Sometimes, while trying to find what you're searching for, something else better comes along.
We were on the hunt for FAAH inhibitors. That's a mouthful and we'll leave the details to below but you're going to want to know what it does.
When the CRSPR gene editing revolution comes online in the next few years, FAAH will be one of the big targets after the more obvious diseases like Sickle Cell and Parkinsons.
We covered the woman who can't feel pain, anxiety, or depression due to a rare genetic variation in her FAAH gene.
So...pain, anxiety, and depression. Sound relevant to today's world?
You'll fully understand why below but as we said, we were looking for FAAH inhibitors or blockers.
CBD has been shown to block FAAH. That's the basis (partially) behind its effects on anxiety, depression, and yes...pain.
Schizophrenia is a more potent example however.
Certain molecules in soy (soy isoflavones) also block FAAH.
Then there's PEA. Palmitoylethanolomide. Don't let the long name scare you away...it's a safe and simple compound that our body makes by the second.
We're surprised that it's taken this long for this class of chemicals to come to the front.
LifeExtension, a monster on the supplement market, just did a major review of its cousin, OEA.
Wait till you see how these two elements directly support our endocannabinoid system (where CBD and THC work) but without tolerance, psychoactive effects, or side effects really.
Huge possibilities for inflammation, mental health, autoimmune, pain, and more.
We'll cover these area:
- A quick introduction to palmitoylethanolamide or PEA
- How PEA works in the endocannabinoid system
- PEA for FAAH and Anandamide
- PEA and PPAR
- PEA and neurotransmitters - dopamine and serotonin
- PEA and mental health
- PEA and immune response with a focus on autoimmune
- PEA and pain
- PEA and inflammation
- PEA safety
Let's get started. First, an introduction.
A quick introduction to palmitoylethanolamide or PEA
PEA is a simple fat. It's generally found in eggs, soy beans, and other substances with fat.
In fact, it was originally discovered as scientist tried to figure out what in eggs was reducing inflammation.
Our bodies and brains make PEA all the time and almost immediately break it down.
A constant cycle of PEA creation and destruction which is very common for the endocannabinoid system.
Chemicals made as needed.
We'll explain more about this system below but some key takeaways on PEA.
Scientist have since found the PEA has the following qualities:
- Anti Inflammatory
- Neuroprotective
- Anticonvulsive
- Pain relieving
Almost all our modern diseases of both the body and brain revolve around 1 or more of these areas with inflammatory and neuroprotective being the biggest.
Autoimmune. Mental illness. Cancer. Neurodegenerative diseases.
We just covered 70% of the TV ads for medications.
We looked at the COX2 pathway for pain in our comparison of CBD and Tylenol but PEA is a more basic, root-level player in all these systems...including pain.
To understand how, we need to look at the system it works in...the endocannabinoid system.
How PEA works in the endocannabinoid system
Stress.
We don't mean the narrow definition of stress like being late for an appointment.
We're in the world of biology so we mean anything that pushes on our systems one way or the other.
An outside (or even internal) influence (cold, hunger, heat, lack of oxygen, danger, etc) that makes one of our key systems go out of balance.
Think of if your standing and someone pushes on you.
If you're rigid and unable to change, you'll just fall over.
However, if you can adjust and move your feet, you'll account for the push and remain upright.
Now apply that to very complicated and integrated systems that manage your health:
- Nervous system - including neurotransmitters
- Endocrine system - hormones both steroidal, metabolic, and everything in between
- Immune system - inflammatory agents and cellular birth/death cycles
Goodness. The endocannabinoid system is tasked with balancing these key systems in adjustment to….stress.
And yes, even the more specific effect of stress (late for appointment) as well.
As for the brain, there's also chronic stress, trauma, social rejection, infection, etc.
In fact, the newest research is really showing early trauma or infection can dysregulate our stress response...through life.
See why this is so important to almost every health issue we have?
So...what is PEA's role?
Technically, it's not an endocannabinoid because it doesn't directly affect our two key receptors, CB1 and CB2.
PEA does affect other receptors that eventually will probably be called CB3, etc.
More importantly, it binds to FAAH, our mystery guest from above.
FAAH is tasked with breaking down our primary endocannabinoids, 2AG and anandamide.
If FAAH is reduced by PEA, we have more anandamide and 2AG!
It's a unique work around to support this system without direction interacting with it.
Why does any of this matter? What's the big deal with anandamide?
