IngredientsOxaloacetate (systematically named 3-carboxy-3-oxopropanoic acid; abbreviated OAA) is a natural chemical that participates in the Krebs cycle and acts as a glutamate scavenger. It is also widely known under the synonyms oxaloacetic acid and oxalacetic acid. Oxaloacetic acid is a crystalline short-chain keto acid found in bacteria, plants, and animals. Its CAS registry number is 328-42-7. In chemical terms, OAA is a four-carbon, alpha-keto dicarboxylic acid that exists in two tautomeric forms: the predominant keto form and the less stable enol form.
Oxaloacetate is a 4-carbon dicarboxylate intermediate of the citric acid cycle (Krebs cycle or tricarboxylic acid cycle), involved in energy production within the mitochondria. It is endogenously synthesized in virtually all living organisms and is not considered a classical dietary nutrient, as the body produces it continuously through intermediary metabolism. Nevertheless, OAA is present at detectable concentrations in a variety of plant-based foods. It is found in blueberries, blackberries, tangerines, plums, spinach, beets, quinoa, as well as in legumes and nuts, which also have high OAA content. Oxaloacetic acid is also found in citrus fruits, wild rice, canola, and peanuts. Oxaloacetic acid can be found in a number of food items such as daikon radish, sacred lotus, cucurbita (gourd), and tarragon, which makes it a potential biomarker for the consumption of these food products.
Oxaloacetate forms in several ways in nature. A principal route is upon oxidation of malate, catalyzed by malate dehydrogenase, in the citric acid cycle. It is also produced from pyruvate via the enzyme pyruvate carboxylase, and from phosphoenolpyruvate via phosphoenolpyruvate carboxylase in bacteria and plants. In nature, there are many biochemical reactions that involve oxaloacetate, including gluconeogenesis, the glyoxylate cycle, glyoxylate degradation, mixed acid fermentation, anaerobic respiration, aerobic respiration (Krebs cycle), aspartate biosynthesis and degradation, and glutamate degradation.
OAA presents significant formulation challenges because of its chemical instability. Initially this compound was not used as a nutritional supplement, medical food, or drug due to very serious stability problems. Oxaloacetate commercially produced needs to be stored at −10 to −20 degrees Celsius, unless manufactured in the enol-oxaloacetate form, with water content less than 2%, and isolation from water sources (such as the atmosphere or other ingredients). Water catalyzes the conversion of enol-oxaloacetate to the lower energy state of the keto-oxaloacetate, which then spontaneously decays into pyruvate and carbon dioxide, making it difficult to use as a nutritional supplement, medical food, or drug.
The solution to this stability problem led to the principal commercial form used in supplements: Anhydrous Enol-Oxaloacetate (AEO) is a patented thermally stabilized oxaloacetate compound with a multiple-year stability rating that, when ingested, forms bioidentical oxaloacetate. Commercial capsule formulations pair thermally stabilized oxaloacetate (Anhydrous Enol-Oxaloacetate) with vitamin C to support stability and absorption. A US patent method to prevent the degradation of oxaloacetic acid involves creating anhydrous enol-oxaloacetate and isolating it with water content less than 2% from moisture with a sealed encapsulation. An early clinical stabilization method used sodium salt (sodium oxaloacetate), which was employed in the landmark 1968 Yoshikawa study. The supplement has been marketed under the brand name BenaGene, among others. A nutritional supplement called BenaGene™ consisting of oxaloacetic acid is used for improving brain health and cognitive function.
OAA has no substantive history of use in traditional ethnobotanical or herbal medicine systems as an isolated compound. Its entry into scientific consciousness was driven entirely by laboratory biochemistry rather than folkloric therapeutic tradition.
Early research into oxaloacetic acid began in the 1890s and 1900s, during investigations into acid production in bacteria. In 1919, Harold Raistrick, the "father of the study of fungal metabolites," and Anne Clark hypothesized that oxaloacetic acid was a precursor of citrate in fungi. In 1935, Albert Szent-Györgyi observed that C4 dicarboxylic acids, including oxaloacetic acid, acted as catalysts in oxidation reactions, a discovery that laid groundwork for the subsequent elucidation of cellular respiration. In 1937, Hans Krebs described OAA's role in the citric acid cycle, which earned Krebs a share of the 1953 Nobel Prize in Physiology or Medicine.
