It's interesting how waves of knowledge lap upon the general population over time.
Oxidative stress and antioxidants were all the rage for a good decade (see CBD and oxidative stress to learn why).
Inflammation is all abuzz now and with good reason….most of our modern diseases are tied in inflammatory states whether in the body or brain.
New powerful players are starting to show in mainstream media recently, soon to be household stirrings:
- Neurogenesis and BDNF - repair and growth of brain tissue
- CRISPR technology - gene editing is about 2 years away for dogs and 5-7 for humans
- Psilocybin - interesting applications of magic mushrooms for mental health
- Senescent zombie cells and aging
Of course, CBD has been the latest craze and after 1 million+ words on it in detail, we're clearly on board there.
Let's go out 3-5 years though...what does research already know about but the general public is yet to learn?
We'll introduce one new pocket of exciting research which may turn out to be the linchpin for most modern diseases.
Don't get spooked by the technical name...we'll go deep into what this actually means.
More importantly, we'll look at how 80% of our modern diseases are directly tied to this pathway.
- Mental health
- Allergic reactions
Umm...that's pretty much every TV ad you see for medications these days (please don't come to Netflix!!).
Below, we'll see why these are the net result of our modern lifestyle and maybe, more importantly, are their tools to offset this imbalance.
Here are the topics we'll cover:
- What is the endocannabinoid system
- The players on the endocannabinoid stage
- Why is modern life primarily hitting the endocannabinoid system?
- What is an endocannabinoid deficiency
- Endocannabinoid deficiency and autoimmune
- Endocannabinoid deficiency and pain
- Endocannabinoid deficiency and mental health
- Endocannabinoid deficiency and allergic responses
- What about THC for endocannabinoid deficiency
- CBD for endocannabinoid deficiency
- PEA for endocannabinoid deficiency
- How much CBD and PEA for endocannabinoid deficiency
- What's the best CBD and PEA for endocannabinoid deficiency
Let's get started before your neighbors start to bring this up to you as the next big thing!
What is the endocannabinoid system?
Think of the endocannabinoid system as a thermostat.
Instead of temperature, it governs just about every key system in our body to find balance.
Technically, it responds to stress but we don't just mean missing your bus or being late for an appointment (although that's also in play).
The stress here is anything that pushes a key pathway up or down.
Let's take an example!
We have cut on our arm. Since we're swimming in bacteria (outnumber our cells 10,000 to 1), there's an immediate immune response.
This is inflammation in all its glory! We see it as redness, swelling, etc but the machinery is much more complicated with scores of little assassins moving to the site to fight off bacteria.
Other powerful players are called into seal the area, cut off blood supply, and eventually, healing and growth factors arrive to actually rebuild.
Once, the cut is healed, this system should ramp down and go back to normal.
In this case, the cut was stress. It caused a massive ramp-up of inflammation and immune response which eventually "resolves".
The endocannabinoid system is critical to changes in this response...up or down!
We share this system with every living animal and it's dated back to about 600 million years old.
Under its sway are the following key systems which we'll focus on below:
- Immune system - inflammatory agents and cell birth/death cycles (key to cancer)
- Endocrine system - hormones across the body and brain
- Nervous system - neurotransmitters in the brain, gut, and throughout
The endocannabinoid system is not limited to these with effects everywhere (bone formation, reproduction, heart function, etc) but we'll narrow our focus to see how so much of what ails us is tied to these three.
Let's meet the primary actors in this system since they'll come up again and again below.
The players on the endocannabinoid stage
We'll try to keep this simple as it can quickly devolve into alphabet soup.
Here are key players we'll focus on:
That's enough to get us started.
Let's start with anandamide, the star of our show.
Anandamide is named after the Hindu goddess of bliss, Anand. That's a good indication of how it feels.
In general, anandamide is a wet blanket on biological activity. It slows things down.
This is critical to the rebalancing back to normal after "stress" moves any system in one direction.
You see the impact of this effect everywhere you look.
Anandamide calms glutamate activity and acts as a stress response buffer in the brain
Glutamate is our brain's "gas" pedal and hyperactive glutamate is tied to a range of mental health issues including:
- Just about every mental health issue has a glutamate/GABA component
Many people who use cannabis DAILY talk about how it slows things down.
They generally mean repetitive or negative thoughts and actions but you'll understand why below in the THC section.
We did a full review of whether people chronically use cannabis to calm glutamate activity.
Remember the thermostat analogy above?
In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits.
NMDAR is the primary receptor for glutamate (see CBD and glutamate).
Endocannabinoids (like anandamide) keep its activity in the range which is critical.
Too much glutamate is actually toxic. Too little means the brain is functioning at half-mast.
Just look at what happens:
Unfortunately, a series of neurological disorders concur with dysfunctions of these glutamatergic receptors, such as those produced by the excitotoxicity resulting from their excess activity.
Too much glutamate is bad and endocannabinoids are tasked with keeping it bound in a range.
This also figures into pain believe it or not which is shown in the research behind ketamine.
- Pain sensors can get stuck "on" with excess glutamate. We'll get into that in the pain section.
- What about the immune function which is key to inflammation, autoimmune, and more?
A great deal of research shows that anandamide has powerful immune modulation and anti-inflammatory actions.
One of the newest one (which we'll translate after):
As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA.
To translate the Klingon, very new and sophisticated research showed that anandamide would turn off many genes tied to inflammation.
Again, that gets really specific in a wide sea of research but it zeros in on actual cause/effect.
Anandamide is a dominant player in the endocannabinoid system but it's not the only one.
Let's meet 2-AG
We'll keep with its abbreviation to avoid scaring away, people
2-AG is the dominant endocannabinoid in the nervous system (brain and gut).
So, what's the difference between 2-AG and anandamide?
2-AG has carried a bigger punch on the CB1 and CB2 receptors...it's called a full agonist.
Anandamide is a partial agonist...so...half the power.
Interestingly, they both have different enzymes that break them down (FAAH for anandamide and MAGL for 2-AG).
We're going focus on anandamide and FAAH since there are powerful effects with these two players as it relates to disease.
Perhaps 2-AG does the heavy lifting and establishes endocannabinoid tone and anandamide is the turbo booster when needed.
Research is pointing to this:
Despite the fact that both AEA and 2-AG similarly act to regulate presynaptic transmitter release, it is believed that these two molecules of the ECB system may operate in phasic and tonic modes
Think of tonic as the ocean...general levels while phasic would be the waves, peaks in water level.
Anandamide would be the latter.
In fact, studies show anandamide go up in response to a slew of disease states as if the system is trying to right the ship.
We'll zoom into that below.
Let's look at FAAH as it is fascinating!
We covered the woman who can't feel pain, anxiety, or depression due to a FAAH gene variant (doesn't make any of it).
FAAH breaks down anandamide constantly. The two are in a recycling tug-of-war.
FAAH is one of the first candidates for CRISPR gene editing as you can literally turn anxiety or pain down (to off).
Think about that for a second...one gene has such a profound effect.
We'll get into the implications of this below but it begs the question…
Is the FAAH the root of our stress "thermostat" being set wrong for our modern life?
Let's go there now.
Why is modern life primarily hitting the endocannabinoid system?
Our basically genetic "setting" was set 10,000 to 100,000 years ago.
Needless to say, our world is quite different outside of a few small pockets on Earth.
Remember, the endocannabinoid system is tasked with balancing other key systems during stress (in all its many splendors).
Let's zero down on just a few possible triggers for imbalance:
- Chemicals and pesticides we come in contact with, especially in the gut
- Chronic stress - the new normal
- Sun exposure - the research on Vitamin D is critical (and so over-looked)
Needless to say, this just a sampler of tumult but you'll see just how powerful they are.
Let's start with chemicals our DNA was never programmed to encounter with a focus on the gut.
Remember...inflammation needs to resolve...it was never intended to run at full speed indefinitely.
If it does, the response team (endocannabinoid system) is going to get exhausted.
That sets the stage.
- Chemicals and pesticides we come in contact with, especially in the gut
- Chronic stress - the new normal
- Sun exposure - the research on Vitamin D is critical (and so over-looked)
We'll start with chemicals.
Chemicals and pesticides we come in contact with, especially in the gut
We are swimming in a sea of chemicals, many ingested, that our body doesn't recognize.
