Written by Karen Pilkington and the CAM-Cancer Consortium.
Updated September 11, 2013

Ozone therapy

What is it?

Description

Ozone (O3) is a gas which was discovered in the mid 19th century.1 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 system.2,3 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 sunlight.3 Excessive concentrations of ozone can be toxic to living organisms.3 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 ozone.2

Scientific name

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

Ingredient(s)/Components

Ozone is an unstable, colourless gas. Molecules of ozone consist of 3 oxygen atoms arranged in a cyclic structure.2

Application and dosage

Ozone therapy can be used in a variety of ways including local application to tissues, through introduction via the nasal, auricular, oral, rectal or intravaginal routes or cutaneous application.4,6 Ozone, either in gaseous form or as ozonated water, has been used in the treatment of dental caries.7 Ozonated water has also been injected into joints in arthritic conditions or applied to the skin for wound treatment.4 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 available.6

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 This technique involves blood being withdrawn from the patient’s vein and treated with ozone before reinfusion or injection into a vein or muscle.5 Cases have been reported where direct infusion of ozone intravenously has resulted in pulmonary embolism and death.2 Consequently, this method of administration has been prohibited in Germany since 1984 and is generally contraindicated.2

No typical dose has been recognised.4 In research, gas mixtures comprising no less than 95% oxygen and no more than 5% ozone have been used while websites offering ozone autohaemotherapy refer to concentrations ranging from 1 to 100 micrograms per millilitre (µg/ml), corresponding to an ozone/oxygen mixture at ratios between 0.05 % ozone to 99.95 % oxygen and 5 % ozone to 95 % oxygen.8 Guidelines on the use of ozone in medicine produced by the German Medical Association of Ozone Application in Prevention and Therapy recommend that concentrations of 80 μg ozone per ml whole blood and above are not used as there is an increased risk of haemolysis.9 These guidelines suggest concentrations between 10 and 40 μg, in exceptional cases up to 60 μg ozone per ml whole blood are used. Total doses are given as 500 μg – 1000 μg 2 x per week for 10 treatments, possibly repeated several times per year.

History/provider(s)

Ozone was first identified by Schönbein, a professor of Chemistry at the University of Basel in 1840 and the formula was determined in 1865.10 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 wounds.2 In the 1920s, ozone and hydrogen peroxide were used experimentally to treat the flu.11 It has a history of use in Europe, particularly in naturopathy, and it has been used in medical treatment since the late 19th century.4 Wider medical use prompted by Wolff, a German doctor who used ozone in his practice and trained other doctors but its use in medicine continues to be controversial.12 Ozone therapy is offered in a number of countries and a European collaboration involving medical ozone societies from Austria, Germany, Switzerland and Italy has been established.8 A similar society exists in Spain. It has been suggested that, while in some countries naturopaths and others practice ozone therapy, ozone autohaemotherapy should only be carried out by physicians.13

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 metabolism.5 In general terms, it is suggested that ozone therapy causes immunomodulation and immunoactivation.9

Alleged indication(s)

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 disinfection.4,9

Mechanism(s) of action

Several theories have been proposed. 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 components.14 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, the proposed mechanism of action is based on the discovery by Warburg in the 1930s, that cancer cells have a lower respiration rate than normal cells and that they thrived in hypoxic environments.15 It has been suggested that tumours thrive in hypoxic environments because they can metastasize and secrete angiopoietins.15 Tumour hypoxia has also been reported to cause an increase in resistance to radiotherapy and chemotherapy.16 Theories on the mechanism of action for ozone therapy are based on idea that increasing the oxygen levels in the vicinity of cancer cells, will adversely affect them and potentially cause apoptosis. 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 tumors can vary widely.16

Prevalence of use

Prevalence of use in Europe is difficult to assess as ozone therapy has not been recorded in recent surveys.17-19 However, it appears to be widely available, and, for example, one clinic in Germany reported treating over 500 cancer patients per year with various therapies including ozone.20

Legal issues

Ozone therapy is available in many countries. However, in the USA the Food and Drug Administration has placed restrictions on devices generating ozone (FDA 2011), stating that ‘any such device will be considered adulterated and/or misbranded ….. if it is used or intended for use(s including) ….In any medical condition for which there is no proof of safety and effectiveness.’21

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 required.9

Citation

Karen Pilkington, CAM-Cancer Consortium. Ozone therapy [online document]. http://cam-cancer.org/The-Summaries/Other-CAM/Ozone-therapy. September 11, 2013.

Document history

Updated/assessed as up to date by Barbara Wider in September 2013.
Summary first published in October 2012, authored by Karen Pilkington.

