Review A Perspective on the Role of Metformin in Treating [...] (ME/CFS) and Long COVID (2025) Fineberg et al

[Jonathan Edwards]

Last time I looked at the data for salt and water for POTS I was unconvinced. There is a huge bias towards getting a positive result in this sort of situation. I want to keep reviewing this because at some point hopefully there will be good data.

Medical science is very bad at salt and water mechanisms. I think people are unaware that it is relatively easy to establish facts about structure and chemistry but dynamic function is often difficult to prove.

Take the two most basic things students are taught about water balance in disease:

1. The feet swell with water in heart failure because of a rise in capillary/venular hydrostatic pressure.
2. The feet swell with water in nephrotic syndrome because of a reduced capillary/vanular oncotic pressure.

Both of these are wrong and you can be sure they are wrong from simple clinical observation of cases and arithmetic.

Giving salt and water to people with orthostatic intolerance makes superficial sense but as soon as you consider what we know about normal fluid control it makes no sense at all. The long list of unproven treatments given by the cardiologist in the video on POTS are linked by the fact that they are all supposed to raise blood pressure through water retention. People believe they work because they seem to make sense. In the absence of adequate trials there is no way of knowing whether they work. And a detailed analysis of the physiology doesn't make it very plausible.

The need is to get clinicians to be responsible and do trials. I know that you are on board with that, but it needs to be made clear that muddling along with these things without trials just delays getting things done properly.

 

[Sasha]

I want to second whoever said, 'Thanks for engaging,' @MelbME - people having good-faith discussions on these things is always clarifying and useful.

That is a very patronising view of pacing - that people can't and don't work out things for themselves, that they have to have a clinician tell them how to do it. Virtually everyone can and does work things out for themselves. Personality and circumstances can make it harder for some people to do it than others of course. Where did you get this view of pacing as something that people require instruction in?

Too often pacing advice becomes overly complicated, wrapped up in complicated formulae for which there is no good evidence, focusing on the minutiae of scheduled 15 minute rests, and removing people's agency.

At the beginning, I think a lot of people who have just got ME will struggle to accept just how much activity they have to give up in order to avoid getting worse - and they will often be under tremendous pressure from other people to keep going, such as employers and family members. It's a huge adjustment to make at a frightening and confusing time and some new PwME are likely to be in denial. I think early advice that PwME need to pace is crucial - as opposed to telling PwME exactly how they should pace.

I remember meeting a new PwME who ran her own business, which would collapse and leave her broke if she stopped working. She was beating herself up about being 'lazy'. I don't think it would be patronising for a doctor at that point to spell out that continuing to push it could be disastrous, that ME/CFS was real and serious (which is not what society tells everyone), and that the PwME ought to cut right back, with some real-life-PwME examples of what that would look like that are not based on the nonsense the clinics spout. This is the sort of S4ME factsheet that we've been talking about, and we don't consider that patronising.

I think this may be the kind of support that @Jonathan Edwards is talking about.

 

[Trish]

Well what you and I agree on is what should happen in an ideal world.

What I'm trying to say in the world we are in there is already advice being circulated on treatments or management strategies to trial.

So at what point do you attempt to try sift through that advice to find better vs worse advice in the world that exists currently in an attempt to push it towards the better? Or as an idealist do you just ignore it all?

This is an interesting discussion, and I think and important one in the context of suggested treatments such as the paper this thread is about suggests.

I think it's fine for biomedical scientists and physicians to put their head together and come up with possible drug treatments that might be helpful for ME/CFS and Long Covid, and to propose clinical trials. If there is good biomedical logic for trying metformin in ME/CFS, and experienced clinical trial doctors able to get funding to run properly set up trials, go for it.

I'll be interested to see the outcome. But we have members here on metformin for other reasons whose ME/CFS didn't change, so it's clearly not the magic bullet for everyone.
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The problem comes when such hypothesis papers are used as the basis, or justification, for doctors to go ahead and recommend the drug to their patients, and for pwME on social media to encourage their friends to try it.

As others have said, no drug is completely risk free, so there needs to be very good reason for doctors to recommend them to their patients, and if the impetus for trying the drug comes from pwME desperate to get well, doctors surely have a responsibility to point out to the pwME that there is no clinical trial evidence to support its use in that context, and to draw attention to possible side effects.
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What I'm concerned about in this discussion is your assumption that some of us are warning against doctors promoting unevidenced drugs to patients, on the assumptions that our objections are based on idealism.

For me, and I'm aware for some others, our objections to doctors giving unevidenced advice to patients is based on experience, not idealism. We are all desperate to get better, or at least to see some improvement. Some of us are bedridden, or housebound. Of course we want to be cured.

What we don't want is the constant pressure from others to keep trying every treatment going the rounds on social media and pushed by family, friends, clinicians, doubtless with the best of intentions.

Spoiler: My experience with experimenting

I've had ME/CFS for 36 years. I spent the first years trying everything suggested to me and everything else I could find - mostly in my case alt med nonsense like Reiki and aromatherapy and acupuncture, but I also have boxes of supplements that failed to make any difference lurking on top of my wardrobe. I also tried, to my detriment, some of the quack brain training nonsense. I was a single mother at the time, struggling to continue working part time to support my kids and could ill afford to pay for this rubbish. But I kept trying. Each time the treatment failed, I felt a failure, to myself and to my children. I even persuaded my GP to get the NHS to pay for me to go to a doctor 100km away practising a weird mixture of alt med which cost me a lot in fares and pills that made me sicker.

