THE POSSIBILITIES OF USING THE EFFECTS OF OZONE THERAPY IN
Ján MASAN1,2,3, Miron SRAMKA2 , Daria RABAROVA3
1 University of St. Cyril and Methodius in Trnava, Slovak Republic.
2 St. Elizabeth University of Health Care and Social Work in Bratislava, Slovak Republic.
3 Trnava University in Trnava, University Hospital Trnava, Slovak Republic.
Correspondence to: h.Doc. MUDr. Ján Mašán, PhD.
St. Elizabeth University of Health Care and Social Work in Bratislava, Slovak Republic
E-MAIL : firstname.lastname@example.org
Keywords: Ozone therapy. Major ozone therapy. Neurodegenerative disorders. Antioxidant
system. Oxidative stress biomarkers. Multiple sclerosis. Stroke. Neuropathy. Phantom limb
OBJECTIVES: The beneficial effects of ozone therapy consist mainly of the promotion of
blood circulation: peripheral and central ischemia, immunomodulatory effect, energy boost,
regenerative and reparative properties, and correction of chronic oxidative stress. Ozone
therapy increases interest in new neuroprotective strategies that may represent therapeutic
targets for minimizing the effects of oxidative stress.
METHODS: The overview examines the latest literature in neurological pathologies treated
with ozone therapy as well as our own experience with ozone therapy. The effectiveness of
treatments is connected to the ability of ozone therapy to reactivate the antioxidant system to
address oxidative stress for chronic neurodegenerative diseases, strokes, and other
pathologies. Application options include large and small autohemotherapy, intramuscular
application, intra-articular, intradiscal, paravertebral and epidural, non-invasive rectal,
transdermal, mucosal, or ozonated oils and ointments. The combination of different types of
ozone therapy stimulates the benefits of the effects of ozone.
RESULTS: Clinical studies on O2-O3 therapy have been shown to be efficient in the
treatment of neurological degenerative disorders, multiple sclerosis, cardiovascular, peripheral
vascular, orthopedic, gastrointestinal and genitourinary pathologies, fibromyalgia, skin
diseases/wound healing, diabetes/ulcers, infectious diseases, and lung diseases, including the
pandemic disease caused by the COVID-19 coronavirus.
CONCLUSION: Ozone therapy is a relatively fast administration of ozone gas. When the
correct dose is administered, no side effects occur. Further clinical and experimental studies
will be needed to determine the optimal administration schedule and to evaluate the
combination of ozone therapy with other therapies to increase the effectiveness of treatment.
Abbreviations: O3 – ozone, GSH – glutathione, NADPH – nicotinamide adenine
dinucleotide, (SOD) – superoxide dismutase, PUFA – unsaturated fatty acids, LOP – lipid
ozonation products, ARE – antioxidant response elements, ATP – adenosine triphosphate,
ROS – reactive oxygen species, DNA – deoxyribonucleic acid, NADH – nicotinamide
Van Mauren was first to discover the distinctive odor of O3 in 1785 (Altman 2007).
However, its first identification as a distinct chemical compound was made by Schönbein in
Basel in 1840. In 1896, Nikola Tesla patented a generator for producing ozone. The use of
ozone became normal practice after the studies of Dr. H.H. Wolff. In 1915, during World War
I, ozone was used to treat war wounds. Following Bocci’s studies, ozone therapy has been
incorporated into the treatment of chronic inflammatory diseases in the orthopedic field.
When used in appropriate doses, it has been shown to be effective in inducing well-tolerated
oxidative stress. Ozone is a metastable substance and must be generated on-site.
Contraindication of O3 therapy is lung inhalation, activating factors triggering an
inflammatory response (Bocci 2006; Pryor et al. 2019). Jacobs (1982) carefully examined all
the possible negative effects of ozone therapy. Despite the famous “toxicity” of ozone, it
appears that the incidence is only 0.0007%, one of the lowest in medicine. Four deaths due to
direct IV injection of the gas were included in his data but, since 1982, other deaths due to
malpractice have occurred, of which at least three were in Italy (Bocci 2010).
