CBD and PEA for Histamine and Mast Cell Activation

cbd and pea for histamine, allergies, mast cell issues

Talk about timing.

Just last night, I had an intense histamine response right before bed.

  • Itching
  • Swallowing was labored
  • Heart raced quickened


And oh yes...up till 3:30 am.  We looked at the whole connection between histamine and insomnia here.  

Deep at the heart of this process is a specialized cell that is a critical player in the whole allergic process.

Mast cells.

Triggering these cells can be the difference between calm and anaphylactic shock!

Here's the deal...roughly 40-60% of people have histamine issues.

This number goes up as we get older and for women (Thanks for leaving, progesterone).

Hyperactive mast cell activity is tied to everything from insomnia (I can attest) to anxiety.

Histamine is a powerful neurotransmitter in its own right!

We'll get into all of it.

Most importantly, we'll look at the effect of CBD and PEA on mast cells along with other tools we've found in research.

Here are the topics we'll cover: 

  • A quick introduction to your allergic arsenal - mast cells
  • The tie between mast cells and inflammation (beyond allergies)
  • Mast cell and allergies
  • Mast cell activation and mental health
  • Mast cell activation and sleep
  • Mast cell activation and gut inflammation
  • Why is mast cell activation disorder becoming "the" modern disease
  • Research on CBD and mast cell activation
  • Research on PEA and mast cell activation
  • Dosage levels for CBD and PEA
  • What's the best type of CBD for mast cell activation


Let's get started...before I fall asleep at the keyboard.

A quick introduction to your allergic arsenal - mast cells 

First...the broad strokes:



The visual of mast cells give good clues to its name...assuming you know German.

Originally discovered by a German scientist, they were given the name "mastzellen" which means well-fed.

This speaks to their being packed with granules of histamine and heparin (among dozens of other chemicals).

Mast cells are part of our immune response with a primary task of responding to foreign entities that must be removed from the body...fast!

Think of a bee sting.  The venom creates an immediate response for mast cell activation and histamine spills out in volumes to get the venom out of the body.

This can be triggered by any potential foreign chemical, allergen, or entity.

All the telltale symptoms of mast cell activation act to speed the removal of intruders.

Swelling (surround).  Itching.  Redness.  Couching.  Sneezing.  

Get out!

This is the proper (and needed) function of mast cells but the issue is when they're hyperactivated!

They are created in the bone marrow and move around the body to sites where they are prevalent: 

  • Mucous linings
  • Airways
  • Vascular system


Interestingly, they're also in charge of vascular dilation (constriction and opening of veins and arteries) and peristalsis (movement within the bowel).

This ties into their ability to respond to foreign intruders.

Get them out!

The issue with mast cells is when: 

  • There are too many
  • They produce too much histamine
  • They respond to simple triggers
  • They exhibit an autoimmune quality 


Any of these can lead to mast cell activation disorder...to a constant state of war within the body.

With casualties of course as inflammation is a double-edged sword.

The key is balance.  That's a great segue into the endocannabinoid system.

The endocannabinoid system and mast cell activation 

This is a  powerful system that's been around for about 600 million years.

We share it with every living animal so clearly, Mother Nature stumbled on something she liked.

It's tasked with balancing other key systems: 

  • Nervous system - including neurotransmitters like histamine
  • Endocrine system - hormones
  • Immune system - inflammatory responders like mast cells!


Remember, mast cells are one leg within our immune response.

There are times (bee sting) where we really need mast cells to do their job.

It's the "resolution" of the response that has become an issue in our modern world.

Bringing the mast cell activation under reign so to speak.

THAT is exactly the role of the endocannabinoid system so barring genetic variants of mast cells (called mastocytosis), you can argue that issues with mast cells are really a problem with their regulators...the endocannabinoids.

Let's introduce some now.

  • Anandamide - our bliss molecule with a calming effect across multiple pathways
  • 2-AG - a big player in the brain and nervous system
  • PEA - a key support player and a direct stop sign to mast cell activation


So...what does research show?

Let's start with anandamide.

Let's look at the mucus pathway specifically (think nose, throat, and lungs).

AEA and CB1 in modulating human mast cell functions were further confirmed by the observation that in human airway mucosal mast cells, maturation and excessive activation were inhibited by the endocannabinoid tone through CB1 stimulation. 


