mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

[eljefe19]

@XenForo i can relate to your last paragraph more than you know. I will be joining you on Rapamune as soon as (hopefully) today. Pray for me.

 

[Marky90]

@adreno
thanks mate. anyone know where to buy this online. sounds like a weeks worth should give a good indication

Its a strong immunosupressor, I don think its allowed to sell online?

 

[eljefe19]

Its a strong immunosupressor, I don think its allowed to sell online?

I have a source shipped from India if anyone is interested.

 

[dreampop]

From my dashboard, here on PR, it looks like no one is reading the PM's I had sent. @eljefe19 , @dreampop, @knackers323, check your PM's.

Checked. Did you have a sudden/gradual onset and constant or relapse/remitting symptoms?

 

[XenForo]

Checked. Did you have a sudden/gradual onset and constant or relapse/remitting symptoms?

Sudden onset. Relapse remitting, though it's never really "disappeared" for more than a month at one time.

 

[XenForo]

Argh. I was in bed all day yesterday afternoon and early evening. That day was a total washout. Today my armpit lymph nodes are sore, but I'm back to my new self again. That is a typical "bad" day experience for me (pre Rapamune.) Boo. Hiss. But good news that I rebounded so fast after just one day, and not a week or two months like last time.

 

[Jesse2233]

Argh. I was in bed all day yesterday afternoon and early evening. That day was a total washout. Today my armpit lymph nodes are sore, but I'm back to my new self again. That is a typical "bad" day experience for me (pre Rapamune.) Boo. Hiss. But good news that I rebounded so fast after just one day, and not a week or two months like last time.

That's a good sign! Seems like Rapamune helped you recover more quickly

 

[Jill]

Does anyone know what metronidazole is - is it in anyway a macrolide. I do will on it and wonder how it fits in here

 

[adreno]

If you go back to basics and see AMPK as a primitive intracellular energy sensor, there's logic in thinking its activation should lead to higher Akt, in the context of extracellular nutrients being available, as long as mTorC1 is concurrently inhibited.

One more example of a compound (cordyceps) which seemingly activates both AMPK and Akt/mTOR:

In conclusion, we have successfully confirmed that Cordyceps militaris induces fatigue recovery via activating AMPK and AKT/mTOR pathways and regulating serum hormone level. Our data provides experimental evidence in supporting clinical use of Cordyceps militaris as an effective agent against fatigue.

They do write:

Although our results suggest AKT/mTOR signaling is involved in the antifatigue activities of CM, we fail to explain the relationship between AMPK and AKT/mTOR.

https://www.hindawi.com/journals/ecam/2015/174616/

Would this fit the bill?

 

[adreno]

Also of interest is that cordyceps enhances AMPA receptor activity, which in turn activates BDNF and mTOR, an effect similar to that of ketamine:

Aside from increasing dopaminergic and noradrenergic activity, its antidepressant effects are also attributed to a rapid increase in AMPA receptor activity.[30] In both the prefrontal cortex and the hippocampus, an enhancement of AMPA signaling is seen just 45 minutes after treatment. The effect lasts up to 5 days of treatment. Its effects are akin to that of ketamine which acts via the AMPA receptors in the hippocampus and the prefrontal cortex to upregulate mTOR and BDNF.[31][32] Both mTOR and BDNF increase cell growth and proliferation which in turn increases neurogenesis.

https://www.neuronootropic.com/cordyceps/

 

[Tunguska]

One more example of a compound (cordyceps) which seemingly activates both AMPK and Akt/mTOR:
They do write:
https://www.hindawi.com/journals/ecam/2015/174616/
Would this fit the bill?

They didn't distinguish between mTorC1 and mTorC2, they don't even describe the measurement they used for mTor, so presumably it's one or the other. Some of their statements are strange. If simultaneous I'd think it'd have to be mostly AMPK/mTorC2, which I think might be an under-reported case more than anything. Not impressed by this study.

Also of interest is that cordyceps enhances AMPA receptor activity, which in turn activates BDNF and mTOR, an effect similar to that of ketamine:
https://www.neuronootropic.com/cordyceps/

That one is great information, thanks.

(I haven't tried it and avoided mushroom extracts due to some being 5-AR enzyme inhibitors of varying strength... I don't know if this is; if not, I might try it eventually)

 

[AdamS]

Okay so i'm super confused. I thought mTOR was believed to be under-activated in ME/CFS patients and from memory Davis said in his video NOT to inhibit it...but according to this, inhibiting mTOR does the following:

In summary, we have identified a mitochondrial mTOR complex that appears to function as a cellular switch regulating glycolytic and respiratory metabolism. Inhibiting mTOR, which is now the basis of treatment of certain cancers, enhances aerobic glycolysis and induces a state of increased dependence on aerobic glycolysis in leukemic cells.

I realise that the context is different (Leukemic cells), but isn't this what we want and perhaps why Rapamune/Sirolimus helps?

Oxidation of glucose under aerobic conditions results in 32 mol of ATP per mol of glucose but under anaerobic conditions, only 2 mol of ATP can be produced...the difference is huge.

Maybe this is why alcohol (another mTOR inhibitor) helps me feel like a normal human again within around an hour.

