Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial

Physiological Fatigue is familiar to most persons, primarily resulting from exertion [1]. It can also be caused by sleep loss or extended wakefulness, disrupted circadian rhythm or increased workload [2]. In contrast, Pathological Fatigue or pathological exhaustion is more than tiredness [3] and refers to physical and mental fatigue that may be caused by viral infection, bacterial infection, trauma, disease, over-work, over-training, epigenetic or genetic alteration that results in physical and mental fatigue that is not improved by bed rest and may be worsened by physical or mental activity.

Physiological Fatigue is caused by neurological changes, calcium level changes, blood flow and oxygen levels, reduced ATP energy levels and glycogen levels, and an increase in intracellular metabolites such as H + , lactate, Pi and ROS  [4]. Most importantly, these physiological changes are reversed by rest.

In contrast, while Pathological Fatigue may involve some of the same physiological changes seen in physiological fatigue, there are many additional metabolic changes that occur in Pathological Fatigue, including changes in energy production pathways, redox of the cells, inflammation response, mitochondrial malfunction, reduced AMPK activation (and related glucose uptake into tissues) and reduced Vitamin D in older subjects [5]. Unlike Physiological Fatigue, the metabolic changes in Pathological Fatigue are not reversed by rest, and the fatigue may, for example, last long after the virus has been conquered, the bacterial invasion has been defeated, or the damaged tissue repaired [6].

Specific examples of this include the disorder Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and “Long COVID”. There are many metabolic changes that link ME/CFS and Long COVID [7] and indeed COVID infection may lead to a diagnosis of ME/CFS [8].

Physiological muscle fatigue is easily cured by rest, allowing the nutrients to be taken in by the muscles and waste products such as lactate to be removed by normal cellular processes. In contrast, with pathological fatigue due to damage, whether from viral or bacterial infection, trauma, disease or other cellular assault, the cellular metabolism changes do not always re-set after providing energy for the defense/repair of the body [6]. The failure of metabolism to re-set back to a normal state leads to on-going mental and physical fatigue, which can last for years, even after the original insult to the body is resolved.

ME/CFS Patients that met the Fukuda definition [25], agreed to complete a 6-week course of anhydrous enol-oxaloacetate, and to complete three online validated fatigue surveys were selected from the existing patient base of the authors and were offered to join this study. Long-COVID patients that experienced at least 6 months of fatigue and did not have prior fatigue were recruited through social media. Patients completed this trial in their homes.

Patients first completed baseline on-line validated fatigue surveys including the Chalder Fatigue Questionnaire [26], the Fatigue Severity Score [27] and the PROMIS Short Form Fatigue 7A survey [28]. Fatigue surveys were repeated at 2 weeks and 6 weeks for each group. Any adverse events were recorded. Fatigue survey scores were then analyzed for statistical significance. As this was a “Proof of Concept” study, sample groups approximated 23 participants.

After establishing baseline fatigue scores via online fatigue questionnaires, the participants were supplemented with 500 mg anhydrous enol-oxaloacetate (AEO) capsules BID for 6 weeks. After review of any potential side effects indicated safety, the dose was increased in the next patient group to 1000 mg AEO BID for 6 weeks. Finally, after safety review of the 1000 mg AEO BID dose, the dosage of the next group of patients was increased to 1000 mg TID. No incentives were provided.

In this simple study, no stratification of the groups was used. Dose escalation was used with new recruits to the study being placed in the current or next higher dosage group. There was no blinding in this study. The smallest unit that is being analyzed to assess intervention effects is a group of 21 patients.

Fatigue Scores were summarized as means and standard deviations, standard error and confidence intervals were calculated. Changes were summarized as effect sizes, normalized to a 0–100% scale, wherein 100% is the highest amount of fatigue that can be measured with the survey instrument. Significance was calculated from student’s T Test scores in Excel by comparison to baseline. Clinical significance was measured by reductions to four or less in the Chalder fatigue score using bimodal scoring, and by overall significant reductions in fatigue in all tests.

Comparison was made to a historical placebo group, that also used the Chalder Fatigue Score and used an oral placebo. Wearden et. al used an oral capsule in a randomized placebo-controlled trial. 34 patients were given placebo, 5 dropped out of the study. Only two patients (5.9%) of the patients that did not drop out saw clinical improvement on the Chalder Fatigue Questionnaire [29].

While the author Dr. Kaufman had access to many ME/CFS patients due to his specialized practice, and quickly filled the recruitment for the ME/CFS portion of the clinical trial, Long COVID patients were not part of his practice. Participants for the Long COVID trial were recruited via Face Book advertising after meeting recruiting criteria, which included verification of initial COVID infection, verification of COVID infection remission, no historical fatigue prior to COVID infection, and ongoing fatigue for at least 6 months after COVID infection.

All patients in this study provided written acceptance of Informed Consent documents, and that this initial “Proof of Concept” trial was unblinded.

Participant flow for this trial is shown in the attached diagram. Recruitment began March 2021 and continued into February 2022.

The clinical trial is an open label, dose escalating “Proof of Concept” study for the use of anhydrous enol-oxaloacetate in the treatment of fatigue. It was initially set up with ME/CFS patients then extended to include arms of Long-COVID patients due to the similarities of the two conditions.