CB1 is the primary endocannabinoid receptors.   

Read that last bit…" Excessive activation was inhibited" by endocannabinoid function.

Goodness...essentially, this system was in charge of keeping mast cell activity within range.

See why this system may be the linchpin?

Anandamide also calls in the guards to bring things under control...

AEA was also shown to recruit special cells in the body that turn down the mast cell activation response: 

AEA activation of CB1 in mast cells induced monocyte chemotactic protein-1-mediated recruitment of monocytic and anti-inflammatory myeloid-derived suppressor cells 


That's technical but the myeloid-derived suppressor cells are important!

They are suppressors of immune response...part of the resolution process.

This is key to autoimmune, allergies, and mast cell activation.  See CBD and autoimmune to learn more.

Another common issue is having too many mast cells!

Over proliferation!

The endocannabinoid system controls this as well!

Endocannabinoids limit excessive mast cell maturation and activation in human skin


So...both activation (release of histamine) and mast cell numbers themselves are controlled by the endocannabinoid system.

We'll save PEA for its own section as its a key player in this system.  One we can directly supplement.

The net-net is this: 

The generally immunosuppressive role of classical eCBs (AEA and 2-AG) on the different immune cell populations is abundant compared with their congeners (PEA) and is reasonably equivalent in both mice and humans, making them ‘master regulators’ of the innate-adaptive immune axis.


"Master regulators" of the immune response.  Game on!

Let's turn to the collateral damage of mast cell hyperactivation to understand why regulation here is so important.

We'll start with the obvious.

Mast cell and allergies 

This is the most common effect of mast cell activation...the one we all know.

Allergies are simply the physical effects of mast cells releasing chemicals designed to remove foreign entities.

It can run the gamut from simple seasonal allergies to systemic shock called anaphylaxis.

Your common allergy medications focus on reducing histamine, the primary foot soldier in our allergic response.


We'll see below how addressing mast cell activation (CBD or and PEA) may be a better option.

Stop the response at the source!

This is important since histamine has 4 different receptors that all do different things across the body.

For example, antihistamines make you sleepy and can rip acetylcholine, a critical neurotransmitter for the brain with a risk for dementia!  See Acetylcholine review.

It's tricky taking a hammer to histamine that way...especially if you're using heavy machinery.

The question is why do some people have such strong allergic reactions (even constant) and why can they get out of control (asthma, etc)?

We have to look to the mast cells (too many or too active)!


The list of symptoms is growing from the excess release: 

These symptoms (Table 1) originate from mediators secreted (released) from mast cells and include flushing, pruritus, hypotension, gastrointestinal complaints, headaches, irritability, malaise, memory loss, and neuropsychiatric issues.  


Pruritus is itching but looks towards the end of the list...neuropsychiatric issues?

We'll look at that below.

Why are most types of allergic diseases increasing over the past few decades?

Our immune system is based on the past 40,000+ years (if not 100,000 years).

We've introduced a veritable chemistry set of new things to react to.

One example of 1000's: 

Just yesterday, a report came out that showed how an industrial enzyme used in the processing of dairy, baked goods, and meats may be the trigger for gluten insensitivity. 


That's a whole other article but check out CBD and the gut barrier or CBD and probiotics here.

All roads lead to the gut!

Also, check out our section on progesterone which is key to calming our immune response.

It drops by 50% at age 40 and continues from there (hello autoimmune).

Let's go further on the spectrum of mast cell effects on health.  To inflammation.

The tie between mast cells and inflammation (beyond allergies) 

It's not just about bee venom or tree pollen.

As a member of the immune system, mast cells have a direct effect on inflammation and disease tied to inflammation (just about everything these days).

Look at arthritis, a classic autoimmune disease.

Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice.  


To translate...when mast cells were reduced, so was the inflammation and disease progression in arthritis.

Using pretty sophisticated tools, the studies directly tied mast cell activity to this inflammatory disease

We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown.

Remember...it's not just histamine and heparin (blood thinner) that is stored in mast cells.

There's a veritable arsenal of inflammatory weapons at the mast cells beck and call.

In some respects, mast cells can trigger an onslaught of cytokines and inflammatory assassins.

The clarion call is a chemical called tryptase which not only calls for backup from the immune system but sets up a chain reaction with surrounding mast cells.