They're even showing up in 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.
We have an entire system designed to be on alert for "foreign" entities and remove them...quickly!
It's the allergic response but the players are histamine and mast cells, where histamine and a host of nasty inflammatory agents reside.
Diseases of this system have been on the rise for about 40 years now.
- Celiac disease
- Food allergies
What on earth is driving this?
If the alarm bell is going off with every meal you have, eventually, this system is going to break down.
Especially in the gut!
The gut and our microbiome (the bacteria stew in our gut) is Rome these days for inflammation.
All roads lead there.
Let's take just one example (of 1000's).
Glyphosate...the ubiquitous pesticide that's in 90% of corn, soy, and wheat.
We did a big review of this at our CBD and PEA for mast cell activation but let's zero in on the endocannabinoids to see how this daily onslaught is death by a thousand cuts.
Glyphosate has been shown to cause an inflammatory response in the gut and breakdown the gut barrier.
Who gets called in to repair this damage?
You guessed it:
The homeostatic role of the ECS also extends to the control of intestinal inflammation.
ECS is an endocannabinoid system (anandamide and 2AG). Homeostatic just means balance.
So...glyphosate and all the artificial colors, flavors, preservatives, etc cause inflammation in the gut.
The body responds with increased endocannabinoid response.
This is fine for a one off...that's what the system is designed for...
What about every day for decades. 4 decades to be exact.
1974 is when glyphosate hit the market and you can see the connection between use (rise and drop) with death due to intestinal infection/inflammation or celiac here:
Goodness...someone better lawyer up!
It was easier to say it was just happenstance until the use of glyphosate dropped around 2009 and the issues started to drop as well.
The various diseases tied to chronic gut inflammation are all in play:
It was posited that inflammatory and disease states in the gut rendered the ECS more functionally important.
That statement followed a detailed look at how anandamide is critical to the functioning of the gut in the face of inflammation at a cellular level.
Hmmm...and for IBS, the most common inflammatory ailment of the gut:
Thus, a rationale exists for therapeutic interventions that would boost AEA levels or desensitize TRPV1, such as cannabidiol (CBD), to treat the condition.
TRPV is one of the channels affected by endocannabinoids.
We showed our cards too early with CBD which we'll touch on later.
So...that's just one pesticide. Now imagine the swirl of chemicals our gut is trying to mitigate.
Learn all about CBD and PEA for mast cell activation.
Again, this calms the response but you still have to remove the chemicals from your diet and environment.
It's safe to assume our ancestors 40,000 years ago (or even 100 years ago) didn't come in contact with glyphosate, PFOA (the forever chemical), and chlorinated sugar (fake sugar).
Next up...chronic stress.
Chronic stress - the new normal
Trauma and acute stress have clear effects but what about just low level, chronic stress?
Same pathways...same effects...just slower process.
We covered the impact of this across many reviews:
- CBD and neuroinflammation
- Tryptophan's reaction to stress and anxiety
- Is serotonin a buffer from stress
- CBD and cortisol (our stress hormone)
Now, we're turning our attention to endocannabinoid function in the brain and nervous system.
To put it simply:
The evidence reviewed here demonstrates that endocannabinoid signaling is involved in both activating and terminating the hypothalamic-pituitary-adrenal axis response to both acute and repeated stress
Both "activating and terminating". See how it's tasked with adjusting to changes?
Thermostat with a low and high limit.
What if it's running high all the time? Chronic stress?
So...anandamide is the backup battery when 2-AG is being drawn down from stress.
Look at what happens when even anandamide can't keep up:
studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory, and synaptic plasticity.
Let's break that down because it's incredibly important.
- When anandamide drops, the whole stress machinery is set in motion.
- 2AG is tasked with helping you deal with the situation (pain thresholds, memory, etc).
In this way, a drop in anandamide (used up) is a signal that somethings wrong… a potential threat.
You don't want to feel "bliss" when a tiger locks eyes with you out in the wild!
"Those" people didn't survive long enough to pass on the genes.
The problem is that this same pathway is constantly triggered on a daily basis in our current world.
Here you go:
Similar to what has been reported with exposure to acute stress, repeated exposure to the same stressor (chronic homotypic stress), such as restraint stress and social defeat stress, seems to reliably reduce AEA content in the amygdala, hippocampus, hypothalamus, and mPFC.
You just listed off the key brain regions tied to mental health!
- Amygdala - emotional seat with huge implications for anxiety umbrella of issues
- Hippocampus - key controller of mood which is very vulnerable to stress
- Hypothalamus - controller of the stress response
- mPFC - our newest addition to the brain with master control over impulse control and emotion
We did a big review on these players at our CBD and mental health but really, neurogenesis (brain repair) is the key there.
Did you also catch that the stress can be physical but also emotional (social defeat stress)!
This is powerful as trauma, abuse, and other triggers can tip the scale.
Social rejection is just as stressful to the endocannabinoid system as any other stress!
Let's turn to another fascinating avenue!
Sun exposure - the research on Vitamin D is critical (and so overlooked)
Go back 10,000 years.
We spend most of our waking day in the sun.
The sun directly powers our body in two ways:
Red light boosts our mitochondria which literally fuel our cells
UV light powers vitamin D production, a key steroid tied to every pathway in our body.
Vitamin D is so important that we did a full review here.
Interestingly, it has profound effects on...wait for it...immune response, mental health, and pain.
Hmmm...curious overlap with endocannabinoid deficiency.
So what's the connection between D and endocannabinoid deficiency?
First, understand that almost half the population has a D deficiency with numbers approaching 80% for African Americans and 60-70% for Latin Americans.
And this is based on the 30 nmol/ng level which is primarily for rickets.
Endocrinologist wants us at 70-80 in newer research.
A fascinating study looked at the connection between D and endocannabinoid deficiency as it applies to disease.
Essentially, researchers depleted Vitamin D levels in mice and then looked at the gut microbiome:
vitamin D deficient mice showed tactile allodynia associated with neuronal hyperexcitability and alterations of endocannabinoid system members (endogenous mediators and their receptors) at the spinal cord level.
Goodness. Allodynia is increased pain sensitivity. Hyperexcitability is the glutamate connection for mental health we described above but it also figures into pain throughout the body.
And as a result of D depletion, anandamide and 2AG levels were altered.
Here's the kicker:
Remarkably, the anti-inflammatory anandamide congener, palmitoylethanolamide, counteracted both the pain behavior and spinal biochemical changes in vitamin D deficient mice, whilst increasing the levels of Akkermansia, Eubacterium, and Enterobacteriaceae, as compared with vehicle-treated mice.
That's PEA, one of our guest stars.
Another study looked at a D precursor for children with autism where there is a known endocannabinoid imbalance:
GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group.
It did this at the genetic level and primarily in the immune system.
Remember, a hyperactive immune system (which D modulates and endocannabinoids buffer) is the new rising star of research for all things mental health.
See CBD and neuroinflammation for anxiety to see why.
Needless to say, we don't get as much sun as we used to 10,000 years ago.
Okay...these are only 3 examples from 100's maybe in terms of how our "thermostat" might be set wrong.
We were betting people, we would put our money on FAAH.
FAAH is the enzyme that breaks down anandamide.
Here's the fascinating piece...for the very rare person who has the genetic variant where they don't make FAAH, they have normal health aside from the fact that they don't feel pain, anxiety, depression, or the other issues associated with endocannabinoid deficiency.
How can this be?
Perhaps our FAAH setting (genetically and even epigenetically) is set too high for modern life.
Just look at the immune response angle.
Our ancestor's world was not nearly as sanitized as our current one.
Maybe FAAH needed to be ratcheted up with its pro-inflammatory response as we were swimming in bacteria and pathogens out to get us.
There's a huge push for FAAH inhibitors in big Pharma right now. Again, it's one of the first targets for CRSPR (just pain alone would be a billion-dollar drug as we've learned with opioids).
Interestingly, we already have two ways to affect the FAAH-anandamide balance:
- CBD reduces FAAH and increases anandamide
- PEA increases anandamide directly
With ridiculous safety profiles.
See why we're excited?
Let's dive into what happens when our natural endocannabinoid tone is low so we can understand just how important the statement above really is.
What is an endocannabinoid deficiency?
Essentially, endocannabinoid deficiency is a reduction in anandamide and 2AG pathways.