The first direct therapeutic investigation in humans came from Japan. It was known that a decoction of Eunymus alata Sieb growing in Japan had a blood-sugar-lowering action. The effective component was isolated, crystallized, and identified as oxaloacetic acid (OAA) by infrared spectral analysis. A stable salt of OAA (OAA-sodium) was prepared, and its administration brought about lowering of the blood sugar level in normal and alloxan-diabetic animals. The same drug was given to diabetic patients, and it was found effective in all 10 of Type I and in 6 of 11 of Type II diabetics. This 1968 Yoshikawa study published in Tohoku Journal of Experimental Medicine (PMID: 4884771) represents the first controlled human administration of an isolated OAA preparation.
Interest in OAA as a dietary supplement arose primarily in the 2000s and 2010s, driven by emerging research into caloric restriction mimetics and mitochondrial medicine, and was advanced in large part by the commercial development of stable AEO formulations.
Oxaloacetate is central to energy use in all known living things. It is part of the citric acid cycle, also known as the Krebs cycle (or tricarboxylic acid cycle), which releases the energy stored in carbohydrates, fats, and proteins. Within the cycle, OAA condenses with acetyl-CoA — catalyzed by citrate synthase — to form citrate. The reaction is thermodynamically very favorable and effectively pulls the preceding step (formation of OAA from malate by malate dehydrogenase) forward. OAA is made by malate dehydrogenase (MDH); the MDH reaction is energetically unfavorable (ΔG +29.7 kJ/mol), but in reality this is overcome by the next reaction in the Krebs cycle (citrate synthase, ΔG −31.5 kJ/mol), so OAA gets removed as soon as it is made, pulling the cycle forward.
Oxaloacetic acid plays a role in amino acid synthesis, particularly through transamination reactions using glutamate from the TCA and urea cycles, and is directly involved in the synthesis of two non-essential amino acids, aspartate and asparagine. Aspartate is produced from oxaloacetate, which is a central metabolite of the citric acid cycle. OAA is also a critical branch point for gluconeogenesis: oxaloacetate is subsequently decarboxylated, shuttled out of the mitochondrion, and then phosphorylated by PEPCK in a reaction that requires GTP, committing carbon toward new glucose synthesis.
A key proposed mechanism underlying OAA's putative anti-aging and metabolic effects is its ability to shift the cellular redox balance. In Caenorhabditis elegans, supplementation with oxaloacetate increases the ratio of NAD⁺ to NADH to activate AMPK and FOXO signaling pathways similar to what occurs in calorie restriction. The increase in the NAD⁺/NADH ratio is due to the reaction of oxaloacetate to malate in the cytoplasm via the enzyme malate dehydrogenase. While reduced glucose levels can activate AMPK, the enzyme is also especially sensitive to NAD⁺ and NADH. High levels of NAD⁺ activate AMPK, whereas NADH inhibits the activity of AMPK. High levels of NAD⁺, relative to NADH, may support other age-related mechanisms in the cell. These include the sirtuins and AMPK, which have been linked to increased lifespan and reduced rates of degenerative diseases in animal models.
A distinct and well-studied mechanism is OAA's ability to reduce circulating and brain glutamate levels. Oxaloacetate reduces glutamate levels by breaking it down (to α-ketoglutarate). More specifically, when oxaloacetate and glutamate encounter an enzyme called glutamate oxaloacetate transaminase (GOT), the enzyme transforms them both, and they emerge as aspartate and α-ketoglutarate. In medical research, this is called glutamate scavenging, and it could help prevent high levels of glutamate from building up in the brain and becoming destructive.
A study found that oxaloacetate (OAA) inhibits human lactate dehydrogenase A (LDHA) in cancer cells, reversing the Warburg effect. Various cellular and molecular studies have proposed that instead of fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), gliomas prefer to use glycolysis (the Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for accelerated mitosis. OAA's inhibition of LDHA represents a potential strategy to redirect cancer-cell metabolism toward mitochondrial oxidative phosphorylation.
Oxaloacetate, a key intermediate of the citric acid cycle, has demonstrated the potential to modulate cellular metabolism, enhance mitochondrial biogenesis, and reduce neuroinflammation in preclinical models.
