What is Oxaloacetate?
Oxaloacetate, or oxaloacetic acid (OAA), is a naturally occurring dicarboxylic acid that is a central component of the citric acid (Krebs) cycle, a process fundamental to cellular energy production. As a key intermediate, it plays a vital role in metabolism, including gluconeogenesis (the creation of glucose) and amino acid synthesis. Given its central metabolic role, oxaloacetate has been explored as a dietary supplement for its potential to support cellular energy, mimic calorie restriction, and offer neuroprotective benefits by scavenging excess glutamate. Because it is a natural part of human metabolism, supplementation introduces a compound the body already produces, though supplement stability and bioavailability can be a challenge.
Clinical Evidence on Oxaloacetate Safety
Several human clinical trials have investigated the safety and tolerability of oxaloacetate, particularly in patients with neurological and metabolic conditions. These studies have consistently pointed towards a favorable safety profile for the supplement at tested doses.
Tolerability in Alzheimer's Patients
In a Phase Ib study called TOAD (Trial of Oxaloacetate in Alzheimer's Disease), patients with Alzheimer's were given either 500 mg or 1000 mg of OAA twice daily for one month. The primary outcome was safety, and researchers found that both doses were safe and well-tolerated, with no severe adverse events reported. This suggests that even higher doses are safe for short-term use in this population, although no cognitive improvements were observed in this specific study.
Safety in ME/CFS and Long COVID Patients
Studies involving patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID have also supported the safety of oxaloacetate. In the REGAIN and RESTORE ME trials, patients were given OAA supplementation to address fatigue and cognitive issues. In these studies, OAA was very well-tolerated, with adverse events being mostly mild or moderate. Common issues included mild gastrointestinal symptoms, headaches, and nausea, affecting only a small percentage of participants.
ALS and Other Conditions
Safety has also been monitored in other contexts. A dose-escalating trial for patients with Amyotrophic Lateral Sclerosis (ALS) tested doses up to 2500 mg twice daily. While overall tolerability was high, mild GI distress was common, particularly at higher doses. Concerns about potential kidney stone formation have been raised in online forums, but these are based on rare, unconfirmed reports and not supported by substantial clinical data.
Reported Side Effects and Tolerability
While generally safe, oxaloacetate is not without potential side effects, which tend to be mild and often manageable.
- Gastrointestinal Distress: The most commonly reported side effects across several studies are gastrointestinal in nature. This includes nausea, heartburn, stomach upset, abdominal pain, and diarrhea. Many users with sensitive stomachs find relief by taking the supplement with food.
- Insomnia: Some reports, including a small study in Parkinson's patients, have linked OAA supplementation to insomnia, though the evidence is limited. The stimulating effect on cellular energy may be the cause. Taking the supplement earlier in the day is recommended to avoid this issue.
- Headache: Headaches were reported by a small percentage of participants in the RESTORE ME trial.
- Possible Interactions: Clinical work on drug interactions is limited, and specific interactions are not well-documented. Individuals on medication, particularly for diabetes or other metabolic conditions, should consult a doctor due to OAA's effect on glucose metabolism. Large doses could potentially lead to hypoglycemia.
Dosage and Considerations
Clinical trials have utilized a range of dosages, from 100 mg twice daily up to 2500 mg twice daily. These dosages have typically been found to be safe and well-tolerated over short-term periods of a month to a few months. However, there is currently no long-term safety data available for sustained use, and the optimal dose can vary by individual. Overdosing could potentially cause metabolic disturbances. It is important for individuals to discuss OAA with their healthcare provider to determine an appropriate and safe dosage for their specific health needs.
Comparison of Adverse Events in Clinical Trials
| Study | Dosage | Population | Common Adverse Events | Incidence | Source |
|---|---|---|---|---|---|
| REGAIN Trial | Up to 2,000 mg/day | Long COVID | GI issues (vomiting, diarrhea, abdominal pain), URI | <5% | |
| RESTORE ME Trial | 1,000-2,000 mg/day | ME/CFS | Headaches, Nausea, Abdominal pain | 3-5% (Nausea/Headaches) | |
| TOAD Study | 1,000 mg twice daily | Alzheimer's | Well tolerated, no severe events | Minimal | |
| ALS Dose Study | Up to 2,500 mg twice daily | ALS | GI issues, tachycardia, fatigue | Variable, up to 100% in one cohort |
The Bottom Line: Conclusion
Based on the available evidence from several human clinical trials, oxaloacetate is generally considered safe and well-tolerated for short-term use at dosages up to 2,000 mg or more per day. Adverse effects are typically mild and mostly involve gastrointestinal discomfort, which can often be mitigated by taking the supplement with food. While oxaloacetate is a natural metabolite, more research is needed to fully understand its long-term safety, especially in high doses and for certain populations. Potential supplement users should consult with a healthcare provider to ensure it is appropriate for them, particularly if they have underlying metabolic conditions or are on other medications due to limited data on drug interactions. For further research details on specific studies, information is available on public databases like the NIH clinical trials registry (ClinicalTrials.gov).
Potential Risks and Limitations
While OAA appears generally safe, some limitations and risks exist, including:
- Limited Long-Term Data: Most human studies are relatively short-term (1-3 months), meaning the long-term effects of chronic OAA supplementation are not yet fully understood.
- Bioavailability Issues: Oxaloacetate can be unstable in solution, and supplement manufacturers must address this to ensure efficacy and proper dosing. The lack of consistent increases in blood levels seen in some studies highlights the need for further investigation into optimal delivery methods.
- Unclear Drug Interactions: Due to the limited clinical work on drug interactions, caution is advised for individuals taking prescription medications, as potential interactions are largely unknown.
- Overdosing: As with any substance, excessive intake could potentially disrupt metabolic balance, emphasizing the importance of staying within clinically tested dosage ranges.
Navigating Oxaloacetate Supplements Safely
If considering an oxaloacetate supplement, take the following steps to ensure safe usage:
- Consult a Healthcare Provider: Discuss your health status and any other supplements or medications you take with a doctor or registered dietitian.
- Choose Reputable Brands: Select supplements from established brands that provide transparent information about their sourcing and testing procedures to ensure quality and accurate dosing.
- Start with a Low Dose: Begin with the lowest recommended dose to assess your body's tolerance before considering an increase.
- Take with Food: To minimize the risk of gastrointestinal side effects like heartburn, take the supplement with a meal.
- Monitor Your Body's Response: Pay attention to any side effects and discontinue use if you experience adverse reactions.
- Avoid Late Evening Doses: If you experience insomnia, avoid taking oxaloacetate in the late afternoon or evening.
Conclusion: Overall Safety Profile
In summary, oxaloacetate is an endogenous metabolic compound that has demonstrated a favorable safety profile in limited human clinical trials for various conditions, including Alzheimer's, ME/CFS, and Long COVID. The most common adverse effects are mild, transient gastrointestinal issues. However, the lack of long-term studies means chronic safety is not yet established. Individuals should proceed with caution, always consult a healthcare professional, and prioritize high-quality supplements to minimize risks associated with bioavailability and manufacturing variability.
The Final Word
While existing data suggests oxaloacetate is safe for short-term use, especially at lower doses, the scientific understanding is still evolving. More extensive, long-term human studies are needed to fully explore its efficacy and safety across diverse populations. Until then, a cautious and informed approach, guided by professional medical advice, is the best path forward for anyone considering this supplement.
Disclaimer
This article is for informational purposes only and does not constitute medical advice. Always consult a healthcare professional before starting any new supplement regimen.