Oh...wait till you see below.
PEA for FAAH and Anandamide
Anandamide is named after the Hindu goddess of bliss, Anand.
That's a pretty accurate naming of it.
Of all the research we've done, anandamide appears to act like a wet blanket or dampener of stress' response in our body and brain.
A counter-weight.
We did a huge review on whether people who are really drawn to cannabis (to the point of addiction...about 9% of users) are using it to slow down glutamate, our brain's "gas" pedal.
We need glutamate to think and function but too much is a bad thing.
Anxiety. Eventually, depression. OCD. Repetitive thoughts. Mental illness. Actual brain loss.
THC, the primary chemical in cannabis, mimics anandamide in the CB1 receptor and the net effect:
Activation of cannabinoid CB1 receptors reduces glutamatergic synaptic transmission in the rodent striatum and is involved in the normal control of motor function by the basal ganglia. H
https://www.jneurosci.org/content/jneuro/23/35/11073.full.pdf
You see this throughout. That striatum area is interesting for schizophrenia and bipolar (see CBD and schizophrenia and CBD and bipolar).
Anandamide is a critical player in protecting the brain and calming damage and the effects of stress.
The issue with THC is that it builds tolerance, can cause addiction (via dopamine system - see CBD and addiction), and doesn't break down like anandamide.
Remember how the endocannabinoids are constantly cycled...made and broken down as needed?
The brain can't break down THC in the same way so it lingers and stimulates CB1 activity much longer than what anandamide does.
This leads to the psychoactive effects we see...another type of imbalance.
Remember, our neurotransmitters are governed by this system!
Serotonin is the master regulator of all HUMAN behavior. See CBD and serotonin.
Rather than pumping up CB1 activity, the better angle is to reduce the removal of anandamide and 2AG.
That's where FAAH comes into play. Again, the woman who has no real FAAH activity (genetic variation) isn't "high" or unable to think.
She's just flooded with available anandamide.
Anandamide squashes pain sensitivity, anxiety, and the damage that leads to depression.
So...that's one big avenue for PEA to operate and it's involved in EVERY pathway of the body.
Cancer?
Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1222054/
Blood pressure?
Overall, it is concluded that the PEA-induced diuretic and natriuretic effect is independent of FAAH-mediated hydrolysis and the CB1 receptor, and that PEA can serve as an antihypertensive regulator in the renal medulla that may be regulated by medullary interstitial cells.
https://scholarscompass.vcu.edu/etd/5776/
Diuretics? You just named the biggest class of blood pressure meds but without the nasty side effects of pushing too hard on that pathway.
Again, we can pick almost any system in the body and reducing FAAH has a positive effect.
You can think of the endocannabinoid pathway as a tuning system for our body and brains and it's as if we're out of tune to our modern way of living.
We're tuned to 40,000 maybe 400,000 years ago and FAAH clearly worked better then at a higher level.
We'll leave that to the researchers to tease out but it's interesting to see effect across such different pathways.
What does PEA do with FAAH?
A recent study showed that, rather than directly inhibiting AEA hydrolysis by substrate competition, PEA a¡ects the degradation of AEA by downregulating the expression of FAAH
https://core.ac.uk/download/pdf/82425333.pdf
Newer research is showing that PEA binds to FAAH, thus taking it out of commission.
That's just one (albeit a powerful one) pathway for PEA.
Let's look at PPAR.
PEA and PPAR
PPAR is short (thank goodness) for Peroxisome proliferator-activated receptor.
Okay, so before, you shut down...what on Earth is the point to this?
PPAR gained popularity among researchers for its powerful effect on metabolic function...insulin, obesity, etc.
A whole class of medications boost PEA for cholesterol, triglycerides, and just about every element of our metabolic balance (endocrine system under endocannabinoid control).
OEA, PEA's cousin is a known anorexic (appetite suppressant) with strong effect.
The dial has since turned to inflammation and immune response as has much of health and mental health research.
PPAR receptors are maestros of gene activity. Researchers turn them on and off and have knock-on effects from those changes.
They're interesting "tuning" forks in this respect and may as well be called CB3 receptors but PPAR sticks.
- CBD directly interacts with PPAR receptors.
- Anandamide and 2AG? Both activate PPAR receptors.
What about PEA and PPAR?
Here, we identify the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) as the molecular target responsible for the anti-inflammatory properties of PEA.
https://pubmed.ncbi.nlm.nih.gov/15465922/
Ah-ha! Anti-inflammation.