The bioavailability of orally administered OAA is an area of active debate. OAA levels were not increased at 30 minutes but were increased at 60 minutes after 200 mg were orally administered to three subjects; on average, OAA levels rose from 0 µg/100 mL to 2.3 µg/100 mL. Yoshikawa tested an oral preparation of sodium oxaloacetate on three patients, and found that 200 mg of oxaloacetate was found in the bloodstream after 1 hour, in amounts that calculate out to be about 2 to 5% of the dose provided. Critics have raised questions about whether orally ingested OAA can reach intracellular compartments in meaningful concentrations. It is unlikely that 100 mg of oral OAA would appreciably increase the level of this metabolite in tissues. Essentially, non-esterified OAA at a low external concentration will not get into cells, and unfortunately that is where the MDH enzyme (required for the claimed mechanism of action) is located. This represents a significant unresolved question in the field.
This is the area with the most developed clinical trial evidence to date.
The energy metabolite oxaloacetate is significantly lower in the blood plasma of ME/CFS subjects.
Open-label non-randomized trial (Cash & Kaufman, 2022): 76 ME/CFS patients (73.7% women, median age 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 twice daily to 27.6% for 1000 mg twice daily to 33.3% for 1000 mg three times daily. Long COVID patients' fatigue was significantly reduced by up to 46.8% in 6 weeks. This trial had a critical limitation: concerns have been raised regarding the methodology and reporting of this clinical trial and an incomplete declaration of competing interests, which were investigated by the Editor-in-Chief, with further editorial action indicated as appropriate. Additionally, one author (Alan Cash) is an officer in a pharmaceutical company that provided funding for the clinical trial; funding was provided by Terra Biological LLC.
RESTORE ME — Randomized, Double-Blind Controlled Trial (Cash et al., 2024): 82 ME/CFS subjects were enrolled in a 3-month randomized, double-blinded, controlled study, receiving either 2,000 mg of oxaloacetate or control per day. The primary endpoints were safety and reduction in fatigue from baseline. This 3-month, double-blinded, randomized, controlled clinical trial showed that oxaloacetate was well tolerated in ME/CFS patients at a dosage of 2,000 mg/day (1,000 mg twice daily with a meal). The study showed significant and sustained reductions in fatigue from baseline, ranging between 27 and 32%, which were not observed in the control group. Intergroup analysis showed a significant reduction in fatigue levels in the oxaloacetate group, which was absent in the control group. The trial enrolled primarily white women with mild-to-moderate ME/CFS, as participants were specifically selected because changes in their fatigue level could be measured using existing validated surveys without encountering the "ceiling effect" caused by excessively high fatigue levels, limiting generalizability to more severely affected patients. Funding source and conflict-of-interest considerations similar to those for the earlier open-label trial apply.
Evidence strength: Preliminary to moderate. Signals from both open-label and one blinded RCT are consistent, but sample sizes are small, the research group has industry ties, and independent replication is lacking.
REGAIN — Randomized, Controlled Clinical Trial (2025): This was a single-center, randomized, double-blind, controlled clinical trial investigating the use of anhydrous enol-oxaloacetate (oxaloacetate, OAA) to reduce fatigue in long COVID patients. The primary objective was to determine the safety and effectiveness of oxaloacetate in reducing fatigue. The effects of oxaloacetate supplementation on physical and cognitive impairment were also explored. The DSQ responder rates (defined as a ≥10% reduction in the total DSQ-SF score from Visit 1 to Visit 3) were 63% in the OAA group and 41% in the control group.
Evidence strength: Preliminary. A single RCT showing favorable trends; independent replication required.
The rationale for investigating OAA in Alzheimer's disease (AD) is based on the well-established observation that brain glucose metabolism is defective in AD. One bioenergetic medicine agent of particular interest is oxaloacetate. OAA reportedly reduces hyperglycemia in type II diabetes and extends longevity in C. elegans. Due to its bioenergetic, anti-inflammatory, and neurogenetic properties, OAA has been postulated as a possible treatment for AD.
Pharmacokinetic/Safety Pilot Study (Swerdlow et al., 2016): A PK-safety study in AD subjects used 100 mg OAA capsules administered to 6 subjects from the University of Kansas Alzheimer's Disease Center. Subjects continued on 100 mg twice daily for one month, then returned for follow-up blood sampling, safety labs, and cognitive tests. There were no drop-outs, pre- and post-treatment cognitive scores were comparable, safety labs were unremarkable, and no side effects were reported.
