Ozone (O₃) as a Therapeutic Agent: A Comprehensive Pharmacological and Clinical Review

1. Executive Summary

Ozone (O3​), a triatomic allotrope of oxygen, presents one of the most significant paradoxes in modern pharmacology. Widely recognized as a toxic atmospheric pollutant and a potent industrial disinfectant [1], it is simultaneously investigated and applied in various medical contexts as a therapeutic agent.[3] This report provides a comprehensive analysis of ozone (DrugBank ID: DB12510), synthesizing the available evidence on its chemical properties, pharmacological mechanisms, clinical efficacy, safety profile, and deeply divided global regulatory status.

The therapeutic rationale for ozone is not based on classical receptor-ligand interactions but on the principle of hormesis. When administered in controlled, non-toxic doses via specific non-pulmonary routes, medical ozone induces a mild and transient oxidative stress. This controlled biochemical challenge does not cause damage but instead triggers a cascade of adaptive responses within the body.[3] The molecule itself reacts almost instantaneously with biological fluids, generating secondary messengers—primarily reactive oxygen species (ROS) like hydrogen peroxide (

H2​O2​) and lipid oxidation products (LOPs). These messengers subsequently activate the master regulator of the endogenous antioxidant system, Nrf2, leading to the upregulation of a wide array of protective enzymes. This mechanism effectively enhances the body's resilience to oxidative stress, modulates immune responses, and improves microcirculation and oxygen delivery.[6]

Clinical evidence for ozone therapy is most prominent in musculoskeletal and pain disorders, particularly for herniated lumbar discs and knee osteoarthritis. Multiple meta-analyses report outcomes comparable to surgical discectomy for herniated discs, with a significantly lower risk of complications.[7] Similarly, systematic reviews suggest efficacy in pain reduction for osteoarthritis.[9] Evidence also supports its use in accelerating the healing of chronic wounds, such as diabetic foot ulcers.[11] However, a critical examination reveals a consistent pattern across these fields: the body of evidence, while quantitatively substantial, is qualitatively weak. The positive findings are frequently derived from primary studies with significant methodological flaws and a high risk of bias, precluding definitive conclusions about efficacy.[9]

This evidentiary ambiguity is reflected in a profound global schism in regulatory acceptance. In the United States, the Food and Drug Administration (FDA) maintains a strict prohibitive stance, classifying ozone as a "toxic gas with no known useful medical application" and actively prosecuting its unapproved medical use.[1] In stark contrast, many European nations, including Germany, Spain, and Italy, permit its use, and the European Medicines Agency (EMA) lists it as an authorized active substance.[13] This divergence underscores the central conflict between ozone's established toxicological profile and its proposed therapeutic potential.

In conclusion, ozone therapy occupies a controversial and scientifically intriguing space. It is a modality whose safety and efficacy are critically dependent on precise control over dose and administration route, distinguishing its medical application from environmental exposure. To transition from a fringe therapy to an evidence-based medical tool, the field must address the persistent lack of high-quality, methodologically robust clinical trials.

2. Compound Identification and Physicochemical Profile

A comprehensive understanding of ozone's therapeutic application begins with its fundamental chemical and physical identity. Its properties as a highly reactive gas inform both its industrial utility and the biological mechanisms and safety concerns associated with its medical use.

2.1. Chemical Identity and Nomenclature

Ozone is an elemental molecule and an allotrope of oxygen, composed of three oxygen atoms. Its molecular formula is O3​.[15] It is commonly referred to as triatomic oxygen.[17] In the DrugBank database, it is registered under the accession number DB12510.[19] Its primary Chemical Abstracts Service (CAS) registry number is 10028-15-6.[16] The molecule is recognized by numerous synonyms across different languages and databases, including "ozono," "trioxygen," "Ozon," and "trioxygene".[18] Its formal IUPAC name is "ozone".[18] A consolidated list of its key identifiers is provided in Table 1.

2.2. Physical and Chemical Properties

At standard temperature and pressure, ozone is a colorless to pale blue gas with a characteristic, pungent odor that is detectable by humans even at low concentrations (less than 2 ppm).[18] It is an unstable molecule that can condense into a dark blue liquid or form blue-black crystals.[3] With a molecular weight of approximately 48.00 g/mol, it is heavier than air and is only very slightly soluble in water.[15]

Chemically, ozone is defined by its powerful oxidizing capability.[19] This high reactivity is the basis for its classification as an oxidant, a photochemical oxidant, and a noxa (a harmful or toxic substance).[19] It belongs to the chemical class of "other non-metal oxides," which are inorganic compounds containing an oxygen atom in a -2 oxidation state bonded to another non-metal.[19]

2.3. Industrial and Commercial Uses

The potent, non-specific reactivity of ozone has led to its widespread use in various industrial and commercial applications that predate its medical investigation. It is a highly effective disinfectant for air and water, an antimicrobial agent, and a bactericide.[15] Its applications in water treatment include disinfection, color removal, and control of taste and odor in bottled drinking water and swimming pools.[15] It is also employed as a potent bleaching agent for waxes, oils, textiles, and paper.[15] Other uses include detoxification of cyanide wastes, organic chemical synthesis, and serving as an inhibitor of mold and bacteria in cold storage environments.[17]

