- Ozone is an unstable, colourless gas present in the atmosphere
- Evidence on ozone therapy in cancer patients is lacking
- Inhalation and direct injection can result in severe adverse effects. Safety of mixing with blood which is re-injected is not proven
Ozone (O3) is an unstable gas found in the atmosphere where it protects against solar radiation. It has been produced by specialised generators for therapeutic use.
Ozone therapy can involve body saunas, insufflation into body cavities (not the lungs), application to joints and lesions, and mixing with the patient’s blood and reinjection (autohaemotherapy). It has also been used as a disinfectant.
It has been claimed that ozone therapy has immunomodulatory and immunoactivating properties, and can reverse local hypoxic conditions required by some cancer cells. There have been few trials in humans for any condition and no randomised controlled trials in cancer patients.
Ozone has been shown to be toxic to the lungs and dangerous if directly injected intravenously. Assessment of safety of ozone therapy has been limited to date.
While apparently widely used, evidence on the proposed benefits in cancer patients is lacking and safety has not been proven..
Fully updated and revised in June 2017 by Karen Pilkington.
Updated/assessed as up to date by Barbara Wider in September 2013.
Summary first published in October 2012, authored by Karen Pilkington.
Karen Pilkington, CAM-Cancer Consortium. Ozone therapy [online document]. September 11, 2013.
Ozone (O3) is a gas which was discovered in the mid 19th century1. It is denser and more soluble in water than oxygen. It is also more unstable as each molecule consists of 3 oxygen atoms while oxygen gas molecules are composed of 2 atoms (O2)2. Ozone is present in low levels in the atmosphere and provides protection from ultraviolet (UV) radiation but it rapidly breaks down, particularly at lower atmospheric levels into oxygen plus a single, reactive oxygen atom. It is a potent oxidising agent and can form products that are toxic to the respiratory system2,3. Ozone is formed naturally from oxygen through the action of ultraviolet light and electrical discharges as in an electric storm. At ground level, ozone is not emitted directly into the air, but is a product of chemical reactions between oxides of nitrogen and volatile organic compounds in the presence of sunlight3. Excessive concentrations of ozone can be toxic to living organisms3. For medical use, it is produced in generators by passing oxygen through a high voltage gradient, the gas produced being a mixture of oxygen and ozone2.
Scientific name: ozone; other names: O3, medical ozone, therapeutic ozone, ozone autohaemotherapy, ozonised water, trioxygen (ozone therapy is also included under broader terms such as hyperoxygenation therapy or oxygen therapies)4,5.
Ozone therapy should not be confused with hyperbaric oxygen or other conventional forms of oxygen therapy (see Application and dosage section for explanation of the specific therapy referred to in this summary).
Ozone is an unstable, colourless gas. Molecules of ozone consist of 3 oxygen atoms arranged in a cyclic structure2.
Application and dosage
Ozone therapy has been used in a variety of ways including local application to tissues, through introduction via the nasal, oral, rectal or intravaginal routes or cutaneous application4. Ozone, either in gaseous form or as ozonated water, has been used in the treatment of dental caries.6 Ozonated water has also been applied to the skin for wound treatment4. Ozone saunas or ozone bagging involve the body (except for the head) being surrounded by or submerged in ozone. Ozone-infused drinking water is also commercially available6.
The method of administration that has been specifically related to cancer is ozone autohaemotherapy. This technique involves blood being withdrawn from the patient’s vein and treated with ozone before reinfusion or injection into a vein or muscle5. Cases have been reported where direct infusion of ozone intravenously has resulted in pulmonary embolism and death2.
Rectal insufflation has been used in management ofloval inflammatory reaction, such as proctitis, which may result from radiotherapy8.
No typical dose has been recognised4. Guidelines on the use of ozone in medicine have been produced by a German medical ozone society but the basis for the recommendations in these is not reported8,9.
Ozone was first identified by Schönbein, a professor of Chemistry at the University of Basel in 1840 and the chemical formula was determined in 18659. By the end of the 19th century, ozone was being used as a disinfectant and, in the First World War, it was used to disinfect wounds2. It has a history of use in Europe, particularly in naturopathy, and it has been used in medical treatment since the late 19th century4. Wider medical use was prompted by Hans H. Wolff (1979 as cited in 10), a German doctor who used ozone in his practice and trained other doctors but its use in medicine continues to be controversial10. Ozone therapy is offered in a number of countries and a European collaboration involving medical ozone societies from ten countries including Austria, Germany, Spain, Switzerland and Italy has been established7.
Claims of efficacy
It has been claimed that in many diseases, including cancer, ozone therapy along with other ‘oxygenation’ therapies has a range of benefits such as destroying cancer cells and pathogens and stimulating metabolism5. In general terms, it is suggested that ozone therapy causes immunomodulation and immunoactivation8.
Ozone therapy has been used for intervertebral disc herniation and dental caries, diabetes, ischemic heart disease and circulatory disorders, wounds and other skin lesions, intestinal conditions, infections, AIDS, Parkinson's disease, rheumatic diseases, macular degeneration and cancer as well as a range of other conditions. Ozone has also been used for disinfection4,8.
