Oxaloacetate for Chronic Fatigue Syndrome

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Terra Biological LLC

Must not be taking: Stimulants, Immunosuppressants

Disqualifiers: Diabetes, Severe ME/CFS, others

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a supplement called anhydrous enol-oxaloacetate (AEO) can reduce fatigue in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It compares AEO to a placebo (a harmless pill with no active ingredient) over 90 days to assess any differences in energy levels and overall well-being. Individuals with ME/CFS who engage in 2 to 6 hours of daily standing or walking activity might be suitable candidates. The trial also evaluates the safety and tolerability of AEO for participants. As an unphased trial, this study provides a unique opportunity to contribute to understanding potential new treatments for ME/CFS.

Will I have to stop taking my current medications?

The trial requires participants to refrain from taking medications that could affect the study's assessment of the dietary supplement's effectiveness. If you're on medications, you may need to stop them, but it's best to discuss this with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that anhydrous enol-oxaloacetate (AEO) is generally safe for people. One study had participants take 1000 mg of AEO twice daily for a month, and it was safe while also improving brain energy in individuals with Alzheimer's disease. Another study tested doses between 1000–3000 mg per day and found it safe and well-tolerated. These findings suggest that AEO does not cause serious side effects, making it a promising option for those considering joining a trial for Chronic Fatigue Syndrome. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Most treatments for Chronic Fatigue Syndrome (CFS) focus on managing symptoms through lifestyle changes and medications like antidepressants, pain relievers, or stimulants. However, oxaloacetate is unique because it targets energy metabolism directly. Oxaloacetate is a key player in the Krebs cycle, which is crucial for energy production in cells. By potentially enhancing energy metabolism, oxaloacetate offers a novel approach that could address the root cause of fatigue in CFS, rather than just alleviating symptoms. Researchers are excited about this treatment because it represents a shift towards targeting cellular energy production, which could lead to more effective management of CFS.

What evidence suggests that anhydrous enol-oxaloacetate might be an effective treatment for chronic fatigue syndrome?

Research has shown that anhydrous enol-oxaloacetate (AEO), which participants in this trial may receive, may help reduce tiredness in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In a study involving 76 patients, those treated with AEO experienced a noticeable decrease in fatigue. Another report found that fatigue decreased by 63% in patients who responded well to the treatment. Additionally, people with ME/CFS and Long-COVID saw significant improvements in both physical and mental tiredness when using AEO. These findings suggest that AEO could effectively help reduce fatigue for those with ME/CFS. ^{1 3 6 7 8}

Who Is on the Research Team?

Suzanne D Vernon, Ph.D.

Principal Investigator

Bateman Horne Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with ME/CFS who've been stable for the past 3 months, can do daily activities for more than 2 but less than 6 hours, and are not pregnant or at risk of becoming pregnant. Participants must meet specific diagnostic criteria for ME/CFS and agree to avoid certain medications during the study.

Inclusion Criteria

I often feel extremely tired and worse after physical activity.

I have been diagnosed with ME/CFS according to the 2015 IOM criteria.

My illness allows me to be active for 2 to 6 hours daily.

Exclusion Criteria

Active or uncontrolled co-morbidities which may interfere with study participation

My symptoms are not caused by another mental or physical health issue.

Pregnancy, or while breast feeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person), telephone screening

Treatment

Participants receive either oxaloacetate or placebo capsules for 90 days

12 weeks

4 visits (in-person), bi-weekly phone check-ins

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Anhydrous Enol-Oxaloacetate
• Placebo

Trial Overview

The RESTORE ME trial is testing whether a medical food called Anhydrous Enol-Oxaloacetate (AEO) can reduce fatigue in people with Chronic Fatigue Syndrome compared to a placebo. It's a randomized, double-blind study measuring effects on fatigue after 90 days using the Chalder Fatigue Score.

How Is the Trial Designed?

