Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Hip]

@nandixon
More on ketamine as a mTOR activator: this study says ketamine induces mTOR activation:

There is an inverted U-shape associated with ketamine-induced mTOR activation, with higher doses having no effect.

So with ketamine, as with leucine/glutamate, there seems to be an optimum dose, and if you go higher, you lose the effect.

They also mention that:

other antidepressants, including 5-HT2C receptor antagonists, citalopram ... all increase mTORC1 levels

However, the SSRI, sertraline, and the TCA, imipramine, actually have anti-proliferative effects that are mediated by inhibition of mTOR

However, this idea that boosting mTOR may be helpful in ME/CFS does not fit in with the fact that azithromycin inhibits mTOR, yet azithromycin is considered a useful immunomodulator drug for treating ME/CFS.

 

[A.B.]

yet azithromycin is considered a useful immunomodulator drug for treating ME/CFS.

According to whom?

 

[temple88]

However, this idea that boosting mTOR may be helpful in ME/CFS does not fit in with the fact that azithromycin inhibits mTOR, yet azithromycin is considered a useful immunomodulator drug for treating ME/CFS.[/USER]

I find this interesting. High dose clarithromycin (also a macrolide-same class as azithro) is the only thing that has ever reversed my cfs. And I don't just mean it helped, it completely eliminated all symptoms and I was perfectly well. Effect lasted a week. This has happened twice in 12 years.

 

[adreno]

I find this interesting. High dose clarithromycin (also a macrolide-same class as azithro) is the only thing that has ever reversed my cfs. And I don't just mean it helped, it completely eliminated all symptoms and I was perfectly well. Effect lasted a week. This has happened twice in 12 years.

This may be due to mehanisms totally unrelated to mTOR inhibition.

 

[temple88]

This may be due to mehanisms totally unrelated to mTOR inhibition.

Very true. If I knew the mechanism involved, I'd be well and on my way.

 

[Hip]

According to whom?

See Azithromycin in Chronic Fatigue Syndrome (CFS), an analysis of clinical data

I find this interesting. High dose clarithromycin (also a macrolide-same class as azithro) is the only thing that has ever reversed my cfs. And I don't just mean it helped, it completely eliminated all symptoms and I was perfectly well. Effect lasted a week. This has happened twice in 12 years.

That's interesting, because when I was taking a course of erythromycin (also a macrolide) 800 mg plus ampicillin 500 mg daily, I noticed that the PEM I get from social interaction was noticeably reduced.

In my experiments with azithromycin, this also seemed to help a bit: I felt less groggy, and sleep seemed more refreshing. Nothing major though, just minor improvements.

Azithromycin is a bit expensive, but erythromycin is quite cheap, so at some point I want to try erythromycin again, to see if I can get the same results.

The macrolides roxithromycin, erythromycin, clarithromycin and azithromycin have been shown to inhibit IL-1β, TNF-α and IL-6 (the sickness behavior cytokines). Ref: 1 (full text).

And amoxicillin significantly decreases IL-6 plasma levels by the 7th day of therapy. Ref: 1

 

[Hip]

Note: in my post above it says that 5-HT2C receptor antagonists increase mTORC1 levels (though I am not sure if this is the same as increasing mTORC1 activation), so the following may be helpful for increasing mTOR:

5-HT2C Antagonists (boost mTORC1):

Agomelatine
CEPC
Eltoprazine
Etoperidone
Fluoxetine
Methysergide
Nefazodon
Norfluoxetine
O-Desmethyltramadol
Tramadol
Trazodone — this is used to improve sleep in ME/CFS and fibromyalgia


5-HT2C Receptor Inverse Agonists should boost mTORC1 as well; these include:

Mirtazapine — improves fibromyalgia symptoms as well as depression. Ref: 1
Amitriptyline
Quetiapine

Source: here.

 

[Snow Leopard]

Sorry to be a party pooper, but many of the GPCR pathways can potentially lead to mTORC activation (lots of signals lead to mTORC pathway activation!). It is far too nonspecific to expect that stimulating one of these pathways selected without particular reasons (eg without evidence that the particular pathway is dysfunctional), if that pathway is functioning correctly, then you will be shifting it into dysfunction, potentially causing problems if the cells feedback loops are insufficient.