References

  1. Elvis AM. Ekta JS. (2011) Ozone therapy: A clinical review. Journal of Natural Science Biology & Medicine. 2(1):66-70.
  2. Bocci V.A.(2006) Scientific and Medical Aspects of Ozone Therapy. State of the Art. Archives of Medical Research. 37 (4) (pp 425-435).
  3. United States Environmental Protection Agency.(2012). Ground Level Ozone Basic Information. Available at: http://www.epa.gov/glo/basic.html. Accessed 11th September 2013.
  4. Natural Medicines Comprehensive Database: professional version. Ozone therapy monograph. Stockton (CA): Therapeutic Research Faculty. Available at: http://naturaldatabase.therapeuticresearch.com. Accessed 11th September 2013.
  5. Cassileth B. (2009) Oxygen therapies. Oncology (Williston Park). 23(13):1182.
  6. Natural Standard/Harvard Medical School (2008). Ozone therapy. Available at: http://www.intelihealth.com/IH/ihtIH/WSIHW000/8513/34968/358849.html?d=dmtContentAccessed: 20th August 2012.
  7. Burke FJ.(2012). Ozone and caries: a review of the literature. Dent Update. 39(4):271-2, 275-8.
  8. European Cooperation of Medical Ozone Societies EUROCOOP (Ärztliche Gesellschaft für Ozon-Anwendung in Prävention und Therapie). Information for patients. Available at: http://www.ozongesellschaft.de/information_for_patients_60.htm. Accessed 11th September 2013.
  9. German Medical Association of Ozone Application in Prevention and Therapy. Available at: http://www.ozonosan.de/images/upload/File/Guidelines%20OSE%201212%20published.pdf. Accessed 11st September 2013.
  10. Rubin MB. (2001). The History Of Ozone. The Schönbein Period, 1839-1868. Bull. Hist. Chem., 26 (1). Available at: http://www.scs.illinois.edu/~mainzv/HIST/awards/OPA%20Papers/2001-Rubin.pdf. Accessed 11th September 2013.
  11. American Cancer Society (2008). Pharmacological and Biological Treatment: Oxygen Therapy. Available at: http://www.cancer.org/Treatment/TreatmentsandSideEffects/ComplementaryandAlternativeMedicine/PharmacologicalandBiologicalTreatment/oxygen-therapy. Accessed: 11th September 2013.
  12. Bocci V. Biological and clinical effects of ozone. Has ozone therapy a future in medicine? Br J Biomed Sci. 1999;56(4):270-9.
  13. Bocci V. Borrelli E, Zanardi I, Travagli V. (2011). Oxygen-Ozone Therapy Is At A Cross-Road. Available at: http://www.isco3.org/files/O3_CrossRoad_Bocci_paper_2011.pdf. Accessed 11th September 2013.
  14. Sagai M., Bocci V. (2011). Med Gas Res. 2011 Dec 20;1:29. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress? Medical Gas Research. 1 (1). Article Number: 29.
  15. Bocci V., Larini A., Micheli V. (2005). Restoration of normoxia by ozone therapy may control neoplastic growth: A review and a working hypothtesis. Journal of Alternative and Complementary Medicine. 11 (2): pp 257-265.
  16. Höckel M, Vaupel P.(2001). Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 93(4):266-76.
  17. Hunt KJ, Coelho HF, Wider B, Perry R, Hung SK, Terry R, Ernst E. (2010). Complementary and alternative medicine use in England: results from a national survey. Int J Clin Pract. 64(11):1496-502. doi: 10.1111/j.1742-1241.2010.02484.x.
  18. Molassiotis A, Fernadez-Ortega P, Pud D, Ozden G, Scott JA, Panteli V, Margulies A, Browall M, Magri M, Selvekerova S, Madsen E, Milovics L, Bruyns I, Gudmundsdottir G, Hummerston S, Ahmad AM, Platin N, Kearney N, Patiraki E. (2005). Use of complementary and alternative medicine in cancer patients: a European survey. Ann Oncol. 16(4):655-63. Epub 2005 Feb 2.
  19. Molassiotis A., Ozden G., Platin N., Scott J.A., Pud D., Fernandez-Ortega P., Milovics L.,Panteli V., Gudmundsdottir G., Browall M., Madsen E., Patiraki E. & Kearney N. (2006). Complementary and alternative medicine use in patients with head and neck cancers in Europe. European Journal of Cancer Care 15: 19–24.
  20. Jacobson JS, Grann VR, Gnatt MA, Hibshoosh H, Austin JH, Millar WS, Neugut AI. (2005). Cancer outcomes at the Hufeland (complementary/alternative medicine) klinik: a best-case series review. Integr Cancer Ther. 4(2):156-67.