TOAD — Trial of Oxaloacetate in Alzheimer's Disease (Vidoni et al., 2019/2021): Researchers orally administered 500 or 1000 mg OAA twice daily for 1 month to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, they performed fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance spectroscopy before and after the intervention. Pharmacokinetics and cognitive performance were also assessed. Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG-PET glucose uptake across multiple brain regions (P < 0.05), and the higher dose increased parietal and frontoparietal glutathione (P < 0.05). Consistent blood level changes were not demonstrated, and cognitive scores did not improve. The authors concluded that OAA 100 mg capsules twice per day for one month is safe in AD subjects but does not result in a consistent and clear increase in the OAA blood level, thus necessitating future clinical studies to evaluate higher doses.
Evidence strength: Preliminary. The TOAD study demonstrated safety and a pharmacodynamic signal (improved brain glucose uptake) at higher doses, but no cognitive benefit was observed. The study was small, short-duration (one month), and did not establish consistent pharmacokinetics.
Yoshikawa 1968 (Human study): Prior to modern OAA clinical studies, the literature reported only one human study of OAA: a 1968 study that evaluated its potential anti-hyperglycemic effects. This study, performed in human diabetics, reported OAA was well-tolerated and provided limited pharmacokinetic data. The same drug was given to diabetic patients, and it was found effective in all 10 of Type I and in 6 of 11 of Type II diabetics. In humans, this 1968 study showed that oxaloacetic acid reduced hyperglycemia in type II diabetes, but more recent evidence is lacking.
In animal models, oxaloacetic acid has been shown to activate the insulin signaling pathway in murine models. Oxaloacetic acid supplementation has been hypothesized to mimic calorie restriction, which may help to reduce fasting glucose levels and improve insulin resistance.
Evidence strength: Very weak in humans. The single human study from 1968 is small and methodologically limited by contemporary standards. No modern RCTs have evaluated OAA specifically for glycemic control.
The evidence base here is largely preclinical (animal models), with no completed human trials.
Ischemic stroke is associated with an excessive release of glutamate into the neuronal extracellular space; a decrease in blood glutamate levels could provide a mechanism to remove it from the brain by increasing the brain-blood gradient. In this regard, the ability of glutamate oxaloacetate transaminase (GOT) to metabolize glutamate in blood could represent a potential neuroprotective tool for ischemic stroke. In an animal model of cerebral ischemia, oxaloacetate-mediated GOT activation inhibited the increase of blood and cerebral glutamate after middle cerebral artery occlusion. This effect was reflected in a reduction of infarct size, smaller edema volume, and lower sensorimotor deficits with respect to controls. The systemic administration of oxaloacetate represents a novel neuroprotective strategy to minimize the deleterious effect of glutamate in brain tissue after ischemic stroke. The neuroprotective effect of oxaloacetate is based on the capacity of this molecule to reduce brain and blood glutamate levels as a result of the activation of the blood-resident enzyme glutamate-oxaloacetate transaminase.
Evidence strength: Preclinical only. Consistent findings in rodent models of ischemic stroke, but no human clinical trial evidence exists for this indication.
OAA has been recognized by the US FDA for use in GBM (glioblastoma multiforme) patients, triggering a review to revisit the cellular mechanism of its therapeutic action. Anhydrous Enol-Oxaloacetate has been shown to significantly increase survival and decrease tumor growth rates in animal models of glioblastoma and hepatocellular carcinoma. Studies revealed that OAA supplementation reduced Warburg glycolysis, improved neuronal cell bioenergetics, and triggered brain mitochondrial biogenesis, thereby enhancing the efficacy of standard treatment. OAA has been found in preclinical investigations to be able to decrease tumor development and survival rates by blocking the conversion of glutamine to alpha-ketoglutarate (alpha-KG) in the TCA cycle and lowering NADPH levels. OAA is a safe adjuvant that has the potential to be an effective therapy in gliomas when combined with temozolomide (TMZ) chemotherapy and routine surgery, though this conclusion is based on preclinical data. Further human experience data are available from a case series by Kesari, in which human subjects with gliomas were administered oxaloacetate at doses far greater than 500 mg twice daily; this case series includes 8 subjects whose single dose was 1000 mg and 6 subjects whose single dose was 2000 mg.
Evidence strength: Preliminary. Supportive preclinical data in animal and cell models, plus a small uncontrolled case series in glioma patients. No completed randomized controlled trials in oncology.
