mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

Jesse2233

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Keeping track of those taking rapamycin...

XenForo - major response
eljefe19 - major response
made_lman / Dallas patient #1 - major response
Ken Lassen blog reader - major response

Dallas patient #2 - positive response of unknown degree
Dallas patient #3 - positive response of unknown degree
Dallas patient #4 - positive response of unknown degree
Dallas patient #5 - positive response of unknown degree

perovyscus - discontinued

nandixon - pending
Hip - pending

steve4andrea - no response
Montoya Reddit patient - no response
BadPack - no response
 
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Tunguska

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What would be the benefit of adding the arginine? It activates mtor doesn't it? While Rapamycin inhibits it.
Arginine is a substrate first and I'd expect Rap to divert its metabolism, and the biggest change would be in macrophages.

Since the current state is less than clear I don't know if the result would be good or bad - that's the question - or strong enough, but I'd expect something. It's also just a popular supplement on the forum (that F&M talked about reluctantly).

[You could also try this with any other high-dose amino to see what happens to their metabolism when mTor is ablated]
 

Tunguska

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I should be clearer on the bad part: the shift in macrophages is toward iNOS production. If it's not being used productively, then it's purely doing damage. (the regular cells need NAD+ and ROS scavengers to survive it)

At the extreme it could be a reason for a low-arginine diet and supplementing Lysine while on Rap.

It would probably be safer to try high-dose Lysine or another amino before Arginine for experimentation purposes.
 

Jesse2233

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From Ken Lassen's blog on the microbiome altering affects of Rapamycin

https://www.google.com/amp/s/cfsrem...lide-sirolimus-a-gut-altering-antifungal/amp/

Sirolimus (INN/USAN), also known as rapamycin, is a macrolide compound” [wikipedia]

We know the general characteristic of macrolides.. favorable shifts in the microbiome [post] and this family is also used by MDs Jadin and Botelo in their protocols for CFS and other related conditions. As with strains with probiotics, each member of a antibiotic family has it’s own characteristics.

Sirolimus is well studies (18K articles on pubmed)

  • “a large number of small molecules such as farnesol, fatty acids, rapamycin, geldanamycin, histone deacetylase inhibitors, and cell cycle inhibitors have been reported to modulate the yeast-to-hypha transition in C. albicans.” [2011, Full Text]
    • “Rapamycin, a hydrophobic macrolide produced as a secondary metabolite by the soil bacterium Streptomyces hygroscopicus, was initially discovered as an antifungal agent against C. albicans (139).”
  • “Rapamycin markedly prolonged lifespan and health span in cancer- and infection-prone mice supporting disease mitigation as a mechanism for mTOR suppression-mediated longevity extension. It modestly altered gut metagenomes,” [2015]
  • Chronic Repression of mTOR Complex 2 Induces Changes in the Gut Microbiotaof Diet-induced Obese Mice[2016]. [Full Text]
    • ” the abundance of unclassified Marinilabiliaceae and Turicibacterdecreased in response to .. rapamycin (mTOR).”
    • “Mechanistic target of rapamycin (mTOR) is a central regulator of energy storage and consumption, and is implicated in deleterious states such as cancer, metabolic diseases and ageing17. Because over-activation of mTOR complex 1 (mTORC1) signaling by excessive energy intake plays a crucial role in metabolic disorders17,”
    • “rapamycin changed the relative abundances of Turicibacter, unclassified Marinilabiliaceae, Alloprevotella, unclassified Porphyromonadaceae, Ruminococcus, Bifidobacterium, Marvinbryantia, Ruminococcus (Lachnospiraceae), Helicobacter, and Coprobacillus to those observed in HFD-fed mice”
 

Hip

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I have ordered some rapamycin, which should be arriving within a week. So I will be testing it soon.

I am thinking about taking a dose of 3 or 4 mg of rapamycin each week, but I am also going to be drinking grapefruit juice, because as was mentioned earlier in this thread, drinking 8 ounces (around a quart of a liter) of grapefruit juice a day increases rapamycin blood levels by 350%. See this article.

So in effect, by drinking grapefruit juice daily, my 4 mg of rapamycin per week will be equivalent to 4 x 350% = 14 mg per week (= 2 mg per day).

Grapefruit juice inhibits the liver enzyme CYP3A4 which metabolizes many drugs, including rapamycin.

And if you take more potent CYP3A4 inhibitors such as ketoconazole, the article says that this drug was found to raise blood levels of rapamycin by 500%. Clarithromycin and itraconazole are also potent CYP3A4 inhibitors, so may raise rapamycin blood levels by a similar amount to ketoconazole. See the list of CYP3A4 inhibitors here.


