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Oxaloacetate (Anhydrous Enol)

Oxaloacetic acid (anhydrous enol form, AEO) — endogenous TCA cycle intermediate
Evidence Level
Limited
4 Clinical Trials
5 Documented Benefits
2/5 Evidence Score

Oxaloacetate is a Krebs cycle intermediate available as a supplement (typically the anhydrous enol form, marketed as benaGene™). Clinical interest comes from its proposed effects on cellular energy metabolism, longevity pathways (NAD+ ratio modulation, AMPK activation), and cognitive function. Animal studies show lifespan extension and metabolic benefits; human trials are smaller and more limited but show some cognitive and metabolic effects. Also being investigated for chronic fatigue syndrome and post-COVID fatigue, with emerging clinical data. The honest framing: an interesting longevity-oriented supplement with strong mechanistic rationale but limited rigorous human evidence; reasonable for early-adopters of longevity protocols but not yet a validated cognitive enhancer or fatigue treatment. Expect more clinical data over the next few years.

Studied Dose 100–300 mg/day anhydrous enol oxaloacetate; cognitive 100–200 mg twice daily; fatigue up to 1,000–2,000 mg/day.
Active Compound Anhydrous enol-oxaloacetate (AEO), a stabilized form of oxaloacetate (OAA); a 4-carbon dicarboxylic acid and TCA-cycle/gluconeogenesis intermediate.

Benefits

Cellular energy metabolism support

Oxaloacetate is a key Krebs cycle intermediate that supports cellular ATP production. Mechanism explains the interest in metabolic and energy applications — supplementation may support mitochondrial function in conditions of metabolic stress.

Supported by Trial 4

NAD+ ratio modulation

Oxaloacetate raises the NAD+/NADH ratio in cells, indirectly mimicking some effects of caloric restriction. Mechanism overlaps with NMN, NR, and other longevity-targeted supplements — different pathway, similar downstream effects.

Supported by Trial 4

AMPK activation for longevity

Oxaloacetate activates AMPK — the same metabolic pathway targeted by metformin, berberine, and exercise. Activation supports the longevity-oriented marketing claims and has mechanistic support across multiple pathways.

Supported by Trial 4

Chronic fatigue syndrome support (emerging)

Early clinical trials in chronic fatigue syndrome and post-viral fatigue suggest oxaloacetate may reduce fatigue scores at high doses. Effects are promising but evidence is limited to small open-label or pilot studies.

Supported by Trial 3, Trial 1

Cognitive function support

Emerging trials suggest cognitive benefits with oxaloacetate supplementation, possibly through energy metabolism and AMPK-mediated effects in the brain. Clinical evidence is preliminary and effect sizes are still being established.

Supported by Trial 1, Trial 3

Mechanism of action

1

TCA (Krebs) cycle intermediate

Oxaloacetate combines with acetyl-CoA to form citrate at the entry point of the TCA cycle, and is regenerated at the cycle's end. Adequate oxaloacetate flux is rate-limiting in some metabolic states; supplementation provides substrate where endogenous synthesis is impaired. Low plasma OAA has been measured in ME/CFS, consistent with a substrate-deficiency hypothesis.

2

Gluconeogenesis intermediate

Oxaloacetate is the entry point for gluconeogenesis, where it is converted to phosphoenolpyruvate by PEPCK. Relevant to glucose metabolism during fasting and exercise.

3

Glutamate scavenging (excitotoxicity protection)

Oxaloacetate combines with glutamate to form aspartate via aspartate aminotransferase. Plasma OAA elevation may scavenge excess extracellular glutamate, reducing excitotoxic signaling. This is the proposed mechanism for the cognitive improvements observed in REGAIN's secondary endpoints.

4

AMPK activation (caloric restriction mimetic)

Oxaloacetate activates AMPK and FOXO pathways in C. elegans, pathways central to calorie-restriction effects on lifespan. This mechanism underlies the longevity-research interest, though human translation is preclinical-stage only.

5

NAD+/NADH ratio modulation

Conversion of oxaloacetate to malate consumes NADH and elevates the NAD+/NADH ratio — relevant to mitochondrial function and cellular redox state. Mechanistic rationale for the metabolic-support positioning.

Clinical trials

1
Long COVID Clinical Trial (Most Rigorous, Mixed Results)

Clinical evidence on Oxaloacetate (Anhydrous Enol) for the indications and outcomes described.

Clinical population described in trial publication.

Vernon SD et al. 2025, Frontiers in Neuroscience 19:1627462. Randomized double-blind single-center controlled trial at the Bateman Horne Center, n=69 long COVID patients, 2,000 mg/day anhydrous enol-oxaloacetate vs control for 42 days. NCT05840237. Primary endpoint (Chalder Fatigue Questionnaire) was not statistically significant. Secondary/exploratory: DSQ-SF fatigue improved significantly, DANA Brain Vital cognitive battery improved (memory and processing speed), symptoms improved earlier (by 3 weeks). The most rigorous trial to date — mixed interpretation.

2
Restore — ME/CFS Clinical Trial (n=82)

Clinical evidence on Oxaloacetate (Anhydrous Enol) for the indications and outcomes described.

Clinical population described in trial publication.

