{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T18:05:30Z","timestamp":1780596330593,"version":"3.54.1"},"reference-count":30,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: Ozone therapy has been proposed across multiple clinical conditions based on hormetic, antioxidant, and immunomodulatory effects, but its efficacy and safety remain controversial. We conducted an umbrella review to appraise the effectiveness and safety of ozone therapy using evidence from meta-analyses of randomized controlled trials (RCTs). Methods: We searched MEDLINE, Web of Science, Embase, and the Cochrane Library from inception to 14 February 2025, with an updated search performed on 9 May 2026. Eligible studies were systematic reviews with meta-analyses comparing ozone therapy with non-active controls, including placebo, sham, saline, or standard care. Methodological quality was evaluated with AMSTAR-2 and certainty of evidence with GRADE. Results: Of 1243 records identified, seven meta-analyses representing four clinical indications (chronic periodontitis, COVID-19, diabetic foot ulcers, and impacted mandibular third-molar surgery) were included. In chronic periodontitis, evidence was mixed: one meta-analysis found no significant adjunctive benefit, whereas a more recent meta-analysis reported improvements in probing depth and gingival index, but not in bleeding on probing, plaque index, or clinical attachment level. For COVID-19, ozone therapy reduced PCR positivity at follow-up (RR 0.07; 95% CI 0.01\u20130.34), although this was considered a clinically non-important surrogate endpoint, and showed no significant benefit for hospital stay, intensive care unit admission, or mortality. For diabetic foot ulcers, ozone therapy was not superior to control treatment for ulcer healing (RR 1.69; 95% CI 0.90\u20133.17) or reduction in ulcer area. In third-molar surgery, ozone therapy did not reduce swelling or improve mouth opening, but was associated with improved short-term quality of life and reduced analgesic use. Safety outcomes were inconsistently reported, and available data did not allow firm conclusions regarding adverse events. The certainty of evidence was low or very low for all outcomes. Conclusions: Despite mechanistic plausibility, current meta-analytic evidence from RCTs remains inconsistent, methodologically fragile, and largely based on low- or very low-certainty findings. Routine clinical use is not justified pending adequately powered, blinded RCTs with standardized dosing and delivery, patient-centered endpoints, and rigorous safety monitoring.<\/jats:p>","DOI":"10.3390\/medsci14020289","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:11:04Z","timestamp":1780593064000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effectiveness and Safety of Ozone Therapy in Humans: An Umbrella Review of Systematic Reviews with Meta-Analyses of Randomized Clinical Trials"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-3775","authenticated-orcid":false,"given":"Stefano","family":"Cacciatore","sequence":"first","affiliation":[{"name":"Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4329-3128","authenticated-orcid":false,"given":"Gabriele","family":"Abbatecola","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Orthopedics and Rheumatology, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5472-2365","authenticated-orcid":false,"given":"Riccardo","family":"Calvani","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Orthopedics and Rheumatology, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario \u201cAgostino Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9328-289X","authenticated-orcid":false,"given":"Nicola","family":"Veronese","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4103\/0976-9668.82319","article-title":"Ozone therapy: A clinical review","volume":"2","author":"Elvis","year":"2011","journal-title":"J. Nat. Sci. Biol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"212","DOI":"10.4103\/2045-9912.215752","article-title":"Ozone therapy: An overview of pharmacodynamics, current research, and clinical utility","volume":"7","author":"Smith","year":"2017","journal-title":"Med. Gas Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1186\/s40001-024-01976-4","article-title":"Ozone therapy in musculoskeletal medicine: A comprehensive review","volume":"29","author":"Jeyaraman","year":"2024","journal-title":"Eur. J. Med. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4103\/2045-9912.235139","article-title":"Ozone therapy in conjunction with oral antibiotics as a successful primary and sole treatment for chronic septic prosthetic joint: Review and case report","volume":"8","author":"Rowen","year":"2018","journal-title":"Med. Gas Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"172","DOI":"10.4103\/2045-9912.372819","article-title":"Clinical effectiveness of medical ozone therapy in COVID-19: The evidence and gaps map","volume":"13","author":"Serra","year":"2023","journal-title":"Med. Gas Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"579","DOI":"10.2147\/TCRM.S255247","article-title":"Oxygen-Ozone (O2-O3) Therapy in Peripheral Arterial Disease (PAD): A Review Study","volume":"16","author":"Juchniewicz","year":"2020","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_7","first-page":"CD008474","article-title":"Ozone therapy for treating foot ulcers in people with diabetes","volume":"2015","author":"Liu","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_8","unstructured":"(2025, May 21). U.S. Food and Drug Administration Code of Federal Regulations, Available online: https:\/\/www.ecfr.gov."