mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

Jesse2233

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To summarize some of the scientific discussion earlier in the thread, here are some potential mechanisms of rapamycin

- immune suppression
- clearing of diseased proteins via neuronal autophagy
- increasing AKT
- anti viral / fungal
- increases glycolysis
- blocking proinflammatory cytokines
 

TreePerson

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This is so interesting. I notice that @made_lman has been troubled by severe head symptoms. I am wondering if the drug has been as helpful to people with predominantly body symptoms? I.e. Extreme muscle fatigue? Anyone know?
@XenForo @Steve4Andrea I don't seem able to tag the others.
 
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This is so interesting. I notice that @made_lman has been troubled by severe head symptoms. I am wondering if the drug has been as helpful to people with predominantly body symptoms? I.e. Extreme muscle fatigue? Anyone know?
@XenForo @Steve4Andrea I don't seem able to tag the others.
I still rate my body fatigue as the primary symptom. And the sirolimus def helped with that as well. I think the severe cognitive trouble does not kick in until we (or at least me) are generally in the "severe" category, which I was for quite some time this relapse. Perhaps only the severely ill with symptoms similar to mine (overactive immune) can benefit from whatever the Sirolimus does. Could be that patients that have other co-morbidities have different metabolic functioning that inhibits the actions of and mTOR inhibition. I have yet to hear of a severe me/cfs patient that does not suffer significant sensory or overall cognitive issues. I'm leaning towards the immune cytokines causing all or most of the problem. The Davis/Montoya study guiding this plausible theory. Lots of other dysfunctions acting in concert as well but something profound is centered around these cytokines. But still want to understand the mechanism of the drug... Wish Ron Davis, Montoya or Fluge/Mella would weigh in to someone on their thoughts.

would love Jared Younger take on all this also.
 
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TreePerson

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Thanks @made_lman .
It has also been my experience that head symptoms really kick in as ME worsens particularly light sound sensitivity. But for me this fluctuates and I definitely get days off from brain fog whereas the muscle fatigue that keeps me in bed is ever present.

Did you have any testing done to establish that you have an overactive immune system? I suspect that I do too because I almost never catch colds. Although I did get shingles recently. My pattern has been to steadily but only very slightly improve for about 15 years (got up to about 4/5). Now steadily and rather worryingly deteriorating for 5 years. (1/2) I've been interested in the theory of some kind of autoantibody. Not quite sure where that fits in with cytokines.

It's so encouraging that this drug is helping people.
 

nandixon

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...I take a really good multivitamin with Metafolin, still take LDN at 5.5 mg, a blood pressure med, and metformin for pre-diabetes. (Both are long term RX)...
@made_lman

You mentioned on your thread here that your current relapse started in late 2014 and that you began taking sirolimus (aka rapamycin or Rapamune) in January of this year.

I was wondering when you started taking the metformin?

You noted that you've had a relapsing/remitting form of ME/CFS where for some 40 years, if I understand correctly, you've typically been in remission and well for a couple of years and then relapse and are ill for one or two months and then go back to being well again, and that this pattern repeated itself over and over until late 2014 when the relapse, for the first time, became much longer.(?)

Metformin is pretty toxic to mitochondria, including in the brain. It depolarizes the mitochondrial membrane and inhibits Complex I of the mitochondrial respiratory chain (among other problems).

So one possibility for your case might be a metformin-related (and/or age-related) decline in mitochondrial function that exacerbated your ME/CFS to a new level (depending on when you began taking the metformin).

Interestingly, metformin, like sirolimus, is also a potent inhibitor of mTOR/mTORC1. (See this study.)

But while metformin may be detrimental to mitochondrial function, sirolimus may be beneficial and/or neuroprotective.

One of the reasons metformin came to mind as a potential hidden problem (again depending on when you started taking it) is that a few years ago I'd been taking a low dose of trazodone to help with deep sleep for a couple of years when I suddenly found my already very impaired energy level was much worse, and that the trazodone, which can also negatively affect mitochondrial function, was clearly causing this - even though I'd taken it for two years without any problem.

(I actually think now that any mitochondrial dysfunction in ME/CFS is probably a secondary effect and that chances are that ME/CFS is a T cell mediated disease. Just with respect to T cells alone, including CD8+, Tregs, etc, there are at least a half dozen different ways that sirolimus might possibly be helpful for a subset of ME/CFS patients. Overall there are many dozens of different effects that sirolimus might possibly be having, making it very difficult to sort out how it might be helpful at present - assuming sirolimus is found to be useful for a significant ME/CFS subset.)
 
