Ozone Therapy for Fibromyalgia and Chronic Fatigue Syndrome

Fibromyalgia and chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) are very difficult conditions where patients seem to experience great benefits from ozone therapy. Conventional medicine considers these conditions to have no known cause, although many researchers speculate that mitochondria may play a role. Many alternative practitioners also consider mold, Lyme, long haul, and other infections or toxic exposures as potential contributors. This article shares potential mechanisms along with information from a number of published clinical trials using ozone therapy to treat these conditions.   

What are fibromyalgia and chronic fatigue syndrome / myalgic encephalomyelitis?

Fibromyalgia

Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, heightened pain sensitivity, and a constellation of systemic symptoms [1]. 

It affects about 2–4% of the global population, predominantly women, yet it remains one of the most misunderstood and underdiagnosed syndromes in modern medicine.

The hallmark symptom is persistent, diffuse pain lasting more than three months, often described as burning, aching, and stabbing [2]. 

Table source [3]

However, fibromyalgia is rarely limited to pain alone. Patients frequently report:

• Non-restorative sleep
• Chronic fatigue
• Brain fog
• Irritable bowel syndrome or irregularity
• Headaches
• Mood disorders
• Temperature dysregulation

Symptoms may worsen with stress, overexertion, hormonal changes, poor sleep, and even weather changes.

The current standard of care is multidisciplinary and mainly about symptom management. Pharmacological options include antidepressants, anticonvulsants, and muscle relaxants, along with other symptomatic treatments [4]. While these may reduce pain or improve sleep, their efficacy is variable. They also result in unpleasant side effects such as sedation, weight gain, and gut issues.

Non-pharmacologic interventions such as aerobic exercise, cognitive behavioral therapy, sleep hygiene, and nutritional support are also widely recommended, often with greater long-term benefit but requiring significant patient engagement.

Despite these approaches, many patients continue to suffer with unrelenting fatigue and pain [5].

CFS/ME

Chronic fatigue syndrome, also referred to as myalgic encephalomyelitis (ME), is a complex, multi-system condition defined by profound, unrelenting fatigue that is not improved by rest and is worsened by physical or cognitive exertion (post-exertional malaise). 

Post-exertional malaise is a hallmark feature of CFS/ME. It is a diagnosis of exclusion, often made after an extensive workup fails to reveal another clear cause for the symptoms [6].

In addition to fatigue, patients may experience:

• Unrefreshing sleep
• Brain fog
• Orthostatic intolerance or postural orthostatic tachycardia syndrome (POTS)
• Muscle and joint pain
• Sensory hypersensitivity
• Sore throat
• Enlarged lymph nodes

These symptoms may wax and wane but can become profoundly disabling, leaving many patients bedbound or homebound for extended periods.

Current treatments focus primarily on symptom management, as there are no FDA-approved medications for CFS/ME. 

So, doctors often recommend energy conservation strategies such as self-pacing, graded exercise, cognitive therapy, and autonomic stabilization.

Pharmacologic options, ranging from low-dose naltrexone and antivirals to stimulants and beta-blockers, are often used off-label, with mixed results. 

Notably, traditional exercise recommendations can worsen symptoms due to post-exertional malaise, making CFS/ME distinct from conditions like depression or deconditioning.

Despite decades of research, CFS/ME is not a very well understood condition. This leaves patients vulnerable to misdiagnosis, invalidation, and therapeutic trial-and-error [7].

Causes and contributors to fibromyalgia and CFS/ME that ozone therapy may help with

There is no single known cause of fibromyalgia and CFS/ME. However, the following contributing factors may explain many of the symptoms and how ozone therapy may hypothetically help.

Cell Danger Response

First described by Dr. Robert Naviaux, the cell danger response (CDR) is a survival mechanism triggered by cellular stresses such as infections, toxins, injuries, and traumas. It’s part of a freeze response when fight or flight cannot remove the danger [8]. It explains the chronic low-grade inflammation and key features of many chronic diseases, including fibromyalgia and CFS/ME.

The mitochondria sense the danger and initiate CDR, suppressing normal energy production and immune operations to contain and defend from the dangers, which can lead to:

• Mitochondrial dysfunction, which can reduce oxygen use
• Immune hypersensitivity
• Neuroimmune dysregulation

How Ozone Therapy May Help

Ozone introduces a controlled oxidative signal that jumpstarts cellular pathways stuck in defense mode. Through Nrf2 signaling and immune modulation, the ozone-oxygen therapy stimulates glutathione production and nudges the mitochondrial function back to normal.

The oxygenation can also counteract the lack of oxygen that can impair mitochondrial function and contribute to pain, especially in muscle and neural tissues. 

Chronic Infections

Chronic infections, whether overt or subclinical, can contribute to fibromyalgia and CFS/ME. 

