Mechanisms of Action in Ozone Therapy: Is Healing Induced via a Mild Oxidative Stress? (2011 Review)

September 20, 2026

Background

Ozone has a reputation as a toxic gas, and for the lungs that reputation is deserved. Yet ozone has also been used in medicine for decades. This review, by Dr Masaru Sagai and Professor Velio Bocci of the University of Siena, sets out to explain that apparent contradiction - the authors call it the ozone paradox - and to propose a single mechanism that could account for the benefits reported in clinical use.

Bocci spent much of his career studying what happens when measured doses of ozone meet human blood, and this paper draws heavily on that laboratory work.

Study design

This is a narrative review, not a clinical trial. The authors bring together their own laboratory findings on ozonated blood, published work on how cells respond to oxidative stress, and clinical reports - chiefly in peripheral arterial disease, where poor circulation in the legs causes pain and ulcers. There was no systematic search and no pooled analysis, so the paper should be read as an expert explanation and a hypothesis, not as proof of clinical benefit.

Findings

Why the lungs are different. The fluid lining the air sacs of the lung is described as a film only a fraction of a micron thick, with very little antioxidant protection. Inhaled ozone reacts directly with the delicate surface beneath it and triggers inflammation. Blood is the opposite: litres of fluid with a large and quickly renewed antioxidant reserve. The authors state plainly that ozone must never be inhaled.

Ozone does not travel - its messengers do. When ozone meets blood it reacts at once with antioxidants and with unsaturated fats. Two kinds of messenger result: hydrogen peroxide, which is very short-lived, and lipid oxidation products such as 4-hydroxynonenal, which last longer and circulate. The authors note that ozone does not enter cells, and that it behaves the same way on moist skin or the lining of the bowel, dissolving immediately in the surface water and reacting there.

Effects on red blood cells. In ozonated blood the authors report faster sugar metabolism in red cells, with more ATP and more 2,3-DPG - a compound that helps haemoglobin release oxygen to the tissues. Within the dose range they studied, damage to red cells was negligible.

The proposed switch: Nrf2. The central idea of the paper is that the strength of an oxidative signal decides the outcome. A severe signal activates NF-kB, a driver of inflammation. A moderate one is proposed to release Nrf2, a protein normally held inactive in the cell, which then moves to the nucleus and switches on a family of protective enzymes - superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, haem oxygenase-1 and others.

The exercise comparison. The authors place ozone alongside exercise and calorie restriction as examples of hormesis - a small, controlled stress that leaves the body better defended. Other signalling proteins, including HIF-1 alpha, are suggested as a reason ozone has been reported to help in circulation disorders.

What the authors concluded

Sagai and Bocci conclude that the therapeutic effect of ozone comes from a controlled and moderate oxidative stress, and that the line between benefit and harm depends on the strength of that stress. They are clear that ozone therapy is not a panacea, and they call for further research to confirm whether Nrf2 and the other transcription factors they discuss are in fact the mechanism.

Limitations of this study

This is an opinion-led narrative review by two long-standing advocates of ozone therapy, one of whom carried out much of the underlying laboratory work. It was not a systematic review and did not assess the quality of the clinical studies it cites.

In 2011 the link between ozone and Nrf2 was a hypothesis built largely on analogy with other mild stressors. Direct evidence in people came later and is still limited - see our summary of the 2019 Nrf2 review for what has been shown since.

Most of the experimental data concern blood treated outside the body, as in clinic-based autohaemotherapy. The paper mentions the bowel lining only briefly, so it does not by itself establish that other routes produce the same effects.

The clinical results described, mainly in peripheral arterial disease, come from small and mostly uncontrolled studies. Ozone therapy is a complementary approach and should be discussed with your healthcare practitioner.