We have over 1 million+ words of research and reviews on CBD and various specific pathways across the body and brain.
This begs the fundamental question…how does CBD really work in the body and brain?
We already did a deep dive on what CBD is here but let's try to explain how it can have such different and profound effects.
Otherwise, it's all just marketing and there's plenty enough of that out there online!
It turns out that CBD has a unique role in a very specific system but that system has tentacles into every other system in the body.
How CBD interacts is the key though and separates it from THC and just about every medication out there.
We'll get into this as well. With each section, we'll mention the health issues that rest heavily on given pathways. It's not a full list but hits the big targets.
Here are the topics we'll cover so you have a great baseline understanding of what's going on below the surface with CBD:
- CBD's feedback mechanism - the star of the show
- CBD and anandamide - the mother pathway of action
- CBD and serotonin - master regulators of all human behavior
- CBD and GABA - the excitability balancing system
- CBD and Glycine - backup brake pedal
- CBD and the Opioid system - both physical and psychological pain
- CBD and immune response (including histamine)
- CBD and downstream pathways
Here's a quick lay of the land but don't worry...we'll break it all down below!
Let's get started!
CBD's feedback mechanism - the star of the show
First, it's a question of tolerance. Not kumbaya but drug tolerance.
The body and brain are very finely tuned (generally) and they don't like outside hammers on important pathways.
For example, taking a benzo will juice up GABA (our brain's brake pedal) much stronger and longer than what naturally occurs.
As a result, with longer use (pretty fast actually…about 2 weeks), the body will actually start to reduce natural GABA levels and even boost the opposing force (glutamate).
This is absolutely the wrong way to go and it's why you have drug withdrawals and tolerance….a need for more and more of the med to get the same result.
Eventually, you're taking massive amounts just not to feel horrible.
The technical term is agonist or antagonist. This means that a substance pushes in one direction on a given pathway. You may know a few of these:
Some also pump up dopamine which drives addiction (a misaligned form of learning - see CBD and addiction).
Even without the dopamine kick, tolerance is brutal.
So…what about CBD?
This may be the single most important thing you have ever learned about CBD.
Technically, it's called an allosteric positive modulator.
Basically, it works like a feedback mechanism and supports pathways…when too low or high!
In fact, across every pathway we study, we see varied responses depending on the state of the system.
One (very powerful) example:
- Healthy cell with low inflammation - CBD will have no effect
- Healthy cell with high inflammation - CBD will reduce inflammation
- Cancerous or virally infected cell - CBD will BOOST inflammation
Read that back over. What is going on in the third example?
Our immune system actually uses inflammation (oxidative stress technically) to kill faulty cells.
CBD will boost this immune response in a cancerous cell and NOT the surrounding healthy cells!
See CBD and cancer for more but think that through.
It's pretty profound and a big reason we've spent 1000's of hours studying and writing about the nuances of CBD.
There are only a few substances we have come across that have this feedback mechanism but the key pathway that CBD works in is what makes it special.
Let's go there now.
CBD and anandamide - the main pathway of action
This is really the heart of CBD's mechanism with huge ripple effects across the rest of the body and brain.
We all have an endocannabinoid system…it dates back about 600 million years and is highly conserved across multicellular life (yes…your dog has one :)
Mother nature seems to like it!
This system is tasked with balancing other systems when they're pushed too hard in one direction or the other.
Technically it's about stress but not exactly the stress you're thinking of (although that stress also applies).
If I'm walking down a street and a car veers in my direction, my body and brain is immediately thrown into a state of fight or flight. Heart races. Blood flows to the muscles. Etc.
Once the car gets back on track and I'm safe, the body needs to get back to balance.
What rights the ship?
Hello, endocannabinoid system!
And it's EVERYWHERE. Brain. Gut. Heart. Reproduction system. Everywhere. Only red blood cells don't have receptors.
