Effectiveness and Safety of Ozone Therapy in Humans: An Umbrella Review of Systematic Reviews with Meta-Analyses of Randomized Clinical Trials
Cacciatore S, Abbatecola G, Calvani R, Veronese N. Medical Sciences (Basel), 2026.
- Study type
- Systematic review / meta-analysis
- People studied
- Total not recorded
- Population
- Systematic reviews with meta-analyses of randomized trials comparing ozone therapy with non-active controls in any condition; seven were included, covering four indications
- Published
- 2026, Medical Sciences (Basel)
- Identifiers
- PMID 42346828, DOI 10.3390/medsci14020289
What the authors reported
Seven meta-analyses (from 1243 records) were included, covering periodontitis, COVID-19, diabetic foot ulcers, and third-molar surgery. Ozone therapy showed no consistent benefit over non-active controls. Safety was inconsistently reported; the one pooled safety analysis found no significant difference in adverse events (RR 2.27; 95% CI 0.48-10.79). Evidence certainty was low or very low.
What limits this result
An umbrella review of published meta-analyses without individual patient data; only four indications had eligible reviews, and adverse events were pooled in one of them (three trials). The authors cite possible omission of recent trials, varied ozone routes and doses, and the limited quality of the included reviews: two of seven were rated high confidence on AMSTAR-2.
Harms reported after ozone therapy, and studies of how ozone exposure affects health. One study rarely settles a medical question; our guides weigh each paper against the rest of the evidence.
How the study was done
- Design
- Umbrella review of systematic reviews with meta-analyses of randomized controlled trials
We conducted an umbrella review to appraise the effectiveness and safety of ozone therapy using evidence from meta-analyses of randomized controlled trials (RCTs).
- Setting
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, USA (first-listed affiliation); co-authors in Rome, Italy
- Read from
- Read from the full text of the paper. Read on October 2, 2026.
Source: Abstract on PubMed
Study arms
| Group | Participants | What they received |
|---|---|---|
| Included meta-analyses | 7 | Ozone therapy compared with non-active controls (placebo, sham, saline, or standard care) in chronic periodontitis, COVID-19, diabetic foot ulcers, and third-molar surgery |
Source: Full text on PubMed Central
What it measured
- Search and selection
- Of 1243 records, seven meta-analyses covering four indications were included
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.
- Chronic periodontitis
- Mixed: one meta-analysis found no adjunctive benefit; a more recent one found improved probing depth and gingival index but no difference in bleeding on probing, plaque index, or attachment level
- COVID-19
- Lower PCR positivity at follow-up (RR 0.07; 95% CI 0.01-0.34), judged a non-important surrogate; no significant benefit for hospital stay, ICU admission, or mortality
For COVID-19, ozone therapy reduced PCR positivity at follow-up (RR 0.07; 95% CI 0.01-0.34), although this was considered a clinically non-important surrogate endpoint, and showed no significant benefit for hospital stay, intensive care unit admission, or mortality.
- Diabetic foot ulcers
- Not superior to control for ulcer healing (RR 1.69; 95% CI 0.90-3.17) or reduction in ulcer area
- Impacted third-molar surgery
- No reduction in swelling or improvement in mouth opening; improved short-term quality of life and less analgesic use
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.
- Pooled adverse events (Cochrane review of diabetic foot ulcers, the only pooled safety analysis)
- No significant difference between ozone and control (RR 2.27; 95% CI 0.48-10.79)
Pooled analysis did not show a significant difference between ozone therapy and control groups in terms of adverse events (RR 2.27; 95% CI 0.48–10.79).
- Certainty of evidence (GRADE)
- Low or very low for all outcomes
- Quality of the included reviews (AMSTAR-2)
- Only two reached a high confidence rating; most were low or critically low
The AMSTAR-2 appraisal highlighted that only two meta-analyses reached a high confidence rating, whereas the majority were classified as low or critically low confidence.
Safety as reported
Safety outcomes were inconsistently reported across the included reviews, and the data did not allow firm conclusions on adverse events
Source: Abstract on PubMed
Funding and conflicts
No external funding
Source: Full text on PubMed Central
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