This well-established industrial profile is fundamental to understanding the controversy surrounding its medical use. The very properties that make ozone a valuable industrial tool—its capacity for aggressive, non-specific oxidation and destruction of organic matter—are the primary source of skepticism and regulatory concern in a medical context. Regulatory bodies like the U.S. FDA and EPA have developed their safety standards based on this destructive potential, particularly the well-documented toxicity associated with inhalation.[1] Their perspective is firmly rooted in toxicology, which views ozone as a harmful substance to be avoided. In contrast, proponents of ozone therapy advocate for a paradigm of hormesis, where a low, controlled dose of the same substance is proposed to elicit a beneficial, regulatory biological response rather than damage.[3] This creates a profound conceptual clash. The burden of proof lies with medical proponents to demonstrate that controlled administration via specific, non-pulmonary routes fundamentally alters the molecule's biological effect from one of indiscriminate destruction to one of precise, therapeutic modulation. The entire debate hinges on this repositioning of a known industrial oxidant into a nuanced biological response modifier.

Table 1: Chemical and Physical Identifiers for Ozone (DB12510)

Identifier Type	Value	Source(s)
Generic Name	Ozone	19
DrugBank ID	DB12510	19
CAS Number	10028-15-6	17
Molecular Formula	O3​	15
Molecular Weight	48.00 g/mol	15
IUPAC Name	ozone	18
InChIKey	CBENFWSGALASAD-UHFFFAOYSA-N	19
UNII	66H7ZZK23N	18
Appearance	Colorless to bluish gas; dark blue liquid; blue-black crystals	18
Odor	Characteristic, pungent odor at <2 ppm	18
Water Solubility	Very slightly soluble	20
Key Classifications	Oxidant, Gas, Noxa, Photochemical Oxidant	19

3. Pharmacological Profile: The Paradox of a Pro-Oxidant Therapy

The mechanism of action of medical ozone is fundamentally different from that of conventional pharmaceuticals. It does not operate through specific receptor binding but rather as a biological response modifier, leveraging the principle of hormesis to induce a cascade of adaptive physiological responses. This process is initiated by a controlled oxidative challenge that paradoxically enhances the body's own antioxidant, anti-inflammatory, and regenerative capacities.

3.1. The Principle of Hormesis: A Controlled Biochemical Challenge

At the core of ozone therapy is the concept of hormesis, wherein a low dose of a substance that is toxic at high doses can induce a beneficial, adaptive response.[3] The therapeutic efficacy of ozone is entirely dependent on the administration of a dose sufficient to create a mild, transient, and controlled oxidative stress.[5] This carefully calibrated stress acts as a signal, activating the body's protective mechanisms. The distinction between a therapeutic effect and a toxic one is therefore a direct function of the administered dose and concentration.[22] A moderate level of oxidative stress activates protective nuclear transcription factors like Nrf2, whereas a severe oxidative stress would overwhelm cellular defenses and activate pro-inflammatory pathways, such as those mediated by NF-κB, leading to tissue injury.[5]

3.2. Formation of Secondary Messengers: ROS and LOPs

A crucial aspect of ozone's pharmacology is that the ozone molecule itself does not enter the systemic circulation or cells when administered via methods like autohemotherapy.[22] It is highly reactive and dissolves in the aqueous component of plasma, where it reacts almost instantaneously (in less than a second) with available biomolecules.[3] Its primary targets are the polyunsaturated fatty acids (PUFAs) present in cell membranes and lipoproteins, as well as antioxidants and water.[3]

This initial reaction generates a cohort of secondary messengers that are the true effectors of the therapy. These messengers fall into two main categories:

1. Reactive Oxygen Species (ROS): The principal ROS formed is hydrogen peroxide (H2​O2​), a well-known intracellular signaling molecule.[3]
2. Lipid Oxidation Products (LOPs): A mixture of ozonated lipid derivatives is created, including aldehydes like 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), as well as lipoperoxyl radicals, hydroperoxides, and ozonides.[3]

These ROS and LOPs, which are chemically similar or identical to molecules produced endogenously during normal metabolic and signaling processes, then circulate throughout the body and transduce the therapeutic signal. This mechanism positions ozone not as a traditional pro-drug, which is typically converted into an active form by enzymes, but as a unique trigger for a cascade of reactive chemical messengers that hijack and amplify the body's own redox signaling pathways.[4] This model explains the broad, pleiotropic effects of the therapy; by activating master regulatory pathways, it can influence a wide range of downstream cellular processes.

3.3. Upregulation of Endogenous Antioxidant Systems via the Nrf2 Pathway

The moderate oxidative stress signaled by the generated H2​O2​ and LOPs serves as a potent activator for the transcription factor Nuclear factor-erythroid 2-related factor 2 (Nrf2).[3] Nrf2 is the master regulator of the cellular antioxidant response.[5] Upon activation, Nrf2 translocates to the cell nucleus and binds to Antioxidant Response Elements (AREs) in the promoter regions of numerous target genes.[3]

This binding initiates the transcription and subsequent synthesis of a broad spectrum of protective enzymes. These include key antioxidant enzymes such as Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx), and Glutathione-S-transferase (GSTr), as well as stress-response proteins like Heme-oxygenase-1 (HO-1) and Heat Shock Proteins (HSP).[5] The result is a significant enhancement of the body's total antioxidant capacity. This process, often termed "oxidative preconditioning," makes cells more resilient to subsequent, more severe oxidative insults, which is a key mechanism in counteracting the chronic oxidative stress characteristic of many degenerative diseases.[6]

3.4. Immunomodulatory and Anti-inflammatory Effects

The secondary messengers generated by ozone exert complex, dose-dependent effects on the immune system. The H2​O2​ produced can diffuse into immune cells and act as a second messenger, modulating various signaling pathways.[6] At low concentrations, this can lead to a controlled activation of the immune system, including increased production of important signaling cytokines such as interferon (IFN), tumor necrosis factor (TNF-α), and interleukins like IL-2 and IL-8.[6] This can enhance the body's ability to fight infections.

Conversely, in the context of chronic inflammation, ozone therapy can exhibit potent anti-inflammatory effects. Studies in models of rheumatoid arthritis have shown that ozone application can significantly decrease the levels of key pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α.[6] This dual-action capability—stimulating immune response in some contexts while suppressing inflammation in others—is characteristic of a biological response modifier. The balance appears to be mediated by the differential activation of transcription factors; moderate stress favors the activation of protective Nrf2 and may suppress the pro-inflammatory NF-κB, whereas severe stress would strongly activate NF-κB and drive inflammation.[5]

3.5. Vascular, Hematological, and Oxygen-Delivery Enhancements

Ozone therapy has been shown to produce significant beneficial effects on blood rheology and oxygen transport, which is particularly relevant for treating ischemic conditions.[3] The mechanisms are multifaceted:

• Improved Oxygen Unloading: In red blood cells, ozone administration can increase the rate of glycolysis, leading to higher levels of 2,3-Diphosphoglycerate (2,3-DPG). Increased 2,3-DPG shifts the oxyhemoglobin dissociation curve to the right, which weakens the bond between hemoglobin and oxygen and facilitates the release of oxygen into peripheral tissues.[6]
• Vasodilation: Ozone can stimulate the production of vasodilators. This includes increasing levels of prostacyclin, a potent vasodilator, and activating nitric oxide synthase (NOS), which increases the production of nitric oxide (NO), another key mediator of vasodilation and improved blood flow.[6]
• Enhanced Microcirculation: The combination of vasodilation and changes to the physicochemical properties of blood leads to improved microcirculation, increasing perfusion and oxygen supply to tissues that were previously hypoxic.[6]

4. Clinical Evidence and Investigational Uses

The clinical application of ozone therapy spans a wide range of conditions, primarily focused on pain management, musculoskeletal disorders, and wound healing. The body of evidence supporting these uses is extensive but marked by significant variability in methodological quality. A critical analysis reveals a consistent pattern of promising results reported in systematic reviews and meta-analyses, which are often tempered by acknowledgements of low-quality primary data in the underlying trials.

4.1. Musculoskeletal and Pain Disorders: A Critical Review of Efficacy

4.1.1. Herniated Lumbar Disc Disease

Ozone therapy for herniated lumbar discs is one of its most well-documented applications. The primary administration method involves image-guided injection of an oxygen-ozone mixture directly into the disc (intradiscal) and/or the surrounding paravertebral muscles.[7] The proposed mechanism involves the oxidation of proteoglycans within the nucleus pulposus, which reduces their water-retaining capacity and leads to a shrinkage of the disc volume, thereby decompressing the affected nerve root.[7] Additional anti-inflammatory and analgesic effects also contribute to pain relief.[7]

A major meta-analysis covering almost 8,000 patients demonstrated statistically and clinically significant improvements in pain and function. The analysis reported a mean improvement of 3.9 points on the Visual Analogue Scale (VAS) for pain and 25.7 points on the Oswestry Disability Index (ODI) for function.[7] The likelihood of a positive outcome based on the modified MacNab scale was 79.7%.[7] Several studies have compared ozone injections to surgical discectomy, concluding that the efficacy is comparable or "non-inferior," but ozone therapy offers a significantly lower complication rate (less than 0.1% versus 3-6% for surgery) and a much shorter recovery time.[8] Based on this evidence, some researchers have proposed ozone injection as a first-line alternative to surgery for patients who have failed conservative treatment.[28] However, it is important to note that the level of evidence for long-term pain relief is considered moderate, and a significant limitation of the existing literature is the lack of placebo-controlled trials.[30]

4.1.2. Knee Osteoarthritis (KOA)

For knee osteoarthritis, ozone is typically administered via intra-articular injection. The therapy is believed to exert its effects by reducing intra-articular inflammation, counteracting the pro-oxidative environment of the arthritic joint, and stimulating the synthesis of chondrocytes and fibroblasts.[9] An umbrella review of systematic reviews concluded that ozone therapy has beneficial effects on pain control and a strong safety profile for KOA.[9] Multiple reviews have found it to be effective for reducing pain and inflammation and improving joint function, with the most pronounced effects observed in the short-term (up to 6 months).[10]

When compared to other intra-articular treatments, ozone has been shown to be superior to placebo for pain relief.[9] In direct comparisons with hyaluronic acid (HA), one review noted that ozone was slightly better for pain and stiffness, while HA was slightly better for functionality, though these differences were not statistically significant. Given that ozone therapy is considerably less expensive than HA, some authors suggest it as a more cost-effective option.[10]

The primary and most significant caveat in this area is the quality of the evidence. The same umbrella review that highlighted beneficial effects also used the AMSTAR2 instrument to assess the quality of the underlying systematic reviews and found that all of them were of "critically low confidence".[9] This rating was due to major methodological flaws in the primary randomized controlled trials (RCTs) they analyzed, including high risk of bias, lack of standardized treatment protocols, and inadequate reporting. This finding exemplifies the central challenge in evaluating ozone therapy: a large quantity of published data suggests efficacy, but the low quality of that data prevents the formation of definitive, evidence-based conclusions.

4.1.3. Other Pain Syndromes

Research into ozone's analgesic effects is ongoing for other conditions. A recruiting clinical trial (NCT06133712) is currently investigating the efficacy of local ozone injection as part of a combination treatment with dexamethasone and dexmedetomidine for pain relief in patients with Carpal Tunnel Syndrome.[31] This indicates continued interest in its potential for treating entrapment neuropathies and other localized pain syndromes.

4.2. Wound Healing and Dermatological Applications

Ozone therapy, particularly in topical forms such as ozonated water, ozonated oil, or "limb bagging," has been extensively studied for the treatment of chronic, non-healing wounds. Its therapeutic action in this context is attributed to a combination of potent antimicrobial activity, reduction of local inflammation, improvement of local microcirculation and oxygenation, and stimulation of growth factors like Vascular Endothelial Growth Factor (VEGF).[32]

A systematic review and meta-analysis of nine RCTs involving 453 patients with chronic wounds (including diabetic foot ulcers, venous ulcers, and burns) found a statistically significant improvement in wound closure in groups treated with ozone compared to controls.[11] One study focusing on diabetic foot ulcers reported that the ozone therapy group had a higher overall wound healing rate, required fewer inpatient days, had a shorter duration of antibiotic use, and experienced lower rates of reinfection and readmission.[32] Mechanistic studies using ozonated oil have shown that it can accelerate wound healing by promoting the migration of fibroblasts, a key cell type in tissue repair, via the PI3K/Akt/mTOR signaling pathway.[34] While the results are consistently positive across studies, the systematic review concluded that there is not yet conclusive evidence to suggest that ozone therapy is definitively

superior to other standard or advanced wound care treatments, and called for further high-quality research.[11]

4.3. Dental and Post-Surgical Applications

The anti-inflammatory and antimicrobial properties of ozone have led to its investigation in dentistry and oral surgery. A completed clinical trial (NCT05875506) evaluated the efficacy of an ozone gel for the treatment of Dry Socket Syndrome (alveolar osteitis), a painful post-extraction complication, comparing it to standard treatments like doxycycline-saturated chitosan dressing and Alveogyl.[35] Another completed trial (NCT06900907) assessed the effects of different post-operative protocols, including ozone, hyaluronic acid, and methylprednisolone, on outcomes following the surgical extraction of impacted mandibular third molars.[36] These studies highlight an emerging role for ozone as an adjunct therapy to reduce pain, control infection, and promote healing in the post-surgical oral environment.

4.4. Neurological Applications: Emerging Research

The application of ozone therapy in neurological conditions is a newer and less developed area of research. A notable recruiting Phase 2 clinical trial (NCT06799351) is examining the gut microbiome profiles of patients with Chemotherapy-Induced Peripheral Neuropathy (CIPN) who are undergoing ozone therapy.[37] This trial is investigating ozone for the treatment of neuropathic symptoms like paresthesia (abnormal sensations) and hypoesthesia (reduced sensation). This research represents a novel direction, exploring systemic effects that may be relevant to complex neurological disorders.

Table 2: Summary of Key Clinical Trials for Ozone Therapy (DB12510)

ClinicalTrials.gov ID	Condition(s)	Purpose	Phase	Status	Other Drugs in Trial	Source(s)
NCT05875506	Dry Socket Syndrome (Alveolar Osteitis)	Treatment	Not Available	Completed	Doxycycline, Poliglusam	35
NCT06900907	Post-Surgical Extraction of Impacted Third Molars	Treatment	Not Available	Completed	Hyaluronic acid, Methylprednisolone	36
NCT06133712	Carpal Tunnel Syndrome	Treatment	Not Available	Recruiting	Dexamethasone, Dexmedetomidine	31
NCT06799351	Chemotherapy-Induced Peripheral Neuropathy (CIPN), Paresthesia, Hypoesthesia	Screening	2	Recruiting	None specified	37

5. Modalities of Therapeutic Administration

The administration of medical ozone is highly varied, with different methods designed to produce either systemic or localized effects. The choice of method is critical and depends on the condition being treated. A core principle across all legitimate methods is the strict avoidance of direct inhalation of ozone gas, which is toxic to the lungs.[38] The therapeutic mixture is typically composed of 95-99.5% medical-grade oxygen and only 0.5-5% ozone, with concentrations carefully controlled by a medical ozone generator.[21]

5.1. Systemic Therapies

These methods are designed to elicit effects throughout the body by introducing ozone's secondary messengers (ROS and LOPs) into the bloodstream.

• Major Autohemotherapy (MAH): This is the most prevalent and well-studied systemic method.[3] A volume of the patient's blood, typically 50-100 mL, is drawn into a sterile, vacuum-sealed container. A precise volume and concentration of an oxygen-ozone gas mixture is then added to the container, and the blood is gently mixed to allow for the reaction to occur ex-vivo. The ozonated blood, now containing the therapeutic secondary messengers, is then reinfused back into the patient intravenously.[38]
• Minor Autohemotherapy (mAH): This method is primarily used for immunostimulation. A much smaller volume of blood (e.g., 3-10 mL) is withdrawn, mixed with the oxygen-ozone gas, and then injected back into the patient intramuscularly (typically into the gluteal muscle). This process is thought to act as a form of auto-vaccine, modulating the immune system.[39]
• Rectal Insufflation: A specified volume of the oxygen-ozone gas mixture is slowly and gently introduced into the rectum via a catheter. The gas is absorbed by the rich vascular network of the intestinal mucosa and enters the portal circulation, allowing for systemic effects. This method is considered one of the safest systemic applications and is often used for general revitalization and in the treatment of intestinal disorders.[3]
• Ozonated Saline Infusion: In this technique, a physiological saline solution is saturated with ozone gas immediately prior to administration and then infused intravenously. This method is noted as being particularly common in Russia.[40]

5.2. Localized Injections

These methods deliver ozone directly to a specific site of pathology to achieve high local concentrations and targeted effects.

• Intra-articular Injection: The oxygen-ozone mixture is injected directly into the synovial space of a joint, such as the knee, shoulder, or hip. This is a common treatment for osteoarthritis, arthritis, and other joint diseases, aiming to reduce local pain and inflammation.[26]
• Intradiscal and Paravertebral Injection: This highly specialized technique is used for treating herniated discs. Under fluoroscopic or CT guidance, a needle is positioned into the nucleus pulposus of the affected disc, and a small volume of gas (e.g., 1-3 mL) is injected. This is often followed by a larger injection (e.g., 7-9 mL) into the adjacent paravertebral muscles to reduce muscle spasm and inflammation.[7]
• Other Injections: Ozone gas can also be injected subcutaneously (e.g., for cellulite), intramuscularly (for trigger points), or into soft tissues (peri-articular) to treat a variety of localized pain and inflammatory conditions.[39]

5.3. Topical and Other Methods

These methods apply ozone externally to the skin or into body cavities.

• Ozone Bagging (Limb Bagging): This non-invasive method is used for treating conditions on the extremities, such as diabetic foot ulcers, gangrene, burns, and severe skin infections. The affected limb is enclosed in an ozone-resistant plastic bag, which is then filled with the oxygen-ozone gas mixture for a set duration. The skin is typically moistened beforehand to facilitate the reaction of ozone with the tissue surface.[38]
• Ozonated Water and Oil: Ozone gas can be bubbled through water or oils (like olive oil) to create ozonated liquids. Ozonated water is used as a disinfectant wash for wounds, burns, and in dental surgery. Ozonated oil, which is more stable, is applied as a topical salve or balm for various skin conditions, providing a low-dose, long-term exposure.[38]
• Insufflation (Non-Rectal): Using specialized devices, ozone gas can be introduced into other body cavities, such as the ear canal (aural insufflation), vagina, or bladder, for treating local infections and inflammatory conditions.[39]
• Ozone Steam Sauna: This method combines steam therapy with transdermal ozone application. The patient is seated in a cabinet where the body is exposed to steam, which opens the pores of the skin. Ozone is then introduced into the cabinet, allowing it to be absorbed through the skin into the bloodstream, fat, and lymphatic system.[39]