Thus grapefruit juice makes the rapamycin protocol much cheaper. Rapamycin costs around $6 per 1 mg tablet. So if I were taking 14 mg weekly, that would cost $84 per week. But using grapefruit juice, you can get the same effect from 4 mg weekly, which costs $24 per week — thus a big saving.

The oral bioavailability of rapamycin is modestly increased (by 35%) by taking the tablets with a high fat meal. Ref: 1 So it would seem to be a good idea to take rapamycin with your main meal of the day. @XenForo has also reported that "rapamune didn't seem to work at all" unless it was taken with fatty food (see this post and this post).



How Quickly Do The Benefits of Rapamycin Appear?

@eljefe19, who had a major response from rapamycin at a dose of 1 mg a day, told me that he only began to see initial improvements in his ME/CFS symptoms after around 5 weeks of rapamycin, and then things continued to improve further over the following months. He has recently gone up to 2 mg per day.

Similarly, @Joe Smoe, taking a rapamycin dose of 5 mg once a week, started to see dramatic improvements after around 4 to 6 weeks. See this post.

Marcia (the first ME/CFS patient to post about the major benefits she observed with rapamycin), saw significant improvement in physical and cognitive functionality after one month on rapamycin at 2 mg per day. See her comment on Health Rising here. Marcia later reduced her dosage to 2 mg three times per week, with no decline in function or increase in symptoms (reports @Jesse2233 in this post). On this forum, Marcia goes by the username of @made_lman.

@XenForo takes a dose of 0.5 mg daily (see this post), but tends to start and stop rapamycin. Once, when re-starting this drug, he/she said it took 10 days for the benefits to re-manifest (see this post); but @XenForo does not say how long the improvements in ME/CFS symptoms took to manifest when first starting rapamycin. @XenForo also found that the benefits of rapamycin persisted for several weeks even after stopping the rapamycin, and there were even further continued improvements after stopping (see this post).


From these above accounts, it sounds like the benefits of rapamycin appear at around the one month stage; sometimes these benefits can be initially small at this stage (as in @eljefe19's case) and then further improvements appear later; but in other cases, major improvements in ME/CFS will have manifested by the one month point.

So in order to adequately test rapamycin, to see if it may benefit your ME/CFS, a trial of one or two months would appear to be a good idea, based on the above reports.
 
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Hip

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Is this your first time trailing an immunosuppressant?
Yes, it is the first time, apart from some very brief tests using low dose hydrocortisone 10 mg to 20 mg daily (which I did not notice anything from).

Although I suppose it depends how you define immunosuppressant; for example, I tried Wellbutrin which inhibits interferon gamma, and various anti-inflammatories, which inhibit aspects of immunity.
 

Hip

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Rapamycin and Diabetes Risk

This is an interesting article to read:

The two faces of rapamycin – why a life-extending drug also increases risk of diabetes

The article says that the anti-aging and longevity effects of rapamycin (which increase mice lifespan by up to 14%), comes from this drug's inhibition of mTORC1.

But a downside of rapamycin comes from its effects on mTORC2, which results in a reduced ability to stabilize sugar levels in the blood, and the article says that people who take rapamycin for a long time become resistant to insulin, and intolerant to sugar.

This diabetes risk was also touched on earlier in this thread (see here).


This paper echos the above, that rapamycin has anti-aging benefits, but also adverse effects such as increased type 2 diabetes risk:
Rapamycin, an inhibitor of the mTOR pathway, can extend lifespan and improve age-related functional decline in mice, thereby providing the first proof of principal that a pharmaceutical agent can slow the aging process in mammals
Part of the challenge in addressing the potential of rapamycin (or its analogs) as a pro-longevity therapeutic lies in its known clinical risks for adverse side-effects. Primary amongst these are metabolic defects that include hyperglycemia, hyperlipidemia, insulin resistance and increased incidence of new-onset type 2 diabetes.
Several recent studies have elegantly shown that chronic treatment with rapamycin inhibits mTORC2 signaling which may be a primary culprit in its alteration of glucose metabolism.
But the paper says the negative effects on murine glucose metabolism appear to be reversible on discontinuation of the drug:
However, once we ended the rapamycin treatment, all markers of glucose homeostasis almost completely returned to normal; i.e., glucose homeostasis in previously rapamycin-treated mice was no different from those never treated with rapamycin. Perhaps most interestingly, this reversal occurred in a relatively short period of time (1-2 weeks) even after long term (4 months) rapamycin treatment, suggesting that these metabolic side effects are a consequence of ongoing use of this drug and are not permanent alterations to the glucose homeostatic network.
However, the study quoted below found the effects on glucose metabolism were only partially reversible on rapamycin discontinuation.

Paper: Chronic rapamycin treatment causes diabetes in male mice
Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis.
We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes.
So male mice given rapamycin are at risk from diabetes, but female mice are not at risk.



