Given that my Monday post for my not-so-secret other blog ended up being a lot longer than expected and the previous Monday’s post is now basically out of date, making my tradition of reposting it a week later not particularly viable, I was left without a good topic for this Monday, something that I could handle quickly. Of course, COVID-19 quackery is always a relevant topic, unfortunately. So it was late last night that I saw an article with what might be the wackiest quackery for COVID-19 that I’ve seen since President Trump suggested that taking disinfectants internally or using UV light to kill coronavirus could be viable treatments for COVID-19. I’m referring to rectal ozone to treat COVID-19, as described by Brazilian microbiologist Natália Pasternak and journalist Carlos Orsi:
I’ve written about ozone therapy (and the related quackery of intravenous hydrogen peroxide) on a number of occasions before. Both are quack treatments beloved of naturopaths. Basically, at the moment parts of Brazil, which is being hard-hit by the pandemic, appear to be a quack’s paradise, complete with homeopathy and rectal ozone as treatments for COVID-19:
The town of Itajai in the southern Brazilian state of Santa Catarina has been the focus of much puzzlement during the ongoing COVID-19 pandemic. The town’s mayor – who is a medical doctor – has adopted a particularly striking strategy: to throw at the virus every conceivable alternative therapy or social media hype he can find.
It started with homeopathy, which he wanted to distribute as a prophylactic, using healthcare agents to deliver it personally to people’s homes, before moving on to hydroxychloroquine, then ivermectin and more recently, ozone therapy delivered by rectal insufflation. You don’t have to be an expert in medical terminology to work out how the ozone makes its way into the patient.
This last one, announced in early August, attracted a lot of attention – not just because of the obvious cheap jokes, but also because, in Brazil, the most vocal promoters of ozone therapy have strong links with the antivaccination movement, and they have powerful friends in high places.
“Ozone therapy” is the putative use of ozone to treat health complaints. As it is common in the world of so-called complementary and alternative medicine, ozone has been proposed as a cure for every disease and condition under the sun, from HIV infection to cancer. Predictably, it has also been offered as a form of relief for COVID-19.
Because of course it is. If there’s one thing about quackery that I’ve learned, it’s that if a quack claims a treatment is good for one condition or disease, he’ll claim it’s good for a whole lot of conditions and diseases, even if their pathophysiologies have nothing to do with each other. Indeed, naturopaths tout ozone therapy for a wide variety of diseases and conditions, including, but not limited to, cancer, autoimmune disorders, cardiovascular disease, Alzheimer’s, diabetes, and HIV. But how, pray tell, does ozone work, supposedly? Well, this paper published in May, besides making lots of claims for high dose intravenous vitamin C for COVID-19 (another treatment beloved of naturopaths that’s used for just about everything, from cancer to heart disease to, now I guess, COVID-19), makes a number of claims. After explaining that ozone is generated by passing oxygen through a voltage gradient, first, it tries to reassure readers by arguing that the ozone concentration being used is really quite low, with most of the gas being just oxygen:
This yields a gas mixture consisting of at least 95% oxygen and no more than 5% ozone; for example, a concentration of 50 µg contains 97.5% oxygen and 2.5% ozone. A medical ozone generator produces ozone concentrations ranging from 1 to 100 µg/ml, but concentrations of 15–70 µg/ml are used for medical purposes. Ozone therapy is simple to administer, extremely effective, well tolerated, and has virtually no side effects.
Always with the “no side effects” claim! Yet ozone is unstable and highly reactive, the most powerful natural oxidizing agent known because of the oxygen free radicals that it generates upon decomposition, molecules that oxidize and can destroy biological molecules. Even the widely cited and trusted (by alternative and “integrative” medicine practitioners, anyway) Natural Medicines Comprehensive Database classifies ozone therapy as “likely unsafe,” which means that there is enough reliable clinical evidence showing significant adverse outcomes. Its summary even concludes that there is insufficient evidence to rate ozone therapy as effective for any medical condition.
