Oxaloacetate

Oxaloacetate or oxaloacetic acid (OAA) or Anhydrous Enol-Oxaloacetate or (AEO) is a nutritional supplement which has received attention as a treatment for chronic fatigue and mental fatigue in ME/CFS and Long COVID.

Theory

Oxaloacetate is part of the Citric acid cycle and is formed from pyruvate. It is crucial in replenishing the citric acid cycle by acting as an acceptor for Acetyl coenzyme A. Additional oxaloacetate may provide mitochondrial support in ME/CFS.

Evidence

Cash et al. (2022) reported that "76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the "'Chalder Fatigue Questionnaire' of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks."

Cash et al. (2024) reported that "Oxaloacetate significantly reduced fatigue by more than 25% from baseline, while the control group showed a non-significant reduction of approximately 10%. Intergroup analysis showed a significant decrease in fatigue levels in the oxaloacetate group (p = 0.0039) with no notable change in the control group. A greater proportion of subjects in the oxaloacetate group achieved a reduction in fatigue greater than 25% compared to the control group (p < 0.05). Additionally, 40.5% of the oxaloacetate group were classified as “enhanced responders,” with an average fatigue reduction of 63%. Both physical and mental fatigue improved with oxaloacetate supplementation."

Vernon et al. (2025) reported that "The oxaloacetate (OAA) group showed greater cognitive improvement over time, with a significant between-group difference at Visit 3, 60 days into the trial, (p = 0.034) and trends at other visits. Higher fatigue was significantly associated with reduced cognitive gains in the OAA group (β = −0.34, p < 0.0001), but not in controls. UP Time increased modestly in the OAA group, reaching significance at Visit 2, day 30 (p = 0.044), though fatigue was not a strong predictor of UP Time in either group. At Visit 4, day 90, Global and Fatigue Only Responders were more frequent in the OAA group, while Cognitive Only Responders were more frequent in controls, though group differences did not reach statistical significance (p = 0.10)."

It is important to note that all three of these studies have significant conflicts of interest, being conducted primarily by the owner and employees of Terra Biological, the sole global producer of oxaloacetate. At least one of these studies is currently under investigation for major methodological and reporting accuracy concerns.

Costs and availability

Oxaloacetate is currently available solely from the US company Terra Biological in the products Oxaloacetate CFS, benaGene, and Jubilance. The sale of oxaloacetate by Terra Biological is controversial due to its high price (US$500 for Oxaloacetate CFS, 90 Capsules, 500mg) and the company's history of violating FDA regulations around the sale of new drugs and "medical foods"

Notable studies

• 2025, Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for myalgic encephalomyelitis/chronic fatigue syndrome
• 2024, RESTORE ME: a RCT of oxaloacetate for improving fatigue in patients with myalgic encephalomyelitis/chronic fatigue syndrome
• 2022, 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 - (Full text)