This can be the result of many things:
- Genetic predispositions especially around CB1, CB2 receptors, and/or FAAH activity
- The effects of chronic stress, trauma, and injury - exhaustion of endocannabinoids
- Nutritional deficits especially surrounding essentially fatty acids
- Gut microbiome imbalance as we saw with the Vitamin D deficiency
For most people, the second one will be somewhere in the mix.
Interestingly, there's a lot of overlap between diseases where physical states are often misinterpreted as psychosomatic.
- Irritable bowel syndrome
- Complex regional pain disorders
As we saw with endocannabinoid's effects on mental health, pain, and gut health, the likelihood of crossover is very high.
There is no separation of body and brain as far as endocannabinoid system deficiency is concerned.
Anxiety and depression are a result of this deficiency...not a cause of the pain symptoms.
The clues are slowly mounting for this system as the root of many issues.
For example with IBS:
Genetic variation affecting endocannabinoid metabolism was observed in diarrhea-predominant IBS patients.
increased function in AEA membrane transporter and AEA hydrolase (now known as fatty acid amidohydrolase [FAAH], the enzyme that catabolizes AEA) in platelets of women with migraine without aura was observed in comparison with patients with episodic tension headache or controls with no headaches.
To translate, women with migraine showed higher levels of FAAH (and thus reduced anandamide).
Another study looked at cerebral fluid levels of anandamide:
AEA levels in 15 chronic migraineurs versus 20 controls with a phenomenal statistically significant difference (p<0.0001) (Fig. 2). The authors opined concerning what they termed a system failure in migraine
What about autoimmune diseases like MS?
Direct assays of AEA and 2-AG in the CSF of MS patients versus controls confirm significant deficits in affected patients, particularly in secondary progressive cases, confirming an impaired endocannabinoid system
So...much lower levels of anandamide and 2-AG.
Again, we have endocannabinoid receptors in every cell of our body (aside from the red blood cells...go figure).
Let's dive directly into the four areas of interest that beset the modern world.
Endocannabinoid deficiency and autoimmune
We covered the mechanics of autoimmune in our CBD and autoimmune review.
A quick synopsis, autoimmune diseases are tied to a hyperactive immune response that targets our own tissue.
New research is pointing to initial issues with leaky gut (see CBD and gut barrier) and protein mimicry (misreading bacteria signatures for ones similar to our own cells).
You can learn all about it there but we want to focus on endocannabinoid deficiency.
First, what's the role of the endocannabinoid system for the immune response?
Our primary endocannabinoids can actually have biphasic effects….up or down depending on the state of the system and levels.
Remember...it's a thermostat with low and high bounds.
Always back to balance if working correctly! Technically, it's called homeostasis.
Let's cut to the chase and look at specific autoimmune diseases...we'll focus on some of the most common ones.
We'll use these examples as a way to tease out the immune effects of endocannabinoids in disease states.
First, rheumatoid arthritis.
RA is noted by its increase in specific cytokines, immune response inflammatory agents.
Look at anandamide's effect here:
Anandamide dose-dependently decreased the production of IL-6, IL-8 and MMP-3 by activating classical cannabinoid receptors.
Anandamide reduced the suspects in question!
The endocannabinoid system is a powerful player in skin health but we're looking at the autoimmune response.
Psoriasis is primarily characterized by too much skin production.
The ECS (endocannabinoid system) governs cellular birth/death cycles so this should be right in play.
What is anandamide's effect here?:
Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterized in part by epidermal keratinocyte hyper-proliferation.
So, anandamide blocks this excess skin production.
Research has established that endocannabinoids are "deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration"
This is the CRUX of psoriasis.
There is an autoimmune cause behind this skin mayhem and it involves the cytokine IL17.
CB1 activation by AEA suppressed production and release of signature TH1- and TH17-polarizing cytokines, IL-12 and IL-23, respectively.
The net effect as it applies to psoriasis (and many autoimmune diseases)?
Taken together, these findings demonstrate that AEA suppresses highly pathogenic T cell subsets through CB1-mediated mammalian target of rapamycin inhibition in human keratinocytes.
"Highly pathogenic" - translation...very damaging when in excess.
Where? The human skin cells directly tied to psoriasis called keratinocytes.
Finally, MS...multiple sclerosis.
MS is an autoimmune disease that attacks our nervous system itself!
Hence the horrific effects.
So...is there a connection between MS and endocannabinoids?
Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system.
Okay...so what about tampering with the levels?
EAE is the mouse model for MS that's used in research.
Look what happens when FAAH genes are deleted:
Genetic deletion of Fatty Acid Amide Hydrolase results in improved long-term outcome in chronic autoimmune encephalitis
This is fascinating.
The mice with FAAH removed (and therefore more anandamide) had an initial inflammatory response but then it resolved compared to the controls.
There's a long history of cannabis research for MS but we'll discuss below why CBD and PEA are better long-term fits than THC.
So...we looked at 3 of the big autoimmune diseases.
What about general immune function underlying these diseases? What's going on?
First, endocannabinoids are powerful players in maintaining our gut health and gut barrier...the trojan horse for bacteria to gain entry to the body and trigger chronic, hyperactive immune response.
Researchers looked at how resveratrol had a positive effect after high-fat diets because of its effect on the endocannabinoid system:
These data indicate that the ECS, particularly the expressions of CB1 and CB2, appears to play a crucial role in the RSV induced anti-NASH effect by maintaining the gut barrier integrity and inhibiting gut inflammation.
The endocannabinoid system is the "manager" of gut inflammation and we now know there's a clear connection between gut and brain (as well as body) inflammation.
A thermostat, if you will!
It goes deeper than that though.
The immune system quickly spirals into ridiculous complexity so we'll dance around the edges.
There are powerful anti-inflammatory pathways primarily stimulated by endocannabinoids.
Say hello to PPAR.
There is a vast amount of literature (including many excellent reviews) on the anti-inflammatory roles of the different PPARs in a multitude of inflammatory diseases
Autoimmune diseases are primarily of a flavor involving T cells, an immune response player.
- PPAR governs the creation and activation of T cells!
- We'll see more of this pathway below with CBD and PEA.
Let's jump to pain!
Endocannabinoid deficiency and pain
Pain is there for a reason.
One of the issues with the people who have no FAAH is that they feel zero pain.
There's a story of a woman who only knew her leg was on fire from the smell.
This is why the genetic variation is so rare...few survived to pass it on.
What about if we have too much pain though?
Endocannabinoid tone is all over pain!
Pick your poison (a type of pain).
Peripheral pain (throughout the body):
Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
This effect was due to suppressed FAAH activity and let the conclusion:
Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.
What about neuropathic pain?
AM404, an inhibitor of anandamide uptake, prevents pain behavior and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain
Let's decipher that a bit.
A synthetic FAAH not only blocked pain but calmed immune response and protected neurons (apoptosis is the death of neurons).
New studies are pointing to glutamate excess as the key to pain in nerves.
Remember that anandamide calms glutamate activity!
See CBD and glutamate to learn more.
What about the FAAH pathway...is there an impact on pain?
A synthetic FAAH inhibitor had the following effects:
PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain.
Again, synthetics always have side effects so we want natural FAAH inhibitors (CBD and PEA!!).
Then there's serotonin...a master regulator of pain sensitivity in the brain.
This is your pain "threshold" at work.
results from an in vivo extracellular recording study show that systemic administration of FAAH inhibitors, which presumably increases anandamide levels in the CNS, enhances the firing activity of DR 5-HT neurons via the activation of CB1 receptors
- Blocking FAAH leads to more anandamide
- More anandamide boosts serotonin function (5-HT)
More anandamide = increased serotonin function.
We'll show below in the CBD section how chronic pain can deplete serotonin and lead to anxiety, depression, and lowered pain thresholds.
Speaking of serotonin, let's turn to mental health.
Endocannabinoid deficiency and mental health
This is maybe the most exciting section for us since the level of suffering is matched by the research on endocannabinoids to resolve it.
Check out CBD and mental health to learn about these pathways.
Let's zero down into endocannabinoid function (and the lack thereof).
Not one mental health issue is left untouched from endocannabinoid imbalance.
