Oxaloacetate was quite the ticket for some people.
The GIST
- Oxaloacetate became a thing in ME/CFS after Dr. David Kaufman saw it was low in a metabolomic study and began trying the supplement on his patients.
- Because oxaloacetate starts the Krebs cycle – which makes up the first part of the aerobic energy production process – energy production gets hit very early in the energy production process.
- An earlier proof of concept, open-label trial reported that 33% of the patients with ME/CFS, and up to 46.8% of long-COVID patients, received more than 25% reduction in fatigue. This trial, though, was the first placebo-controlled, randomized oxaloacetate trial.
- Eight-two people (ME/CFS-42; HC-40) took 1,000 mg/2xs a day dose in a 3-month trial at the Bateman Horne Center. Fatigue was reduced in the oxaloacetate group by 32% (Chalder Fatigue Score) and 35% (RAND 36). The placebo group improved somewhat (but not significantly).
- Concerning functionality, the group that received oxaloacetate went from 9.1 (moderate to severe fatigue) to 6.6 (moderate fatigue) on the Chalder fatigue scale. Regarding their ability to carry out daily activities, they went from having “significant fatigue that may affect their daily activities and overall well-being” to “noticeable fatigue that could impact their daily life”.
- About 40% of the oxaloacetate group, however, were considered “enhanced responders” (>25% improvement). The paper did not provide their Chalder Fatigue data, but a doubling of their fatigue scores would have left them, if my numbers are right, with an average Chalder Fatigue score of 3.7 or “mild to moderate” fatigue – a big jump from the severe fatigue the entire group started with.
- The Harvard dataverse data showed that the response to the supplement was very heterogeneous. Half the participants (21/42) either had no or very moderate (0 to +2 point) improvements in their fatigue or got a bit worse (-1 to -4). Approximately 40% of the group (n=16) received a score of +3 or higher received at least a 25% improvement in fatigue. Twenty percent of the group with scores of +6 or higher surely received major benefits. Finally, 7% of the group (n=3) with scores of +9 to +11 must have hit the ball out of the park.
- When oxaloacetate helped, it really helped – which brings up the question why and how it helped those it did. The authors outlined several ways oxaloacetate may be helping (lactate reduction, antioxidant protection, reduced inflammation, restoring NAD+/NADH levels, and increased glucose uptake).
- Happily, this is not a one-and-done study that simply tells us whether a substance helps or not. The authors reported that metabolic analyses “underway at several facilities” are attempting to learn how oxaloacetate helped the ME/CFS patients it did. Those data should then help us understand what’s going on in ME/CFS, and identify which patients it might help.
- In the end, given oxaloacetate’s cost ($4-500/month), these analyses could be the most significant thing to come out of this study, as they’re looking at what is potentially a sizeable subset of ME/CFS patients.
- With one other oxaloacetate study and two Rapamycin studies – all of which will be digging into the biology of the participants – we should be learning much more about the role the mitochondria are playing in ME/CFS/FM and long COVID.
Looking at what oxaloacetate does, it’s easy to see why Kaufman did that. Without oxaloacetate, the whole energy production process stops. More accurately, it never really gets started.
Dr. Kaufman zeroed in on one of dozens of dysregulated metabolites.
There are two parts to aerobic energy (oxygen-derived) metabolism: the first – called the Krebs, citric acid, or TCA cycle (take your pick of names) – produces the two electron carriers (NADH, FADH2) which transport electrons in the second part of the cycle – the OXPHOS cycle – where the bulk of the ATP is produced. Oxaloacetate begins the Krebs cycle and at the end of it, is regenerated. Low oxaloacetate levels inevitably result in low levels of the two-electron transporters – NADH and FADH2 – an inhibited electron transport chain and low ATP production.
That process, the authors proposed, triggered ME/CFS patients’ cells to compensate by using the “Warburg Effect”, a means by which cells create energy using glycolysis instead of aerobic energy production. Glycolysis occurs outside the mitochondria, produces a toxic substance called lactate, and produces much, (much), less energy. Oxaloacetate, it turns out, regulates the Warburg Effect. While we don’t know if the Warburg Effect is alive and well in ME/CFS, some studies suggest it is.
Kaufman called oxaloacetate’s effects in some of his patients “extraordinary” and said he’d rarely seen such dramatic effects on fatigue. In 2021, he reported that at 1,000 mg/2x a day, fatigue dropped about 35% on average in 52 patients he had been tracking.
