Trial Report Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy, 2025, Ruan et al

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Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy

Brian T. Ruan, Sarojini Bulbule, Amy Reyes, Bela Chheda, Lucinda Bateman, Jennifer Bell, Braydon Yellman, Stephanie Grach, Jon Berner, Daniel L. Peterson, David Kaufman, Avik Roy, C. Gunnar Gottschalk

Background
mTOR activation is associated with chronic inflammation in ME/CFS. Previous studies have shown that sustained mTOR activation can cause chronic muscle fatigue by inhibiting ATG13-mediated autophagy. This highlights the pivotal role of mTOR in the pathogenesis of ME/CFS.

Methods
We conducted a decentralized, uncontrolled trial of rapamycin in 86 patients with ME/CFS to evaluate its safety and efficacy. Low-dose rapamycin (6 mg/kg) was administered, and core ME/CFS symptoms were assessed on days 30 (T1), 60 (T2), and 90 (T3). Plasma levels of autophagy metabolites, such as pSer258-ATG13 and BECLIN-1, were measured and correlated with clinical outcomes, specifically MFI.

Results
Rapamycin (6 mg/week) was tolerated without any SAEs. Of the 40 patients, 29 (72.5%) showed strong recovery in PEM, fatigue, and OI, along with improvements in MFI fatigue domains and SF-36 aspects. High levels of BECLIN-1 were detected in T3. Plasma pSer258-ATG13 levels were strongly downregulated at T1. Spearman’s correlation analysis indicated an association between autophagy impairment and reduced activity.

Conclusions
Low-dose rapamycin effectively reduced PEM and other key symptoms in patients with ME/CFS, as measured by BAS, SSS, MFI, and SF-36. Future studies should encompass dose optimization and develop a diagnostic tool to identify responders with mTOR-mediated autophagy disruption.

Link | PDF (Preprint: ResearchSquare) [Open Access]
 
We found that a significant proportion of the patients who finished the three month trial period of rapamycin (an mTOR inhibitor) showed improvements in both clinical features of the illness (PEM) and saw improvement in blood based markers of autophagy function
https://twitter.com/user/status/1929884619094053303


Autophagy can be inhibited when mTOR activity is high. Rapamycin helps induce autophagy function. This is critical for the removal of metabolically inactive proteins and recycling mitochondria.
https://twitter.com/user/status/1929884621161787674


Our goal with this observational trial was to see if low dose rapamycin could change blood markers of autophagy function, specifically pATG13 based on our previous publication which found it to be elevated in patients with ME/CFS
https://twitter.com/user/status/1929884623154094210
 
We were thankful to run into David Kaufman, MD who has been using rapamycin in his patients and together with this new hypothesis we initiated this trial back in Nov. 2023. Our clinical trial team has grown to include 8 clinical sites including
@GrachStephanie
and
@BatemanHorn
https://twitter.com/user/status/1929884627566461133


This trial is not placebo controlled and we understand the limitations; however, our goal was to try and develop a predictive diagnostic to help objectively identify potential responders to therapy. This would be helpful in clinical practice and future double blinded placebo controlled trials.
https://twitter.com/user/status/1929884629743411569


Expect more updates soon! Our partnership with
@agelessrx_
will help us lead to new therapies (and combinations) using FDA-approved agents in placebo controlled trials.
https://twitter.com/user/status/1929884633811800407
 
I have some reservations about the study itself, but even if the results replicate in a more stringent trial, I'm skeptical of attributing any benefit of rapamycin to autophagy. Rapamycin inhibits mTOR, and mTOR does 1001 important things, only one of which is regulate autophagy. You will almost certainly get autophagy markers changing in response to rapamycin even if the effect of rapamycin on ME/CFS is not mediated through autophagy at all, just because that's something that rapamycin also does.

To actually confirm whether it's (lack of) autophagy that leads to negative outcomes, you'd need to do some sort of in-vitro or animal model study where you show that the positive effect of rapamycin is blocked if you also inhibit autophagy directly.

It still would be interesting and useful to confirm if rapamycin has a clinically relevant benefit in ME/CFS--I just strongly caution against jumping the gun and assuming that the pathological mechanism of ME/CFS is related to autophagy based on findings like this study.

[Edit: frankly, I really hope that this big logical error, in their title no less, is corrected during peer review because it's really misleading]
 
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Sadly, I don't think this study is going to tell us anything, being uncontrolled and multi centre. I do not see the justification of recruiting such a large number of people to an uncontrolled pilot study without at least doing a dose response curve. With four graded doses this study could have given us very meaningful data, even without a control group.
 
Jonathan Edwards said:
I do not see the justification of recruiting such a large number of people to an uncontrolled pilot study without at least doing a dose response curve.
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Agreed--that's my biggest reservation. Claiming a benefit without a control group or dose response is already very sketchy. Claiming a benefit due to autophagy when you can't even compare to control--that's just flagrant.
 