I said that intravenous hydrogen peroxide “therapy” is highly related to intravenous ozone. That is because, as Saul Green wrote in Quackwatch a long time ago, once in the bloodstream, ozone reacts with the water in the blood to produce hydrogen peroxide and reactive free radicals. He also notes that infusion of ozone into the blood is not safe:
At the end of his paper on how to infuse hydrogen peroxide intravenously, Farr cautions that the capacity of the lungs to allow gas embolism diffusion is limited. A continuous infusion of peroxide that results in 0.01 volume per 100 ml blood can cause an arterial gas embolism and irreversible lung damage . That such adverse reactions do occur is clear from reports in the medical literature. These incidents include: oxygen gas emboli, necrosis and gangrene following peroxide enemas or colonic lavage [37-41,]; emphysema following peroxide mouth wash or gargle ; and ulcerative colitis, gas embolism, and emphysema following deep wound irrigation [43-45]. Peroxide ingestion results in respiratory arrest, seizures, gas embolism in the portal circulation, shock, and acute hemolysis. [46-48] Stroke and multiple cerebral infarcts  and venous embolism follow irrigation of anal fistula and irrigation of surgical wounds . In contrast, the literature published by proponents of oxygenation therapy contain no report of adverse clinical incidents resulting from ingestion or infusion of hydrogen peroxide.
We worry about gas emboli all the time in medicine whenever we infuse anything into patients, particularly if the infusion is into the central venous system through a catheter sitting in the superior vena cava or in the femoral veins draining straight into the inferior vena cava, as both veins drain directly into the heart, with the blood going out to the arterial circulation from there. It’s why special care is taken to make sure that no more than tiny bubbles are introduced into the IV line, particularly when that line goes into the central venous circulation. Moreover, procedures that involve using gas to insufflate structures (such as during laparoscopy, when carbon dioxide is used to “inflate” the peritoneal cavity in the abdomen) can result in gas emboli, as the increased pressure of gas in the abdomen can find its way into the circulation. Really large gas emboli can cause the heart to cease to be able to pump, as bubbles introduced into the right atrium and ventricle can result in outflow tract obstruction.
Claiming that its biological properties suggest that “ozone therapy could be administered to complement standard COVID-19 treatment regimens,” the authors next claim:
The coronavirus envelope is rich in cysteine, and viral activity depends on the conservation of these residues. Cysteine contains a thiol or sulfhydryl group (–SH); many viruses, including coronaviruses, require these reduced sulfhydryl groups for cell entry and fusion.36 Sulfhydryl groups are susceptible to oxidation, and therefore to the oxidizing effect of ozone. Peroxides created by ozone administration oxidize cysteines37, 38 and show long-term antiviral effects that can further reduce viral load. Once their capsid is removed, virions cannot survive or replicate, and the creation of dysfunctional viruses due to the action of ozone offers unique therapeutic possibilities.
Ozone also has an immunomodulating action through the activation of various cytoplasmic transcription factors by second messengers, specifically: (1) hypoxia-inducible factor 1-alpha (HIF-1-alpha), (2) nuclear factor Kappa B (NF-κB), and (3) nuclear factor erythroid-2-related factor 2 (Nrf2). These factors release proteins that set in motion all the beneficial mechanisms associated with ozone. Some are activated or modulated before others, which is why ozone therapy is a cumulative dose treatment.
This is pure speculation. Ozone can inactivate HIV in a test tube as well, but it’s never been shown to have any clinically relevant therapeutic effect in patients with HIV infection. The claim for immunomodulation is also pure nonsense. I used to study how a certain treatment affected NF-κB activity, and I know that all sorts of nonspecific stimuli can also activate this particular signaling pathway. Similarly, stress alone can cause HIF-1α activation. These are basically nonspecific responses that could be induced by oxidation of the cell membrane.
