Is the Endocannabinoid System Key to MCAS?
February 23, 2025We already looked at how the endocannabinoid system might be key to all our modern diseases.
MCAS is front and center on this list and for very good reason.
It involves the immune system being hyperactivated and mast cells are just the canary in the coal mine.
So…running too hot. Over-reactionary.
This begs the question…what system in the body is in charge of calming this response?
Hello endocannabinoid system!
Wait till you see how this system works in relationship to MCAS and then lets look at tools to support a system clearly under duress.
We'll cover these topics:
- The basic mechanics of MCAS
- Understanding the endocannabinoid system
- Is the endocannabinoid system key to MCAS
- How to support the endocannabinoid system for MCAS
Let's get started.
The basic mechanics of MCAS
We have a deeper dive into MCAS but let's get a lay of the land.
MCAS stands for Mast Cells Activation Syndrome.
The mast cells are repositories of the immune system. They are forward guards in the defense of our body against pathogens and dangerous chemicals we come in contact with.
They're essential!
The word actually comes from a German word meaning "fattening" and it speaks to the fact that they are filled to the brim with a host of weopons just waiting to be activated:
- Histamine - key to the allergic reaction to get things out of the body fast
- Cytokines - immune assassins which are key to inflammatory responses
- Heparin - an anticoagulant that speeds things up (to get them out!)
These are the big three among others but we can focus on these.
We have giant reviews on inflammation and the immune system to better understand these players.
The net net…
Our environment is blasting this threat detection system with the following (not a complete list):
- Pesticides
- Artificial flavors, scents, and preservatives
- Microplastics and PFOA (forever chemicals)
- Hormone disruptors
- Viral infections and medications
Basically, anything that chronically pushes the immune system to respond is going to get the mast cells involved.
The key word there is "chronic". This chronic inflammation is even tied to aging and it's called "inflammaging".
During ageing, chronic, sterile, low-grade inflammation — called inflammaging — develops, which contributes to the pathogenesis of age-related diseases.
https://www.nature.com/articles/s41574-018-0059-4
The symptom list from MCAS is long and as varied as well…the list of modern disease!
We looked at neuroinflammation and mental health as just one example.
Let's look at the other side of the equation.
Understanding the endocannabinoid system
This is a fascinating system.
We all have and it's tied to balancing every system in your body.
The key word is "homeostasis" which just means balance.
Some of the main systems under direct management from the endocannabinoid system:
- Nervous system - including neurotransmitters
- Endocrine system - hormones both steroidal and endocrine
- Immune system - umm….mast cells???
Let's understand how this works.
The body comes into contact with something nasty. A pesticide. Chemical. Maybe a virus.
Signals are sent to the immune system of this entry. The mast cells respond and gush out their contents.
Inflammation. Speeded up factors. Get these things OUT of the body fast.
Think allergic reaction. Pulse quickens. Gut speeds up. Dilation.
Eventually, the bad actor has been addressed. Neutralized.
Then what? We can't keep in a state of heightened response or the system burns out (hello MCAS).
That's the endocannabinoid system!
It is now well established that all body districts and tissues produce eCBs as part of a homeostatic system that acts at almost every level of biological life, with the aim of controlling several physiopathological states and maintaining human health.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576605/
Let's break that apart.
"Homeostatic".
A state of balance among all the body systems needed for the body to survive and function correctly.
This is all about responding to changes in the environment. If a pathogen enters the body, it must respond forcibly and fast.
It then needs to bring everything back to balance after this response. The system in charge of this is the endocannabinoid system.
Let's bring these two worlds together. You're going to be pleasantly surprised.
Is the endocannabinoid system key to MCAS
We have a system that running amok (Mast cells).
We have another system which out-gunned in calming the response to outside forces (endocannabinoid system).
So…what does research say?
There have been clues out there for a while around issues tied to mast cell activation.
You see this everywhere from asthma to cancer (yes, the immune system kills cancer naturally).
It's been known that a endocannabinoid called Anandamide directly blocks the release (called degranulation) of mast cells:
Anandamide (AEA), one of the most well-studied endocannabinoids, inhibits FcεRI-dependent mast cell degranulation and cytokine synthesis through the activation of two receptors (the cannabinoid receptor 2, CB2; and G protein-coupled receptor 55, GPR55).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136699/
So…anandamine is a function lever the endocannabinoid system uses to calm mast cells.
We've covered this "bliss" molecule in detail at our endocannabinoid system review.
Another endocannabinoid shares duties here when Anandamide gets exhausted:
PEA reduced mast cell activation associated with the inflammation process by decreasing the antigen-evoked serotonin release from RBL-2H3 cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136699/
We looked at PEA directly here since you can supplement it.
The studies are getting more sophisticated and fine-tuned.
For example…
we show that normal skin MCs are tightly controlled by the endocannabinoid system.
https://pubmed.ncbi.nlm.nih.gov/22226549/
Let's look to more detail…
This limits excessive activation and maturation of MCs from resident progenitors via "tonic" CB1 stimulation by locally synthesized endocannabinoids.