Others here are formerly self supporting independent adults forced back into the care of their parents, or at the mercy of professional carers, because of their serious illness, and may be subjected to whatever doctors and therapists advise their parents or GP they should try, often making them sicker.

So your apparent approval of doctors being willing to try what 'seems to work' for some patients, is not harmless, however apparently benign the drugs involved may be. It can lead to false hope, to patients feeling like failures or being accused of not wanting to get better, to being accused of unrealistic idealism, to feeling pressured by others to put ourselves through another bout of side effects and possible long term harm to prove we want to get better. It can also cost a lot of money the pwME may struggle to find.

When we reach the end of the road with treatments that have harmed us, whether it has harmed our health, or finances, or broken relationships, or lost hope and feelings of failure, some or us turn to science, not through idealism, but through bitter experience. It is a relief in a strange sort of way, for me to realise that my scientific training of my youth was right all along, and to turn back to sound science to look for answers and to step away from the endless pursuit of the next possible cure to try.
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There are other members of this forum who are willing to try anything and desperate to find a doctor who will prescribe the latest drug they have read about on social media or heard a doctor or scientist suggesting, or read about in a hypothesis paper. I do not judge patients for pursuing hope, I've been there. I wish them well.

 

[EndME]

I haven't seen anything promising from Long COVID.

The treatments I think have strongest weight of evidence amongst majority of clinicians with least risk (though without trials) are pacing for ME, LDN for Fibro, salt/water for POTS.

With all due respect, like I already mentioned above, that is simply not the case. LDN has been trialled in a large RCT for Fibromyalgia with negative results. It very much looks like to me that people are actually not concerned with looking at the evidence if this isn't even known.

You can argue about the trial not being able to pick up benefits due to x,y,z but then one has to construct an argument on how clinicians can see these benefits if they aren't apparent in the trial and that is not happening and people will actually have to look at the evidence. This just looks like the opposite with people simply not arguing logically.

 

[Kitty]

Right, but based on what I understand from others in this thread, nothing should be promoted by GPs for ME/CFS as no trial has proven that anything works yet, not even pacing.

Not at all. There are trialled treatments for symptoms like pain, nausea and poor sleep. Having ME/CFS doesn't negate those trials.

Pacing doesn't need trialling because it isn't a treatment and will not improve ME/CFS. It's a pattern of resting after reaching or surpassing an activity threshold before being active again, so as not to feel crap. Everyone does it. The only difference is the height of the threshold and the length of the recovery time in ME/CFS.

Nothing should be promoted by GPs to treat the main feature of ME/CFS—PEM—because nothing has been shown to work. It would be unethical for a GP to experiment on patients.

I'm not even sure how we've got into such a tangle over it!

 

[Evergreen]

I want to echo @EndME , @Sasha and others and say that these debates are really valuable, and thank you for sticking around.

To pick up on some of your replies to others:

So you're equating any non-trialled advice or recommendation as equal. Giving something with a high risk of harm and few reports of helping patients is equal in your opinion to trying something with low risk of harm and many reports of helping people. Is that right?

I think this is a slippery slope. What one person considers to have a high risk of harm is not what another considers to have a high risk of harm. Ditto with the frequency of reports of helping people. Depends a lot on beliefs and very little on anything resembling evidence. There are many people who would put exercise, GET and similar in the latter category. What's more, there's some trial evidence that would give at least superficial support to those beliefs, which is more than can be said for all the non-trialled stuff out there.

Treatments get trialled on patients already if they have minor side effects. Only the treatments that are seen as risky or very expensive have rapidly gone in to treatment trials for ME.

But we don't know the side effect or safety profile until something gets trialled, recommended, and then we get the post-marketing data from vast numbers of people. Individual clinicians have no chance of getting a representative picture. When patients are told that they are unlikely to get side effects, that will affect their reporting of side effects back to that clinician, and how that clinician interprets that report.

With LDN, there seems to be an assumption that there will be minimal side effects because it is used in addicts at significantly higher doses. It seems to me that a lot more side effects are reported than you'd expect based on that logic.

I'm glad there are trials happening in ME/CFS now. Given how trials in fibromyalgia are panning out, despite a lot of anecdotal hype, I'll be pleasantly surprised if it works in ME/CFS in any clinically significant way. Polo et al.'s report suggests to me that one area it's unlikely to help is pain - only 17% reported less pain. That could be less than placebo.

That was the major flaw in the PACE trial - they supposedly trialled pacing, but almost all of the participants would have been already pacing, they would have found some balance between activity and rest that did not result in a worsening, and so we would not expect the 'pacing' treatment arm to show any benefits. Ridiculous imposed schedules as in the APT arm is not pacing.

Agree wholeheartedly, @Hutan .

In addition, from the APT manual in the PACE trial, it looks like there was an emphasis on reducing activity. If a person doesn't need to reduce activity, then being encouraged to reduce activity might well reduce functioning. Similarly, if a person is actually able to increase activity, then being encouraged to reduce it or manage it rather than increase it would also show up as inhibiting functioning on a group level.

Too often pacing advice becomes overly complicated, wrapped up in complicated formulae for which there is no good evidence, focusing on the minutiae of scheduled 15 minute rests, and removing people's agency.

Agree. Therapists getting involved has meant a lot of weird rules being introduced that patients often try hard to stick to. It can take a long time to realise, oh right, they're just making stuff up.