Inflammation (the chronic kind) lurks under the covers for almost every mental health (see CBD and neuroinflammation) and health issue.
Dementia? Those little amyloid plaques are immune responders to infection (see CBD and dementia).
A very specific type of inflammation is a secret way to kill (accumulating needle-like fibrils that actually does more damage to us left unchecked) bacteria.
We'll cover the net effects of this antiinflammatory effects specifically below but a few stray targets.
PEA and TRPV, GP55, GR119, and more
The research on endocannabinoids is relatively new.
There are a slew of "orphan" receptors that directly interact with PEA and endocannabinoids.
Some are profound.
We did a full review on GPR55 for anxiety here.
PEA directly drives GPR55 such as with this:
Palmitoylethanolamide Modulates GPR55 Receptor Signaling in the Ventral Hippocampus to Regulate Mesolimbic Dopamine Activity, Social Interaction, and Memory Processing
https://pubmed.ncbi.nlm.nih.gov/28861501/
Okay...before your eyes glaze over...the hippocampus is definitely a part of the brain you want to know.
It's key to memory and mood control.
It's also incredibly vulnerable to chronic stress, trauma, immune response, etc.
Check out CBD and hippocampus neurogenesis.
As for dopamine regulation? That's critical to addiction (see CBD and addiction) or any of the mental health issues tied to development (schizophrenia, bipolar, autism, borderline personality disorder).
The primary antipsychotic medications squash dopamine function (with a slew of different side effects as a result).
Then there's TPRV. Transient potential receptors of vanillinoid type.
Okay...what is this?
It's a cellular sensor of sorts. Our own internal eyes and ears for outside stress in the form of heat, pain, cold, taste, pressure, etc.
Endocannabinoids directly interact with these channels of course since they're both engage in the "tuning" mechanism.
What about PEA?
Activation of PPARα and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA-induced [Ca2+]i transients in sensory neurons
Okay...PEA works through TRPV1 to reduce "sensation". Why does this matter?
Pain. For one.
Pain, especially peripheral pain can be the result of pain receptors (called nociceptors) being stuck "on" by an initial injury.
PEA is able to tune down this response and allow the system to normalize.
We'll dive deeper into this in the pain section below.
GP119 is another receptor that's directly (maybe solely) affected by PEA and its class of fats.
GP119 is a powerful player in the entire complex of metabolism:
- Fat creation
- Cholesterol
- Insulin
This may be how the endocannabinoid partially interacts with our hormone system that governs weight, obesity, and energy.
Okay...we're quickly falling down the rabbit's hole...let's come up for air a bit and look at practical effects of all this biology.
PEA and neurotransmitters - dopamine and serotonin
We'll start in the brain since we've just spent a few 100 hours researching CBD and mental health.
Let's look at the big players in a healthy, functioning brain:
- PEA and serotonin
- PEA and dopamine
- PEA and glutamate/GABA
- These messengers carry out the actions of the brain but they have to exist in delicate balances.
To make things more complicated, they're all affecting each other!
When they get off-balanced, mental health suffers.
Interestingly, many serious mental health issues show anandamide (our "bliss" molecule) is exhausted or abnormal with many mental health issues.
Essentially, there's a fire in the brain and the water hydrant (anandamide) has run dry. Exhausted.
The "fire" can be any of the following:
- Hyperactive immune response
- Excessive glutamate "gas" pedal
- Chronic stress
- Trauma
- Social isolation or rejection
- Drugs and chemicals
All the above?
This can affect the "balance" of key players in our brain's function.
We'll start with the big one...serotonin.
Serotonin is the target for the common antidepressants, SSRIs (see CBD versus SSRIs).
It is truly a master regulator of human behavior, gut function, and a range of pathways.
Too much (serotonin syndrome) or too little is brutal.
Almost every negative behavior can "pop up" in the side effect profile on either side.
- Compulsion. Check
- Risky behavior. Check
- Depression. Check
- Low or high libido. Check Big review on PSSD
- Homicidal or suicidal thoughts? Check (see CBD vesus SSRI for suicidal or homicidal thoughts).
Weird things like standing up for yourself when being offered a bad option (see tryptophan and social rejection stress).
Serotonin's secret weapon though is its effect on BDNF, our brain's fertilizer.
