Oxaloacetate: The missing link in long COVID

Functional medicine approaches to lower spike protein burden and mitigate symptoms

Long COVID is a chronic condition in which people suffer from an array of symptoms (Table 1) months or years after the acute phase of COVID. It has become common enough that practitioners frequently have to address this problem in their patients. According to 2024 statistics, an estimated 7% of adults in the US (approximately 17 million people) were experiencing long COVID during that time.¹ This latest data demonstrates long COVID rates remained relatively consistent over the last year, suggesting they may persist over time unless new forms of prevention or treatment are unveiled. Other statistics indicate more than 70% of COVID survivors suffer from ongoing symptoms four months post-infection.²

There are many functional medicine approaches for long COVID^3-13 that seek to lower spike protein burden and/or may help mitigate symptoms (Table 2). Many of these approaches have yielded notable clinical success. In this article, we will examine the research from the peer-reviewed literature regarding the addition of supplemental stabilized oxaloacetate to augment existing functional medicine protocols to support patients with long COVID (Figure 1).

Mitochondrial dysfunction’s role in long COVID

Although many approaches are currently being used in functional medicine to support patients presenting signs and symptoms of long COVID; this article will focus on mitochondrial dysfunction, which has been implicated in both the duration and wide variety of long COVID symptoms. Mitochondrial dysfunction leads to cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances and endothelial dysfunction, which all could play a role in long COVID.

Mitochondrial dysfunction is a key mediator in similar post-infectious states caused by other diseases. There is potential overlap between the symptoms of long COVID and the well-known negative results of mitochondrial dysfunction.¹⁴

Research has identified mitochondrial dysfunction in people suffering from long COVID.^15,16,17

Scientists have found impaired mitochondrial respiration and bioenergetics and mitochondria-related gene expression in peripheral blood mononuclear cells (PBMCs) in this group of patients.

Oxaloacetate: An important addition to a long COVID protocol

Oxaloacetate is a key intermediate of the citric acid cycle and is important to mitochondrial health. Oxaloacetate modulates cellular metabolism, enhances mitochondrial biogenesis and reduces neuroinflammation in preclinical models.^18,19,20 Consequently, scientists have studied its effects in long COVID, with promising results.

In a randomized, controlled clinical trial of oxaloacetate for symptoms of long COVID, 69 participants were randomized into a group who received either 2,000 mg/day of oxaloacetate or a placebo for 42 days. At day 21, participants taking oxaloacetate experienced statistically significant improvement in fatigue as measured by the DePaul Symptom Questionnaire Short Form (DSQ-SF). Total symptom burden improved at day 21. Oxaloacetate supplementation also significantly improved cognitive performance; the reduction in long COVID symptoms after oxaloacetate supplementation correlated with cognitive improvement.

In another study, researchers investigated the effects of oxaloacetate treatment for mental and physical fatigue caused by either myalgic encephalomyelitis, chronic fatigue syndrome or long COVID.²¹ In a non-randomized, controlled, open-label, dose-escalating “proof-of-concept” study, participants were given oxaloacetate or a placebo for six weeks. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) groups were given 500 mg BID (n=23), 1000 mg BID (n=29), or 1000 mg TID (n=24); long COVID groups were given 500 mg BID (n=22) or 1000 mg BID (n=21).

At six weeks, 76 ME/CFS patients experienced an average reduction in fatigue. As measured by the Chalder Fatigue Questionnaire, both physical and mental fatigue were significantly improved over baseline and placebo. Fatigue reduction dose dependently increased in ME/CFS patients from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Fatigue in long COVID patients significantly declined by up to 46.8% in six weeks.

The evidence suggests oxaloacetate may counteract fatigue through mechanisms that improve mitochondrial health, including the restoration of NAD+/NADH balance, enhancement of mitochondrial biogenesis, antioxidant action, reduction of glycolysis and lactate production, decreased NF-κB activity and increased glucose uptake via AMPK activation.

Final thoughts

Long COVID causes an array of symptoms that interfere with patients’ activities of daily life. Mitochondrial dysfunction is implicated in the pathogenesis of long COVID. The addition of oxaloacetate to your existing long COVID protocol may potentiate outcomes, as it is a known promoter of mitochondrial biogenesis. Taking this approach can lead to enhanced energy, cognitive function and vitality in patients suffering from this debilitating condition.

Note: Further scientific information on the science of oxaloacetate can be received from one of the co-authors of the REGAIN study and long COVID study, Alan Cash acash@benagene.org.

CHRIS D. MELETIS, ND, is an educator, international author and lecturer. His mission is “Changing the World’s Health, One Person at a Time.” He believes that when people become educated about their bodies is the moment positive change begins. He is widely recognized as a world-renowned expert on the science of CBD and has authored 16 books and more than 200 national scientific articles. He served as dean of naturopathic medicine and chief medical officer for seven years at National University of Natural Medicine (NUNM), the oldest naturopathic medical school in North America. He has received numerous awards, including the prestigious Physician of the Year Award from the American Association of Naturopathic Physicians, an Excellence Award for his work treating and advocating for the medically underserved and most recently, the NUNM Hall of Fame Award. He represents TruGen3 and can be contacted at drmeletis.com.

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