Darigabat

[Verity]

Many patients report benefit from taking benzodiazepines both during exertion to prevent/reduce PEM and during PEM to reduce symptoms. In my opinion, benzos have by far the strongest anecdotal signal in ME, and we should pay attention to them. For obvious reasons, though, they are not good candidates for taking daily.

There’s an investigational benzo-like drug called darigabat (Wikipedia link) that is thought to be less dependence-forming (paywalled source) based on animal studies. It seems to be a drug in want of a disease. It’s been tested for a few things and did well in a small trial for photosensitive epilepsy but failed for anxiety and chronic pain (source). Given that we may be most interested in its excitability-reducing properties, the fact that it failed in the latter two disorders doesn’t seem like a big problem.

A drug that could reproduce the effects of benzos for patients and be taken daily could be a huge step forward. Does anyone else think this drug is a good candidate for testing in ME?

 

[Kitty]

I don't know about benzodiazepines, but tramadol is excellent at reducing moderate PEM symptoms. So good that it's potentially unhelpful.

It's apparently not a straightforward painkiller, it also acts on the serotonin system. I don't really understand it, but DHC never gave me that effect. I had to stop taking that over a decade ago because the drug is bulked up with lactose, which gives me IBS. I switched to tramadol instead.

 

[Trish]

@Verity, can you please link the sources of this information?

 

[Verity]

@Trish Done! Unless you meant sources for the patient reports of benefits from benzos. Those are just all over ME forums. Let me know if you were wanting links to some of those instead.

 

[Trish]

@Trish Done! Unless you meant sources for the patient reports of benefits from benzos. Those are just all over ME forums. Let me know if you were wanting links to some of those instead.

Excellent, thanks, that's what I was asking for.
No I don't expect you to find the benzos links on the forum.

 

[Dude]

That's an interesting finding!

There is a review by Wirth and Scheibenbogen discussing a possible imbalance between excitatory and inhibitory neurotransmitter systems in ME/CFS, particularly glutamate and GABA:

Wirth & Scheibenbogen – Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in ME/CFS

I'm also interested in an MRS study that found elevated glutamate levels in ME/CFS and Long COVID:

MRS study – Glutamate abnormalities in ME/CFS and Long COVID

Theoretically, increased GABAergic signalling could help counterbalance excessive excitatory neurotransmission.

Against this background, the medication could potentially represent an interesting therapeutic approach.

Other drugs targeting the glutamatergic system were already used in clinical practice for ME/CFS by J. Goldstein (see his book Betrayal by the Brain). Examples include pregabalin (also at higher doses) and lamotrigine.

In my opinion, riluzole (for ALS) could also be an interesting candidate, as it reduces glutamatergic neurotransmission through several mechanisms.

I've looked into these connections some time ago. I've also been trying to get access to lamotrigine for quite a while, unfortunately without success so far.

 

[Verity]

Other drugs targeting the glutamatergic system were already used in clinical practice for ME/CFS by J. Goldstein (see his book Betrayal by the Brain). Examples include pregabalin (also at higher doses) and lamotrigine.

In my opinion, riluzole (for ALS) could also be an interesting candidate, as it reduces glutamatergic neurotransmission through several mechanisms.

Thanks for the links! I’ve been looking into other drugs that might do this sort of thing as well. I think lamotrigine is common enough that we’d know if it worked for a lot of people, but I would think riluzole has to be next to impossible to get, so I doubt many people have tried.

 

[Verity]

If I wanted to approach someone about testing this, does anyone have suggestions for ME doctors who are known to prescribe benzos and who have drug trial experience?

I really think this is worth pursuing. Some very severe patients describe benzos as a miracle drug. Even if it wasn’t a cure, having the option of one that can be taken daily could be huge for them.

 

[bicentennial]

I don't really understand it, but DHC never gave me that effect. I had to stop taking that over a decade ago because the drug is bulked up with lactose, which gives me IBS. I switched to tramadol instead.

@Kitty, I was told on the good authority of a pharmacist, that a GP can prescribe for the pharmacist to obtain from a specialist laboratory, a special drug formulation without ingredients that aggravate their patient.