Check out CBD and serotonin, how SSRIs really work, or CBD and BDNF to learn more.
This is the really new crux of mental health for the next decade.
Here's how PEA comes into play.
Remember that PEA allows more anandamide (bliss molecule) to be available and it primarily acts on CB1 receptors.
Look at what that does to serotonin (5HT):
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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110547/
PEA is exactly such an FAAH inhibitor.
The key is this...we see don't serotonin syndrome as a side effect of PEA supplementation in research.
It works within the natural bound of our existing system...a tuning system designed to find balance.
How does it do this?
Other research shows that PEA can calm glutamate (brain's "gas" pedal) to serotonin neurons!
It's not all in one direction. Again...balance.
What about dopamine?
PEA and dopamine
One note...serotonin and dopamine are highly integrated with serotonin having some master control ability over dopamine function.
Research is teasing out just how nuianced PEA is this complicated chemical dance:
Palmitoylethanolamide Modulates GPR55 Receptor Signaling in the Ventral Hippocampus to Regulate Mesolimbic Dopamine Activity, Social Interaction, and Memory Processing
https://www.liebertpub.com/doi/10.1089/can.2016.0030
That's a mouthful...let's translate.
PEA "modulates" that receptor we talked about above which is critical to mood...GPR55.
It did this in the "mood control" center of the brain...the hippocampus. So far so good.
The net effect was correction of imbalance dopamine (from a different chemical used to upset the balance) in our "reptilian" brain...the very old structures that govern emotion and motivation.
Too much dopamine in these areas is tied to a host of issues from schizophrenia to social anxiety.
Better put:
Functional interactions between the vHipp, VTA, and nucleus accumbens (NAc) involving dopaminergic transmission have been shown to be critical for controlling the contextual and emotional salience of various cognitive and affective behaviors
This may sound very technical but just focus on the last part..
That's technical speak for... our ability to correctly read the emotional importance of various outside factors.
"Affective behaviors" is just a grab-bag of all the different ways this can go wrong from borderline personality disorder to poor self-esteem to eating disorders.
PEA was able to offset these effects when brought out by another chemical.
And it all revolved around dopamine balancing!
This isn't about slamming down dopamine like antipsychotics do because you would see a slew of nasty side effects from depression to weight gain to..Parkinson's!
Just check out the side effect panel for Abilify!
That's the beauty of the endocannabinoid system...by supporting it directly, the goal is balance in the downstream pathways.
Okay...there are dozens of studies on neurotransmitters and PEA. Let's see why this actually matters.
PEA and mental health
We already know that PEA has anti-inflammatory and neuroprotective effect from above.
Let's zero in to specific research around different mental illnesses.
We'll look at the following:
- PEA and anxiety
- PEA and depression
- PEA and schizophrenia
- PEA and bipolar
- PEA and OCD
- PEA and autism
We'll start there!
PEA and anxiety
First, remember that by blocking FAAH (which PEA does), there's a known effect on anxiety born out by genetic deletion tests:
Genetic deletion and pharmacological inhibition of FAAH reduce anxiety and improve emotional responses and memory in rodents and humans.
https://www.nature.com/articles/s41386-018-0274-7
As we covered in our CBD and the mechanisms of anxiety, there's a known disruption between GABA (our brain's "brake" pedal - the target of benzos) and glutamate (our brain's "gas" pedal).
Very complicated research has found that FAAH can drive too much glutamate activity (and even future activity) leading to anxiety states.
In fact, reduced PEA may be partially what is causing this:
The impaired PEA signaling may also have contributed to the functional and behavioral alterations in FAAH-overexpressing mice, likely through PPARs and/or GPR55 pathways.
Why does GPR55, a primary target for PEA, matter for anxiety?
Look what happens when researchers boost its activity...
First, they administered GPR55 to rats and there was an immediate anti-anxiety (anxiolytic) effect:
Central administration of GPR55 receptor agonist and antagonist modulates anxiety-related behaviors in rats.
https://www.ncbi.nlm.nih.gov/pubmed/25620584/
Check out our review on GPR55 and anxiety as there are fascinating studies specific to this pathway.
Let's turn to depression where we're seeing some actual clinical trials.
PEA and depression
We covered the mechanisms in-depth at our CBD and depression review.
Inflammation. Gluatamate excess. Gut microbiome issues. Serotonin/BDNF.
PEA is right in the wheelhouse for all these pathways.
Let's jump right to the studies.