The authors also claim that ozone can increase tissue oxygenation, based on its ability to increase oxyhemoglobin through the increase of a molecule known as 2,3-DPG, but this is also untrue. Basically, ozone produced by ozone generators is mostly oxygen, and in the average human the oxygen-carrying hemoglobin in the red blood cells is saturated. Adding a little more oxygen in the aqueous solution of plasma in which the red blood cells float won’t do much, if anything. Sure, seriously ill COVID-19 patients have low blood oxygen levels leading to low oxygen saturation, but adding a little ozone in oxygen to the blood is not going to raise the hemoglobin level in these patients. To do that, you’d need to bypass the lungs and place the patient on ECMO.
But why rectal insufflation, in which the gas is introduced exactly where you think? Searching for “rectal ozone COVID-19” sent me right down quite the rabbit hole, including this preliminary clinical trial from Spain of rectally insufflated ozone in patients with severe COVID-19 pneumonia:
Several studies (from Cuba, Italy, Germany, Russia, and Spain) and years of experience have shown that ozone (O3) is capable of modulating inflammation and pain, in addition to having demonstrated a bactericidal, fungicidal, virucidal, and antiparasitic effect [4, 5]. These antimicrobial properties have made ozone recognized as a disinfectant so effective that it is used in many water purification plants worldwide . In this context, in a recent review, Fernández-Cuadros et al. reasonably considered that ozone has a place in the management of the present SARS-CoV-2 pandemic, due to its virucidal, immunomodulatory, stimulating cellular and humoral immunity properties, and as a facilitator of O2 transport in hypoxemic tissues .
In the SARS-CoV-2 infection, three evolutionary stages are recognized (early infection (stage 1), normoxic and hypoxic lung phase (Stage 2a and b), and systemic hyperinflammation or cytokine storm (stage 3)), with characteristic signs and clinical symptoms . In this scenario, Fernández-Cuadros et al. consider that at least 4 biological properties of O3 could allow its use as adjuvant therapy in the different phases of SARS-CoV-2 infection. Ozone could inactivate the virus by direct (O3) or indirect oxidation (ROS (reactive oxygen species) and LOPs (lipid oxidative products)) and could stimulate the cellular and humoral immune system being useful in the early COVID-19 infection phase (stage 1 and 2a). Ozone improves gas exchange, reduces inflammation, and modulates the antioxidant system, making it useful in the hyper inflammation or cytokine storm phase, and in the hypoxemia and / or multi-organ failure phase (stage 2b and stage 3)  (Table 1).
The objective of this article is to show the preliminary results on the effectiveness of rectal O3 in a small series of COVID-19 patients with severe bilateral pneumonia admitted at the Santa Cristina University Hospital in Madrid, Spain.
This is quackademic medicine at its most egregious! The authors describe this as a “prospective quasi-experimental before-and-after” study. They looked at four patients with severe COVID-19 pneumonia admitted in April and May 2020, whom they treated with something called the Madrid International Ozone Therapy Declaration, which involves administering intrarectally a volume of 100 mL of rectal ozone, at a concentration of 35 μg/mL for 5 to 10 days, according to the severity of the patients.. These patients had also received several other treatments prior to rectal ozone, including hydroxychloroquine and azithromycin (of course!), corticosteroids (which actually do help in severe disease), and other treatments that varied somewhat between patients. I can’t help but note that, although there were inclusion and exclusion criteria listed, there’s no clear statement of how these patients were selected, which of course allows for the possibility of cherry picking patients. Moreover, just because these patients ultimately got better does not mean that the rectal ozone had anything to do with it.
There is a strange disconnect at the heart of “natural” medicine, as practiced by naturopaths and “integrative medicine” practitioners. After all, how “natural is it”to generate ozone using an electrical generator on oxygen artificially isolated from the air and then shooting the gas up a patient’s butt? And if that’s “natural,” then why isn’t it also “natural” to synthesize a drug chemically based on a natural compound and then to use that to treat a disease?