Table 3: Overview of Ozone Therapy Administration Methods

Method	Description of Procedure	Primary Clinical Application(s)	Key Considerations/Risks	Source(s)
Major Autohemotherapy (MAH)	50-100 mL of blood is ozonated ex-vivo and reinfused intravenously.	Systemic diseases, circulatory disorders, viral diseases, immune modulation.	Requires sterile technique; risk of contamination if performed improperly. No free gas is infused.	38
Minor Autohemotherapy (mAH)	3-10 mL of blood is ozonated ex-vivo and injected intramuscularly.	Immunostimulation, allergic diseases.	Acts as an autovaccine. Standard risks of intramuscular injection.	40
Rectal Insufflation	Oxygen-ozone gas is introduced into the rectum via a catheter.	Systemic effects, intestinal diseases (e.g., colitis), liver support.	Considered very safe; non-invasive systemic option.	3
Intra-articular Injection	Oxygen-ozone gas is injected directly into a joint capsule.	Osteoarthritis, arthritis, joint pain, and inflammation.	Requires precision; risk of joint infection if not sterile.	26
Intradiscal Injection	Gas is injected into the disc nucleus and/or paravertebral muscles under imaging guidance.	Herniated discs, low back pain.	Highly specialized procedure; requires imaging guidance for safety and accuracy.	7
Limb Bagging	An extremity is enclosed in a bag filled with ozone gas.	Non-healing wounds, diabetic ulcers, skin infections, gangrene.	Non-invasive; skin must be moist. Exhaust gas must be safely removed.	38
Ozonated Oil/Water	Ozone is bubbled through oil or water for topical application or irrigation.	Skin conditions (eczema, fungi), wound disinfection, burns.	Ozonated oil provides stable, low-dose application. Water is used for immediate disinfection.	38

6. Safety, Toxicology, and Risk Mitigation

The safety profile of ozone is a subject of intense debate and is central to its controversial status. A nuanced analysis requires a clear distinction between the well-established toxicity of inhaled, environmental ozone and the specific risks associated with its controlled administration in a medical setting via non-pulmonary routes. The safety of ozone therapy is not an intrinsic property of the molecule itself but is critically dependent on the dose, concentration, route of administration, and the skill of the practitioner.

6.1. Inhalation Toxicity and Environmental Health Standards

There is universal scientific consensus that inhaling ozone is toxic to the respiratory system.[2] Ozone is a potent pulmonary irritant that causes oxidative damage to the delicate tissues of the lungs.[2] Even at the low concentrations found in urban smog, exposure can cause chest pain, coughing, shortness of breath, and throat irritation. It can also exacerbate chronic respiratory conditions like asthma and increase susceptibility to respiratory infections.[2]

Reflecting these dangers, government agencies have established strict safety limits for ozone in ambient air and workplaces. The U.S. Occupational Safety and Health Administration (OSHA) limits worker exposure to an 8-hour time-weighted average of 0.10 parts per million (ppm). The Environmental Protection Agency (EPA) has set the National Ambient Air Quality Standard for ozone at a maximum 8-hour average concentration of 0.08 ppm.[2] Furthermore, the Food and Drug Administration (FDA) mandates that any indoor medical device must not produce ozone at a level exceeding 0.05 ppm.[2] These standards are based on the clear evidence of harm from inhalation and form the toxicological foundation for the FDA's deeply skeptical stance on any medical use of ozone.

6.2. Risks Associated with Medical Administration

When ozone is administered for medical purposes, the route of exposure is fundamentally different, and therefore, so is the risk profile. Legitimate ozone therapy protocols strictly prohibit inhalation.[38] However, improper administration via other routes can lead to serious adverse events.

• Gas Embolism: This is the most severe and widely cited risk. It can occur if the oxygen-ozone gas mixture is injected directly and rapidly into a blood vessel (intra-arterial or intravenous). The gas bubbles can travel through the circulation and block blood flow to vital organs, which can be fatal. This method of direct intravenous gas injection is now considered malpractice by the vast majority of ozone practitioners and professional societies.[1] Modern systemic methods like Major Autohemotherapy are designed to prevent this by mixing the gas with blood outside the body before reinfusion, ensuring no free gas enters the patient's circulation.[22]
• Hemolysis: High concentrations of ozone can cause oxidative damage to the membranes of red blood cells, leading to their rupture (hemolysis). This risk is mitigated by using appropriate, non-toxic concentrations of ozone in the therapeutic gas mixture.[44]
• Other Risks: As with any injection-based procedure, there is a risk of infection if sterile equipment and techniques are not used.[44] Some individuals may experience localized pain or irritation at the injection site. Allergic reactions are considered rare.[44] On direct contact, liquefied ozone can cause severe irritation and chemical burns to the skin and eyes.[20]

6.3. Documented Contraindications

There are specific medical conditions in which ozone therapy is considered unsafe and should not be administered.

• Absolute Contraindications:
• Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (Favism): Individuals with this genetic enzyme deficiency have red blood cells that are highly susceptible to oxidative stress. Ozone therapy could trigger massive hemolysis in these patients.[32]
• Uncontrolled Hyperthyroidism: The therapy may overstimulate an already hyperactive thyroid gland.[45]
• Leukemia: This is listed as a definite contraindication.[45]
• Relative Contraindications: Conditions where ozone should be used with extreme caution or may be contraindicated depending on the patient's specific state include pregnancy, severe anemia, severe coagulation disorders, acute alcohol intoxication, and recent myocardial infarction.[45]

6.4. Distinguishing Inherent Adverse Events from Malpractice

Proponents of ozone therapy argue that when administered according to established, safe protocols by properly trained professionals, the therapy has an exceptionally high safety record.[45] A meta-analysis of nearly 8,000 patients undergoing ozone treatment for herniated discs reported a complication rate of just 0.064%.[7] It is argued that nearly all severe complications reported in the literature are the result of malpractice—specifically, the use of dangerous and outdated techniques like direct intravenous gas injection—rather than an inherent risk of controlled, modern methods.[1] This distinction is critical. The safety debate is not simply about whether the

O3​ molecule is toxic, but whether specific medical procedures can harness its reactivity for therapeutic benefit without causing harm. The evidence suggests that while the potential for harm is real and significant if protocols are not followed, the risk can be effectively mitigated with proper training, equipment, and adherence to contraindications.