First, a look at palmitoylethanolamide and major depression:
At week 2, patients in the PEA group demonstrated significantly greater reduction in HAM-D scores compared to the placebo group (8.30 ± 2.41 vs. 5.81 ± 3.57, P = .004).
https://www.pal2020.com/pdf/Mellar%20Davis_Palmitoylethanolamide.pdf
This effect continued through the trial.
This study is great because it gives us some guidance on how long it takes PEA to show results.
Fascinating that it's about the same time as SSRIs which points to neurogenesis a key player.
Learn more about this at CBD and brain repair or how SSRIs actually work.
That study was along side an SSRI.
Many other studies looked at PEA by itself or even against SSRI's.
For example, an animal study compared PEA to fluoxetine (Prozac):
PEA (dose range of 5–40 mg/kg) administered orally reduced immobility in TST and FST, comparable to the antidepressant effect of fluoxetine, and had no effect on spontaneous activity in mice.
https://www.sciencedirect.com/science/article/abs/pii/S1734114011705965
So...the same effect as paxil in terms of depressive symptoms.
Let's look at an interesting study on TBI.
This gets to the heart of how long term anxiety can cause depression as can trauma (short-term, explosive anxiety).
Look at the progression of symptoms following TBI:
Fourteen-day mTBI mice developed anxious, aggressive, and reckless behavior, whilst depressive-like behavior and impaired social interactions were observed from the 60th day onward.
https://www.frontiersin.org/articles/10.3389/fphar.2017.00095/full
First comes anxiety and much later, depression.
If the immune system can't resolve its inflammatory setting, damage occurs in the brain over time...especially key areas tied with mood (hippocampus and prefrontal cortex).
Check out CBD and TBI or CBD and neuroinflammation to learn more.
Researchers in this study then looked at PEA's effect on this process and found the following:
Compared with vehicle, PEA restored the behavioral phenotype and partially normalized the biochemical and functional changes occurring at the supraspinal level.
https://www.frontiersin.org/articles/10.3389/fphar.2017.00095/full
Supraspinal basically means the brain.
Chemical and electrical function was restored and this lead to recovery of normal behavior!
PEA is almost like our brain's shock absorber...be it physical, chemical, or immune related in nature.
Another study pinpointed PEA's anti-depressant effect to PPAR pathways in the hippocampus (mood control area).
Scientists applied chronic unpredictable stress to mice.
This is known to lead to depression-like symptoms.
They found PEA resolved the symptoms but more importantly, pointed to neurogenesis (brain repair/growth) in the hippocampus as the primary driver.
This was caused by PPAR activity which when blocked, made the positive effects go away.
PEA reversed the abnormal levels of several oxidative stress biomarkers and increased the concentrations of two neurotrophic factors in the hippocampus of CUMS-induced rats. In addition, PEA alleviated the decrease in hippocampal weight
https://jpet.aspetjournals.org/content/jpet/early/2019/01/11/jpet.118.254524.full.pdf
New research is showing that PPAR turns on the switch for metabolism (energy) needed for building new brain.
Check out CBD and BDNF or CBD and brain repair.
Let's turn to developmental issues.
PEA and schizophrenia
We covered the mechanism with great detail in our CBD and schizophrenia review.
There's a huge connection between schizophrenia and anandamide.
As such, these results suggest that anandamide may normalize, in a compensatory fashion, the neurochemical disturbances associated with the acute phase of psychosis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034083/
Essentially, the brain is trying to compensate for the imbalance or firestorm of schizophrenia in the brain with anandamide (fire hose).
Why on earth would THC at higher doses cause psychosis then if it mimics anandamide?
First remember that it doesn't break down fast like anandamide so there starts to be an imbalance but they are not entirely the same of course.
For example:
In addition, Δ9-THC does not bind vanilloid receptors, contrarily to ECBs. As mentioned earlier, this latter finding could explain why anandamide decreases striatal dopamine release, whereas Δ9-THC increases it
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034083/
Dopamine imbalance is a key player in the symptoms of schizophrenia.
Too much of it in the striatum. Too little in the prefrontal cortex.
See how anandamide calms dopamine release in the striatum!
The TPRV receptors appears to mediate this effect as a difference between the two.
OEA, PEA's cousin makes this more clear:
Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson´s disease
https://www.researchgate.net/profile/Rosario_Moratalla/publication/258059997
We already know that PEA equally interacts with TRPV1 receptors.