Intermittent Rapamycin Safer (Lowers Diabetes Risk)?

The first paper above says one way to prevent these negative effects on glucose metabolism might be taking rapamycin intermittently:
One possibility could be intermittent treatment with rapamycin; Leontieva et al recently showed that a once-weekly treatment with rapamycin extends lifespan in high fat-fed mice without altering glucose or insulin levels
The study examining the effects of intermittent rapamycin is this one. It says that:
We recently identified an intermittent rapamycin treatment regimen-2mg/kg administered every 5 days-with a reduced impact on glucose homeostasis and the immune system as compared with chronic treatment
intermittent rapamycin administration had minimal impact on glucose homeostasis in young mice ... These results sharply contrast with the impaired glucose tolerance observed during continuous administration of rapamycin to mice
So intermittent rapamycin means taking a dose once every five days, rather than say daily. The mouse dosage of 2 mg/kg used corresponds to a human dose of 0.16 mg/kg, which for an 80 kg human would be an oral dose of 12.8 mg taken once every five days.

This article clarifies the logic of intermittent rapamycin:
mTORC2 is inhibited only by long-term, chronic treatment with rapamycin. Therefore, we hypothesized that intermittent treatment with rapamycin would more selectively target mTORC1 than mTORC2, and by doing so, reduce the negative effects of rapamycin while still extending lifespan.


Rapamycin Plus Metformin Safer (Lowers Diabetes Risk)?

This article suggests that taking the drug metformin along with rapamycin could prevent diabetes from arising. Although metformin has some mitochondrial toxicity, so may need to be used with caution in ME/CFS (but I have taken metformin before, and had no issues). See also the next section.



Rapamycin Plus Dietary Restriction Safer (Lowers Diabetes Risk)?

This paper examines the metabolic effects of both dietary restriction (eating fewer calories) and the drug metformin in mice given rapamycin. The found that in mice given rapamycin, dietary restriction mitigates glucose intolerance and insulin insensitivity compared mice given rapamycin alone. Dietary restriction is known to increase insulin sensitivity, and this acts to counter the decrease in insulin sensitivity (increase in insulin resistance) cause by rapamycin.

The paper also proposed a theory of why rapamycin induces insulin resistance and diabetes:
Rapamycin’s inability to activate fatty acid β-oxidation and ketogenesis in mice could generate an imbalance resulting in the accumulation of NEFAs, which may play a role in the development of insulin resistance. Activation of fatty acid β-oxidation by either DR or metformin corrects this imbalance and might lead to improved insulin sensitivity in animals treated with rapamycin.
NEFAs = nonesterified fatty acids

This theory is based on the fact that both dietary restriction and rapamycin inhibit lipogenesis and fat storage, thereby increasing the generation of non-esterified fatty acids (NEFAs) via lipolysis. So in that respect, dietary restriction and rapamycin have similar effects on lipid metabolism. However, only dietary restriction, but not rapamycin, is also able to induce increased metabolism of these fatty acids by stimulating beta-oxidation and then production of ketone bodies.

So with rapamycin, you get increased NEFAs, but no increase in the beta-oxidation that would counterbalance this. But since both dietary restriction and metformin are able to stimulate beta-oxidation, they can mitigate the negative effects that rapamycin has on glucose metabolism, mitigating the problems of glucose intolerance and insulin insensitivity that can led to diabetes.

So in essence, the theory is that by stimulating beta-oxidation, both dietary restriction and metformin may reduce the rapamycin diabetes risk.



Possible Mechanism by Which Rapamycin Benefits ME/CFS?

I wonder though if rapamycin's effects on glucose and pyruvate metabolism (via its mTORC2 inhibition) could be the reason this drug improves ME/CFS symptoms?

If we look at some of the metabolic studies on ME/CFS, there appears to be an altered energy metabolism in ME/CFS, which involves the way glucose is processed in glycolysis (Ron Davis's theory) and/or the way pyruvate is processed in the mitochondria (Fluge and Mella's findings).

So could rapamycin's normally detrimental effects on glucose and pyruvate metabolism actually be beneficial in ME/CFS, and the reason why rapamycin improves ME/CFS symptoms?
 
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Tunguska

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Rapamycin and Diabetes Risk

This is an interesting article to read:

The two faces of rapamycin – why a life-extending drug also increases risk of diabetes

The article says that the anti-aging and longevity effects of rapamycin (which increase mice lifespan by up to 14%), comes from this drug's inhibition of mTORC1.

But a downside of rapamycin comes from its effects on mTORC2, which results in a reduced ability to stabilize sugar levels in the blood, and the article says that people who take rapamycin for a long time become resistant to insulin, and intolerant to sugar.

This diabetes risk was also touched on earlier in this thread (see here).

