During the COVID-19 pandemic, ozone therapy was used by clinics worldwide as both an acute treatment and a recovery tool, generating a wave of clinical reports and small trials. The rationale was straightforward: ozone modulates the immune system, improves oxygen delivery, and has anti-inflammatory effects, all mechanisms relevant to a disease that attacks the lungs and triggers dangerous immune overreaction. While ozone therapy never entered mainstream COVID treatment protocols, the published evidence provides useful data on its potential role in viral respiratory infections and post-viral syndromes.
This article covers the clinical evidence for ozone during acute COVID-19, its application for long COVID, the proposed mechanisms, and how it compares to hyperbaric oxygen therapy (HBOT) for post-COVID recovery.
Key Takeaways
- A 2021 systematic review by Izadi et al. found that ozone therapy was associated with improved oxygenation and reduced inflammatory markers in hospitalized COVID-19 patients1
- Proposed mechanisms include immune modulation via Nrf2 activation, improved oxygen delivery through 2,3-DPG upregulation, and direct virucidal effects on enveloped viruses2
- The most studied modality was Major Autohemotherapy (MAH), used in hospitalized patients alongside standard care
- For long COVID, ozone therapy targets persistent inflammation, fatigue, and brain fog through immune rebalancing
- No large randomized controlled trial has confirmed ozone’s efficacy for COVID-19 or long COVID
- HBOT has a stronger evidence base for post-COVID neurological symptoms compared to ozone therapy
The Rationale: Why Ozone Was Explored for COVID-19
COVID-19 presented two distinct treatment challenges. The first was the acute phase, where the virus triggered a cytokine storm and acute respiratory distress syndrome (ARDS) in severe cases. The second was long COVID, where patients experienced persistent symptoms for months or years after the initial infection.
Ozone therapy’s proposed mechanisms aligned with both challenges:
| Mechanism | Relevance to Acute COVID | Relevance to Long COVID |
|---|---|---|
| Nrf2 activation | Counteracts oxidative damage from cytokine storm | Addresses chronic oxidative stress and inflammation |
| 2,3-DPG upregulation | Improves oxygen release from hemoglobin to hypoxic tissues | May help with persistent fatigue and exertional intolerance |
| Cytokine modulation | May dampen excessive inflammatory response | Targets chronic immune dysregulation |
| Direct virucidal action | Ozone can inactivate enveloped viruses on contact | Less relevant (viral persistence debated) |
Evidence for Ozone in Acute COVID-19
Izadi et al. (2021) – Systematic Review
The most comprehensive review of ozone for COVID-19 was published by Izadi et al. in the International Immunopharmacology journal. The review analyzed available clinical reports and case series of ozone therapy used in hospitalized COVID-19 patients.1
Key findings across the reviewed studies:
- Improvements in SpO2 (oxygen saturation) in patients receiving MAH alongside standard care
- Reductions in inflammatory markers including CRP, IL-6, and D-dimer
- Shorter time to clinical improvement in some case series
- No serious adverse events attributable to ozone therapy
The review concluded that ozone showed “promising signals” but emphasized the need for large randomized controlled trials before any clinical recommendations could be made.
Franzini et al. (2020) – Italian Case Series
An early report from Udine, Italy described 36 hospitalized COVID-19 patients treated with ozone autohemotherapy. Patients showed statistically significant improvements in PaO2/FiO2 ratio (a measure of lung function) and reductions in CRP after 5 ozone sessions.3 Again, this was uncontrolled and small.
Shah et al. (2021) – Indian RCT
One of the few randomized studies came from India. Shah et al. randomized 60 moderate-to-severe COVID-19 patients to receive either standard care alone or standard care plus rectal ozone insufflation. The ozone group showed faster clinical recovery and reduced need for supplemental oxygen compared to the control group.4
“Ozone therapy for COVID-19 was never about replacing antivirals or ventilators. It was explored as a supportive intervention to modulate the immune overreaction that caused most COVID deaths.”
Ozone Therapy for Long COVID
Long COVID (post-acute sequelae of SARS-CoV-2, or PASC) affects an estimated 10-30% of people who contract COVID-19. Common symptoms include fatigue, brain fog, exercise intolerance, shortness of breath, joint pain, and autonomic dysfunction.5
The proposed mechanisms linking ozone to long COVID relief:
- Chronic inflammation: Long COVID involves persistent elevation of inflammatory markers. Ozone’s NF-kB modulation and Nrf2 activation may help normalize immune signaling.2
- Mitochondrial dysfunction: Many long COVID patients show impaired mitochondrial function. Ozone has been proposed to support mitochondrial biogenesis through hormetic stress.
- Microclot formation: Research by Pretorius et al. identified persistent microclots in long COVID patients that trap inflammatory molecules. Some practitioners theorize that ozone’s effects on blood rheology may address this, though no direct evidence exists.6
- Autonomic rebalancing: Ozone’s effects on the vagus nerve and autonomic nervous system are proposed but unproven.
Clinical evidence for ozone specifically in long COVID is largely anecdotal. Multiple integrative medicine clinics report using MAH and rectal insufflation protocols for long COVID patients, but published data consists mainly of case reports and small case series.