This speaks to the so-called "positive" symptoms of schizophrenia...hallucinations, paranoia, delusions, etc.
Check out CBD and hallucinations or CBD and paranoia to learn more.
Speaking of CBD, there's a very interesting study on schizophrenia where it shows effects similar to a leading amulsipride without the side effect profile (double blind/placebo).
Look at a curious effect of this:
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.
https://www.nature.com/articles/tp201215
So...CBD improves symptoms. CBD increases palmitolyethanolamide (and OEA). Interesting.
There are currently clinical trials and we look forward to reporting their results.
Interesting research is pointing to PEA's pathways for bipolar as well (see CBD and bipolar).
Let's turn to autism.
PEA and autism
We looked at detailed pathways at CBD and autism.
Excess glutamate and brain inflammation are key elements of autism.
The "primed" immune system from prior trauma, stress, or infection.
This is right up PEA's alley:
A study looked at PEA in conjunction with risperidone, an antipsychotic commonly given for autism irritability.
Double blind/placebo.
At trial endpoint (week 10), combination of PEA and risperidone had superior efficacy in ameliorating the ABC-irritability and hyperactivity/noncompliance symptoms (Cohen's d, 95% confidence interval (CI) = 0.94, 0.41 to 1.46, p = 0.001) compared with a risperidone plus placebo regimen.
https://pubmed.ncbi.nlm.nih.gov/29807317/
To decipher, when PEA was added to the mix, results were much better for irritability and hyperactivity.
The side effect profile for risperidone is pretty severe (as is common with anti-psychotics - dopamine's kind of a of a big deal in the brain).
Another study looked at mice bred to exhibit their version of autism.
First...the top level review:
Autistic-like behaviour of BTBR mice are reversed by PEA through PPAR-α activation.
https://www.sciencedirect.com/science/article/pii/S0889159118305488
That's good and all but what sparked our attention were the noted underlying pathways.
It's the who's who of brain health:
- Restores BDNF (our brain's fertilizer) in the hippocampus
- Resets the inflammatory setting in the brain
- Improves the gut's microbiome (where inflammation starts!)
Goodness...we couldn't think of a better alignment with what research is showing for autism and mental health in general.
Keep in mind that serotonin and GABA/glutamate are tied to almost every mental health issue.
Serotonin covers the entire suite of mood disorders while GABA/glutamate is tied to the "anxiety" umbrella of issues including OCD, PTSD, and more.
Check out CBD and glutamate, CBD and GABA, or CBD and serotonin to learn more.
Another study on the mouse model of autism:
Co-ultraPEA-LUT treatment ameliorated social and nonsocial behaviors in valproic acid-induced autistic mice and improved clinical picture with reduction in stereotypes in a 10-year-old male child.
https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.12648
Let's turn a closely related topic (believe it or not)...PEA and immune response.
PEA and immune response with a focus on autoimmune and mental health
We're not even talking about infection, although PEA was originally discovered as it helped children avoid rheumatic fever following Strep A infection:
https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.12648
The immune response is key to cancer, inflammation, mental health, and the entire cellular birth/death balance.
The biggest class of disease over the last 50 years is clearly autoimmune (with mental health a quickly approaching second).
We covered it in detail at our CBD and autoimmune.
Since PEA is our body's natural anti-inflammatory, what is the role with autoimmune?
Let's dive right into specific research for some of the biggest autoimmune diseases.
We'll look at the following:
- PEA and MS
- PEA and rheumatoid arthritis
- PEA and dementia
- PEA and diabetes
First, MS.
PEA and MS
Big review on CBD and the pathways of MS.
A double-blind, placebo study looked at PEA to address the negatives of interferon treatment (pain, etc) and found that plus more:
Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed.
https://pubmed.ncbi.nlm.nih.gov/26857391/
QoL is qualify of life.
That's the pain part...but look what else happened which is more core to the disease progression itself:
and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group.
Those are inflammatory agents tied directly to MS disease progression.
More interesting to our discussion, by giving PEA, there was a significant increase in Anandamide AND OEA as well.
This really shows that this class works in a team effort.
FAAH is the linchpin there since it breaks down all of them!
See why we were originally looking for an FAAH inhibitor?
Another study found similar downregulation of inflammatory markers in a mouse model when combined with leutiolin:
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.
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1514-4
EAE is the mouse model for MS and autoimmune disease.