It is currently applied in a wide range of medical fields: surgery, orthopedics,
neurology, oncology, dermatology, cardiology, psychiatry, radiology, rheumatology,
gynecology, gastroenterology, angiology, dentistry, etc.
The effects of medical ozone as a substance can be attributed to those defined by
hormesis (from the Greek word hormáein = to set in motion), i.e. referring to the hypothesis
regarding the beneficial effects of low doses. At the same time, it triggers a response with
high doses, thus increasing the body’s resistance.
Induction of the response to stress by short low doses usually protects the body for a
longer period of time and against other possible types of doses (Rattan et al. 2009). The
administration of O3 therapy varies based on treatment goals and treatment focus. Ozone
therapy combines a mixture of oxygen (O2)-O3 with a diverse therapeutic range (10–80
μg/ml of gas per ml of blood) (Bocci 2006). Human blood contains a large number of
antioxidants such as uric acid, ascorbic acid, cysteine, glutathione, albumin, certain chelating
proteins such as albumin, and enzymes such as catalase, the redox system of GSH, NADPH
(nicotinamide adenine dinucleotide), and superoxide dismutase (SOD) (Bocci et al., 2005).
Like any other gas, ozone dissolves upon contact with body fluids according to
Henry’s Law in relation to temperature, pressure, and ozone concentration. It reacts
immediately as soon as it is dissolved: O3 + biomolecules → O2 + O2 + energy. Atomic
oxygen behaves as a reactive atom. The fundamental ROS (reactive oxygen species) molecule
is hydrogen peroxide H2O2, which is a non-radical oxidant able to act as an ozone Messenger
responsible for eliciting several biological and therapeutic effects. In physiological amounts,
they act as regulators of signal transduction and represent important mediators of host defense
and immune responses (Dattilo et al. 2015).
The reaction of O3 with water causes the formation of one mole of hydrogen peroxide
(H2O2) and two moles of lipid oxidation products with polyunsaturated fatty acids (PUFA),
forming a mixture of lipid ozonation products (LOP) (Barone et al. 2015) including
lipoperoxyl radicals (Inal et al. 2011). Moderate oxidative stress caused by O3 increases the
activation of the transcription factor of the pathway-mediated nuclear factor-related erythroid
factor 2 (Nrf2) (Bocci et al. 2015, Re et al. 2014), which is responsible for activating the
transcription of antioxidant response elements (ARE). After their induction, the concentration
of antioxidant enzymes increases in response to the transient oxidative stress O3 (Bocci et al.
POTENTIAL APPLICATION OF OZONE THERAPY
Vascular and Haematological Modulation The production of antioxidant enzymes
affects the whole body (Gonzalez et al. 2004; Valacchi 2000). O3 is a stimulator of O2
transmembrane flow. Increased intracellular O2 levels secondarily form the mitochondrial
respiratory chain (Madej et al. 2007). In red blood cells, O3 increases phosphofructokinase
activity, thereby increasing the rate of glycolysis. Increased glycolytic rate increases ATP and
2,3-diphosphoglycerate (2,3-DPG) in the cell. Following a long treatment cycle of the elderly,
Bocci et al. 2011 noted a significant increase in the 2,3-diphosphoglycerate level in
oxyhaemoglobin. As a result of the Bohr effect, its dissociation curve shifts to the right,
making it easier to transfer oxygen. Under physiological conditions, the endothelium regulates
vascular tone (Molinari et al. 2017). Ozonised blood increases the release of prostacyclin
(PGI2) and angiopoietins, both important factors in improving ischemic vasculopathy
(Fernández et al. 2008; Elvis et al. 2011).
The correction of chronic oxidative stress via the increase of antioxidant enzymes can
increase erythroblast differentiation. This leads to a progressive increase in erythrocytes and
preconditions them to having resilience towards oxidative stress, to an increase of
erythrocytes with improved metabolic properties, as well as ensuring that young erythrocytes
contain more G6PDH than older cells generated prior to the treatment, which is a type of
“super-gifted erythrocytes” capable of correcting hypoxia in vascular diseases (Chang et al.