Mechanism(s) of action
Several theories have been proposed11. It has been suggested that perceived therapeutic effects of ozone therapy may be partly due the ‘controlled and moderate’ oxidative stress produced by ozone reacting with several biological components14. Further, that the difference between its therapeutic and toxic effects depend on the extent of oxidative stress: that in severe oxidative stress nuclear transcriptional factor kappa B is activated which causes an inflammatory response and tissue injury, while in moderate stress another factor, nuclear factor-erythroid 2-related factor 2, is activated which induces the transcription of antioxidant response elements. These cause the production of numerous antioxidative enzymes which together with free antioxidants protect cells from oxidation and inflammation and may also reverse the chronic oxidative stress.
In cancer, theories on the mechanism of action for ozone therapy are based on the idea that increasing the oxygen levels in the vicinity of cancer cells, will adversely affect them and potentially cause apoptosis15. Thus studies have focused on measurement of tumour oxygenation levels after ozone application and these suggest an increase occurs. However, the relationship between oxygen and cancer cells has been shown to be complex and the range of hypoxia in malignant tumours can vary widely13. tudies involving ozone-oxygen in animal cancer models have been conducted since the 1970s, t
Prevalence of use
Prevalence of use in Europe is difficult to assess as ozone therapy has not been recorded in recent surveys14-16. However, it appears to be widely available.
Ozone therapy is available in many countries. In the USA the Food and Drug Administration has placed restrictions on devices generating ozone (FDA 2017), particularly ‘if it is used or intended for use(s including) ….In any medical condition for which there is no proof of safety and effectiveness’18.
Cost(s) and expenditures
Costs in Europe are not available, but US websites provide an indicative cost of US$ 110-US$ 150 (equivalent to 90-120 Euros per treatment). A course may include up to 10 treatments and 2 or 3 courses of treatment may be required8.
Systematic reviews, meta-analyses
No systematic reviews of ozone therapy in relation to cancer have been published. Systematic reviews have been published on other uses, for example, in the field of dentistry and in herniated discs19,20.
No randomised controlled trials have been conducted to assess the effects of ozone therapy in cancer patients.
An open uncontrolled study of ozone therapy in chemotherapy-resistant cancer patients was initiated in 200318. Preliminary findings revealed that, in patients with a Karnofsky performance score of less than 40% (on a scale of 0 to 100% where 0 represents death and 100% reflects normal activity/function and no evidence of disease), no effect on disease progression was observed. Patients with a Karnofsky score of 70% or less reported an improvement in quality of life after 30-45 treatments. The lack of a control group and subjective nature of the outcome measure prevent definitive conclusions being reached, a point conceded by the researcher.
Results of a pilot, uncontrolled study of ozone therapy for tumour oxygenation were published in 200422. Eighteen patients with metastases or advanced tumours accessible to physical examination were enrolled in the study. All patients had a Karnofsky performance status of > 70%, 15 were male and 14 had head and neck tumours, 2 had gynaecological tumours and 2 had bone metastases in the chest wall. Ozone autohaemotransfusion was administered on 3 alternate days in one week. Tumour oxygenation levels were measured using needle probes. No overall statistically significant change was observed. No adverse effects were recorded. Due to the small sample size and uncontrolled nature of the study, these can only be considered preliminary findings. In addition, the clinical relevance of the observed changes in tumour oxygenation is not entirely clear although tumour hypoxia has been reported to adversely affect prognosis in tumours such as those of the head and neck tumours23,24.
A further controlled study by this research group from Spain focused specifically on patients with advanced head and neck tumours who were undergoing radiotherapy25. Nineteen patients were recruited and studied over a 3 year period. Twelve patients received chemotherapy in addition to radiotherapy while 7 received ozone therapy plus radiotherapy. The two groups were not well-matched as the ozone therapy group was older with greater lymph node involvement. However, no significant difference in overall survival was recorded between the two groups.
Ozone has been investigated for other uses in cancer patients. These include a single case report described intravesical instillation of ozonized water in a patient with progressive radiation-induced haematuria26. Osteonecrosis of the jaw has also been reportedly managed with treatments including ozone in myeloma patients (n=12, 27 and n=127) as well as a separate series of 10 patients with bone metastases28. Preliminary findings on the effects of ozone by rectal insufflations and/or by local application of ozonized-oil, in small uncontrolled studies in patients (19,17 and 12 respectively) with severe and/or refractory radiation-induced haemorrhagic proctitis or bleeding29 To date, none of these preliminary findings have been confirmed with randomised controlled trials.
Much of the research on safety of ozone has focused on its effect in the atmosphere. These large scale studies have revealed that an increase in exposure to ozone is associated with a significant increase in the risk of death from respiratory diseases35.
With regard to ozone used therapeutically, websites offering ozone therapy quote the results of a large observational “study” reportedly conducted by the German Medical Society for Ozone Therapy in 1980 involving 644 therapies and 384,775 patients who had received a total of over 5.5million treatments. A full report of this cited experience could not be found and therefore valid conclusions are not possible.