In 2022, a proof of concept, open-label trial in 76 people with ME/CFS and 43 people with long COVID reported that 33% of the patients with ME/CFS, and up to 46.8% of long-COVID fatigue patients, received more than 25% reduction in fatigue.
The Study
What we really needed was a randomized, placebo-controlled trial – and now we have it in “RESTORE ME: an RCT of oxaloacetate for improving fatigue in patients with myalgic encephalomyelitis/chronic fatigue syndrome“.
This trial dispensed with the lower doses explored in the earlier study and went straight to the 1,000 mg/2xs a day dose. Eight-two people (ME/CFS-42; HC-40) participated in the 3-month trial which took place at the Bateman Horne Center. The participants were described as having mild-moderate ME/CFS. Thirty-five percent were still working.
The Chalder Fatigue Scale was the primary endpoint – the endpoint by which studies are judged a failure or success. Fatigue was reduced in the oxaloacetate group by 32% (Chalder Fatigue Score) and 35% (RAND 36). The placebo group improved somewhat (but not significantly).
Concerning functionality, the group that received oxaloacetate went from 9.1 (moderate to severe fatigue) to 6.6 (moderate fatigue) on the Chalder fatigue scale. Regarding their ability to carry out daily activities, they went from having “significant fatigue that may affect their daily activities and overall well-being” to “noticeable fatigue that could impact their daily life”.
The dataset shelved at a Harvard dataverse shows that the fatigue reductions held firm over time; that is, similar fatigue reductions were found at the end of month 3 as were found in months 1 and 2.
Who You Are Matters
About 40% of the oxaloacetate group, however, were considered “enhanced responders” (>25% improvement). The paper did not provide their Chalder Fatigue data, but a doubling of their fatigue scores would have left them, if my numbers are right, with an average Chalder Fatigue score of 3.7 or “mild to moderate” fatigue – a big jump from the severe fatigue the entire group started off with.
Oxaloacetate hit the mark in one group of patients.
The Harvard dataverse data showed that the response to the supplement was very heterogeneous. Half the participants (21/42) either had no or very moderate (0 to +2 point) improvements in their fatigue or got a bit worse (-1 to -4). Approximately 40% of the group (n=16) which received a score of +3 or higher reported at least a 25% improvement in fatigue. Twenty percent of the group with scores of +6 or higher surely received major benefits. Finally, 7% of the group (n=3) with scores of +9 to +11 must have hit the ball out of the park.
ME/CFS, then, is as tricky as ever, and heterogeneous responses to treatments remain the norm. Researchers are catching on, though, and are now more often looking to pluck out subsets of patients who respond well. Oxaloacetate is so expensive (@$400-$500/month) that, depending on how much money you have, it might only be worth it if you were in the enhanced response group.
The oxaloacetate was well tolerated. The only two side effects noted were headaches (in only 3/42 participants) and nausea (3/42 participants) (which disappeared when they took the supplement with meals).
But Why?
When oxaloacetate helped, it really helped – which brings up the question why and how it helped those it did.The authors outlined several ways oxaloacetate may be helping (lactate reduction, antioxidant protection, reduced inflammation, restoring NAD+/NADH levels, and increased glucose uptake).
Happily, this is not a one-and-done study that simply tells us whether a substance helps or not. The authors reported that metabolic analyses “underway at several facilities” are attempting to learn how oxaloacetate helped the ME/CFS patients it did. Those data should then help us understand what’s going on in ME/CFS, and identify which patients it might help.
The researchers are digging into what happened in the enhanced response group.
In the end, given oxaloacetate’s cost, these analyses could be the most significant thing to come out of this study, as they’re looking at what is potentially a sizeable subset of ME/CFS patients.
Asking AI ChatGPT what might have caused the low oxaloacetate levels brought up (unfortunately) a wide variety of possibilities. They included:
- low carbohydrate availability (a possibility given the increased breakdown of amino acids in ME/CFS?),
- low biotin/B3-niacin (a group focused on niacin supplementation in ME/CFS has emerged),
- mitochondrial dysfunction,
- low acetyl-CoA levels,
- hypoxia (low oxygen conditions),
- starvation (interesting, given findings suggesting that, metabolically, ME/CFS resembles a state of starvation).