The big players are:
- Nervous system - including neurotransmitters
- Endocrine system - hormones; metabolic and steroidal
- Immune system - inflammation and cellular birth/death cycles
You just addressed 90% of all major ailments that afflict the modern world.
So what goes wrong if we have the balancing actor constantly monitoring systems?
If we have abrupt hits (trauma) or chronic weathering away of pathways (stress), the endocannabinoid system eventually loses footing.
Either trauma, infection, or chronic stress are big players here.
Then there's the loss of key support players as we age…steroidal hormones are huge players here.
Progesterone drops by 50% by age 40. Estrogen plummets late 40's. Testosterone drops around 1% every year starting early 20's.
Goodness…these are not just about reproduction as Mother Nature likes to multitask.
You have receptors in everybody for each of these (both sexes).
One example…Estrogen and Testosterone drive serotonin (our feel "right" master regulator) and Progesterone drives GABA (key to calm and sleep) and calms inflammation.
Autoimmune hits women 8:1 versus men and generally during the 40s/50s. Go figure!
We'll dig into some of the powerhouses below but back to CBD.
We have two big players in the endocannabinoids system:
- Anandamide - the "bliss molecule"
Anandamide is our focus here. It's the backup reserve stress buffer when other systems fail.
It's made as needed and quickly destroyed.
Simply put…it's the backup when we're not handling stress in any given pathway well.
In fact, with major mental health issues, anandamide can be elevated as the body is desparately trying to find balance.
CBD's role here is simple…but powerful.
CBD eats up FAAH, the key enzyme that breaks down anandamide. This allows anandamide to hang around longer but at natural levels.
In fact, we did a deep dive on people who can't make FAAH. They can't feel pain, anxiety, depression, etc.
It's very rare since we need to feel pain in order to stay alive (unfortunately) but what about chronic pain?
That's a case of a system (opioid, GABA, serotonin, inflammatory, etc) being outgunned.
THC mimics anandamide but it hangs around too strong and too long. Hence the "high" and other effects of THC.
Because of this, it builds tolerance. The body will actually reduce CB1 receptor (where anandamide plugs in) numbers and activity.
Again…the wrong direction longer term (see THC versus CBD).
CBD doesn't do this…it supports when low at a level the body naturally produces.
It's really a gift down here!
The repercussions of this sleight of hand are profound and widespread.
Let's look at just a few pathways that are most studied.
We'll start with serotonin.
CBD and serotonin - master regulator of all human behavior
This may be our favorite since it's the lens through which you experience and see the world.
It's a master regulator of every aspect of human behavior:
- Brain repair
Goodness…this is THE player for mental health. It's also the reason that SSRIs are handed out like candy now (especially to young people)...
The problem is that SSRIs build tolerance so you're slowly reducing your natural serotonin function.
We did a deep dive on CBD versus SSRIs CBD versus SSRIs since the data on their effectiveness is…well, you can read it.
The tolerance piece alone is a huge red flag.
The biggest secret behind serotonin for mental health is actually a less-known player called BDNF.
BDNF is the brain's fertilizer and when it's blocked, SSRIs lose their effects! (till tolerance kicks up).
We did a deep dive on brain repair here but you want to get to know BDNF.
Even psilocybin's effect partially rests on an explosion of BDNF. More on that here.
The problem with serotonin is that it's very finicky. It needs to be range-bound.
Too much might even be worse (called serotonin syndrome - don't ask!!) than too little and there's no way for a doctor to test your brain levels.
Yes, the endocannabinoid system has management duties over serotonin function, and CBD figures in there as well.
You see lots of words in research like "modulates", "normalizes", etc.
For example, a study looked at CBD's effect after chronic pain exhausted serotonin (serotonin manages our pain thresholds…hint hint fibromyalgia, etc sufferers):
repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
Let's break that down:
- CBD reduced anxiety
- CBD reduced pain
- CBD "Rescued" serotonin function (5HT)
"Rescued" is the most important word there.
