Questions from the Clinic:
Is adjuvant ozone (O 3 ) therapy effective in minimizing chemo-radiotherapy- induced toxicity? Does O 3 have any other clinical benefits that are currently under-appreciated in the oncology setting?
I. Historical Context
Ozone, or O3, is a relatively unstable allotrope of oxygen found in trace quantities throughout the Earth’s atmosphere. Concentrated primarily in the stratosphere, O3 shields life on Earth by absorbing ultraviolet radiation from the Sun’s rays.(1) Since the 1980s, conservation efforts have largely succeeded in preserving this protective atmospheric layer by curbing the use of industrial chloroflurocarbons, or CFCs.(2) That said, O3 has been known to humanity since the mid-19th century, when it was discovered by Christian Schonbein in a German lab. Soon after its discovery, O3 gradually found applications in medicine because of apparent antimicrobial and anti-inflammatory properties.(3) Despite this history, O3 is a heterodox therapy in modern medicine, and it has been roundly rejected by regulatory agencies like the U.S. Food and Drug Administration.(4) To understand the controversy surrounding O3, it is essential to examine its functions within the human body at the cellular level.
II. Mechanisms of Action & Route of Administration
The effects of O3 depend greatly on its route of administration. When inhaled, O3 at concentrations exceeding 0.1 ppm can cause damage to the respiratory system and extrapulmonary organs.(5) Inside the body, inhaled O3 reacts with polyunsaturated fatty acids that populate the linings of alveoli – the air sacs in the lungs that serve as sites of gas exchange. The products of this chemical reaction, sometimes called lipid ozonation products, activate enzymes like phospholipase A2 or phospholipase C. In turn, these lipases trigger the release of arachidonic acid, which is readily converted into signaling molecules mediating inflammation, namely prostaglandins and platelet activating factors.(6) O3 will also readily react with water present in the respiratory system to create aldehydes (4-hydroxynonenal) and hydrogen peroxide (H2O2). It is these secondary messenger molecules, rather than O3 itself, that are implicated in lung toxicity.(7)
Because aerosolized or inhaled O3 has well-documented deleterious effects on human health, it is most commonly introduced to the body through either rectal insufflation or autohemotherapy. In autohemotherapy, clinicians extract blood from patients, mix it with clinical formulations of O3 (10-60 μg/mL blood), then reintroduce the ozonated blood intravenously.(8,9) At these concentrations, O3 triggers oxidative stress through secondary messengers like H2O2 and enhances erythrocytic glycolysis, metabolism, and the immune system.(6) Rectal insufflation of 200 to 400 cc of ozone leads to rapid absorption through the colonic mucosa achieving lower concentrations in the blood than autohemotherapy but enable an option for home delivery. In the context of cancer, researchers hypothesize that O3 inhibits the Nf-κB transcription factor, which regulates genes involved in innate and adaptive immune system responses in the body. Re-establishing equilibrium in Nf-κB Nrf2 pathway may lead to benefits in patients with cancer.(8) Ozone also breaks down to oxygen and enhances oxygenation to marginally hypoxic tissues and thus aid normal tissue vitality and cancer cell sensitivity to radiation therapy.
III. Completed Studies
Previous misapplications of O3 to treat patients with HIV/AIDS may, in part, explain the dearth of recent clinical research examining this treatment’s utility in human cancer.(10) That said, results from a few studies suggest that specific applications of O3 may have some use in an oncologic context. In a randomized clinical trial (n=40) of patients with advanced non-small cell lung cancer, researchers compared the efficacy of standard chemotherapy with and without additional O3 autohemotherapy once weekly for 12 weeks and subcutaneously administered Viscum album fermentatum (mistletoe). Patients in the combination treatment arm reported significantly better quality-of-life scores on the quality-of-life questionnaire-core 30 (QLQ-C30), decreased plasma values of reactive species metabolites, and increased biological antioxidant potential. The extent to which O3 contributes to this effect versus Viscum album fermentatum remains unclear, nor does the intervention appear to cure the underlying cancer.(11)
Other experimental findings in animal models suggest O3 can ameliorate side effects associated with doxorubicin chemotherapy and complement the effects of radiotherapy. Across multiple studies, investigators have noted that various applications of O3 in rat models can reduce doxorubicin-associated cardiotoxicity, testicular toxicity, and skin necrosis.(12,13,14) In addition to modulating the Nf-κB Nrf2 pathway, O3 also appears to diminish the expression of hypoxia-inducible factor 1α (HIF-1α) in rats.(15) Theoretically, by abolishing HIF-1α activity, O3 can inhibit tumor neoangiogenesis and further metastases.(16) Aqueous O3 solutions also appear to be particularly well-tolerated and may be useful in treating necroses induced by tumor tissue. Local administration of ozonated water inhibited proliferation of tumor cells in a dose-dependent manner and spared normal tissues from adverse effects.(17) Although intriguing, these findings in rats cannot necessarily be extrapolated to human beings, and better quality evidence is required to gain a clearer understanding of this therapy’s use in cancer.
