IACFS/ME Lecture On Therapeutic Use of Oxaloacetate in ME/CFS and Long COVID by Dr. Vernon of Bateman Horne Center
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Dr. Susan Vernon Discusses Clinical Data of Oxaloacetate Showing Fatigue and Cognitive Function Improvements in ME/CFS and Long COVID patients
At the forefront of ME/CFS research, the Bateman Horne Center is renowned for its contributions to understanding and treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID. A significant part of this pioneering work involves exploring the therapeutic potential of medical foods like Oxaloacetate CFS.
IACFS/ME is a leading international, non-profit organization of clinicians, scientists, professionals, patients and advocates dedicated to the care and research of people affected by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), fibromyalgia and related conditions.
At the October 2025 IACFS/ME Virtual Conference, Dr. Susan Vernon of the Bateman Horne Center presented the above lecture describing the latest clinical data of Oxaloacetate for improving fatigue and cognitive function in ME/CFS and Long COVID patients. Available for reading below is Dr. Vernon’s complete lecture.
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Hi everyone. Today I'll be discussing how oxaloacetate may help restore energy metabolism and cognitive function in ME/CFS and long COVID. These are conditions where fatigue and cognition are deeply intertwined, suggesting shared neurometabolic dysfunction. I'll highlight evidence from two randomized controlled trials, Restore ME and REGAIN, and show how oxaloacetate appears to strengthen what we call the fatigue-cognition axis.
The Fatigue-Cognition Axis
This concept reflects a measurable link between self-reported fatigue and objectively measured cognitive reaction time. We'll also explore how oxaloacetate may act at a metabolic level, potentially reversing a chronic Warburg-like shift and restoring mitochondrial efficiency. Let's begin with the Warburg effect.
The Warburg Effect
Normally, our cells make ATP efficiently through oxidative phosphorylation. But under stress, cells may switch to glycolysis even when oxygen is available, producing energy faster but far less efficiently. This is the Warburg effect. In healthy situations, it's adaptive, allowing cells to respond quickly to injury or repair needs.
Chronic Disease and Energy Efficiency
But in chronic disease, this shift can become stuck, trapping the cell in a low energy efficiency state. The result is less ATP, more lactate, and sustained redox stress. Understanding this metabolic shift helps us see why fatigue, cognitive slowing, and other symptoms may persist even when basic energy substrates appear adequate. In ME/CFS and long COVID, we see evidence of a chronic Warburg-like state.
Metabolomic Research Findings
Metabolomic studies show reduced oxaloacetate and disrupted TCA cycle intermediates, indicating that Krebs cycle isn't being refilled, what's called anaplerotic effect. Redox pathways are also impaired, leading to mitochondrial stress. In long COVID, these disturbances appear even broader, affecting NAD to NADH balance and oxidative metabolism.
The Potential of Oxaloacetate
Together, these findings suggest that cells are relying on glycolysis long-term, even with sufficient oxygen. That persistent metabolic adaptation could explain the energy shortage and cognitive impairment many patients experience. Oxaloacetate sits at a critical junction in energy metabolism. It bridges glycolysis, glutamine metabolism, and the TCA cycle. By inhibiting lactate dehydrogenase A, oxaloacetate prevents excess pyruvate from turning into lactate and instead redirects it into the mitochondria for efficient ATP generation.
Restoration of Energy Balance
In doing so, it restores redox balance by converting NADH to NAD and helps normalize oxidative metabolism. Clinically, supplementing oxaloacetate could rebalance cellular energy systems, reducing reliance on glycolysis and improving mitochondrial throughput. In essence, oxaloacetate acts as a bridge, a metabolic bridge, and a normalizer of the Warburg effect.
Clinical Trials: Restore ME and REGAIN
To test these ideas, we conducted two randomized controlled trials: Restore ME in ME/CFS, and REGAIN in long COVID. The objective was simple—to determine whether oral oxaloacetate could safely reduce fatigue. Patients were followed across multiple visits, completing standardized fatigue questionnaires and cognitive reaction time tests.
Efficacy and Mechanistic Insights
Because oxaloacetate is an endogenous metabolite with established safety, our focus was on efficacy and mechanistic insights. What we observed went beyond fatigue reduction. It revealed a consistent pattern linking fatigue improvement with better cognitive performance. Here's what the regression analysis showed: fatigue and cognition track closely together when fatigue scores improved, so did cognitive reaction time.
The Responder Analysis
In contrast, there is no consistent relationship between fatigue and time spent upright with feet on the floor, suggesting that the fatigue patients report is tightly linked to brain energy metabolism. Recognizing this distinction led us to perform a responder analysis to see whether oxaloacetate increased the proportion of participants who improved in both fatigue and cognition simultaneously.
Integrated Improvement
The responder analysis confirmed that pattern. Participants on oxaloacetate were more likely to experience global improvement, meaning both reduced fatigue and better cognition compared with controls. Controls tended to improve in fatigue only without corresponding cognitive gains. Cognitive-only responses were rare in both groups, so oxaloacetate didn't just improve energy levels. It appeared to relink fatigue and cognition, strengthening what we call the fatigue-cognition axis.
Conclusion
This integrated improvement suggests a systemic rebalancing of neurometabolic function rather than isolated symptom relief. This brings us to the concept of the fatigue-cognition axis. In both ME/CFS and long COVID, we see that when fatigue improves, cognition improves too. Oxaloacetate enhances this coupling, suggesting a shared neurometabolic mechanism, possibly at the level of mitochondrial or redox regulation in the brain.
Future Implications
Interestingly, fatigue did not track with upright time, meaning that cognitive and perceptual energy changes may proceed or occur independently of physical improvement. We believe this axis represents a targetable therapeutic pathway, one that links cellular metabolism directly to brain performance and symptom relief. Mechanistically, oxaloacetate may reverse the chronic Warburg effect. It replenishes TCA cycle intermediates, anapleurotic respiration restoration, helping mitochondria produce ATP more efficiently.
Mechanistic Understanding
It also can rebalance Redox status by converting NADH back to NAD, reducing lactate accumulation and oxidative stress. These combined effects enhance energy yield per glucose molecule and restore neurometabolic coupling. Improved mitochondrial function in both the brain and periphery may explain why fatigue relief and cognitive clarity occur together.
Summary
In essence, oxaloacetate appears to push metabolism from chronic glycolysis back toward oxidative phosphorylation. To summarize, fatigue and cognitive reaction move together in ME/CFS and long COVID, forming a definable fatigue-cognition axis. Oxaloacetate strengthens this axis, producing more global responders who improve in both domains.
Closing Thoughts
Mechanistically, this may reflect the reversal of a chronic Warburg effect, restoration of NADH to NAD balance, and improved mitochondrial efficiency. The result is better neurometabolic coupling. Patients have improved reaction time and are less fatigued, even if physical stamina remains limited. Moving forward, clinical trials should use multidimensional outcomes such as fatigue cognition, plus time upright, and integrate biomarker-guided designs to fully capture the benefits of metabolic restoration therapies like that with oxaloacetate. Thank you for your time. - Dr. Susan Vernon
View the full clinical data reports of the trials referenced by Dr. Vernon.