 

[bicentennial]

In my opinion, benzos have by far the strongest anecdotal signal in ME, and we should pay attention to them. For obvious reasons, though, they are not good candidates for taking daily. ... A drug that could reproduce the effects of benzos for patients and be taken daily could be a huge step forward. Does anyone else think this drug is a good candidate for testing in ME?

@neophyte32, when and if you easily can, your anecdotal signalling observations could be apreciated, here. And maybe you know of some interested doctors for:

If I wanted to approach someone about testing this, does anyone have suggestions for ME doctors who are known to prescribe benzos and who have drug trial experience?

I really think this is worth pursuing. Some very severe patients describe benzos as a miracle drug. Even if it wasn’t a cure, having the option of one that can be taken daily could be huge for them.

 

[V.R.T.]

This is exciting and I would be thrilled if something like this could improve my situation and the situation of other pwME.

But I also want to point out that oxycontin was originally marketed as much less addictive than other opiates, so we should be cautious about taking what pharma companies say about addictiveness at face value.

 

[neophyte32]

Yes, I think benzodiazepines are probably among the medications that provide the greatest relief for some patients with severe or very severe ME/CFS.

There are countless patient reports supporting this, and I don't think we can simply dismiss them all by systematically attributing the improvements to the placebo effect. Of course, we still lack rigorous clinical trials to establish their actual effectiveness, but the improvements reported by some patients are sometimes remarkable.

It's somewhat similar with LDA (low-dose aripiprazole), which can produce absolutely spectacular improvements in some patients, only to unfortunately lose its effectiveness after a few weeks or months. A lucky few manage to maintain these benefits for years. Those people really are blessed by the gods!

As for darigabat, I looked into it and, unfortunately, its development appears to have been abandoned. Apparently, no further trials are planned. It's a real shame, because its mechanism of action on GABA-A receptors could have been particularly interesting. I would love to see an ME/CFS researcher consider studying it.

Because while we wait to understand the true mechanisms underlying our disease, and perhaps identify therapeutic targets that could at least partially restore normal functioning of the central nervous system, we desperately need effective symptomatic treatments.

Not necessarily to cure us immediately, but simply to help us hang on. To get through the next five or ten years without having to endure an existence so unbearable that some patients eventually consider euthanasia.

Personally, I have to admit that I wish I could benefit more from the effects of benzodiazepines. At the moment, I only take a very small dose in the evening to help me sleep. But I completely understand why some very severe patients seek more consistent relief throughout the day, even though the risks of tolerance, dependence and withdrawal make long-term use particularly complicated.

I'm thinking especially of the testimony of a formerly very severe German patient named Martin, who spent five or six years confined to his bedroom and was even tube-fed for a period of time. He attributes a significant part of his recovery to a combination of lorazepam (Ativan, more than 4 mg per day) and pregabalin (more than... 1,000 mg!), at doses he describes as extremely high. Of course, I cannot verify these dosages, and they should absolutely not be seen as examples to follow.

What strikes me most about his story is how long his improvement has lasted. It has now been around three years since he reportedly moved from very severe ME/CFS to a moderate state, sometimes even mild. And these improvements seem to have been sustained.

Of course, a patient testimony, however impressive, is not scientific evidence. But I do think that observations like this deserve to be seriously investigated rather than simply ignored.

And once again, this brings me back to the central nervous system. If certain medications acting on neurotransmission can produce such significant functional improvements, what might that tell us about the mechanisms underlying ME/CFS?

Once again, this seems to fit with Professor Edwards' hypothesis that ME/CFS might fundamentally be a disorder of hypothalamic function.

 

[Verity]

But I also want to point out that oxycontin was originally marketed as much less addictive than other opiates, so we should be cautious about taking what pharma companies say about addictiveness at face value.

Yes, this is very much something that has been in my mind while considering this idea. The animal data does look good compared to benzos, but of course that’s animals.

@neophyte32 Thank you for all that info! I think a researcher may still be able to get access to darigabat if they wanted to from what I understand.

