What is the role of ozone therapy in "brain fog"?


Brain fog, or mental fatigue, is a recently coined term that gained popularity especially in the context of post-viral syndrome. It is a condition where a person feels confused, forgetful and lacking the mental clarity. People describe thinking as sluggish and fuzzy. This can be transient and completely normal e.g when ill, overworking, not sleeping or when stressed. It can also be a side effect of some medication such as antidepressants or antihistamines. It becomes pathological when it is more persistent, lingering and has no clear explanation or when it is associated with other physical symptoms. Causes of brain fog are diverse with clearly identifiable causes in some people e.g thyroid problems or low vitamin B12. However the recent increase in the incidence of this condition is probably related to the post-viral syndrome. It is well known that some viruses can invade the brain and the nerves, causing a multitude of conditions such as encephalitis, loss of smell (damage to the nerve concerned with smell which is in direct connection with the brain), or the damage can be causes by the body’s vigorous immune response. 


Before delving in to alternative and complementary therapies, it is important that people with persistent "brain fog" visit their doctor to ensure no treatable causes are missed. If no cause(s) is identified, there are a number of strategies to help. Exercise, good sleep, healthy diet or vitamins are a good start. 


Ozone has been suggested as a possible treatment for brain fog, especially in the context of post-viral syndrome. A cardinal feature of any severe illness or infection is the imbalance of the oxidant/antioxidant system. Certain infections are capable of vigorously provoking the immune system leading to a severe and prolonged oxidative stress. Consuming more antioxidants eg vitamin C or the more powerful antioxidants glutathione (infusions) to counteract the oxidative stress nevertheless has limitations. The concentration of these nutritional antioxidants may not reach the required levels in the blood, especially after oral ingestion, or they are rapidly metabolised and excreted by the body thus limiting their long term effect. In contrast, ozone therapy raises the anti-oxidant capacity by improving the body's mechanisms to produce more anti-oxidants. 


The Cuban Health Ministry recently commissioned a study on the use of ozone therapy in patients with prolonged post viral symptoms, including mental and physical fatigue compared to an antioxidant supplement. The results are in favour of ozone therapy. Please follow the link to the published study. This study is high quality evidence despite it being done on a small number of patients. 

Does ozone work in Lyme disease?

There are reports of ozone therapy being used to successfully treat patients with this illness. Apart from isolated case reports, there are no trials involving larger numbers. The German ozone Society for the use of medical ozone confirms the positive role of ozone in empowering the immune system to fight off infections, including those that evade the surveillance of the immune cells, although it makes no specific reference to Lyme disease. Similarly, the Madrid Declaration on Ozone Therapy in its latest edition does not specifically mention Lyme disease, although it makes reference to ozone being useful in chronic infections in general.


The significant number of anecdotes of a positive response from ozone in Lyme disease should not be ignored. However, in the absence of larges trials it is difficult to make any claims or give a decisive answer. We at Leicester Ozone Clinic have not accumulated the numbers (and I do not think anyone has) needed to be able to comment on the use of ozone in Lyme disease. However anecdotally patients feel better and more energetic after ozone therapy but they may require as many as 20 therapies to reach that level with some needing maintenance therapy once or twice a month. Boosting immunity, improving the antioxidant capacity and tissue oxygenation are the right recipe to help with most chronic infective and inflammatory processes, including lyme disease. 



What is the difference between hyperbaric oxygen and Ozone therapy?


Hyperbaric Oxygen Therapy (HBOT) involves breathing in pure oxygen under increased pressure in a special pressurised chambers. This form of therapy is available on the NHS for specific medical condition, e.g for radiotherapy side effects. It has also been promoted as a complementary therapy e.g for chronic fatigue and post-viral illnesses. 


Most oxygen carried in the blood is bound to haemoglobin with only a small percentage of oxygen dissolved in the plasma (the liquid part of the blood). It is this proportion of oxygen that can be increased if oxygen is inhaled at high pressure. Breathing oxygen at high pressure thus increases the blood oxygen-carrying capacity by allowing the plasma to carry more oxygen. The proportion carried in plasma can be sufficient on its own to support tissues without a contribution from haemoglobin. As the oxygen is in solution, it can reach physically obstructed areas where red blood cells cannot pass. This enables tissue oxygenation even with impaired haemoglobin oxygen carriage, such as in carbon monoxide poisoning and severe anaemia. This can create an environment that is more conducive to healing such as in trauma, severe infections, radiotherapy damage to blood vessels and skin grafts.  


Extra oxygen in the blood however causes vasoconstriction (narrowing of blood easels) but this is more than compensated for by increased plasma oxygen carriage with the net result in favour of more tissue oxygenation. Such vasoconstriction does however reduce tissue swelling, a desirable effect in crush injuries and burns.


HBOT also has an effect on fighting infections, particularly those caused by bacteria that prefers low-oxygen environments (anaerobic bacteria). Oxygen also facilitates an oxygen-dependent defence system by which the white cells kill bacteria. 