[...]
I wonder though if rapamycin's effects on glucose and pyruvate metabolism (via its mTORC2 inhibition) could be the reason this drug improves ME/CFS symptoms?

If we look at some of the metabolic studies on ME/CFS, there appears to be an altered energy metabolism in ME/CFS, which involves the way glucose is processed in glycolysis (Ron Davis's theory) and/or the way pyruvate is processed in the mitochondria (Fluge and Mella's findings).

So could rapamycin's normally detrimental effects on glucose and pyruvate metabolism actually be beneficial in ME/CFS, and the reason why rapamycin improves ME/CFS symptoms?
The mTorC2 inhibition was mostly characterized in the liver. There it's exclusively bad.

The other place this appears to might happen is in the macrophages. mTorC2 inhibition - which really just means Akt inhibition - alters their polarization and behavior (more complex than I can put together). Could be something similar in T-cells. However I don't believe it could benefit normal cells at all much the opposite.

Good luck
 
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Hip

After suffering from severe CFS for 36 years, attempting a miriad of treatments and mutiple long stay hospital and care home admissions, I have concluded that I now have no alternative but to trial rapamycin, cyclosporine, cyclophodpmide and rituximab, probably in this order.

I have come to the conclusion that there are currently only heavy duty drug options that are viable treatments for severe patients. If anything is going to give the illness a jolt, I feel that this must be drugs that have a major effect.

I am not so concerened over long term side affects as I currently have very little quality of life.

I am monitoring peoples progress on rapamycin with keen interest.
 

Hip

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I am not so concerened over long term side affects as I currently have very little quality of life.
Whether someone wants to risk the serious side effects of a drug is a personal decision, and usually best reached with the help of a willing doctor. However, it is important to make the risks clear in advance.

And if there are ways to reduce or avoid the risk of serious side effects, then that is very useful info. The concomitant use of metformin with rapamycin, and/or the intermittent rapamycin protocol, detailed above are possible ways to reduce the risk of developing diabetes from rapamycin.
 
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Dont get me wrong, I would rather do without added long term health problems from heavy medication. Those of us who are severe have a very serious, soul destroying illness. No amount of vitamins or natural remedies will move the needle for us. This I know for sure. It is pointless me trying these types of solutions any more. We are just kidding ourselves.
We are not the worried well. We are seriously ill. You need s big hammer to knock a big nail in.
 
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Whether someone wants to risk the serious side effects of a drug is a personal decision, and usually best reached with the help of a willing doctor. However, it is important to make the risks clear in advance.

And if there are ways to reduce or avoid the risk of serious side effects, then that is very useful info. The concomitant use of metformin with rapamycin, and/or the intermittent rapamycin protocol, detailed above are possible ways to reduce the risk of developing diabetes from rapamycin.

Yes metformin seems a sensible precutionary measure. I'm thankful for any info. Good luck. Without people such as yourself, I think I would now be devoid of hope.
 
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Hip

After suffering from severe CFS for 36 years, attempting a miriad of treatments and mutiple long stay hospital and care home admissions, I have concluded that I now have no alternative but to trial rapamycin, cyclosporine, cyclophodpmide and rituximab, probably in this order.

I have come to the conclusion that there are currently only heavy duty drug options that are viable treatments for severe patients. If anything is going to give the illness a jolt, I feel that this must be drugs that have a major effect.

I am not so concerened over long term side affects as I currently have very little quality of life.

I am monitoring peoples progress on rapamycin with keen interest.
Sorry to hear that you have suffered so long @MrTop . CFS is such an insidious disease.

In weighing up the possibility for trying Rapamycin, consider the potential that it may make your condition worse. As outlined earlier, the known 'ontarget' activities of Rapamycin do 2 things that could be a serious problem in terms of CFS patients. Firstly, Rapamycin suppresses the immune system and has been shown to increase the likelihood of infections (something that could worsen complications in CFS). Secondly, Rapamycin, through inhibition of mTOR, suppresses catabolic pathways for generating ATP (energy) and so could actually worsen the lack of energy and PEM suffered by CFS sufferers.

I guess I dont really understand the biological rationale for why a drug that suppresses the immune system and suppresses catabolic pathways for energy production would provide therapeutic benefit in CFS. If anything, blocking immune function and reducing energy generation should make CFS symptoms worse?

I am curious however @MrTop , I hadnt seen the suggestion of using cyclophosphamide for CFS (or was that a typo?). Cyclophosphamide is a chemotherapy agent and one of the major side-effects of chemotherapy in cancer patients is fatigue. Cyclophosphamide would wipe out alot of blood cells and could lead to pan-cytopenia which would could have serious complications if not closely monitored. Have CFS patients found that cyclophosphamide improves symptoms? Is it used at the same doses as in chemo? Who has tried it?

best of luck

Rodger