How to Treat Endocannabinoid Deficiency

CBD and PEA for Endocannabinoid Deficiency


We covered why endocannabinoid deficiency may very well be the crux of modern illnesses in great detail (8000+ words).

When you look at how it dovetails with autoimmune, mental health, and more, the signs become pretty apparent.

Then combine how the role of the endocannabinoid system is specifically under duress from our modern living and the pieces start to fall into place.

We'll leave that review for the dozens of research on both accounts.

Here, we want to focus on how to support the endocannabinoid system.

There are two stars here with many supporting players.

CBD and PEA (palmitoylethanolamide) are the marquee players.


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We'll also look at how Vitamin D, Omega fats, and other players are needed for this entire system to function.

Here are the topics we'll cover:

  • A quick intro to the endocannabinoid system 
  • Why the ECS is under duress 
  • CBD to treat endocannabinoid deficiency
  • PEA to treat endocannabinoid deficiency
  • Other keys to treating endocannabinoid deficiency pathways
  • How much CBD and PEA for endocannabinoid deficiency
  • What's the best CBD and PEA for endocannabinoid deficiency

Let's get started!

A quick intro to the endocannabinoid system 

Before we jump into what goes wrong, let's first get a lay of the land.

You have two primary endocannabinoids:

  • Anandamide
  • 2AG

They do the heavy lifting in this system.

The system itself dates back about 600 million years and all vertebrates have one.

Clearly, Mother Nature stumbled on something important!

Indeed it is...the ECS is generally tasked with bringing balance to other key systems:

  • Nervous system - neurotransmitters and more
  • Endocrine system - hormones
  • Immune system - inflammation and cellular birth/death cycles

These systems are consistently in flux...moving in one direction or another.

For example, if we get a cut, the immune system rushes in with inflammatory responses.

This involves fighting bacteria but also repairing the area...literally building new tissue!

When it's all repaired, the system then pulls back and calms down.

It resolves!

This ebb and flow is partially under the control of the ECS.

What happens when the immune system is under constant attack (see CBD and leaky gut barrier) or actually trained to attack our own cells?

A great deal of bad.  This is the root of autoimmune and it's increasingly the biggest health issue we face.

Just pay attention (if you dare) to an ad on TV or in a magazine.

There's a good chance it's autoimmune (including diabetes and dementia).

The technical term is "homeostasis" which basically means to bring a system or pathway back to balance.

That's the role of the ECS and anandamide and 2AG are primary actors.

Anandamide, named after the Hindu goddess of bliss, Anand is a powerful player in calming response.

2AG is the other major player with a different set of tasks in the system.

You also have a family of supporting casts including OEA, PEA, and others.

They are "amides" that can directly boost anandamide and 2AG.

Anandamide and 2AG both can stimulate our endocannabinoid receptors (CB1, CB2) while the supporting cast interacts with other receptors (TRPV, PPAR, etc).

Here's the interesting piece we can use to our advantage.

There's a system for breaking down these chemicals constantly.

FAAH is a big one for anandamide and this is the key to how substances like CBD and PEA work.

We were on a search for a FAAH inhibitor (which is how we found PEA).


Just read about the woman who can't feel pain or anxiety (because she doesn't make FAAH) to understand.

What if we could reduce pain, anxiety, depression, and more!

That's the opioid epidemic (CBD versus Tylenol).  The anxiety explosion (see CBD versus benzos).  The dirge of depression (see CBD and depression or CBD versus SSRIs).

In fact, just look at our CBD and mental health to really understand the potential.

So...a quick intro of the inner workings before we move on.

We're going to focus on anandamide since it appears to be the backup lever (tonic) while 2AG is more consistent (phasic).

Think of 2AG as the ocean water level while anandamide is the waves that can form intermittently (or as needed by stress).

Anandamide is constantly made as needed and almost immediately broken down.

That's the big difference with THC.

THC mimics anandamide but it stays around much longer and at much higher concentrations.

This is why you have side effects, psychoactive effects, and with longer-term use...tolerance.

The body/brain will actually start to downregulate endocannabinoid function after prolonged exposure to THC.

It makes endocannabinoid deficiency worse with time!

Check out CBD versus THC or CBD for tolerance to understand more.

We needed to address that because there's a misconception that THC is great for ECS deficiency.

Only if you want to reduce the number and sensitivity of CB1 receptors where anandamide and 2AG operate!

Back to FAAH.  This is our most powerful lever to press.

If we can reduce the available FAAH (perhaps by making it busy breaking down other stuff), we're left with more anandamide.

THAT is the ticket we want to punch for endocannabinoid deficiency as well as reducing the load on the system to begin with.  

More on that below.

Before we go there, a quick look at why the ECS might be deficient to begin with.

Why the ECS is under duress 

If the ECS is tasked with balancing key systems, then the question begs…

What is throwing things out of balance?

Take your pick...the number is in the 100's of 1000's.