2005). An improvement in blood circulation and oxygen supply to ischemic tissues has been
recorded, leading to an increased supply of O2 to hypoxic tissues (Brigelius-Flohé et al. 2011).
Activation of the Immune System. O3 has been shown to react with antioxidants and
alter peroxidation compounds. H2O2 has been shown to act as a regulatory step in signal
transduction by diffusing into immune cells and by facilitating a myriad of immune responses
(Gulmen et al. 2013; Caliskan et al. 2011). An increase in interferon, tumor necrosis factor,
and interleukin (IL)-2 was observed. IL-2 increases were initiated by immune response
mechanisms (Elvis 2011). In addition, H2O2 activates nuclear factor-kappa B (NF-κB) and
transforms growth factor-beta (TGF-β), thus increasing the immunoactive release of cytokines
and tissue refurbishment.
After each restarted therapy, a small percentage of immune cells are activated and
these cells release cytokines into the micro-environment, activating neighboring cells and, as
a result, slowly enhancing immune responses. Only submicromolar concentrations can reach
all organs, particularly bone marrow, liver, central nervous system, endocrine glands, etc.,
where they act as signaling molecules of an ongoing acute oxidative stress (Mancuso et al.
1997). These molecules can elicit the upregulation of antioxidant enzymes. The induction of
HO-1 has been described as one of the most important antioxidant defense and protection
enzymes. Throughout the treatments, LOP acts as an acute oxidative stressor in the bone
marrow micro-environments and thus activates the release of metalloproteinases, of which
particularly MP-9 may favor the detachment of staminal cells. These cells, once in the blood
circulation, may be attracted to sites where a previous injury has taken place (Mancuso et al.
Lahodny (2021) collected ten blood samples with 70 μg/ml of ozone and reinfusion from a
patient as part of a session to implement the therapeutic concept. This therapy generated a
significant activation of stem cells, and subsequent rapid healing of wounds and inflammation
were documented in patients (Rowen 2018). Thanks to this therapy, a several-year defect was
cured in a mere 14 days (Mašán 2018).
Ozone therapy has a neuroimmunomodulatory effect, it activates the psychosomatic
system, thus allowing the release of the growth hormone ACTH-cortisol, neurotonic
hormones, and neurotransmitters. We clarified why patients report a feeling of euphoria and
wellness during therapy: the disappearance of asthenia and depression, a reduction of
pessimism syndrome, associated with a lack of side effects, represent positive results
(Fernández et al. 2008; Mancuso 2017).
CLINICAL APPLICATION OF OZONE THERAPY IN NEUROLOGY
The first beneficial effects of ozone in the treatment of neurological disorders refer to the
treatment of headaches and facial pain associated with pathological changes in the optic
thalamus. Ozone is used to treat allodynia, neuropathic pain, and hyperalgesia (Kal et al.
2017; Hu et al. 2018).
Neurodegenerative diseases – Parkinson’s disease, Alzheimer’s and Wilson’s disease, senile
and vascular dementia, amyotrophic lateral sclerosis, optic nerve dysfunction, bilateral
sensorineural hearing loss, and maculopathy, Huntington’s disease, cognitive and movement
disorders of the elderly who experience common effects of oxidative stress (Aso et al. 2012).
The process of aging is characterized by the loss of homeostasis, leading to pathologic
formation of reactive oxygen species (ROS), mitochondrial dysfunction, and metabolic
unbalance (Dugger et al. 2017). These pathophenotypes determine abnormal aggregation of
specific proteins (Yanar et al. 2020), given the connection between excessive ROS
accumulation and impairment in the proteostasis network. A natural bioactive molecule with
an antioxidant property such as ozone (O3) can be indicated as a potential new strategy to
delay neurodegeneration. This hypothesis is based on the evidence regarding the interaction
between O3 and Nrf2 (Galie et al. 2018; Siniscalco et al. 2018; Re et al. 2014; Vaillant et al.
2013). Molecular mechanisms related to antioxidant/anti-apoptotic/pro-autophagy processes
targeted by O3 administration via an Nrf2 biological pathway.