The low oxaloacetate levels, then, could be due to general problems (mitochondrial dysfunction, oxidative stress, low oxygen levels) or to something more specialized (genetic mutation pyruvate carboxylase, problems with malate and/or citrate synthase).
Mitochondrial Enhancers Getting Attention
Another oxaloacetate trial appears to be underway at Dr. Natelson’s center. Instead of metabolomics, it will use brain imaging to determine if oxaloacetate improves antioxidant levels in the brain.
Pair the two oxaloacetate studies with the two Rapamycin trials underway – each will also investigate different biological aspects – and we suddenly have a nice set of ME/CFS/long-COVID mitochondria trials.
Plus let’s not forget David Systrom’s mitochondrial enhancer trial – which ultimately failed – but provided potentially valuable biological data. We stand to learn much more about the mitochondria’s role in these diseases.
Digging into the data is fun! If that’s what you want to see please support us!
Health Rising Donation Drive Update
Thanks to the over 220 who have contributed to Health Rising’s End of the Year donation drive!
This blog demonstrates what we love to do in Health RIsing – dig into the data. For instance, the paper did not report on the day-to-day impacts of oxaloacetate – we had to dive into the meaning of the Chalder Fatigue scores to get that. Likewise, it took checking out a separate dataset to uncover the range of oxaloacetate’s effects.
Digging into that stuff is what makes blogs fun. If that supports you – please support us!
Drs Kaufman and Ruhoy covered this paper and pathway in detail and were excited like kids with a new toy.. Recent research is also showing that stress response through sympathetic tone affects T-cell exhaustion through beta1 adrenergic receptors on T-cells. Drs Kaufman and Ruhoy and other mast cell doctors are very excited as they think it explains a lot of what they see. They say that it is an alternative to the HPA axis. The mito respiration switch from oxphos to glycolysis affects oxaloacetate production and also makes other epigenetic changes to immune cells. This is my favourite explanation of why oxaloacetate is low in so many ME/CFS patients. We have seen huge response in all neuropsychiatric symptoms at just 100mg oxaloacetate. Oxaloacetate in low doses is also used for PMS. In PMS it is thought to increase glucose levels in the brain through gluconeogenesis
https://www.nature.com/articles/s41586-023-06568-6
This pathway can potentially explain how mast cells or other immune triggers can affect glucose metabolism and neuropsychiatric symptoms through exhausted T cells.
does anyone know where to get this supplement at a reasonable price… less than $100
Scott H
I’m so sorry to see how slowly your fundraiser is going. I am guessing that we are a very hard group to get money from since most of us don’t have jobs. I would love to give you a lot more than what I gave, if it were only possible. I don’t have my own income or any government income. But my family does help me pay for any doctors’ expenses, food, supplements, and other necessities.
Anyway, maybe if all of us gave $5 to $15, that would help? This is my encouragement to all of us to give the little bit that we can give.
Recently I mentioned to the group some nutrition/supplementation options which could be started now, and
I mentioned that if there is dysbiosis, the gut may be failing to make enough
Butyrate for its own energy needs
Acetate– for the body’s acetate needs.
OXALOACETATE… is a form of acetate.
Acetylcholine is made of choline and Acetic acid in the motor neuron synapse to get that ionotropic channel opened and kept open to allow Na+, K+ and Ca2+ flow. Acetyl Coa is required in the Krebs cycle to donate carboxly groups to make Citrate.
“Acetyl-CoA … derived from pyruvate oxidation, or from the beta-oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix,
and is never regenerated.”
That seems crucial. one molecule is consumed and never regenerated. So where is all of this Acetyl CoA supposed to come from?
It seems to me that not only is Oxaloacetate going to possibly provide Acetate that may be lacking from dybiosis, but also many functional medicine doctors have recommended Oxaloacetate as a main supplement for fatigue. I believe I have even read that here.
Another main supplement is N-Acetylcysteine.
Now, I am not saying that it provides Acetate. What I read is that l-cysteine is the precursor to glutathione. NAC is the “acetylated” version of l-cysteine. So… if it gets deacetylated… does that make acetate available also?
I did not think it was the best time for me to go into the subject of mitochondrial heavy-hitters, but if I had I would have cited:
Oxaloacetate — a supplement
NAC-seems to be a drug or “pro-drug” for the creation of Glutathione, the mother of all antioxidants.
