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The original was posted on /r/cfs by /u/Numerous_Mammoth838 on 2024-11-16 20:20:28+00:00.

Hey again! I’m really trying to wrap my head around the whole hypothesis and its implications.

Bottom line Na/K-ATPase (NKA) doesn’t seem to work properly under high load due to beta2 receptor downregulation. Leading to Na and subsequent Ca overload and mitochondrial damage.

I’ve read this paper on NKA regulation in skeletal muscle. You’ll find the beta2 receptor mentioned in the paragraph about catecholamines.

More interesting - NKA is activated or upregulated by many more mechanisms. Some of which are insulin, AMPK and aldosterone.

Here’s where my idea comes in. Admittedly, it’s still very fresh and I haven’t had the mental resources to look into all the pathways involved properly. Please chime in if you have deeper knowledge. Here we gooo (shout-out to Dak):

We know that metformin activates AMPK and increases insulin sensitivity. We also know that fludrocortisone is a mineralocorticoid like aldosterone and it has higher affinity to MR than cortisol, cortisone and aldosterone (I asked Claude.ai about this, as I couldn’t find this in a quick search - so take it with a grain of salt!). Fludrocortisone should thus have an effect on the kidney (helps with POTS) by activating NKA there and it should also have an effect on skeletal muscle NKA.

Interestingly enough, both insulin and aldosterone increase the NKA isoform (alpha2beta1) that is associated with activity during exercise and not with the isoform (alpha1beta1) that’s activated basaly in “idle”.

I know these drugs doesn’t sound magical at all, as they are already used in ME, but I am not sure if they have been tested together? Does anybody have experience with metformin and fludrocortisone? Has anybody on fludrocortisone noticed less PEM and more vigor during exercise?

Finally, another substance I would like to point out is Zembrin. Supposedly a naturally occurring SSRI and PDE4 inhibitor. The latter is very interesting. Here PDE4 inhibition was linked to NKA activity increase. Meditocure is working on a PDE7 inhibitor, which would have similar effects on NKA as a PDE4 inhibitor. Another PDE4 inhibitor - ibudilast - is currently in trials. Very interesting. Has anybody tried Zembrin (25-100 mg per day) and can report any changes?

I’m doing this literature research to find alternatives to Meditocure and waiting another 10 years. Brainfog unfortunately didn’t allow me to go deeper into it yet, but I will do and will refine the hypothesis if there’s anything to it.

Hoping for feedback and discussion!

TLDR: Fludrocortisone, Metformin and/or Zembrin could maybe help? These drugs do not affect the beta2 downregulation (and thus diminished NKA activity) but might upregulate NKA through alternative pathways.