Viral or bacterial fragments may persist in tissues and continue to provoke immune activation, particularly in individuals with genetic or acquired immune hypersensitivity [9].

This may explain why some patients report fibromyalgia flares after viral infections, dental procedures, or extreme stress periods [10], [11].

Many cases of CFS/ME begin after a viral infection, most notably [12], [13], [14]:

• Epstein-Barr virus
• Human herpesvirus
• Enteroviruses
• SARS-CoV-2 (long COVID) [15]

This points to a post-infectious or post-viral onset in many patients. The infections cause improper activation of immune cells (CD8+ T cells, NK cells) and elevated proinflammatory cytokines.

Caption: Entry points for ozone therapy in the dysfunctions affecting CFS patients. Ozone therapy increases 4-HNE, stimulates HO-1, and increases H2O2, which inhibits NF-kB. Image from [16].

These unresolved infections tend to provoke a chronic inflammatory state without resolution.

How Ozone Therapy May Help

Ozone therapy is uniquely suited to address chronic infections as ozone or ozonated byproducts can help with:

• Direct antimicrobial action 
• Immune modulation
• Improved tissue oxygenation
• Reduction of viral reactivation 
• Reduction of Herxheimer reactions

Medication Side Effects

Many medications can interfere with mitochondrial function or contribute to CDR, especially statins and antibiotics [17], [18], [19]. In some rare cases, these can cause changes in mitochondrial function, gut flora, toxic load, or nutrient status that contribute to fibromyalgia and CFS/ME.

How Ozone Therapy May Help

If fibromyalgia or CFS/ME arise after medications, ozone therapy may help with:

• Jumpstarting the mitochondria or the affected immune or gut microbiome responses.
• Supporting detoxification and reducing drug burden [20].
• Otherwise mitigating the symptoms to minimize more drugs or other interventions.

Ozone therapy may not replace all medications, but it has the capacity to reduce the therapeutic burden by addressing some root causes instead of compensating for them. 

Central Nervous System Dysfunction

Central to CFS/ME is autonomic nervous system dysregulation, particularly of the sympathetic (“fight or flight”) branch. This can lead to [21]:

• Orthostatic intolerance
• POTS (postural orthostatic tachycardia syndrome)
• Poor perfusion of muscles and brain tissue
• Difficulty with temperature regulation

In fibromyalgia, the term “central sensitization” causes the brain to have:

• A lower pain threshold
• Hypersensitivity to light touch or noise
• Exaggerated responses to physical or emotional stress

Functional MRI studies have shown abnormal activation patterns in various regions of the brain, even when there is no damage in the pain area [22].

How Ozone Therapy May Help

Ozone therapy impacts vascular tone and microcirculation through improved nitric oxide balance and oxygen delivery [23]. This can aid in correcting low blood supply common in CFS/ME [24]. 

Systemic ozone therapy may also have regenerative effects on the brain, for instance by increasing brain-derived neurotrophic factor (BDNF), which can mitigate brain fog [25], [26]. It may also increase levels of the relaxing neurotransmitter gamma-aminobutyric acid (GABA), which may improve pain modulation. Both GABA and BDNF improve sleep [26].

Test tube evidence suggests that ozone therapy may stimulate neural stem cells [27], while animal evidence suggests it may stimulate mesenchymal stem cells [28]. These are potential ways that ozone therapy can support the recovery of fibromyalgia and CFS/ME. 

Gut-Brain-Immune Axis

Dysbiosis and leaky gut contribute to many chronic diseases, including fibromyalgia and CFS/ME, though it’s unclear which is the cause and the effect [29], [30]. These gut issues can lead to changes in beneficial postbiotics and exposure of microbial byproducts to the immune system [31], [32]. For these two conditions, the gut disruptions lead to problems with the gut-brain-immune axis, which lead to inflammation both inside and outside the brain.

How Ozone Therapy May Help

As mentioned above, ozone therapy helps rebalance and regenerate the nervous and immune system. Also, systemic ozone therapy, especially rectal insufflation, helps normalize the gut flora, partly by jumpstarting the mitochondrial function in the gut barrier [33]. This creates a hospitable environment for good bacteria [34].

Clinical evidence supporting the effectiveness of ozone therapy for fibromyalgia and CFS/ME

Fibromyalgia

Study 1: A prospective clinical study enrolled 200 patients who were diagnosed with fibromyalgia (FM). All participants reported chronic widespread pain, muscle stiffness, fatigue, poor sleep, and mood disturbances consistent with FM diagnostic criteria [35].

The study evaluated the therapeutic effectiveness of autohemotherapy (O₂-O₃-AHT) in reducing pain and restoring musculoskeletal function.

Participants underwent 3–4 sessions of major autohemotherapy. Pain intensity was measured using a modified 10-point scale before the first treatment and one month after completing the therapy cycle.