7. Global Regulatory Status and Ethical Considerations

The regulatory landscape for ozone therapy is one of the most polarized in modern medicine, characterized by a stark divide between prohibitive policies in some countries and widespread acceptance or investigation in others. This schism reflects the ongoing tension between ozone's toxicological profile and its purported therapeutic benefits, as well as the varying quality of the scientific evidence presented to different regulatory bodies.

7.1. The United States FDA: A Position of Prohibition and Enforcement

In the United States, the Food and Drug Administration (FDA) maintains a clear and unwavering position of prohibition against the medical use of ozone. This stance was first formalized in 1976 and has been consistently reiterated, with the agency stating that "ozone is a toxic gas with no known useful medical application in specific, adjunctive, or preventive therapy".[1] The FDA's regulation (21 CFR 801.415) explicitly forbids the use of ozone in any medical condition for which there is no proof of safety and effectiveness.[1]

The agency's reasoning is rooted in toxicological principles, emphasizing that for ozone to be effective as a germicide, it must be present in concentrations far greater than can be safely tolerated by humans and animals.[1] This position primarily addresses the dangers of inhalation but is applied broadly to all medical uses. The FDA has backed this stance with enforcement actions, and since 1991, has prosecuted and incarcerated individuals who have marketed ozone therapy products as medical cures or operated clinics offering ozone for human illness.[1] Despite this federal prohibition, the regulatory environment at the state level can be ambiguous. Some state medical boards may not regulate specific procedures performed in a physician's office but will caution practitioners that using a non-FDA-approved therapy is considered experimental and that any patient complaints would be a cause for serious concern.[47] This has allowed some clinics to operate in a gray area, offering ozone therapy as an "alternative" or "integrative" treatment, with the explicit disclaimer that it is not FDA-approved.[49]

7.2. The European Union and EMA: A Heterogeneous Landscape

The regulatory environment in Europe is markedly different and far more permissive. There is no single, EU-wide prohibition on ozone therapy. Instead, its regulation is handled at the national level, resulting in a heterogeneous landscape of acceptance and practice. The therapy has a long history of use, particularly in Germany, Switzerland, Italy, and Spain.[13] In Spain, for example, ozone therapy is integrated into the services of pain units and diabetic foot units within the public hospital system.[14]

The European Medicines Agency (EMA), the EU's centralized drug regulatory body, includes ozone on its list as an "authorized active substance" and has active research projects involving ozone listed in its clinical trial registry.[14] This indicates a regulatory acknowledgement of ozone as a substance with potential medical relevance, in stark contrast to the FDA's position. The European Parliament has also been formally questioned regarding the status of ozone therapy, its benefits, and whether member states could be urged to make more regular use of it, signaling a level of political and scientific interest in its potential.[13] Ozone therapy often falls into a category between a medicinal product and a medical procedure, which can complicate regulation and leads to the varied approaches seen across different member states.

7.3. International Perspectives and Legalization Trends

Outside of the US and Europe, the status of ozone therapy is also varied. In 2023, the Brazilian government officially legalized ozone therapy as a "complementary therapy." This decision was made despite an open letter from the Brazilian National Academy of Medicine requesting a veto due to what it cited as a lack of sufficient scientific evidence.[1] This case highlights a trend where political or public demand can influence regulatory decisions, sometimes in opposition to the consensus of mainstream medical bodies. The therapy has also been used for decades in countries like Cuba and Russia, where methods such as ozonated water have been developed and applied for a variety of intestinal and gynecological conditions.[38]

7.4. The Controversy: Unproven "Quackery" vs. Legitimate Medical Tool

This deep regulatory divide fuels an ongoing and often acrimonious debate. Skeptics and major medical organizations, such as the American Cancer Society, have characterized ozone therapy as "pure quackery," especially when it is promoted with unsubstantiated claims as a cure for serious diseases like cancer or HIV/AIDS.[1] This view is bolstered by the FDA's strong prohibitive stance and the low quality of much of the existing clinical research.

On the other side, proponents argue that ozone therapy is not "alternative medicine" but a practice based on sound biochemical and physiological principles.[21] They point to the large volume of scientific literature available on platforms like PubMed and contend that the therapy has an excellent safety record when performed correctly by trained professionals.[13] This conflict creates significant ethical considerations for clinicians and patients. The use of a non-approved therapy requires rigorous informed consent, where the patient is made fully aware of the regulatory status, the potential risks, and the limitations of the supporting scientific evidence.