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@made_lman

You mentioned on your thread here that your current relapse started in late 2014 and that you began taking sirolimus (aka rapamycin or Rapamune) in January of this year.

I was wondering when you started taking the metformin?

You noted that you've had a relapsing/remitting form of ME/CFS where for some 40 years, if I understand correctly, you've typically been in remission and well for a couple of years and then relapse and are ill for one or two months and then go back to being well again, and that this pattern repeated itself over and over until late 2014 when the relapse, for the first time, became much longer.(?)

Metformin is pretty toxic to mitochondria, including in the brain. It depolarizes the mitochondrial membrane and inhibits Complex I of the mitochondrial respiratory chain (among other problems).

So one possibility for your case might be a metformin-related (and/or age-related) decline in mitochondrial function that exacerbated your ME/CFS to a new level (depending on when you began taking the metformin).

Interestingly, metformin, like sirolimus, is also a potent inhibitor of mTOR/mTORC1. (See this study.)

But while metformin may be detrimental to mitochondrial function, sirolimus may be beneficial and/or neuroprotective.

One of the reasons metformin came to mind as a potential hidden problem (again depending on when you started taking it) is that a few years ago I'd been taking a low dose of trazodone to help with deep sleep for a couple of years when I suddenly found my already very impaired energy level was much worse, and that the trazodone, which can also negatively affect mitochondrial function, was clearly causing this - even though I'd taken it for two years without any problem.

(I actually think now that any mitochondrial dysfunction in ME/CFS is probably a secondary effect and that chances are that ME/CFS is a T cell mediated disease. Just with respect to T cells alone, including CD8+, Tregs, etc, there are at least a half dozen different ways that sirolimus might possibly be helpful for a subset of ME/CFS patients. Overall there are many dozens of different effects that sirolimus might possibly be having, making it very difficult to sort out how it might be helpful at present - assuming sirolimus is found to be useful for a significant ME/CFS subset.)
@nandixon I started metformin in early 2000's but was not consistent with taking it. Took half dose most of the time because of gastro issues it caused. You mentioned age related decline in mito function. Total possibility, as we patients tend to get worse over time or develop other co-morbidities. However also need to consider timing of this relapse episode as relates to immune system. I become ill again shortly after the flu shot in fall 2014. So many factors to consider as you said. Coincidentally I am unable to tolerate Trazadole also.
 
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Thanks @made_lman .
It has also been my experience that head symptoms really kick in as ME worsens particularly light sound sensitivity. But for me this fluctuates and I definitely get days off from brain fog whereas the muscle fatigue that keeps me in bed is ever present.

Did you have any testing done to establish that you have an overactive immune system? I suspect that I do too because I almost never catch colds. Although I did get shingles recently. My pattern has been to steadily but only very slightly improve for about 15 years (got up to about 4/5). Now steadily and rather worryingly deteriorating for 5 years. (1/2) I've been interested in the theory of some kind of autoantibody. Not quite sure where that fits in with cytokines.

It's so encouraging that this drug is helping people.
@TreePerson I am so very sorry to hear about your struggles. I did also have some days off brain fog but was always temporary and and always worsened after stimulation or exertion, mental or physical. No I have not had any testing to confirm overactive immune system. Just anecdotally I noticed about 4 months into this relapse that I was not getting sick with colds or sore throats or sinus infections, etc which were quite common for me, and definitely part of other relapses. I have seen immunologists and infectious disease specialists and been tested for tons of pathogens but not for immune function.
 

ghosalb

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Hi anyone...does one need a prescription to buy this drug ?.....if not, is it safe to use it on my own without a doctor's supervision ?.....why is not there more interest in this drug considering how good the outcomes are (granted small sample size) ?...thanks in advance
 

rodgergrummidge

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There have been many comments in this forum regarding Rapamycin and its Rapalogs. I thought it important to highlight some important risks in using Rapamycin or Rapalogs to treat CFS. Hopefully the overview below provides an understanding of the clinical potential and hazards of Rapamycin/Rapalogs for CFS treatment. I tag @XenForo , @eljefe19 , @made_lman , @Steve4Andrea and @Joe Some as they have been involved in some of the discussions.

What is Rapamycin? Rapamycin was initially discovered as an antifungal metabolite produced by Streptomyces hygroscopicus from a soil sample of Easter Island. It has since been found that rapamycin has potent pharmacological properties including the ability to suppress the immune system as well as the ability to block cell division. Rapamycin and its derivatives (rapalogs) that include temsirolimus, everolimus, ridaforolimus, 32-deoxo-rapamycin, and zotarolimus inhibit the activity of a protein called “mammalian target of rapamycin”, also known as mTOR or TORC1.