  21. United States Food and Drug Administration. (2012). Title 21--Food And Drugs.Chapter I--Food And Drug Administration Department Of Health And Human Services. Subchapter H--Medical Devices. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=801.415. Accessed 11th September 2013.
  22. 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.
  23. 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.
  24. 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.
  25. Muller-Tyl E, Salzer H, Reisinger L, Washuttl J, Wurst F. [Ozone-oxygen therapy for gynecologic carcinomas. The effect of parenteral-ozone oxygen mixture administration on free fatty acids and triglycerides in patients with gynecologic carcinomas]. Fortschr Med 1979; 97(10):451-454.
  26. Enzelsberger H, Metka M, Salzer H. [Effect of a parenteral ozone-oxygen mixture on the concentration of immunoglobulins (IgA, IgG, IgM), of vitamin A and lysozyme activity in patients with cervical cancer]. Geburtshilfe Frauenheilkd 1987; 47(12):343-345.
  27. 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.
  28. 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.
  29. 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.
  30. Clavo B, Ruiz A, Lloret M, López L, Suárez G, Macías D, Rodríguez V, Hernández MA, Martín-Oliva R, Quintero S, Cuyás JM, Robaina F. Adjuvant Ozonetherapy in Advanced Head and Neck Tumors: A Comparative Study. Evid Based Complement Alternat Med. 2004 Dec;1(3):321-325. Epub 2004 Oct 16.
  31. Parkhisenko I, Bil'chenko SV.(2003). [The ozone therapy in patients with mechanical jaundice of tumorous genesis]. Vestn Khir Im I I Grek 162(5):85-87.
  32. 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.
  33. Subbotin VM, Zitta DV, Terekhina NA. (2007)[Prophylaxis of acute postoperative gastroduodenal ulcers at the patients with colorectal cancer]. Khirurgiia (Mosk) (3):4-6.
  34. 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.
  35. 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.
  36. 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.
  37. Grundner HG, Erler U. [Animal experiments on ozone therapy of non-irradiated and irradiated tumors. II. Ehrlich ascites carcinoma in vivo]. Strahlentherapie 1976; 151(6):522-529.
  38. Schulz S, Haussler U, Mandic R, Heverhagen JT, Neubauer A, Dunne AA et al. Treatment with ozone/oxygen-pneumoperitoneum results in complete remission of rabbit squamous cell carcinomas. Int J Cancer 2008; 122(10):2360-2367.
  39. Kesik V., Uysal B., Kurt B., Kismet E., Koseoglu V. Cancer Biology and Therapy. 8 (17) (pp 1623-1628), 2009.
  40. Sweet F, Kao MS, Lee SC, Hagar WL, Sweet WE. Ozone selectively inhibits growth of human cancer cells. Science 1980; 209(4459):931-933.
  41. Karlic H, Kucera H, Metka M, Schonbauer M, Soregi G. [Effect of ozone and ionizing radiation on an in vitro model--a pilot study of 4 gynecologic tumors]. Strahlenther Onkol 1987; 163(1):37-42.
  42. Bocci V, Luzzi E, Corradeschi F, Silvestri S. Studies on the biological effects of ozone: 6. Production of transforming growth factor 1 by human blood after ozone treatment. J Biol Regul Homeost Agents 1994; 8(4):108-112.
  43. Zanker KS, Kroczek R. In vitro synergistic activity of 5-fluorouracil with low-dose ozone against a chemoresistant tumor cell line and fresh human tumor cells. Chemotherapy 1990; 36(2):147-154.
  44. Bucci B., Cannizzaro A., Brunetti E., Martinelli M. Ozone treatment inhibits proliferation in human neuroblastoma SK-N-SH cells. Rivista Italiana di Ossigeno-Ozonoterapia. 5 (2) (pp 85-92), 2006.
  45. Jerrett M, Burnett RT, Pope CA 3rd, Ito K, Thurston G, Krewski D, Shi Y, Calle E, Thun M. Long-term ozone exposure and mortality. N Engl J Med. 2009 Mar 12;360(11):1085-95.
  46. 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.
  47. Ripamonti CI, Maniezzo M, Pessi MA, Boldini S. Treatment of osteonecrosis of the jaw (ONJ) by medical ozone gas insufflation. A case report. Tumori. 2012 May-Jun;98(3):72e-75e.