Hypoxia in Long COVID and Its Impact on the Krebs Cycle

The Current Understanding of Long COVID in Western Medicine

Long COVID, officially known as Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), remains a poorly understood condition despite its significant prevalence and impact. Western medicine has identified common symptoms such as fatigue, brain fog, dysautonomia, and exercise intolerance, but the exact mechanisms driving these symptoms remain elusive. Hypotheses center around immune dysregulation, persistent inflammation, mitochondrial dysfunction, microclots impairing oxygen delivery, and potential viral persistence. However, no definitive cause has been established, and treatment options are largely focused on symptom management rather than to address underlying dysfunctions. While progress in research continues, Long COVID highlights critical gaps in understanding chronic, systemic illnesses within the Western medical framework.

The sympathetic dysregulation seen in long COVID is not just about the physical symptoms, which are crushing, but about the broader systemic effects. PT, RT, and rehabilitation cannot succeed under parasympathetic dominance (freeze states) or mixed autonomic patterns because the immune system shuts down. Extreme autonomic dysregulation, compounded by hypoxia, limits the brain’s capacity for neuroplasticity. Cranial nerve involvement often indicates a partial dorsal freeze state and the loss of this capacity.  Recovery from long COVID requires rebuilding autonomic pathways in the vestibular system and addressing spasticity in tissues, which are replaced rather than repaired. Ancillary providers play a role by helping to maintain autonomic balance which allow the brain to create new pathways. This process cannot be resolved by medication or steroids; rather, patients must reintegrate portions of their nervous system. Collaboration across modalities is essential, and PT, RT combined with ancillary techniques and minimal supplementation support the internal processes so that PT and RT can be effective.

Context and the Need for an Integrative Approach

Earlier this summer, I attended an online CEU class that sought to discuss Long COVID through the lens of Traditional Chinese Medicine (TCM), specifically by referencing common kitchen herbs. While the intention may have been to offer concepts for practical application, the approach felt dismissive and trivializing given the complexity of Long COVID. This condition is not merely a collection of lingering symptoms but represents a profound disruption in autonomic function and systemic balance.

Long COVID cannot be addressed effectively through any single modality, whether it be TCM, Naturopathy, chiropractic adjustments, or western medicine. These tools, while valuable, are insufficient to resolve the interplay of hypoxia, autonomic dysregulation, and metabolic dysfunction that underlies this condition. To truly address the challenges of Long COVID, an integrative approach is essential, combining insights from TCM, biomedical science, and other therapeutic frameworks to restore systemic balance and functionality.

Introducing the Hypoxia Hypothesis in Long COVID

Long COVID has baffled clinicians and researchers with its persistent and wide-ranging symptoms, from fatigue and brain fog to muscle weakness and autonomic dysfunction. Despite the absence of an active viral infection in many cases, patients remain trapped in a state of profound physical and cognitive dysfunction. One promising avenue to understand this phenomenon lies in the dynamic between oxygen availability, mitochondrial function, and cellular metabolism.

Central to this discussion is the role of hypoxia — a condition where cells lack adequate oxygen. In the context of Long COVID, hypoxia may not only result from acute infection but also drive ongoing metabolic and physiological disturbances. The hypothesis suggests that persistent hypoxia disrupts the cell's ability to generate energy efficiently, forcing it into less effective anaerobic pathways. This cascade of events may explain the chronic and debilitating symptoms in these patients.

Hypoxia and Metabolic Disruption

At the core of cellular energy production lies the Krebs cycle (citric acid cycle), a mitochondrial process requiring oxygen to produce ATP, the body’s energy currency. Under normal conditions, glucose metabolism produces up to 36 ATP molecules per glucose through glycolysis, the Krebs cycle, and oxidative phosphorylation. However, hypoxic conditions—where oxygen is insufficient—disrupt this process. Cells shift to anaerobic glycolysis, a less efficient pathway that produces only 2 ATP per glucose molecule.

This metabolic shift, while essential for survival during acute oxygen deprivation, is maladaptive when prolonged. The reliance on anaerobic glycolysis results in lactate accumulation, cellular acidosis, and systemic energy deficits, which are particularly damaging to high-demand tissues like the brain and muscles. These deficits likely explain hallmark Long COVID symptoms such as chronic fatigue, cognitive impairment, and exercise intolerance.

