Thank you for checking out this article. However, with the enormous amount of research being invested in COVID-19, it is very likely to be outdated. For in-depth info, I advice you to check out some more recent resources. The post below is left there, for the sake of reference.

Thank you for reading! Please note that this article hasn’t been updated since April 9th 2020

Updates
– Clarification that the original article referenced to is not a medical publication or written by a doctor or other authority in the field. It is a well-compiled blog with a self-created narrative referencing to various evidence-based resources. The article is not peer-reviewed as far as I know.
– Addition that the WHM breathing or other forms of deep breathing could potentially spread the SARS-CoV-2 further through the lungs, quoted from infectious disease expert ‘Ashita Batavia’
– Addition of my personal experience with the WHM breathing (likely) during COVID-19
– Importance of timing of supplementation, as update by new article [14], found in the section ‘Dosages’

– Update: protective and damaging effects of NLRP3, in reference to the new article [14], found in the section ‘Dosages’: strategies to reduce NLRP3 inflammasome activity (such as supplementing with vitamin C, melatonin, or doing Wim Hof Method breathwork) might be best timed during the inflammatory peak of COVID-19, not during early stages, as this might prevent the use of the inflammasomes protective properties (remember the NLRP3 inflammasomes is part of our innate immune system) and worsen the progression of the disease.

– Addition of reference and quote ‘increased NO production through humming’

Here follows the article:

A few days ago, one of my friends working for over 11 years in the big pharma industry sent me the following amazingly clarifying article, dissecting SARS-CoV-2 key pathways and offering theories and hypotheses on the infectiousness, severity as well as the age specific effects of SARS-CoV-2, along with potential interactions, through which we might be able to alleviate some of the COVID-19 symptoms. Though this article is based upon and references too various medical or evidence-based publications, please note that the article itself is not a scientifically peer-reviewed article, and not written by an authority in the field of virology or immunity. 

Seeing its enormous potential value I want to share it here with you, in a more readable format. What follows is a digest of that article with some personal additions. My intention is to make this available to everyone without diminishing its validity or accuracy. In order to do that, I use quotations and scientific terminology (for the not so science savvy, bare with me) just to follow up with a summary in somewhat layman’s terms at the end of each section. While the core foundation here is the article mentioned above, I do offer and add my own hypotheses and offerings, such as in the sections “Nose breathing & Nitric Oxide”, “Synergies” and “the Wim Hof Method”. I am not a doctor nor an expert working in the field. With my additions I intend to further explore, elaborate on, and discuss potential mechanistic pathways and their implications. I will make sure to highlight the difference and not present my own hypotheses as evidence-based research. If you are interested, I definitely recommend reading through the original article! It is not a medical article, though it does reference to medically grounded or science-based articles.

First a disclaimer, please understand that all that follows is NOT MEDICAL ADVICE or a statement on what to do while sick. Please consult your trusted physician regarding COVID-19 treatment. Here follows a mechanistic exploration of COVID-19, offering potentially supportive methods which could alleviate some of the COVID-19 symptoms. These methods would always be IN ADDITION TO THE REGULAR PROTOCOLS PRESENT SUCH AS SOCIAL DISTANCING AND REGULAR HANDWASHING. The following is a theoretical approach at, NOT a field-tested and proven treatment of, the current SARS-CoV-2. Please think for yourself. Most of what is written here is based on so called ‘mechanistic evidence’ or hypotheses. This evidence is termed mechanistic evidence because it stems from knowledge of the chemical reactions and biochemical processes, instead of being field tested. It is key to understand that the final supplemental options or breathwork techniques are in no way field tested or proven to work with COVID-19. 

Medical digest: Key pathways of SARS-CoV-2

The purpose of this article is to inform you, in a scientifically grounded manner on SARS-CoV-2’s as is laid out by the related article, and possibly, to offer additional precautions for your consideration, that could be effective at best and simply ineffective at worst (if followed by appropriate guidelines). There will still be some scientific terminology, so as said, to make it readable for everyone I will add summarizations wherein I keep those terms to a minimum.

Here follows:

• Step-by-step overview (of the SARS-CoV-2’s mechanism of action)     
• Breakdown and elaboration on that overview             
• Interactions:                                
  
  • Nose Breathing & Nitric Oxide    
  • Melatonin                             
  • Vitamin C                       
  • Synergies                       
  • Selenium & ACE inhibitors                 
  • Dosage                               
  • Wim Hof Method (Breathing)                  
• Final Take Away
• Final Words
• Literature

Let’s start with getting an overview

Overly simplified, this is how it seems to work:

SARS-CoV-2 pathogenicity comes through its stimulation of the immune responses.

In a sentence, SARS-CoV-2, the virus causing COVID-19, works through progressively uncontrolled inflammation, markedly in the lungs, possibly leading up to fatal edema & lung damage.

So first, a step-by-step overview.

