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

Ozone therapy

Abstract and key points

  • 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 correct tumour hypoxia.

In vitro and animal studies have shown changes in various biological parameters but 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. Few adverse effects have been reported for autohaemotherapy but assessment of safety 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.

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

Does it work?

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 discs.22,23

Narrative reviews

A series of narrative reviews have been published subsequently by researchers from Italy summarising the findings of their own research on ozone therapy.2,12,15,24 One review focuses on ozone therapy in cancer but primarily addresses pre-clinical research and a hypothesis related to restoration of normoxia in neoplastic growth.15 One study in chemotherapy-resistant cancer patients was described (further details below).

Clinical trials

No randomised controlled trials have been conducted to assess the effects of ozone therapy in cancer patients.

Early studies in cancer patients reported effects of ozone therapy on various parameters. In 40 patients with gynaecological cancer, ozone therapy was reported to cause a statistically significant decrease in levels of fatty acids and triglycerides.25 A second early study, in 21 women with progressive cervical cancer (Stages III and IV), assessed the effect of ozone autohaemotherapy in addition to conventional radiotherapy on immunological status.26 Small differences in IgG, IgA and IgM were observed but changes were not statistically significant.

More recently, an open study of ozone therapy in chemotherapy-resistant cancer patients was initiated in 2003.15 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 study of ozone therapy for tumour oxygenation were published in 2004.27 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. Oxygenation did, however, improve in the most hypoxic tumours and 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 tumours.28,29

A further study by this research group from Spain focused specifically on patients with advanced head and neck tumours who were undergoing radiotherapy.30 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. The researchers suggest that it is possible that ozone therapy had a beneficial effect but it is also possible that the study was too small to detect a difference in outcome between the two groups.

Ozone has been investigated for other uses in cancer patients. These include the treatment of obstructive jaundice in 90 patients with gastro-intestinal tumours.31 A single case report described intravesical instillation of ozonized water in a patient with progressive radiation-induced haematuria.32 Another report suggested possible beneficial effects in prevention of postoperative gastrointestinal ulcers in 86 colorectal cancer patients.33 Osteonecrosis of the jaw has also been reportedly managed with treatments including ozone in myeloma patients (n=12, 34 and n=1, 47) as well as a separate series of 10 patients with bone metastases.35 The most recent report is a preliminary findings on the effects of ozone by rectal insufflations and/or by local application of ozonized-oil, in 19 patients with severe and/or refractory radiation-induced hemorrhagic proctitis.36 To date, none of these preliminary findings have been confirmed with randomised controlled trials.

Pre-clinical studies

Animal studies

Studies involving ozone-oxygen in animal cancer models have been conducted since the 1970s.37 One recent study involved peritoneal insufflations of an ozone/oxygen gas mixture compared with oxygen in rabbits with squamous cell carcinomas at an advanced stage. More rabbits in the ozone group survived and showed tumour regression and absence of lung metastases. The mechanism of action was unclear.38 A further animal study suggested that pre-treatment with intraperitoneal ozone reduce tissue damage in the ileum due to the cytotoxic agent, methotrexate.39

In-vitro studies

A series of in-vitro studies have shown effects such as a dose-dependent inhibition of the growth of human cancer cells from lung, breast, and uterine tumours,40 a potential radiosensitising effect and selective cytotoxic action on ovarian carcinoma cells,41 inhibition of proliferation of human neuroblastoma cells,42 a synergistic effect of ozone with 5-fluouracil43 and inhibition of the proliferation of neuroblastoma cells.44

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.45

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 Italy.46 Ozone therapy has also been associated with a case of dangerously lowered blood cell counts and one case of an HIV patient experiencing psychotic hallucinations.6

Shortness of breath, blood vessel swelling, poor circulation, heart problems or stroke have been reported. Insufflation into the ear may damage the eardrum, and rectal insufflations may increase the risk of bowel rupture.6 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.2,9 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 administration.4

Contraindications

Theoretical contraindications include the following:9
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

Interactions with other drugs, herbs or therapies have not been reported.4

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

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