Benefits
Fatigue scores in a 3-month controlled trial
In 82 adults with ME/CFS, 2,000 mg a day for 3 months cut fatigue scores by more than 25% from baseline versus about 10% on rice-flour control (p = 0.0039), and more people improved by over 25%. In 69 adults with long COVID, the main fatigue scale did not differ from control after 42 days. Both trials were funded by the maker.
Cognitive test scores (reaction time and attention)
In the long COVID trial, the oxaloacetate group improved on a phone-based reaction-time and attention test battery, an exploratory outcome. In the ME/CFS trial, a later analysis found better cognitive test scores than control at day 60 (p = 0.034) but not at the other visits. Both were maker-funded.
Premenstrual mood, anxiety and stress scores (with vitamin C)
Tested as 200 mg oxaloacetate plus 300 mg vitamin C a day, not oxaloacetate alone, in 48 women with premenstrual mood symptoms. Over one cycle, self-rated depression improved 54% versus 31% on placebo, and anxiety and stress also improved more. The crossover order was set by enrollment, not randomized, and the supplier funded the study; its CEO is a co-author.
Lifespan in worms (C. elegans)
Oxaloacetate added to the diet extended lifespan in the roundworm C. elegans, and the effect depended on AMPK and FOXO, pathways also needed for the lifespan effect of dietary restriction. This is an animal finding; no study has measured lifespan or healthy aging in people.
Mechanism of action
Citric acid (Krebs) cycle intermediate
Oxaloacetate combines with acetyl-CoA to form citrate at the start of the citric acid cycle and is regenerated at its end. Blood levels of oxaloacetate were reported to be lower in people with ME/CFS, which is the rationale for the fatigue trials.
Glucose production intermediate
Oxaloacetate is also the starting point for gluconeogenesis, the pathway the liver uses to make glucose during fasting.
Link to aspartate and glutamate
Inside cells, oxaloacetate and glutamate are interconverted with aspartate and alpha-ketoglutarate by aspartate aminotransferase. Whether supplements change brain glutamate in people has not been shown.
AMPK and FOXO signalling (worm study)
In C. elegans, the lifespan effect of oxaloacetate required AMPK and the FOXO factor DAF-16, the same pathway needed for lifespan extension by dietary restriction. This has not been tested in people.
NAD+ and NADH balance
Converting oxaloacetate to malate uses NADH, which in principle raises the NAD+ to NADH ratio in cells. This is textbook biochemistry, not a measured effect of supplements in people.
Clinical trials
Randomized, double-blind, controlled trial: 2,000 mg a day of anhydrous enol oxaloacetate or rice-flour control for 3 months; primary endpoints were safety and fatigue reduction. (Cash et al. 2024, Front Neurol)
82 adults with ME/CFS.
Fatigue fell by more than 25% from baseline with oxaloacetate versus a non-significant fall of about 10% with control (between-group p = 0.0039); 40.5% of the oxaloacetate group were enhanced responders with a 63% average fall. Well tolerated. Funded by Terra Biological; the lead author is a company officer.
Randomized, double-blind, controlled single-center trial: 2,000 mg a day of oxaloacetate or rice-flour control for 42 days; the primary outcome was the Chalder Fatigue Questionnaire. (Vernon et al. 2025, Front Neurosci)
69 adults with long COVID in Salt Lake City, Utah.
The primary outcome was null: Chalder fatigue scores did not differ between groups. The DePaul symptom questionnaire showed greater fatigue and symptom improvement at day 21 only, and reaction-time test scores improved in the oxaloacetate group (exploratory). Treatment-emergent adverse events occurred in 43% on oxaloacetate and 29% on control, mostly mild. Funded by Terra Biological.
Secondary analysis of the 90-day randomized, double-blind ME/CFS trial of 2,000 mg a day oxaloacetate versus rice flour, looking at cognitive tests and upright time. (Vernon et al. 2025, Front Neurol)
82 adults with ME/CFS.
Cognitive test scores improved more with oxaloacetate, reaching a significant between-group difference only at day 60 (p = 0.034), and upright time was higher at day 30 (p = 0.044). Responder differences at day 90 were not significant (p = 0.10). One co-author was employed by Terra Biological.
Open-label, non-randomized, dose-escalating trial of 500 mg twice daily up to 1,000 mg three times daily for 6 weeks, compared with a historical placebo figure. (Cash et al. 2022, J Transl Med)
76 adults with ME/CFS and 43 with long COVID.
Chalder fatigue scores fell 22.5% to 27.9% from baseline in ME/CFS (P < 0.005), rising with dose, and by up to 46.8% in long COVID. With no concurrent placebo group, these figures cannot separate the supplement from placebo effects. Funded by Terra Biological.
Laboratory study in the roundworm Caenorhabditis elegans; not a human trial. (Williams et al. 2009, Aging Cell)
Roundworms (C. elegans), not people.
Oxaloacetate supplementation increased lifespan, and the effect depended on AMPK and the FOXO factor DAF-16. There are no human lifespan or aging data.