It is best to implement ozone therapy (O2-O3) in an early phase before the potential
development of a neurodegenerative pathology (Scassellati et al. 2020). The O2 availability
affects the expression of different hypoxia-inducible factors (HIFs) and plays the role of a
cellular adapter to hypoxia (Curro et al. 2018; Zhang et al. 2014; Re et al. 2014), leading to
the activation of trophic proteins and, consequently, to specific biological processes, including
erythropoiesis and angiogenesis (Zhou et al. 2019).
Antioxidant Property of Ozone (O3): Oxidative stress is a condition where ROS production
exceeds the cellular antioxidant defense system, leading to an imbalance between the two
systems, and this may contribute to neuronal damage. It has implications on the pathogenesis
and progression of neurodegenerative diseases (Singh et al. 2019).
Oxidative damage may impair the cells in their structure and function as a result of the
reduced activity of mitochondria. The damage is not confined to the brain but is also evident
in peripheral cells and tissues, which require a high-energy source such as the heart, muscles,
brain, or liver. To function properly, neurons rely on the mitochondria, which produce the
energy required for most of the cellular processes, such as neurotransmitter synthesis,
including synaptic plasticity.
Mitochondrial dysfunctions cause an increase in ROS for lowered oxidative capacity and
antioxidant defense, resulting in increased oxidative damage to protein and lipids, decreased
ATP production, and accumulation of DNA damage. Moreover, mitochondrial bioenergetic
dysfunction and the release of pro-apoptotic mitochondrial proteins into the cytoplasm initiate
a variety of cell death pathways (Garcia-Escudero et al. 2013; Reutzel et al. 2020).
Ozone therapy stimulates the Krebs cycle by enhancing the oxidative carboxylation of
pyruvate and stimulating the production of adenosine triphosphate (ATP) (Guven et al. 2008).
It causes a significant reduction of nicotinamide adenine dinucleotide (NADH), an increase of
the coenzyme A levels to fuel the Krebs cycle, and oxidizes cytochrome C (Brigelius-Flohe et
al. 2011; Elvis et al. 2011).
Ozone(O3)-influenced pro-oxidative and antioxidant defense biomarkers and their role in
aging processes and neurodegenerative disorders (ND). Twenty-nine biomarkers implicated in
oxidative stress, in endogenous antioxidant, and in vitagene systems have been identified.
These biomarkers have been studied and found modulated after O3 therapy performed in in
vivo (human and animal models) samples. Neurodegenerative disorders are characterized by
progressive loss of cognitive and behavioral deterioration (Scassellati et al. 2020).
Molecular Mechanisms Involving Ozone Therapy and Their Biological Relevance in
Neuroprotection of Nrf2, and the Vitagene Network. Oxidative stress is a condition where
ROS and nitrogen (RNS) production exceeds the cellular antioxidant defense system, leading
to an imbalance between the two systems and this may contribute to neuronal damage and
abnormal neurotransmission. ROS and RNS are also major factors in cellular senescence that
leads to an increase in the number of senescent cells in tissues on a large scale (Liguori et al.
2018). Cellular senescence is a physiological mechanism that stops cellular proliferation in
response to damage that occurs during replication. Senescent cells acquire an irreversible
senescence-associated secretory phenotype (SASP), involving secretion of soluble factors
(interleukins, chemokines, and growth factors), degradative enzymes such as matrix
metalloproteases (MMPs), and insoluble proteins/extracellular matrix (ECM) components.
When O3 is administrated, it dissolves immediately in the plasma/serum and it reacts with
PUFA (polyunsaturated fatty acids), leading to the formation of the two fundamental
messengers: hydrogen peroxide (H2O2) as a ROS and 4-hydroxynonenal (4HNE) as a lipid
oxidation product (LOP) (Bocci et al. 1998).
LOPs diffuse into all cells and inform them of minimal oxidative stress. After the
oxidative/electrophilic stress challenge (Ishii et al. 2004), other aldehydes (Levonen et al.
2004) induced by O3 (Galie et al. 2018, Siniscalco et al. 2018, Re et al. 2014, Vaillant et al.
2013) inhibit the Nrf2 conjugation, provoking the nuclear accumulation of Nrf2. This leads to
the decreased expression of pro-inflammatory cytokines.