Baseline fatigue prior to treatment was assessed by the Chalder Fatigue Scale, the Fatigue Severity Scale and the PROMIS–Fatigue-Short Form 7a. Scores were summarized as mean and standard deviations, standard error and confidence intervals were calculated. Changes are also summarized as effect sizes, normalized to a 0–100% scale, wherein 100% is the highest amount of fatigue that can be measured with the survey instrument. Dose ranging was performed with the first group of patients receiving 500 mg anhydrous enol-oxaloacetate BID, the second group received 1000 mg anhydrous enol-oxaloacetate BID and the third group of ME/CFS patients received 1000 mg anhydrous enol-oxaloacetate TID. The Long COVID patients received 500 mg anhydrous enol-oxaloacetate BID and then 1000 mg anhydrous enol-oxaloacetate BID.

A historical placebo effect in ME/CFS patients was used as a comparator to the data generated in these studies. The historical placebo data showed a Chalder Fatigue Score, Likert scoring, improvement of 5.9% over baseline with an oral intervention placebo over a 26 week period. It is noted that as per a meta-analysis of ME/CFS treatment studies, the placebo effect is small in ME/CFS patients [29].

Initially a total of 76 men and women aged 18–72 with ME/CFS were selected for the clinical trial. An additional 43 patients with Long COVID were added as additional arms of the study. Because women are much more likely to have ME/CFS, most of the ME/CFS patients are women (73.7%). The average length of time that a patient has had ME/CFS is 8.9 years and mean baseline fatigue scores range from 76 to 92% of maximum measurable fatigue for the group (Chalder Fatigue Scale, Likert Scoring). The Chalder Fatigue Scale is often used to measure ME/CFS fatigue. It can be scored in “Likert” method assigning a score range of 0–4 points per question, or it can be scored in “Bimodal” fashion, scoring “0” for normal fatigue levels and “1” for high fatigue levels. After 6 weeks of 500 mg anhydrous enol-oxaloacetate treatment, 5 out 23 patients (21.7%) reduced their measurable fatigue to a score of 4 or less (bimodal scoring), indicating a return from ME/CFS fatigue levels to “normal fatigue” levels. As the average length of ME/CFS illness in this group was over 6 years, seeing > 23% of the participants return to normal fatigue levels with 6 weeks of treatment is very promising. In the 1000 mg AEO BID treatment group, 8 out of 29 patients (27.6%) saw their fatigue drop to 4 or less on the Chalder bimodal fatigue scale. Increasing the dosage to 1000 mg TID, 8 out of 24 patients (33.3%) had fatigue scores drop to 4 or less, showing a consistent dose response of oxaloacetate supplementation vs. drop in clinically relevant fatigue. The reduction in fatigue was also seen with increased time of dosage, improving at 6 weeks over 2 weeks.

Using Likert scoring in the Chalder Fatigue Scale, the Long COVID 500 mg BID group had highly significant reduced fatigue levels from their baseline values by 22.5% in 6 weeks. The Severity Score was highly significantly reduced by 11.7% from baseline, and the PROMIS Fatigue Short Form 7A showed a non-significant 5.9% reduction in fatigue from baseline.

The Long COVID 1000 mg BID group increased effectiveness of the treatment further, with highly significantly reduced fatigue levels by 27.9% from baseline at 6-weesks. The Severity Score showed a non-significant reduction of 2.9%, and the PROMIS Fatigue 7a score was reduced in highly significant fashion by 10.0% within 6-weeks.

In comparison with historical placebo [29], 75.0% of the ME/CFS participants (57/76) saw an improvement in fatigue over what would be expected by placebo effect. 62.8% (27/43) of the Long COVID patients saw improvement over historical placebo.

Not only physical fatigue was improved, but mental fatigue was highly significantly improved in both ME/CFS patients and post-COVID fatigue patients. No ancillary analyses were performed at this time (Tables 2, 3).

The results document a 21.7–33.3% highly significant improvements in fatigue over baseline with the supplemental addition of 500 and 1000 mg anhydrous enol-oxaloacetate BID and TID in ME/CFS patients within 6-weeks. In post-COVID fatigue patients, improvements of up to 46.8% over baseline were seen (Chalder Fatigue Bimodal Score). Improvement at the higher dosage of 1000 mg BID in Long-COVID patients was lower due to 9 out of 22 dropping out of the trial, and the continuation of the previous data forward. Without the addition of the dropped-out scores, Chalder Fatigue (Likert Scoring) decreased 47.5%. The high dropout rate was probably due to the recruitment of the COVID portion of the trial from social media, no bonus payment for retention, and four capsules had to be taken each day.

We hypothesize that the improvements in fatigue may be due to the normalization of dysfunctional metabolic pathways. Below, we discuss several effects of oxaloacetate on metabolic pathways identified in human and animal studies, and why repletion of oxaloacetate with a medical food may help fatigue amelioration.

This small, non-randomized open-label dose escalating “Proof-of-Concept” clinical trial yielded impressive highly significant improvements in fatigue in both ME/CFS patients and Long-COVID patients. Clinical Efficacy was measured by the decrease in the Chalder Fatigue bimodal score from above 4 to 4 or below. Up to 33% of the patients with ME/CFS and up to 46.8% of Long COVID fatigue patients achieved clinical efficacy against fatigue with oral anhydrous enol-oxaloacetate treatment at 6 weeks. This compares well with historical placebo that achieved 5.9% clinical improvement in ME/CFS patients. Both physical and mental fatigue were significantly improved in both ME/CFS and Long COVID fatigue patients. 1000–3000 mg anhydrous enol-oxaloacetate daily was both safe and tolerable in this population for the duration of the trial. This proof-of-concept study supports the further development of anhydrous enol-oxaloacetate for the treatment of ME/CFS patients and Long COVID fatigue patients with longer randomized placebo-controlled studies. Potential clinical applications with anhydrous enol-oxaloacetate, currently a commercial nutritional supplement, may help reduce fatigue in ME/CFS and Long-COVID patients.