There are critical pathways of mental health affected directly:
- Inflammation and immune response for mental health
- Neurotransmitter balance and tone for mental health
- Brain area growth, maintenance, and removal for mental health
- Immune system balance? Check
- Neurotransmitters balance? Check
- Brain repair/maintenance? Check
Believe it or not, the latter is really a function of our immune system.
The new holy grail of mental health is BDNF and/or neurogenesis.
Literally the process of building new neurons and connections in the brain.
Guess what lies at the heart of this process?
CB1 affected the stages of adult neurogenesis that involve intermediate highly proliferative progenitor cells and the survival and maturation of new neurons.
CB1 is the primary receptor for….anandamide and 2AG!
When the knock out CB1 receptor genes, neurogenesis goes away.
What about the neurotransmitters?
We'll focus on our big three:
- Serotonin - key to human behavior and mood
- Dopamine - critical for addiction and motivation
- GABA/Glutamate - the brake and gas pedal of the brain
Simply put, the endocannabinoid system is tasked with keeping this melee in balance.
A complicated task since they're all interactive, interdependent, and differing depending on the brain area.
It helps to look at specifics.
We'll focus down on the following:
- Endocannabinoid and anxiety (low serotonin, low GABA, high glutamate)
- Endocannabinoids and depression (low serotonin, high glutamate, high inflammation)
- Endocannabinoids and schizophrenia (high and low dopamine, high glutamate)
Talk about a game of Jenga.
Let's start with anxiety including its big tent inclusion of OCD, PTSD, and more.
Endocannabinoid deficiency and anxiety, OCD, PTSD, panic, etc
One hallmark of this family of diseases is excess glutamate and reduced GABA.
GABA is our brake pedal of the brain when deficient, anxiety can display especially when our emotional brain (amygdala) is left unchecked.
Serotonin has a higher level management role in our stress response generally.
So...how does anandamide and FAAH figure into this?
We'll start with this...the ECS appears directly in control of fear extinction.
That's the ability to forget or move past fear and anxiety causing emotions.
In fear memory paradigms, the ECS is mostly involved in the two opposing processes of reconsolidation and extinction of the fear memory. Whereas ECS activation deteriorates reconsolidation, proper extinction depends on intact CB1 receptor signaling.
The ECS is the bridge between stress and fear and how we internalize it!
Put another way:
eCB signaling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioral responses
Really think about that statement.
How come some people can deal with scary or hard situations and not really be phased?
Others are riddled with fear and anxiety.
This "lens" is determined by the ECS!
Remember the root of anandamide's name. "Bliss".
That's literally the opposite of anxiety and depression.
What about anandamide and GABA/glutamate balance?
GABA is the target of benzodiazepines...the primary class of drugs for anxiety.
Valium. Ativan. Xanax. Etc.
They're also couched with horrible risks for addiction.
They primarily boost GABA (until the brain panics and pushes back - called tolerance).
And anandamide and 2ag?
2AG acts like a booster when GABA gets too low:
The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABAA receptors at low concentrations of GABA.
"At low concentrations" - like low setting on a thermostat!
As for anandamide, it works on the other side by calming glutamate activity (GABA's opposing force).
Maybe, more importantly, anandamide feeds directly into our stress response.
In fact, for mental health, this may be the critical vulnerability for endocannabinoid deficiency.
A study looked at the direct relationship between stress, FAAH, anandamide, and anxiety.
It's a powerful send-off:
central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition.
Let's translate because this is too cool.
- They used an injury to deplete anandamide.
- This depletion leads to anxiety
- Anandamide levels were boosted and anxiety went away
This is important because it shows how boosting anandamide created (versus just coincidence) a change in an anxiety state.
See how pain is so important...especially chronic pain.
By the way...this system is unable to really distinguish between physical pain and psychological pain (social rejection, abuse, etc).
It's a one-trick pony and early abuse is a key trigger for mental health later on.
In terms of PTSD, it can be at any time!
Check out CBD and mechanisms of anxiety for more.
Speaking of which, chronic anxiety can lead to depression. Let's go there now (figuratively of course).
Endocannabinoid deficiency and depression
We already covered endocannabinoid deficiency and pain above.
Here's the curious connection:
Depression and pain co-exist in almost 80% of patients
As far as medical research goes, 80% is off the charts!
We've looked at the pathways of depression in detail at our CBD and depression review.
It's a mix of brain inflammation, excess glutamate, and immune response overpowering our natural brain's ability to recover and rebuild (neurogenesis).
All these components sit squarely in the endocannabinoid camp!
Here's where it gets interesting.
A study found that women with minor depression had elevated levels of anandamide while women with long-term depression had reduced levels.
Remember that anandamide is a stress buffer...called in to support stress response when 2AG isn't keeping up with regular maintenance.
The initial response to the drivers of depression is to increase anandamide:
Exposure of these patients to psychological stress produced an initial increase in 2AG and anandamide levels followed by a subsequent decrease.
Here's the problem and see it across so many pathways (serotonin, GABA, insulin, etc).
With chronic stress or imbalance, the anandamide can desensitize or become exhausted.
We see this same effect with THC which mimics anandamide and we'll cover that below.
So...what about if we add anandamide to the mix during a depression? What's the effect?
Researchers gave chronically stressed rats a drug called URB597 who were displaying depressive-like symptoms (again, chronic stress is a total brain disturber):
After five weeks of treatment, the stressed rats treated with the drug were behaving similarly to a comparison group of unstressed animals.
What is URB597 you may ask?
URB597 works by inhibiting FAAH, an enzyme in the body that breaks down anandamide.
Goodness...it's a FAAH blocker...the very thing we were after when we discovered PEA.
Both CBD and PEA are FAAH inhibitors without all the nasty side effects.
Another study targeted CB1 receptor activity directly:
AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain
This was a study in diabetic rats who are exposed to a chemical that drives up oxidative stress in the brain.
Remember how brain inflammation is critical to depression (and anxiety...typically a cause of depression when long term).
See CBD and oxidative stress for more info.
That's why we're such big fans of NAC (N-acetylcysteine) which directly supports our system to neutralize oxidative stress (see CBD and glutathione).
Remember that the endocannabinoid system is a stress-response buffer.
What happens when this buffer breaks or falls behind?
Ample evidence from behavioral studies also suggests that eCBs are important regulators of stress responses and a deficit in eCB signaling contributes to stress-related disorders such as anxiety and depression.
Let's look at serotonin since it's the target of the primary antidepressants, SSRIs (see How SSRIs actually work).
In the end, the primary result of SSRIs (until tolerance builds) is an increase in neurogenesis...the repair side of the coin.
A major leg of this repair/build process is called synaptic plasticity.
This literally means the building and strengthening of new connections in the brain.
Simply put for the endocannabinoid system:
eCBs are the major retrograde signaling molecules that fine-tune synaptic transmission and mediate several forms of short-term and long-term synaptic plasticity
They're essentially saying that the endocannabinoid is the primary manager of this process!
How does serotonin, our mood manager come into play?
Stress eats up serotonin which also works as a stress buffer (maybe the primary with ECS as first responder).
Look what happens when we knock endocannabinoids out of play:
Similarly, genetic deletion of CB1 receptor profoundly enhances the secretion of stress hormones (i.e. ACTH and corticosterone) elicited by an array of stressors
The literal messenger of stress goes way up!
Endocannabinoids are the first gate to stress response.
When the ECS is stimulated, look at the result:
The results of these studies show an increased expression and function of 5-HT1A receptors in the hippocampus
We've covered the hippocampus in detail since it's so critical to mood and especially vulnerable to stress.
Serotonin is a major driver of BDNF, our brain's fertilizer and ECS is intimately tied in with serotonin function.
As usual...how can we get at this effect?
For instance, FAAH inhibition promotes an increase in firing activity of serotonergic neurons in the dorsal raphe nucleus
Blocking FAAH again.
Let's wrap up our mental health section with schizophrenia as a representative of developmental diseases wrapped in inflammation.
Endocannabinoid deficiency and schizophrenia
We covered the various pathways at our CBD and schizophrenia.
Schizophrenia is one of the most powerful examples of endocannabinoid imbalance.
The first clue is that anandamide was significantly spiked in the cerebral fluid of patients with schizophrenia but not just that:
We found that CSF anandamide levels are eight-fold higher in antipsychotic-naïve first-episode paranoid schizophrenics (n=47) than healthy controls (n=84),
Goodness...what is going on here?