Another mechanism involves casein kinase 2 (CK2), another regulator of Nrf2 activity
through its phosphorylation. It has been demonstrated that O3 influences CK2 levels together
with Nrf2 phosphorylation, reducing oxidative stress and pro-inflammatory cytokines in
multiple sclerosis patients (Delgado-Roche et al. 2017). Similarly, O3 inhibits oxidative stress
through inhibition of the mitogen-activated protein kinase phosphatase (MAPK) 1 signaling
pathway (Wang et al. 2018a).
Oxidative stress is one of the major drivers of protein misfolding that, accumulating and
aggregating as insoluble inclusions, can determine neurodegeneration (Hohn et al.
2020; Knowles et al. 2014). It is known that Nfr2 promotes the clearance of oxidized or
otherwise damaged proteins through the autophagy mechanism (Tang et al. 2019),
Interestingly, O3 can also modulate the degradation protein systems, not only via the Nrf2
pathway but also via activation of the AMP-activated protein kinase (AMPK)/mammalian
target of rapamycin (mTOR) signaling pathway, as demonstrated (Zhao et al. 2018).
O3 can protect against the overproduction of nitric oxide (NO) when NO is a toxic oxidant.
NO can rapidly react with other free radicals such as O2 − the highly reactive oxidant
peroxynitrite (ONOO) - and other RNS, which in turn damage the biomolecules (e.g. lipids,
protein, DNA/RNA), playing a key role in chronic inflammation and neurodegeneration
(Massaad, 2011; Toda et al. 2009), It has been demonstrated that O3 downregulates inducible
nitric oxide synthase (iNOS), which generates NO (Manoto et al. 2018; Smith et al.
2017) via NF-κB signaling.
CO acts as an inhibitor of another important pathway, NF-κB (nuclear factor kappa B subunit
1) signaling, which leads to the decreased expression of pro-inflammatory cytokines, while
bilirubin also acts as an important lipophilic antioxidant. Furthermore, HO-1 directly inhibits
pro-inflammatory cytokines and activates anti-inflammatory cytokines, leading to a balancing
of the inflammatory process (Ahmed et al. 2017). Our research group confirmed that mild
ozonization, tested on in vitro systems, induced modulation of genes including HO-1
(Scassellati et al. 2017),
In addition, Nrf2 also regulates the constitutive and inducible expression of antioxidants
including, but not limited to, Superoxide Dismutases (SOD), Glutathione Peroxidase (GSH-
Px), Glutathione-S-Transferase (GST), Catalase (CAT), and NADPH quinone oxidoreductase
1 (NQO1), phase II enzymes of drug metabolism and HSP (Galie et al. 2018, Bocci et al.
2015, Pedruzzi et al. 2012).
In this context, Nrf2 is considered a hormetic-like pathway (Calabrese et al. 2010). It
has widely been reported that the activation of Nrf2 by several different mechanisms (calorie
restriction, physical exercise, polyphenols) can be a way to improve health due to its
transcriptional modulation on the vitagene network. Nfr2 is strongly implicated in aging
processes (Zhang et al. 2015; Schmidlin et al. 2019; Silva-Palacios et al. 2018). These
conditions share common mechanisms, and the results represent a first attempt to structure
Nrf2 as a common therapeutic medicine approach. Research on the antioxidant activities of
O3 correlated with the interaction with Nrf2 (Galie et al. 2018; Siniscalco et al. 2018; Re et al.
2014; Vaillant et al. 2013). Different antioxidants can combat many associated pathologies,
including neurodegenerative disorders (Leri et al. 2020; Calabrese 2020). The mechanisms of
the positive effects of O3 are attributed not only to up-regulation of cellular antioxidant
enzyme activity, but also to the activation of the immune and anti-inflammatory systems,
modulation of NPRL3 inflammasome, action on the proteasome, enhancement in the release
of growth factors from platelets, improvement in blood circulation and O2 delivery to
damaged tissues, and enhancement of general metabolism (Scassellati et al. 2020).
