Ozone therapy | Cam-Cancer

Ozone therapy

Abstract and key points

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 (RCTs) in cancer patients have been published in full in English. Other reports are either uncontrolled observations or the clinical relevance is unclear.  

Antitumour treatment

  • Survival – no rigorous evidence is available from one small controlled study on the effect of ozone on survival

Supportive care

  • Adverse effects of radiotherapy – no rigorous evidence and very low quality evidence from anecdotal reports of effects of ozone therapy on radiotherapy-related adverse effects
  • Oral mucositis – very limited evidence is available from one RCT of an effect on pain but not grade in mucositis; the reliability of this evidence is unclear
  • Quality of life -  very limited evidence is available from two controlled trials of an effect on quality of life in cancer patients but the reliability of this evidence is unclear
  • Other outcomes - no rigorous evidence exists of effects on other outcomes

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.

Document history

Updated in August 2020 by Karen Pilkington
Fully updated and revised in December 2018 by Karen Pilkington.
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.

Citation

Karen Pilkington, CAM Cancer Consortium. Ozone therapy [online document], http://cam-cancer.org/en/ozone-therapy. September 7th, 2020.

What is it?

Description

Ozone (O3) is a gas which was discovered in the mid-19th century (Elvis 2011). 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) (Bocci 2006). 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 (Bocci 2006; United States Environment Protection Agency, US EPA 2020). 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 (US EPA 2020). Excessive concentrations of ozone can be toxic to living organisms (US EPA 2020).  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 (Bocci 2006).

Scientific name: ozone; other names: O3, medical ozone, therapeutic ozone, ozonated autohemotherapy, ozonised water, trioxygen (ozone therapy is also included under broader terms such as hyperoxygenation therapy or oxygen therapies) (Natural Medicine Database (NMD) 2020; Cassileth 2009).

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).

Scientific name

Ozone; other names: other names: O3, medical ozone, therapeutic ozone, ozonated autohemotherapy, ozonised water, trioxygen (ozone therapy is also included under broader terms such as hyperoxygenation therapy or oxygen therapies) (Natural Medicine Database (NMD) 2020; Cassileth 2009).

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).

Components

Ozone is an unstable, colourless gas. Molecules of ozone consist of 3 oxygen atoms arranged in a cyclic structure (Bocci 2006)

Background and prevalence

Ozone was first identified by Schönbein, a professor of Chemistry at the University of Basel in 1840 and the chemical formula was determined in 1865 (Rubin 2001). 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 (Bocci 2006). It has a history of use in Europe, particularly in naturopathy, and it has been used in medical treatment since the late 19th century (Elvis and Ekta 2011). Wider medical use was prompted by Hans H. Wolff (1979 as cited in Bocci 1999), a German doctor who used ozone in his practice and trained other doctors but its use in medicine continues to be controversial (Bocci 1999). 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 established (Medical Society Ozone, 2020a).

Prevalence of use in Europe is difficult to assess as ozone therapy has not been recorded in recent surveys (Hunt 2010; Molassiotis 2005; Molassiotis 2006). However, it appears to be widely available.

Alleged indications

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 (Elvis and Ekta 2011; Medical Society Ozone 2020b).

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 (Cassileth 2009). In general terms, it is suggested that ozone therapy causes immunomodulation and immunoactivation (Medical Society Ozone, 2020b).

Mechanisms of action

Several theories have been proposed (Sagai 2011). 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 (Sagai 2011). 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 apoptosis (Bocci 2005). 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 widely (Höckel 2001). Consequently, while studies involving ozone-oxygen in animal cancer models have been conducted since the 1970s, this theory is still being examined and discussed (Luongo 2017).

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 application (NMD 2020). Ozone, either in gaseous form or as ozonated water, has been used in the treatment of dental caries (Burke 2012). 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 (Burke 2012).

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 (Cassileth 2009). Cases have been reported where direct infusion of ozone intravenously has resulted in pulmonary embolism and death (Bocci 2006).

Rectal insufflation has been used in management of local inflammatory reaction, such as proctitis, which may result from radiotherapy (Medical Society Ozone 2020b).

No typical dose has been recognised (NMD 2020). 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 reported (Medical Society Ozone 2020b). A global consensus document (The Madrid Declaration on Ozone Therapy) is available to health professionals that use ozone therapy (ISCO, 2015).

Legal issues

Ozone therapy is available in many countries. In the USA, the Food and Drug Administration (FDA) has placed restrictions on devices generating ozone, 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’ (US FDA 2019).

Costs 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 (Medical Society Ozone 2020b).

Does it work?

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 discs (Magalnaes 2012; Rickard 2004).

An overview of research on potential use of ozone as an adjuvant during cancer treatment concluded that only in vitro, animal studies and isolated clinical reports were available and that randomised controlled trials (RCTs) are required (Clavo et al 2018).         Similar findings (uncontrolled studies and reports plus basic research studies) were identified in a systematic literature search on ozone application in glioblastoma management (Megele et al. 2018) and in a review on ozone in the management of chemotherapy-induced toxicity (Clavo et al 2019). The latter review highlights the fact that RCTs are underway.       