It's as if the tug of war is significantly out of whack and the body is trying to right the scales as hard as it can (with anandamide).
Let's dig deeper.
Dopamine is known to be a major player in schizophrenia.
Too much of it in the striatum (positive symptoms like paranoia, hallucinations, etc) and too little of it in the prefrontal cortex (negative symptoms like depression, social isolation, cognitive impairment, etc).
Remember...the ECS is tasked with balancing neurotransmitters and clearly, something is off in the dopamine pathway.
Look at this clue here:
For instance, dopamine-D2 receptor overactivity is associated with an increase of anandamide release in rodents [
Too much dopamine causes a release of anandamide.
Follow up studies found that the lower the anandamide level, the quicker the onset of the disease:
More precisely, that study showed that lower anandamide levels were associated with earlier transition time to acute psychosis.
When patients are given antipsychotics (which primarily pound dopamine levels), anandamide levels normalize (called off duty).
This is all well and good but what can we do about it?
Look at the studies on CBD and schizophrenia...specifically the mechanism at work.
It's as close to a smoking gun as we can find:
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
They compared it to a leading anti-psychotic, amisulpride with comparable results and the following:
Patients undergoing either cannabidiol or amisulpride treatment showed significant clinical improvement, assessed by the reduction in PANSS total score (P<0.001, day 28 vs day 0, Figure 2a) as well as for all subcategories of symptoms of schizophrenia
Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement.
Double-blind with placebo.
Luckily, they measured levels of FAAH and anandamide to catch the mechanism behind the results.
Just look at the results:
Anandamide levels were higher in subjects exposed to cannabidiol than in those exposed to amisulpride
And here's the secret bonus that most people won't know about (unless you've read our review of PEA here):
Importantly, the serum levels of two additional FAAH substrates—the non-cannabimimetic lipid mediators palmitoylethanolamide (Figure 4b) and oleoylethanolamide (Figure 4c)—were also elevated in schizophrenic patients treated with cannabidiol, compared with those treated with amisulpride.
There's PEA!!! (palmitoylethanolamide). OEA is its cousin. They both work with anandamide in a group effort.
CBD drove up PEA and anandamide by blocking FAAH.
See...FAAH may be where our thermostat is set wrong for the modern world.
There's fascinating research on bipolar, autism, and more but each needs its own breakout.
Keep in mind that stress and more important, stress response and repair systems are tied to every known mental health issue!
You can think of mental health as a brain on fire with inflammation essentially.
As for the two leading triggers for addiction relapse?
- Stress hormone levels
- BDNF (brain repair after stress)
Check out CBD and mental health to learn more.
Let's turn to another type of inflammation.
Endocannabinoid deficiency and allergic responses
After autoimmune diseases, allergic issues are on a similar rise in the last 40 years.
They're intimately connected.
We covered CBD, PEA, and mast cells in detail.
Mast cells are the repositories of histamine and the full payload of the allergic reaction.
Histamine is the messenger of the allergic response itself aside from being a powerful neurotransmitter in its own right (wake cycle, etc).
Many diseases are characterized by hyperactivation of mast cells or chronic activation.
What is the role of the ECS on this response?
Look at ECS activity in skin (think eczema, psoriasis, dermatitis, etc):
This limits excessive activation and maturation of MCs from resident progenitors via "tonic" CB1 stimulation by locally synthesized endocannabinoids.
The keyword there is "excessive". It's literally the key to an allergic response.
Let's look at some of the big ones:
- Food allergies
First, endocannabinoids and asthma.
Do we see the same elevation as a compensation to allergic asthma?
Increased levels of AEA have been reported in the bronchoalveolar lavage fluid of allergic asthma patients upon allergen challenge and the mRNA levels of CB1 are increased in asthmatics
So...there's clear elevation.
How do we know that anandamide is helping and not causing the allergic reaction?
Aside from anandamide natural ability to block mast cell activation (the source of allergic response), we see the following:
Treatment with CP significantly reduced these abnormalities. Pre-treatment with SR, AM or both reverted the protective effects of CP, indicating that both CB1 and CB2 receptors are involved in lung protection.
CP is a CB1 agonist...it essentially boosts CB1 activity the way that anandamide and 2AG do.
When they block this activity with other chemicals, the reduction in allergic response AND protection of the lungs went away.
A lot of the research on directly affecting these pathways comes from...wait for it...CBD and PEA which we'll discuss below.
First, we need to address some questions on THC.
What about THC for endocannabinoid deficiency
Since THC mimics anandamide, why not just use THC?
THC directly stimulates the CB1 and CB2 receptors like anandamide but they are very different.
Anandamide is constantly made and broken down as needed.
It doesn't linger.
THC does...the brain/body is not able to break it down (via FAAH) so it stimulates CB1 activity much longer and much stronger than anandamide.
That's why you can get psychosis from too much THC...a constant pounding of CB1 activity.
This system is about balance.
Here's the problem...with long term use of THC, the brain panics and starts to push back the other way.
It actually will reduce CB1 receptor numbers and sensitivity!
This is the process of normalization or tolerance.
You start to see the opposite effects over time.
Essentially, the brain will start to downregulate the endocannabinoid system by reducing the sensitivity and numbers of CB1 receptors (where both anandamide and THC interact).
This means that your natural stress response system is being ratcheted down over time.
If you read our review on CBD and addiction, this is a very common effect across all the addictive drugs along with a kick from dopamine, our reward center messenger.
THC is only addictive in about 10% of users which begs the question…
Are those 10% just people with classical endocannabinoid deficiency?
If you dig deeper on the various addictive drugs, they all fill in holes:
- Alcohol - GABA and serotonin
- Nicotine - acetylcholine
- Caffeine - acetylcholine, and glutamate
- Amphetamine - glutamate
- Cocaine - glutamate, and dopamine downstream agents like norepinephrine
- Opioids - endorphins and perhaps...endocannabinoids
THC is just a substitute for anandamide!
The other issue is that THC works in one direction….it boosts CB1 activity!
The downside to this is that pushing any major pathway in one direction rarely works out long term in the body.
That's why you have side effects with too high a dose.
For example, THC will suppress immune response regardless of what's going on in the body.
We obviously don't want this during the time of infection!
CBD works completely differently!
Let's go there now.
CBD for endocannabinoid deficiency
CBD doesn't directly boost CB1 activity like THC.
Technically, it's called an allosteric negative modulator which really means one thing.
Feedback mechanism in the endocannabinoid system!
- We're all full here...stop sending
- We're running low, send more!
Since the endocannabinoid system is everywhere in the body, you see CBD's effect equally across very different pathways.
We have full reviews across mental health, addiction, sleep, inflammation, and pain as examples.
What about endocannabinoid deficiency?
Here's the holy grail of this entire article...FAAH inhibitors.
In fact, it was the CBD and schizophrenia study (double-blind, placebo) that really showcased this effect.
CBD also inhibits FAAH, which results in increased anandamide levels.
So...CBD blocks FAAH which results in more anandamide.
Since CBD doesn't directly boost CB1 activity, you don't see the side effect profile of THC and even synthetic CBD's.
There is no recorded overdose with levels up to grams!
How? If we're directly supporting such a pivotal pathway in the body, how can we avoid the side effects?
Here's the beauty of CBD and really the endocannabinoid system itself…
It's all about balance.
CBD has been shown to have different results depending on the state of the system.
Cellular removal (called apoptosis - a function of the immune system) is a perfect example.
- Healthy cell with low inflammation - CBD has no 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 attribute of CBD.
Keep in mind that our body's natural way to get rid of awry cells is to boost inflammation and kill them.
Essentially, chemo and radiation treatment for cancer are huge doses of inflammation (technically, oxidative stress).
This speaks to CBD's safety profile.
Let's dig deeper into CBD's effects on issues directly tied to endocannabinoid deficiency.
- CBD and fibromyalgia
- CBD and mast cell activation
- CBD and migraines
- CBD and stress response
- CBD and inflammation
- CBD and autoimmune
- CBD and mental health
Let's get started. We'll just hit the highlights since we're covering so much (and you're probably exhausted by now).