It induces the expression of mRNA for IL‐1β, which may be important for the recruitment of inflammatory cells to sites of mast cell activation 



IL-1B is a heavy hitter in the inflammatory world.


Tryptase from mast cells is literally turning DNA machinery on to crank up IL-1B.  We'll look at this in the mental health section below.

It's one example of 100's in our incredibly complicated immune and inflammatory response.

Keep in mind that mast cells, when in a healthy range, carry out a slew of essential functions for us.

Blood supply to the heart.  Cancer-fighting mechanisms.  

The issue is when the call to respond never ends!

Check out CBD and inflammation or CBD and neuroinflammation to learn how this becomes an issue.

Remember the neuropsychiatric symptoms of mast cell release?  Let's go there now.

Mast cell activation and mental health 

We have a full review of CBD and mental health here.

There are key similarities across the range of mental health issues including: 


How do mast cells figure into this process?

Let's start with stress which is also a common denominator for most mental health and their flare-ups: 

Stress conditions activate mast cells to release prestored and newly synthesized inflammatory mediators and induce increased blood-brain barrier permeability, recruitment of immune and inflammatory cells into the brain and neuroinflammation. 


Goodness..that's a whole lot of bad in terms of mental health.

Let's decipher.

Stress (via a hormone called CRH - see CBD and CRH) triggers mast cells to release their payload.

Here's the rub...our immune response is complicated but very much a one-trick pony in that it's unable to recognize if an attack is a bacterial or viral infection or a missed train (stress).  

Both are stress and both bring on the same immune response.

Check out our review on whether tryptophan is the tie between stress and depression (or anxiety) to understand better.

Back to that summary...reduced blood-brain barrier.  

This is to allow inflammatory responders to rush to the brain - the heart of neuroinflammation.


brain inflammation and anxiety


This is fine for a one-off but if it's constant, you're looking at the root of most mental illness.

See CBD and blood-brain barrier.

Mast cells are just a call for inflammation back up and the brain will make the call even if there isn't something to get out of us (which should be the classic mast cell response).

Stress is stress...regardless of the source and look at the result: 

Psychological and environmental stress induces or worsens anxiety and depression, activates neurons, microglia, and induces neuronal dystrophy 


Let's look at anxiety for a clue.

There's a known effect of anti-histamines to have reduced anxiety.

In fact, they can rival benzos (see CBD versus benzos), the de facto medication for anxiety (with a huge risk of addiction and tolerance).

There has been clear evidence of the anxiolytic efficacy of hydroxyzine. In a controlled trial in generalized anxiety disorder patients, hydroxyzine demonstrated greater and more rapid cognitive improvement compared to lorazepam. 


Lorazepam is Ativan, a newer addition to the benzos (very addictive due to half-life and drop off).

Anxiolytic means anti-anxiety.

So...what on earth is going on here?  How can an antihistamine have more of an effect on anxiety than one of the top medications prescribed for it (with a black box FDA warning for addiction)?

Histamine in our brain is a very different bird.

It's a maestro of other key neurotransmitters such as GABA, serotonin, dopamine, and more.

In general, think of histamine as excitatory...like glutamate (our brain's gas pedal).

Too much excitation can feel like….anxiety!

In fact, the "coming out of my skin" feeling with a histamine response is very akin to anxiety.

This all makes sense when you think of the role of histamine.

Something in the outside world is attacking us...a little panic is needed to actually care to respond.

When you're stung by a bee, you ramp up into high alert..and not just from the pain (one signal).

Picture how you respond when a bee is buzzing around your head...anxiousness.  

Evolution always has a reason for an underlying response.

Think of histamine on a spectrum: 

  • No histamine - sleep
  • Low histamine release - calm (no anxiety)
  • Medium histamine release - wakeful, alert
  • High histamine - anxiety! 


Mast cells are inflammatory and excitatory and too much of this for too long is tied to every mental health issue.

Our CBD and neuroinflammation is a great introduction to this process.

If histamine is excitatory, what's the opposite (drop-in histamine).


Mast cell activation and sleep 

Histamine is a critical player in the sleep-wake cycle.  In fact, many (if not all) of the sleep tools diretly calm histamine!


The leading side effect of antihistamines?  Drowsiness.  Sedation even.

In fact, millions of people (especially women who are losing their estrogen and progesterone) use Tylenol PM and over the counter antihistamines to get to sleep.