Typical Ozone Protocols Used for COVID-Related Conditions
| Application | Modality | Protocol | Cost per Session |
|---|---|---|---|
| Acute COVID (hospital) | MAH | 1-2 sessions daily for 5-7 days | $200-400 |
| Acute COVID (outpatient) | Rectal insufflation | Daily for 5-10 days | $75-200 |
| Long COVID | MAH or 10-Pass | 2x/week for 10-20 sessions | $250-1,500 |
| Long COVID (maintenance) | MAH or rectal insufflation | Weekly to biweekly, ongoing | $75-400 |
Ozone vs. HBOT for COVID Recovery
Both ozone therapy and hyperbaric oxygen therapy have been explored for COVID recovery, but they work through different mechanisms and have different evidence bases.
| Factor | Ozone Therapy | HBOT |
|---|---|---|
| Primary mechanism | Immune modulation, oxidative preconditioning | Direct tissue oxygenation, angiogenesis, stem cell mobilization |
| Evidence for long COVID | Case reports and small case series | Multiple RCTs including Zilberman-Itskovich (2022) |
| Best for | Immune dysregulation, systemic inflammation | Neurological symptoms, brain fog, cognitive deficits |
| Cost per course | $2,000-8,000 (10-20 sessions) | $4,000-16,000 (40 sessions typical) |
| Session time | 30-60 minutes | 60-90 minutes |
HBOT currently has stronger evidence for post-COVID cognitive symptoms, particularly from the Zilberman-Itskovich et al. randomized controlled trial that showed significant improvements in cognitive function, psychiatric symptoms, and pain in long COVID patients treated with 40 HBOT sessions.7 Some practitioners combine both therapies for comprehensive post-COVID recovery.
Limitations and Concerns
Several important caveats apply to all ozone-COVID research:
- Small sample sizes: No study enrolled more than 60 patients
- Lack of blinding: Most studies were open-label, making placebo effects likely
- Publication bias: Positive results are more likely to be published than negative ones
- Concurrent treatments: All hospitalized patients received standard care alongside ozone, making it impossible to isolate ozone’s contribution
- Evolving disease: COVID-19 variants and vaccines have changed the clinical picture since most ozone studies were conducted
- No FDA authorization: Ozone has no emergency use authorization or approval for COVID-19 in any country with a major regulatory agency
Bottom Line
Ozone therapy showed promising but preliminary signals as a supportive treatment during acute COVID-19, particularly for improving oxygenation and reducing inflammation. For long COVID, the evidence is even thinner, consisting mainly of clinical anecdotes and small case series. HBOT has a stronger evidence base for post-COVID neurological recovery.
If you are dealing with long COVID symptoms, proven approaches include structured rehabilitation, pacing strategies, and addressing specific symptoms with targeted treatments. Ozone therapy may be worth exploring as an adjunct if conventional approaches have not provided adequate relief, but set realistic expectations and choose a practitioner who measures objective outcomes rather than relying solely on symptom reports.
References
- Izadi M, Cegolon L, Javanbakht M, et al. “Ozone therapy for the treatment of COVID-19 pneumonia: a scoping review.” International Immunopharmacology, 2021;92:107307. DOI: 10.1016/j.intimp.2020.107307
- Viebahn-Haensler R, Leon Fernandez OS. “Ozone in medicine. The low-dose ozone concept and its basic biochemical mechanisms of action in chronic inflammatory diseases.” International Journal of Molecular Sciences, 2021;22(15):7890. DOI: 10.3390/ijms22157890
- Franzini M, Valdenassi L, Ricevuti G, et al. “Oxygen-ozone (O2-O3) immunoceutical therapy for patients with COVID-19.” International Immunopharmacology, 2020;88:106879. DOI: 10.1016/j.intimp.2020.106879
- Shah M, Captain J, Vaidya V, et al. “Safety and efficacy of ozone therapy in mild to moderate COVID-19 patients: a phase 1/2 randomized control trial.” International Immunopharmacology, 2021;91:107301. DOI: 10.1016/j.intimp.2020.107301
- Davis HE, McCorkell L, Vogel JM, Topol EJ. “Long COVID: major findings, mechanisms and recommendations.” Nature Reviews Microbiology, 2023;21(3):133-146. DOI: 10.1038/s41579-022-00846-2
- Pretorius E, Vlok M, Venter C, et al. “Persistent clotting protein pathology in long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin.” Cardiovascular Diabetology, 2021;20(1):172. DOI: 10.1186/s12933-021-01359-7
- Zilberman-Itskovich S, Catalogna M, Sasson E, et al. “Hyperbaric oxygen therapy improves neurocognitive functions and symptoms of post-COVID condition: randomized controlled trial.” Scientific Reports, 2022;12(1):11252. DOI: 10.1038/s41598-022-15565-0
Medical Disclaimer
The content on BaricBoost.com is for informational purposes only and is not intended as a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
Author
Seph Fontane Pennock is the founder of BaricBoost.com and Regenerated.com, a clinic directory for regenerative medicine serving 10,000+ providers across the United States. He previously built and sold PositivePsychology.com, which grew to 19 million users and became the largest evidence-based positive psychology resource on the web. Seph brings direct experience as an HBOT patient, having completed protocols at clinics across three continents while navigating mold illness, systemic inflammation, and autoimmune conditions. His treatment journey includes hyperbaric oxygen therapy, peptide protocols, NAD+ therapy, and consultations with specialists from Dubai to Cape Town to Mexico. This combination of entrepreneurial track record and lived patient experience shapes everything published on BaricBoost.com. Every article is grounded in peer-reviewed research, informed by real clinical encounters, and written for patients making high-stakes treatment decisions. Seph's focus is on bringing transparency, scientific rigor, and practical guidance to the hyperbaric oxygen therapy space.
