Can CBD Help With Viral Cytokine Storm?

CBD and the cytokine storm

 

First, an important point.  The FDA has not approved or tested CBD for coronavirus or Covid19.  We're only going to look at pathways affected by CBD on immune response to viral infection in research only.   

 

As if the virus wasn't bad enough.

 

Now, research is showing that our immune response to it may be the difference between a bad cold and a death sentence.

 

The term is cytokine storm and it's a pretty vivid explanation of what's going on.

 

The stories of people literally drowning in lung fluid speaks to this effect.

 

Interestingly, that fluid is the product of our immune response primarily.  An overabundance of it.

 

We'll get into the whole process below but more importantly, we'll look at research on whether CBD might be helpful in immune over-response.

 

 

These are the areas we'll cover: 

  • What is a cytokine storm
  • Viruses and cytokine storms
  • The endocannabinoids system and immune response to viruses
  • Can CBD help with the cytokine storm response

 

Let's get started...clouds are gathering.

What is a cytokine storm 

First, a step back is required.

 

What is a cytokine?

 

A cytokine just a member of the varied and complex army that our immune system uses to fight off the "other".

 

The "other" being bacteria, viruses, fungi, etc.

 

Anything that the body recognizes from an age-old arms race with outside players looking to gain entry to our bodies.

 

You can generally think of these agents as "inflammatory" in the way we, as humans, actually perceive them.

 

In their battle with outside forces, there can be collateral damage.

 

Think of a cut to the skin.

 

It becomes inflamed, reddened, painful.

 

That's not the cut per-se but our immune response to the countless bacteria seeing this new entry as a perfect invitation to our body.

 

The cytokines swarm to that area in defense and there's just a touch of scorched earth with the surrounding good cells.

 

A cytokine storm is a very exaggerated extension of this same process.

 

If the immune system "panics", it can swell the ranks to a certain area and actually cause damage depending on where that is.

 

If the area is the skin, it might result in pain and inflammation.

 

What about the lungs?

 

That's a very different story.

 

The resulting lung inflammation and fluid buildup can lead to respiratory distress and can be contaminated by a secondary bacterial pneumonia -- often enhancing the mortality in patients. 

https://www.sciencedaily.com/releases/2014/02/140227142250.htm

 

There's that pneumonia we can see from viral and bacterial infections.

 

Why do infections primarily drive this response in the lungs?   

 

There's interesting research on that front.  Let's go there now.

Viral infections and cytokine storms 

The entire SARS family appears to have a "gain of function" or a newly adopted trick.

 

It centers around how the virus gains entry to cells and which cells in particular.

 

This family has a special talent for gaining access to ACE2 receptors.

 

These receptors usually interact with angiotensin, a natural substance we make to constrict the inner-lining of our veins and cardiovascular system.

 

It's a big (the biggest) target for the blood pressure meds as a result (ACE2 inhibitors, ARB's, etc).

 

Needless to day, ACE2 receptors are found primarily in the cardiovascular system (lungs and heart).

 

Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels.4  

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext

 

The theory is that this special focus makes the virus much more likely to spread (and survive) since coughing will expel new virus particles (called virions) from the lungs to infect others.

 

Natural selection at its best.  

 

Also, look at the risk factors: 

  • Heart disease
  • Diabetes (autoimmune)
  • Hypertension!!  

 

The last one had the highest co-morbidity or associated risk.

 

Why?

 

Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study. 

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext

 

In fact, a new study showed that people on blood pressure meds may have a higher risk as a result of increased numbers of ACE2 receptors resulting from the medication.

 

The body always tries to find balance and if you're blocking ACE2 activity, it will respond with more receptors.

 

We've seen this effect with benzos and GABA receptors or SSRIs and serotonin receptors.

 

Interestingly enough, a new study found a knock-on effect for men who were infected by SARS viruses…

 

Reduced testosterone production!

 

It turns out that there's a high number of ACE2 receptors in the testicles as well.

 

Great.  Mother nature is pushing back.

 

But by far, the majority of ACE2 receptors are in the lungs and cardiovascular system.

 

So...what happens when the immune system sees a brand new virus (not yet interacted with) exploding in numbers from easy access to a key system of our body (lungs).

 

Panic mode.

 

Cytokine storm.

 

We've seen it before: 

This little-understood phenomenon is thought to occur in at least several types of infections and autoimmune conditions, but it appears to be particularly relevant in outbreaks of new flu variants. 

https://www.sciencedaily.com/releases/2014/02/140227142250.htm

 

"New" variants.

 

Researchers have looked specifically at SARS for elevated cytokines in people who died versus those that survived.

 

There were elevated levels for many members of the cytokine storm but one stood out: 

It is concluded that an interferon-gamma-related cytokine storm was induced post-SARS coronavirus infection, and this cytokine storm might be involved in the immunopathological damage in SARS patients. 

https://www.ncbi.nlm.nih.gov/pubmed/15602737/

 

Interferon Gamma.  Our immune system's primary response to viral pathogens.