As we mentioned above, the issue is that this rips acetylcholine which is a big no-no for dementia risk.

Simply put: 

Strong and consistent evidence exists to suggest that histamine, acting via H1 and/or H3 receptor has a pivotal role in the regulation of sleep-wakefulness.  


Put histamine in the "wakefulness" camp.

The H3 receptor really appears to be key here: 

The H3 receptor functions as an auto-receptor and regulates the synthesis and release of histamine. Activation of the H3 receptor decreased histamine release and promoted sleep.


Again, mast cell activation is required for histamine release.  That's its primary reservoir.

Researchers have really dived into the effects of histamine and sleep with fascinating results: 

Acute optogenetic inhibition of HA neurons swiftly switches mice from wake to NREM sleep


Translation...they use light triggers to block histamine function and mice rapidly go from awake to sleep.

The connection between histamine and mast cells?

Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors.  


Again, chemicals that boost histamine activity lead to insomnia.

We'll look at the effects of CBD and PEA on sleep and insomnia.

Let's first turn to the gut.

Mast cell activation and gut inflammation 

Mast cells are prevalent everywhere our inner body comes in contact with the outside world...again...to get foreign invaders out!

Skin.  Mouth.  Lungs.

Gut! The biggest trojan horse available for outside intruders and chemicals.

A large swath of mast cell activation symptoms actually resides in the gut.


Remember...chronic stimulation of mast cells in inflammatory and scientists are teasing out the results on gut issues and autoimmune: 

Next, not only the mast cell content but also the degranulation of mast cells was markedly altered in the mucosa of IBD patients as evidenced by an increased expression of TNFα, IL6, substance P and elevated histamine, prostaglandins, leukotrienes and tryptase levels  


IBD is irritable bowel syndrome.

You see histamine and tryptase (the defining signature of mast cell activation) among other inflammatory nasties.

Remember how mast cell activation in the brain would break down the blood-brain barrier above?

Only second to the brain our gut barrier and look at the result: 

Mast cell tryptase controls paracellular permeability of the intestine. 


As they put it: 

During stress and inflammation, mast cells mediate increased mucosal permeability by unknown mechanisms. 


This is critical for system inflammation, mental health, and most importantly autoimmune.


See CBD and autoimmune, CBD and neuroinflammation, or CBD, and the gut barrier.

The connection with autoimmune is very interesting.

Both hit women predominantly for one.

Once you understand the role of progesterone (see progesterone review) in our calming our immune response, this all makes sense.


Women who don't give birth (long periods of heightened progesterone) have a higher risk for autoimmune and mast cell activation.

In fact: 

During pregnancy many autoimmune diseases go into remission, only to flare again in the early post-partum period.  


The reason we bring up autoimmune is that the main gateway for bacteria to escape into our body and set the state for improper immune response is the gut!

Of the top 5 comorbidities (other diseases tied to mast cell activation disorder), 2 are tied to the gut:

  • GERD - #1 at 35% sharing percentage
  • Abdominal pain - #5 at 22%


A further tie with autoimmune and gut inflammation in general has been teased out: 

These observations demonstrate a central role for IL-9 and mast cells in experimental intestinal permeability in oral antigen sensitization and suggest that IL-9–mediated mast cell responses have an important role in food allergy. 


Essentially, mast cells and an inflammatory agent (IL9) would break the gut barrier and lead to the precursor of autoimmune response...in this case for certain foods.

We could spend a whole day (with many studies) on this process but understand that the mast cell response in the gut acts as a trigger across the body for autoimmune and inflammation.

GERD has exploded in the last 40 years.

As have food allergies.  And mast cell activation disorders not to mention autoimmune.

The question is why?  The gut may be the linchpin there.

Why is mast cell activation disorder becoming "the" modern disease 

We like to think of the mast cell pathway as a canary in the coal mine.

An initial signal that something isn't right (could be downright dangerous).

Think of the role for mast cells again from a basic job task view.

They are there to get potentially bad things out of the body.

What has changed so much in the last 40 years to send this whole process into overdrive and imbalance?

We are now swimming in 1000's of chemicals that completely new to the body.  

Not to mention the gut!

As we noted above, an industrial enzyme used in food is directly tied to food allergies (a mast cell response) and eventual celiac (the result of chronic mast cell activity and inflammation).

Many bowls of cereal have BHT, a derivative of petroleum.

