Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial. — ME/CFS Atlas
Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial.
Cash, Alan, Kaufman, David Lyons · Journal of translational medicine · 2022 · DOI
Quick Summary
This study tested whether a supplement called oxaloacetate could help reduce fatigue in ME/CFS and Long COVID patients. Over 6 weeks, patients taking oxaloacetate showed significant improvements in both mental and physical fatigue—with ME/CFS patients improving by 22–33% depending on dose, and Long COVID patients improving by up to 47%—compared to expected placebo improvements of about 6%.
Why It Matters
With no FDA-approved treatments for ME/CFS fatigue and millions suffering from persistent post-COVID fatigue, this study offers preliminary evidence for a potential low-risk nutritional intervention. The dose-dependent response pattern and improvements substantially exceeding historical placebo suggest oxaloacetate warrants further rigorous investigation in this severely understudied patient population.
Observed Findings
ME/CFS patients receiving 500 mg BID showed 21.7% fatigue reduction; those receiving 1,000 mg BID showed 27.6% reduction; and those receiving 1,000 mg TID showed 33.3% reduction (dose-dependent response).
Long COVID patients showed fatigue reductions up to 46.8% over 6 weeks.
Both physical and mental fatigue components improved significantly in both patient populations compared to baseline (P < 0.005).
Improvement exceeded historical placebo control average of 5.9%.
Inferred Conclusions
Oxaloacetate may effectively reduce pathological fatigue in both ME/CFS and Long COVID patients, with higher doses associated with greater benefit.
The medication-like efficacy combined with its classification as a nutritional supplement suggests it could bridge an important treatment gap for millions of patients.
Further rigorous randomized controlled trials are warranted to confirm efficacy and establish optimal dosing.
Remaining Questions
Does oxaloacetate reduce fatigue through specific biological mechanisms (e.g., ATP production, mitochondrial function) or through placebo/expectancy effects in this open-label design?
What is the optimal effective dose, and does tolerability or safety change at higher doses over longer treatment periods?
What This Study Does Not Prove
This study does not prove oxaloacetate is effective because it lacks a concurrent randomized control group receiving placebo in parallel—relying instead on historical placebo data introduces bias and cannot control for concurrent environmental or temporal factors. The open-label design is subject to placebo response and expectancy effects, and the study cannot establish whether oxaloacetate specifically alleviates fatigue through a biological mechanism or through other unmeasured factors.
Tags
Symptom:Fatigue
Biomarker:Metabolomics
Phenotype:Long COVID Overlap
Method Flag:PEM Not DefinedWeak Case DefinitionExploratory OnlyMixed Cohort
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →