Signe E. Beebe, DVM, CVCMP
American Journal of Traditional Chinese Veterinary Medicine, Oak Harbor, WA, USA
What is ozone?
Ozone (O3) is a chemically unstable gas consisting of three atoms of oxygen and is a potent antioxidant. This is in comparison to oxygen (O2) that we breathe, which is a very stable gas and has only two atoms of oxygen. O3 occurs naturally in the stratosphere and acts as a filter to protect the Earth from harmful ultraviolet radiation. O3 can also be formed from electrical discharges that catalyze the formation of ozone from atmospheric oxygen during lightning strikes and can often be smelled after a storm. As O3 is a highly reactive and unstable form of oxygen, it cannot be stored, and due to its instability, the half-life of ozone is temperature dependent and quite short (at 20°C, O3 concentration will be reduced by half within 40 minutes), upon which it reverts back to the more stable form of oxygen.1-3 The instability of ozone makes it want to achieve a more stable form by giving away its additional oxygen atom via oxidation. This free oxygen atom is then able to combine with different chemicals/tissues in the body, and it is this property that makes ozone so valuable for medical use. The word “ozone” comes from the Greek word “ozein,” which means “smell,” and was first isolated by the German-Swiss chemist Christian Friedrich Schönbein in the mid-nineteenth century.4
The effects of O3 have been studied and recorded for over 150 years, and the medical use of O3 for water treatment and disinfection and its antimicrobial properties have been well documented.1-3 O3 was initially used as a microbicidal molecule in 1856 and subsequently used as an operating room disinfectant and in water treatment. The use of O3 has since been expanded for use as a medical modality, and its use today is based on its antioxidant, immunostimulant, antimicrobial, and anti-protozoal properties, and current research shows the potential use of O3 to treat HIV and as a treatment for cancer and individuals undergoing chemo and radiation therapy.5-7
Medical O3
Medical O3 (also known as oxygen-ozone therapy) is produced by a medical generator that uses high-voltage electrical discharge as the source of energy to produce a standardized medical oxygen-ozone gas. Medical O3 concentration should be composed of no less than 95% O2 and no more than 5% O3. 2,8 In this process, oxygen molecules are pulled apart and reorganized in the form of O3. Ozone has been shown to have a paradoxical mechanism of action. Chronic inflammatory processes are characterized by high oxidative stress, reactive oxygen species, suppression of antioxidant capacity, and immunologic dysregulation, each of which, in turn, creates a perpetual cycle of promotion and maintenance of the inflammatory process. In these cases, medical O3 therapy is thought to act as a bioregulator to help control and stop these chronic processes.9-12
Ozone Paradoxical Mechanism of Action O3
Ozone paradoxical mechanism of action O3 is one of the most powerful known oxidizing agents known.1,12-14 O3, as an oxidant, shows a paradoxical activity when it comes into contact with organic molecules, causing a powerful antioxidant response. Antioxidants are critical for the maintenance of cellular integrity and cytoprotection. Once O3 contacts body fluids and tissues, it rapidly reacts with all macromolecules (lipids, proteins, carbohydrates, and DNA) of the cellular membranes15 to create hydrogen peroxide (ROS-reactive oxygen species) and a mixture of lipid ozonation products (LOP). These two important groups of by-products, ROSs rapidly stimulate important biochemical processes in the early phase, and LOPs, in the later phase, act as secondary messengers to promote and modulate the nuclear factor-erythroid-derived 2-related factor 2 (Nrf2) pathway.