Now let’s unpack that a bit more in depth. (If you’re not into the science, you can skip this)

Furin Enzymes (step 1)

SARS-CoV-2 or Severe acute respiratory syndrome-related coronavirus, is able to bind to Furin Enzymes. Furin enzymes are protein activators which cleave the to-be-removed sections of inactive proteins to activate them.  “The presence of furin enzymes on all cell surfaces cleaves and activates the SARS-CoV-2 in a wide range of tissues and organs.“

The current hypothesis in this article is that, while “This cleavage site is not present in SARS-CoV” (SARS-CoV-2’s predecessor), the ability of the new SARS-CoV-2 to be activated by furins, leads to its much higher infectivity rate, as it is able to “replicate in multiple tissues and organs”.  “The presence of furins on almost all cell surfaces allow a dramatically increased ability to fuse to host cells”, “The furin cleavage allows efficient virus entry into basically all cell types, making the COVID-19 easily transmissible at rates up to 1,000 times greater than the virulent SARS coronavirus”.  

In short, SARS-CoV-2 has novel mutations, relative to its predecessor (SARS-CoV), that allow the virus to be activated by most cell surfaces and to fuse with basically all cell types, making COVID-19 a lot more infectious than its predecessor.

NLRP3 Inflammasomes (step 2)

Once SARS-CoV-2 is activated, it starts releasing NLRP3 Inflammasomes. Inflammasomes are protein complexes, a part of our innate immune system, responsible for the activation of inflammatory responses. The NLRP3 Inflammasomes than start the “overproduction of proinflammatory IL-1β” (Interleukin-1β). “The production of IL-1β is tightly controlled and is dependent upon NLRP3 inflammasome activation”. 

Again in short, once SARS-CoV-2 is activated it starts an inflammatory response, leading to the overproduction of pro-inflammatory cytokines.

IL-1β & the ‘Cytokine Storm'(step 3, 4 & 5)

(3 & 4) IL-1β is a proinflammatory cytokine and a type of signaling molecule. “Proinflammatory cytokines defend host cells from invading pathogens, but they are also capable of driving pathological inflammation. During viral infections, inflammation can act in dynamically opposing antiviral and proviral roles.”

“Interleukin 1 beta (IL-1β) is a potent proinflammatory cytokine that is implicated in the pathogenesis of acute respiratory distress syndrome because the initiation of hypoxemia (below normal oxygen levels in blood) is induced by IL-1β signaling”. Also, “In the blood of patients with COVID-19, there was a marked increase in interleukin 1β (IL-1β)” [Article 14].

“Acute respiratory distress syndrome and acute lung injury (ARDS/ALI) are often characterized by the accumulation of neutrophils in the lungs and the increased production of inflammatory cytokines, chemokines, proteases and oxidants. The initiation and development of ARDS/ALI is dependent upon the activation of inflammasomes.”

Again, “the activation of NLRP3 inflammasomes, resulting in the overproduction of pro-inflammatory IL-1β cytokines.” This is also known as a ‘cytokine storm’. A new article on COVID-19 and Melatonin wrote “the attenuation of the cytokine storm by targeting several key steps in the process could bring about improved outcomes.”

In other words, the IL-1β that is part of our innate immune response, is now overproduced by the NLRP3 inflammasomes (that are released after the activation of the SARS-CoV-2) and accumulates in the lungs where it induces acute respiratory problems. This way SARS-CoV-2 stimulates our immune response.

Acute respiratory distress syndrome & Acute lung injury (step 6)

ARDS or Acute respiratory distress syndrome is a type of respiratory failure characterized by the widespread onset of inflammation in the lungs. 

“Recently, the NLRP3 inflammasome has been identified as key to the induction of ADRS/ALI”). 

“The initiation and development of ARDS/ALI is dependent upon the activation of inflammasomes”.

“When ARDS progress to the acute phase, alveolar flooding (edema), interstitial inflammation and compression atelectasis, as well as increase in lung tissue and reduction in lung gas volume are observed”. “Edema is the major determinant of ARDS that could result in death. Whenever E protein ion channel activities were observed, both edema and IL-1β mediated proinflammatory response were elevated.”

Translated, further progressing ARDS can lead to the accumulation of fluid in the lungs, which again seems to be IL-1β mediated, and progressing difficulty to breathe. This is why COVID-19 patients with severe ARDS require intubation and mechanical ventilation.

Okay, so now we know more about SARS-CoV-2 & COVID-19.

What could we potentially do in addition to the protocols in place?

Let’s take a look at a breathing technique, 2 safe and common-use household supplements, and then speculate on the potential of breathwork in working with early stage COVID-19 and their overlapping biomolecular pathways.

First, let’s take a look at Nose breathing & Nitric Oxide
As a breathwork facilitator and Wim Hof Method Instructor I am definitely biased towards using nose breathing as a regular breathing pattern in general. With that I mean, the type of breathing you use during your general day-to-day. It is something I generally recommend. For this article however, I will go into the potential benefits of nose breathing, specifically related to COVID-19 and the immune system. 

“In the nasal airways, there is a continuous production of NO” (Nitric Oxide) [Article 4]. “Nitric oxide produced in nasal passages is possibly part of the defense system against bacterial and viral infections”. “In Kartagener’s syndrome, patients lack NO in nasal air and have severe problems with recurrent airway infections”. “We conclude that there is a continuous and large production of NO in the paranasal sinuses”, “NO produced in the sinuses will continuously enter the nasal cavity and may therefore also have biological effects in more distal parts of the airways following inhalation. Thus, sinus-derived NO may affect pulmonary blood flow or even participate in the first line of defence against airborne infectious agents that are sensitive to this gas”. Thus, “NO may serve important host defence functions” [Article 4]. “In rodent sepsis models, nitric oxide was demonstrated to inhibit NLRP3 activation” and IL-1β secretion (Step 3). Also, humming greatly increases (15-fold) nasal Nitric Oxide compared to quiet exhalation [Article 12].