Ozone autohemotherapy resulted in:

• 76% of patients experiencing complete rehabilitation of musculoskeletal function and significant pain reduction after one month.
• Major improvement in pain scores from 10 to 1–3 in 23.5% of participants after only two treatment sessions.
• 64.5% of the cohort demonstrated a clinically meaningful response overall.

These effects were significant, though age-dependent. These findings support ozone therapy as a promising adjunct or alternative to conventional fibromyalgia treatments.

Study 2: A randomized clinical trial of 51 patients with chronic musculoskeletal pain were randomized into three groups to the effects of the following on pain intensity and mitochondrial redox status [36]:

• A received ozone trigger point injections
• B received betamethasone injections
• C received a combination of ozone and betamethasone

The primary outcomes included changes in Visual Analog Scale (VAS) pain scores, reduced/oxidized glutathione ratio, and mitochondrial DNA copy number as indicators of redox and mitochondrial status. Measurements were taken at 3 days, 1 week, and 3 weeks post-treatment.

Treatments results showed that Group A (ozone) and Group C (combined) displayed:

• A significantly greater pain reduction (VAS) at all time points (p < 0.02) than Group B.
• Significantly improved reduced/oxidized glutathione ratio compared to Group B (p < 0.008), suggesting antioxidant restoration.
• Significantly higher mitochondrial copy number compared to Group B (p < 0.002).

Ozone therapy, alone or in combination with corticosteroids, led to greater and longer-lasting pain relief than steroid therapy alone, while also improving mitochondrial function and redox balance. 

These findings support the use of ozone therapy as a mitochondrially targeted and redox-restoring intervention in chronic musculoskeletal pain, which may be relevant to fibromyalgia pathophysiology.

Study 3: A clinical trial assessed the short/medium-term efficacy of major ozone autohemotherapy on core fibromyalgia symptoms and functional limitations on 25 patients diagnosed with fibromyalgia syndrome (FMS) [37].

Patients received 10 sessions of major autohemotherapy (MAH), administered twice weekly over five weeks. Outcomes were measured at baseline, immediately post-treatment, and six months post-treatment.

MAH resulted in:

• Pain scores (Visual analog scale, VAS) decreasing significantly from 6.4 to 3.68 immediately post-treatment (p < 0.001).
  
  • A modest rise to 4.12 at six months (p = 0.01), indicating sustained though partially attenuated pain relief.
• Tender points dropping significantly from 14.36 to 9.8 (p < 0.001).
• Functional scores (Fibromyalgia Impact Questionnaire for daily function) improving significantly from 59.2 to 39.08 (p < 0.001).
• Significant improvements in fatigue, sleep quality, anxiety, and depression scores, with similar trends of initial benefit followed by partial symptom return.

Study 4: A randomized, double-blind controlled clinical trial of 66 patients diagnosed with fibromyalgia (FM) and 25 healthy individuals evaluated whether ozonated water enemas could alleviate fibromyalgia symptoms. Outcome measures included pain, anxiety, sleep disturbances, and medication (duloxetine) needed through modulation of intestinal dysbiosis [38]. 

Participants were randomized into two groups:

• Ozone group: received ozonated water enemas
• Control Group: received deionized water enemas

Ozonated water enemas resulted in:

• Statistically significant improvements in all measured symptoms, including reductions in pain, anxiety (Hamilton Anxiety Scale), sleep disturbance (Pittsburgh Sleep Quality Index), and pain distribution (Widespread Pain Index), compared to the control group at each follow-up (p < 0.001).
• Significantly lower duloxetine doses compared to controls (p < 0.001), suggesting reduced reliance on pharmaceutical intervention.
• Improvements in microbial diversity and balance based on fecal stool microbiota, bringing patients' profiles closer to that of the healthy comparison group.

These results may have been influenced by confounders such as diet, medication use, and environmental factors. The trial had a modest sample size, and long-term symptom tracking beyond three months was not included.

These findings support the gut-muscle-nerve axis as a targetable pathway in fibromyalgia and position ozone-based therapies as promising interventions.

Study 5: An uncontrolled open-label pilot study examined the effects of ozone rectal insufflation on fibromyalgia symptoms in 33 female and 3 male patients.

The treatments included 24 sessions during a 12-week period, where 8 mcg of ozone in 200 mL of gas were administered at the following frequencies:

• 5 days a week during the first two weeks
• Twice a week during weeks 3–6
• Weekly from weeks 7–12

The Fibromyalgia Impact Questionnaire scores decreased significantly, especially during the first four weeks. Depression scores and physical summary scores also significantly improved. Ten (27.8%) of the patients experienced clinically relevant improvement in fibromyalgia severity, while 15 (41.7%) showed lower clinically relevant pain scores. 