That's chemicals we come in contact with which are not vetted for safety (in the US anyway) until proven guilty.

Glyphosate (looked at research at our CBD and gut barrier or CBD and endocannabinoid deficiency).

BPA.  The can lining.  When we did a deep dive on oxytocin (fascinating hormone for mental health), exposure to mice would decrease oxytocin for four generations!  

Hello, autism.

PFOA - the forever chemical is everyone's blood right now.  Even blood cord samples from newborns.

Sunblock, cosmetics, and preservatives filled with hormone disrupters.

Again...we could go on and on.

Researchers measured polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), perfluorinated compounds (PFCs), mercury and lead, among other chemicals, in the women and in their babies’ umbilical cord blood.


Of the 287 chemicals we detected in umbilical cord blood, we know that 180 cause cancer in humans or animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

That's quite a bit for the ECS to keep up with.

We focused on glyphosate as a representative of the pesticide class since so much of our modern disease profile originals in the gut.

Gut barrier breakdown is at the root of autoimmune, inflammatory diseases, dementia, gut issues, mental health issues, and more.

Check out the endocannabinoid deficiency review but it's clear...our system tasked with righting the boat is quickly taking on water (and pesticides).

Add to that:

  • Constant stress (ECS is primarily a stress response system)
  • Low Vitamin D (wait till you see its effect below)
  • Poor sleep and diet
  • Hormone deficiency (both natural and due to hormone disrupters)

It's a recipe for disaster.  Enough doom and gloom.

Let's look at we can do about it!

The first thing to do is….stop the bleeding.

How to reduce the load on the endocannabinoid system

Most of our systems in the body are finite.  There's only so much in a given pathway and then it has to recover.

For example, if you stare at a red light for a few minutes and look away, you probably won't be able to see red for a while.

You exhausted the cones specific to red light detection.

ECS is the same.

It's incredibly important to reduce the load on this system in addition to supporting it.


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To that effect:

  • Reduce intake of artificial sugars, preservatives, colors, pesticides
  • Make sure to get good fats (Omega 3s and 6s) - the brain runs on fat and the ECS players are literally made out of it!
  • Exercise, meditate (mindful), and sleep well
  • Watch out for medications which are known to deplete pathways (see Drug Muggers book)
  • Support basic nutrients needed for ECS function and stress response

Let's touch base on the last one because stress eats up endocannabinoids (and hormones and serotonin!)

There are key nutrients that are essential for stress response:

  • Magnesium glycinate - mag calms glutamate activity which is the gas pedal of the nervous system
  • Glycine - supporting role to GABA (our brake pedal) great before bed
  • Tryptophan - supports Serotonin, our primary stress responders (see CBD and serotonin)
  • Berberine - supports gut barrier and inflammation
  • NAC - a powerful supporter of our detox and antioxidant system (see CBD and oxidative stress)
  • Vitamin D - essential player in so many pathways - get tested but start here!
  • Progesterone - for women, this is THE calming hormone - learn more since it drops by 50% at age 40


Let's finally get to the key players that directly affect endocannabinoid deficiency itself.

CBD to treat endocannabinoid deficiency

Some of the big studies on CBD with very serious issues noted that the effect was primarily via the anandamide and FAAH channel.

CBD doesn't directly boost CB1 activity, which is avoids tolerance...the enemy of support (such as with THC).

CBD works as a feedback mechanism with the ECS.

We see this prominently with key neurotransmitters such as GABA, serotonin, and more.

Let's focus on anandamide directly.

A big study on CBD and schizophrenia were able to monitor its effect on anandamide directly which is critical to that disease.

The net net:

Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH)

Ah-ha!  It doesn't spike up anandamide or CB1 activity directly.

It blocks the breakdown (FAAH) of anandamide so that it can catch up.

This is why CBD doesn't display side-effect or safety issues up to very high doses.

When you push anandamide activity up in one direction, you reach a different type of imbalance and side effects occur (like with THC).

Serotonin is a perfect example of this.

The side effects of too much serotonin (see CBD and serotonin syndrome) are just as bad (if not worse) than too little serotonin (see CBD versus SSRIs).

Interestingly, the woman who doesn't make any FAAH due to a genetic defect has pretty functional health except for she can't feel pain, anxiety, depression, etc.

This speaks to anandamide's role as being the reinforcements for 2AG when needed.

2AG has a different enzyme that breaks it down (MAGL).

Monoacylglycerol lipase (MAGL) is found presynaptically and is the main enzyme responsible for metabolizing 2-AG, whereas fatty acid amide hydrolase (FAAH) is located post-synaptically and is the main enzyme that mediates anandamide degradation

That makes FAAH our best approach to dealing with endocannabinoid deficiency.

CBD blocks FAAH and this shows up in many issues from anxiety to schizophrenia to autoimmune.

The quest for FAAH inhibitors has been ongoing with Big Pharma but we have one right under the nose with a strong safety profile.

You can learn exactly how CBD works here.

What about PEA?