In other words, breathing through our nose, and more so with humming, infuses the air that enters our lungs with Nitric Oxide. Nitric Oxide (NO) has been shown to have a sterilizing effect in the nasal airways, and to be able to inhibit the NLRP3 inflammasomes (Step 3) (in vivo and within cell), that lead to the progressively escalating immune response during COVID-19 within cells. 

Our ability to infuse the air we breathe in with Nitric Oxide through nose-breathing, is potentially an intrinsic part of the first line of defence (similar to how nose hairs or our skin protects us) of our immune system. Thus, possibly, increasing our NO levels both in the airways (through nose-breathing) or at a cellular level, might aid us in working with COVID-19.

Now, I do want to highlight that these are two different pathways here. One being NO release in the airways, the other being cellular NO leading to the NLRP3 inflammasome inhibition. I am not aware of any relationship between these two. Or in other words, I do not know whether increasing airway NO through nasal breathing, increases system-wide and celulair NO levels, leading to NLRP3 inflammasome inhibition during COVID-19. Nevertheless, increased NO in the airways seems to have a sterilizing effect. “Our findings, together with the well-known bacteriostatic effects of NO, suggest a role for NO in the maintenance of sterility in the human paranasal sinuses.”

Note that the effects of nose-breathing on SARS-CoV-2 have in no way been proven or (as far as I know) clinically tested, so always please stick to the current protocols already in place (social distancing, handwashing etc.). Nevertheless, I do want to offer nose breathing to you for your consideration, as general day-to-day nose breathing (over mouth breathing) is harmless, likely to have various benefits in itself, and there is a chance it can aid in reducing the transmissibility of SARS-CoV-2 as suggested by the articles above and in the original article.

Now, let’s take a look at Melatonin

Melatonin is generally known for its ability to regulate the circadian rhythm and sleep-wake cycles. It is used as a sleep supplement and its internal secretion is known to be dampened by particularly blue or green light (for example through computer screens). While less known, melatonin also possesses anti-inflammatory characteristics and seems to be involved in anti-viral actions. “Melatonin is not viricidal but it has indirect anti-viral actions due to its anti-inflammation, anti-oxidation and immune enhancing features”. [Article 14]

More specifically, melatonin seems to be a potent inhibitor of NLRP3 inflammasomes (Step 3), as among others, has been found in a study on mice, ““melatonin blunts the NF‐κB/NLRP3 connection during sepsis” together with a “blunted IL‐1β maturation” [Article 15], and “Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation” [Article 16]. Furthermore, melatonin seems to be able to upregulate anti-inflammatory markers, while down-regulating pro-inflammatory markers, “melatonin causes a reduction in the pro-inflammatory cytokines. TNF-α, IL-1β, IL-6, and IL-8, and an elevation in the level of anti-inflammatory cytokine IL-10″. Also, “administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung.” (Step 4). “In previous respiratory syncytial virus models, melatonin caused down-regulation of acute lung oxidative injury, pro-inflammatory cytokine release and inflammatory cell recruitment.” [Article 14]

Also, ”chronic low doses of melatonin in aged mice could prevent increase in inflammation”, “acute administration of melatonin could counteract severe inflammatory responses” and “Melatonin was shown to inhibit NLRP3 inflammasomes in mice with myocardial septic conditions, transforming severe myocardial inflammation into milder symptoms, preventing cardiac failure, and significantly enhanced survival rates of septic mice”.

Thus, through Melatonin’s inhibition of NLRP3 Inflammasomes early on in the cascade (Step 3) it could not only potentially diminish ARDS, but it could also have the potential to reduce inflammation in the heart muscle tissue and inflammation induced cardiac failure. This is very relevant as “The manner in which SARS-CoV-2 infects host cells by binding to ACE2 receptors makes this coronavirus especially dangerous for patients with underlying cardiovascular diseases, increasing their risk of death”, but also for those without comorbidities “It is not unreasonable to assume that there can be substantial damage to the cardiovascular system over the long term as a result of COVID-19 infections.”, “NLRP3 inflammasomes are also one of the primary reasons why COVID-19 causes cardiovascular complications”. “Patients with underlying CVD (Cardiovascular disease) conditions may greatly benefit from the use of melatonin in the treatment of COVID-19”. 

Now, “The fact that the pro-inflammatory cytokine storm effects are induced by the activation of NLRP3 inflammasomes, the ability of melatonin to INHIBIT NLRP3 inflammasome elevates this powerful molecule to a truly unique position in the fight against COVID-19”.

The figure below, as taken from the valuable article that was just published “COVID-19: Melatonin as a potential adjuvant treatment“, illustrates the various pathways through which Melatonin could potentially help alleviate COVID-19 symptoms. Namely through reducing inflammation, oxidative stress and immune modulation. For more information, please read that article.

