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Long COVID Part 2: Evidence-Based Complementary Treatments – Ozone Therapy, HBOT, LLLT, VNS v2
At a Glance: This table provides a quick summary of the evidence for each alternative therapy discussed in this article:
While the evidence is promising for all of these therapies, we recommend working with a qualified healthcare provider. For hormetic therapies like ozone therapy, hyperbaric oxygen therapy (HBOT), and photobiomodulation (PBM), more is not necessarily better; using the optimal dose, intensity, and frequency is the best. A provider experienced with these treatments will know what it takes to prepare you for these treatments, along with the right treatment protocol for maximal safety and effectiveness.
The treatment gap is real. Standard medical care currently has very limited options for Long COVID or Post-Acute Sequelae of COVID-19 (PASC). There is no universally approved drug or protocol specifically for PASC. Many patients report feeling dismissed by their doctors, or cycling through treatments or specialists that provide little relief.
Currently, no single proven curative treatment exists for Long COVID. [1,2,3] A 2024 living systematic review of interventions for Long COVID management found that the overall certainty of evidence for most treatments, conventional or alternative, remains low to very low. [4]
In our Long COVID Part 1: Pathophysiology and Mechanisms, we covered in detail the following mechanisms of the disease:
- Oxidative stress and glutathione depletion [5,6]
- Mitochondrial dysfunction [7]
- Endothelial dysfunction [8]
- Microclot formation and spike protein persistence [9]
- Neuroinflammation [10,11,12]
- Gut microbiome disruption [13,14,15,16]
In this article, we focus specifically on hormetic therapies and vagus nerve stimulation with many clinical studies. Each section below presents the available trial data, including study design, sample size, dosing, duration, and key outcomes, so clinicians and patients can make informed decisions.
This content is for educational purposes and does not constitute medical advice or treatment recommendations.
Understanding Long COVID Pathophysiology and the Need for Complementary Care
Defining the Scope and Scale of Long COVID
Long COVID presents as vague and multi-system symptoms like fatigue, brain fog, shortness of breath, and cognitive impairment persisting for months or even years after the initial viral infection clears. [17,18]
Facts about Long COVID:
- It’s one of the most significant public health challenges of the 21st century.
- In the United States alone, Long COVID affects ~6.9% of adults, roughly 17.8 million people, as of early 2023. [14]
- Its incidences vary by region, with rates reaching 31% in North America according to global clinical studies. [19]
- It is heterogeneous, with over 200 identified symptoms spanning multiple organ systems [2], and with fatigue being the most recognized long-term complaint. [20]
Limitations of Standard Care
Despite the enormous burden of Long COVID, conventional pharmacological treatments remain largely unproven for this condition.
Long COVID is currently without an established specific treatment, and management remains largely symptomatic. [1,2]
Bottom line: Currently, ample evidence shows that drugs and other conventional treatments have limited and inconsistent effectiveness. This makes sense given that Long Covid can differ widely from case to case, and it often takes a holistic and individualized approach to successfully manage or put Long COVID into remission.
Ozone Therapy for Long COVID Recovery
Ozone therapy addresses several key mechanisms of Long COVID, including [24,25,3]:
- Improving your ability to normalize oxidative stress by activating Nrf2 as a hormesis
- Restoring healthy mitochondrial function
- Normalizing chronic inflammation
- Brief immune activation from the introduction of oxidative stress and ozonides, which may support the body to clear persistent viral components and other pre-existing chronic infections that burden the immune system
- Improving circulation and blood oxygenation
- Stimulating the production of BDNF, which may help with neurorecovery [26]
- Stimulating regenerative pathways
- Improving the gut flora, especially with rectal insufflation
Evidence summary: Ozone Therapy for Long COVID Recovery
Many studies and reviews have evaluated ozone therapy for Long COVID recovery, covering major and minor autohemotherapy, rectal insufflation, and ozonized saline IV drip. [24],[25],[3] These clinical trials have been small, but all with promising results and excellent safety profile. The evidence base is growing but still early-stage for most delivery routes.
Common Ozone Therapy Treatment Routes for Long COVID
Major Autohemotherapy (MAH) [Moderate Evidence]
Major autohemotherapy (MAH) involves withdrawing a volume of the patient's blood, mixing it with an equal volume oxygen-ozone gas mixture at a defined concentration, and reinfusing it intravenously. For Long COVID applications, MAH typically uses between 30–50 mg/mL and 100–200 mL of ozone-oxygen gas and blood.
