an unevidenced drug or supplement is useful for them, and actively promoting the medication to new patients. Both of those options can be defensible, particularly if you have thoroughly and critically reviewed the evidence and careful records of changes in function over time are made. But, writing a paper saying that doctors around the world need to be trained in providing the unevidenced medication to ME/CFS patients takes the certitude to another level again.

I would have thought that if you are going to set yourself up as world-leading expert in a position to tell other clinicians what to do, you would carefully look at the evidence yourself. It is very clear that that is not what happened with this paper.

 

[Hutan]

No one is going to spend money on for example a blinded CoQ10 trial as the anecdotal evidence isn’t there.

That's the thing. People actually have spent money on blinded CoQ10 trials and some of those trials are okay in other respects too. We have a decent amount of decent evidence for that supplement, but it has been ignored in this paper.

Obviously there is a large dearth of evidence for the use otherwise of these medications and supplements. Hopefully patients are told about the lacking evidence at least.

Well, this paper calling for clinicians to be educated in the use of the lists of medications doesn't discuss the problems with the evidence base. Claims of utility are made with great certainty. So, I'm not sure what the chances of patients being adequately informed at are. And regardless, if a clinician from Mayo Clinic is saying 'well, the evidence base for this isn't great, but we prescribe this to a lot of patients and I think it could help you' - of course most patients who have invested a lot in getting to the clinic are going to say 'sure, lets try it'.

I don't think we can rely on new patients to be the ones making great decisions about what they try and what they don't. It is the clinicians, the clinical guidelines and the patient charities that have to be providing the well-reasoned advice. And that's why we need them all to do better.

The medications and supplements identified in our study and the above discussion represent options for ME/CFS symptom reduction; more research is needed to identify disease-modifying treatments and, ultimately, curative therapies. For example, stellate ganglion blocks are emerging as an intervention for sympathetic reduction in long COVID as well as in ME/CFS.