In summary, HBOT has complex effects on immunity, oxygen transport and haemodynamics. The positive therapeutic effects come from a reduction in hypoxia and oedema, enabling normal host responses to infection and ischaemia.


From the above description you can see some similarities between ozone therapy and HBOT, in particular the improvement in tissue oxygenation and the effect on the immune system. However there are some important differences in the underlying mechanisms of action. For example: HBOT improves tissue oxygenation by directly providing more oxygen to the tissues from breathing 100% oxygen at high pressure. This effect does not persist long after the end of of the session, a reason why HBOT usually needs prolonged daily or even twice daily sessions. This is because oxygen is rapidly utilised by the body once the external source of oxygen is interrupted. Ozone therapy on the other hand improves delivery of oxygen to the tissue by a completely different mechanism: ozone increases the level of a specific enzyme in red blood cells called 2,3-diphosphoglycerate (2,3-DPG) which helps the red cells to offload more oxygen to tissues. The levels of 2,3-DPG do not fall immediately following cessation of the ozone session thus allowing a prolonged and a more natural increase in tissue oxygenation. 

Secondly, the effect on the immune system is more complex with ozone therapy with signalising cascades put in motion creating a whole host of effects on the immune cells, including inducing the cytokines system. Ozone also has a direct toxic effect on micro-organisms. 


It is also important to remember that ozone therapy involves giving at least 95% oxygen in addition to ozone. The oxygen simply works as a career to deliver ozone to interact with the blood, or when locally applied such as in the treatment of ulcers, oxygen and ozone work together to improve tissue oxygenation (both) and sterilising the ulcer (ozone only). 


In summary: Ozone and HBOT share some similarities with ozone having more modes of action and more sustained effect. Ozone is also delivered as a mixture with oxygen but most of the beneficial actions are mediated by the ozone.  


The "10 passes" and "EBOO" vs low ozone concept, which is better?

There are 2 ways to deliver ozone into the body:


1- The Extracorporeal (outside the body) method: This entails extracting blood and mixing it with ozone outside the body. In this category, there are 3 main techniques: a) the Major Autohaemotherapy (AHT): this is the preferred European technology using vacuum bottles; b) the multi-passes system: Repeated (up to 10) volumes (also called passes) are extracted and mixed with ozone before returning each pass back to the body; c) EBOO (Extracorporeal Blood Oxygenation and Ozonation which is similar to performing haemodialysis and adding ozone to the blood as it passes through the machine in low steady concentrations.   


2- The Intracorporeal (inside the body) method: This entails injecting the ozone directly in the veins where it circulates and mixes with the blood inside the body. There are 2 ways to do this: a) Direct gas injection: This is dangerous and prohibited by all ozone scientific societies around the world; b) Ozonated Saline: This is the Russian traditional method (see next QA) and the only method of safe intracorporeal administration. It is done by continuously passing ozone gas through the infusion solution and administering the mixture. 

Despite the publicity of the EBOO and the 10-passes, the fact remains that these methods are not endorsed by the reputable ozone societies in the countries that pioneered ozone therapy e.g European countries (including the German Ozone Society) or Russia. These scientific societies advocate a different approach where the volume of blood and the dose of ozone has to be carefully calculated based on body weight and the body's tolerance to ozone in order to give the maximum benefit without toxicity. The practice of high doses ozone is however prevalent in some private clinics in countries where ozone therapy practice is not regulated eg UK and USA.

It is claimed that the 10 passes or EBOO give better results because of the higher volume of blood ozonated. It is also claimed that the 10 passes ozonate 10 times the blood volume in comparison with the Major AHT, which could amount to 2 litres (about half of the blood volume in an adult). This conclusion is based on this simple calculation: 200 ml per pass x 10 times = 2 L.

The above argument may seem logical but it is scientifically incorrect. Firstly: The blood inside the body is not stationary, the heart pumps the whole blood volume every 1 minutes. This means that when the ozonated "pass" is injected back into the body, it mixes with the rest of the non-ozonated blood so when the next "pass" is extracted for ozonation, some of already ozonated blood will also be extracted again. Professor Dr Eugeny Nazarov, a Russian Ozone expert, calculated that to ozonate 95% of the blood using the multi-pass technique, we need to perform  97 passes, 150 ml each. You can watch this conference lecture by clicking on this link (discussion of this point starts on the 25th minute into the presentation). Secondly: The amount of anticoagulant needed for the 10 passes is 10 times the amount needed for Major AHT thus significantly increasing the risk of internal bleeding especially in the hours immediately following therapy. 


Furthermore, it is technically possible to administer high concentration of ozone using ANY method by simply increasing the concentration and / or the volume of blood mixed with blood without having to repeatedly extract new volumes. As explained in the mechanism of action of ozone, ozone does not act directly. Once exposed to the blood, zone interacts within 1 second with the components of the blood to produce secondary messengers that perform the desired actions. When the ozonated blood is returned back to the body, these secondary messengers mix with the whole volume of blood inside the body so there is no need for the ozone gas to come in contact with all of the blood to get the desired effect. 