The Role of the Brain and Autonomic Nervous System

The brain’s reliance on glucose as its primary energy source makes it highly susceptible to these metabolic disruptions. With only 2 ATP generated per glucose molecule in anaerobic states, the brain’s energy-intensive processes, such as synaptic function and ion gradient maintenance, falter. This energy shortfall likely drives symptoms like “brain fog,” memory lapses, and difficulty concentrating.

Additionally, hypoxia’s effects on the autonomic nervous system may worsen the condition. The brainstem’s autonomic centers depend on a steady energy supply to regulate essential functions like heart rate, blood pressure, and respiratory rhythms. Energy deficits in these areas can lead to dysautonomia, manifesting as orthostatic intolerance, heart rate variability, and temperature dysregulation, all frequently reported in Long COVID patients.

Fear Paralysis, Cranial Nerve Involvement, and Long COVID

The persistent symptoms of Long COVID seem to include a reactivation of primitive autonomic responses, particularly the fear paralysis reflex, which has roots in the autonomic nervous system and cranial nerves. This reflex, is governed by the dorsal vagal complex and associated cranial nerves.  It  acts as a survival mechanism during overwhelming stress or trauma.

When reactivated, the fear paralysis state triggers a partial dorsal vagal response, which reduces metabolic activity to conserve resources. Unlike a complete freeze state, this partial activation creates a “mixed” autonomic state, blending sympathetic overactivation with dorsal vagal suppression. The energy-intensive demands of cranial nerve functions, such as respiration, digestion, and vocalization, become compromised, exacerbating hypoxia and metabolic dysfunction.

Patients who show signs of cranial nerve involvement, such as dysphonia, dysphagia, or autonomic instability, demonstrate these characteristics. The re-emergence of primitive reflexes, such as fear paralysis, indicates brainstem dominance in the absence of effective cortical regulation, creating a cycle of energy deficits and autonomic dysregulation.

Evidence Supporting Hyperbaric Oxygen Therapy, Liposomal Delivery, and NAD⁺ Precursors

Emerging research suggests that Hyperbaric Oxygen Therapy (HBOT),liposomal formulations, and NAD⁺ precursors, such as Nicotinamide Riboside (NR), could offer therapeutic benefits for individuals experiencing Long COVID.

Hyperbaric Oxygen Therapy (HBOT):

• Mechanism: HBOT delivers pure oxygen in a pressurized environment, improving oxygen delivery to tissues and aiding recovery from hypoxia-induced damage.

NAD⁺ Precursors (Nicotinamide Riboside - NR): Liposomal Formulations

• Mechanism: Liposomal NR acts as a precursor to NAD⁺, a coenzyme essential for energy metabolism and mitochondrial repair.

IV and intranasal Delivery

IV and intranasal administration of N-Acetylcysteine (NAC) or NAD⁺ precursors offers a promising route to address the metabolic and neurological challenges seen in Long COVID. Intranasal delivery bypasses first-pass metabolism, allowing rapid and efficient absorption directly into the central nervous system. IV methods pass through the blood brain barrier to allow the antioxidants and Krebs co-factors to entre the brain.  

IV NAC acts as a potent precursor to glutathione, supports antioxidant defenses, reduces oxidative stress, and enhances mitochondrial health. It may counteract neuroinflammation and repair cellular damage. Similarly, intranasal NAD⁺ precursors restore depleted NAD⁺ levels, improve mitochondrial function, and boost energy production and restore cognitive pathways. This targeted approach strengthens the brain and autonomic nervous system, alleviates brain fog, fatigue, and dysautonomia, and improves overall metabolic resilience.  