PEA to treat endocannabinoid deficiency

We stumbled on PEA (palmitoylethanolamide) while researching FAAH inhibitors specifically.

Our goal was to boost anandamide availability in a natural way in order to calm glutamate activity.

Many people who use cannabis chronically speak about "slowing things down".

Anandamide works like a wet blanket on hyperactivation which can lead to repetitive thoughts, rumination, anxiety, OCD, and more.

Glutamate is downright toxic to neurons when excessive (see CBD and glutamate).

PEA is one of the supporting cast for anandamide along with OEA.

In fact, the "A" in PEA is "amide" just like on the end of anandamide.

They're in the same family of chemicals but with a very distinct difference.

Anandamide (and 2AG) directly stimulate CB1 activity in the nervous system.

PEA does not.  It can stimulate downstream receptors like PPAR and TRPV which are tied to inflammation, pain, and more.

A great deal of its benefits comes directly from PPAR (see PEA review).

As for endocannabinoid deficiency, how does it help if it can't work on endocannabinoid receptors?

Guess what breaks down PEA?


Remember how we spoke of pathways getting exhausted?

Essentially, FAAH has to break down anandamide, PEA, OEA, and that family of chemicals.

If it's busy with PEA, there's less firepower for anandamide!

It's a backdoor way to boost anandamide.

In our review of PEA, research shows how PEA supplementation directly boosted levels of anandamide, PEA (of course), and OEA.

Essentially, it's an FAAH exhauster.

The beauty of PEA and CBD is that they have almost no side-effect profile or safety issue.

CBD needs to be taken away from medications and PEA has no known drug interactions.

Otherwise, the safety aspect is fascinating considering the powerful pathways affected (neurotransmitters, immune agents, hormones, etc).

This speaks to the beauty of targeting the endocannabinoid system itself versus one of the components directly (such as benzos for GABA or SSRI's for serotonin, or immune suppressors for autoimmune, etc).

It's why we think endocannabinoid deficiency is going to be the next big thing over the following decade.

Let's turn our attention to a critical piece of the puzzle.


Other keys to treating endocannabinoid deficiency pathways

How much CBD and PEA for endocannabinoid deficiency

We don't have hard research on dosage for CBD in terms of endocannabinoid deficiency but we can look to neurogenesis as a good basis.

Neurogenesis is the process of repairing, re-mapping and building the brain and/or connections.

It's critical to mental health and addiction alike.

Research shows that CBD has a bell-curve effect on neurogenesis with peak levels at 300 mg/daily.

Beyond that amount, neurogenesis starts to go down.

For longer-term use (which endocannabinoid deficiency would require), 300 mg then becomes the top level.

Other studies have looked at higher doses of 600-800mg for more acute issues like public speaking for social anxiety, opioid withdrawal symptoms, etc.

Endocannabinoid deficiency however is a systemic issue that requires repair.

Based on the million+ words and 100's of studies, between 100mg and 300mg would be the ideal range long term (see long term effects of CBD).

As for PEA, the research was generally around 600 - 1200 mg daily.  

We've tried both and you don't feel a difference other than pain reduction perhaps.

PEA is so safe, that 1200 is probably the target at least to start.

What about the type of CBD and PEA for ECS deficiency?

What's the best CBD and PEA for endocannabinoid deficiency

For the CBD, there are basic requirements that must be met:

  • Organically grown in the US at FDA registered farms
  • 3rd party tested
  • CO2 processed
  • No pesticides
  • No solvents
  • No heavy metals
  • No pesticides
  • No bacteria or mold

We test ours twice since the whole family uses it.

Then, there's the question of full-spectrum versus CBD isolate (see the comparison here).

Keep in mind that endocannabinoid deficiency commonly reflects histamine (allergy) issues.

This makes sense...for example, PEA literally shuts down mast cell release of histamine.

40-60% of the population has histamine issues and this goes up as we get older and for women.

We see the difference in the side effect profile between CBD isolate and full-spectrum as do many people in our reviews.

It's actually how we found isolate after having a bad response to many of the biggest brands of full-spectrum CBD.

Then there's the question of cost.

If we're aiming for 300 mg daily, the cost per mg of CBD becomes very important.

We price our 6000 mg bottles (200 mg per dropper) at 2 to 3 cents per mg of CBD before discounts up to 30%.

As for PEA, we've tested 3 different kinds.

This may be due to sublingual (under the tongue) bypassing of the liver.

There are cheaper options versus capsules and we even tried a straight powder form of it.

The powder is less easy to work with but also appears to have a more immediate impact.

The dosage is usually between 400-600 mg with 1200 mg being a higher amount.

The beauty of CBD and PEA is that they don't build tolerance (the body will not push back with long-term use) and the safety profile at 300mg of CBD and 1200 mg of PEA is very strong.

For endocannabinoid deficiency, along with reducing the load (stress stress stress), CBD, and PEA are impressive allies.


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Always work with a doctor or naturopath with any supplement!

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



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