Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and… (Cash et Kaufman, 2022)

Consul

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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

Abstract

Background
There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue.
Methods
ME/CFS and Long-COVID patients were enrolled in an open label dose escalating “Proof of Concept” non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection.
Results
76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the “Chalder Fatigue Questionnaire” of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks.
Conclusions
Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted.



The study https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03488-3
 

Springbok1988

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I’ve been taking OAA for a month and a half now. I’ve seen a small but significant reduction of fatigue and brain fog at just 100 mg a day. I tried ramping up with it but found the higher the dose, the worse my anhedonia became. At 500 mg a day I became depressed. I believe this has to do with reduction of glutamate from Glutamate Oxaloacetate Transaminase activity.
I’ve found other medications and supplements that reduce glutamate have the same effect on me when the dose is too high.
The other downside, of course, it the cost. OAA is very expensive.
I wonder if malic acid would have the same impact as OAA since it enters the Krebs cycle as malate which gets converted to OAA.
 

Wishful

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Hmmm, from a quick search, it seems that oxaloacetate doesn't have a transporter into the mitochondria; it gets converted into aspartate, which does have a transporter. So, wouldn't supplemental aspartate be more effective? Unless our innate aspartate production system is malfunctioning, we don't need supplemental aspartate.

Supplementing oxaloacetate doesn't seem as easy as buying a bottle of pills. A solution breaks down in hours. I see that pill forms are available, but it has a half-life in the body of only 2 hrs, so the marketing claims of it getting into all your mitochondria and boosting their function may be a bit of an exaggeration. The studies do look promising, but even if there's no direct conflict of interest claimed, many researchers really want positive-looking results. I'll await further studies.
 

Richard7

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from a quick glance at the paper it would seem that aspartate would be better than malate.

They list six metabolomic changes that come from adding oxaloacetate to the mitochondria and one of them is the change in the NAD+/NADH ratio that comes from turning oxaloacetate into malate. So adding malate to the mitochondria would presumably push this in the wrong direction.
 
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Is there any way to figure out if this is getting into the mitochondria, and helping with the Krebs cycle? Or is this exogenous oxaloacetate helping with some other extra-cellular pathway? We know it is a potent glutamate scavenger, for example.

I ask that because it is not the first time I hear about someone getting some benefits for some time, and then not helping them anymore. And it is not like the Krebs cycle can "develop tolerance" to Oxaloacetate, that part does not change.
 

Springbok1988

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Hmmm, from a quick search, it seems that oxaloacetate doesn't have a transporter into the mitochondria; it gets converted into aspartate, which does have a transporter. So, wouldn't supplemental aspartate be more effective? Unless our innate aspartate production system is malfunctioning, we don't need supplemental aspartate.
The aspartate transporter is used to transport aspartate/OAA out of the mitochondrial matrix. OAA, being of low molecular weight, can pass into mitochondria through the outer mitochondrial membrane. To enter the matrix, it is converted to malate and is transported using the malate- a-ketoglutarate transporter. That had me wondering if malic acid would work just as well or better.
 
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Pyrrhus

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I tried a 150mg dose of malic acid once.

It gave me a brief energy boost, followed by a 2-week crash. But that's just me.

The weird thing is that there is 500-2000mg malic acid in a single apple, but I can eat apples without any problem. This is just an example of a larger observation I have made: purified nutrients in supplement form often have much stronger effects on me than the same nutrients in food form. Differential absorption/transport/utilization?