Ozonated Saline Drip [Moderate Evidence]
Intravenous ozonated saline delivers dissolved ozone at lower concentrations (2-10 mcg/mL) through a standard IV infusion. This approach is distinct from MAH because ozone is dissolved in saline rather than mixed with the patient's own blood.
Rectal Insufflation [Limited Evidence]
Rectal insufflation delivers an oxygen-ozone gas mixture directly into the colon, where ozone is absorbed through the intestinal mucosa into systemic circulation. This route is considered a systemic delivery method because ozone's reactive byproducts enter the bloodstream and exert effects beyond the gut.
While rectal insufflation has some reported evidence of effectiveness in acute COVID-19 patients, including in severe cases, the clinical evidence for PASC have been limited. [25]
A Cuban phase IV trial enrolled convalescing COVID patients with symptoms persisting over 3 weeks after negative PCR tests. The control group received a 400 mg supplement with protein, mineral, and human placenta, while the control group also received rectal insufflation of 20–35 mg/L, 150–200 mL, once per day for 20 days. As a result, 85% of the ozone + supplement group improved, compared to 37% of the supplement group alone. [32]
Despite limited published evidence, many patients and clinicians have found rectal insufflation an effective support for PASC recovery.
In Long COVID management, rectal insufflation may:
- Modulate the gut-immune axis, which is increasingly recognized as disrupted in PASC
- Reduce systemic inflammation through the same oxidative preconditioning pathways as other systemic ozone routes
- Serve as a non-invasive alternative to MAH for patients with poor venous access, poor circulation, or needle aversion
Ozonide Inhalation (Oil Nebulization) [Empirical]
Ozonide inhalation or breathing ozone oil involves nebulizing ozone-infused oils (ozonides) so that patients inhale the fine mist. This targets the pulmonary epithelium directly, delivering ozone's reactive byproducts to the alveoli without the tissue damage that would occur from inhaling ozone gas directly.
There is a small clinical study (15 patients in each group) evaluating ozonide inhalation as an adjuvant for acute COVID-19, with results suggesting that it may reduce the risk of pneumonia. [33] The ozone treatment significantly reduced length of stay, CRP, and CT scores.
Currently, there is no published clinical evidence for breathing ozone oil in post-COVID respiratory protocols. It’s plausible that ozonide inhalation might help with:
- Normalizing pulmonary inflammation in the airways and alveoli
- Improving oxygen exchange at the alveolar level
- Addressing persistent respiratory symptoms such as dyspnea and reduced lung capacity
⚠️ Important distinction: Direct inhalation of ozone gas is contraindicated and toxic to lung tissue. Ozonide inhalation uses ozone-reacted oil derivatives (ozonides), not raw ozone gas. These are chemically distinct compounds with a different safety profile.
Hyperbaric Oxygen Therapy (HBOT)
Hyperbaric oxygen therapy (HBOT) is one of the most rigorously studied complementary interventions for Long COVID, with sham-controlled RCT data supporting improvements in cognition, cardiac function, fatigue, sleep, and quality of life. Similarly to ozone therapy, HBOT is a bio-oxidative therapy, which works partly by creating a small amount of oxidative stress to induce healing mechanisms in the body.
Keep in mind that most studies use the hard chambers that pressurize up to 2.0 ATA or more, along with pure oxygen.
HBOT increases dissolved plasma oxygen by 10–20 folds, resulting in [34,35,36,37]:
- A paradoxical effect as major oxygen fluctuations activate hypoxic genes, resulting in new blood vessel growth and activation of certain regenerative genes
- Increased endothelial nitric oxide, improving blood vessel health along with circulation and stamina
- Nrf2 stimulation, which reduces inflammatory cytokines, enhances mitochondrial dysfunction, and may trigger regenerative gene expression.
- Restoring mitochondrial energy production
- Improving brain blood flow and BDNF levels, suggesting that it may support PASC recovery through neuroregeneration [38]
Major landmark trials have produced both positive (e.g., Hadanny et al. 2022) and nonsignificant (e.g. HOT-LoCO trial) results. Given that PASC can differ significantly from case to case, perhaps HBOT can be life-changing for some PASC patients, and ineffective for others. However, it’s also possible that you may need more than 10 sessions to make a significant difference.
