Ozone Therapy

I was recently asked if ozone therapy is scientifically legitimate. It’s an excellent example of how challenging it can be to answer what may seem like a straightforward question. This difficulty is exacerbated by the culture of alternative medicine, which actively seeks to blur the lines of science and pseudoscience and exploit the complexity and gray zone of clinical evidence.

The question, as asked, is unanswerable, other than to say – it depends. What you really need to ask is if a specific type of ozone therapy is safe and effective for a specific indication. Asking if hyperbaric ozone is effective for healing skin ulcers is very different than asking if autohemotransfusion of ozone is effective for fibromyalgia. But often practitioners operating outside the bounds of a science-based approach to medicine will use evidence for a narrow scope of effect to say that a treatment is generally effective (without qualification). They might claim that acupuncture works or homeopathy works, which are nonsensical statement. They are equivalent to saying surgery works, or drugs work. However, there is no convincing evidence that acupuncture or homeopathy work for anything, so that is one difference.

Ideally we would also want to dive deeper than specifying treatment type and indication. Clinically, we also want to know the dose and duration of treatment, and if there are any patient demographics that modify the safety or efficacy of the treatment. For example, a clinically useful and scientifically valid statement might be – ozonated oil at a specific dose, when applied at a specific frequency over a determined length of time, had a specific and measurable beneficial effect in diabetic patients with infected skin ulcers of a certain range of severity.

From a basic science perspective, we also like to know what the mechanism of action is. While this is not necessary in order to establish clinical safety and efficacy, it does potentially modify the amount and quality of evidence that would be necessary to reach a threshold of recommending the treatment. If the putative mechanism (such as with homeopathy) is that it’s magic, then that threshold should be extremely high. If the mechanism is plausible and already shown to have some biological effect, a more standard threshold can be used.

Let’s apply this approach to the broader question of ozone therapy, breaking it down appropriately. Ozone is a highly reactive gas comprised of three oxygen atoms (O3). It is found in the upper atmosphere, and is important in its UV blocking effects. You may also encounter ozone when electrical equipment shorts out, the energy creating ozone from oxygen in the atmosphere, and you likely have smelled it.

One potential biological effect of ozone is antimicrobial. Because it is a highly reactive gas it may break down bacterial cell membranes. This reaction will liberate oxygen, which can have further negative effects against anaerobic bacteria. This seems to be the one well-established effect of ozone. Treatments which expose external skin infections to ozone have been shown to be effective in promoting wound healing. However, I need to point out that the FDA has not approved it for this use, and more research is needed to make specific recommendations.

This specific effect, however, cannot be used to support the efficacy for ozone therapy for any other indication or any other putative mechanism. There may be other potential mechanisms of action, but at this point they are hypothetical. One that is often cited is that exposure to ozone may trigger a temporary upregulation of antioxidant enzymes. I find this putative mechanism  particularly unconvincing, since the anti-oxidant hypothesis has been shown to be far more hype than reality. This is also often offered as an all-purpose mechanism by alternative practitioners for any fad treatment they wish to sell.

Putative mechanisms include:

i) Increasing oxygen levels, glucose and ATP transporter molecules in ischemic tissues; ii) increasing the activity of bone marrow stem cells, so as to promote angiogenesis and tissue regeneration; iii) the upregulation of the expression of antioxidant enzymes in blood; iv) Promoting the neuronal medium rise; and v) Inducing growth factors

Again, I find these potential mechanisms frequently appear promoting dubious treatments. That does not mean they are wrong or can’t possibly be effective, but I find they are commonly over-called. A lot of basic science research looking for possible mechanisms of action fall into the “stuff happens” category. Cells, tissue, and organisms react to stimulation, especially trauma. The immune system will respond, and compensatory homeostatic mechanisms will kick in. This does not mean they are a mechanism for any meaningful or enduring biological effect that can be exploited for clinical benefit. That is a huge leap, one that cannot be made automatically, and historically the one that most often fails. Most putative mechanisms turn out not to be clinically meaningful, or have more downsides than upsides.

There is also commonly a lot of post-hoc reasoning. Anything that happens can be spun into a potential benefit – increasing or decreasing some measure of immune activity, increasing or decreasing oxygen, increasing or decreasing blood flow. It’s all good.

At this time the FDA states about ozone therapy:

Ozone is a toxic gas with no known useful medical application in specific, adjunctive, or preventive therapy. In order for ozone to be effective as a germicide, it must be present in a concentration far greater than that which can be safely tolerated by man and animals.

That is the key – even if there are effects which are potentially beneficial, we need to know if these effects occur at a dose and type of exposure that will not cause intolerable side effects.