Only two RCTs have been conducted to assess the effects of ozone therapy in cancer patients and neither has been published in full in English.

Antitumour treatment

  • Survival – no rigorous evidence is available from one small controlled study on the effect of ozone on survival

Supportive care

  • Adverse effects of radiotherapy – no rigorous evidence and very low quality evidence from anecdotal reports of effects of ozone therapy on radiotherapy-related adverse effects
  • Oral mucositis – very limited evidence is available from one RCT of an effect on pain but not grade in mucositis but the reliability of this evidence is unclear
  • Quality of life -  very limited evidence is available from two controlled trials of an effect on quality of life in cancer patients but the reliability of this evidence is unclear
  • Other outcomes - no rigorous evidence exists of effects on other outcomes

Description of studies

Survival

No RCTs have assessed survival.

One trial which involved a control group focused specifically on patients with advanced head and neck tumours who were undergoing radiotherapy (Clavo 2004). 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.

Oral mucositis

One RCT has assessed the effect of ozone therapy on oral mucositis but has only been published as a conference abstract. A total of 102 paediatric cancer patients, aged 3-14 years with chemotherapy related oral mucositis, were treated with ozone therapy or sham therapy (placebo) for four consecutive days from the day of diagnosis (Bardellini et al, 2017). Improvement in both groups by day 7 was reported but no significant difference in reduction in the grade although a difference in pain was reported (p<0.005). Further details on methods are not available as this has only been published as a conference abstract. However, the only outcome for which there was a significant effect (pain) is subjective and the risk of bias is unclear.

Adverse effects of radiotherapy

No RCTs have assessed ozone therapy on adverse effects of radiotherapy. Several small case series have involved the application of ozone therapy in the treatment of adverse effects. To date, none of these preliminary findings have been confirmed with RCTs.

Other outcomes (quality or life, physiological measures)

Two controlled trials have reported beneficial effects on quality of life with ozone acupoint injections as adjuvant to chemotherapy (He 2015; Chu et al 2015). Full details on the methods are not available as the publications have been in Chinese, however, the likely lack of blinding and subjective nature of the outcome suggests a risk of bias and so the reliability of the reported results is uncertain.

No RCTs have assessed other outcomes in cancer patients except for the RCT mentioned above which assessed effects on the CD4/CD8 ratio. The CD4/CD8 ratio was reported to have increased in the group treated with ozone acupoint injection (P <0.01), but decreased in the control group (P<0.01) compared with pre-treatment (He 2015). Further detail on the methods are required for a full assessment of these results and their implications.

Fifty patients with various types of cancer and fatigue were treated with ozone auto haemotransfusion twice weekly for one month and then twice monthly as maintenance therapy (Tirelli et al 2018) in an uncontrolled trial.  No side effects were found and a significant improvement (> 50%) of the symptoms was reported in 35 patients (70%) but the lack of a control group precludes any conclusions being drawn.

Is it safe?

Adverse events

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 diseases (Jerrett 2009).

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. An evidence review by researchers, two of whom are from the  Medical Society for the Use of Ozone in Prevention and Therapy, collated results of various types of studies (including case reports) (Viebahn-Hänsler et al. 2016). The studies involved 11,000 systemic ozone treatments in the form of Major Ozone Autohemotherapy (MAH) in 577 patients and ≥ 47,000 Rectal Insufflations (RI) in 716 patients. Based on their review, the authors claimed that these treatments are safe but standard systematic review methods were not used so the reliability of the conclusions is unclear.

A cluster of hepatitis C virus infections associated with ozone-enriched transfusion of autologous blood were reported in Italy (Faustini 2006).

Cases have been reported where direct infusion of ozone intravenously has resulted in pulmonary embolism and death (Bocci 2006). Consequently, this method of administration has been prohibited in Germany since 1984 and is generally contraindicated (Bocci 2006; NMD 2020).

An overall assessment of the safety of ozone concluded that ozone used intravenously is ‘likely unsafe’, that it is possibly unsafe when injected into the spinal area or inhaled, and that there is and there is insufficient reliable information on the safety of other methods of administration (NMD 2020).

Contraindications

Contraindications include the following:

  • Glucose-6-phosphate dehydrogenase deficiency (favism, acute haemolytic anaemia), hyperthyroidism, leukaemia, advanced stages of HIV.
  • Direct gas injections and intra-arterial injections are contraindicated due to the potential for pulmonary embolism and death.
  • Hyperbaric medical ozone infusions are also contraindicated.
  • Insufficient evidence is available on use in pregnancy and lactation.
    (Medical Society Ozone 2020b; Ozone Society UK, 2019; NMD 2020)

Interactions

Interactions with other drugs, herbs or therapies have not been reported (NMD 2020).