As a short recap, melatonin has been found among others to be a potent inhibitor of the NLRP3 inflammasomes (Step 3), and is therewith able to lower IL‐1β levels (Step 4). This means that supplementing melatonin could potentially significantly diminish the chances of developing ARDS & Cardiovascular complications (Step 5), and thus lower the severity of COVID-19.

And finally, from a most recent article (update) “There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients”.

“As reviewed previously, short-term use of melatonin is safe, even in those given high doses, and the reported adverse effects are limited to occasional dizziness, headache, nausea and sleepiness; in general melatonin’s safety in humans is very high”, “Also, even when melatonin was given to humans at dose of 1 g/d for a month, there were no adverse reports of the treatment” [Article 14]. However, IF you are taking ACE inhibitors, have cardiac conditions, hypertension, you need to consult your physician before taking high doses of melatonin.  Melatonin may lower blood pressure and cause hypotension at higher dosages.

Now more about Vitamin C, also known as ascorbic acid.

This one we are most familiar with. When you were sick, mom brought you orange juice!

Vitamin C, or ascorbic acid, is an essential water soluble vitamin, an antioxidant and among many things its effects indicate a prominent role in immune system regulation. 

During infections Vitamin C seems to be rapidly consumed, as can be read here “Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress.” and Vitamin C levels are generally lower in the elderly. During sickness it seems important to avoid Vitamin C or Zinc deficiency, as “A deficiency in one of these essential nutrients weakens immunity”.  [Article 5]

“Ascorbic acid, in addition to supporting the production of nitric oxide, can act on multiple levels, reducing oxidative stress, regulating hypoxia signaling, mitochondrial membrane potential, furin expression, and modulation of immune defenses to stem the progression of cytokine storms”. “vitamin C has an inhibitory effect on the activation of the NLRP3 inflammasome in vitro and in vivo, “The result showed that vitamin C, dose-dependently, decreased IL-1β secretion, indicating that the NLRP3 inflammasome was inhibited by vitamin C” [Step 3, Article 18].

As vitamin C is water soluble, this generally means that even when you take excess amounts, the surplus vitamin C will be excreted. This means that “Vitamin C is generally thought to be safe, although at higher doses (2,000-6,000mg) may cause diarrhea” [Article 6]. Also, supplementation of 1000mg Vitamin C “was associated with a statistically significant 2-fold increased risk” for kidney stones in men. [Article 13]

To summarize, Vitamin C plays an important role in general immune functioning, supports the production of Nitric Oxide and has the ability to inhibit NLRP3 Inflammasomes therewith decreasing IL-1β secretion [Step 3]. Taking Vitamin C might therefore lessen the severity of COVID-19 and seems to be generally safe to take.

Synergies

The following elaboration, I have added myself and is not only derived from the original article.

As you have read, Vitamin C, cellulair Nitric Oxide and Melatonin all seem to target a similar link in the COVID-19 chain, the NLRP3 Inflammasome. In this section we will explore some synergistic mechanisms and suggestions by the original article. 

Something particularly interesting, is the synergistic potential between Melatonin and Vitamin C in inhibiting NLRP3 inflammasomes, as both seem to do so through a different pathway. This means that combining the two might inhibit NLRP3 inflammasomes from 2 different directions. 

Though it is very much in-depth, for those interested, it can be seen in the following image that both NF-kB (Signal 1), suppressed by melatonin, and mtROS (Signal 2), scavenged by Vitamin C, are involved in NLRP3 inflammasome activation. 

“The combined use of melatonin and ascorbic acid may prove to be most effective in the treatment for COVID-19 patients, especially those with cardiovascular and hypertension comorbidities.” [original article].

Selenium, Ibuprofen & ACE inhibitors

There has been quite some going back and forth in the news around this topic, with the WHO issuing a warning about ibuprofen, recommending paracetamol instead and retracting it two days later. Also in scientific literature I have read some contradictory ‘expert opinions’. Keeping in mind that I do not have all the info, there currently seems to be a lack of reliable data and consensus on this matter. “The role of NSAIDs in the course of viral infections is still controversial.” 

Keeping in mind the lack of consensus by experts in the field, this is what the original article offered:

While “Selenium is a strong scavenger of free radicals” and “is believed to be effective against viruses such as Ebola, HIV and influenza A virus”, “selenium may also be an effective inhibitor of angiotensin-converting enzyme (ACE). Patients suffering from cardiovascular diseases, hypertension and diabetes are often prescribed drugs that either inhibit ACE or block angiotensin II type-I receptor (ARB). Both types of drugs increase the expression of ACE2”. “SARS-CoV-2 infects host cells through binding with ACE2 receptors”. “Ibuprofen has been demonstrated to induce an overexpression of ACE2 when used in diabetic rats and this effect might theoretically increase the susceptibility and worsen the clinical course of COVID -19 infection in treated patients”. [Article 19]

In summary, SARS-CoV-2 infects host cells through binding with a specific receptor called ACE2. Certain types of medication such as ibuprofen and Selenium might increase the expression of those receptors, potentially making it easier for the virus to spread. Again, this is controversial and there is no consensus here as far as I know, with many suggestions that there is a lack of evidence to suspect this, such as “There is currently no scientific evidence establishing a link between ibuprofen and worsening of COVID‑19”.