CBD and fibromyalgia
Cannabis really gained a foothold here and no wonder...look at the results:
Pain relief was reported by 94% of CC, while 93% reported improved sleep quality, 87% reported improvement in depression, and 62% reported improvement in anxiety.
Since THC and CBD are the two main players in cannabis, the question then is, what is CBD's effect directly since THC's will diminish with time (and even downregulate the endocannabinoid system).
The cannabis used was a high CBD strain called bediol (13.4-mg THC, 17.8-mg CBD)
Interestingly, THC performed better for pain while CBD performed better for inflammation.
The effects of CBD appear to be elsewhere (sleep, anxiety, mood, etc).
For example, this study on general quality of life:
Patients reported a mean increase of 13.6 points (P<0.001) on the EQ-VAS scale describing overall quality of health. Patients with non-cancer pain and mental-health symptoms achieved improvements to patient-reported pain and depression and anxiety symptoms
We're actually excited about PEA below for pain and CBD for the overall inflammatory response.
Speaking of inflammation…
CBD and mast cell activation
Remember the allergic reaction and mast cells?
CBD directly boosts a type of receptor called PPAR. PPAR is a powerful antinflammatory agent in the body.
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 so your eyes don't glaze over.
Essentially, CBD triggered the brake petal (MDSC) to mast cell release of histamines and inflammation.
Learn all about what this means for asthma, eczema, and more at our CBD and mast cell activation review.
One issue that is slowly being tied to endocannabinoid deficiencies is migraines.
CBD and migraines
Interestingly, migraines start off as vascular mismanagement issues.
The endocannabinoid system is integral to managing our plumbing system in the body (and brain!).
Vessels expand rapidly and the body panics by constricting them.
We did a big review on magnesium glycinate for migraines which gets into this whole process.
We know that CBD is a FAAH blocker which leads to elevated availability of anandamide.
Look at the connection between migraines and anandamide:
Clinical observations, in particular, show that the levels of anandamide (AEA)—one of the two primary endocannabinoid lipids—are reduced in cerebrospinal fluid and plasma of patients with chronic migraine (CM), and that this reduction is associated with pain facilitation in the spinal cord
They go on to say…
Inhibition of AEA degradation via FAAH is a promising therapeutic target for migraine pain
Indeed. CBD fits this bill.
We look forward to studies on CBD and migraines directly.
Let's go to the heart of the matter….stress response.
CBD and stress response
The endocannabinoid system, first and foremost, is a stress response buffer.
Remember that unchecked stress causes damage across the body which eventually manifests as inflammation, mental health issues, and more.
Let's turn to CBD and various aspects of this system.
First, we'll introduce cortisol, our primary stress response hormone.
An interesting study looked at stress and people at a high risk of psychosis.
- They compared health controls,
- people with high risk - placebo
- People with high risk getting CBD
For cortisol, anxiety, and negative self-statement (how you feel about yourself), CBD results were in between the healthy controls and the placebo group.
Significantly different from the placebo group.
Check out CBD and cortisol for more.
Let's go to the initial trigger of stress. CRH corticotropin-releasing hormone.
Interestingly, cannabidiol at low (5 mg/kg) and intermediate doses (15 mg/kg) successfully blocked the effects induced by acute stress on corticotropin-releasing factor, pro-opiomelanocortin and glucocorticoid receptor gene expression.
Goodness...that's a sea of stress chemicals and CBD actually downregulated the genes for these.
It was shown to have this effect by bolstering serotonin...our primary stress defense in the brain.
Check out CBD and CRF.
What about oxidative stress in the brain?
CBD reduces oxidative conditions by preventing the formation of superoxide radicals, which are mainly generated by xanthine oxidase (XO) and NADPH oxidase (NOX1 and NOX4).
Let's turn to inflammation...the root of all evil (if excessive).
CBD and inflammation
A hallmark of endocannabinoid deficiency is increased inflammation.
This speaks to the systemic pain phenomenas that often accompany it.
Remember that the endocannabinoid system is generally anti-inflammatory in nature….cleanup in aisle 5 after the emergency has passed.
This may be CBD's most well-known trick.
Where to start….how about the cytokines...our little inflammatory assassins.
A study looked at CBD's effects on asthma (allergic disease) and found the following:
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 an anti-inflammatory player….key to resolving inflammation after the flareup.
Let's go to the brain now.
We have a whole review on CBD and neuroinflammation but we'll focus on the instigators...microglia.
Hyperactivation of microglia is showing up all over the mental health landscape.
A study of Alzheimer found the following:
In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD.
Let's turn to autoimmune.
CBD and autoimmune
We have a massive review of new research on CBD and autoimmune.
There's fascinating new information on gut barrier breakdown, protein mimicry, and hyperactive immune response.
This is all in the wheelhouse of the endocannabinoid system and indeed, it's finally coming to light:
The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis
Anandamide is elevated as we saw with schizophrenia...the body is trying to put out an inflammation fire.
The original sin leading to autoimmune may be the gut barrier or break therein.
Check out CBD and leaky gut but the take away:
Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells
This is critical as c-diff is a perfect example of what's attacking our gut barrier and allowing stray pathogens to escape into the body and brain (see CBD and brain-blood barrier).
Then comes the hyperactive immune response!
Let's look at one example (of many in our review).
A study showed that two endocannabinoids were present in the joints of people that are not in healthy controls.
The endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) were identified in the synovial fluid of OA and RA patients.
Look at CBD's effect:
CBD was associated with a decrease in cytokine release and production as well as a decrease in lymphocyte proliferation
Cytokines = inflammation. What about lymphocytes?
B lymphocytes play several critical roles in the pathogenesis of rheumatoid arthritis. They are the source of the rheumatoid factors and anticitrullinated protein antibodies, which contribute to immune complex formation and complement activation in the joints
CBD calmed both down.
Let's look at CBD.
CBD and mental health
This may be where CBD's effects are most profound.
First, remember how serotonin is a key stress response bulwark alongside anandamide?
Stick with us here...we'll translate:
Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain
Allodynia is a reduced pain threshold. Sound familiar?
Think system-wide pain.
Anxiety is self-explanatory. Neuropathy? Again...telltale endocannabinoid deficiency.
Anandamide actually turns off the pain signal and calms glutamate hyperactivity at the nerve throughout the body!
Later in the summary, the partially attribute these effects to:
rescues impaired 5-HT neurotransmission under neuropathic pain
"Rescues impaired" are the keywords there.
5-HT is serotonin.
Serotonin can be exhausted from injury (as in this study), chronic stress, trauma, chronic infection (think leaky gut and autoimmune).
No wonder depression/anxiety is commonly associated with pain.
Check out CBD and serotonin to learn more.
Then there's GABA and glutamate balance.
This is critical for the entire suite of anxiety-related issues (OCD, PTSD, Panic attacks, etc).
CBD is a feedback mechanism for GABA as well!
The maximal level of enhancement seen with either CBD or 2-AG were on α2-containing GABAA receptor subtypes, with approximately a 4-fold enhancement of the GABA EC5 evoked current
Essentially, GABA would boost the function of the GABA pathway to which it's anti-anxiety and sleep effects were credited.
We could go on and on with neurotransmitters but let's turn to brain inflammation.
This is increasingly where research is pointing for mental health.
We have a full review of CBD and neuroinflammation but some quick takeaways.
As we noted above, anandamide can be low or high (working overtime) in certain mental health conditions.
CBD affects a range of pathways in this space but the net effect:
CBD decreases the production of inflammatory cytokines, influences microglial cells to return to a ramified state, preserves cerebral circulation during ischemic events, and reduces vascular changes and neuroinflammation
In this way, it supports the efforts of anandamide and our endocannabinoid system.
Again, check out CBD and mental health where we have links to full reviews for each mental health (dozens of in-depth reviews).
Let's turn to PEA!
PEA for endocannabinoid deficiency
We've written over 1 million words on CBD but we're almost as excited about PEA as we are about CBD.
They work differently but complement each other for endocannabinoid deficiency.
PEA is also a FAAH inhibitor which means more anandamide will be available.
It also boosts levels of OEA and other members of the anandamide family.
We covered the full interaction at our PEA review.
Essentially, PEA is a support player for anandamide levels in the body.
When supplemented, research shows that anandamide, OEA, and others go up.
This happens because PEA eats up the capacity of FAAH so it's unable to break down anandamide and others.