Not boosted. Not an agonist. Brought it back to balance.
THIS….is the endocannabinoid system.
The side effects of too much serotonin (check out serotonin syndrome) are bizarre and brutal.
Serotonin controls dopamine (our reward circuit) downstream as well as just about everything in our brain.
CBD's "rescue" effect is the correct move versus agonist that boost it in one direction.
Serotonin is a primary stress response buffer. Anandamide is the backup.
When it's exhausted, you see issues with:
- Gut (serotonin's a big player in the gut)
- Mental health
Again, estrogen and testosterone drive serotonin so get your levels tested and watch out for the "your numbers are fine for your age…here's an SSRI".
That's literally how/why we discovered CBD (that horror story is here).
- CBD and serotonin
- How I weaned off SSRIs
- Tryptophan inflammation and serotonin
- How to support resilience
Let's turn to the most prevalent neurotransmitter in the brain.
CBD and GABA - the excitability balancing system
GABA is the nervous system's "brake" pedal. It's a finely tuned balancing act with glutamate (gas pedal).
Guess what's balancing the two? Yes…the endocannabinoid system.
GABA also happens to be the target of benzos, one of the most prescribed classes of medications despite the brutal tolerance and addiction risks (Xanax has many street names and values).
GABA levels actually cascade with effects:
This trajectory follows the overdose profile for GABA agonists such as barbiturates, alcohol, and benzos (especially with opioids).
GABA has to hold the fort against a range of different opponents:
- Cortisol - stress hormone
- Histamine - excitatory agent in the brain released by the immune system
- Pain - especially nervous system signaling
- Glutamate - hyperactive immune system response just leaks excess glutamate
Trauma and infection can permanently downregulate GABA and upregulate cortisol and immune response!
Even early (in utero…especially the 3rd trimester).
Then throw in a major pandemic and watch GABA gets decimated!
CBD is also a positive allosteric modulator for GABA when exhausted. Feedback support when outgunned!
This speaks to the excitability balance in the brain between GABA and glutamate.
Glutamate makes everything run but it's toxic when running too high. We have powerful systems in place to keep it in check with GABA being the heavy lifter (followed by glycine and glutathione).
When glutamate runs unchecked, you have the usual suspects:
- Depression (longer term, glutamate eats up brain connections and neurons themselves)
- Seizures, migraines, etc
- Pain - glutamate burns out nerve cells so neuropathy, etc results
- Sleep issues - GABA is basis for most sleep meds
Just about every mental health issue has ties to excess glutamate.
The immune system when hyperactivated is a huge source of excess glutamate (see CBD and neuroinflammation).
We don't see the downward cascade with CBD and GABA..even at levels tested up to 1500mg daily.
No overdoses. No sedation. No tolerance. No addiction.
Again, this is the beauty of how it works in the endocannabinoid system. THC very much has these issues longer term as a comparison.
Let's turn to one of those backup's we discussed above.
CBD and Glycine - backup brake pedal
We love glycine. It's really a hidden gem for wellness.
A simple amino acid you can supplement (especially at night for sleep), researchers are slowly teasing out all that it does for longevity and health.
We have a massive review of glycine but let's understand its key role.
Glycine is a backup "brake" pedal to GABA and it primarily operates as a "sink" for excess glutamate.
We mentioned how excess glutamate is incredibly destructive in the brain (like red-lining a car engine) and is tied to every mental health issue out there!
The connection with the immune system is incredibly important since the immune system is the future of mental health (more here).
Glycine has a side hustle which makes it really interesting.
Glycine is the "switch" to start sleep. Yes, that weird pause between being awake and being asleep??
Glycine has its finger on the toggle there.
Check out the following for more info on how CBD also works as a feedback mechanism:
Let's turn to pain.
CBD and the Opioid system - both physical and psychological pain
There are lots of misgivings around this system after the whole opioid epidemic.
