Written by Mark Hyman MD
Oxygen/Ozone Therapy References

Oxygen/Ozone Therapy References

Oxygen-ozone therapy has a long history of safe use to support and improve health. It can support the body to activate its own healing mechanisms, including inhibiting inflammatory pathways, activating anti-inflammatory pathways, and increasing your body’s own antioxidant and detoxification systems to improve overall health.

Prolozone Therapy

Prolozone therapy is a safe and effective way to address chronic musculoskeletal complaints and support the regeneration and repair of joints and tissues.

Potential Benefits of Oxygen Ozone Therapy

  1. Directly germicidal.  The initial and quickly extinguished oxidative burst  (ozone’s half-life is milliseconds) from ozone mimics our endogenous immune defense systems which produces hydrogen peroxide (H2O2) and ozone (O3) which are directly germicidal. (1)
  2. Modulation of cytokines and interferons. Ozone Inhibits NfKb and all its downstream inflammatory consequences. It also activates the Nrf2 pathways (2) inhibiting inflammation and oxidative stress (3,4) and modulates the NLRP3 inflammasome. (5)
  3. Improves oxygen metabolism. It increases cellular oxygenation by improving the hexose-monophosphate shunt, due to the activation of 2,3-DPG which, by binding to the β–chain of hemoglobin, causes a shift to the right of the Hb dissociation curve, enhancing oxygen release into hypoxic tissues. There is also an improvement of the glycolytic pathway on erythrocytes significantly increasing their ATP content, recovering the elasticity of the red cell membrane thus improving blood rheology and capillarity. There is a significant improvement in blood flow and oxygenation of ischemic tissues due to ozone treatment. (6,7)
  4. Activation of endogenous antioxidant defenses including superoxide dismutase, glutathione peroxidase, glutathione-S-transferase and catalase, etc. The re-equilibration of the cellular redox state achieved with the ozone therapy is also important in the induction of cytokines synthesis in monocytes and lymphocytes and in the release of heat shock proteins which are potent activators of the immune system. (8)
  5. Induction of nitric oxide and nitrosothiols.  Nitric oxide (9) and nitrosothiols (10) are active metabolites induced by ozone in the blood (11), and are capable of modifying (palmitoylation) the spike protein (S) of the virus inhibiting receptor binding. Oxidation of cysteine inhibits viral binding and entry into the host cells. (12)  Ozone metabolites are capable of oxidizing cysteine residues, making it difficult for the virus to enter the host cell, and preventing viral replication. (13,14,15)
  6. Activation of HO-1 by increasing the release of CO and bilirubin thereby reducing inflammation. (16,17)
  7. Reduction in coagulopathy. Ozone has an antiplatelet effect, increases some prostacyclins and modulates antithrombin III. All these effects can help to decrease the hypercoagulation phenomena. (18,19)
  8. Inhibition of viral replication.  Ozone can block the virus’ ability to replicate by balancing the cellular redox state, through the control of Nrf2 which regulates and blocks the activity of spike protein (S) and ACE2. (20)



  1. Wentworth P Jr, McDunn JE, Wentworth AD, et al. Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation. Science. 2002;298(5601):2195–2199.
  2. Pall ML, Levine S. Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors. Sheng Li Xue Bao. 2015;67(1):1–18.
  3.  Re L, Martinez-Sanchez G, Bordicchia M, et al. Is ozone pre-conditioning effect linked to Nrf2/EpRE activation pathway in vivo? A preliminary result. Eur J Pharmacol. Nov 5 2014;742:158-162.
  4.  Bocci V, Valacchi G. Nrf2 activation as target to implement therapeutic treatments. Front Chem 2015;3:4. Doi: 10.3389/fchem.2015.00004
  5.  Ricevuti, G. Oxygen-ozone immunoceutical therapy in COVID-19 outbreak: facts and figures, [Ozone Therapy 2020; 5:9014]
  6. Sagai M, Bocci V. Mechanisms of action involved in ozone therapy: is healing induced via a mild oxidative stress? Med Gas Res 2011;1:29. 
  7.  Hernández F, Calunga JL, Turrent J, Menéndez S and Montenegro A. Ozone therapy effects on blood biomarkers and lung function of asthma patients. Arch Med Res 2005;36(5):549-554.
  8. Bocci V, Aldinucci C, Mosci F; Carraro F; Valacchi G. Ozonation of human blood induces a remarkable upregulation of heme oxygenase-1 and heat stress protein-70. Mediators Inflamm 2007;2007:26785.
  9. Akerström S, Gunalan V, Keng CT, Tan YJ, Mirazimi A. Dual effect of nitric oxide on SARS-CoV replication: Viral RNA production and palmitoylation of the S protein are affected. Virology 2009;395:1-9. 
  10. Keyaertsa E, Vijgena L, Chenb L, Maesa P, Hedenstiernab G, Ranst MV. Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound. Int J Inf Dis. 2004;8:223-226.
  11. Valacchi G, Bocci V. Studies on the biological effects of ozone: 11. Release of factors from human endothelial cells. Mediators Inflamm 2000;9:271-276.
  12. Millet, J. K. & Whittaker, G. R. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology 2018;517:3-8.
  13. Aran M, Mora-Garcia S, Rimmaudo L, Wolosiuk RA. Reevaluación de los residuos cisteína en el señalamiento redox. Química Viva 2009;8(3):162-184.[Accessed 12 April 2020].
  14. Virender K Sharma, Nigel JD Graham. Oxidation of amino acids, peptides and proteins by ozone: A Review. Ozone-Sci Eng 2010;32:81-90
  15.  Dussault PH, George AD, Trullinger TK. Peroxides as oxidative enzyme inhibitors: Mechanism-based inhibition of a cysteine protease by an amino acid ozonide. Bioorg Med Chem Lett. 1999;9:3255-3258.
  16. Pecorelli A, Bocci V, Acquaviva A, Belmonte G, Gardi C, Virgili F, Ciccoli L, Valacchi G. NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells. Toxicol Appl Pharmacol 2013;267:30-40.
  17.  Schulz S, Ninke S, Watzer B, Nusing RM. Ozone induces synthesis of systemic prostacyclin by cyclooxygenase-2 dependent mechanism in vivo. Biochem Pharmacol 2012;83:506–513.
  18.  Martínez Y, Zamora Z, González R, Guanche D. Efecto del precondicionamiento oxidativo con ozono en el tiempo de sangrado y formación de trombo venoso en un modelo de choque séptico en ratas. Revista CENIC. Ciencias Biológicas. 2010;41. [Accessed 12 April 2020]. ISSN: 0253-5688. [Available from: https://www.redalyc.org/articulo.oa?id=1812/181220509054].
  19.  Schulz S, Ninke S, Watzer B, Nusing RM. Ozone induces synthesis of systemic prostacyclin by cyclooxygenase-2 dependent mechanism in vivo. Biochem Pharmacol 2012;83:506–513.
  20.  Ricevuti G, Franzini M, Valdenassi L. Oxygen-ozone immunoceutical therapy in COVID-19 outbreak: facts and figures. Ozone Therapy 2020;5:9014.


Hashemi M, Jalili P, Mennati S, et al. The Effects of Prolotherapy With Hypertonic Dextrose Versus Prolozone (Intraarticular Ozone) in Patients With Knee Osteoarthritis. Anesth Pain Med. 2015;5(5):e27585.

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