Table 4: Comparison of Regulatory Stances on Medical Ozone

Region/Agency	Official Stance	Key Regulatory Statements/Actions	Practical Reality/Prevalence	Source(s)
United States (FDA)	Prohibitive	"Toxic gas with no known useful medical application." (21 CFR 801.415). Has prosecuted and jailed providers.	Used in some "alternative" or "integrative" clinics, explicitly as a non-FDA-approved therapy.	1
European Union (EMA/National)	Heterogeneous / Permissive	EMA lists ozone as an "authorized active substance." Regulation is primarily at the national level.	Widely practiced in several member states (e.g., Germany, Spain, Italy), sometimes in public hospitals.	13
Brazil	Legalized	Legalized as a "complementary therapy" in 2023.	Legal status granted despite opposition from the National Academy of Medicine.	1
Other (e.g., Cuba, Russia)	Accepted	Long history of use and development of specific protocols (e.g., ozonated water).	Integrated into medical practice for various conditions.	38

8. Synthesis and Expert Recommendations

Ozone therapy exists at the confluence of established toxicology, emerging biochemical understanding, and a body of clinical evidence that is simultaneously promising and problematic. A final synthesis of the available data reveals a complex picture that demands a nuanced approach from clinicians, researchers, and regulatory bodies.

8.1. Summary of Evidence: Balancing Potential Efficacy Against Established Risk and Low-Quality Data

The therapeutic potential of ozone is predicated on a plausible and scientifically intriguing mechanism of action: the principle of hormesis, mediated by secondary messengers that upregulate the body's endogenous antioxidant and repair systems. A significant volume of literature, including numerous systematic reviews and meta-analyses, suggests that this mechanism translates into clinical efficacy for a defined set of conditions, most notably herniated lumbar discs, knee osteoarthritis, and chronic non-healing wounds. In some cases, such as for herniated discs, the reported outcomes are comparable to the surgical standard of care but with a markedly better safety profile.

However, this body of positive evidence is fundamentally undermined by the poor methodological quality of many of the primary studies upon which it is built. Critical appraisals consistently reveal high risks of bias, lack of adequate blinding, and non-standardized protocols, which severely limit the confidence that can be placed in the reported outcomes. Therefore, the current state of evidence can be best described as demonstrating potential rather than proven efficacy.

On the safety front, the debate is defined by the route of administration. The toxicity of inhaled ozone is undisputed and provides a valid basis for regulatory caution. For medical applications, which exclusively use non-pulmonary routes, the safety profile appears to be very good when performed by well-trained professionals adhering to established protocols and contraindications. The most severe adverse events are almost universally linked to malpractice and the use of outdated, dangerous techniques.

8.2. Gaps in Research and Future Directions

To resolve the long-standing controversies surrounding ozone therapy and establish its true place in medicine, the research community must address several critical gaps.

• Lack of High-Quality Randomized Controlled Trials (RCTs): The single most significant deficiency is the scarcity of large-scale, multi-center, double-blind, placebo-controlled RCTs. Future trials must be designed and executed according to the highest methodological standards (e.g., CONSORT guidelines) to provide definitive, low-bias evidence.
• Need for Protocol Standardization: The wide variability in ozone concentrations, total dosages, administration techniques, and treatment schedules across studies makes it difficult to compare results and establish optimal therapeutic protocols. International consensus efforts are needed to standardize these parameters for specific medical conditions.
• Further Mechanistic and Biomarker Studies: While the general mechanism is understood, more research is needed to elucidate the precise downstream effects in humans. Future clinical trials should incorporate the measurement of relevant biomarkers (e.g., markers of oxidative stress, antioxidant enzyme levels, inflammatory cytokines) to correlate biochemical changes with clinical outcomes.

8.3. Recommendations for Stakeholders

• For Clinicians: In jurisdictions where ozone therapy is prohibited (e.g., the United States), its use outside of an approved research setting is contrary to federal regulations. In regions where it is permitted, clinicians should exercise significant caution. Given the limitations of the current evidence base, the therapy should be considered an integrative or experimental option rather than a first-line standard of care. The ethical imperative for comprehensive informed consent is paramount. Patients must be made fully aware of the therapy's regulatory status, the controversial nature of the evidence, and the potential risks, particularly those associated with improperly administered treatment.
• For Researchers: The primary focus must be on generating high-quality evidence. The field must move beyond small, methodologically flawed studies and invest in rigorous RCTs that can provide definitive answers. Collaborative, international research networks could be instrumental in developing standardized protocols and pooling the resources necessary to conduct such trials.
• For Regulatory Bodies: The starkly different approaches of the FDA and European agencies highlight the need for a more nuanced regulatory evaluation. While the FDA's position is grounded in valid toxicological concerns about inhaled ozone, a regulatory framework that distinguishes between different routes of administration could be considered. A pathway for the rigorous investigation of non-pulmonary applications, perhaps under an Investigational New Drug (IND) application, could allow for the generation of the high-quality data the agency requires. For regulatory bodies in regions where the therapy is already permitted, the focus should be on promoting the development of standardized clinical guidelines, mandatory training and certification for practitioners, and post-market surveillance to ensure patient safety and mitigate the risks of malpractice.

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