The Synergy Trial: Phase 2 results out

[nanonug]

I doubt it's the primary culprit.

Sure, PDH impairment is most likely a consequence of "something." The problem is that currently we don't know what that "something" is. Therefore, and until then, addressing what we know which is PDH impairment makes sense to me. That's why I take DCA and successfully so. In my case, nothing else has the same dramatic effect.

It's interesting to note the similarities and differences between cfs and pyruvate dehydrogenase complex deficiency. In both, there's too much lactic acid, and fatigue, but with the latter, its a lot more severe, not to undermine cfs. But in the latter people die often very young from the lactic acidosis.

This argument was raised by Bliksrud here: https://tidsskriftet.no/en/2017/12/...yndrome-and-pyruvate-dehydrogenase-deficiency

And addressed by Tronstad/Fluge/Mella here: https://tidsskriftet.no/comment/11354

Thiamine, especially high dose, may serve a similar purpose as DCA. Lipoic acid, biotin also.

None of the things you mention inhibit the various pyruvate dehydrogenase kinases. DCA, on the other hand, does.

 

[frozenborderline]

Sure, PDH impairment is most likely a consequence of "something." The problem is that currently we don't know what that "something" is. Therefore, and until then, addressing what we know which is PDH impairment makes sense to me. That's why I take DCA and successfully so. In my case, nothing else has the same dramatic effect.



This argument was raised by Bliksrud here: https://tidsskriftet.no/en/2017/12/...yndrome-and-pyruvate-dehydrogenase-deficiency

And addressed by Tronstad/Fluge/Mella here: https://tidsskriftet.no/comment/11354



None of the things you mention inhibit the various pyruvate dehydrogenase kinases. DCA, on the other hand, does.

Yes, they don't inhibit the pyruvate dehydrogenase kinases, but they are used for treatment of impaired PDH/reductive stress.

I personally doubt they'd be enough, but it seems like there's real concern about DCA toxicity. Doesn't it basically inhibit aerobic and anaerobic glycolysis? That's a big deal.

Nevertheless, it's cool that people are experimenting with it, and the fact that you get dramatic results from it is illuminating just in terms of solidifying the idea that there's an issue with PDH/reductive stress that is possible to treat. I only hope that less toxic treatments can come out of further study.

My initial objection was toward making a definitive statement that DCA is the only thing that is likely to help. The forum is loaded with stories of people getting dramatic relief with everything from thyroid hormone to IVIG, to high dose b supplementation.

 

[frozenborderline]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102924/

Even if PDH was considered the main issue, there may be less toxic treatments than DCA, like phenylbutyrates

 

[nanonug]

but it seems like there's real concern about DCA toxicity.

I detail my particular experience with DCA here, in which I also address toxicity: From brain fog to clarity in 30 minutes. That particular thread is actually misnamed now given that at my current dosage of DCA (1.5g/day) there is zero brain fog: I wake up from sleep fully energized. And there might even be an explanation for that, here: Sleep and Brain Energy Levels: ATP changes during sleep.

Doesn't it basically inhibit aerobic and anaerobic glycolysis?

DCA makes sure pyruvate is converted to acetyl-CoA instead of lactate. Acetyl-CoA is subsequently fed into the Krebs cycle leading to the production of ATP in the mitochondrial electron transport chain. With DCA, you get less lactate and more ATP. Note that DCA doesn't inhibit the production of lactate, it simply prevents most of the pyruvate from ending up converted to it. This is due to the fact that pyruvate dehydrogenase is subject to product inhibition: too much acetyl-CoA will inhibit pyruvate dehydrogenase. This works as negative feedback to prevent over-production of acetyl-CoA.

My initial objection was toward making a definitive statement that DCA is the only thing that is likely to help.

Understood, although you keep forgetting that what I said was "anything without dichloroacetate will probably won't help a great deal." (I'm even keeping the broken English!) Note my use of "probably" and "a great deal." This assertion of mine is based on Fluge et al conclusion that:

"The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by
increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4"
​

Increased expression of the various PDKs is not the same as PDH deficiency. As such, what might work for a genetic PDH deficiency won't necessarily work for increased PDK expression.