 

Researchers are still furiously working out what is going on with the immune response to SARS viruses but here's the key point.

 

Our immune response is all about balance. 

 

  • Too little and the virus takes over
  • Too much and our immune system kills us

 

It's a very complex system with constant constraint and rebalancing needed...even in the heat of a viral infection.

 

What system is tasked with that balancing?

 

Glad you asked.

The endocannabinoids system and immune response to viruses 

We have a system dated back to about 600 million years.

 

We share it with almost all living animals (insects were early to the party so they don't have one).

 

It's tasked with balancing other key systems: 

  • Nervous system - neurotransmitters like GABA, serotonin, etc
  • Endocrine system - hormones 
  • Immune system - cytokines! 


That last one might be critical for our discussion.

 

We've covered some of this interaction at our CBD and inflammation or CBD and neuroinflammation (key to mental health and dementia).

 

Usually, it's in the context of too much immune response such as with autoimmune diseases.

 

What about the other way...in protection against viruses?


It turns out the endocannabinoid system is highly integrated across the entire spectrum: 

The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686045/

 

Like we said, our immune response and all the many players are quite complex.

 

Let's zoom into one area directly tied to the SARS family of viruses and where it strikes.

 

There's a common virus that infects most humans (usually when young) which primarily attacks the lungs.

 

It's called the Respiratory syncytial virus (RSV).

 

Researchers wanted to see how intertwined our endocannabinoid system was to the immune response to this virus.

 

They blocked the CB2 receptors which are endocannabinoid receptors directly tied to immune response.

 

The results: 

In mice, the blockade of CB2 by AM630 during RSV infection enhanced the influx of BAL cells and the production of cytokines/chemokines while exaggerating lung pathology.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955186/

 

There are the cytokines we're discussing.  BAL is interesting, it's essentially lung fluid.

 

The most important piece was increased lung damage (pathology).

 

That's when they blocked the CB2 receptors.

 

What about when they boosted CB2 activity?

 

The exact opposite: 

CB2 activation by JWH133 reduces the influx of BAL cells and the production of cytokines/chemokines while alleviating lung pathology.

 

Calms the cytokine and lung fluid assault while improving lung function.

 

This function is at the heart of cytokine storm!

 

So...are there ways to support our endocannabinoid and calm the response?

Can CBD help with the cytokine storm response 

It's a fine balancing act. 

 

We want a strong immune response but not an overly aggressive one.

 

We should be well acquainted with this via autoimmune response.

 

Here's where it gets really interesting with CBD.

 

We'll start with THC as a reference example.

 

THC acts in one direction and is generally immune suppressant.  

 

A study looked at THC's effect on lung function and cytokines from influenza: 

Collectively, these results suggest that Delta(9)-THC treatment increased viral load, as assessed by H1 mRNA levels, through a decrease in recruitment of macrophages and lymphocytes, particularly CD4(+) and CD8(+) T cells, to the lung. 

https://www.ncbi.nlm.nih.gov/pubmed/17726158

 

This is going the wrong direction...across multiple fronts if it's only in one direction (which it is with THC).

 

The virus was able to thrive as immune responders were suppressed.

 

Again, what might be good for autoimmune (or asthma) is the very opposite of what we want for a viral infection.

 

It's the opposite of cytokine storm...viral storm! 

 

What about CBD?


The fascinating piece is that it can have bi-phasic (different results depending on the situation).

     

    We see this throughout various pathways (GABA and Serotonin for example) and we'll explain why later but how does CBD affect immune response.

     

    Is it one-directional like THC (suppress function)?

     

    In inflammatory states (such as cytokine storm), CBD can calm inflammation. 

    , 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin1, interleukin-6, and interferon (IFN), from LPS-activated microglial cells.  

    https://www.jbc.org/content/285/3/1616.full.pdf

     

    This is relevant with issues such as autoimmune, neuroinflammation, etc.

     

    Here's where CBD splits off from THC (in many ways really - see CBD versus THC).

     

    Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events.  

    https://www.jbc.org/content/285/3/1616.full.pdf

     

    The most important word there is "homeostatic".

     

    It's the whole role of the endocannabinoid system - to find balance.

     

    Not too much (cytokine storm).  Not too little (runaway infection).

     

    Stat3 is fascinating.  It's an upstream immune responder (in addition to much more).

     

    We're going to show you just how complicated our immune interaction with viruses are but also decipher along the way on just one aspect (from 1000's) of the machine (STAT3).

     

    There a unique quirk with certain viral families that mirrors what happens with HIV.

     

    This isn't surprising since some HIV-esque proteins are found in the shell of newer viruses (sure it's not from China's only level 4 lab in Wuhan - sarc).

     

    Hence, the buzz about an HIV drug called Remdesivir (see How does Remdesivir work).

     

    Initial reports on SARS viruses showed a collapse in T cells (immune attack and command agents).  HIV attacks T helper cells in a similar fashion.

