Rapamycin for ME/CFS: Could mTOR Inhibition Unlock Recovery?
Rapamycin—also known as sirolimus—is an FDA-approved drug used for decades to prevent organ transplant rejection. But in recent years, it’s attracted attention well beyond transplant medicine. From longevity research to neurodegenerative disease trials, rapamycin is being investigated for its ability to regulate metabolism, immunity, and inflammation.
For people living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or long COVID, these effects may be particularly relevant. Early clinical trials and patient reports suggest rapamycin might help address some of the core biological abnormalities in these conditions, but it’s still very much experimental.
How Rapamycin Works
mTOR Inhibition, Fasting, and Ketogenic Metabolism
Rapamycin works by inhibiting mTOR (mechanistic target of rapamycin)—a key protein that senses nutrient and energy availability inside cells (Saxton, 2017). mTOR acts like a cellular switch: when it’s active, cells focus on growth and reproduction; when it’s suppressed, cells shift toward repair, cleanup, and energy conservation.
Suppressing mTOR has several potential benefits:
It promotes autophagy, the cell’s way of clearing damaged components
It improves mitochondrial quality control
It reduces oxidative stress and inflammation
mTOR Dysregulation and the “Metabolic Trap” in ME/CFS
One of the most consistent biological findings in ME/CFS is disrupted energy metabolism. Studies have shown:
Impaired ATP production
Inefficient mitochondrial function
A shift away from energy-efficient pathways
The metabolic trap hypothesis (Naviaux, 2020) proposes that in genetically susceptible individuals, a viral trigger can push tryptophan metabolism into a maladaptive, stuck state. This may lead to ongoing mTOR dysregulation and low cellular energy, even long after the original infection.
When mTOR becomes overactive or poorly regulated, it can:
Inhibit mitochondrial function
Block autophagy (cellular cleanup)
Increase production of reactive oxygen species (ROS), leading to oxidative stress and further cell damage
This sets the stage for a self-perpetuating cycle of energy depletion, inflammation, and mitochondrial dysfunction.
2. Immune Exhaustion and Dysregulation
Immune studies in ME/CFS consistently show that natural killer (NK) cells — an important part of the body’s first‑line defense — don’t work as well as they should (Brenu, 2011; Eaton‑Fitch, 2019). There’s also evidence of “tired” or exhausted T cells, which are less able to fight infections.
A major UK Biobank-linked study by Cliff et al. (2019) found that people with ME/CFS have fewer active naïve and memory T cells and higher levels of T-cell exhaustion markers like PD‑1. This pattern suggests the immune system has been worn down by ongoing exposure to viral or other triggers.
In a human clinical study, rapamycin reduced surgery‑induced T‑cell exhaustion in patients, evidenced by a significant decrease in T‑cell exhaustion markers (Svatek, 2015). This ability to calm an overactive immune system while restoring immune function when depleted makes rapamycin especially interesting for postviral illnesses like ME/CFS.
Where Rapamycin Fits In
By inhibiting mTOR, rapamycin may help “reset” this dysfunctional energy-sensing system. It can:
Re-activate autophagy
Improve mitochondrial function
Lower oxidative stress
This kind of metabolic reset could, in theory, help break the vicious cycle of fatigue and poor recovery that defines ME/CFS and long COVID.
Fasting, Ketones, and Other Ways to Influence mTOR
Interestingly, dietary strategies can also influence mTOR. Periods of fasting or very-low-carbohydrate ketogenic diets naturally suppress mTOR activity.
Ketone bodies—especially β-hydroxybutyrate—further signal cells to shift into a repair-focused mode, similar to the effects of rapamycin. Because of this overlap, rapamycin is often described as a “pharmacologic fasting mimetic.”
I’ve covered fasting, time-restricted eating, and ketogenic diets in other articles, and they may offer non-drug options for modulating the same cellular repair pathways—without the side effects of pharmaceutical intervention.
3. Rapamycin and Neuroinflammation
Advanced brain scans have shown signs of neuroinflammation in ME/CFS, with overactive microglia—immune cells in the brain—in many regions (Nakatomi, 2014). When microglia stay activated for too long, they can release chemicals that may worsen fatigue, slow thinking, and increase sensitivity to light, sound, or pain.
Rapamycin can cross the blood–brain barrier and has been shown to reduce certain patterns of microglial activation. By calming overactive microglia, rapamycin may help lower brain inflammation and possibly improve mental clarity, focus, and sensory tolerance.
Interestingly, low‑dose naltrexone (LDN) may work through a similar microglia‑modulating pathway, although by a different mechanism. I’ve discussed LDN’s role in ME/CFS in this article.
4. Mitochondrial Dysfunction and Impaired Autophagy
Research shows clear mitochondrial problems in ME/CFS, including reduced oxidative phosphorylation (OXPHOS)—the main way cells turn fuel into ATP energy—and slow recovery of mitochondrial function after exertion (Tomas, 2017). These defects mean that energy production is already limited, making it harder for patients to tolerate even mild activity.
