Review article: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Where Will the Drugs Come From? 2021, Toogood et al

Yes, this feels like quite a step forward.

A lot of the possibilities were written up rather more positively than I think is warranted though, although I understand that the purpose of attracting interest requires some hopeful statements.

For example this one for NADH and CoQ10: my conclusion from looking at the study was

"The decrease in the fatigue measure after accounting for the placebo effect was about 3% - hardly clinically significant. And, even if there is a real benefit, we don't know if it was the CoQ10 or the NADH, or some synergy between them. And there are potential conflict of interest issues, with the producer of the supplements supporting the study."​

Other evidence for CoQ10 is not convincing.

The paper mentions methylphenidate a couple of times as potentially being of benefit. We have a thread on KPAX2 here with these posted comments"

"the results of the "phase 2 randomized, double-blinded, placebo-controlled trial" on KPAX002 published by Jose Montoya and colleagues [1] that, from an intention-to-treat point of view, reported no significant statistical difference in self-reported group scores of fatigue and other measures between active treatment and a placebo."
"I'm a little bit disappointed that the authors weren't more forthright in how the results weren't statistically significant on any and all measures included for study."
"Finally, once again, I note that under the heading 'Disclosure of conflict of interest', the word 'none' appears as per the last research occasion [2]. Personally, and with no malice intended, I would have listed the detail that at least one of the authors is an employee of the manufacturer of KPXA002 given the affiliation details and email address for further correspondence provided on the paper."​

 

As an off-the-wall and circuitous answer to the question "where will the drugs come from?":

Ciguatera poisoning can cause long term sequelae that look a lot like ME/CFS - fatigue, brain fog and pain, with relapses triggered by exercise. The mechanisms are better, although still not well, understood though, with mention of sodium channels being quasi-permanently disabled by a toxin that attaches to them, with downstream impacts on calcium signalling (with issues with TRP channels, which the Griffiths University team have suggested are involved in ME/CFS). Ciguatera is a significant problem and will become more so with warming seas encouraging the growth of the dinoflagellates that cause the toxin to accumulate in the food chain. It's a medical and food supply problem that needs a solution.

There are communities, such as those in the Pacific Islands, that have been coping with ciguatera poisoning for a long time. They depend on reef fish for protein, the fish that can contain the toxin. While they have traditional knowledge that helps them reduce the risk of poisoning (e.g. 'don't take fish from certain sides of an island in certain seasons'), they have had to regularly deal with it, because there is no way to identify a contaminated fish from its smell or appearance. Papers on ciguatera mention that these communities use specific indigenous plants to treat poisonings. Those plants could be analysed to identify compounds that might be of use.

It might be possible to trial those compounds on cells treated with the ciguatera toxin. Or, if the mechanism is better understood, existing drugs might be able to be repurposed.

Coming up with a treatment that reduces the impact of the acute ciguatera illness, and prevents and treats subsequent chronic illness is a useful thing to do. And, it's probably something that can be achieved, as the molecule causing the problem, and something of the mechanism, is already known. Furthermore, the process of doing that might just possibly also help with the understanding and treatment of ME/CFS. So a drug company that develops a ciguatera drug treatment might have an advantage in developing an ME/CFS/Long Covid drug treatment.

I know it's a highly speculative and, very likely, stupid idea. But we've seen published papers where 'animal models of CFS' have consisted of rats put in buckets and forced to swim until exhaustion. It's not as stupid as that.

 

I've added a thread for it here:
Does Methylphenidate Reduce the Symptoms of Chronic Fatigue Syndrome?, 2006, Blockmans et al