Nrf2 is a key transcription factor that coordinates the expression of genes encoding antioxidant and detoxifying enzymes and stimulates the synthesis of several substances, such as γ-glutamyl transferase, γ-glutamyl transpeptidase, HSP-70, HO-1, and antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase, and glucose-6-phosphate dehydrogenase (G6PDH). This process represents the basis of the paradoxical phenomenon for which an oxidizing molecule, such as O3, triggers a potent antioxidant reaction.9-15 At a therapeutic dose, O3 acts as a modulator or pro-drug and, by inducing secondary messengers, facilitates the ensuing adaptive responses by the body. The main goal behind the use of repeated O3 treatments is to create resistance against oxidative stress (oxidative preconditioning) through the stimulation of the antioxidant system to produce cytoprotective effects in order to help treat and control different pathological conditions, including cancer.14-17
Ozone has been shown to optimize oxygen levels (increases/improves tissue oxygenation and efficiency), enhance overall metabolism and blood circulation, is immunomodulatory, (regulates/balances the immune system), mediates oxidative stress (anti-oxidant/prevention of cellular damage), and has potent anti-inflammatory (decreases pain and swelling) and anti-microbial (kills bacteria, viruses, fungi) activity.1-3,7,12,14 The primary actions of ozone therapy include increased oxygen efficiency, immune modulation, mediated oxidative stress, improved microcirculation, and pain relief.
Ozone and Cancer
At a therapeutic dose, ozone can increase oxygenation of cancer cells to prevent and decrease tumor growth. It also modulates oxidative stress by inducing secondary messengers that activate a number of physiological processes to protect the body against the toxic effects of chemo/radiation therapy while protecting normal cells and body systems and can promote a higher quality of life for cancer patients post-chemo/radiation therapy. Tumor ischemia and tumor hypoxia are well-known factors in the development and growth of cancer cells, according to the Warburg effect. These factors promote resistance to radiotherapy and chemotherapy as well as the progression and development of metastasis. Ozone can cause an increase in tumor oxygenation by several mechanisms that include enhancement of blood oxygen saturation, induction of vasodilation that increases blood flow to the tumor, and a reduction in blood viscosity or clotting. Other properties of ozone that make it effective against cancer include its potent immunomodulatory and antioxidant properties. It also has significant anti-inflammatory actions where it has been shown to inhibit inflammatory cytokines that are involved in the transformation of normal cells to malignancy in chronic conditions.14-17
Radiotherapy and chemotherapy mechanisms of action depend on the increase of intracellular free radicals and reactive oxygen species (ROS) to kill cancer cells. In general, the damage is mediated by ROS and high oxidative stress. Radiation and chemotherapy toxicity is mediated by a local perpetuation of the ischemic process, pro-inflammatory, and pro-oxidative status. The goal of using repeated O3 treatments is to create resistance against oxidative stress through the stimulation of the antioxidant system to control and stop these processes and prevent cell and tissue damage.15-17
Ozone Methods of Administration for the Treatment of Cancer
O3 generators today can generate a precise volume and oxygen-ozone concentration where ozone constitutes 3–5% of the total. The therapeutic effects of O3 are dose-dependent and safe when given by the recommended route. The same type of precautions for systemic administration of any medication should be taken when using medical O3. The use of the appropriate product or concentration of O3 for the condition is essential to avoid toxicity.1,2,12 Rapid administration is to be avoided, and breathing in O3 directly can be toxic to the lungs. Adverse effects occur when ozonation products overwhelm the body’s antioxidant system and can lead to toxicity that includes the formation of free radicals and reactive intermediates, induction of lipid peroxidation chain reaction, destruction of biomolecules and enzymes, and alteration of cellular membranes with tissue destruction.16
O3 can be administered via the systemic and local routes, and the volume of ozone will be different depending on the route of administration. Ozone can be administered topically or locally (applied directly in oils or in water to the ears, skin, and legs), subcutaneously (alone or mixed in saline given under the skin), insufflation (ozone is blown into a body cavity: rectally, vaginally, into the urinary bladder, and nasal cavity) intra-articular (in joints), and intravenously. Ozone is very safe when used/administered correctly by a licensed medical professional.
Major Autohemotherapy (MAHT)
This term is used to describe O3 therapy as applied to the blood. It is considered to have immunomodulatory, anti-inflammatory, and analgesic effects. A small amount of blood is taken from the patient, mixed with a specific concentration of ozone, and then intravenously infused back into the patient. The ozonized blood is typically a much brighter red than the drawn blood. MAHT has been used to treat antibiotic-resistant skin infections in dogs, chronic active hepatitis, chronic antibiotic-resistant UTI, immune deficiency, and cancer.