 

[Hip]

@Snow Leopard Are you alluding to G-protein-coupled receptor desensitization?

 

[nandixon]

Sorry to be a party pooper, but many of the GPCR pathways can potentially lead to mTORC activation (lots of signals lead to mTORC pathway activation!). It is far too nonspecific to expect that stimulating one of these pathways selected without particular reasons (eg without evidence that the particular pathway is dysfunctional), if that pathway is functioning correctly, then you will be shifting it into dysfunction, potentially causing problems if the cells feedback loops are insufficient.

(My bold in the above.) Yes, any focus on activating mTORC1 - for purposes of improving PDH complex function, for example - has to consider this. That's why we really need to identify and fix the problem further upstream that's causing the under-activation of mTORC1.

 

[adreno]

Another example of a pathway that stimulates mTOR is through angiotensin. Mine is always low, and I have no idea why, except perhaps because of high NO. It really is problematic in terms of OI.

 

[J.G]

However, this idea that boosting mTOR may be helpful in ME/CFS does not fit in with the fact that azithromycin inhibits mTOR, yet azithromycin is considered a useful immunomodulator drug for treating ME/CFS.

I find this interesting. High dose clarithromycin (also a macrolide-same class as azithro) is the only thing that has ever reversed my cfs. And I don't just mean it helped, it completely eliminated all symptoms and I was perfectly well. Effect lasted a week. This has happened twice in 12 years.

This may be due to mehanisms totally unrelated to mTOR inhibition.

These words from Naviaux's Q&A come to mind:

Some patients do better on drugs that we would consider to be inhibitors of mitochondrial function. This may not have anything to do with the conventional pharmacologic classification of the drugs as antibiotics, antivirals, anticonvulsants, antidepressants, neuroleptics, or anticholesterol agents. Most drugs have metabolic effects beyond their primary action. Because the field of metabolomics is so new, these “pharmacometabolomic” effects of drugs have not yet been studied well.

There is more detail in Q&A question 7. Link here.

 

[nandixon]

However, this idea that boosting mTOR may be helpful in ME/CFS does not fit in with the fact that azithromycin inhibits mTOR, yet azithromycin is considered a useful immunomodulator drug for treating ME/CFS.

That's the first seeming inconsistency I've seen in the many dozens of papers I've read related to the hypothesis in my signature.

The study seems valid to me (they appear to be demonstrating direct inhibition of the enzyme), but we don't want any further inactivation of mTORC1 (that'll make the PDH problem worse), and we probably don't want any further T cell suppression (Tregs have been shown to be high in several ME/CFS studies), both of which azithromycin (AZM) causes.

It's just a guess but perhaps the favorable effect of AZM in ME/CFS might possibly be due to its antibiotic action, perhaps by altering the gut microbiome.

I actually tried AZM in the late 1990's (when it wasn't generic yet and very expensive), when I had a bacterial infection and I found that it made my ME/CFS symptoms significantly better, but it only lasted for a few days.

I noticed the same effect years later from the antibiotic Xifaxin (rifaximin), which supposedly has negligible systemic absorption and only acts in the gastrointestinal tract, suggesting that both it and AZM might be having a beneficial effect on the gut microbiome. Not sure though, of course.

 

[eljefe19]

Drugs listed at the bottom promote ceramide elevation by hindering glycosylation via the glucosylceramide synthase (gcs) route (ketoconazole, our unpublished data).

Most of these drugs are pretty serious and side effects probably outweigh the benefits. However, I recognized Toremifene as it's a SERM sold on ceretropic. Tamoxifen is a SERM as well, and as far as I can tell both have excellent safety and side effect profiles. Food for thought.

 

[Hip]

It's just a guess but perhaps the favorable effect of AZM in ME/CFS might possibly be due to its antibiotic action, perhaps by altering the gut microbiome.

Yes, that occurred to me too: that the benefits of azithromycin for ME/CFS may outweigh its anti-mTOR effect.


I've just been reading some of the latest NIH research on ketamine for depression: the latest finding is that ketamine itself does not have an antidepressant effect, but rather its metabolite hydroxynorketamine (HNK) is responsible. The antidepressant mechanism is thought to involve mTOR activation, and HNK is a far more potent mTOR activator than ketamine.