References

Bardellini E, Amadori F, Merlo J, Chiappini D, Majorana A. Ozone therapy for the treatment of paediatric chemotherapy-induced oral mucositis: a randomized double blind controlled study. Supportive care in cancer. 2017;25(2):S130‐S1

Bianco E, Maddalone M, Porcaro G, Amosso E, Baldoni M. Treatment of Osteoradionecrosis of the Jaw with Ozone in the Form of Oil-based Gel: 1-year follow-up. The journal of contemporary dental practice. 2019;20(2):270-6.

Bocci V. Biological and clinical effects of ozone. Has ozone therapy a future in medicine? Br J Biomed Sci. 1999;56(4):270-9.

Bocci V., Larini A., Micheli V. (2005). Restoration of normoxia by ozone therapy may control neoplastic growth: A review and a working hypothesis. Journal of Alternative and Complementary Medicine. 11 (2): pp 257-265.

Bocci V.A.(2006) Scientific and Medical Aspects of Ozone Therapy. State of the Art. Archives of Medical Research. 37 (4) (pp 425-435).

Burke FJ.(2012). Ozone and caries: a review of the literature. Dent Update. 39(4):271-2, 275-8.

Cassileth B. (2009) Oxygen therapies. Oncology (Williston Park). 23(13):1182.

Chu YL, Huang RY, Jiang Y, Chen PF. Effect of chemotherapy combined with ozone point injection on quality of life in patients with advanced non-small cell lung cancer. Journal of anhui TCM college[an hui zhong yi xue yuan xue bao]. 2013;32(4):52‐4.

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.

Clavo B, Rodriguez-Esparragon F, Rodriguez-Abreu D, Martinez-Sanchez G, Llontop P, Aguiar-Bujanda D, et al. Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects. Antioxidants (Basel, Switzerland). 2019;8(12).

Clavo B, Santana-Rodriguez N, Llontop P, Gutierrez D, Suarez G, Lopez L, et al. Ozone Therapy as Adjuvant for Cancer Treatment: Is Further Research Warranted? Evidence-based complementary and alternative medicine : eCAM. 2018;2018:7931849. Epub 2018/10/03.

Elvis AM. Ekta JS. (2011) Ozone therapy: A clinical review. Journal of Natural Science Biology & Medicine. 2(1):66-70.

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.

He YK. Comparative study of Ozone Point Injection combined with chemotherapy treatment and simple chemotherapy treatment for advanced non-small cell lung cancer. Clinical medical & engineering [lin chuang yi xue gong cheng]. 2015;22(7):897‐8.

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.

Höckel M, Vaupel P.(2001). Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 93(4):266-76.

ISCO (International Scientific Committee of Ozone Therapy). Madrid Declaration on Ozone Therapy. 2015. Accessed 18th August 2020.

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.

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.

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.

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.

Medical Society Ozone (Medical Society for the use of ozone in prevention and treatment, Ärztliche Gesellschaft für Ozon-Anwendung in Prävention und Therapie). European Cooperation.  Accessed 17th August 2020. (2020a)

Medical Society Ozone (Medical Society for the Use of Ozone in Prevention and Therapy, Ärztliche Gesellschaft für Ozon-Anwendung in Prävention und Therapie). Guidelines. Available online. Accessed 17th August 2020. (2020b)

Megele R, Riemenschneider MJ, Dodoo-Schittko F, Feyrer M, Kleindienst A. Intra-tumoral treatment with oxygen-ozone in glioblastoma: A systematic literature search and results of a case series. Oncology letters. 2018;16(5):5813-22

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.

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.

NMD, Natural Medicines Database: professional version. Ozone therapy monograph. Somerville (MA): Therapeutic Research Faculty. Available online. Accessed 19th August 2020 .

Ozone Society. Medical Ozone Therapy: Contra-indications and Contra-applications. 2019. Accessed 17th August 2020.

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.

Rubin MB. (2001). The History Of Ozone. The Schönbein Period, 1839-1868. Bull. Hist. Chem., 26 (1). Available online. Accessed 11th April 2017.

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.

Tirelli U, Cirrito C, Pavanello M, Del Pup L, Lleshi A, Berretta M. Oxygen-ozone therapy as support and palliative therapy in 50 cancer patients with fatigue - A short report. European review for medical and pharmacological sciences. 2018;22(22):8030-3.

United States Environmental Protection Agency. (2012) Ground Level Ozone Basics. Updated August 2020. Accessed 3rd Sept. 2020.

United States Food and Drug Administration. (2019). Title 21--Food And Drugs. Chapter I--Food And Drug Administration Department Of Health And Human Services. Subchapter H--Medical Devices. Accessed 3rd Sept 2020.

Viebahn-Hänsler R, León Fernández OS & Fahmy Z (2016) Ozone in Medicine: Clinical Evaluation and Evidence Classification of the Systemic Ozone Applications, Major Autohemotherapy and Rectal Insufflation, According to the Requirements for Evidence-Based Medicine, Ozone: Science & Engineering, 38:5, 322-345.

CAM Cancer is hosted by NAFKAM

Norway's National Research Center in Complementary and Alternative Medicine

Read more about NAFKAM

Other websites from NAFKAM: