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 is the optimal dose, and are there subgroups requiring different dosing strategies?
- Does oxaloacetate improve other ME/CFS symptoms beyond fatigue (e.g., post-exertional malaise, cognitive dysfunction, autonomic dysfunction)?
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.
Topics
Tags
Metadata
- DOI
- 10.3389/fneur.2024.1483876
- PMID
- 39664752
- Review status
- Machine draft
- Evidence level
- Replicated human evidence from multiple independent studies
- Last updated
- 7 April 2026