In response to the interest generated from our Q&A on the use of Oxaloacetate in ME/CFS, this blog delves deeper into the research.

New Research Links Cognitive Gains to Fatigue Reduction in ME/CFS Trial of Oxaloacetate

A new clinical trial led by researchers at the Bateman Horne Center (BHC) offers encouraging evidence that targeting metabolism may help improve both brain function and daily activity in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex and disabling disease with no FDA-approved treatments.

Published in Frontiers in Neurology, the study, “Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for ME/CFS,” was authored by Bateman Horne Center staff members: Suzanne D. Vernon, PhD, Candace Rond, Jennifer Bell, Bella Rond, Brayden Yellman, MD, and Lucinda Bateman, MD.

A Closer Look at Fatigue, Cognition, and Function

ME/CFS is marked by unrelenting fatigue, post-exertional malaise, cognitive problems (“brain fog”), and reduced physical function. Researchers at BHC have long recognized that these symptoms are deeply interconnected, yet rarely studied together.

The 90-day randomized, double-blind trial, called RESTORE ME, enrolled 82 adults with ME/CFS to test whether oxaloacetate (OAA), a naturally occurring compound involved in cellular energy production,  could improve fatigue and related symptoms. Participants were randomly assigned to take either 2,000 mg/day of OAA or a placebo of rice flour.

To track changes over time, researchers used a multi-dimensional approach:

• Fatigue was measured using the Chalder Fatigue Questionnaire.
• Cognition was assessed through DANA Brain Vital, a smartphone-based app that measures reaction time and attention.
• Physical activity was objectively tracked through a wearable ankle sensor that recorded “UP Time,” or minutes per day spent upright with feet on the floor.

The Science Behind OAA

OAA is a molecule found in every cell of the body, and a critical part of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, which converts food into usable cellular energy (ATP). When this cycle slows down or becomes inefficient, cells produce less energy, leading to fatigue and impaired organ function.

In pre-clinical studies, OAA has been shown to:

• Boost mitochondrial biogenesis, helping cells make more of the energy-producing organelles that power muscles and the brain.
• Enhance insulin sensitivity, improving the way cells take in glucose for fuel.
• Reduce neuroinflammation and oxidative stress, both of which are thought to contribute to cognitive problems in ME/CFS and long COVID.

By supporting these metabolic and neuroprotective processes, OAA may help the brain and body use energy more efficiently, potentially explaining the improvements seen in both fatigue and cognitive function in this study. (Read more about OAA in relation to ME/CFS in Cort Johsnon’s 2021 article.)

“Energy metabolism is the backbone of every physiological system,” explained Dr. Suzanne Vernon, the study’s first author and BHC’s Research Director. “When we improve how cells generate energy, we may also improve how the brain processes information and how the body recovers from exertion.”

Safety and Availability

OAA has been studied for its role in cellular metabolism and is generally considered well-tolerated at the doses used in clinical research. In this 90-day trial, participants did not report serious adverse events related to treatment. However, researchers note that larger and longer studies are needed to fully assess long-term safety, particularly in people with complex chronic illnesses like ME/CFS.

Currently, OAA is available as a medical food or nutritional supplement, not as an FDA-approved medication. This means it can be purchased over the counter but is not regulated or prescribed in the same way as pharmaceuticals. Individuals considering its use should consult a clinician familiar with ME/CFS before starting supplementation, especially given the potential for variability in product formulations and patient responses.

What the Researchers Found

After 60 days, participants who received OAA showed significant improvements in cognitive efficiency compared to those on placebo, with continued trends at the 90-day mark. Importantly, the team found that fatigue and cognitive performance were closely linked in participants taking OAA: those who reported less fatigue also performed better on cognitive tests.

This connection was not observed in the placebo group, suggesting that OAA may influence brain function through mechanisms tied to cellular energy and mitochondrial performance.

“We found that as fatigue decreased, cognitive performance improved, particularly in those receiving OAA,” said Dr. Vernon. “This fatigue–cognition relationship may be a targetable feature of ME/CFS.”

Physical function, as measured by time spent upright, also improved modestly in the OAA group, reaching statistical significance at 30 days and staying slightly higher throughout the study period.

While group differences in overall responder status did not reach statistical significance, OAA participants were more likely to experience improvements in fatigue or both fatigue and cognition together (“global responders”).

Why This Matters

For decades, ME/CFS research has been hindered by a lack of objective measures and treatment options. This study takes a step forward by combining subjective and objective tools, linking patient-reported fatigue to quantifiable cognitive and physical metrics.

“ME/CFS is incredibly heterogeneous,” said Dr. Lucinda Bateman, BHC’s Founder and Medical Director. “Understanding how fatigue, cognition, and function interact helps us tailor interventions and identify which patients may benefit most.”

The findings also strengthen the hypothesis that metabolic dysfunction, especially within the mitochondria, is central to ME/CFS. By improving energy pathways and reducing inflammatory stress in the nervous system, OAA may offer a way to support both mental clarity and endurance in affected patients.

Looking Ahead

While the results are promising, the authors emphasize that this was an exploratory study. Larger and longer trials are needed to confirm the benefits of OAA and to pinpoint the biological mechanisms linking fatigue and cognition in ME/CFS.

“Metabolism-based interventions like OAA  could open new doors,” said Dr. Vernon. “But equally important is how we measure success — not just by one symptom, but by how people think, feel, and function in their daily lives.”

BHC remains at the forefront of this work, advancing research that integrates patient experience, clinical data, and cutting-edge tools to unravel the biology of complex chronic illnesses, such as ME/CFS and Long COVID.