As I am neither a doctor, nor an expert on this matter, I recommend you follow the latest WHO recommendations and guidelines, and always contact your doctor. 

Personally, because I do not have to take any medication and can thus easily do so, I will refrain from unnecessarily taking substances that increase ACE2 expression, unless I will need to or be told by a medical professional. To be extra clear, I am talking about taking a random ibuprofen. I am NOT talking about not taking any medication.

Well, that was a lot of information..

Let’s summarize and get an overview

In short, SARS-CoV-2, the virus causing COVID-19, seems to work through progressively uncontrolled inflammation, markedly in the lungs, possibly leading up to fatal edema & lung damage and cardiovascular complications. 

Vitamin C, cellulair Nitric Oxide and Melatonin have all been identified as inhibitors of a key protein complex essential for the uncontrolled inflammation leading up to cardiovascular and respiratory complication. Vitamin C, nose breathing and melatonin are generally safe methods to use, and Vitamin C & melatonin potentially work together synergistically. The science and mechanistic implications of the pathways through which these three work, points out that this might very well have a positive impact on, could be of support during, or possibly prevent the severity and escalation of, COVID-19. This however is not proven. Therefore this is a simple offering. Something you could do in addition to following the generally prescribed protocols. As you work with these 3 modalities, I urge you to use common sense, follow the general recommended guidelines for each, and do your own research. An amazing unbiased resource is examine.com, which I’ve been using for around 8 years now.

Dosage

Now, the original article recommends certain dosages, I will not. As said I am not a doctor or an expert on the matter. And right now, as this is all highly experimental and untested in COVID-19, it seems that also experts in the field would not likely be able to give a confident dose recommendation. So first of all, please do your research yourself. Again, you deciding to supplement, and with which dose, is your responsibility and you experimenting on yourself. I have personally used examine.com, to double check the safety & toxicology with high dosages for these supplements. I will however describe common-use dosages for the supplements, and describe the safe upper-limit. this DOES NOT MEAN I recommend the upper-limit. We simply do not know. Sometimes less is more, sometimes it is not. I cannot really be more informative than that on the matter.

One very important thing to note, is the timing of taking these supplements, as is laid out in article 14.

“There is probably a balance of the protective and damaging actions of NLRP3 in the lung. Thus, in a mouse experiment, inhibition of NLRP3 in the early phase of infection increased mortality, whereas suppression of NLRP3 at the peak of infection allowed for a protective effect [51]. This supports the use of melatonin in ALI/ARDS when inflammation is most severe.” [Article 14] As tested in Influenza A mice models, “We have shown that early inhibition of NLRP3 inflammasome exacerbates disease consistent with the protective role previously described using inflammasome-deficient mice. In contrast, late inhibition of the NLRP3 inflammasome by MCC950 alleviated disease and reduced lung inflammation, demonstrating that the NLRP3 inflammasome was contributing to development of a ‘cytokine storm’ and lethality.” [Article 17]

In other words, yes NLRP3 is overactive during COVID-19 and suppression of NLRP3 and thus the ‘cytokine storm’ during its peak might reduce the severity of the symptoms and be an aid in dealing with COVID-19. This however, does NOT mean that it is beneficial to suppress NLRP3 all the time, as the inflammasomes likely have a protective effect early on in the process. At least it seemed to have so in an Influenza A mouse model. Reducing NLRP3 activity early on in the COVID-19 process might actually decrease resilience and worsen the progression of diseases, as has been observed in a mice Influenza A model. Thus, the most effective application of NLRP3 suppression during COVID-19, as implied in “COVID-19: Melatonin as a potential adjuvant treatment“, is likely “the use of melatonin in ALI/ARDS when inflammation is most severe.”, during the peak, not in early stages.

In short, strategies to reduce NLRP3 inflammasome activity (such as supplementing with vitamin C, melatonin, or doing Wim Hof Method breathwork) might be best timed during the inflammatory peak of COVID-19, not during early stages, as this might prevent the use of the inflammasomes protective properties (remember the NLRP3 inflammasomes is part of our innate immune system) and worsen the progression of the disease.

Below I will describe common dosage ranges for Vitamin C and Melatonin, together with the safe upper limit as used in and validated by scientific literature.

For melatonin, the most common application is as a sleep aid, taken around roughly 30min before going to bed. For this the common dosage range is between 0,5 – 5 mg (not to be confused with 500mcg, which would be the same as 0,5mg). As reported in article 14, “even when melatonin was given to humans at dose of 1 g/d for a month, there were no adverse reports of the treatment”. Unfortunately, I can’t really give a lot more guidance than that, as again, we don’t know what an effective dose would be for this application. The original article refers to a dosage range between 5 – 50mg (which again, is not medical literature) and I’m not sure where that is based upon. Personally, I have taken melatonin up to 5 – 10 mg during the COVID-19 peak. (Again, IF you are taking ACE inhibitors, have cardiac conditions, hypertension, you need to consult your physician before taking high doses of melatonin.  Melatonin may lower blood pressure and cause hypotension at higher dosages). Taking melatonin at the wrong time (not congruently with your circadian rhythm) will very likely disturb your sleep-wake cycle.

