Ozonated Saline Added to Medication in Post-COVID Fatigue: A Randomised Study of 140 Patients (2025)

Background

Post-COVID asthenic syndrome is the term used in this study for the cluster of chronic fatigue, cognitive dysfunction, sleep disturbance and anxiety that persists for months after a COVID-19 infection - what most readers would call long COVID fatigue. The authors, a clinician at the Avicenna Clinic in Simferopol and a professor of psychiatry at the Crimean Federal University, set out from the view that oxidative stress is a driver of these symptoms, and asked whether adding systemic ozone to standard medication would reduce that stress and improve how patients felt and functioned.

The route studied was an intravenous infusion of ozonated saline - physiological salt solution passed through an ozone-oxygen mixture just before use. It is one of the systemic routes recognised in the field alongside autohaemotherapy and rectal insufflation, though it is not one used at home.

Study design

This was a prospective, randomised, controlled comparative study run between November 2021 and October 2023. One hundred and forty patients diagnosed with post-COVID asthenic syndrome three to twelve months after infection were allocated by sealed envelope to two groups of 70. Both groups received a 30-day course of an oral medication (meldonium with ethylmethylhydroxypyridine succinate, a combination used in Russia for asthenic conditions). The main group also received ten daily intravenous infusions of ozonated saline. Fifty healthy volunteers of similar age were tested once to give reference values.

Three blood markers of oxidative balance were measured - malondialdehyde (a marker of lipid damage), superoxide dismutase and glutathione peroxidase (two antioxidant enzymes) - along with five validated scales: the Multidimensional Fatigue Inventory, the Montreal Cognitive Assessment, the Insomnia Severity Index, the Hamilton Anxiety Rating Scale and the Clinical Global Impression scale. All were recorded at baseline and again 30 days after treatment. Every patient completed the protocol.

There was no placebo infusion and no blinding: patients and clinicians knew who was receiving ozone. This was a supervised clinical procedure; it is a description of what was studied, not a set of instructions.

Findings

Oxidative damage fell further with ozone. Malondialdehyde dropped 69 per cent in the ozone group (from 4.2 to 1.3 nmol/mL, p < 0.001) against 39 per cent with medication alone, a between-group difference of 48 per cent (p = 0.002).

Antioxidant enzymes rose further. Superoxide dismutase rose 48 per cent with ozone against 27 per cent without (p = 0.036 between groups); glutathione peroxidase rose 52 per cent against 33 per cent (p = 0.028).

Fatigue, sleep, anxiety and cognition all improved more. Fatigue scores fell 75 per cent with ozone against 60 per cent without (p = 0.001); insomnia scores fell 81 per cent against 43 per cent (p < 0.001); anxiety scores fell 73 per cent against 48 per cent (p = 0.001); cognitive scores rose 17 per cent against 5 per cent (p = 0.046).

Global outcome. On the clinician-rated Clinical Global Impression scale, 94 per cent of the ozone group were rated as having no illness at 30 days, against 63 per cent of the medication-only group (p = 0.001).

Safety. No adverse events were reported in either group.

What the authors concluded

The authors conclude that "adjunctive systemic ozone therapy, combined with pharmacological treatment, resulted in a reduction of oxidative stress and a significant improvement in mental status among patients with post-COVID-19 asthenic syndrome", and that "95% of patients in the ozone therapy group experienced a complete or near-complete resolution" of symptoms. They attribute the effect to activation of the Nrf2 pathway and improved mitochondrial handling of pyruvate, leading to lower production of reactive oxygen species and higher antioxidant enzyme activity.

Limitations of this study

The authors state two limitations: sleep was assessed by questionnaire rather than by polysomnography, and the study did not test ozone alongside other classes of drug that may affect the syndrome.

Three points for readers. There was no placebo infusion, so the comparison is between receiving a daily drip and not receiving one, which leaves room for expectation to influence the questionnaire scores; the blood markers are less open to that influence, which is one reason they matter. The medication both groups received is not in routine use outside Russia and neighbouring countries, so the comparison arm is not the "usual care" a New Zealand reader would recognise. And the study used intravenous ozonated saline, a clinic-only route; it does not show that other routes produce the same effect.

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

Major Ozone Autohaemotherapy for Long COVID: A Pilot Randomised Controlled Trial of 73 Patients (2024) - the other randomised study.

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

Ozone Treatment for Chronic Fatigue in Long COVID: A Clinical Perspective (2026) - which cites this study.

Mitochondrial Dysfunction, Oxidative Stress and Low-Dose Ozone: A Systematic Review (2024) - the same three markers across other conditions.

Ozone Therapy and Long COVID: What the Research Shows (2026 Update)

Soldatenko AA, Gumenyuk LN. Dynamics of oxidative stress markers and mental status in patients with post-COVID-19 asthenic syndrome: effects of adjunctive systemic ozone therapy. Russian Open Medical Journal. 2025;14:e0109. doi:10.15275/rusomj.2025.0109