In studying rats given BHT, researchers found an increase in immediate skin allergies, linking it to an allergic response that caused a type of white blood cells, known as mast cells, to release the chemicals histamine and leukotrienes.  


Then there are the fake sugars, fake fats, etc.

Again, 1000's of colors (tied to Adhd), flavors, preservatives, etc.

Throw in the "forever" chemical...PFOA are used in Teflon which we all have in our blood supply now.  Again, forever since it takes forever to breakdown.

In fact, look at what their finding in the baby's umbilical cords: 

researchers at two major laboratories found an average of 200 industrial chemicals and pollutants in umbilical cord blood from 10 babies born in August and September of 2004 in U.S. hospitals.  


In the mix…

Among them are eight perfluorochemicals used as stain and oil repellants in fast food packaging, clothes, and textiles — including the Teflon chemical PFOA, recently characterized as a likely human carcinogen by the EPA's Science Advisory Board — dozens of widely used brominated flame retardants and their toxic by-products; and numerous pesticides.


Goodness.  This is a critical period of brain development.

Guess what part of the body is tasked with getting all of this out?

Mast cells!

No wonder we have a modern epidemic of inflammatory disease.

Let's zero in on just one pesticide...glyphosate.

It's used in about 90% of traditional soy, corn, and wheat.  In fact, it's genetically stitched into the plant itself in what's called...Roundup Ready seed.

So...how is glyphosate tied to everything above?


It's literally listed as a trigger of mast cell activation: 


You see the tell-tale signs: 

It is interesting that the most widely used herbicide glyphosate induces IL-33 expression and airway inflammation


IL33 is an inflammatory cytokine.

What about the gut?

Glysophate creates a situation in which pathogenic bacteria kill off healthy gut bacteria interfering with complex nutrient assimilation resulting in extreme nutrient deficiencies. 


This leads to celiac disease and a range of gut issues.

Remember...the gut balance sets the stage for our body's inflammatory response.

What about autoimmune?

Another common herbicide, glyphosate, was previously associated with incident RA in AHS female spouses


It did not have this effect in men but remember, women are losing their primary immune suppressor...progesterone.

Recall that RA (rheumatoid arthritis) subsides during pregnancy!

Let's drill down to the mechanics as these are all "results" from an underlying process that's pretty well established now.

First, gut lining integrity.

In this section, we first discuss the role of pathogens in inducing the breakdown of tight junctions in enterocytes lining the small intestinal wall. We then show that glyphosate is associated with an overgrowth of pathogens along with inflammatory bowel disease in animal models. 


There's an entire micro-universe of bacteria, viruses, and more that reside in our gut.

This "microbiome" functions as a separate organ and if it's disturbed, serious health issues spike up across the body and brain.

The link above shows all the pathways that glyphosate affects directly.  Just look at the connection (up and down) between glyphosate on wheat and intestinal infection death: 


That's just the gut!

We haven't discussed the chemicals that go on the skin (makeup, skin, and hair cair, etc).

Most sunblocks have powerful chemicals that interfere with hormones.

So...our mast cell "removal" pathway is overworked, overburdened, and freaking out!


One note...early trauma/infection (even inutero) can setup lifelong hyperactivation including mast cells. 



Big review here but outside of loss of steroidal hormones (progesterone especially), early trauma is probably the most exciting avenue to pursue in research!

Finally, besides avoiding these chemicals (when able), what can we do about it?

Let's introduce two interesting tools to use for calming mast cell activation and inflammation in general.

Research on CBD and mast cell activation 

First, how does CBD work within the endocannabinoid system?

CBD acts as a feedback mechanism!

Technically, it's called a negative allosteric modulator.  

This is very important for key neurotransmitters but we're more interested in its side hustles.

CBD is a powerful anti-inflammatory!

Let's zero in on CBD and mast cells specifically.

Look at CBD and the inflammatory agents called cytokines: 

The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF-α were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels 


What's the deal with IL10?  It's actually a player to resolving inflammation!

How about the direct response on mast cells.

We have to get a little technical but we'll explain as we go.  It's just too important!

There's a very important cell to learn in this whole process...the MDSC or myeloid-derived suppressor cell.

Goodness, what does that mean?

Simply put...MDSC's are the brake pedal to mast cell activity!

They work in tandem with mast cells to find the right balance.