 

[ScottTriGuy]

I have a source shipped from India if anyone is interested.

Yes, please.

 

[Marky90]

I have a source shipped from India if anyone is interested.

I would be interested in the info as well..

 

[cigana]

hi XenForo

have you ever taken any other macrolides, did they have an effect?

i had very good improvement on clarithromycin and azithromycin within a day. and back to hell within a day of stopping. so its unlikely it was due to them killing anything.

its known that macrolides have immunomodulatory effects but do you know if they effect mTOR?

I also had spectacular rapid improvement on high dose azithromycin. Could never figure it out at the time but now I wonder about the mTOR angle.

 

[adreno]

I realise that the context is different (Leukemic cells), but isn't this what we want and perhaps why Rapamune/Sirolimus helps?

I think that info is wrong. Inhibiting mTOR should inhibit glycolysis.

 

[XenForo]

Argh. I saw my GP and they advise against taking an immunosuppressant. I'm going to go off the Rapamune, and try a few less risky treatments recommended by my GP. No fun, but sounds like it might be the best course for me for now I'm not looking forward to the soon-to-come crash. Boo. Hiss.

 

[Jesse2233]

Argh. I saw my GP and they advise against taking an immunosuppressant. I'm going to go off the Rapamune, and try a few less risky treatments recommended by my GP. No fun, but sounds like it might be the best course for me for now "" I'm not looking forward to the soon-to-come crash. Boo. Hiss.

Ah bummer. Why did they advise against it? Were you still having improvements?

 

[XenForo]

Ah bummer. Why did they advise against it? ...

Risk of cancer. It does make sense to me to exhaust other, less risky, options first. I don't have other obvious autoimmune issues going on, that we know of.

I was improving greatly. Except for one crash for most of 1 day, I just kept getting better and better.

 

[nandixon]

Okay so i'm super confused. I thought mTOR was believed to be under-activated in ME/CFS patients and from memory Davis said in his video NOT to inhibit it...but according to this, inhibiting mTOR does the following:



I realise that the context is different (Leukemic cells), but isn't this what we want and perhaps why Rapamune/Sirolimus helps?

Oxidation of glucose under aerobic conditions results in 32 mol of ATP per mol of glucose but under anaerobic conditions, only 2 mol of ATP can be produced...the difference is huge.

In these cancer cells, aerobic glycolysis is considered to be the process of (1) glycolysis followed by (2) the reduction of pyruvate to lactate.

In order to obtain the 30+ moles of ATP you're thinking about, there must be (1) glycolysis followed by (2) mitochondrial respiration (an aerobic process), which means that the pyruvate from glycolysis is converted to acetyl-CoA which enters the Krebs/Citric Acid Cycle and drives the electron transport chain (i.e., the process of oxidative phosphorylation).

In the study you quoted, rapamycin appears to do the opposite of what would be desirable in ME/CFS:

Pyruvate, the end product of glycolysis, can be converted either into acetyl CoA by mitochondrial pyruvate dehydrogenase or into lactate by cytoplasmic lactate dehydrogenase. Inhibition of mTOR by rapamycin increased lactate production in Jurkat cells within 25 min (Fig. 1). We observed no significant changes in glucose consumption at this time point.

In agreement with the hypothesis that inhibition of mTOR shifts glucose metabolism away from mitochondrial respiration, we observed an immediate buildup of intracellular lactic acid.

We found decreased levels of all 6 mitochondrially metabolized organic acids measured following the inhibition of mTOR. Five of these are tri-carboxylic acid (TCA) cycle intermediates; the other, orotic acid, is synthesized in the mitochondria during purine metabolism. This striking decrease in mitochondrial organic acids, in conjunction with diminished oxygen consumption, is indicative of a decrease in mitochondrial metabolism.

Overall, the profile indicates an immediate and profound change in cellular metabolism caused by inhibition of the FKBP12/rapamycin-sensitive functions of mTOR, consistent with enhanced aerobic glycolysis.

The rapamycin-induced increase in lactate production and decrease in uncoupled respiration without detectable change in mitochondrial content led us to hypothesize that inhibiting mTOR diverts the metabolism of pyruvate away from the mitochondria by exerting control over the mitochondrial substrate availability.

So you can see that, assuming rapamycin performs the same way in normal cells as it does in the leukemic cells, then the use of rapamycin in ME/CFS would seem to be a complete disaster based on the Fluge & Mella study, which showed that not enough pyruvate was entering into the Krebs Cycle in the mitochondria due to impairment of the PDH complex.

So either rapamycin must be doing something else that beneficially offsets that seeming disaster, or diversion of pyruvate away from the mitochondria is actually beneficial in ME/CFS.

Other possibilities for why rapamycin might be beneficial include that perhaps a subset of people with ME/CFS are needing increased glycolysis (i.e., production of pyruvate) rather than increased mitochondrial respiration. Or perhaps a subset actually have an undiagnosed autoimmune disease for which rapamycin might be effective.

One thing I'll be interested to see is if the subset of people with ME/CFS who find LDN (low dose naltrexone) helpful is the same subset that responds to rapamycin. (There also may be the possibility of a favorable synergy between rapamycin and LDN.)