This study doesn’t directly compare with major autohemotherapy; the percentage of patients with clinically relevant improvements are lower than the MAH studies. The lower percentage of patients with improvements than in studies 1–3, suggests that rectal insufflation is beneficial, but possibly less so than autohemotherapy or that higher doses may be better.

CFS/ME

Study 1: An open-label, observational clinical study of 200 CFS/ME patients evaluated the efficacy of autohemotherapy in reducing fatigue [39].

Patients received major autohemotherapy and treatment outcomes were measured using the Fatigue Severity Scale (FSS). Patients were assessed at baseline and 30 days post-treatment, with follow-up extending to three months.

Autohemotherapy resulted in the following:

• 43.5% of patients reported the maximum possible improvement, transitioning from an FSS score of 7 (severe fatigue) to 1 (minimal fatigue). 
• 77.5% of patients showed a clinically significant improvement of 4–6 points on the FSS scale. 
• Patients reported a sustained disappearance of fatigue for up to three months post-treatment. 
• No adverse effects were reported, and treatment response was independent of sex or age.

Study 2: An observational clinical case series evaluated the clinical efficacy and safety of autohemotherapy in 65 patients with CFS using standardized fatigue metrics and long-term observation. The cohort included 50 females and 15 males, ranging in age from 13 to 60 years, with disease duration between 1 to 15 years [40].

The protocol according to the iScientific Society of Oxygen Ozone Therapy involved:

• Twice-weekly major autohemotherapy sessions for one month
• Followed by twice-monthly maintenance therapy

Treatment resulted in:

• 80% (52 out of 65) of patients reported a >50% improvement in fatigue symptoms. 
• No side effects were reported across the treatment population. 
• Patients frequently experienced enhanced well-being and mood stabilization

The authors speculated that these improvements may relate to better hormonal and neurotransmitter function, as well as muscle metabolism and oxidative stress balance.

This was the largest cohort study for ozone therapy for CFS.

Ozone Therapy Protocols for Fibromyalgia and CFS/ME

Across these studies, protocols vary in delivery method, frequency, and duration. Despite that, several consistent patterns emerge.

Delivery methods include:

• Major Autohemotherapy (MAH): The most studied and often administered twice weekly for 4–5 weeks, followed by maintenance sessions (e.g., biweekly or monthly).
• Rectal Insufflation, such as 8 mcg of ozone in 200 mL of ozone-oxygen gas.
• Ozonated Water Enemas: A non-invasive alternative, administered at similar frequencies.
• Local Injections: Such as trigger point ozone, may offer benefits extending beyond localized pain relief.

Dosing typically follows established SIOOT protocols, using low to moderate ozone concentrations (20–40 μg/mL) depending on route and individual tolerance.

Safety Profile

No significant adverse events have been reported in all the clinical trials that collectively included hundreds of patients. Some studies even report secondary benefits like improved mood and vitality, possibly due to ozone’s modulation of brain pathways and anti-inflammatory signaling. The only side effect of rectal ozone insufflation is temporary gas or flatulence.

Anecdotally, many people with fibromyalgia and CFS/ME are very sensitive, especially if their symptoms relate to toxicity or infections. Some have anecdotally reported temporary flares after an ozone treatment. Therefore, it’s crucial to work with an experienced practitioner, like Drs. Christine Schaffner and Jess Peatross, to:

• Address the foundations and ensure that the detox pathways are open.
• Gradually introduce binders. 
• Titrate up ozone doses from low-dose to optimal dose, to minimize Herxheimer. reactions. I do not recommend starting with the highest possible doses of ozone, such as EBOO or 10-Pass.

Sustainability of Benefits

Most studies report robust short-term gains in pain, fatigue, and mood, with some degree of partial regression by 3 to 6 months. If a patient wanted to sustain ozone benefits, maintenance therapy, dietary and lifestyle alignment, and personalized treatment schedules would be important to incorporate. 

Patient Expectations

Individuals with FM or CFS/ME considering ozone therapy should not expect an immediate cure, but rather progressive symptom relief across domains like energy, sleep, pain, and mood. 

Responses are typically dose- and time-dependent, and treatment may need to be repeated cyclically or maintained over time for sustained benefits.

Conclusion

Conventionally, fibromyalgia and CFS/ME remain hard to diagnose and treat. Yet, ozone therapy can be tremendously helpful for both symptom management and recovery of these conditions, whether alone or combined with other therapies.

To be clear, ozone is not a panacea. It does not erase trauma, cure infections overnight, or substitute for the foundational work of sleep, nutrition, and nervous system regulation. 

In some rare cases, it does feel like a miracle cure. Keep in mind, however, that it can also trigger flares and you want to approach it cautiously, ideally with professional guidance. 

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