The effects are far and wide for diseases tied to mast cell activation: 

Collectively, our results demonstrate that MDSCs suppress Th2-dominant inflammation and improve lung function in asthmatic mice in vivo. 


So...why does this matter with CBD?

Together, the results suggest that CBD may induce activation of PPARγ in mast cells leading to secretion of G-CSF and consequent MDSC mobilization.  


Let's translate!

PPAR is a powerful pathway for calming inflammation.  CBD directly increases its activity when there is excessive inflammation!

By this means, it increases MDSC activity...the brake for mast cell activation.

C-CSF is just fertilizer for MDSC cell production in this situation.

PPAR may eventually be called the CB3 receptor as it's a critical "pedal" for endocannabinoids to bring balance to various systems

Let's turn to where it all starts (and by "all", we mean disease)...

The gut:

Histological, biochemical, and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment


The net effect of this was reduced damage: 

These actions lead to a reduction of intestinal damage mediated by PPAR gamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.

There's that PPAR again!  


CBD calms the gut mast cell activation in the gut specifically!


We have a whole article on CBD and leaky gut here but the key take away: 

Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells


After adding a very dangerous bacteria (c diff) to the gut, CBD was able to stabilize the gut barrier which leads to a host of positive upstream effects.

If CBD is calming mast cell activation, we would expect to see effects on diseases directly tied to this imbalance.

  • Asthma.
  • Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma 


What about eczema? 

Based on skin evaluations (hydration, TEWL, elasticity), clinical questionnaires (SCORAD, ADI, PASI), and supported by photographic data and investigators' clinical assessment, the results showed that topical treatment with CBD-enriched ointment significantly improved the skin parameters, the symptoms and also the PASI index score.  



CBD suppresses the inflammatory reaction of allergic contact dermatitis in vitro, without cytotoxic effects. 


Remember, these are all examples of mast cell activation that's too strong!

Finally, remember how anandamide is a natural mast cell suppressor?

FAAH breaks it down in the body.

This is one of CBD's other avenues of action: 

CBD also inhibits FAAH, which results in increased anandamide levels. 


This is really important as it has effects across the body but because CBD works as a feedback mechanism, it doesn't just jack up anandamide indefinitely.

THC, on the other hand, mimics anandamide but lingers for too long and only works in one direction (up up up for CB1 activity).  That builds tolerance!

This is where CBD is so different.

Look at the effects on inflammation: 

  • Healthy cell with low inflammation - CBD has little effect
  • Healthy cell with high inflammation - CBD reduces inflammation
  • Cancerous or virally infected cell - CBD INCREASES inflammation


Read that back over because it may be the most important part here.

CBD responds depending on the state of the system.

Remember, we need mast cells to do their job...they remove poisons from our body.

Too much is bad.  Too little...equally bad.  

That's the beauty of supporting the endocannabinoid system versus a particular pathway...it's all about balance.

That brings us to another player in this system.

Research on PEA and mast cell activation 

We have an entire review of PEA here but let's focus down on its interaction with mast cell activation.

Simply put, PEA is the natural brake for mast cell activation!

PEA reduces mast cell migration and degranulation and reduces the pathological overactivation of these cells [21]. Mast cells shift from activated immune- to resting phenotypes under influence of PEA. 


Goodness...a smoking gun.  Let's break that down because it's key to our entire discussion.

Migration is the process of mast cells moving to an area of inflammation...calling in the troops so to speak.

Degranulation is the release of histamine and other inflammatory agents.

The important phrase there is "reduces the overactivation" of these cells.


This is the beauty of the endocannabinoid system as we saw above with CBD.

We don't want to completely stop mast cell activity.

They're essential for removing nasty substances from the body.

As with all things immune-related, the key is to calm the storm after the initial swell of mast cell activity.

That's the "resting" phenotype which is another word for the setting.

PEA also works on our other immune responder primarily in the brain, microglia.

The results of this: 

Applied exogenously, PEA has proven efficacious in mast cell-mediated experimental models of acute and neurogenic inflammation. 


See CBD and microglia to learn more about how this figures into mental health.

PEA works in conjunction with anandamide, OEA, and other members of the family.

When PEA is taken, anandamide and OEA levels both increases.

In this way, PEA works like a backup support for anandamide which has profound effects across the body and brain.