I really wish one of the ME doctors who prescribes benzos for severe patients would publish a case series on them. It concerns me that this major drug effect is essentially invisible to pharma companies because it isn’t in the literature. Someone shopping around for a matching disease for a drug would never come across it.

And I agree with you, we need symptomatic treatments even if they’re not treating the root of the disease. Look at narcolepsy—they just got a much better drug, but at least they had something for years before that.

Also, am I remembering correctly that you are French? Have you ever heard of any ME patients trying etifoxine?

 

[Verity]

I have identified one physician who I believe has done some unpublished research on benzodiazepines in ME. Will be reaching out.

 

[fst]

Have you ever heard of any ME patients trying etifoxine?

I tried a short course of it due to my good experiences with Ativan. Wanted something similar but suitable for long-term use / less risk of dependence.

Unfortunately, there was no effect at all. Didn't sleep better, no improved light/sound sensitivity, not sure if it had an effect on PEM either. Basically none of the benefits I get from Benzos.

Drugs like Etifoxine, Darigabat, and also Riluzole have been disappointing in most trials. Sometimes they may target the wrong mechanism and would work better for a different condition, but more often I think they just aren't very effective.

 

[Kitty]

@Kitty, I was told on the good authority of a pharmacist, that a GP can prescribe for the pharmacist to obtain from a specialist laboratory, a special drug formulation without ingredients that aggravate their patient.

Yes, but if there's a straightforward alternative it makes sense to try that first. Turned out it worked a lot better, fortunately.

As for conventional benzodiazepines: my view is somewhat coloured by having spent seven years recovering from addiction to lorazepam! It was prescribed for ME/CFS when I was still a child, with no clinical rationale and no warning about the severe risk of dependence and potential for long term side effects after withdrawal. The late Viv Stanshall once described it as being more addictive than heroin, and even if the two aren't directly comparable I have some sympathy with his view.

Lorazepam didn't help in the slightest with ME/CFS, it just made me feel thick-headed, emotionless, and even more exhausted than I'd been before. A fairly low dose (2mg) was enough to make my memory hazy and create gaps that I've never recovered. My risk awareness was impaired too, leading to a couple of accidents and an assault by someone I'd never have allowed into my flat if I'd been properly alert.

Apart from research, the only application I can see for my illness would be to reduce the "wired and tired" phenomenon I get in the opening stages of PEM. But the effect would reduce with habituation and those symptoms are a good reminder to avoid PEM anyway, so it wouldn't be worth the risk.

 

[Verity]

Drugs like Etifoxine, Darigabat, and also Riluzole have been disappointing in most trials.

I would hesitate to lump darigabat in with etifoxine. Darigabat has actually been shown to significantly enhance GABA-A receptors, and I don’t think that’s actually been shown for etifoxine.

What we don’t know if is α1 modulation is required for the effect on PEM. I think darigabat would be worth testing in part to elucidate this, although it wouldn’t be a clean test.

 

[fst]

I would hesitate to lump darigabat in with etifoxine. Darigabat has actually been shown to significantly enhance GABA-A receptors, and I don’t think that’s actually been shown for etifoxine.

Would something like this count?

My point is, it's a drug that was supposedly dropped for lack of efficacy for indications where we know GABA-A modulation works, because other approved drugs do it. So chances are, it's just not a good drug.

What we don’t know if is α1 modulation is required for the effect on PEM.

That might be, but if it's about trials, I would make sure that Benzos actually work first.

 

[Verity]

Would something like this count?

My point is, it's a drug that was supposedly dropped for lack of efficacy for indications where we know GABA-A modulation works, because other approved drugs do it. So chances are, it's just not a good drug.

I’m a little too crashy to read that right now, but I’ll come back to it! Thanks for linking it.

I will go back and look some other time, but I was not convinced its particular failures meant much for our purposes. When it was tested along with lorazepam in benzodiazepine-responsive photosensitive epilepsy, it did fine. I think what we’re interested in is whether patients known to be benzodiazepine-sensitive respond to it. I’m not too worried about it failing for treatment-resistant generalized anxiety disorder.