Let's quickly look at research on PEA and the following issues tied to endocannabinoid deficiency (just like CBD):
- PEA and fibromyalgia
- PEA and mast cell activation
- PEA and migraines
- PEA and stress response
- PEA and inflammation
- PEA and autoimmune
- PEA and mental health
PEA and fibromyalgia
A study looked at PEA's effect on fibromyalgia with the following results:
In the prospective observational study (DLX + PGB + PEA), PEA introduction after 3 months of therapeutic regimen with DLX + PGB provided a significant improvement in pain symptoms, with a further reduction in the number of TPs and significant reduction in pain, compared to combined DLX + PGB only
They added the PEA to two other meds and found a big benefit.
Another study found improvements in pain and quality of life for fibromyalgia:
Fibromyalgia really looks like a prime example of endocannabinoid deficiency as no other tests are showing up skewed.
We look forward to more clinical trials of PEA.
What about mast cell activation?
PEA and mast cell activation
Simply put, PEA is the brake pedal for mast cell activation, the key to allergic reactions and inflammation itself.
This is evident across a range of studies.
First, one study studied PEA's effect after a known mast cell stimulant (Substance P) was introduced:
SP increased the number of degranulated RBL-2H3 cells and triggered the release of histamine. PEA counteracted these effects in a manner antagonized by AM630
So...substance P triggered the release of mast cells and PEA countered this effect.
Interestingly, PEA also impacted 2AG levels in this study:
PEA concomitantly increased the levels of 2-AG
In studies on spinal cord injury, brain inflammation, and mast cell hyperactivation, PEA has the following effect:
PEA is produced and hydrolyzed by microglia, it downmodulates mast cell activation, it increases in glutamate-treated neocortical neurons ex vivo and in injured cortex, and PEA levels increase in the spinal cord of mice with chronic relapsing experimental allergic encephalomyelitis
Let's look at some typical mast cell and allergy-based diseases.
PEA and asthma
Asthma related inflammation was shown to eat up PEA levels and supplementing PEA helped to calm this pathway:
These findings demonstrate that allergen sensitization negatively affects PEA bronchial levels and suggest that its supplementation has the potential to prevent the development of asthma-like features.
Interesting new research is showing that NGF (nerve growth factor) is tied to mast cells and inflammation.
PEA directly affects this process to reduce mast cell activation:
In this regard, NGF can be one of the targets of PEA in asthma
Let's look at migraines.
PEA and migraines
A study looked at PEA for pain due to MS:
in our study the chronic administration of um-PEA to patients with MA in combination with NSAIDs, induced a significant pain relief allowing the reduction of the NSAID dosage.
Look at the "side effect":
Remarkably, the compound was also able to reduce the number of migraine attacks.
Remember that migraines are initially a vascular imbalance issue (dilation followed by contraction).
There is a lot of research on PEA and our entire vascular system such as this study:
Three-month PEA intake reduced IOP and led to significantly improved FMD values in OH patients compared to placebo, by ameliorating peripheral endothelial function, and its positive effect lasted longer than the period of PEA consumption.
Let's translate, please!
Essentially, PEA normalized the blood flow and vascular function for people who have increased eye pressure.
It did this by direction boosting the pathway of our vascular lining (like the skin of our arteries).
- There are big impacts on this across the cardiovascular system but a net bonus is for migraines!
- On a side note, PEA's effect on pain is striking.
There's a huge review of PEA's effect on multiple pathways of pain but the net effect:
all available clinical trials reported significantly reduced pain intensity and an almost complete absence of unwanted effects, the latter confirming early field studies of PEA in healthy individuals
The side effect profile is ridiculous with no drug interactions.
What about the stress response, a key aspect of endocannabinoid deficiency?
PEA and stress response
Look at how the body naturally uses PEA with stress (as it pertains to depression):
PEA is increased in stress conditions, and a randomized, double-blind study in depressed patients indicated a fast-antidepressant action of PEA when associated with citalopram.
Call in the backup (to anandamide)!!
Remember...this system is all about responding to stress and righting the ship.
PEA is a clear backup when the system is overrun:
PEA is an endogenous molecule in humans and many other living organisms that can play a very important role in maintaining cellular homeostasis and in counteracting exogenous stressful events that can lead to an inflammatory reaction.
Balance when dealing with stress.
We rest our case!
Stress comes in many forms. Perimenopause is a perfect example of an internal stress from loss of extreme fluctuation of estrogen.
In studies of mice with ovaries removed, imbalances in hormones that drive metabolism, weight gain, and energy become critical (again, estrogen is everywhere in women's bodies).
Look at the effect of PEA:
We showed that PEA caused a reduction of food intake, body weight, and fat mass. The mechanisms underlying PEA effects involved an improvement in hypothalamic leptin signaling,
We know that OEA (PEA's cousin) has a powerful anti-appetite effect but this points directly to PEA.
Again, stress means any imbalance across multiple pathways in the body and brain!
What about inflammation itself!
PEA and inflammation
Simply put, PEA is our body's natural anti-inflammatory.
There are many studies supporting this effect.
For example, PEA's effect following spinal cord injury:
Mechanical hyperalgesia caused by chronic inflammation was significantly reduced by both intraperitoneal and intra-articular injections of PEA.
Hyperalgesia is systemic pain.
PEA was originally discovered by its ability to prevent children from getting the symptoms of rheumatic fever after coming in contact with the underlying bacteria.
A study looked at PEA and MS with the following results:
We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group.
Those are all inflammatory markers of MS!
Again, we could cite dozens of NIH studies on all types of inflammatory markers.
Let's see how this manifests with autoimmune.
PEA and autoimmune
Check out our CBD and autoimmune review for the basic mechanisms.
First, PEA and gut barrier support.
Researchers introduced a chemical to mice that is known to cause gut inflammation and colitis.
PEA counter this effect:
PEA improves murine experimental colitis, the effect is mediated by CB2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels.
Remember, gut inflammation is the first step in barrier breakdown which allows bacteria and other pathogens to escape into the body.
Interestingly, PEA naturally goes up in response to the gut inflammation but adding additional PEA further helped:
Exogenous PEA (i.p. and/or p.o., 1 mg·kg−1) attenuated inflammation and intestinal permeability, stimulated colonic cell proliferation, and increased colonic TRPV1 and CB1 receptor expression
Exogenous just means "added" from outside.
Here's where it gets interesting (for us anyway).
A study looked at the effect of Vitamin D deficiency and gut barrier inflammation.
Look at PEA's effect:
Remarkably, the anti-inflammatory anandamide congener, palmitoylethanolamide, counteracted both the pain behavior and spinal biochemical changes in vitamin D deficient mice, whilst increasing the levels of Akkermansia, Eubacterium and Enterobacteriaceae, as compared with vehicle-treated mice.
Goodness. This is fascinating.
From our Vitamin D study, we know it directly supports the gut barrier.
Those types of bacteria are incredibly important for health (and especially mental health).
See CBD and probiotics to learn more.
Akkermansia is a fascinating player in mental health!
We know that PEA calms immune hyperactivation.
Let's look at some of the most common autoimmune diseases.
- PEA and rheumatoid arthritis
- PEA and MS
- PEA and dementia
First, rheumatoid arthritis.
PEA is showing interesting effects on this common autoimmune disease:
Treatment with PEA or PEA + luteolin ameliorated the clinical signs at days 26 to 35 and improved histologic status in the joint and paw.
The key there is inflammation:
Plasma levels of the proinflammatory cytokines and chemokines were significantly reduced by PEA + luteolin treatment.
Key inflammatory agents in the tissue directly affected by RA were directly affected:
IL-6, IL-8 and MMP-3 (determined only in synovial fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and OA after AEA, PEA and OEA treatment.
Again, there's anandamide and OEA as well….they work as a group!
What about MS?
PEA and MS
Again, PEA directly reduced the inflammatory agents tied directly to MS:
We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group.
The body is trying to put out the fire with natural inflammation retardants!
PEA was given to mice who are genetically altered to get the mice version of MS (called EAE) with the following:
The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE.
The PEA was given luteolin.
What about dementia?
PEA and dementia
Let's turn to the brain on our way to mental health.
As we mentioned, we covered the mechanics of dementia in research at our CBD and dementia review.
Part inflammation. Part leaky gut. All immune!