What are the normal functions of mTOR? When mTOR is active in our cells, it stimulates protein synthesis, lipid synthesis and energy production. In addition, the active form of mTOR prevents a process called ‘autophagy’ in which proteins and fats are broken down and recycled to produce energy in the mitochondria. Thus, when diet provides ample fuel and nutrients for generating energy, mTOR is activated and stimulates anabolic pathways for building muscle and fat reserves. However, if diet is inadequate or if we are fasting, inactivation of mTOR occurs leading to increases in catabolic pathways where proteins in many tissues including the muscle are degraded and used as fuel to generate energy (ATP). In this way mTOR acts like a switch: When dietary nutrients are sufficient, mTOR is turned on and promotes energy production together with new tissue formation and repair. However, when dietary nutrients are limited, mTOR is turned off and ‘emergency metabolism’ is activated in which metabolic fuel is obtained by degrading proteins and fats from our tissues.

Rapamycin and Rapalogs as anti-cancer drugs. Cell division is critical for many processes in the body including the production of blood cells, repairing damaged or injured tissues and replacing old or defective cells. In contrast to normal cells, cancer cells grow and divide in an unregulated manner. Because of the ability of rapamycin to block protein synthesis, energy production and cell division, it has been examined in clinical trials for anti-cancer activity. However, Rapamycin/Rapalogs have proved to be disappointing with little or no anti-cancer activity in most human trials. Currently, these drugs are only approved for the treatment of a few cancers including renal cell carcinoma (temsirolimus and everolimus) and for patients with specific types of pancreatic cancer or tuberous sclerosis.

Rapamycin/Rapalogs suppress the immune system: The ability of Rapamycin and Rapalogs to block cell division in T-cell lymphocytes dampens overall immune responses and so they have been used as immunosuppressants following organ transplantation. While the ability of Rapamycin to suppress the immune system is critical for preventing immune rejection in transplant patients, it also comes at the significant risk of an overall suppression of immune defences against many infectious diseases. For example, immune suppression by rapamycin in renal transplant patients resulted in an increased incidence of viral infection (34%) and fungal infections (16%). Clearly, there are significant risks associated of increased infections in any patient treated with rapamycin.

Rapamycin/Rapalogs and aging: One of the intriguing activities of Rapamycin/Rapalogs is that they are able to extend the life spans of multiple laboratory species including fruit flies, worms and mice. It has been suggested that Rapamycin/Rapalogs increase lifespan in laboratory animals by turning off mTOR and inducing a state of ‘emergency catabolism’ where the proteins and fats in tissues are broken down and used as the metabolic fuel to generate energy (ATP) in the mitochondria. The ability of Rapamycin/Raplogs to trigger such an ‘emergency metabolic’ state may, at least in part, mimic what occurs in long-term calorie restricted diets which can also turn off mTOR and significantly increase life-span. Based on these laboratory experiments, some ‘Wellness Clinics’ and ‘Anti-Aging Clinics’ have been spruiking Rapamycin and Rapalogs to people as an anti-aging treatment. However, such treatments are potentially very dangerous. The ability of Rapamycin/Rapalogs to increase the life-span of laboratory animals occurs in a pathogen-free environment in which infections from bacteria, viruses and fungi do not occur. Humans on the other hand are surrounded by many pathogens, many of which can be lethal in the absence of a fully functional immune system. As mentioned above, the ability of Rapamycin/Rapalogs to suppress the immune system results in a significant increase in infection rates. Thus, while Rapamycin/Rapalogs can increase life-span in laboratory animals, the findings may be an artefact of the pathogen-free environment that is unique to particular experimental models. Unfortunately, the use of such drugs as anti-aging treatments by ‘rogue’ practitioners is incredibly dangerous and exploits vulnerable people whose long-term health may suffer as a consequence.

Rapamycin and mitochondrial diseases. There maybe some very specific cases where Rapamycin/Rapalogs treatment may be warranted in the future. For example, Leigh Syndrome is caused by mutations in genes responsible for energy production (ATP) in the mitochondria. Many of the symptoms in Leigh Syndrome are similar to those of CFS patients which include i) defects in mitochondrial energy production, ii) disease onset can occur in situations where there is an extra burden energy production such following infections or surgery and iii) lactic acidosis can occur particularly following exercise. Recent studies in a mouse model of Leigh Syndrome have shown that rapamycin improved their symptoms and survival. The similarly between the symptoms of Leigh Syndrome and CFS can lead to the mistaken diagnosis of CFS in people with Leigh Syndrome. It might be possible that in some very specific mitochondrial diseases that Rapamycin/Rapalog treatment could be effective. However, there is currently no clinical evidence that such treatments may be effective in any mitochondrial disease.