     

    This info actually dates back to the original SARS epidemic.

     

    The earlier results here: 

    As STAT3 acts as an activator of transcription in the nucleus, these results suggest that STAT3 lacks its activity on transcription in SARS-CoV-infected Vero E6 cells. 

    https://www.ncbi.nlm.nih.gov/pubmed/15527783

     

    So, infection with SARS blocked STAT3 activity.

     

    Why does this matter for STAT3? 

    During viral infection, mice lacking STAT3 in T-cells display impairment in the ability to generate T-follicular helper (Tfh) cells and fail to maintain antibody-based immunity. 

    https://en.wikipedia.org/wiki/STAT3

     

    Goodness...the same players affected by HIV.

     

    So a quick recap before our eyes glaze over: 

    • SARS blocks STAT3 activity
    • STAT3 is needed for T cells, our immune system's commander
    • CBD boosts STAT3 activity during viral infection!

     

    So...even though CBD can decrease cytokines during periods of high inflammation (such as asthma...very relevant for viruses that primarily act in the lungs): 

    CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels. CBD seems to be a potential new drug to modulate the inflammatory response in asthma.


    https://www.hindawi.com/journals/mi/2015/538670/

     


    IL-10 is an anti-inflammatory cytokine by the way.  We need more of that to calm the cytokine storm.

     

    Remember, we don't want to suppress immune response...only over-active response which seems like an impossible target.

     

    Let's look at other studies with different viruses.

     

    Hepatitis C is a relevant target since it's able to "hang around" as a retrovirus (like HIV).

     

    That's the difference between viruses we can "beat" like colds and flus versus those that we can't like HepC and HIV.

     

    They literally write their DNA into ours so they can get re-processed over and over.

     

    Pretty sneaky and sinister.

     

    The SARS family is an RNA based virus so they use a similar machinery although the jury's still out on retrovirus status.

     

    How does CBD affect Hep C, another RNA based virus?

     

    CBD inhibited HCV replication by 86.4% at a single concentration of 10 μM with EC50 of 3.163 μM in a dose-response assay.  

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330095/

     

    This was a similar effect in the study to interferon (which has a pretty significant side effect profile).

     

    So...why does CBD display both cytokine suppression and cytokine support effects depending on the state of our system?

     

    This goes to the heart of how CBD works which is very different from all the other endocannabinoids.

     

    Our favorite NIH chart to explain this is here: 

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345356/table/T1/

     

    You'll notice that CBD works very differently than THC and even the other cannabinoids.

     

    Let's first introduce key modes of action: 

    • Agonist - boost activity in a given pathway
    • Antagonists - suppresses activity in a given pathway
    • Inhibitor - blocks the activity
    • Allosteric Reverse Agonist, Antagonist, or Modulator

     

    What was the last one??

     

    That's CBD.

     

    The other cannabinoids in that chart are mainly agonists...they push a pathway in one direction.

     

    For example, THC mimics anandamide (our bliss molecule) and boosts CB1 activity.

     

    Up, up, up!

     

    CBD works very differently...like a constraint on different pathways.

    • Agonist, antagonists, and inhibitors send a signal from one neuron to another 
    • Reverse agents like CBD send a return signal from the RECEIVING neuron or cells!

     

    It's a feedback mechanism.  That's why it's possible to see different responses depending on the state of the system and it's not just our immune system.

     

    Cancer is a perfect example.

     

    CBD's effect depending on the state: 

    • Healthy cell with low inflammation - CBD doesn't have an effect
    • Healthy cell with high inflammation - CBD reduces inflammation
    • Cancerous or pre-cancerous cell - CBD INCREASES inflammation! 


    Please read that over one more time.  It's fascinating.

     

    Also, realize that inflammatory responses are part of the immune system.

     

    Inflammation = cytokines!

     

    Why would this occur?

     

    Inflammation is the natural way our body kills faulty cells all the time.

     

    Radiation and chemo are just massive dumps of oxidative stress to kill cells, mimicking our own body's natural process.

     

    It's nearly impossible to either boost or suppress the immune system without under or overshooting.

     

    Finding the sweet spot is the role of the endocannabinoid system and CBD appears to support that system with its bi-phasic (sometimes tri-phasic) response.

     

    One follow up note.

     

    New studies are showing high doses of Vitamin C may be helpful in dealing with the cytokine storm.

     

    NAC is also showing benefits: 

    N-acetylcysteine (NAC), a modified form of the amino acid cysteine, was shown to inhibit both H5N1 replication and H5N1-induced production of pro-inflammatory molecules (e.g., IL6, CCL5, CXCL8, and CXCL10) in lung epithelial cells 

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/

     

    Both are very safe.  

     

    With NAC, Vitamin C, Quercetin (See how quercetin shares a key pathway with hydroxychloroquine), and CBD, there are safe and potential insurance policies in the time of viral infection and fear.  

     

    Always work with a doctor or naturopath with any supplement!

    The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.

     

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