Group I: Oxaloacetate Experimental Treatment 1 Intervention

500 mg anhydrous enol-oxaloacetate in hypromellose capsules (veggie caps). 2 capsules with breakfast and 2 capsules with lunch (1,000 mg BID) for 90 days.

Group II: Placebo Placebo Group 1 Intervention

500 mg white rice flour in hypromellose capsules (veggie caps). 2 capsules with breakfast and 2 capsules with lunch (1,000 mg BID) for 90 days.

Who Is Running the Clinical Trial?

Terra Biological LLC

Lead Sponsor

Trials

7

Recruited

320+

Bateman Horne Center

Collaborator

Trials

3

Recruited

210+

Published Research Related to This Trial

Low-dose naltrexone (LDN) has shown potential efficacy in treating chronic immune-modulated disorders, with case reports indicating varied responses in patients with chronic fatigue syndrome, ranging from significant improvement to partial symptom relief.

Despite promising anecdotal evidence and small-scale trials for other conditions, there is a lack of clinical trials specifically investigating LDN for chronic fatigue syndrome, suggesting a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose naltrexone as a treatment for chronic fatigue syndrome. Bolton, MJ., Chapman, BP., Van Marwijk, H.[2020]

In the PACE trial involving 641 participants with chronic fatigue syndrome, serious adverse events were rare, while non-serious adverse events were common, with no significant differences in their occurrence across different treatment groups.

Physical deterioration was most frequently reported after adaptive pacing therapy (APT), affecting 25% of participants, indicating that while treatments did not significantly differ in adverse events, APT may be associated with a higher risk of worsening physical function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome. Dougall, D., Johnson, A., Goldsmith, K., et al.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11632837/

RESTORE ME: a RCT of oxaloacetate for improving fatigue ...

Treatment with anhydrous enol-oxaloacetate (AEO) in a 6-week, 76-patient proof-of-concept open-label trial showed significant reductions in ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05273372

NCT05273372 | RESTORE ME -- RCT of Oxaloacetate on ...

Initial case studies have shown an improvement in fatigue in ME/CFS with anhydrous enol-oxaloacetate (AEO). This randomized, double blinded, placebo controlled ...

3.

mecfs-research.org

mecfs-research.org/wp-content/uploads/2025/06/Alan-Cash_International-MECFS-Conference-2025_Anhydrous-Enol-Oxaloacetate-Treatment-of-MECFS.pdf

Oxaloacetate CFS

The Average improvement within the. Oxaloacetate Enhanced Responders. Group was a 63% Reduction in Fatigue. Terra Biological LLC, Inc. Page 10. DANA Brain Vital ...

4.

translational-medicine.biomedcentral.com

translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03488-3

Oxaloacetate Treatment For Mental And Physical Fatigue ...

Patients with ME/CFS and Long-COVID treated with oral Anhydrous Enol-Oxaloacetate capsules achieved highly significant reductions in physical and mental ...

5.

frontiersin.org

frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1627462/full

REGAIN: a randomized controlled clinical trial of ...

Recent clinical trials of oxaloacetate supplementation have shown promising effects in reducing fatigue in both myalgic encephalomyelitis/chronic fatigue ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9238249/

Oxaloacetate Treatment For Mental And Physical Fatigue ...

1000–3000 mg anhydrous enol-oxaloacetate daily was both safe and tolerable in this population for the duration of the trial. This proof-of- ...

7.

oxaloacetatecfs.com

oxaloacetatecfs.com/pages/cfs-safety?srsltid=AfmBOoqq5wPCpb2R8mKa7QDx8hA0vO270MZWbeBV_ryRzN5kBLDyqd4X

Safety with Anhydrous Enol-Oxaloacetate

The Investigators conclusion was that 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.

8.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04592354

Anhydrous Enol-Oxaloacetate (AEO) on Improving Fatigue ...

We will conduct a double arm, randomized, double-blinded placebo controlled trial of oxaloacetate for treatment of fatigue in women with a history of COVID-19 ...