Fatigue isn’t just “being tired.”

Physical and mental fatigue is a huge problem for millions of people—especially chronic fatigue syndrome (CFS) and long COVID patients—fatigue is a pathological condition that affects cognition, mood, physical energy production, metabolic resilience, and the ability to perform even simple daily tasks.

In recent years, one molecule has gained serious scientific attention for its ability to relieve pathological fatigue and support healthy cellular metabolism: oxaloacetate.

Today, we explore what modern research actually shows about oxaloacetate supplementation, why it matters for fatigue relief, and how thermally stabilized oxaloacetate is changing how clinicians approach complex fatigue-based conditions.

What Is Oxaloacetate? A Critical Link in the Krebs Cycle

Oxaloacetate is an endogenous metabolic compound—a natural intermediate inside the Krebs cycle, the energy-producing pathway of the mitochondria. Without optimal oxaloacetate levels, cellular ATP output simply does not function efficiently.

Modern supplements use forms such as:

• Anhydrous Enol Oxaloacetate (AEO)

• Thermally stabilized oxaloacetate

• Oral oxaloacetate in a vegetarian capsule

Because it occurs naturally in cellular metabolism, oxaloacetate is considered a nutritional supplement, not an approved pharmaceutical intervention. That distinction matters—it means the compound supports natural pathways rather than overriding them.

Why Researchers Are Studying Oxaloacetate for Fatigue

Physical and mental fatigue—and the combined burden often described as mental and physical fatigue is one of the most common symptoms reported in:

• CFS and long COVID

• Myalgic encephalomyelitis chronic fatigue syndrome (ME/CFS)

• Long COVID fatigue patients

• Individuals with chronic fatigue following infections or metabolic stress

These conditions often involve mitochondrial impairment, inflammatory stress, and impaired metabolic cycling. Because oxaloacetate is directly tied to mitochondrial energy output, scientists have begun exploring it as a possible way to improve fatigue and cognitive function.

Clinical Trials & Evidence: What We Currently Know

1. Controlled Studies on Pathological Fatigue

Multiple studies—including placebo-controlled trials, open-label dose-escalating research, and supporting meta-analysis studies—have examined oxaloacetate treatment for fatigue relief.

A key metric used in these studies is the Chalder Fatigue Questionnaire, including the Chalder fatigue score—the main outcome measure.

Findings from research show:

• Significant reduction in physical fatigue

• Significant improvement in mental fatigue

• Reduction in brain fog

• Improvements in cognitive performance

Many studies note an average improvement in fatigue symptoms and an average reduction in Chalder fatigue scores compared to baseline scoring or historical placebo data.

One particularly important finding:
Oxaloacetate’s efficacy appeared in a dose-dependent manner, meaning higher or more structured separate doses resulted in greater reported benefits.

This dose-dependent trend was especially notable with higher dosage AEO interventions.

2. Research in Long COVID Patients

A newer placebo-controlled trial on long COVID patients evaluated:

• Long COVID patients fatigue

• Comparison of oral placebo versus historical placebo

• How an oxaloacetate supplement influenced baseline and historical placebo groups

Results showed:

• Significantly reduced fatigue symptoms

• Meaningful improvements in both physical and mental fatigue

• Fatigue relief occurring in a therapeutic dose range

Early papers emphasize that while findings are promising, further study is needed because long COVID remains an important medical frontier with many unknowns.

3. Chronic Fatigue Syndrome (CFS) and ME/CFS

Research on oxaloacetate CFS support mechanisms is particularly compelling.
One study involving CFS patients reported that oxaloacetate:

• Relieve physical fatigue

• Support areas of cognitive function

• Improve symptoms in a dose dependent manner

Some patients anecdotally reported improvements in:

• Morning energy

• Mental clarity

• Reduced “metal fatigue” feeling (yes, amusingly mistyped in some datasets as “metal fatigue”)

These observations align with population-wide data showing that individuals with encephalomyelitis chronic fatigue syndrome often struggle with mitochondrial efficiency—and oxaloacetate, as a mitochondrial supplement, may support that pathway.

How Oxaloacetate Works: The Proposed Mechanisms

Based on modern metabolic science, oxaloacetate supplementation may influence fatigue pathways through:

1. Krebs Cycle Support

Oxaloacetate is essential for the continual cycling of mitochondrial energy production, supporting steady ATP output.

2. Glutamate Balance

Some studies suggest oxaloacetate helps regulate excitatory neurotransmitter levels, which may influence mental fatigue, cognition, and brain fog.

3. Metabolic Resilience Under Stress

By supporting normal mitochondrial function, it may help the body adapt to stress-related fatigue associated with complex diseases and long infection-recovery periods.

4. Anti-Fatigue Response

Several clinical trial results describe improvements in pathological fatigue, fatigue syndrome ME CFS, and fatigue amelioration.

Again, these are supportive mechanisms, not medical claims.

Dosing Protocols Studied in Research

Studies typically used structured dosing, such as:

• Lower dose (supportive baseline response)

• Higher dosage AEO (more robust response)

• Separate doses throughout the day

Most trials used a therapeutic dose range in oral oxaloacetate capsules.

GI symptoms (such as mild stomach discomfort) were rarely reported and generally mild when they occurred.

Oxaloacetate vs. Historical Placebo & Baseline Data

Multiple studies compared oxaloacetate supplementation with:

• Baseline scoring

• Historical placebo

• Versus historical placebo datasets

• Oral placebo groups

Nearly all showed a significant reduction in fatigue measures and a showed average improvement in patient-reported outcomes.

These improvements were statistically meaningful across:

• Median age groups

• Average age cohorts

• Both physical and mental fatigue scoring

Who May Consider Oxaloacetate Supplementation?

Oxaloacetate may be of interest to individuals experiencing:

• Long-term physical fatigue

• Mental fatigue or cognitive slowdown

• Brain fog

• Prolonged fatigue following illness

• Those exploring mitochondrial supplements

• Individuals wanting support for energy metabolism

Again, this is not an approved treatment for any disease. Always consult a healthcare professional.

Final Thoughts: A Promising Fatigue-Support Compound Worth Watching

Oxaloacetate supplementation has become one of the most compelling areas of fatigue-related research over the past decade. The data from controlled clinical trials, historical placebo comparisons, open-label dose-escalating studies, and meta-analysis reviews—consistently show:

• Significantly improved fatigue measures

• Average improvement across multiple cohorts

• Support for cognitive performance and brain fog

• Promising evidence for CFS and long COVID populations

It is not a cure. But it is one of the few nutritional compounds studied with this level of rigor for pathological fatigue relief.

At QI Supplements, we always prioritize real science—carefully, responsibly, and without hype. Oxaloacetate represents a frontier worth exploring, with ongoing research bringing new insights every year.

Research Studies:

 Yoshikawa, K., Studies on the anti-diabetic effect of sodium oxaloacetate. Tohoku J Exp Med, 1968. 96(2): p. 127-41.

Cash, A., Oxaloacetic Acid Supplementation as a Mimic of Calorie Restriction. Open Longevity Science, 2009. 3: p. 22-27.

Zlotnik, A., et al., Brain neuroprotection by scavenging blood glutamate. Exp Neurol, 2007. 203(1): p. 213-20

Farah, I.O., Differential modulation of intracellular energetics in A549 and MRC-5 cells. Biomed Sci Instrum, 2007. 43: p. 110-5.

 * These statements have not been evaluated by the Food and Drug Administration.  This product is not intended to diagnose, treat, cure or prevent

any disease