"Significantly reduced the development of clinical signs" is the key part there.
Basically, the symptoms!
Let's turn to RA.
PEA and rheumatoid arthritis
Big review on CBD and RA.
Key inflammatory agents tied to RA were directly affected by PEA:
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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644337/
Fibroblasts (too much activity) are directly tied to cartilage destruction in RA.
The researchers found this was due to TRPV1 activity primarily.
Inflammation is one piece but what about pain?
A study compared PEA to ibuprofen for TMJ pain. Triple blind, placebo study and the results:
Pain decrease after two weeks was significantly higher in Group A than Group B
https://www.drsvanderveen.nl/Palmitoylethanolamide/
They were also able to open their mouth wider.
Group A was PEA by the way.
Dosage was 900 mg PEA daily for 7 days and then 300 mg PEA daily for another 7 days
Let's turn to the brain now.
PEA and dementia
Check out CBD and dementia to really get into how this is a disease of immune response.
Let's look at different aspects of PEA and dementia.
First, the little immune assassins themselves, Amyloid beta particles:
In their pioneering work, the authors evaluated the ability of PEA (10−7 M) to mitigate Aβ (Aβ1–42; 1 μg/ml)-induced astrogliosis in primary cultures of rat astrocytes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667638/
This basically says that PEA downregulated AB activity and production.
Secondly, PEA was able to calm the inflammatory storm that accompanies dementia (likely causes it).
PEA was able to blunt Aβ-induced neuroinflammation by significantly diminishing either the altered expression of pro-inflammatory molecules
We'll avoid the alphabet soup of inflammatory agents that followed but you can check them out on that review (a good one, by the way).
Interestingly, the researchers were able to block these effects by blockin PPAR activity.
We have a suspect!
A fascinating study injected AB particles into the mice of brains which subsequently lead to learning and memory issues.
PEA's effect AFTER injection:
PEA reduced (10 mg/kg) or prevented (30 mg/kg) behavioral impairments induced by Ab25–35 injection.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667638/
When PPAR was blocked, the positive effects of PEA went away.
We're still waiting for clinical trials to investigate further. We only have one anecdotal study on a male with cognitive decline:
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).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667638/
"Almost normal".
We look forward to the trials which unfortunately, will likely come from Europe and not the US.
What about diabetes?
PEA and diabetes
We have studies on PEA for the "symptoms" of diabetes including…
Neuropathy:
Statistical analysis (ANOVA) indicated a highly significant reduction in pain severity (P < 0.0001) and related symptoms (P < 0.0001)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996286/
Retina protection:
PEA has been evaluated for glaucoma, diabetic retinopathy, and uveitis, pathological states based on chronic inflammation, respiratory disorders, and various pain syndromes in a number of clinical trials since the 70s of 20th century.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667059/
What about protection of the actual islet cells themselves? The root of the illness?
Our findings demonstrated that PEA relieves mechanical allodynia, counteracts nerve growth factor deficit, improves insulin level, preserves Langerhans islet morphology reducing the development of insulitis in diabetic mice.
https://pubmed.ncbi.nlm.nih.gov/25921749/
There's lot in there so let's unpack.
Allodynia is physical pain. Nerve growth factor is key to neuropathy.
Insulin levels get better? That's different than just tamping down pain.
Islet cell improvement? That's the core driver of the disease.
This requires a entire deeper dive than we're doing here.
Let's turn to the real star of PEA research. Pain.
PEA and pain
We already saw the comparison of PEA to Ibuprofen for TMJ pain and mobility.
Let's dig deeper.
First, anandamide is a natural pain suppressor:
In particular, the body releases an endogenous cannabinoid called anandamide, a name which is derived from the Sanskrit word meaning "internal bliss." When the body senses pain, anandamide binds to CB-1 and nullifies pain by blocking the signaling.
https://www.scripps.edu/newsandviews/e_20010813/
FAAH quickly breaks this down however so the effects are short term. See why we were interested in FAAH blockers?
Remember that the woman who can't feel pain at all has a genetic variant on the FAAH gene where she makes almost no FAAH.
She could be on fire and not feel it.
Obviously, we don't want to go there but tipping the advantage away from FAAH would go a long way to reducing pain across the body and that's one of the key targets for CRPSR gene editing in the works.
It will probably be about 5 years till that's available.
Let's look at studies.
