Rectal Ozone Insufflation in Long COVID: A 12-Week Preliminary Study of 23 Patients (2026)

Background

Long COVID, also called post-acute COVID-19 syndrome, is a multisystem condition that the authors note affects more than 400 million people worldwide, with fatigue, weakness and reduced quality of life among its most common features and few established treatments. Their rationale for testing ozone rests on its reported anti-inflammatory, immunomodulating and antioxidant actions: earlier studies suggest that a controlled low dose of ozone activates the cell's own defence pathways and lowers pro-inflammatory cytokines.

Earlier long COVID ozone studies used autohaemotherapy, in which blood is drawn, ozonated and returned. This team, from the San Antonio Catholic University of Murcia in Spain with a co-author from Cuba's National Centre for Scientific Research, chose rectal insufflation instead, and added infrared thermography - a non-invasive way of tracking metabolic and circulatory change - to the usual questionnaires.

Study design

This was an open-label preliminary clinical study with no control group. Twenty-three adults (18 women, 5 men) with long COVID diagnosed at least five months earlier, and a documented positive SARS-CoV-2 test, enrolled and all completed the 12-week protocol. People with gastrointestinal disorders, cardiovascular disease, medicines affecting temperature regulation, or significant cognitive impairment were excluded.

Ozone was given by rectal insufflation in a clinical setting, 24 sessions over 12 weeks: five a week for the first two weeks, two a week for weeks three to six, then one a week for weeks seven to twelve. The protocol used a fixed volume and concentration at each session, delivered from a Hyper Medozon comfort medical ozone generator.

Three things were measured at baseline (T0), six weeks (T1) and twelve weeks (T2): handgrip strength, the SF-12 quality-of-life questionnaire (split into a physical and a mental score), and abdominal skin temperature by infrared thermography.

It is a description of what was studied in a supervised research setting, not a set of instructions.

Findings

Grip strength rose. Handgrip went from 24.6 kg at baseline to 27.7 kg at six weeks (p = 0.0003, a large effect size of 0.88) and stayed at 27.7 kg at twelve weeks.

Physical quality of life improved. The SF-12 physical score rose from 25.6 to 30.6 at six weeks (p = 0.0038) and 31.6 at twelve weeks. For context, the general-population average on this scale is about 50, so participants started well below it and remained below it.

Mental quality of life improved. The SF-12 mental score rose from 38.5 to 46.1 at six weeks (p = 0.0088) and was 44.1 at twelve weeks.

Skin temperature fell. Abdominal skin temperature dropped from 32.3 °C to 31.5 °C at six weeks (p = 0.0465), then drifted back towards baseline by week twelve. The authors read this as a change in local metabolic or inflammatory activity, though its meaning is not settled.

The gains came early and then plateaued. None of the four measures changed significantly between week six and week twelve, the period when sessions had dropped to once a week. No differences were seen between women and men.

Tolerability. The authors report excellent tolerability, with no adverse events of interest recorded across 552 sessions.

What the authors concluded

The authors conclude that medical ozone given by rectal insufflation was well tolerated in this preliminary exploratory study, and that improvements in quality of life, muscle strength and thermographic measures were observed during the intervention. They state that these results "should be considered preliminary and need to be confirmed through more specific study designs with larger sample sizes", because although the changes are consistent with the biological mechanisms proposed for ozone, those mechanisms were not directly investigated. They call for larger randomised controlled trials that include metabolic, inflammatory, redox and other biomarkers to confirm both clinical efficacy and the pathways involved.

Limitations of this study

The authors list their limitations plainly: a small sample that restricts what can be concluded; an open-label design with no control group, so a placebo effect cannot be ruled out; an imbalance of women to men; no neurocognitive or cardiopulmonary assessment, which matters in a condition where brain fog and breathlessness are common; no follow-up after the twelve weeks, so nothing is known about how long any benefit lasted; and no direct measurement of the mechanisms they propose.

We would add for readers that people with brain fog were excluded, so the results do not speak to that symptom. All sessions were delivered in a clinic under supervision. And the plateau after week six, when sessions became weekly, is an observation the study was not designed to explain.

Long COVID should be diagnosed and managed with a doctor. Anyone considering ozone therapy alongside their care should discuss it with their own GP or specialist.

Related reading

Fatigue in Long COVID Treated with Oxygen-Ozone Autohaemotherapy: 100 Patients - the earlier Italian series using the clinic route.

Oxygen-Ozone Autohaemotherapy and Fatigue in ME/CFS: A 200-Patient Study

Ozone Therapy and Gut Microbiota in Constipation-Predominant IBS - what rectal ozone does in the gut.

How Ozone Therapy Works: The Science in Plain Words

Sacristan Perez R, Martínez Vivas MJ, Menéndez-Cepero S, Cabizosu A, Hidalgo Tallón FJ. Ozone therapy by rectal insufflation in long COVID syndrome: a preliminary study with thermographic evaluation and quality of life measurement. Future Science OA. 2026;12(1):2704605. Published 20 July 2026. doi:10.1080/20565623.2026.2704605