Ultra-Immunotherapy or Ultraviolet Blood Irradiation (O3UV)
O3UV is known as ultra-immunotherapy or ultraviolet blood irradiation and is similar to MAHT, except that the ozone-blood mixture is then passed through UV light before it is re-infused back into the patient. UV light is a spectrum of ultraviolet light that kills cancer cells, viruses, bacteria, and fungi. The use of this application is similar to MAHT and is more effective in cases with immune deficiency and dysregulation and is the choice for immune-mediated diseases and cancer. The technique described here is from O3Vets. An IV bag using 1 ml/lb of saline and blood from the patient using a heparinized syringe is added to the bag. The IV bag with the saline, blood, and ozone is then passed through the UVB light and is then re-introduced to the patient intravenously. The frequency of administration depends on the severity of the cancer.
Rectal Ozone
Rectal ozone administration is used for treating gastrointestinal, pancreatic, prostate, and bladder cancers. Ozone is administered rectally through an ozone rectal catheter, where it is immediately absorbed into the surrounding tissues. The systemic effects of rectal ozone have recently been compared to MAHT and have been found to be similar in effectiveness in treating many of the same conditions, including cancer.
Minor Autohemotherapy (mAHT)
Minor autohemotherapy (mAHT) is the intramuscular injection of ozonized blood, using equal parts ozone and blood. The mixture is shaken to obtain a homogenous blend of ozone and blood and then injected into the muscles. This method is often used to treat cancer, IVDD, dermatitis, wounds, allergies, and local pain. It can also be used in acupuncture points for an enhanced effect.
Ozone Gas Injection
Ozonated gas can be injected directly into, around, and under tumors to shrink them on a weekly or twice-weekly basis. Ozone can be injected intra-lesionally; however, it may cause a significant inflammatory response. Therefore, it is recommended to first inject around or around the tumor for an effect before doing intra-lesional therapy and begin intra-lesional by using a smaller dosage to begin.
Local or Topical Therapy
Local or topical therapy includes the use of ozonated creams, oils, water, or saline. Topical ozonated oils and creams can be applied to the surface of the body for skin disorders or for skin cancers and wound healing. The use of ozone bagging is especially helpful for skin cancer, cancer of the extremities, skin infections, and non-healing wounds. Its application is in the form of a transcutaneous O3 gas bath in a closed system, so there is no escape of O3 into the surroundings; breathing in the gas is to be strictly avoided.
Ozonated Saline Infusion
This technique can be used to treat tumors of the vaginal canal or urinary bladder, where saline is directly infused into these areas to treat tumors. Ozone infusions can also be used to flush eyes, ears, and wounds; udder/mammary gland infections; to clean infections; and, in surgery, as an abdominal rinse and have routinely been used by many practitioners in dental procedures and for rinsing the mouth following regular prophys.
Ozone Infiltration
Ozone infiltration refers to the administration of ozone gas directly into different tissues of the body. It can be given subcutaneously, intra-muscularly, intra-articular, peri-articular, intra-discal, and intra-lesional. This technique is used to treat disorders of the musculoskeletal system, such as skin cancer, non-healing wounds, lick granuloma, herniated disk, osteoarthritis, tendinitis, and back and neck pain.
How Often is Ozone Therapy Given?
This depends on the type and severity of the cancer/condition and route of administration. In general, UVO3 and MAHT are given every three to four weeks; however, in severe cases, they may be administered once or twice weekly and then tapered.
There are few research studies available on medical O3 therapy in veterinary medicine, and most of the current literature is specific to its use in humans. Two excellent systematic reviews of the current literature on the use of O3 therapy in veterinary medicine were published in 2020 and 2021. Both of these reviews discussed the application of O3 therapy in multiple species. O3 therapy in veterinary medicine is in the early stages of development, and the information presented here can be expected to change as more research becomes available.
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