The gradual escalation of the ozone dose enhances cerebral blood flow, improves metabolism,
and corrects chronic oxidative stress. Neuronal cells may reactivate the synthesis of
antioxidant enzymes, which is crucial to normalize the redox state and avoid cell death. The
local induction of haeme oxygenase-1 played a critical role in reducing oxidative damage.
The enzyme caused the local release of CO and bilirubin that acts as a potent antioxidant of
peroxynitrite (Clavo et al. 2004). The trace amounts can pass through the blood-brain barrier
to reach the sites of neurodegeneration and upregulate the cellular synthesis of antioxidant
enzymes, which is a crucial step towards readjusting the impaired cell redox system.
Neurodegenerative disorders affect approximately 50 million people globally and have a
terrific and increasingly negative social-economic impact on families and society. A better
understanding of degenerative events and the effects of ozone therapy during the early stage
of the disease may be able to slow down the demise of critical populations of neurons and
thus provide patients with a better quality of life through ozone therapy. The use of ozone in
the treatment of various diseases can have a therapeutic effect, provided that the correct dose
is administered at the right time interval and depending on the antioxidant capacity of the
tissue exposed, as well as ensuring the concentration is used within a non-toxic range. The
versatility of ozone therapy is due to the cascade of ozone-derived compounds able to act on
several targets leading to a multifactorial correction of various pathological conditions. Ozone
therapy can improve well-being and delay the negative effects of aging. The aging process is
essentially linked to the balance of oxidants and antioxidants, advanced glycation end
products (AGE), the role of genes and the immune system, the importance of telomeres and
telomerase, hormones, nutrition, environmental factors, and certain other factors. Stem cell
therapy, virtual reality rehabilitation, electromagnetic fields, and ozone therapy are among the
therapeutic approaches in the treatment of neurodegenerative disorders (Mitrečić et al. 2020).
Ozone Autohaemotherapy Induces Cerebral Metabolic Changes in Multiple Sclerosis
The oxygenated hemoglobin concentration is increased and the chronic oxidative stress level
typical of MS sufferers is reduced (Molinari et al. 2014). Ozone has an effect on biomarkers
of oxidative stress and inflammation, it significantly improves the activity of antioxidant
enzymes and increases the reduced cellular glutathione levels, and demonstrates antioxidant
and anti-inflammatory effects.
Ozone promotes Nrf2 phosphorylation, reducing oxidative stress and pro-inflammatory
cytokines in multiple sclerosis patients (Delgado-Rosche et al. 2017).
Mechanisms of vascular pathophysiology in multiple sclerosis patients treated with ozone
therapy demonstrate revascularisation and regeneration of the blood-brain barrier as a result
of immunoreactive glial cells coming into contact with blood vessel walls during ozone
therapy (Ameli et al. 2019; Biomed 2019). The cerebrovascular system enhanced by ozone
autohemotherapy in multiple sclerosis patients increases brain metabolism and helps them
recover from the lower activity levels that predominate in MS patients (Molinari et al. 2017).
At both primary and chronic stages of MS, antioxidant therapy is an active approach to
disease progression. O3 therapy increases total tissue-oxygen levels in patients with multiple
sclerosis. Ozone therapy is a therapeutic alternative for patients with multiple sclerosis
(Molinari et al. 2014; Simonetti et al. 2014).
Ozone therapy applied in acute ischemic stroke increases blood oxygen saturation,
improves blood circulation, activates erythrocyte metabolism, improves tissue oxygenation
and oxygen supply, restores cell function, promotes oxygen metabolism, and induces
thrombolysis by hydrogen peroxide (H2O2) formation (Qiu et al. 2021). Ozone was
administered daily via rectal inflation (at an ozone concentration of 40 mg/l and 200 ml) for
15 days. In the clinical phase, an improvement in the quality of life was recorded in 80% of
patients treated with ozone therapy Qiu et al. 2021). Ozone therapy has certain therapeutic
benefits for ischemic stroke patients. Jing Qiu, Hui-sheng Chen (2016) reported that ozonated
autohemotherapy substantially improved neurological function in stroke patients.
