Rapamycin for Chronic Fatigue Syndrome and Post Viral Syndromes (e.g. Long Covid)
November 27, 2025
Low-Dose Rapamycin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Evidence from a 2025 Decentralized Pilot Study
A 2025 open-label, multicenter pilot study published in the Journal of Translational Medicine evaluated weekly low-dose rapamycin (target 6 mg, titrated from 1 mg) in 86 patients with rigorously diagnosed ME/CFS over 90 days. The primary mechanistic hypothesis was that pathologic mTORC1 hyperactivation – a feature shared with subsets of Long COVID/post-acute sequelae of SARS-CoV-2 (PASC) – suppresses autophagic flux, impairs mitochondrial quality control, and drives neuroinflammation and post-exertional malaise (PEM). Inhibiting mTORC1 with rapamycin was therefore tested as a strategy to restore autophagy and metabolic resilience.
Key Clinical Outcomes (please see detailed discussion of scoring systems at bottom of blog)
74.3% of the intent-to-treat cohort (n=86) and 82.5% of day-30 completers (n=70) achieved clinically meaningful improvement across fatigue, PEM, and orthostatic intolerance domains.
Bell CFS Activity Scale increased 14.99% (37.4 → 43.3; p < 0.0001).
Multidimensional Fatigue Inventory (MFI-20) total score improved by 7.35 points (p < 0.0001).
SF-36 physical functioning and vitality subscales rose 15–20% (p < 0.0001).
Patients with documented viral onset (n=36) exhibited the most robust responses, consistent with mTORC1-driven post-viral phenotypes observed in both ME/CFS and Long COVID.
Mechanistic and Biomarker Correlates
Low-dose rapamycin produced clear pharmacodynamic evidence of mTORC1 inhibition and autophagic induction:
2-fold reduction in phosphorylated ATG13 (Ser258), confirming direct mTORC1 target engagement.
1.5-fold upregulation of BECLIN-1 protein expression.
Changes in autophagic markers correlated modestly but significantly with symptom improvement (Pearson r = 0.42–0.48, p < 0.05).
These findings align with emerging models of “mTORC1 syndrome” as a unifying pathophysiologic construct across ME/CFS, Long COVID, and other post-infectious fatigue states.
Safety Profile at Longevity-Relevant Dosing
No serious adverse events occurred. Transient mild adverse effects (grade 1 GI upset, headache) were confined to the titration phase and resolved without intervention. No clinically significant changes in lipids, glucose, CBC, or immune parameters were observed—consistent with the favorable tolerability of intermittent low-dose regimens (≤6 mg/week) well below immunosuppressive transplant exposures.
Mechanistic Rationale: Autophagy Restoration as a Longevity Intervention
Sustained mTORC1 hyperactivity in ME/CFS inhibits ULK1/ATG13 complex formation, blocking autophagosome initiation and resulting in accumulation of damaged mitochondria, protein aggregates, and redox stress—all hallmarks of accelerated biological aging. By relieving this brake, rapamycin re-enables mitophagy, proteostasis, and resolution of sterile neuroinflammation, effectively shifting the cellular milieu from a catabolic, inflammatory state toward anabolic repair. This mechanism mirrors the geroprotective effects seen in preclinical lifespan extension studies and provides a plausible bridge between symptom relief and potential disease modification in post-viral syndromes.
Complementary and Synergistic Interventions
Several agents with orthogonal mechanisms show preliminary efficacy in ME/CFS and Long COVID and may augment rapamycin’s effects:
Low-dose naltrexone (3–4.5 mg qhs): glial modulation and endorphinergic upregulation; retrospective series report 60–70% response rates with ~20–30% SF-36 vitality gains.
Low-dose methylene blue (8–24 mg/day): enhances complex IV activity and mitochondrial redox poise; emerging pilot data in Long COVID demonstrate marked fatigue and cognitive improvement.
N-acetylcysteine ethyl ester (NACET, 100–200 mg/day): superior CNS bioavailability and glutathione repletion compared to standard NAC; addresses the profound oxidative stress documented in ≥80% of ME/CFS cases.
When layered thoughtfully, these compounds protect mitochondria and curb inflammation during rapamycin-induced autophagic flux, potentially amplifying clinical benefit.
Limitations and Next Steps
The pilot was unblinded and lacked a placebo arm, introducing risk of expectancy bias. Objective functional measures (e.g., actigraphy, CPET) were not included, and attrition reduced the day-90 cohort to n=40. A placebo-controlled, crossover trial with wearable-based activity monitoring and explicit Long COVID enrollment launched in February 2025 and will provide higher-level evidence.
Clinical Implications
Intermittent low-dose rapamycin appears to be a safe, mechanistically grounded intervention capable of producing substantial symptom relief in a majority of ME/CFS patients, particularly those with viral onset. Given the 45–58% phenotypic overlap between Long COVID and ME/CFS, these data support cautious off-label exploration in post-acute viral fatigue syndromes under specialist supervision.
Disclaimer: Use of rapamycin for ME/CFS or Long COVID remains off-label and should only be undertaken with physician oversight and informed consent.
Description of Scoring Systems Above
The Bell CFS Activity Scale (also called the Bell Disability Scale) is a simple, clinician- or patient-reported 0–100 scale specifically designed to quantify functional capacity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
It measures overall daily activity level and ability to perform work, household, or social tasks in the context of severe, activity-limiting fatigue and post-exertional malaise.