Rightfully so. Those drugs drive opioid function in one direction (tolerance) and they spike dopamine (the addiction piece).
If you took away anything from above it's that one-directional pushing and the resulting tolerance is worse than doing nothing.
The opioid system is more than just physical pain though with powerful effects on psychological pain, trauma, and even infection.
In fact, our definition of "resilience" is heavily present in this system. See our review on resilience.
Early trauma/infection can downregulate the opioid system later in life just like GABA and serotonin ain bove.
Why can some people take opioids and never touch them again while others are instantly hooked?
The "priming" of this powerful system may be at play.
Anyway….CBD supports the opioid system…when low! It doesn't just spike it up in one direction the way opioids do.
In fact, there are interesting studies on CBD and opioid withdrawal and addiction.
Erasing the epigenetic markup of early trauma/infection may be the most critical piece.
CBD helps with something called "fear extinction"...literally erasing the programmed patterns in the brain from prior pain, trauma, infection, etc.
This is the heart of getting back to health.
Check out the following:
- CBD and pain
- Medicinal mushrooms and mental health
- Immune system and mental health
- CBD and psilocybin and trauma
- CBD versus NSAIDs
One last stop.
CBD and immune response (including histamine)
The next 10 years of health discovery will probably fall very squarely on the immune system.
We think of the immune function as just being about fighting infection. Mother Nature likes to multitask as we've learned above.
Let's look at the big modern diseases:
- Diabetes and metabolic disorders - strong inflammatory processes at work
- Cancer - immune system governs cell birth/death cycles and removing faulty cells
- Autoimmune - hello! It's literally in the title
- Mental health - neuroinflammation, and gut inflammation signatures are involved with every issue
- Cardiovascular - forget cholesterol. It's inflammation and glucose at play
- Longevity - inflamaging is literally a hallmark of getting older and diseases associated
We've left off pain, histamine/mast cell issues, sleep disruption, and more.
Balancing the immune system is critical to total body/brain health and there are a few tools there.
CBD isolate being first and foremost.
Remember that the endocannabinoid system keeps the immune system in check.
When inflammation rages due to infection, trauma, or injury (including psychological!!), the endocannabinoid system is tasked with "resolving" the inflammatory states.
We have lots of deep dives on this process.
- CBD and gut inflammation (the gut is an inflammatory setting for the brain via the vagus nerve)
- CBD and brain inflammation
- CBD and immune system for mental health
- CBD and autoimmune
- CBD for mast cell and histamine response
Okay…we've hit just some of the highlights. That's not the full story of course.
CBD and downstream pathways
Since the endocannabinoid system governs all other systems, there are specific pathways that are just now being teased out which affect everything from cancer to inflammation.
- PPAR - powerful inflammation pathway
- TRPV - pain and sensitivity pathway
- P53 - powerful receptor tied to cancer
- Dopamine - via serotonin, our "reward" circuit
- Acetylcholine - the "calm and focus" neurotransmitter (key to dementia and ADHD)
- BDNF - nervous system fertilizer - key to repair and replenishment; mental health and addiction superstar
Again, anandamide (the primarily reactive endocannabinoid) is tied into every pathway (even reproduction).
CBD supports anandamide by keeping FAAH at bay. This is the primary basis for how it can have so many effects on the body/brain without upsetting apple carts.
It's a very rare combination of traits and skills!
There's tons of research across a range of issues and pathways. Just search up top (magnifying glass).
We focus on CBD isolate (not full spectrum) since all research is based on CBD by itself and histamine response can disrupt many pathways (sleep, anxiety, inflammation, etc).
Big review on CBD isolate versus full spectrum.
Of course, zero THC since it builds tolerance (wrong direction longer term).
Hopefully, you can see why we've spent so much time on CBD isolate. It's a gift down here!
Also check out reviews on:
Tools that don't build tolerance but support many of these same pathways in different ways.
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.