Neurological Deficits Treated with Ozone Therapy. Trigeminal neuralgia, postherpetic
neuralgia, meningitis, cervical myelopathy, demyelinating of nerves. Acoustic neuroma,
muscular neuropathy, and parkinsonism have shown satisfactory improvements
The treatment of trigeminal neuralgia with percutaneous ozone and injections into the
Gasserian ganglion has been shown to have positive long-term effects on pain (An et al. 2018;
Gao et al. 2020).
The treatment of phantom limb pain with ozone injection into the nerve root in the stump
was met with positive results (Li et al. 2020).
Ozone therapy in patients with pain secondary to chemotherapy-induced peripheral
neuropathy with cancer of the colon and rectum treated with oxaliplatin and rectal
insufflation sessions of O3/O2 as part of the ongoing randomized controlled trial
(O3NPIQ) (O3NPIQ) 2020 (Clavo et al. 2019). Chemotherapy-induced peripheral
neuropathy decreases the quality of life of patients and can lead to a decrease in and
interruption of chemotherapy treatment. Potential pathophysiological mechanisms involved in
chemotherapy include chronic oxidative stress and consequent increases in free radicals and
pro-inflammatory cytokines. Several antioxidant‐based therapies have been tested. On the
other hand, ozone therapy can elicit an adaptive antioxidant and anti-inflammatory response
that could prove to be useful (Clavo et al. 2021).
Ozone therapy in cerebral ischemia and hypometabolism in meningioma treated by
stereotactic radiosurgery. Following ozone autohemotransfusion treatment, there was an
improvement in brain perfusion and metabolism, as demonstrated by SPECT and PET scans
(Clavo et al. 2011). Rectal ozone therapy showed positive effects of improving
neurorehabilitation in children with infratentorial ependymoma (Mašán & Golská 2017).
Ozone therapy of resistant meningitis in infants – a mixture of ozone gas with pure oxygen
was used to treat resistant meningitis in infants with hydrocephalus and the infection was
cured (Dahhan 2015).
Endolumbal ozone therapy in the treatment of patients with a complicated spinal injury
in the acute period improved neurological symptoms (Yuldashev et al. 2020).
In the treatment of lumbar discopathy, ozone therapy is used with verified clinical benefits
in the treatment of lumbar disc damage. Ozone application methods can be administered
paravertebrally, juxtaforaminally, intradiscally (De Oliveira – Magalhaes et al. 2012; Mašán
2017; Li et al. 2020; Yuldashev et al. 2020).
Ozone therapy is a biological treatment method with a wide range of applications in
medicine. The versatility of ozone therapy is due to the cascade of ozone-derived compounds
able to act on several targets leading to a multifactorial correction of pathological conditions.
O3 therapy induces moderate oxidative stress when interacting with lipids, increases
endogenous production of antioxidants, local perfusion, and oxygen delivery, as well as
enhances immune responses. Oxidative stress occurs when there is an imbalance between free
radical formation and antioxidant defense and is associated with damage to lipids, proteins,
and nucleic acids. Ozone is being examined as a master regulator of multiple cytoprotective
responses, as a key actor across a wide range of diseases, and as a therapeutic objective for
aging and aging-associated disorders. It provides scientific evidence for the application of
oxygen-ozone (O2-O3) in the treatment of neurological diseases. Oxidative stress is currently
thought to play a significant role in the development of inflammatory diseases, ischemic
diseases, hypertension, Alzheimer’s disease, Parkinson’s disease, muscular dystrophy, and
The versatility of ozone therapy is due to the cascade of ozone-derived compounds able to act
on several targets leading to a multifactorial correction of various pathological conditions, as
well as cardiovascular, peripheral vascular, neurological, orthopedic conditions, skin diseases,
wound healing, diabetes, and lung diseases, including the pandemic disease caused by the
COVID-19 coronavirus. Ozone therapy also promotes tissue perfusion, immunomodulatory
effect, energy effect of the body, and has regenerative and reparative properties. It appears to
be a potentially effective treatment method. When the correct dose is administered, no side
effects occur. Further clinical and experimental studies will be needed to determine the
optimal administration schedule and to evaluate the potential combination of ozone therapy
with other therapies to increase the effectiveness of treatment.
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