High concentration ozone therapy was the norm 20 years ago until replaced (at least in Europe) by the modern “low ozone concept” with high concentrations reserved for treating external infections such as infected ulcers. You can have more information about the low ozone concept from the German Ozone societyWhile it is true that ozone in high concentrations is directly toxic to micro-organisms but it is also equally true that ozone in such high concentrations is also toxic to the human cells. The figure below (from the German Ozone Society Handbook, 2020) depicts the above argument by providing the changes in the level of some of the antioxidants triggered by ozone therapy at various concentrations. You will see that the therapeutic effect is obtained between 10 and 40 mcg/ml with a "sweet spot" around 30 mcg/ml. Other European guideline are in agreement with this. At LOC we employ ozone doses within this range, starting from the bottom of the therapeutic range (10 mcg/ml)aiming to reach 30 mcg/ml gradually depending on the person's tolerance and medical conditions. We use either Major AHT or the Russian method of ozonated saline to achieve this. 

So in summary: ozone is a drug, higher dose does not necessarily mean better response. The dose and the volume of blood have been established beyond doubt by research. The latest advances in our understanding of ozone therapy on the cellular level enabled a shift in the ozone therapy practices towards the low ozone concept.


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Is Ozonated saline any good?

Ozonated saline is rarely practiced outside Russia. Despite this it is probably the most researched method of ozone therapy. The following is an extract from the International Scientific Committee of Ozone Therapy (Madrid Declaration on Ozone Therapy; 3rd edition; www.isco3.org):

This is testimony to this method which is almost unknown in the UK. At LOC we are pleased to announce that we offer this method to our patients, especially for people with thin veins or who prefer a less invasive way of ozone therapy.



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Triple anti-coagulant therapy and long COVID

There has been a lot of debate about what causes post-COVID fatigue; one of the suggestions is that there is a micro-circulation sluggishness caused by clots that are difficult to bust with simple therapies thus requiring "triple therapy" with 2 anti-platelets (Aspirin and Clopidogrel" and an anticoagulant from the new generation of anticoagulants such as Apixaban.


While there is no doubt that acute COVID can cause clots, the situation is less clear with long COVID. We have written a blog about increased "red cell stickiness" in long COVID that can be helped by Ozone therapy and high dose i.v Vitamin C therapy. However this is different to the suggestion that there are multiple micro-clots arresting blood and oxygen supply to the tissue thus causing most of the symptoms of long COVID. There has been claims that the microclots can be identified using a "VQ scan". 

The VQ scans is a form of medical scan, it stands for Ventilation - Perfusion scan. However VQ scans can not detect micro clots. They can detect clots in larger vessels by finding a visible (with naked eye) mismatch between perfusion (blood flow) and ventilation in the lungs. The micro clots can be suspected from raised D Dimer or detected on histology (biopsy). By definition they are in the “micro”circulation which can not be visualised by the naked eye (or by scans or X-rays) but by microscopy. 


The suggestion that all long COVID symptoms are related to micro clots is over simplistic and there are epidemiological data to support this point: For example: people who damaged their blood vessels through smoking and unhealthy life style to the point where there limbs are at risk of amputation and their brains and kidneys are damaged by silent small infarctions rarely describe fatigue as a main symptom. Similarly people with diabetes (diabetes damages organs mainly through its effect on the “microcirculation” - diabetic microangiopathy) are not particularly affected by fatigue or other long COVID symptoms more than general population.


I am not dismissing the fact people with long covid have micro clots but I think this is a manifestation of the underlying ongoing inflammation (high oxidative stress) and their overwhelmed antioxidant system. To treat this with triple therapy is a) not addressing the underling pathology which is inflammation as a result of persistent virus or spike protein and b) high risk of bleeding with devastating consequences. To have 2 antiplatlets (Aspirin and Clopidogrel) alone without an anticoagulant is used in standard practice after heart attacks but only limited to a year. To add an anticoagulant to this mix will raise the possibility of bleeding multiple times. To add an acid suppressant will not help and will induce other problems in the microbiome that may exacerbate inflammation. 



Similarly, breathlessness in long COVID is exclusively caused by low O2 is also simplistic. People with chronic bronchitis live happily on very low oxygen levels and if they are given high doses of oxygen they may die. That is why they used to call them in medical literature the “blue bloaters” because they are blue and bloated from the low oxygen yet they are not that breathless whereas people with emphysema (another form of COPD) have normal oxygen but they are very breathless (used to be called the “pink puffers”). 


So in summary: Long COVID is not as simple as perfusion problem, the anticoagulants are not the answer and they add another layer of risk that may be more dangerous that the problem they intended to treat e.g brain or eye bleed.