For Vitamin C, their is a RDI (Recommended Daily Intake) which is 100-200mg, and also the common-use supplementation of 2gr per day for for immune support with high performing athletes or to reduce the duration of the common cold. In the above mentioned study, where they showed Vitamin C inhibiting NLRP3 and lowering IL-1β levels in mice, the mice received dosages of 200mg/kg. Based on my body weight, that would extrapolate to 16gr of Vitamin C for me. Now, while that seems to be within the safe limit for healthy individuals (other than a likely case of diarrea as “You will experience loose stools, or what is known as hitting Bowel Tolerance if you have saturated your system with ascorbic acid.”), it is not clear to me if that extrapolation (from mice to humans) is even remotely relevant. As said, it is all but speculation at this point. Most of the literature uses dosages within the range of 200mg to 2,000mg. Personally, I have been taking frequent 1g doses of Vitamin C throughout the COVID-19 peak up till 15grams or so (in a day).

As the final kicker, the Wim Hof Method, Breathwork & COVID-19

This section is completely written and added by me, and intended as an exploration of the potential application of breathwork in battling the COVID-19 caused inflammation. Note that I’m currently active as a Wim Hof Method & Breathwork Instructor, and clearly biased towards it. Also, the potential negative consequences of doing the Wim Hof Method breathing during, or in early stages of, COVID-19, have not been researched at all. Therefore it is truly and entirely up to your careful decision-making if you decide to apply the breathing during COVID-19 sickness. Before I go into the cellular mechanisms of the WHM, please note that there is no consensus or clear evidence on whether the Wim Hof Method Breathwork, or breathwork in general could be harmful or beneficial in working with COVID-19. Doing so, is entirely you experimenting on yourself.

Below I will go into the inflammatory processes and the overlap between COVID-19 and the Wim Hof Method Breathing. Before I do that, please note that in this video (55:20), an interview between Scott Carney & Infectious disease expert Ashita Batavia, they talk about deep breathing (specifically around the WHM) could potentially spread the virus throughout the lungs. “We are careful in general about giving patients types of respiratory support, where we are pushing air in. The breathing might on some level simulate that. There may be a theoretical risk.” “I am not sure if I would recommend that methodology”. As far as I know, this statement is based on practical experience with mechanical ventilation.

Let’s take a look at the Wim Hof Method and its endotoxemia experiment

The Wim Hof Method and more specifically the Wim Hof Method breathing has shown astounding effects during an endotoxemia experiment. After being injected with antibodies, the WHM breathing lead to “induction of early anti-inflammatory IL-10 production”, “attenuation of the proinflammatory innate immune response during experimental human endotoxemia”. ”Also, trained individuals experienced fewer endotoxemia-associated flu-like symptoms, and a more swift normalization of fever and cortisol levels, which are likely the result of the attenuated proinflammatory response. This study demonstrates that the in vivo innate immune response can be voluntarily influenced in a nonpharmacological manner through voluntary activation of the sympathetic nervous system” [Article 6]. 

Amazing as these results are, I want to see if there is a direct biomechanical pathway that connects the potent anti-inflammatory effects of the WHM breathing to a possible way of relieving symptoms, or the severity of, COVID-19. This is particularly interesting because, as said earlier, “SARS-CoV-2 pathogenicity comes through its stimulation of the immune responses” and as concluded in the Cox et al. Endotoxemia article, The Wim Hof Method “therefore could have important implications for the treatment of a variety of conditions associated with excessive or persistent inflammation, especially autoimmune diseases”. In other words, the Wim Hof Method could potentially be a novel pathway of treating diseases with an excessive inflammatory immune response, perhaps similar to COVID-19’s mechanics. 

Now, diving back into the microbiology.

During the endotoxemia experiment “TNF-α,IL-6, and IL-8 levels were significantly attenuated, whereas the IL-10 response was greatly augmented compared with the control group (TNF-α, IL-6, and IL-8 levels 53%, 57%, and 51% lower; IL-10 levels 194% higher)”. So, pro-inflammatory markers went down while anti-inflammatory markers went up. One of the key markers we are looking for being IL-1β. “In line with previous reports, plasma levels of the proinflammatory cytokine IL-1β were barely detectable during human endotoxemia”. In other words, the endotoxemia was not set-up to measure changes for cytokine IL-1β. This is very unfortunate, as that would provide a direct link and answer to our question here. 

However, “there were significant inverse correlations between levels of the anti-inflammatory cytokine IL-10 at T = 1 h and peak levels of the proinflammatory mediators TNF-α (at T = 1.5 h), IL-6 (at T = 2 h), and IL-8 (at T = 2 h) in the trained group (Fig. 5 B–D)”. So, not only where the pro-inflammatory cytokines significantly lowered and was the anti-inflammatory marker IL-10 significantly heightened after WHM breathing, the change of these markers inversely correlated. This suggests a relation between the increase of the anti-inflammatory marker IL-10 and the decrease of the proinflammatory markers, worth looking into.