IV. Current Clinical Trials
On the Clinicaltrials.gov database, there is currently one clinical trial assessing medical ozone in patients with chemotherapy-induced peripheral neuropathy (CIPN):
CIPN arises a common treatment-related adverse event after cancer treatment and considerably detracts from patients’ quality of life. In some instances, the condition can force reductions in chemotherapy regimens, which results in poorer patient outcomes. Currently, no effective prophylactic agents or treatments work well to address CIPN, so well-tolerated, effective treatments are in high demand.(8) Results from the trial are anticipated in December 2023 and may help justify the use of O3 as adjunctive therapy that lessens the side effects of other conventional cancer drugs.(18)
V. Cost & Availability of Adjuvant O3 Therapy
Relative to other cancer agents, O3 is inexpensive and available across the United States through naturopathic practitioners. According to PureHealth, intravenous treatments range between $100 and $1,200, whereas joint injections cost between $30 and $350. Home units for purchase require medical grade oxygen and thus a prescription with a set up investment cost of around $1,200.(19) The greatest barrier to widespread access is acceptance, or lack thereof, of O3 within modern medical communities. Statements from regulatory agencies, namely the FDA, brand O3 “a toxic gas with no known useful medical application in specific, adjunctive, or preventative therapy.(4) ” Barrie R. Cassileth, MS, PhD, additionally notes that “serious adverse effects and at least five fatalities associated with oxygen therapies have been reported.(20) ” A lack of financial sponsors and funding for O3 therapy forces research to continue quite slowly, and a paucity of scientific reports validating this approach prevents the treatment from gaining traction beyond a small number of medical professionals.(10)
O3 therapy, delivered through rectal insufflation or autohemotherapy, remains a highly controversial approach in the treatment of patients with cancer. Although results from basic research suggests that O3 can modulate the activity of transcription factors like Nf-κB and HIF-α, these findings have not been rigorously examined and replicated in high-quality, randomized human clinical trials.(8,16) Looking ahead, more research is warranted to better elucidate the treatment’s underlying mechanisms of action and clarify logistics surrounding dosing, route of administration, and patient eligibility. Currently, there is insufficient understanding and validation of O3, at best, to endorse its integration into current cancer treatment paradigms. Future studies should seek to resolve lingering questions around safety and clarify the circumstances in which this alternative therapy can address unmet needs in patients diagnosed with cancer. Given ozone’s low cost and possible home use, there are opportunities in adjuvant therapies that can mitigate treatment-related adverse events tied to traditional chemo-radiotherapies and these need further exploration.
Stay strong, keep smiling and be your own best doctor,
Charles J. Meakin MD, MHA, MS
Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
1 Batakliev T, Georgiev V, Anachkov M, et al. Ozone decomposition. Interdiscip Toxicol. 2014;7(2):47-59.
2 Anderson SO, Halberstadt ML, Borgford-Parnell N. Stratospheric ozone, global warming, and the principle of unintended consequences – an ongoing science and policy success story. J Air Waste Manag Assoc. 2013;63(6):607-647.
3 Elvis AM, Ekta JS. Ozone therapy: a clinical review. J Nat Sci Biol Med. 2011;2(1):66-70.
4 U.S. Food and Drug Administration. CFR – Code of Federal Regulations Title 21. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=801.415. Updated April 1, 2020. Accessed October 15, 2021.
5 National Institute for Occupational Safety and Health. Ozone. https://www.cdc.gov/niosh/npg/npgd0476.html. Updated October 30, 2019. Accessed October 15, 2021.
6 Sagai M, Bocci V. Mechanisms of action involved in ozone therapy: is healing induced via a mild oxidative stress? Med Gas Res. 2011;1:29.
7 Clavo B, Martinez-Sanchez G, Rodriguez-Esparragon F, et al. Modulation by ozone therapy of oxidative stress in chemotherapy-induced peripheral neuropathy: the background for a randomized clinical trial. Int J Mol Sci. 2021;22(6):2802.
8 Clavo B, Rodriguez-Esparragon F, Rodriguez-Abreu D, et al. Modulation of oxidative stress by ozone therapy in the prevention and treatment of chemotherapy-induced toxicity: review and prospects. Antioxidants (Basel). 2019;8(12):588.
9 Hu B, Zheng J, Liu Q, et al. The effect and safety of ozone autohemotherapy combined with pharmacological therapy in postherpetic neuralgia. J Pain Res. 2018;11:1637-1643.
10 Bocci V, Zanardi I, Travagli V. Oxygen/ozone as a medical gas mixture. A critical evaluation of the various methods clarifies positive and negative aspects. Med Gas Res. 2011;1(1):6.
11 Borrelli E. Treatment of advanced non-small cell lung cancer with oxygen ozone therapy and mistletoe: an integrative approach. Eur J Integrative Med. 2012;4(130).
12 Delgado-Roche L, Hernandez-Matos Y, Medina EA, et al. Ozone-oxidative preconditioning prevents doxorubicin-induced cardiotoxicity in Sprague-Dawley rats. Sultan Qaboos Univ Med J. 2014;14:e342-e348.
13 Salem EA, Salem NA, Hellstrom WJ. Therapeutic effect of ozone and rutin on Adriamycin-induced testicular toxicity in an experimental rate model. Andrologia. 2017;49:e12603.
14 Kesik V, Yuksel R, Yigit N, et al. Ozone ameliorates doxorubicine-induced skin necrosis – results from an animal model. Int J Low Extrem Wounds. 2016;15:248-254.
15 Guclu A, Erken HA, Erken G, et al. The effects of ozone therapy on caspase pathways, TNF-α, and HIF-1α in diabetic nephropathy. Int Urol Nephrol. 2016;48(3):441-450.
16 Clavo B, Santana-Rodriguez N, Llontop P, et al. Ozone therapy as adjuvant for cancer treatment: is further research warranted? Evid Based Complement Alternat Med. 2018;2018:7931849.
17 Kuroda K, Azuma K, Mori T, et al. The safety and anti-tumor effects of ozonated water in vivo. Int J Mol Sci. 2015;16(10):25108-25120.
18 King C. 10 Benefits of Ozone Therapy. PureHealth. https://www.purehealthmedicine.com/blog/benefitsofozonetherapy. Published February 16, 2021. Accessed October 27, 2021.
19 Simply O3.
20 Cassileth BR. Cancer quackery: the persistent popularity of useless, irrational ‘alternative’ treatments. Oncology. 2012;26(8):754-758.