},{"key":"ref_9","first-page":"E115","article-title":"Ozone therapy as a treatment for low back pain secondary to herniated disc: A systematic review and meta-analysis of randomized controlled trials","volume":"15","author":"Magalhaes","year":"2012","journal-title":"Pain Physician"},{"key":"ref_10","unstructured":"Sch\u00fcnemann, H., Bro\u017cek, J., Guyatt, G., and Oxman, A. (2025, May 21). GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. Updated October 2013. The GRADE Working Group, 2013. Available online: https:\/\/gdt.gradepro.org\/app\/handbook\/handbook.html."},{"key":"ref_11","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2024). Cochrane Handbook for Systematic Reviews of Interventions Version 6.5 (Updated August 2024), Cochrane. Available online: www.cochrane.org\/handbook."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"j4008","DOI":"10.1136\/bmj.j4008","article-title":"AMSTAR 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both","volume":"358","author":"Shea","year":"2017","journal-title":"BMJ"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.adaj.2021.05.006","article-title":"Efficacy of adjuvant ozone therapy in reducing postsurgical complications following impacted mandibular third-molar surgery: A systematic review and meta-analysis","volume":"152","author":"Chaudhry","year":"2021","journal-title":"J. Am. Dent. Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1007\/s00784-020-03289-2","article-title":"Ineffectiveness of ozone therapy in nonsurgical periodontal treatment: A systematic review and metaanalysis of randomized clinical trials","volume":"24","author":"Moraschini","year":"2020","journal-title":"Clin. Oral Investig."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, J., Huang, Y., Huang, J., Yang, W., and Tao, R. (2025). Effects of ozone therapy as an adjuvant in the treatment of periodontitis: A systematic review and meta-analysis. BMC Oral Health, 25.","DOI":"10.1186\/s12903-025-05639-6"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102907","DOI":"10.1016\/j.ctim.2022.102907","article-title":"Benefits of ozone on mortality in patients with COVID-19: A systematic review and meta-analysis","volume":"72","author":"Shang","year":"2023","journal-title":"Complement. Ther. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"958","DOI":"10.12968\/jowc.2022.0189","article-title":"Ozone therapy as a treatment for diabetic foot ulcers: A systematic review and meta-analysis","volume":"33","author":"Filho","year":"2024","journal-title":"J. Wound Care"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jafari-Oori, M., Vahedian-Azimi, A., Ghorbanzadeh, K., Sepahvand, E., Dehi, M., Ebadi, A., and Izadi, M. (2022). Efficacy of ozone adjuvant therapy in COVID-19 patients: A meta-analysis study. Front Med., 9.","DOI":"10.3389\/fmed.2022.1037749"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2342","DOI":"10.1002\/rmv.2342","article-title":"Assessing severe acute respiratory syndrome coronavirus 2 infectivity by reverse-transcription polymerase chain reaction: A systematic review and meta-analysis","volume":"32","author":"Fomenko","year":"2022","journal-title":"Rev. Med. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e0046921","DOI":"10.1128\/JCM.00469-21","article-title":"Can Testing Predict SARS-CoV-2 Infectivity? The Potential for Certain Methods To Be Surrogates for Replication-Competent Virus","volume":"59","author":"Binnicker","year":"2021","journal-title":"J. Clin. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"111211","DOI":"10.1016\/j.jclinepi.2023.11.001","article-title":"Compelling evidence from meta-epidemiological studies demonstrates overestimation of effects in randomized trials that fail to optimize randomization and blind patients and outcome assessors","volume":"165","author":"Wang","year":"2024","journal-title":"J. Clin. Epidemiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1159\/000431078","article-title":"Myocardial Infarction after Ozone Therapy: Is Ozone Therapy Dr. Jekyll or Mr. Hyde?","volume":"132","author":"Ureyen","year":"2015","journal-title":"Cardiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.ajem.2014.11.041","article-title":"Anton syndrome during oxygen-ozone therapy","volume":"33","author":"Avci","year":"2015","journal-title":"Am. J. Emerg. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114191","DOI":"10.1016\/j.intimp.2025.114191","article-title":"Concerns about haemolysis after oxygen-ozone therapy","volume":"149","author":"Martinelli","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Galie, M., Covi, V., Tabaracci, G., and Malatesta, M. (2019). The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20164009"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cenci, A., Macchia, I., La Sorsa, V., Sbarigia, C., Di Donna, V., and Pietraforte, D. (2022). Mechanisms of Action of Ozone Therapy in Emerging Viral Diseases: Immunomodulatory Effects and Therapeutic Advantages With Reference to SARS-CoV-2. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.871645"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Viebahn-Haensler, R., and Leon Fernandez, O.S. (2021). Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157890"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Malatesta, M., Tabaracci, G., and Pellicciari, C. (2024). Low-Dose Ozone as a Eustress Inducer: Experimental Evidence of the Molecular Mechanisms Accounting for Its Therapeutic Action. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312657"},{"key":"ref_30","first-page":"100745","article-title":"The ozone therapy controversy and the need for science-based health policies in the Brazilian context","volume":"34","year":"2024","journal-title":"Lancet Reg. Health Am."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/2\/289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:25:51Z","timestamp":1780593951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/2\/289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["medsci14020289"],"URL":"https:\/\/doi.org\/10.3390\/medsci14020289","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}