Other side-effects and toxicities of Rapamycin/Raplogs: The use of Rapamycin in renal transplant recipients was found to lead to edema in 60% of patients, aphthous ulcers in 55% of patients, as well as Mucositis in other patient populations. Rapamycin treatment resulted in 90% of patients experiencing alopecia, as well as loss of testicular function and reduced male fertility. In addition, rapamycin treatment leads to metabolic changes, including hyperlipidemia, decreased insulin sensitivity, glucose intolerance, and an increased incidence of new-onset diabetes. Chronic rapamycin treatment has also been associated with gastrointestinal events including diarrhea. Cancer and transplant patients may be willing to tolerate these significant side-effects because benefits of treatment (ie. curing a terminal disease) outweigh the risks.

Rapamycin/Rapalogs and CFS. As outlined above, the use of Rapamycin/Rapalogs have significant risks and toxicities associated with immune-suppression, infection, glucose intolerance, new-onset diabetes, impaired wound healing and muscle wastage. CFS patients wishing to use Rapamycin/Rapalogs need to understand all of these dangers and their potential for seriously impacting on their long-term health. In fact, CFS patients suffer from a range of issues that Rapamycin/Rapalogs could actually make worse. The 2 main concerns in using Rapamycin/Rapalogs to treat CFS are:

1) Many studies have shown that CFS patients have defects in their ability to generate energy (ATP) resulting in reduced exercise capacity and longer recovery times. Thus, CFS patients are metabolically deficient. The ability of Rapamycin/Rapalogs to block catabolic pathways necessary for energy production in CFS patients that are already unable to generate sufficient energy (ATP) for daily life may actually make their symptoms worse and possibly even delay their recovery.

2) Many studies have also shown that CFS patients also have an altered immune systems. In some aspects, immune functions seem to be impaired (e.g. reduced functions of NK-Cells) while in other aspects the immune system seems to be chronically activated (eg. increased circulation of some pro-inflammatory cytokines). Most importantly, there is good evidence that some CFS patients have an impaired immune system that appears unable to completely eradicate fungal, bacterial and/or mycoplasma infections. Treating a CFS patient, who already has a low-level chronic infection due to a weakened immune system, with a drug that further suppresses immune defence could leave the patient with a severe immune-deficiency and allow either existing or new infections to over-run the immune system resulting in serious medical consequences. Even if the CFS patient’s immune system is perfectly functional and they don’t have an underlying chronic infection, treating a CFS patient with Rapamycin/Rapalogs and suppressing their immune system could further burden an already sick patient leading to a worsening of health and reduce their likelihood of recovery.

Thus, doctors need to clearly explain these risks to CFS patients in terms of

i) providing detailed information of the medical risks that can arise due to immune suppression, increased infection, metabolic impairment including glucose intolerance and diabetes,

ii) providing ‘informed consent’ so that patients are fully aware of all the risks and are acknowledging that they are willing to try a non-approved and experimental medicine for CFS

iii) providing patients with frequent and comprehensive monitoring (such as comprehensive biochemical, cellular and metabolic blood/urine testing) so any potential health issues caused by treatment with Rapamycin/Rapalogs can be quickly identified.

Clinical trials that test new medicines are generally very good at following points i-iii above. If you are taking Rapamycin/Rapalogs as part of a CFS clinical trial, you would almost certainly have been made aware of the issues above and would receive regular testing to monitor health.

However, in other cases, ‘rogue doctors’ can recruit patients with unproven and potentially dangerous treatments. In such cases, patients are often not given the opportunity to full understand the risks involved so they can make ‘informed consent’. In such cases, patients are sometimes victims of unscrupulous practitioners and are at risk of adverse outcomes. I would encourage any CFS patient that has been given Rapamycin/Rapalog treatment without being told of the risks outlined above to seek further independent medical advice.

To Rapamycin or not to Rapamycin, that is the question: I couldn’t find any publications for the use of Rapamycin or Raplogs in the treatment of CFS in scientific or medical journals (using PubMed). Reports of cures for any disease in the press and online without any detailed publication in a scientific/medical journal is usually the first alarm bell that warns of potential quackery, medical exploitation or unscrupulous practitioners spruiking costly and sometimes ineffective or dangerous ‘treatments’. The best way to minimize risk in any treatment is to be well informed. In the absence of any cure, this forum provides a wonderful resource and fantastic information for all of us struggling with CFS. In frustration with a disease that stubbornly refuses to respond to most treatments, many of us (including myself) have sometimes tried unproven therapies. It is fantastic that this forum allows us to discuss our outcomes in trying to manage CFS. However, with any unproven treatment, the balance between risk and benefit needs careful consideration.