(NAC. for 8% of people CAN TRIGGER ANAPHYLAXIA)
D-Ribose– a supplement
“D-ribose is a naturally occurring monosaccharide found in the cells and particularly in the mitochondria is essential in energy production. Without sufficient energy, cells cannot maintain integrity and function. Supplemental D-ribose has been shown to improve cellular processes when there is mitochondrial dysfunction.”
Furthermore,
“D-ribose is a naturally occurring monosaccharide within the pentose pathway that assists with ATP production. It is a 5-carbon chain (also called aldopentose) and is a key component of DNA, ribonucleic acid (RNA), acetyl coenzyme A, and ATP (9). Cells produce D-ribose through the pentose phosphate pathway (PPP) that is essential for ATP production. In many diseases or conditions, ATP synthesis is reduced, thus supplementation with D-ribose may provide a solution to impaired cellular bioenergetics”
It has been touted by Dr. Amy Myers of Texas for an itermediate to later recovery step in recovery from Adrenal Fatigue. She spoke of it with regard to the Ribosomes. They make new viruses, unwittingly, when supplied with the viral messenger-RNA, but normally they would be workshops of the cell for DNA/RNA repair.
So my point, above is to definitely cheer on the use of Oxaloacetate, but also to mention two also-very-powerful substances for mitochondrial recovery,
and to maybe eludcidate somewhat *why* they are
important.
I hope this is helpful, but talk to a Doc about NAC, and maybe avoid if you have anaphylactic reactions to other things. !
Recently I mentioned to the group some nutrition/supplementation options which could be started now, and
I mentioned that if there is dysbiosis, the gut may be failing to make enough
Butyrate for its own energy needs
Acetate– for the body’s acetate needs.
OXALOACETATE… is a form of acetate.
Acetylcholine is made of choline and Acetic acid in the motor neuron synapse to get that ionotropic channel opened and kept open to allow Na+, K+ and Ca2+ flow. Acetyl Coa is required in the Krebs cycle to donate carboxly groups to make Citrate.
“Acetyl-CoA … derived from pyruvate oxidation, or from the beta-oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix,
and is never regenerated.”
That seems crucial. one molecule is consumed and never regenerated. So where is all of this Acetyl CoA supposed to come from?
It seems to me that not only is Oxaloacetate going to possibly provide Acetate that may be lacking from dybiosis, but also many functional medicine doctors have recommended Oxaloacetate as a main supplement for fatigue. I believe I have even read that here.
Another main supplement is N-Acetylcysteine.
Now, I am not saying that it provides Acetate. What I read is that l-cysteine is the precursor to glutathione. NAC is the “acetylated” version of l-cysteine. So… if it gets deacetylated… does that make acetate available also?
I did not think it was the best time for me to go into the subject of mitochondrial heavy-hitters, but if I had I would have cited:
Oxaloacetate — a supplement
NAC-seems to be a drug or “pro-drug” for the creation of Glutathione, the mother of all antioxidants.
(NAC. for 8% of people CAN TRIGGER ANAPHYLAXIA)
D-Ribose– a supplement
“D-ribose is a naturally occurring monosaccharide found in the cells and particularly in the mitochondria is essential in energy production. Without sufficient energy, cells cannot maintain integrity and function. Supplemental D-ribose has been shown to improve cellular processes when there is mitochondrial dysfunction.”
Furthermore,
“D-ribose is found within the pentose pathway that assists with ATP production. It is a 5-carbon chain (also called aldopentose) and is a key component of DNA, ribonucleic acid (RNA), acetyl coenzyme A, and ATP (9). Cells produce D-ribose through the pentose phosphate pathway (PPP) that is essential for ATP production. In many diseases or conditions, ATP synthesis is reduced, thus supplementation with D-ribose may provide a solution to impaired cellular bioenergetics”
It has been touted by Dr. Amy Myers of Texas for an itermediate to later recovery step in recovery from Adrenal Fatigue. She spoke of it with regard to the Ribosomes. They make new viruses, unwittingly, when supplied with the viral messenger-RNA, but normally they would be workshops of the cell for DNA/RNA repair.
So my point, above is to definitely cheer on the use of Oxaloacetate, but also to mention two also-very-powerful substances for mitochondrial recovery,
and to maybe eludcidate somewhat *why* they are
important.
I hope this is helpful, but talk to a Doc about NAC, and maybe avoid if you have anaphylactic reactions to other things. !