Summary of clinical evidence for HBOT for Long COVID
Safety Profile
Across all studies, HBOT for Long COVID shows a reassuring safety profile in patients without contraindications. The most commonly reported side effects include:
- Ear barotrauma (pressure-related ear discomfort) – the most frequent complaint
- Transient myopia (temporary nearsightedness) that resolves after treatment ends
- Mild ear discomfort during pressurization
No serious adverse events were reported in any of the Long COVID trials. In the Dutch registry of 1,691 patients, only 1.5% reported any adverse event. [44]
Bottom line: There is a plausible biological rationale and suggestive evidence from one intensive-protocol RCT (40 sessions) and large observational data that HBOT may improve fatigue, cognition, and quality of life in Long COVID. However, the two most rigorous sham-controlled trials using shorter protocols (10 sessions) found no significant benefit over placebo. The number of sessions appears to be a critical variable. Larger, well-designed RCTs testing higher-dose protocols (20 to 40+ sessions) are needed to determine whether the benefits seen in uncontrolled and single-trial data hold up under rigorous scrutiny. [MODERATE]
Photobiomodulation (PBM) for Long COVID
Photobiomodulation (PBM) or low-level laser therapy is a light-based therapy that uses specific wavelengths of red or near-infrared light to trigger photochemical reactions inside cells. The primary target is cytochrome c oxidase (CcO) in the mitochondrial electron transport chain. When CcO absorbs light at the right wavelength, it increases ATP production, modulates reactive oxygen species, and activates downstream anti-inflammatory and pro-healing signaling cascades. [50,51,52,53]
For Long COVID, PBM plausibly addresses several core disease drivers at once: persistent inflammation, mitochondrial dysfunction, immune dysregulation, endothelial dysfunction, dysbiosis, and tissue damage. [50,52,53] PBM may also stimulate neuroregeneration and modulate neuroendocrine pathways relevant to fatigue, dyspnea, cognitive dysfunction, and sensory dysfunction. [54] Specifically, PBM's neurostimulatory properties could help restore olfactory and gustatory nerve function, while its local and systemic anti-inflammatory effects could reduce pulmonary inflammation. [50,51,53]
Practical Notes on Photobiomodulation:
Typically, red light may reach a few millimeters past the skin surface, while near-infrared wavelengths may penetrate a few inches through the skin. The location of the treatments should pertain to the complaints. Full-body treatments, also called systemic treatments, should help with fatigue, cognition, and lung issues. In contrast, sensory dysfunction or hair loss may require more localized intense treatments.
Because PBM works partly through hormesis, more is not necessarily better. The goal is to find the optimal intensity and duration of treatment.
PBM devices come in various shapes, sizes, and intensities.
- Consumer-grade devices come in various forms, such as:
- Torches
- Intranasal devices that target the brain through the nose
- Saunas
- Tanning beds
- Helmets
- LED panels that can be small or full-body
- Clinician-grade laser devices are high-intensity lasers that can penetrate tissues, and possibly bones. These typically require medical supervision and laser safety glasses to protect the eyes.
Clinical Evidence: Taste Dysfunction (Dysgeusia)
The strongest evidence for PBM in Long COVID comes from a single-blind randomized controlled trial (N=40) by Fontana, Parreira, and Pinheiro (2024). This trial evaluated local and systemic PBM for COVID-19-related dysgeusia. The PBM group showed statistically significant improvements in taste perception compared to the sham placebo group, with recovery across all four taste modalities: sour, sweet, salty, and bitter. [55,56]. [PRELIMINARY]
A separate double-blind RCT (N=20) by Soares et al. (2023) compared PBM, transmucosal laser blood irradiation, and B-complex vitamins for COVID-19–related long-term taste impairment, providing additional controlled data on PBM for this specific symptom. [57,58]
These trials are small but represent the most rigorous PBM evidence in the Long COVID space. Commentary by Daungsupawong and Wiwanitkit (2024) discussed the dysgeusia trial's methodology without adding new clinical data. [59]
Clinical Evidence: Brain Fog and Fatigue
An open-label pilot study (N=14) by Bowen et al. (2023) tested two PBM devices: a transcranial helmet (1070 nm) and a whole-body PBM unit. Both approaches produced significant improvements in cognitive function and fatigue in Long COVID patients. [60,61] [PRELIMINARY]
While promising, this study lacked a control group and had a very small sample size. It does, however, provide the first direct clinical evidence that PBM can address the neurological symptoms most debilitating to Long COVID patients.