Cash A et al. 2024, Frontiers in Neurology 15:1483876. Randomized double-blind controlled trial in 82 ME/CFS subjects, 2,000 mg/day oxaloacetate vs control for 3 months. Primary endpoints were safety and fatigue reduction; OAA was well tolerated. Foundational clinical trial-level evidence for the ME/CFS application.

3
Cassileth & — ME/CFS Non-Randomized Trial

Clinical evidence on Oxaloacetate (Anhydrous Enol) for the indications and outcomes described.

Clinical population described in trial publication.

Cassileth &, J. Translational Medicine. Non-randomized controlled trial in 76 ME/CFS and long COVID patients reported 22.5-27.9% Chalder Fatigue Scale reduction at 6 weeks vs historical placebo (P<0.005). Open-label proof-of-concept that motivated the subsequent restore ME and REGAIN clinical trials.

4
C. elegans Lifespan Extension (Preclinical)

Clinical evidence on Oxaloacetate (Anhydrous Enol) for the indications and outcomes described.

Clinical population described in trial publication.

Williams DS et al. 2009, Aging Cell. Oxaloacetate extended lifespan in C. elegans via AMPK and FOXO pathway activation — a calorie-restriction-mimetic mechanism. Foundational preclinical evidence underlying longevity-research interest. Animal model only; no human longevity outcome data exists.

Side effects and drug interactions

Common Potential side effects

Generally well-tolerated; few significant adverse effects in trials.
Mild GI upset (nausea, abdominal discomfort) at high doses.
Possible mood activation in sensitive individuals.
Pregnancy/lactation: insufficient data.
Allergic reactions: rare.
Long-term safety beyond 6 weeks: limited data.

Important Drug interactions

Generally no clinically significant interactions documented.
Theoretical: substrates of aspartate aminotransferase (AST) — affects amino acid metabolism but clinical relevance unclear.
Diabetes medications: theoretical mild glucose-lowering through gluconeogenesis modulation; monitor.
Most medications: compatible at typical doses.
No specific warnings established.

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Frequently asked questions about Oxaloacetate (Anhydrous Enol)

What is oxaloacetate used for?

Oxaloacetate is a compound in the body's energy (Krebs) cycle, marketed for cellular energy, brain health, and as a calorie-restriction mimetic for healthy aging. It is also used by some for fatigue conditions.

What is oxaloacetate good for?

It is studied for supporting brain and metabolic health and for mimicking some effects of calorie restriction (of interest in aging research), and it is used for fatigue and cognitive support. Human evidence is limited and early.

How much oxaloacetate should I take?

It is dosed per the specific (often stabilized) product, since plain oxaloacetate is unstable; follow product labeling. It is taken on an empty stomach in some protocols.

Is oxaloacetate safe?

It appears generally well tolerated in studies. Long-term human safety and benefit data is still developing, so use as directed, and those on medication or with medical conditions should check with a doctor.

What is Oxaloacetate?

Oxaloacetate is a Krebs cycle intermediate available as a supplement (typically the anhydrous enol form, marketed as benaGene™). Clinical interest comes from its proposed effects on cellular energy metabolism, longevity pathways (NAD+ ratio modulation, AMPK activation), and cognitive function.

What is the recommended dosage of Oxaloacetate?

The clinically studied dose is 100–300 mg/day anhydrous enol oxaloacetate; cognitive 100–200 mg twice daily; fatigue up to 1,000–2,000 mg/day. Always follow the product label and check with a healthcare provider for personal advice.

Is Oxaloacetate safe, and does it have side effects?

For most healthy adults, Oxaloacetate is well tolerated at studied doses. Reported effects can include: Generally well-tolerated; few significant adverse effects in trials. Mild GI upset (nausea, abdominal discomfort) at high doses. It may also interact with some medications. Oxaloacetate is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does Oxaloacetate interact with any medications?

Possible interactions include: Generally no clinically significant interactions documented. Theoretical: substrates of aspartate aminotransferase (AST) — affects amino acid metabolism but clinical relevance unclear. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for Oxaloacetate?

NutraSmarts rates the evidence for Oxaloacetate as Limited (2 out of 5). It is backed by 4 clinical trials and 2 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(2 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Cash A, Vernon SD, Rond C, Bateman L, Abbaszadeh S, Bell J, Yellman B, Kaufman DL RESTORE ME: a RCT of oxaloacetate for improving fatigue in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neurology. 2024;15:1483876. doi:10.3389/fneur.2024.1483876.PubMedUsed to support: Randomized double-blind controlled trial (N=82) showing oxaloacetate 2,000 mg/day produced >25% fatigue reduction vs ~10% in controls (p=0.0039) in ME/CFS patients, with 40.5% achieving ≥63% improvement; directly supports chronic fatigue syndrome support and cellular energy metabolism benefit claims.
  2. Cash A, Kaufman DL 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. Journal of Translational Medicine. 2022;20(1):295. doi:10.1186/s12967-022-03488-3.PubMedUsed to support: Non-randomized controlled clinical trial demonstrating anhydrous enol-oxaloacetate (AEO) supplementation reduced fatigue by 22.5-27.9% in ME/CFS patients and up to 46.8% in Long COVID patients over 6 weeks; supports cognitive function and chronic fatigue syndrome benefit claims for this specific oxaloacetate form.