So, a new question: IF IL-10 would be able to lower TNF-α,IL-6, and IL-8, would IL-10 also be able to lower IL-1β levels or IL-1β production? If so, this would mean that the WHM breathing could potentially lower IL-1β, which is a key link (Step 4) in the progression of COVID-19 towards severe complications (Step 5).

In epileptic-seizure mouse model, they have demonstrated “the efficacy of IL-10 in suppressing IL-1β and in inflammasome activation”, “Importantly, we indicated that IL-10 inhibits IL-1β production via IL-10 signaling” and “IL-10 overexpression in microglia and reduced NLRP3 inflammasome activity” [Article 7]. 

In another rat model study for ventilator-induced lung injury they found that “High-pressure ventilation increased the concentrations of macrophage inflammatory protein (MIP)-2 and IL-1beta in bronchoalveolar lavage fluid (BALF) and plasma. This effect was reduced by the inhalation of IL-10 (10microg/kg)” [Article 11].

“In monocyte/macrophage lineage cells, IL-10 reduces the release of various inflammatory cytokines, such as IL-1, IL-6, IL-8, GM-CSF and tumor necrosis factor (TNF)-α.Thus, IL-10 may be a potent regulator of allergic inflammation in the pathogenesis of bronchial asthma” [Article 10]

So, to answer the question, yes, IL-10 seems to be able to reduce IL-1β production (Step 3) and NLRP3 inflammasome activity. The WHM breathing increases IL-10 levels (in the endotoxemia experiment these were “194% higher”), this suggests that the WHM breathing could potentially reduce (Step 3) the “progressively uncontrolled inflammation” that we observe during COVID-19 and that leads up to severe Cardiovascular and respiratory complications. 

“When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6.”

Now, we have already found that besides suppressing IL-1β production, IL-10 also reduces IL-6 levels (as demonstrated in the Endotoxemia experiment). 

“Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections.” [Article 3]

Interestingly, Melatonin seems to also increase IL-10 expression and suppress IL-6 [Article 8], and a melatonin agonist was shown to have “a protective effect against ventilator-induced lung injury” [Article 9]. Such as when mechanical ventilation is needed during severe COVID-19 induced ARDS.

Summing it up

It has been known for a few years now that the Wim Hof Method, and in this case more specifically, the WHM breathing has been able to reduce inflammation in the body. Looking at the SARS-CoV-2 mechanisms of action, its inflammatory producing characteristics, there is a chance that doing the WHM breathing might have a positive impact on COVID-19 in reducing its symptoms and severity. That said, there seems to also be a risk of spreading the virus further throughout the lungs, as reported by an expert in the field. Please note that this is not proven or evidence based, but derived as a possibility from scientific literature and is but an open exploration, NOT MEDICAL ADVICE.

Here follows my personal experience testing the Wim Hof Method breathing while having COVID-19

Over the course of a few days I noticed my active lung capacity slowly declining. After about 5 days, I for the first time actually felt sick. Low energy, lethargy, feverish, hot/cold sensations etc. I knew I was coming on with COVID-19, and so for the sake of experimentation, that night I started breathing my ass off. And REALLY breathing my ass off. Initially it was quite a rough feeling as it was heavy on my lungs, exercise for my body (while all it wants is to do nothing) and gave a scraping feeling in my throat, but as I got into it, at around the 3rd round those feelings faded. I went for it. As I sat laughing and high on breath, on the couch afterwards, I could not really feel I was sick. I felt deeply calm, relaxed and satisfied. I took a little nap right after. As I went to bed a few hours after the breathing, that night, COVID-19 hit me. During the peak I slept with 4 blankets feeling hot and cold while having feverish dreams and balancing sleep-wake states with a very limited shallow slightly heaving breath.
The next day I felt shit. Getting out of bed was a great tiring effort, and the best thing was to lie in bed mindlessly staring at the cealing. I got up and did some breathing again. Again, I felt good after. The rest of the day however, I seemed to feel a bit worse than that morning, wondering if I was getting better or more sick.

Please note that I haven’t actually gotten myself tested for COVID-19. However, as I am very rarely ill, and suddenly get sick, marking most of the COVID-19 symptoms during a global pandemic, it is extremely likely.

The breath being as powerful as it is, I wasn’t suprised that it seemed to also temporarily pull me out of my ‘sickness’ state. As COVID-19 really kicked in that night, I am unsure whether if it is actually beneficial to exercise the breathing while being sick of COVID-19. It is exercise, and exerts the body too in such a delicate state. My subjective experience was that the WHM breathing masked the symptoms and provided a very temporary relief, but did not actually aid in working with the sickness. Therefore, based on my completely subjective experience, I would personally be very mindful and discerning in doing the breathing while being sick. Of course, if you are not sick, and do not have early stage symptoms, breathe your ass off!

I also want to remind you of what I wrote earlier “Reducing NLRP3 activity early on in the COVID-19 process might actually decrease resilience and worsen the progression of diseases, as has been observed in a mice Influenza A model. Thus, the most effective application of NLRP3 suppression during COVID-19, as implied in “COVID-19: Melatonin as a potential adjuvant treatment“, is likely “the use of melatonin in ALI/ARDS when inflammation is most severe.”, during the peak, not in early stages.“

How to practice

To practice the Wim Hof Method breathing I suggest you look at wimhofmethod.com and follow all the appropriate guidelines and regulations there, together with the very important and relevant “feeling is understanding”, “listen to your body”. Not only will this mindset aid you in practicing the method, you might actually notice sooner when you are getting sick. On the website you will find a free app and a free guided breathing video.