CBD feedback endocannabinoid system

Our original interest in PEA was to find an FAAH inhibitor. 

FAAH breaks down anandamide and you can learn more at our review on the woman who can't feel pain, anxiety, or depression (no FAAH activity).  

We're guessing she never gets allergies as well!

The great news on PEA is that it doesn't build tolerance which is so critical.

So many drugs these days will actually make things worse because the body pushes back if critical pathways are pushed up or down in one direction.

THC imitates anandamide but FAAH can't break it down so it lingers for too long and at too high a concentration.

Long term use of cannabis with THC causes the body to reduce the number and sensitivity of CB1 receptors (where both interact) as a result.

This means less natural levels of anandamide going forward!  The wrong direction.

Interestingly, PEA is gaining attention as an aid for THC dependence and withdrawal.

We're not surprised since our theory is that most people who use THC or cannabis daily are either trying to calm glutamate (gas pedal - the key to anxiety, depression, repetitive thoughts, OCD, etc) or raising anandamide.

See our review on cannabis and glutamate here.

Remember how mast cell activation is intimately tied to autoimmune disease?


Look at the net effects of CBD and PEA there: 

Treatment with either CBD (5mg/kg) or PEA (5mg/kg) during disease onset reduced the severity of the neurobehavioral scores of EAE.


EAE is the animal version of MS!

A disease built around inflammatory and altered immune response.

Again, check out the full review of PEA (palmitoylethanolamide) here.

Let's look at practical questions.

Dosage levels for CBD and PEA 

Research is showing that peak neurogenesis (the process of growing new brain cells and connections) peaks at 300 mg/day for CBD.

A great deal of research looks at higher levels (600-800mg) for more serious or acute issues (schizophrenia, opioid withdrawals, social anxiety public speaking, etc).

Long term, 300 mg appears to be the best cap. 

Everyone's system is different so test where you see the response.

For PEA, the research is pointing to between 600-1200 mg per day.

One note...studies show that its effect takes some time to build up...from weeks to months.


Think of a dried-out river bed.  It doesn't fill up with the first rain.

There is no known drug interaction with PEA.

For CBD, it's important to take it 4 hours away from medications and work with your doctor.

The liver processes CBD and most drugs so that is why we want them apart.

What about the type of CBD and PEA?

What's the best type of CBD for mast cell activation 

First CBD.

There are basic requirements: 

  • Organically grown in the US at FDA registered farms
  • 3rd party tested
  • CO2 processed
  • No THC - THC normalizes and reduces long term anandamide function
  • No pesticides
  • No heavy metals
  • No solvents
  • No bacteria
  • No mold 


We test our oils twice to be safe.  Lab results available top of every page.

Then there's the question of CBD isolate versus full spectrum.

This is critical to our discussion of mast cells.


CBD isolate versus full spectrum


All the research above is for CBD isolate.

We have many people who have allergic reactions to full-spectrum CBD (see full spectrum versus isolate for histamines).

In fact, that's how we found CBD isolate to begin with!  All the allergic reactions went away when we switched to isolate.

Then there's the cost.

We want the lowest cost per mg of CBD.  At 300 mg daily, this becomes very important.

That's why we price our 6000 mg bottles at 2-3 cents per mg before discounts up to 50%  (FIRST50 code is 50% off to test).


It's important that people have access to high-quality CBD isolate.

As for PEA, there are two different forms.

  • Chewables 
  • Capsules


We find the chewable have a more immediate effect but the capsules are cheaper.

Since it takes weeks for PEA to really have its major effect, this shouldn't matter in the long run.

You can shop for either here.

Life Extensions has the chewable and we found Lake Avenue (iHerb's own brand) for the capsules.

The safety profile for both CBD and PEA are very strong even for long term use (see CBD and long term use).

In fact, key benefits like neurogenesis take time to work...you're literally building a brain!

Our next foray is into endocannabinoid deficiency which we're guessing is going to be the next hot topic for a decade or so.


PEA and CBD are direct supporters of this system.  


Check out our Top 10 Tips for Calming Histamine with practical guidance:


Be well.  Take care of each other. Take care of yourself.

Other topics around histamine and mast cells:

Histamine and insomnia

Natural mast cell stabilizers

Endocannabinoid deficiency and modern disease


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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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1 comment

Great original research on an important new compound! Thank you for your efforts.

Brett Borders

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