Oxaloacetate is a naturally occurring molecule in the body which may show promise in supporting those who experience low energy due to Chronic Fatigue. At root of Chronic Fatigue is an inability to produce adenosine triphosphate (ATP), the body’s energy currency.
Small amounts of ATP are generated when we burn sugar or glucose as a fuel. But we create the most ATP via the energy pathway known as the Citric Acid or Krebs Cycle which takes place in an organelle in the cell, known as the mitochondria.
There are multiple different mechanisms which can impact our mitochondria and substrate availability. Fatigue can be linked to digestive imbalances, nutrient deficiencies, blood sugar imbalances and poor metabolic health, infections, toxic load, stress and nervous system dysregulation – all of which impact the cell in their own way.
Because so many mechanisms impact our energy, fatigue recovery can be complex. Often there isn’t one magic bullet that fixes everything, however sometimes there are things which can make a big difference for some people in a short space of time.
One of these potential “bullets” is Oxaloacetate. Here we will explore the potential for supplemental oxaloacetate and Chronic Fatigue.
What is Oxaloacetate?
Oxaloacetate (OA) is a four-carbon organic acid that combines with acetyl-CoA. Together they form citrate, starting the Krebs cycle. The cycle metabolises energy from carbohydrates, proteins and fats to make electrons. These electrons are transported along the electron transport chain on the mitochondrial membrane and make ATP.
Therefore, oxaloacetate is highly supportive for energy production via the Krebs cycle and without it, cells would produce less ATP. For this reason, recent research has become interested in the efficacy of supplemental oxaloacetate. In vivo and in vitro research has suggested that Oxaloacetate may improve mitochondrial biogenesis, enhance insulin signaling, reduce neuroinflammation, and increase resistance to muscle fatigue.
Oxaloacetate is a naturally occurring molecule in the body. You can also find OA in very small amounts in certain foods but for those looking to seek the therapeutic benefits of Oxaloacetate and Chronic Fatigue, a supplement in capsule or powder form may be the best choice.
Research In Chronic Fatigue
Human trials investigating Oxaloacetate are limited but promising.
2000mg per day for 90 days
A randomised double-blind controlled study published in 2025 asked 82 adults with ME/CFS to supplement with 2000mg oxaloacetate per day for 90 days. This was administered in 2x 500mg doses, twice daily.
The study concluded that supplementation was associated with improved cognitive performance. The subjects wore a wearable device which would measure how much time they spent lying down versus sitting or standing. The group that took 2000mg per day spent more time sitting or standing and less time lying down, which the study referred to as “UP” time.
6 week trial with ME/CFS and Long Covid
A non-randomised controlled trial asked patients with ME/CFS and Long-COVID to supplement with either 500mg Oxaloacetate twice daily, 1000mg Oxaloacetate twice daily or 1000mg three times per day for 6 weeks. The study reported a reduction in physical and mental fatigue showing improvements of 21.7%-33.3% with greater improvements being associated with higher dosages.
Restore ME Trial
82 subjects with ME/CFS completed a 3 month randomised, double blinded, controlled trial receiving 2000mg of oxaloacetate (or the control) per day. Oxaloacetate was shown to reduce fatigue by 25% from baseline whereas the control group showed a non-significant reduction in fatigue (10%). Within the oxaloacetate group, 40.5% of individuals were classified as “enhanced responders” who collectively had a reduction of 63% in fatigue.
Discussion
Although current research is new and limited, overall these results seem promising and hopeful – especially if you are lucky enough to be an “enhanced responder” and experience a 63% reduction in fatigue. With minimal side effects, there may appear to be no downside to supplementing with Oxaloacetate and Chronic Fatigue.
The challenge I have experienced in clinical practice is accessibility to oxaloacetate as a supplement. Currently the only product I have been able to source is a product called Bene Gene by Advanced Orthomolecular Research which has 30 capsules, each offering 100mg of oxaloacetate.
Recommended dosages in recent trials range between 1000mg and 2000mg per day. This would mean supplementing with 10 to 20 capsules per day and one pot, costing approximately £50 would last 1.5 to 3 days. Supplement fatigue aside, the cost would not be sustainable for most.
That being said, anecdotally, I have had clients report improvements on lower dosages i.e. 100mg taken twice per day. They have reported more resilience against energy crashes or crashes not as low as would normally be expected. Based on anecdotal reports, it may be worth considering supplementing with OA even at lower dosages on a “try and see” basis.
The guidance I am giving my clients is to experiment with 100mg to 2x100mg per day for at least one month. Assess for noticeable improvements and then make a judgement call on whether the continued expense is worthwhile.
How and When To Take
Because oxaloacetate is involved in energy production, it’s generally best taken earlier in the day, when your body is naturally preparing to be more active. Many people choose to take it in the morning, often with breakfast, and find this supports energy without affecting sleep.
If you’re particularly sensitive, starting low and taking it early can help you gently assess how your body responds. Taking oxaloacetate later in the day isn’t usually recommended, as it may feel too activating for some people and interfere with rest.
As always, listening to your body and taking a personalised approach is key — especially when fatigue has already placed limits on your energy.
Who Should Not Take It?
Oxaloacetate is generally gentle and well-tolerated, but, as with any supplement, some people may notice mild effects – especally in individuals who are supplement sensitive. A few people report tummy discomfort, nausea, or slight bloating, which usually settles when taken with food. Rarely, some notice a subtle increase in alertness — another reason it’s best taken earlier in the day.
Long-term research in humans is still limited, so it’s always wise to start with a low dose and see how your body responds. If you notice anything unusual, it’s sensible to pause and check in with a healthcare professional.
For most people, oxaloacetate is a safe, supportive option when used thoughtfully, alongside the lifestyle strategies that help manage chronic fatigue.
Conclusion
The connection between Oxaloacetate and Chronic Fatigue generally seems supportive for energy and brain function, but they work best when your body has a stable foundation to build on. That’s where the Foundational Five come in — five stabilising pillars that help your body and nervous system function at their best:
- Nervous System Balance – supporting resilience and reducing the body’s stress response.
- Blood Sugar Management – keeping energy levels steady throughout the day.
- Pacing – managing activity to avoid post-exertional crashes.
- Sleep and Circadian Rhythms – restoring restorative rest and natural energy cycles.
- Managing Inflammation – supporting the body’s natural healing processes.
By focusing on these five stabilising factors, supplements like oxaloacetate can truly do what they’re meant to do — support your energy, focus, and wellbeing — rather than trying to act as a quick fix.
For those who want guidance on bringing all five pillars together, my Nurturing Resilience Program offers a structured, supportive approach to integrate them into daily life. It’s designed to help you build steady energy, protect your nervous system, and create routines that work for your body — giving supplements like oxaloacetate the best possible chance to support you.