A cluster of hepatitis C virus infections associated with ozone-enriched transfusion of autologous blood were reported in Italy36.
Cases have been reported where direct infusion of ozone intravenously has resulted in pulmonary embolism and death2. Consequently, this method of administration has been prohibited in Germany since 1984 and is generally contraindicated2,6. An overall assessment of the safety of ozone concluded that ozone used intravenously is ‘likely unsafe’ and there is insufficient reliable information on the safety of other methods of administration4.
Theoretical contraindications include the following8:
Glucose-6-phosphate dehydrogenase deficiency (favism, acute haemolytic anaemia), hyperthyroidism, leukaemia.
Direct gas injections and intra-arterial injections are contraindicated due to the potential for pulmonary embolism and death.
Insufficient evidence is available on use in pregnancy and lactation.
Interactions with other drugs, herbs or therapies have not been reported4.
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- Burke FJ.(2012). Ozone and caries: a review of the literature. Dent Update. 39(4):271-2, 275-8.
- European Cooperation of Medical Ozone Societies EUROCOOP. Accessed 11th April 2017.
- German Medical Society for the Use of Ozone in Prevention and Therapy. (Ärztliche Gesellschaft für Ozon-Anwendung in Prävention und Therapie). Guidelines. Available online. Accessed 11th April 2017
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- United States Food and Drug Administration. (2017). Title 21--Food And Drugs.Chapter I--Food And Drug Administration Department Of Health And Human Services. Subchapter H--Medical Devices. Available online. Accessed 11th April 2017.
- Magalhaes FN, Dotta L, Sasse A, Teixera MJ, Fonoff ET. Ozone therapy as a treatment for low back pain secondary to herniated disc: a systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2012 Mar-Apr;15(2):E115-29.
- Rickard GD, Richardson R, Johnson T, McColl D, Hooper L. Ozone therapy for the treatment of dental caries. Cochrane Database Syst Rev. 2004;(3):CD004153.
- Re L, Mawsouf MN, Menéndez S, León OS, Sánchez GM, Hernández F. Ozone therapy: clinical and basic evidence of its therapeutic potential. Arch Med Res. 2008 Jan;39(1):17-26. Epub 2007 Sep 29.
- Clavo B, Pérez JL, López L, Suárez G, Lloret M, Rodríguez V, Macías D, Santana M, Hernández MA, Martín-Oliva R, Robaina F. Ozone Therapy for Tumor Oxygenation: a Pilot Study. Evid Based Complement Alternat Med. 2004 Jun 1;1(1):93-98.
- Janssen HL, Haustermans KM, Balm AJ, Begg AC. Hypoxia in head and neck cancer: how much, how important? Head Neck. 2005 Jul;27(7):622-38.
- Buffa FM, Harris AL, West CM, Miller CJ. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer. 2010 Jan 19;102(2):428-35. Erratum in: Br J Cancer. 2010 Sep 7;103(6):929.
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- Clavo B, Gutierrez D, Martin D, Suarez G, Hernandez MA, Robaina F. (2005). Intravesical ozone therapy for progressive radiation-induced hematuria. J Altern Complement Med 11(3):539-541.
- Petrucci MT, Gallucci C, Agrillo A, Mustazza MC, Foa R. (2007). Role of ozone therapy in the treatment of osteonecrosis of the jaws in multiple myeloma patients. Haematologica 92(9):1289-1290.
- Ripamonti CI, Cislaghi E, Mariani L, Maniezzo M. (2011). Efficacy and safety of medical ozone (O(3)) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: Preliminary results of a phase I-II study. Oral Oncol 47(3):185-190.
- Clavo B, Ceballos D, Gutierrez D, Rovira G, Suarez G, Lopez L, Pinar B, Cabezon A, Morales V, Oliva E, Fiuza MD, Santana-Rodriguez M. Long-term control of refractory hemorrhagic radiation proctitis with ozone therapy.J Pain Symptom Manage. 2013 Jul;46(1):106-12.
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- Faustini A, Capobianchi MR, Martinelli M, Abbate I, Cappiello G, Perucci CA. A cluster of hepatitis C virus infections associated with ozone-enriched transfusion of autologous blood in Rome, Italy. Infect Control Hosp Epidemiol. 2005 Sep;26(9):762-7.
- Yoo C, Kang CS, Choi YL, Kang HY, Kim JM, Koh YH, et al. Long-term control of refractory hemorrhagic radiation proctitis with ozone therapy. Korean J Pathol. 2012;46(5):436-42.
- Clavo B, Santana-Rodriguez N, Llontop P, Gutierrez D, Ceballos D, Mendez C, et al. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients. Evidence-based complementary and alternative medicine: eCAM. 2015;2015:480369.
- Luongo M, Brigida AL, Mascolo L, Gaudino G. Possible Therapeutic Effects of Ozone Mixture on Hypoxia in Tumor Development. Anticancer Res. 2017 Feb;37(2):425-435.