Dr. Avik Roy is the chief scientific officer at the Simmaron Research Institute, a nonprofit organization that conducts research and observational studies on ME/CFS to find treatments for people with this disease. Their continuing efforts have built a strong foundation for using low-dose rapamycin to reduce ME/CFS-associated fatigue. Rapamycin inhibits a protein called mTOR (short for mammalian target of rapamycin). Under certain conditions, mTOR directs cells to grow; under other conditions, it directs cells to conserve resources and recycle unnecessary or damaged components through a clean-up process called autophagy.
Earlier, Simmaron researchers showed that some people with ME/CFS have hyperactive mTOR. In these people, muscle cells do not properly recycle unnecessary or damaged components, contributing to oxidative stress and poor muscle and nerve cell functioning, which manifest as fatigue and post-exertional malaise. In a phase 1 observational study, Simmaron showed that treating these individuals with low-dose rapamycin inhibits mTOR, boosts autophagy, and reduces fatigue.
In this most recent study, the team extended its investigation of mTOR-associated dysfunctions in ME/CFS by studying how low-dose rapamycin affects levels of several purines. Purines are nitrogen-containing, figure-eight–shaped molecules with diverse biological functions. Some purines are assembled into high-energy molecules that cells use to do work or to build genetic material. Some purines are signals, binding to purinergic receptors on cells like nerve cells and immune cells to regulate their activities. (People with gout must avoid foods with lots of purine because purines break down into uric acid, which can crystallize in joints to cause disease.) Purine levels are dysregulated in people with ME/CFS, and this dysregulation may contribute to oxidative stress. Because mTOR regulates both purine metabolism and autophagy, this study was a natural continuation of the team’s earlier work on mTOR dysregulation in ME/CFS. Here, the researchers hypothesized that inhibiting mTOR with rapamycin could modulate purine levels, reverse oxidative stress, and reduce disease symptoms.
Among the 76 adults with ME/CFS taking part in this three-month-long study, low-dose rapamycin reduced levels of specific purines that are associated with oxidative stress (specifically, the purines xanthosine monophosphate and hypoxanthine). Rapamycin treatment lowered activity of IMPDH2, an mTOR-regulated enzyme needed to produce these purines. Treatment also improved blood and immune cell mitochondria function. By lowering levels of stress-associated purines that activate specific pro-inflammatory purinergic receptors on myeloid immune cells, by reducing myeloid cell oxidative stress, and by improving myeloid cell mitochondrial health, rapamycin treatment reduced levels of inflammatory M1-type myeloid cells and increased levels of the anti-inflammatory M2-type cells.
Importantly, treatment was safe and significantly reduced emotional and physical fatigue, post-exertional malaise, body pain, and orthostatic intolerance. It also significantly improved energy, sleep, and general health. Interestingly, treatment reduced symptoms more in people with viral infection–induced ME/CFS than in people whose ME/CFS was not associated with viral infections. Half of the participants with viral infection–associated disease responded to treatment. But only one in five participants with non-viral infection–associated disease responded to treatment.
Overall, these results are important because they show that rapamycin may reduce ME/CFS-associated symptoms not only by reversing mTOR-driven autophagy problems, but also by affecting mTOR-regulated purine metabolism. Rapamycin may especially help people whose ME/CFS followed viral infections, including the growing number of people with Long Covid who also meet criteria for ME/CFS. Because the FDA has already approved rapamycin for other conditions (e.g., reducing organ rejection in transplant recipients), the drug may be repurposed to help people with ME/CFS more quickly than a brand-new drug could be discovered and developed.
This study is also an important example of how to design observational studies and clinical trials to address special challenges faced by people with severe ME/CFS symptoms. The researchers designed it as a decentralized study, meaning participants did not need to travel to a clinic or research center to take part. Instead, Simmaron paid phlebotomists to visit participants at home to collect samples or, in some cases, gave participants standing orders for lab work at nearby Quest clinics. Simmaron also sent participants compounded rapamycin (medicine prepared by a specialized pharmacy), instead of generic rapamycin. Compounded rapamycin is better tolerated, has fewer adverse effects, and more durably reduces symptoms than generic versions. Recognizing that women and men metabolize rapamycin differently, the researchers also gave female and male participants appropriately tailored doses, which they gradually increased over the course of the study to reduce risk of sudden adverse effects. These design choices may have contributed to the higher participant retention in this phase 2 study than in their earlier phase 1 study, and to the lower rates of adverse effects.
The researchers noted several ways future trials could improve on this study. Future studies may more comprehensively identify other purines and purinergic receptors that increase oxidative stress in people with ME/CFS. Second, while some participants collected data by using their own wearable devices, too few did so for the researchers to analyze these data. Future studies may therefore supply all participants with wearable devices to collect additional clinical data.
Also, this study did not include a placebo-treated group; thus, the researchers could not account for confounding variables, like placebo effects. The researchers will next recruit more participants for another study designed to address these points. In this next study, they will use a stepped-wedge designed study. In this design, all participants start by taking placebo; then, group by group, participants switch to receiving rapamycin. This approach lets researchers better account for confounding effects while ensuring that all participants eventually receive rapamycin and potentially benefit from the effects seen in earlier studies.
Watch our recent webinar with the Simmaron team in which they discuss their new publication here.
The researchers thanked Solve M.E. for funding this study through a Ramsay Research Grant in 2022 and an ME/CFS Catalyst Award in 2025. The study appeared in the Journal of Translational Medicine.
Why This Study Matters
•Indicates key questions for future rapamycin trials on ME/CFS:
Highlights need to account for placebo effects (e.g., by using stepped-wedge trials); to find specific purines and purinergic receptors dysregulated in people with ME/CFS; and to use wearable devices to collect more objective and detailed data from participants.
•Lays the groundwork for repurposing treatments:
Presents additional evidence for using the FDA-approved drug rapamycin to reduce mTOR dysregulation–related ME/CFS symptoms, including fatigue, orthostatic intolerance, post-exertional malaise, and poor sleep; also shows how compounded rapamycin may be better tolerated and more effective than generic rapamycin.
•Centers patient experience:
Demonstrates how to design observational studies and clinical trials that better accommodate people with debilitating ME/CFS, including by carrying out decentralized studies and trials (in which phlebotomists visit participants at home), providing high-quality medications to reduce adverse effects, and considering sex-based differences in medicine dosage.