There is a good article about HNK here: NIMH » Ketamine Lifts Depression via a Byproduct of its Metabolism

The advantage of HNK is that unlike ketamine, HNK has no anesthetic, dissociative or addictive side effects; so as a treatment for depression, and as an mTOR activator, HNK is superior to ketamine.

I could not find HNK for sale (apart from at very expensive chemical suppliers), but I would not be surprised if one of these websites selling so called "research chemicals" offer it soon.

 

[nandixon]

I just posted this on the relevant thread:

For the other scientists out there, the present study appears very consistent with the impaired sphingosine-1-phosphate (S1P) signaling hypothesis (see my signature), and I believe the findings are what would be expected if either S1P levels are too low or if there are autoantibodies against a S1P receptor.

S1P signaling is a critical regulator of intracellular calcium concentration/flux and is mediated by S1P both through its receptors (e.g., S1PR1 aka S1P1) on the cell surface and also within the cell itself independently of any receptor. (There are several dozen potential references. See this PubMed search string.)

So, IMO, the TRPM3 receptors are not going to be the primary problem here, but rather impaired S1P signaling, and the modest reductions in function that any single nucleotide polymorphisms (SNPs) in the TRPM3 gene may be making are likely just exacerbating the problem.

 

[JES]

Another study related to S1P that I bumped into:

Researchers have discovered that a trace substance found in caramelized sugar and cola improves regeneration in mice suffering from Duchenne muscular dystrophy (DMD).

Scientists from the Reyes and Ruohola Baker laboratories at the University of Washington discovered that when the sugar substance, a small molecule called 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), was injected into mice suffering from the muscular disease, muscle regeneration was improved.
...
Prior to experimenting on the mice, the researchers discovered that a "pathway" in fruit flies, called sphingosine 1-phosphate (S1P), is critical in improving the effects of muscular dystrophy in the insects.

 

[nandixon]

I've just been reading some of the latest NIH research on ketamine for depression: the latest finding is that ketamine itself does not have an antidepressant effect, but rather its metabolite hydroxynorketamine (HNK) is responsible. The antidepressant mechanism is thought to involve mTOR activation, and HNK is a far more potent mTOR activator than ketamine.

Great find! It's very interesting (understatement) that the effectiveness of ketamine - Dr Jay Goldstein's #1 drug choice after having treated thousands of ME/CFS patients - is measured in various studies in terms of its ability to upregulate mTORC1. And that the Fluge & Mella study is strongly suggesting that mTORC1 is under-activated as the reason for the PDH complex impairment. That seems quite a coincidence if it is one.

That ketamine metabolite, HNK, looks very promising.

 

[Hip]

Dr Jay Goldstein's #1 drug choice after having treated thousands of ME/CFS patients

Yes, ketamine was part of Dr Goldstein's "resurrection cocktail." Though from what I understand, Goldstein's ME/CFS therapies tended to be these flash in the pan type treatments, which worked initially but did not work on a long term basis (and I am sure if regular ketamine treatment provided long term remission or amelioration from ME/CFS, we would all know about it). But if ketamine did work even temporarily for ME/CFS, it's worth trying to figure out why, and mTOR would seem a good place to explore.

 

[MeSci]

Another study related to S1P that I bumped into:
Researchers have discovered that a trace substance found in caramelized sugar and cola improves regeneration in mice suffering from Duchenne muscular dystrophy (DMD).

Scientists from the Reyes and Ruohola Baker laboratories at the University of Washington discovered that when the sugar substance, a small molecule called 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), was injected into mice suffering from the muscular disease, muscle regeneration was improved.
...
Prior to experimenting on the mice, the researchers discovered that a "pathway" in fruit flies, called sphingosine 1-phosphate (S1P), is critical in improving the effects of muscular dystrophy in the insects.

I'm sure that "mice suffering from the muscular disease", although repeated numerous times in articles, is an inaccurate way of reporting the finding. It's quite likely to be a quote from a report from the establishment that carried out the study, and they really should know better.

Mice do not suffer from Duchenne muscular dystrophy.

The finding may translate to humans, but it's just as likely not to. As for fruit flies...