Four peer-reviewed publications examine fatigue, cognition, symptom burden and upright activity across approximately 270 clinical-trial participants
Summarized findings from four peer-reviewed publications evaluating anhydrous enol-oxaloacetate in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID present a robust body of evidence for the efficacy of the medical food treatment.
The publications arise from three clinical trials enrolling approximately 270 participants, together with a secondary analysis of one randomized trial. Researchers assessed several dimensions of illness, including physical and mental fatigue, cognitive performance, overall symptom burden, functional capacity and time spent upright.
The research includes an early dose-ranging study and two randomized, double-blind controlled trials.
Key Findings From the Four Publications
RESTORE ME Randomized Trial in ME/CFS
Published in Frontiers in Neurology, RESTORE ME enrolled 82 adults with ME/CFS at the Bateman Horne Center. Participants received 2,000 mg of oxaloacetate or control daily for 90 days.
Fatigue in the oxaloacetate group declined by more than 25% from baseline, while the control group had a smaller, nonsignificant reduction. The between-group difference was statistically significant. Researchers classified 40.5% of oxaloacetate recipients as “enhanced responders”; this subgroup experienced an average 63% reduction in fatigue. The intervention was reported to be well tolerated.
REGAIN Randomized Trial in Long COVID
REGAIN, published in Frontiers in Neuroscience, studied 69 adults with Long COVID for 42 days using 2,000 mg of oxaloacetate or control per day.
The primary fatigue outcome measured by the Chalder Fatigue Questionnaire did not differ significantly between groups. However, the oxaloacetate group showed significantly greater improvement in fatigue and total symptom burden on the DePaul Symptom Questionnaire Short Form at day 21. Cognitive performance also improved, and those gains were strongly associated with symptom response. Researchers concluded that oxaloacetate may support earlier improvement in symptom burden and cognition, while calling for additional study.
Cognition and Upright Activity Analysis
A later Frontiers in Neurology publication examined cognitive and activity data from RESTORE ME. Compared with control, participants receiving oxaloacetate showed greater cognitive improvement, with a statistically significant difference at day 60. Upright activity increased modestly, reaching a significant between-group difference at day 30. Differences at other time points did not consistently reach statistical significance.
The analysis also identified a strong relationship between fatigue severity and cognitive performance in the oxaloacetate group, suggesting the value of measuring several symptom domains in ME/CFS trials.
Initial Study in ME/CFS and Long COVID
The first publication, appearing in the Journal of Translational Medicine, was a six-week, open-label, dose-escalating study involving 76 people with ME/CFS and 43 with Long COVID.
Reported fatigue reductions among ME/CFS participants ranged from 21.7% at the lowest dosage to 33.3% at the highest. Long COVID participants reported reductions of up to 46.8%. Both physical and mental fatigue improved compared with baseline and historical controls. Because the study was nonrandomized and used historical controls, its findings supported the need for the randomized trials that followed.
A Multidimensional Research Record
Taken together, the publications examine outcomes that can substantially affect daily life: physical and cognitive fatigue, brain fog, broader symptom burden and the ability to remain upright. The findings also show that response varies among individuals and by the measure used.
Alan Cash, founder and Chief Science Officer of Terra Biological, said fatigue improvement of the magnitude reported among some participants can be life-changing for people with ME/CFS.
Study summaries and links to the complete publications are available through the Oxaloacetate CFS clinical studies library.
Oxaloacetate CFS is a medical food for the dietary management of ME/CFS and is intended for use under the supervision of a qualified healthcare professional. The published findings do not mean every patient will benefit, and further research is warranted. This release is educational and does not provide individual medical advice.