The research is readily new on the dementia front.
In 2011, the first study looked at PEA and dementia directly with the following results:
The results indicate that PEA treatment attenuated Aβ-induced astrocyte activation
AB is the little filaments (like fishing wire) that clump up and are the signature of dementia.
Beyond slowing down this process, there was an effect on protecting neurons from existing AB build-up:
PEA was able to blunt Aβ-induced neuroinflammation by significantly diminishing either the altered expression of pro-inflammatory molecules
Another study looked at PEA to protect against AB introduction to mice:
For instance, in a very elegant study, it has been demonstrated that in wild-type (WT) mice, the addition of several acylethanolamides (including PEA) partially reverted Aβ-induced inflammation.
That's all well and good in terms of pathways but what about symptoms in research?
Another study looked at PEA's effect on cognitive decline following addition of AB particles:
The authors demonstrated that, depending on the dose, PEA reduced (10 mg/kg of body weight) or prevented (30 mg/kg of body weight) the cognitive impairments induced by Aβ25–35 peptide injection.
We're still awaiting clinical trials.
The only study we have is anecdotal for one person in conjunction with luteolin:
After a 3-month treatment with PEALut, the patient reported a non-significant cognitive amelioration, whereas her neuropsychological evaluation was almost normal after a 9-month treatment (significant improvement of RAVLT, AM, and TMT in comparison with those in the pre-treatment period).
That NIH review is a pretty amazing summary of many studies. Very fascinating.
Let's turn to mental health.
PEA and mental health
Let's look at some of the big ones through the lens of PEA:
- PEA and anxiety
- PEA and depression
- PEA and schizophrenia
One with GABA issues. One with serotonin issues. One developmental disease.
All with inflammation!
That should be right up PEA's alley.
- PEA and anxiety
- Why would an immune response agent help with anxiety?
The new direction of mental health research focuses on inflammation in the brain.
The neuroinflammation can be triggered by infection, autoimmunity, and toxins, which are defined not just by classical factors, but also by noxious stimuli or psychological stress, such as neurogenic factors.
Psychological stress! Goodness, that's at the heart of all mental health but especially anxiety.
The bigger trigger to hit is the anandamide and FAAH one.
Remember, people who lack FAAH can't feel anxiety. Ever!
Even when they should, oncoming bus, etc.
It goes both ways...what if we have too much FAAH activity (and less anandamide).
A study found that this may be tied with the entire suite of anxiety (health, general, etc).
In fact, there is increased connectivity between the emotional (fear) center called the amygdala and the prefrontal cortex.
Essentially, our more primitive brain has too much access to our "coloring" of situations.
One of the first studies to really look at anandamide's impact on anxiety found the following:
Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.
Check out the full PEA review.
Let's turn to depression.
PEA and depression
This is where we're seeing lots of research.
Some of the first results came after various brain injuries such as TBI and neuropathy:
Preclinical studies have shown antidepressant activity of PEA in animal paradigms of depression and of depression associated with neuropathic pain and traumatic brain injury
Check out CBD and TBI to learn all about it.
A great deal of the work on depression is pointing to the PPAR pathway.
PPAR is probably the dominant target for PEA and looks at what PPAR is involved with:
PPAR–α and PPAR–γ have similar neurophysiological functions that include regulation of the redox response, neuroinflammation, neurogenesis, cellular differentiation, as well as secondary functions in the regulation of cognition, anxiety, and emotional behavior
We want to focus on just one aspect of that...neurogenesis.
This is the term for brain repair and regrowth.
When you dig deeper into how SSRIs work, it all comes down to neurogenesis and BDNF, our brain's fertilizer.
In a study of PEA and dementia:
Under these experimental conditions, the pre-treatment with co-ultraPEALut significantly reduced iNOS and GFAP expression, restored neuronal iNOS and brain-derived neurotrophic factor (BDNF), and reduced the apoptosis
BDNF! This is the key to the breakthrough new research on psilocybin and CBD.
Let's look at a part of the brain directly tied to depression and mood in general...the ever-vulnerable hippocampus:
Palmitoylethanolamide Enhances Brain‐Derived Neurotrophic Factor Production and Neurogenesis in the Hippocampus Following Ischemic Brain Injury
The hippocampus is critical to anxiety and depression.
Let's turn to developmental issues.
PEA and schizophrenia
As we mentioned above, there's a known connection between anandamide and schizophrenia.
Twin pairs discordant for schizophrenia or bipolar disorder had significantly higher levels of anandamide and palmitoylethanolamide compared to healthy twins
Is the higher level causing the disease or a response to the disease?
There's now quite a bit of research showing that schizophrenia, autism, bi-polar and other developmental diseases are awash in brain inflammation.
Look no further than the microglia, our brain's immune response generals.
In our genes, which area has the highest correlation with risk for schizophrenia?
The histocompatibility complex!
This is the area that stores genes tied to our adaptive immune response (making antibodies for new threats not passed down from mother).
The root of autoimmune essentially.
There are numerous risks for schizophrenia that revolve around brain inflammation:
- Exposure to pollution
- Exposure to viral infections (especially in utero or during periods of brain development)
- Gut inflammation
- Exposure to chemicals and drugs
The whole theory of the "Inflamed Brain" has taken hold.
There have numerous tests to try to normalize or calm microglia hyperactivity with one that should be familiar by now:
Another successful approach to restore typical microglial function targeted the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway.
PPAR...the primary target of palmitoylethanolamide and the brake pedal to immune hyperactivity.
Interestingly, PPAR activity is lower in people with schizophrenia and continues to fall as the disease progresses.
What about autism?
Animal models have been showing many effects here such as:
The autistic-like behavior of BTBR mice is reversed by PEA through PPAR-α activation.
Those are mice genetically changed to display autistic like behavior.
What do they pinpoint as the root cause?
PEA restores hippocampal BDNF signaling pathway and mitochondrial dysfunction.
BDNF...our brain's fertilizer.
Mitochondria are a whole different deal as they power our cells and no cell needs more power than brain cells - neurons.
Furthermore, balancing of gut biome was at play as well.
We have to stop somewhere or we would exhaust your energy!
PEA and CBD are both powerful supporters of the endocannabinoid system in different ways.
- PEA is a raw material for the system
- CBD works like a calibrating and balancing agent in the system
They both are FAAH inhibitors are powerful supporters of immune response balance.
CBD's effect on neurotransmitters is more pronounced while PEA's effect on pain and histamine response is stronger.
Together, they are a fascinating tandem across a range of issues.
Let's look at some practical questions!
How much CBD and PEA for endocannabinoid deficiency
We'll focus on two facets that are important.
For CBD, we'll look at neurogenesis.
Research shows that peak neurogenesis occurs at 300 mg/daily of CBD isolate and then starts to go down.
Since this is the key to mental health, addiction, and neurodegenerative disorders, that is our primary focus (or at least up to that amount).
Research shows up to 600-800mg for more serious issues like schizophrenia or social anxiety public speaking.
As for PEA, research is generally at 600 or 1200 mg daily.
The side effect profile for either is very strong.
With CBD, you just don't want to take it closer than 4 hours to other medications and always work with your doctor.
For PEA, there is no known drug interactions.
What about the type of CBD and PEA for endocannabinoid deficiency?
What's the best CBD and PEA for endocannabinoid deficiency
For CBD, it's really important we have the following:
- Organically grown in the USA at an FDA registered farm
- CO2 processed
- 3rd Party Tested
- No Pesticides
- No Solvents
- No Heavy Metals
- No THC (works in one direction and builds tolerance)
- No Bacteria
- No Mold
We also focus on CBD isolate since all the research is based on that and full spectrum can cause histamine release which is just another form of inflammation (see CBD and mast cells to understand why).
As for PEA, ideally, we'll have micronized or ultra micronized (um) before too long.
For now, LifeExtension has a chewable one and iherb's new brand has a capsule.
The capsule is priced better but our testers swear the chewable has more effect (perhaps due to sublingual absorption under the tongue).
Of all the things we've researched, we're most excited about CBD, PEA, and Vitamin D.
In fact, our next topic will be whether Vitamin D deficiency is at the heart of endocannabinoid deficiency.
The crossover of signs and symptoms is eerily similar.
Be well. Take care of each other. Take care of yourself!
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.