Bell Scale – Key Levels (abbreviated)
100: No symptoms at rest; no limitation in normal activities
90: Minor symptoms; able to work full-time with minor difficulty
80: Mild symptoms at rest; near-normal activity with effort
70: Moderate symptoms at rest; can do most daily activities but with significant limitation; usually works part-time or reduced hours
60: Moderate-to-severe symptoms; able to perform basic self-care and light housework, but cannot work
50: Severe symptoms; mostly housebound; needs help with many daily activities
40: Severe symptoms; bedbound most of the day; significant help required
30: Bedbound most/all of the day; very limited self-care
20: Bedbound and requires full-time care
10: Completely bedbound, unable to care for self
0: Bedbound, incontinent, unable to communicate
Typical diagnostic criteria for ME/CFS require a Bell score of ≤70, with most patients scoring 20–50 at presentation.In clinical studies (including the 2025 rapamycin pilot), an increase of 10–20 points is considered clinically meaningful improvement.
Brief Description of the Multidimensional Fatigue Inventory (MFI-20)
The Multidimensional Fatigue Inventory (MFI-20) is a validated 20-item self-report questionnaire specifically developed to assess the multiple dimensions of fatigue in chronic illness, including ME/CFS, Long COVID, cancer, and other conditions.
It measures five distinct subscales (4 items each), scored from 4 (best) to 20 (worst) per subscale, for a total score range of 20–100:
General Fatigue – Overall fatigue experience (“I feel tired”)
Physical Fatigue – Perceived physical exhaustion and ability to perform tasks
Reduced Activity – Extent to which fatigue limits daily activities and work
Reduced Motivation – Lack of desire or mental energy to start tasks
Typical baseline total scores in moderate-to-severe ME/CFS: 75–95 (very high fatigue)
Healthy controls: ~30–45
In clinical trials, a change of ≥6–8 points in total score (or ≥2–3 points per subscale) is considered clinically meaningful.
In the 2025 rapamycin pilot study, the MFI-20 total score improved by 7.35 points (p < 0.0001), reflecting broad, multidimensional fatigue reduction.
Widely used because it captures more than just severity – it reflects the heterogeneous way fatigue manifests in post-viral and neuroimmune conditions.
Brief Description of the DePaul Symptom Questionnaire (DSQ)
(also known as the DePaul Symptom Questionnaire – Revised, DSQ-2, or DSQ-PEM in some versions)
The DePaul Symptom Questionnaire (DSQ) is a comprehensive, validated 54- to 99-item (depending on version) self-report instrument specifically designed to assess the full spectrum of ME/CFS symptoms and case definitions (e.g., Fukuda, Canadian Consensus Criteria, and IOM/SEID criteria).
Key Domains and Scoring
Each symptom is rated on two 0–4 scales over the past 6 months:
Frequency: 0 = none of the time → 4 = all of the time
Severity: 0 = symptom not present → 4 = very severe
These are typically combined into a composite score (0–100) for each item:(composite = (frequency × severity × 25) / 4) → range 0–100 per symptom.
Core Symptom Categories (most relevant to ME/CFS diagnosis)
ME/CFS diagnosis (Canadian or IOM criteria) typically requires ≥8 core symptoms above specific frequency/severity thresholds (e.g., ≥50/100 composite score).
In clinical trials, researchers often report changes in individual symptom severity scores (0–4 scale) or in key clusters (fatigue, PEM, orthostatic intolerance).
In the 2025 rapamycin pilot study, statistically and clinically significant reductions were reported on the 0–4 severity scale:– Fatigue: −1.34 points– PEM: −3.34 points– Orthostatic intolerance: −1.79 points(all p < 0.0001)
The DSQ is considered the gold-standard research tool for ME/CFS because it captures the characteristic pattern and severity of symptoms far better than generic fatigue scales. It is also widely used to identify ME/CFS-like phenotypes in Long COVID cohorts.
Brief Description of the SF-36 (Short Form 36 Health Survey)
The SF-36 is a widely used, validated 36-item patient-reported outcome measure of health-related quality of life. It is not specific to ME/CFS but is the most common generic quality-of-life instrument in ME/CFS and Long COVID clinical trials.
Structure and Scoring
It produces eight subscale scores (0–100, higher = better) and two summary scores:
Physical Component Summary (PCS) – weighted average of physical domains
Mental Component Summary (MCS) – weighted average of mental domains
Eight Subscales
Physical Functioning (PF) – ability to perform daily physical activities
Role-Physical (RP) – limitations in work/role due to physical health
Bodily Pain (BP)
General Health (GH)
Vitality (VT) – energy vs. fatigue level (most sensitive subscale in ME/CFS)
Social Functioning (SF)
Role-Emotional (RE) – limitations in work/role due to emotional problems
Mental Health (MH)
Interpretation in ME/CFS and Long COVID
Healthy population norms: ~50 ± 10 for PCS and MCS
Moderate-to-severe ME/CFS baseline:– PCS typically 25–35– MCS typically 35–45– Vitality subscale often the lowest single score (15–30)
A change of ≥5 points in PCS or MCS, or ≥10–15 points in Vitality, is considered clinically meaningful.
In the 2025 rapamycin pilot study
Statistically significant improvements were reported in both PCS and MCS (p < 0.0001)
The Vitality (energy/fatigue) subscale increased by approximately 15–20 points, representing one of the largest effect sizes seen in any published ME/CFS intervention to date.
Because it is generic and well-normed, SF-36 improvements allow direct comparison of disease burden and treatment response across chronic illnesses (e.g., ME/CFS patients often score lower than advanced cancer or heart failure on physical domains).
