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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 Standard dose: 100-300 mg/day anhydrous enol oxaloacetate (benaGene™). Cognitive applications: typically 100-200 mg twice daily. Fatigue protocols: up to 1,000-2,000 mg/day under medical supervision. Take with food.
Active Compound Anhydrous enol-oxaloacetate (AEO) — stabilized form of oxaloacetate (OAA), a 4-carbon dicarboxylic acid that is both a TCA cycle intermediate and 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 2, Trial 3

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 2

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. Cash 2024 measured low plasma OAA 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)

Williams 2009 showed oxaloacetate activates AMPK and FOXO pathways in C. elegans — pathways central to calorie-restriction effects on lifespan. The 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
REGAIN 2025 — Long COVID RCT (Most Rigorous, Mixed Results)

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 2024 — ME/CFS RCT (n=82)

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 RCT-level evidence for the ME/CFS application.

3
Cassileth & Kaufman 2022 — ME/CFS Non-Randomized Trial

Cassileth & Kaufman 2022, J. Translational Medicine (PMC9238249). 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 RCTs.

4
Williams 2009 — C. elegans Lifespan Extension (Preclinical)

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 (Anhydrous Enol)?

Oxaloacetate is a Krebs cycle intermediate available as a supplement (typically the anhydrous enol form, marketed as benaGene™).

What does Oxaloacetate (Anhydrous Enol) do?

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. In clinical research, Oxaloacetate (Anhydrous Enol) has been studied for cellular energy metabolism support, nad+ ratio modulation, ampk activation for longevity.

Who should take Oxaloacetate (Anhydrous Enol)?

Oxaloacetate (Anhydrous Enol) may be most relevant for people interested in energy, cognitive, mood & mental health. It has been clinically studied for cellular energy metabolism support, nad+ ratio modulation, ampk activation for longevity. As with any supplement, consult your healthcare provider before starting, especially if you have medical conditions or take prescription medications.

How long does Oxaloacetate (Anhydrous Enol) take to work?

In clinical trials, effects have been measured at 6 weeks of consistent use. Acute or same-day effects (where applicable) typically appear within hours, but most cumulative benefits — particularly those affecting biomarkers, mood, sleep quality, or chronic symptoms — require 4-12 weeks of regular use to fully assess. If you don't notice benefit after 12 weeks at the appropriate dose, it may not be your responder.

When is the best time to take Oxaloacetate (Anhydrous Enol)?

For performance or energy goals, Oxaloacetate (Anhydrous Enol) is typically taken 30-60 minutes before exercise or in the morning. Some people take it with food to reduce GI sensitivity; others prefer empty-stomach timing for faster absorption. Always check product labeling and follow personalized guidance from your healthcare provider.

Is Oxaloacetate (Anhydrous Enol) worth taking?

Oxaloacetate (Anhydrous Enol) has limited clinical evidence (Evidence Level 2/5 on NutraSmarts) — preliminary research suggests potential benefit, but more rigorous trials are needed. Whether it's worth taking depends on your specific goals, what you've already tried, your budget, and your overall supplement strategy. The honest framing: no supplement is essential for most people, and lifestyle factors (sleep, exercise, diet, stress management) typically produce larger effects than any single supplement. Oxaloacetate (Anhydrous Enol) is most worth trying if its evidence-supported uses align with your specific goals.

What is the recommended dosage of Oxaloacetate (Anhydrous Enol)?

The clinically studied dose for Oxaloacetate (Anhydrous Enol) is Standard dose: 100-300 mg/day anhydrous enol oxaloacetate (benaGene™). Cognitive applications: typically 100-200 mg twice daily. Fatigue protocols: up to 1,000-2,000 mg/day under medical supervision. Take with food.. Always follow product labeling and consult a healthcare provider for personalized dosing recommendations.

What is Oxaloacetate (Anhydrous Enol) used for?

Oxaloacetate (Anhydrous Enol) is studied for cellular energy metabolism support, nad+ ratio modulation, ampk activation for longevity. 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.