Final Take Away
Lots of info, lots of science, what to take away from this?

If anything, I’d say it is important to understand that:

• “SARS-CoV-2 pathogenicity comes through its stimulation of the immune responses.” and progressively uncontrolled inflammation throughout the body and in specific in the lungs. 
• Vitamin C, Melatonin, Nose breathing and Wim Hof Method Breathing might all contribute to reducing the progressive inflammation during its peak, therewith possibly lowering the severity of or support the overcoming of COVID-19
• Those same practices could potentially worsen disease progression when applied during early stages of the disease
• Vitamin C, Melatonin, Nose breathing and Wim Hof Method Breathing are all generally safe to practice for healthy individuals as long as the appropriate guidelines are followed.
• None of this is medical advice, proven or field-tested. It is derived from looking at how SARS-CoV-2 works, and how these additional strategies might interact with COVID-19. The aim here is to looking at potent options for additional aids during the COVID-19 pandemic.

Final words

Thank you for reading this far. I am sure there is a lot more information that could be added in or links to be made, but I also felt a sense of urgency in writing and finalising this.

The aim of this article is to ‘do no harm’, and to see if I can add some value or insightful information in working with COVID-19. The last I would want is to spread fake news or misinformation (we have enough of both). Therefore, if you have any ‘red flags’, additions or revision notes coming up, please contact me on facebook (Sven Kimenai), Instagram (svenkimenai) or through my website (svenkimenai.com). I will keep this article here on my website so I could potentially edit it, when new info arises. (So please use the link to share instead of copying the content, as that doesn’t allow for revisions)

If you found this valuable yourself, or think it might be of value to someone else, please share this. 

Hope you are well and wishing you all the best.

With love,

Sven

Literature

[Article 1 / Original article] COVID-19, Pneumonia & Inflammasomes – The Melatonin Connection

https://www.evolutamente.it/covid-19-pneumonia-inflammasomes-the-melatonin-connection/

[Article 2] chematic illustration of the NLRP3 inflammasome activation
https://www.researchgate.net/figure/Schematic-illustration-of-the-NLRP3-inflammasome-activation-Upon-exposure-to_fig1_283981397

[Article 3] Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies

https://www.researchgate.net/publication/339984438_Induction_of_pro-inflammatory_cytokines_IL-1_and_IL-6_and_lung_inflammation_by_COVID-19_anti-inflammatory_strategies

[Article 4] High nitric oxide production in human paranasal sinuses

https://www.ncbi.nlm.nih.gov/pubmed/7585069

[Article 5] Immune-enhancing role of vitamin C and zinc and effect on clinical conditions

https://www.ncbi.nlm.nih.gov/pubmed/16373990

[Article 6] “Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans” Kox et al. (2014)

https://www.ncbi.nlm.nih.gov/pubmed/24799686

[Article 7] Interleukin-10 inhibits interleukin-1β production and inflammasome activation of microglia in epileptic seizures

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1452-1

[Article 8] Melatonin enhances interleukin-10 expression and suppresses chemotaxis to inhibit inflammation in situ and reduce the severity of experimental autoimmune encephalomyelitis.

https://www.ncbi.nlm.nih.gov/pubmed/26735612

[Article 9] Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production.

https://www.ncbi.nlm.nih.gov/pubmed/32143642

[Article 10] Interleukin-10 inhibits the production of inflammatory cytokines by antigen-stimulated mononuclear cells from asthmatic patients

https://www.sciencedirect.com/science/article/pii/S1323893015313861

[Article 11] Inhaled IL-10 reduces biotrauma and mortality in a model of ventilator-induced lung injury. 

https://www.ncbi.nlm.nih.gov/pubmed/19006658

[Article 12] Humming Greatly Increases Nasal Nitric Oxide
https://www.ncbi.nlm.nih.gov/pubmed/12119224

[Article 13] Ascorbic Acid Supplements and Kidney Stone Incidence Among Men: A Prospective Study
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1568519

[Article 14] COVID-19: Melatonin as a potential adjuvant treatment
https://www.sciencedirect.com/science/article/pii/S0024320520303313

[Article 15] Melatonin administration to wild‐type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis
https://onlinelibrary.wiley.com/doi/abs/10.1111/jpi.12410

[Article 16] Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome.
https://onlinelibrary.wiley.com/doi/abs/10.1111/jpi.12410

[Article 17] Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition
https://www.nature.com/articles/srep27912
[Article 18] Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS
https://www.researchgate.net/publication/305624280_Vitamin_C_inhibits_the_activation_of_the_NLRP3_inflammasome_by_scavenging_mitochondrial_ROS

[Article 19] COVID-19 infection and rheumatoid arthritis: Faraway, so close!
https://www.researchgate.net/figure/Effects-of-ibuprofen-on-distribution-and-expression-of-TGF-b-1-and-mTOR-N-Normal-D_fig3_275256985