RESTORE ME: a RCT of oxaloacetate for improving fatigue in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Cash, Alan, Vernon, Suzanne D, Rond, Candace et al. · Frontiers in neurology · 2024 · DOI
Quick Summary
This study tested whether a supplement called oxaloacetate could help reduce fatigue in ME/CFS patients. Eighty-two people with ME/CFS took either 2,000 mg of oxaloacetate or a placebo daily for three months. The oxaloacetate group experienced a significant 25% reduction in fatigue, while the placebo group only improved by 10%, and the supplement was well tolerated with no safety concerns.
Why It Matters
Fatigue is the hallmark and most disabling symptom of ME/CFS, and existing treatments are limited. This study provides evidence that targeting a specific metabolic deficiency—low oxaloacetate—may be a viable therapeutic approach, offering potential relief to a patient population with few effective options. The high proportion of "enhanced responders" suggests oxaloacetate could benefit a substantial subset of ME/CFS patients.
Observed Findings
Oxaloacetate supplementation (2,000 mg daily) reduced fatigue by >25% from baseline (p = 0.0039 vs. placebo group).
Control group showed a non-significant ~10% fatigue reduction.
40.5% of oxaloacetate recipients were classified as "enhanced responders" with an average 63% fatigue reduction.
Both physical and mental fatigue domains improved with oxaloacetate.
Oxaloacetate was well tolerated at the tested dose with no notable safety concerns.
Inferred Conclusions
Oxaloacetate supplementation is an effective and safe intervention for reducing fatigue in ME/CFS patients.
A substantial subgroup of ME/CFS patients (enhanced responders) derive substantial benefit (>60% reduction) from oxaloacetate supplementation.
Metabolic interventions targeting low plasma oxaloacetate may represent a promising therapeutic avenue for ME/CFS.
Remaining Questions
What baseline biomarkers or clinical characteristics predict which patients will be "enhanced responders" to oxaloacetate?
Does fatigue reduction persist after discontinuation of oxaloacetate, or is continued supplementation necessary?
What This Study Does Not Prove
This study does not prove that oxaloacetate deficiency is the root cause of ME/CFS fatigue—only that supplementation improves symptoms. It also does not establish optimal dosing, duration of treatment, long-term safety, or whether benefits persist after supplementation stops. The study's 3-month timeframe limits conclusions about sustainability of improvement.
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 →
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