Reduced dietary intake increases lifespan in a wide variety of organisms and retards disease progression. Researchers tested whether dietary supplementation of citric acid cycle metabolites could mimic this lifespan effect. They reported that oxaloacetate supplementation increased lifespan in Caenorhabditis elegans. The increase was dependent on the transcription factor FOXO/DAF-16 and the energy sensor AMP-activated protein kinase, indicating involvement of a pathway that is also required for lifespan extension through dietary restriction. Because of its parallel effects on these pathways, oxaloacetate was proposed as a CR mimetic.
Evidence strength: Animal/invertebrate model only. The C. elegans finding is mechanistically informative but cannot be directly extrapolated to human lifespan. No human longevity data exist.
Oxaloacetate treatment has been reported to preserve motor function in SOD1G93A mice and normalize select neuroinflammation-related parameters in the spinal cord. Oxaloacetate treatment has a neuroprotective effect in rodent models of seizure and neurodegeneration. A Phase 1b dose escalation study was conducted at the University of Kansas Medical Center. 18 clinically definite, probable, or laboratory-supported probable ALS patients were enrolled. Each cohort received the drug for 28 days. The first 3 patients received 1000 mg twice daily, and subsequent cohorts increased by 500 mg per dose to a maximum of 2500 mg twice daily; cohorts ranged from 1000 mg to 2500 mg twice daily. There were no dose-limiting toxicities.
Evidence strength: Preliminary Phase 1 safety data only. Efficacy in ALS has not been established in controlled trials.
OAA has been shown to have a protective effect in liver disease and injury. A 2018 metabolomics study found oxaloacetic acid alleviated liver injury by scavenging reactive oxygen species, increasing ATP, and inhibiting mitochondrial apoptosis.
Evidence strength: Preclinical/in-vitro only. No human clinical trial data on liver protection.
It has been suggested that oxaloacetic acid plays a role in the mechanism of action for the ketogenic diet's beneficial effects on epileptic seizures. Ketogenic diets reduce glucose and pyruvate availability, reducing oxaloacetic acid levels via the TCA cycle. With less oxaloacetic acid, the body struggles to handle high levels of acetyl-CoA generated from fat, leading to ketone production as an alternative energy source. This is a mechanistic hypothesis linking OAA depletion to the ketogenic diet's effects; OAA supplementation has not been studied as a treatment for epilepsy.
The following doses are drawn directly from published clinical research and should not be construed as recommendations:
It is observed that temperature, pH, metal ions (Cu, Fe), and interaction with amines have a strong impact on the decomposition rate of oxaloacetate, which underscores the importance of the specific formulation and storage conditions affecting the actual dose delivered.
Oxaloacetate is probably safe, but there are few human studies. Across the clinical studies conducted to date, the overall impression is of favorable tolerability at doses up to 2,000–5,000 mg/day.
In a small clinical trial of oxaloacetate and Parkinson's disease, 7 out of 18 (39%) people reported that their symptoms had gotten worse, compared with 1 out of 15 (7%) taking the placebo. If a patient has Parkinson's disease, this signal warrants caution pending further research.
There is little clinical work completed and drug interactions are unknown. No formal drug interaction studies for OAA have been published. Given OAA's role in glucose metabolism and insulin signaling, concurrent use with antidiabetic medications warrants particular attention in theory, though no human interaction data exist to quantify this risk.
Krebs reported that multivalent cations such as Al, Cu, Fe(II), Fe(III) catalyze the ketone decompositions of oxaloacetic acid, and these cations do not stabilize alpha-ketonic-dicarboxylic acids. Temperature, pH, metal ions (Cu, Fe), and interaction with amines have a strong impact on the decomposition rate of oxaloacetate. This means that supplement quality, storage conditions, and co-ingredients are directly relevant to whether the labeled dose is actually delivered. OAA is unstable, and a thermally stabilized form should be used.
A fundamental unresolved question bearing on both efficacy and mechanism is whether orally ingested OAA reaches intracellular or blood levels sufficient to exert the proposed pharmacological effects. A human safety study found that 200 mg per day of oral oxaloacetate did not significantly affect levels of oxaloacetate in the blood. The TOAD trial also did not demonstrate consistent blood level changes at the doses tested. Whether higher doses overcome this bioavailability barrier has not been conclusively established.
Health conditions that Oxaloacetic acid may help support.
Body systems that Oxaloacetic acid may help support.
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