A large analysis of many pain studies (10 studies with 786 subjects) with PEA found the following:
PEA was associated with significantly greater pain reduction compared to inactive control conditions (WMD = 2.03, 95% CI: 1.19 - 2.87, z = 4.75, P < 0.001).
https://pubmed.ncbi.nlm.nih.gov/28727699/
As for side effects and safety, fewer people dropped out of the PEA treatment than the group that had no treatment at all (placebo)!
The PPAR pathway appears key to this effect on pain:
This receptor is a regulator of gene networks which control pain and inflammation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500919/
There's also the effect on neuropathic pain and pain derived from inflammation (such as arthritis).
For the neuropathic side:
Indeed, in these cases, PEA – alone or added to standard analgesics – was able to reduce pain by 40%–80% compared to baseline scores on the NRS.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500919/
Inflammatory pain was induced in rats by injecting an acid into the joint and PEA had the following effects:
Mechanical hyperalgesia caused by chronic inflammation was significantly reduced by both intraperitoneal and intra-articular injections of PEA.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645590/
That's a great transition to the next section.
PEA and inflammation and allergic response
We've spent quite some time above on a range of pathways and illnesses.
They all loosely reverberate around inflammation.
- Mental illness
- Pain
- Autoimmune
Chronic imbalances or acute damage and injuries can cause inflammatory states that don't resolve.
With time, this damages tissues and the results are the issues above.
PEA, at its core, is a natural anti-inflammatory. Its entire family including anandamide all operate this way.
Let's zero into aspects of this and maybe wax a bit on why this pathway is the key to all our modern diseases.
First, understand that we have general "settings" for our immune response.
The immune system controls inflammation.
A simple example of PEA's effects can be seen by older mice injected with e coli:
PEA pre-treatment decreases the release of pro-inflammatory markers in the spleen of infected aged mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250830/
Okay...but we need cytokines for infection, right?
Look at the bigger take aways from the PEA treatment:
PEA significantly diminishes bacterial load in the bloodstream, spleen, and liver and tends to reduce bacterial concentrations in the brain
And most importantly:
Prophylactic PEA delays onset of clinical symptoms and prolongs survival in old mice
Goodness. Reduce bacteria load. Longer life. Reduction in inflammation.
Let's turn our attention to allergic reactions...part of the immune response.
Mast cells are little sacs stuffed with histamine that gets flooded when the body's trying to get something out.
One of PEA's key effects is to calm mast cell release.
PEA is produced and hydrolyzed by microglia, it downmodulates mast cell activation,
https://pubmed.ncbi.nlm.nih.gov/23813098/
Check out our histamine toolkit:
The bigger issue with modern diseases is "resolving" inflammation...calming the response after it is no longer needed.
PEA and its cohorts are appearing to be the primary tool there:
PEA may play a role in maintaining cellular homeostasis when faced with external stressors provoking, for example, inflammation.
https://pubmed.ncbi.nlm.nih.gov/26055231/
Homeostasis means to bring back to balance.
- Infection occurs
- Immune response rares up to fight it
- Infection is reduced
- Immune response calms down response so as not to do more damage
It's that last step that appears to be missing.
Let's turn to safety and dosage
PEA safety and dosage
PEA naturally exists in our body.
Research is showing strong safety profiles with no drug interactions which is pretty unhead of:
In our case series, combinations with regular analgesics did not lead to drug–drug interactions, and in all seven patients PEA tolerability was excellent.
A very detailed study of safety at super high doses can be found here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5332261/
Doses for the 90‐day rat oral toxicity study were based on results from the preliminary 14‐day study, that is, 250, 500, and 1000 mg/kg bw/day. The No Effect Level (NOEL) in both subchronic studies was the highest dose tested.
1000 mg per kg is about 72,000 mg day for a 160 pound person.
Which brings up dosage.
The studies we looked at above generally ranged from 300 mg daily to 1200 mg daily.
Some would straddle higher amounts for an initial period (7-14 days) at 1200 and then drop to 300 mg.
This is clearly within the safety bounds and we can't find any drug interactions.
Again, PEA works in a system that promotes balance (endocannabinoid system)...not pushing pathways up or down.
That's where we get into safety and side effect problems.
PEA and CBD are powerful tools to support this system and we look forward to the research on both.
Related Research:
Is the endocannabinoid system the key to modern diseases
How to support endocannabinoids naturally
CBD and PEA for histamine and mast cell activation
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.