"Excessive activation and maturation of MCs (mast cells)".
Read that back over in the context of MCAS. It's EVERYTHING!
The endocannabinoid systems are the brake pedal on mast cell activation. Point.
It's the holy grail for what we're after.
See why we looked at whether our modern disease landscape may point to the endocannabinoid system being outgunned!??
We have deeper dives on the endocannabinoid system generally but let's look at how to support this system without the nasty side effect of tolerance.
How to support the endocannabinoid system for MCAS
We need to be careful here.
Let's explain tolerance.
If a substance pushes a pathway (including those in the endocannabinoid) in one direction, eventually, the body will push back (or exhaust).
This is an issue with almost every medication out there (NSAIDs for pain, SSRIs for mood, and benzos for anxiety, etc).
On and on and on.
This is a big issue with most of the cannabinoids such as THC, CBN, Delta8, and cannabis alone.
We have a big review on CBD versus THC to dive into this. THC suppresses everything in one direction.
It chemically mimics anandamide, the primary endocannabinoid we looked at above but it hits too hard and lasts too long.
As a result, the body will reduce CB1 receptor (where anandamide and THC work) numbers and sensitivity. That's tolerance!
This is going the wrong direction!! We want to support CB1 activity without pushing it too hard!
Is there a way to support this system and calm mast cell activation without tolerance and of course addiction (dopamine effects)?
There are three direct supports:
Our first love, CBD isolate.
CBD is technically an allosteric positive modulator for CB activity.
It blocks the pathway that breaks down anandamide called FAAH (see the woman who can't feel pain).
The net result…more robust anandamide function without the tolerance!
For example with schizophrenia (big review here):
cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/
It's all about the FAAH!
Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH)
https://www.nature.com/articles/tp201215
Just a head's up…a few people walking this Earth have a genetic variant where they don't make FAAH.
They literally can't feel pain, anxiety, depression, or MCAS!
We obviously don't want zero but reducing is positive for MCAS as we see in our CBD as mast cell stabilizer review.
The "isolate" part is really important. Full spectrum CBD can actually trigger mast cells and if you read our reviews, you'll see night and day results from clean CBD isolate versus other CBD options.
Again, we want zero THC for longer term health benefits.
It should be 3rd party tested for no:
- Pesticides
- Mold
- Heavy metals
- Solvents
- Bacteria
After all, our mast cells are on high alert for all these things. We test for all and if only we could get similar testing for all our supplements and even food!!
What about PEA?
PEA and MCAS
PEA (Palmitonolyethalanoalmide…careful, there's another PEA out there) is a fascinating player.
Think of it as the backup support to anandamide.
When anandamide is running low (exhausted from mast cell activation), PEA comes on the scene to share the burden.
We have a giant review on PEA here and you can easily supplement it such as this one here.
The net net…
Palmitoylethanolamide is biosynthesized “on demand” from membrane phospholipids (Cadas et al., 1996; Cravatt et al., 1996; Ueda et al., 2013) and has been proposed to behave as a local autacoid mediator able to down-regulate mast cell activation and inflammation.
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00857/full
"Down regulate mast cell activation and inflammation".
Yes please.
Check out the review and also our mast cell review.
Next up, a basic player.
Magnesium glycinate and MCAS
Don't sleep on magnesium glycinate.
magnesium, as a known calcium channel blocker, can stabilize the mast cell membrane and reduce mast cell degranulation, which could be one of the mechanisms of its effect on neuroinflammation and its analgesic effect
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094402/
And when mag is deficient:
These results clearly indicate that Mg deficiency induces the emergence of mast cells around portal triads of the liver in Sprague-Dawley rats.
https://pubmed.ncbi.nlm.nih.gov/24477254/
Stress just eats up mag by the way? Any connection with your stress level and mast cell activation? Thought so.
We have a massive review on magnesium glycinate but many people are deficient.
The limit is with you start to see the GI tract moving too fast. I personally take 750mg daily to keep migraines at bay.
The "ates" get in better for glycinate, citrate, and threonate. Test where your limit is and keep it close to that.
Check out our top 10 tools to calm Mast Cells.
One additional note for women. Really zero in on Progesterone.
It drops 50% by age 40 and P's primary role in the body (of 1000's) is to calm the immune response.
It's how we found CBD to begin with…a brutal perimenopause.
As P drops, you'll start to see all sorts of telltale signs of allergic reactions to foods, makeup, etc.
The mast cells are left unchecked! Big review on progesterone here to get started. May be the MOST important for women over age 40 with MCAS.
That's a wrap. You'll find the endocannabinoid system offers the best target for addressing not only the symptoms of MCAS but the root cause.
Everything else is just an immunosuppressant and unfortunately, we need the immune system (infection, cancer, etc). We also don't want tolerance which is the enemy longer term.
Be well!