Rodger
References:
Cell Metab. 2014 March 4; 19(3): 373–379.
J Clin Invest. 2013;123(3):980–989
Cancer Cell 2007 12:9
Cell 2012, 149:274,
 
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Coinrx.is has not sent the medication 8 days after paying for it, so I drove down to Mexico to get it, and they do not have it either.
 

Jesse2233

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This a very interesting excerpt from @Cort's blog on the Standord Symposium

Doctor Alert! – During a break Alan and his wife, Kathleen Light, made a plug for rapamycin, (rapamune) case reports in ME/CFS. Several accounts of ME/CFS patients doing better on Rapamune have been making the rounds. The Light’s dearly want those case studies to get written up in the scientific literature. That’s all they need to provide the foundation they need to get Rapamune studied in ME/CFS

https://www.healthrising.org/blog/2...-explored-open-medicine-foundation-symposium/

Perhaps those trailing Rapamycin should contact Alan Light (Alan.Light@hsc.utah.edu)

@XenForo
@eljefe19
@made_lman
@Steve4Andrea
 
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I tolerated 3 mg of sirolimus well, that's 1 mg/20 kg and 1.3 per m2. I am taking it once per week.

Treating drugs like wine, the earthy tones and general body feel of rapamycin are reminiscent of azithromycin. If I am completely cured, I will come back and tell. I'm not worse, that's for sure.

slight anti-depressant effect, no change in executive function, slight improvement in exercise tolerance, erectile dysfunction, slight decrease in short term memory.
 
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ScottTriGuy

Stop the harm. Start the research and treatment.
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Treating drugs like wine, the earthy tones and general body feel of rapamycin are reminiscent of azithromycin.


Thanks for the update - I'm considering my own n = 1.

What constellation of ME symptoms do you have, and how have they been since starting rapamycin?
 

Jesse2233

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I tolerated 3 mg of sirolimus well, that's 1 mg/20 kg and 1.3 per m2. I am taking it once per week.

Treating drugs like wine, the earthy tones and general body feel of rapamycin are reminiscent of azithromycin. If I am completely cured, I will come back and tell. I'm not worse, that's for sure.

slight anti-depressant effect, no change in executive function, slight improvement in exercise tolerance, erectile dysfunction, slight decrease in short term memory.

How long have you been taking it?
 

Tunguska

Senior Member
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Here is a study on real patient cells where rapamycin shifted macrophages toward inflammatory M1 type (normally induced by LPS):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784164/
Rapamycin unbalances the polarization of human macrophages to M1

Plasticity is a hallmark of macrophages, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic (M1) and alternative (M2). Rapamycin (RAPA) is crucial for survival and functions of myeloid phagocytes, but its effects on macrophage polarization are not yet studied. To address this issue, human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon-γ or interleukin-4 (IL-4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M2 but not in M1. Beyond the impact on survival in M2, RAPA reduced CXCR4, CD206 and CD209 expression and stem cell growth factor-β, CCL18 and CCL13 release. In contrast, in M1 RAPA increased CD86 and CCR7 expression and IL-6, tumour necrosis factor-α and IL-1β release but reduced CD206 and CD209 expression and IL-10, vascular endothelial growth factor and CCL18 release. In view of the in vitro data, we examined the in vivo effect of RAPA monotherapy (0·1 mg/kg/day) in 12 patients who were treated for at least 1 month before islet transplant. Cytokine release by Toll-like receptor 4-stimulated peripheral blood mononuclear cells showed a clear shift to an M1-like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M1. These results suggest a role of mammalian target of rapamycin (mTOR) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2-related diseases through mTOR inhibitor treatment.
Difficult to reconcile from one perspective, so may require expert ideas.
 

Tunguska

Senior Member
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The only way I see the study above come out positive is if ME/CFS is that state of "endotoxin tolerance". In that case the macrophages are already polarized to M2 type. This seems to agree with having elevated TGF-beta at least (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239552/). So the shift to M1 reactivates cleaning.

The low level pathway activation (Akt/mTor) looks extra complex/unresearched in macrophages (something for another day/month/year) so I'd just trust the in vivo results. The duration and dosage might be a factor (e.g. due to delayed mTorC2 inhibition by Rap).

I'm obviously not too confident on the assumptions on this one.
 
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