Jonathan Edwards said:
Sadly, I don't think this study is going to tell us anything, being uncontrolled and multi centre. I do not see the justification of recruiting such a large number of people to an uncontrolled pilot study without at least doing a dose response curve. With four graded doses this study could have given us very meaningful data, even without a control group.
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There are some graphs in the supplementary files, but I can’t make sense of them on my own.

If not, maybe someone could ask if they could make a dose response graph?
 
I think figures 1-3 are all uninteresting given the nature of the trial. I think the interesting part is whether the trial showed any relevance of their "markers" BECLIN-1 and/or pSer258-ATG13, i.e. are "responders" also "responders" in terms of these markers. The authors report a correlation between some things on that end but it doesn't read particularly convincing.

The drop out rate is also very high, only 46 of 86 participants completed the trial. Somehow 6 of those 46 are not included in the analysis (maybe its written somewhere why).
 
A total of 109 participants were enrolled in this study between November 2024 and February 2025 (Fig. 2). Following the completion of baseline questionnaires and biospecimen collection, 23 individuals elected not to initiate study drug treatment after consultation with their respective clinical investigators. The remaining 86 participants were initiated on therapy with low-dose rapamycin. Of these, 70 completed the T1 phase (day 36), 55 completed the T2 phase (day 60), and 46 completed the full 90-day study protocol (T3), as shown in the study flowchart.
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So fewer than half who started finished

The “responder” group (N=17) with the most significant fatigue recovery based on MFI and SF-36 evaluations, displayed the strongest response of BECLIN-1 upregulation from BSL to T2 to T3 stages. The “partial responder” (N=18) group and “non-responder” (N=5) groups did not show any significant upregulation in BECLIN-1 levels.
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Is my maths funky or do those 3 groups add up to 40, is so what happened to the other 6 who completed the 90 days? edit: aha @EndME spotted the same while I was writing this!

They seem to recognise the problems with the study (and it seems amazing that patients were funding their own medication and lab costs) so it could be interesting to see what a properly funded one comes up with.
 
Reasons given for dropout of 40 people. No mention of mouth sores or reactivation of viruses which I've seen reports of on social media (those reports may not have been in study).
upload_2025-6-3_13-5-56.png

I think dropping out for cost is valid. Some of the doctors were running frequent extensive lab tests to monitor safety. Some of those tests will only be covered by insurance once per year and you won't be presented with the large bill until the second time you go for testing. Headache and GI symptoms are common with this drug, so large dropout for that is expected.
 
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EndME said:
The authors report a correlation between some things on that end but it doesn't read particularly convincing.
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Same, it came across very muddled to me.
No significant interaction effects were found for BECLIN-1 concentrations, but Dunnett’s test revealed significant increases for responders only from baseline to time points 2 and 3 of 2.6- and three-fold, respectively (*p = 0.01, *p = 0.01, respectively). There were no significant differences between the partial responders and non-responders.

Likewise, there were no significant interaction effects vis-à-vis pSer258-ATG13 concentration
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It really just seems like fishing. But they did find a statically significant increase of these two markers for ALL participants given rapamycin. Which, ironically, makes me feel more confident that any potential benefit of rapamycin is not mediated by autophagy.
 
wigglethemouse said:
Reasons given for dropout of 40 people. No mention of mouth sores or reactivation of viruses which I've seen reports of on social media (those reports may not have been in study).
View attachment 26406

I think dropping out for cost is valid. Some of the doctors were running frequent extensive lab tests to monitor safety. Some of those tests will only be covered by insurance once per year and you won't be presented with the large bill until the second time you go for testing. Headache and GI symptoms are common with this drug, so large dropout for that is expected.
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This doesn't really match what they say in the text. According to the text the primary reason to stop participation is financial barriers, according to the table that is not the case. The most common reason for discontinuition according to the table is a lack of perceived effect which is followed by side effects.

At this point it doesn't seem worthwhile for me to dig deeper into this study.
 
jnmaciuch said:
Rapamycin inhibits mTOR, and mTOR does 1001 important things, only one of which is regulate autophagy
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I think the autophagy angle is coming from their microglia ROS proposal in the 2022 ATG13 paper, but that serum treatment experiment was tested using what I recall to be only a handful of serum samples and also yes it's just one of many possibilities. That was a nice line of methodical enquiry there (beyond what is often seen in the field) but we need to see more samples and the other possibilities explored. We'll need tighter evidence to relate to mechanism and to symptoms.

For those forum members who don't know. mTOR is basically the central agent that controls cell metabolism (it has two functional complexes mTORC1 and mTORC2) it has its fingers in every pie that you can imagine. Because of this and because of cancer I would not be surprised if it is the single most researched protein kinase in history (which is an advantage, we know how it fits into a lot of cell biology in detail)
 
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