When autophagy—the cell’s process for clearing away damaged parts—is impaired, defective mitochondria build up inside cells. These damaged mitochondria can leak reactive oxygen species, worsening oxidative stress and further slowing ATP production.
Rapamycin can stimulate mitophagy, a specific type of autophagy that removes faulty mitochondria. By clearing these defective mitochondria, rapamycin may improve mitochondrial quality and help restore more efficient energy production over time (Chiao, 2016).
Current Clinical Trials Using Rapamycin in Postviral Illness
Rapamycin for ME/CFS
A recent decentralized open-label trial in ME/CFS patients used 6 mg/week rapamycin for several months. About 72% of participants reported improvements in fatigue, post‑exertional malaise, and orthostatic intolerance. Side effects were generally mild, though some experienced mouth ulcers, rash, or digestive upset.
While these findings are promising, it’s important to remember that this is a preprint—meaning it has not yet been peer‑reviewed by independent scientists. Peer review is a critical process that can catch errors, confirm methods, and help determine whether results are reliable. Without it, the study’s conclusions should be viewed as preliminary.
The trial was also small and uncontrolled, meaning there was no placebo group for comparison. This makes it impossible to know how much of the improvement was due to the drug itself versus placebo effects, natural fluctuation in symptoms, or other factors. Larger, placebo‑controlled studies will be needed to confirm whether rapamycin is truly effective for ME/CFS.
Rapamycin for Long COVID/PASC
The Cohen Center at Mount Sinai is running a randomized, placebo-controlled trial of rapamycin in long COVID patients. Results are pending, but the study aims to assess fatigue, cognitive function, and immune biomarkers (NCT06960928).
Rapamycin Risks, Side Effects, and Drawbacks
Rapamycin is not without risks, especially if used long‑term. In transplant and cancer medicine, it is usually taken daily at high doses to suppress the immune system, but this comes with a higher side‑effect burden.
For aging research, longevity medicine, and the current ME/CFS studies, rapamycin is generally taken just once per week—not daily. This is because it has a long half-life of about 60 hours, so its effects on mTOR last for several days after a single dose. Weekly dosing is thought to reduce the risk of chronic immune suppression while still providing metabolic and anti-inflammatory benefits.
Short‑term side effects may include:
Mouth ulcers or canker sores
Skin rashes or acne‑like eruptions
Digestive upset (nausea, diarrhea)
Slower wound healing
Long‑term risks can include:
Higher risk of infections due to immune suppression
Elevated cholesterol and triglycerides
Possible effects on bone density
Impaired wound repair and recovery from surgery
Some longevity clinics use low‑dose intermittent protocols—often 5–10 mg once weekly or every other week—to reduce side effects. However, this approach is untested in ME/CFS, and the safest, most effective dosing schedule for postviral illness remains unknown. Anyone considering rapamycin should work closely with an experienced physician and undergo regular lab monitoring.
Rapamycin for ME/CFS: A Potential Game‑Changing Treatment
Rapamycin is one of the first drugs to directly target nearly every major biological pathway implicated in ME/CFS and postviral illness:
Metabolic reset — Inhibits overactive mTOR and may help “unlock” the metabolic trap, restoring healthier energy sensing and reducing oxidative stress.
Immune rejuvenation — May reverse T‑cell exhaustion and improve immune resilience.
Neuroinflammation reduction — Calms overactive microglia, a mechanism it shares with low‑dose naltrexone (LDN). Potentially, both could work together synergistically.
Mitochondrial renewal — Stimulates autophagy and mitophagy, clearing damaged mitochondria to improve energy production.
This is the first time we’ve had a single therapy with the potential to address all of these core abnormalities. Weekly dosing—used in research settings—also suggests it could be relatively affordable compared to many experimental treatments.
While early clinical results, including the 2025 ME/CFS preprint, are encouraging, rapamycin remains experimental for ME/CFS, long COVID, and other postviral syndromes. The safest way to explore it is within a clinical trial or under the guidance of a physician experienced in both ME/CFS and mTOR‑targeting drugs. If ongoing studies confirm its benefits, rapamycin could be a game‑changer in how we approach treatment for these conditions.
References
Ruan BT, Bulbule S, Reyes A, et al. Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy. Preprint. Res Sq. 2025;rs.3.rs-6596158. Published 2025 Jun 3. doi:10.21203/rs.3.rs-6596158/v1
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960‑976.
Naviaux RK, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. 2016;113(37):E5472‑E5480.
Naviaux RK. Metabolic trap hypothesis of ME/CFS. Mitochondrion. 2018;46:1‑5.
Brenu EW, et al. Immunological abnormalities in chronic fatigue syndrome. J Transl Med. 2011;9:81.
Eaton‑Fitch N, et al. A systematic review of natural killer cells in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2019;17:210.
Cliff JM, et al. Cellular immune function in myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2019;4(6):e125105.
Svatek RS, Ji N, de Leon E, et al. Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer. Cancer Immunol Res. 2019;7(3):466-475. doi:10.1158/2326-6066.CIR-18-0336
Nakatomi Y, et al. Neuroinflammation in patients with chronic fatigue syndrome. J Nucl Med. 2014;55(6):945‑950.
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