Recommendations for TCM Practitioners Treating Long COVID Patients

Patients with Long COVID exhibit pronounced spasticity in the sinew channels, particularly through the cervical region and intercostal muscles of the ribs. This spasticity interferes with baroreceptor function, blocks effective signals, and causes a disconnect between the vestibular system and autonomic regulation. While many TCM practitioners do not address tissue-level issues directly, providers trained in tui na, shiatsu, meridian therapy, or techniques from Traditional Japanese Medicine (TJM) can release accumulations in the intercostal muscles and cervical spine. Techniques such as Anma-style massage, cranial-sacral or lymphatic drainage applied to the neck or rib cage clear restrictions, restore baroreceptor function, and improve autonomic balance. If you are a practitioner that does no tissue work, refer out and work collaboratively. This cannot be addressed by community-style treatments.

• Physical and Respiratory Therapies: Physical therapy (PT) and respiratory therapy (RT) should be prioritized to address physical restrictions and improve oxygenation. PT restores movement patterns, alleviates musculoskeletal tension, and supports recovery. RT enhances breathing mechanics and ensures proper oxygen delivery, which spasticity in the cervical spine and intercostal muscles often compromises.

• Electrical Stimulation is Contraindicated: Electrical stimulation must be avoided due to its potential to exacerbate autonomic dysregulation. Patients with Long COVID often cannot tolerate this kind of stimulation. Alternative approaches include moxibustion for warming and gentle support, Tei-shin style needling for subtle and non-invasive care, and manual therapies to restore balance without overwhelming the system.

• Tissue Patterns and Manual Therapies: Long COVID patients present with spasticity in the cervical sinew channels, particularly in the scalenes, which impinge the carotid artery, and in the intercostals, restricting baroreceptor signaling. Upledger craniosacral therapy and Barral’s neural and visceral manipulation are effective for clearing these restrictions.

• Cold and Depleted Patterns: Many patients present with coldness, exhaustion, and depletion. Moxibustion provides effective warming and tonification. Cupping is not recommended at this time due to poor tissue repair in dorsal states.

• Dietary and Supplementary Interventions: Cooked, warm foods reduce digestive strain. Digestive enzymes improve nutrient absorption. Methylated B complex supports cellular energy production.

• Mind-Body and Physical Therapies: Mindful breathing helps regulate autonomic function. Gentle walking meditation encourages movement without overstimulation. Deliberate breath work restores oxygenation and respiratory function.

Conclusion

Virtually every consultation I have conducted for Long COVID has included clients presenting with primitive reflex demonstrations, dysphagia, and emergent cranial nerve involvement. Again, dorsal root states result in a dramatic decline in ATP production, dropping from 36 ATP in aerobic metabolism to just 2 ATP in anaerobic states. The discovery of this pathway was a shock, and I worked out these connections this morning. I wanted to share this insight quickly to help spread awareness and support for addressing this aspect of Long COVID.

By framing Long COVID through the lens of hypoxia-induced metabolic disruption, we gain insights into its underlying mechanisms and potential therapeutic targets. This hypothesis emphasizes mitochondrial function and oxygen availability while highlighting the need for interventions to restore cellular energy balance. Through targeted mitochondrial support, NAD⁺ supplementation, or oxygen therapy, addressing these metabolic issues offers a promising pathway to alleviating Long COVID’s burden.

References

BMC Infectious Diseases. (2023). Interim analysis of the HOT-LoCO trial: Safety of Hyperbaric Oxygen Therapy in post-COVID conditions. BMC Infectious Diseases. Retrieved from https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-023-08002-8

BMJ Open. (2023). Evaluating Hyperbaric Oxygen Therapy in improving quality of life for Long COVID patients. BMJ Open. Retrieved from https://bmjopen.bmj.com/content/12/11/e061870

Frontiers in Medicine. (2024). Potential of Hyperbaric Oxygen Therapy in addressing Long COVID symptoms. Frontiers in Medicine. Retrieved from https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1354088/full

Massachusetts General Hospital. (2022). Investigating NR supplementation for cognitive and physical symptoms in Long COVID patients. Neurology Research. Retrieved from https://www.massgeneral.org/neurology/mccance-center/2022-7-long-covid-clinical-trial

MDPI Vaccines. (2023). NAD⁺ level restoration during viral infections through NAD⁺ precursors. MDPI Vaccines, 13(1). Retrieved from https://www.mdpi.com/2076-393X/13/1/1