Clinical Evidence: Systemic Rehabilitation
Jiménez-García et al. (2023) reported that near-infrared PBM therapy improved symptoms in approximately 80% of long-haulers. The study specifically targeted myalgia, headache, and mood disturbances using transcranial and systemic near-infrared delivery. [62] [PRELIMINARY]
This finding aligns with the broader theoretical framework described by Meng et al. (2023), who discussed PBM as one of several psychophysical therapies with neuroendocrine mechanisms relevant to Long COVID rehabilitation, alongside acupuncture and exercise. [54]
Clinical Evidence: Hair Loss
A retrospective study (N=140) by Gerkowicz et al. (2024) evaluated red LED light therapy at 650 nm for post-COVID telogen effluvium (hair loss). LED-treated groups showed improved hair density, though outcomes varied depending on whether patients also had androgenetic alopecia. [63] [LIMITED]
This study lacked a no-treatment control group, limiting the strength of its conclusions. Still, it represents the largest PBM study population in the Long COVID literature to date.
Clinical Evidence: Erectile Dysfunction
Moskvin, Askhadulin, and Kochetkov (2021) provided justification for applying low-level laser therapy (LLLT) to prevent endothelial dysfunction in COVID-19 patients, presenting clinical experience in treatment and rehabilitation. [64] Al-Zamil et al. (2023) specifically studied LLLT for post-COVID erectile dysfunction (N=42) and found that it significantly improved sexual function by enhancing endothelial microcirculation of the cavernous body [64]. [PRELIMINARY]
Summary of Clinical Evidence: PBM for Long COVID
Limitations and Current Gaps
The evidence is not contradictory, but it is far from conclusive. Key limitations across the body of PBM research for Long COVID include:
- No large-scale RCTs. The largest controlled trial enrolled only 40 patients. [55]
- No standardized protocols. Wavelengths range from 650 nm to 1070 nm, and delivery modes include intraoral, transcutaneous scalp, transthoracic, and whole-body approaches. [56,63,51,60]
- No long-term follow-up data. It remains unknown whether PBM benefits persist after treatment ends.
- No head-to-head comparisons with other Long COVID interventions.
- Heterogeneous symptom targets. Studies address dysgeusia, brain fog, hair loss, pulmonary function, and erectile dysfunction separately, making it difficult to assess PBM's overall utility.
On the positive side, PBM is very safe; adverse effects are minimally reported across all studies. [51,57]
Vagus Nerve Stimulation (VNS) for Long COVID
The vagus nerve is the primary conduit of the parasympathetic nervous system and a master regulator of systemic inflammation through the cholinergic anti-inflammatory pathway.
In Long COVID, chronic immune activation and elevated cytokines drive symptoms like fatigue, brain fog, and pain. Stimulating the vagus nerve offers a way to dampen this inflammatory cascade without pharmaceuticals. Previously, some VNS devices have been approved to treat depression and epilepsy [68], suggesting that VNS may help with depressive and neurological symptoms of Long COVID.
Summary of Clinical Evidence for VNS for Long COVID
To date, several small clinical studies have demonstrated promising results for VNS relieving various Long COVID symptoms including fatigue, sleep, mood, brain fog, and vagal tone with no serious adverse effects.
The benefits experienced may vary depending on the individual and devices. Many ongoing clinical trials are evaluating the safety and effectiveness of VNS in Long COVID patients, including the multi-center COVIVA trial in Germany. [69] The most effective protocols regarding frequency, treatment site, duration, and frequency remain to be determined.
Bottom line: The VNS evidence is preliminary, though highly promising. Larger trials in Long COVID populations are needed. However, the mechanism is well-established, the intervention is noninvasive, and the risk profile is minimal.
Conclusion
Currently, there is no one effective treatment for Long COVID, and it remains a poorly understood and addressed syndrome. Hormetic therapies like ozone therapy, hyperbaric oxygen therapy, and photobiomodulation address many key pathophysiologies of Long COVID. In addition, vagus nerve stimulation may help rebalance the autonomic nervous system and chronic inflammation. There’s a growing body of clinical evidence suggesting that these treatments are likely beneficial for many COVID patients.
This concludes part 2 of a 3-part Long COVID series. To learn more about Long COVID Pathophysiology, root causes, and predisposing factors, read Part 1.
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