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), presents with symptoms such as fatigue, brain fog, dysautonomia, and exercise intolerance. Despite its prevalence, Western medicine has yet to identify a unifying mechanism behind these symptoms. Proposed causes include immune dysregulation, persistent inflammation, mitochondrial dysfunction, microclotting, and viral persistence. Treatment remains symptomatic and fragmented. The condition exposes critical gaps in how chronic systemic illnesses are approached within the biomedical model.

Limits of Conventional Rehabilitation and the Need for Autonomic Rebuilding

Standard rehabilitation models—PT, RT, and related therapies—fail when patients remain locked in parasympathetic dominance or unstable autonomic states. These patterns suppress immune responses and restrict neuroplasticity, especially when compounded by chronic hypoxia. Cranial nerve involvement often signals a dorsal freeze state which indicates impaired neuroplastic function.  Long COVID recovery requires the reorganization of autonomic and vestibular pathways, as well as resolution of tissue spasticity, where repair is no longer sufficient and replacement may be necessary. Medication alone is ineffective. Cross-disciplinary collaboration is essential: PT and RT must work alongside modalities that support nervous system reintegration. Minimal supplementation may assist, but internal rebalancing is the core therapeutic objective.

Context and the Need for an Integrative Approach

Earlier this summer, I attended an online CEU class that sought to discuss treatment options for Long COVID through the lens of Traditional Chinese Medicine (TCM), specifically using kitchen herbs. While the intention may have been to offer concepts for practical application, the approach was trivializing to our medicine 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.

The Hypoxia Hypothesis in Long COVID

A unifying hypothesis gaining traction connects Long COVID symptoms to chronic hypoxia and mitochondrial dysfunction. Even after viral clearance, many patients remain stuck in a low-oxygen, low-output state, unable to return to homeostasis. This condition disrupts energy metabolism and cascades into multi-system dysfunction.

At the center is the cellular response to oxygen deprivation. The mitochondria’s Krebs cycle—normally producing up to 36 ATP per glucose molecule—breaks down without adequate oxygen. Cells revert to anaerobic glycolysis, producing only 2 ATP per glucose and generating lactic acid. This results in systemic acidosis and energy starvation, particularly in high-demand tissues like the brain and muscles.

Neurological and Autonomic Consequences

The brain depends heavily on aerobic glucose metabolism, making it highly vulnerable to disruptions in oxygen and energy supply. Under hypoxic conditions, cells produce only 2 ATP per glucose molecule through anaerobic glycolysis instead of the normal 36 ATP via the Krebs cycle. This energy shortfall impairs critical brain functions such as synaptic transmission, ion gradient maintenance, and executive processes. The resulting deficits contribute to hallmark symptoms of Long COVID, including brain fog, memory lapses, fatigue, and difficulty concentrating.

Similarly, the autonomic nervous system, governed by centers in the brainstem, requires a continuous and adequate energy supply to regulate vital functions such as heart rate, blood pressure, temperature, and respiratory rhythms. Energy deficits in these autonomic centers can entrench dysautonomia, which manifests clinically as orthostatic intolerance, heart rate variability, temperature dysregulation, and disrupted sleep-wake cycles—symptoms commonly reported in Long COVID patients.

Fear Paralysis, Cranial Nerve Involvement, and Long COVID

The persistent symptoms of Long COVID include a reactivation of primitive autonomic responses including the fear paralysis reflex (FPR), 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 emergent, FPR state indicates a dorsal freeze 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 with Long COVID show signs of cranial nerve involvement, such as dysphonia, dysphagia, or autonomic instability including POTS and tachycardia, demonstrate these characteristics. The re-emergence of primitive reflexes such as FPR indicates brainstem dominance in the absence of effective cortical regulation, creating a cycle of energy deficits and autonomic dysregulation.

Conservative Management and Emerging Therapies for Long COVID

While many aspects of Long COVID’s complex autonomic dysfunction fall outside the scope of classical Traditional Chinese Medicine training, practitioners with additional certifications in functional chemistry or functional neurology can play a valuable role. Conservative, carefully paced supplementation aimed at restoring metabolic function and normal circadian rhythms support neuroplastic recovery, but must be approached cautiously. Many Long COVID patients—especially those with POTS or dorsal freeze—may experience deep agitation or worsening symptoms from aggressive supplements or herbal interventions. Instead, very gentle, slow protocols combined with physical and occupational therapies, and when appropriate, medications like beta blockers, provide a foundation for safe, multidisciplinary care. Understanding the clinical patterns allows practitioners to make timely referrals and integrate care effectively, without overstepping their expertise.

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.  

Considerations 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.  Represented in TCM as the Yin wei mai (upper Chong), this spasticity interferes with baroreceptor function, blocks effective signals,  cand contributes to 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 intercostals to 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

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.

In nearly every Long COVID consultation I have conducted—mostly out of state—I have encountered patients exhibiting primitive reflexes, dysphagia, and cranial nerve involvement. Unfortunately, I have often needed to refer these patients outside of Traditional Chinese Medicine because the biomedical complexities of Long COVID remain largely misunderstood within the field.

TCM practitioners have a vital role to play. Even when treatment falls outside your direct scope, understanding the patterns and symptom clusters can empower you to make timely, informed referrals. This collaboration ensures patients receive comprehensive care and can begin the often slow but necessary process of recovery. With increased awareness and integrative approaches, we can better support these patients on their journey toward restoration.

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