Clinical use of ozone therapy: a critical appraisal of evidence, safety, and methodological quality

Ozone therapy is frequently promoted as a versatile and minimally invasive medical intervention purported to exert a broad range of biological effects, including anti-inflammatory, antimicrobial, immunomodulatory, and regenerative actions. These claims have led to its application across diverse clinical domains, such as musculoskeletal disorders, dermatological conditions, chronic wounds, peripheral vascular disease, chronic inflammatory diseases, infectious pathologies, and, more recently, viral illnesses. In many private clinical settings, ozone therapy is presented as an adjunct or alternative to established treatments, sometimes accompanied by claims of efficacy that overstate the strength of the underlying evidence. Such representations stand in contrast to the principles of evidence-based medicine, which require therapeutic claims to be supported by reproducible, high-quality clinical evidence. At the same time, as detailed below, ozone therapy is legally recognised as a complementary or traditional medical procedure in a substantial number of jurisdictions, and a growing, heterogeneous body of systematic reviews and meta-analyses -several published in the last five years -reports statistically significant benefit for specific indications, alongside other syntheses reporting verylow-certainty or unsupportive evidence for others. This coexistence of supportive, inconclusive, and negative evidence has contributed to ongoing scientific and regulatory debate regarding the appropriate role of ozone therapy in contemporary clinical practice, highlighting the need for balanced evidence synthesis that distinguishes between individual indications rather than evaluating the therapy as a single entity. The present narrative critical review aims to reflect this heterogeneity rather than to characterise ozone therapy uniformly as either validated or disproven, while examining regulatory positions, the quality and direction of clinical studies across indications, historical patterns of adoption, economic and communicative factors, and reported adverse events.This article is conceived as a narrative critical review, not a systematic review with a pre-registered protocol, quantitative meta-analysis, or formal risk-of-bias synthesis performed by the present authors. In line with recommended standards for the reporting of narrative reviews (14), we clarify here the approach used to identify and select the literature discussed below. PubMed/MEDLINE, Google Scholar, and the Cochrane Library were searched using combinations of the terms "ozone therapy", "oxygen-ozone", "autohemotherapy", "ozonated", together with indication-specific terms (e.g., "low back pain", "disc herniation", "diabetic foot ulcer", "peripheral arterial disease", "osteoarthritis", "dental caries", "dermatology") and methodological filters ("systematic review", "meta-analysis", "randomized controlled trial", "umbrella review"). Regulatory and consensus documents, including national and international ozone-therapy society declarations, were also consulted to characterise the legal and institutional status of the practice. Priority was given to systematic reviews, meta-analyses, and umbrella reviews over individual small trials or case reports, and to publications from 2010 onward, supplemented by earlier landmark meta-analyses (e.g., references 5, 6) where they remain the most complete synthesis available for a given indication. Rather than adjudicating primary studies directly, we relied on the risk-of-bias, GRADE, and AMSTAR-2 judgments reported within these secondary sources. This approach, while allowing broader synthesis across ozone's multiple administration modalities (systemic autohemotherapy, intradiscal or periarticular injection, topical application, rectal insufflation, and gas bathing), does not eliminate selection subjectivity inherent to narrative reviews, and no formal database search log, PRISMA flow diagram, or explicit inclusion/exclusion criteria were applied; this is acknowledged here as a methodological limitation of the present work.From a regulatory perspective, ozone occupies a problematic position. The U.S. Food and Drug Administration (FDA) explicitly classifies ozone as a toxic gas with no proven medical utility in specific, adjunctive, or preventive therapy, emphasising that concentrations required to achieve germicidal effects are incompatible with human safety, given ozone's strong oxidative properties and its capacity to damage cellular membranes, proteins, and lipids. In marked contrast, ozone therapy is legally recognised as a complementary or traditional medical procedure in a number of countries and jurisdictions, including Greece (regulated since 1991), Ukraine (since 2001), Italy, Spain, Portugal, Turkey, Russia, Germany, China, Cuba, Mexico, Brazil, and the United Arab Emirates, among others, as documented in the consensus Madrid Declaration on Ozone Therapy issued by the International Scientific Committee of Ozone Therapy (ISCO3) (1). The purposes for which it is authorised vary by jurisdiction: in Cuba, ozone therapy is institutionally embedded within the national Natural and Traditional Medicine system and is administered in hospital-based centres, most prominently for diabetic foot ulcers, peripheral vascular insufficiency, and chronic inflammatory conditions, under standardised dosing and contraindication protocols; in several European countries, regulation has instead proceeded at the regional or professional-association level, permitting use by licensed physicians as a complementary adjunct rather than as a first-line therapy. In parts of the United States, ozone therapy may be practised under general health-freedom or non-allopathic-medicine statutes rather than under a specific therapeutic indication. This heterogeneity illustrates that legal permission reflects jurisdiction-specific regulatory philosophy and does not, by itself, constitute a determination of clinical efficacy. Biologic