CBD, GPR55, and Anxiety Review

CBD and GPR55 for anxiety

Okay...we're in danger of naming robots in Star Wars here.




Almost no one in the general public has heard of this molecule in the brain.


Compare that with how many people have heard of CBD recently.


What's most curious is that CBD has a powerful effect on the GPR55 receptor.


In fact, when they looked at "affinity" which is a measure for the strength of attraction between different "endocannabinoid" receptors, CBD is downright in love with GPR:


CBD affinity for different receptors: 

  • CB1 receptor - under 4.5 pIC50
  • CB2 receptor - under 4.5 pIC50
  • GPR55 receptor - 6.3 pIC50


pIC50 is a measurement of this "attraction" or ability to fit into a receptor.



They only discovered the GPR55 receptor in 1999 but interesting effects are turning up including anxiety.


We're going to take a deep dive into what is known for GPR55 and how it applies to anxiety.


Stay with us...the results are fascinating even if the name is really bad.


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We'll cover these topics:

  • What is GPR55
  • How does GPR55 affect anxiety
  • The endocannabinoid system and GPR55
  • Can CBD help with GPR pathway for anxiety
  • How much CBD to take for GPR55 anxiety effect
  • What's the best CBD for GPR55 anxiety results


Okay, R2D2, let's get started.

What is GPR55

Researchers are still trying to answer that very question.


There's a discussion of calling it the third endocannabinoid receptor (after CB1 and CB2).


It shares similarities but also has very different reactions in the body and brain.


Where chemicals that block CB1 activity seem to increase GPR55 activity.


The traditional CB1 and CB2 receptors appear to be "brakes" on neurotransmitter activity.


Think of a signal (neurotransmitter like serotonin or glutamate" going from one neuron to another.


CB receptors are a way for the receiving neuron to say, "Hey, slow it down...we're all good here" (especially for CBD).


GPR55 doesn't appear to work this way and its effect is more "excitatory".


"Keep it coming….more please!".


A quick note...calcium is the currency of the brain.


If you want to increase activity in a specific neuron, you let more calcium in.


Potassium is the anti-currency...like debt!


GPR55 has been shown to increase calcium:

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current



In this way, it may act as a facilitator (or magnifier) other actors including CBD and THC.


So what do we know about its effect in the body (still learning by the way).


First, there are know effects in the body: 

vasodilatation endothelium-dependent [8], cellular proliferation and migration [12], bone dynamics [13], energy balance [14], gastrointestinal processes [15], inflammation and pain [16], among others.  



We love the "among others".  That's pretty noncommittal.


What about the brain and nervous system?


recent studies suggest that GPR55 could be modulating procedural memory [17], motor coordination [18], anxiety and hippocampal release of glutamate [19]. 


That last piece is what we're curious about (and will get in to).


Right off the bat, it sure does feel like GPR55 is part of the endocannabinoid system from having such widespread effects.


Making new bone and memory??


It points to it having a systemic effect like the endocannabinoid system.


There's a great deal of interest in GPR55 for cancer, inflammation, epilepsy, pain, and more.


Let's zero in on anxiety specifically since we're already in pretty new territory. 

How does GPR55 affect anxiety 

Let's look at what we do know from research.


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.



Conversely, when they blocked GPR55, the result was anxiety.


The next experiment is pretty interesting.


They raised rates in two groups: 

  • Normal rearing
  • Maternal deprivation (which is a proxy for early life stress)


We've covered the effects of early life stress on anxiety in detail at our CBD and stress for anxiety or CBD and long term anxiety.


There are known changes in brain structure from early life stress (even in the womb and from past generations!).


See our article on CBD and brain repair and CBD and neurotrophins like BDNF 


They then studied the results in gene expression across different brain areas including GPR55.


Here's where it gets interesting: 

In males, MD increased the genetic expression of all the genes studied within the frontal cortex, whereas in females such an increase was observed only in the hippocampus.  



MD is short for maternal deprivation.


Essentially, there's was a distinct gender difference. 


Men had more GPR55 activity in their prefrontal cortex (the part of anxiety circuit that puts the brake on the emotional response) and women had higher activity in the hippocampus (the "switch" for anxiety).


Remember that anxiety hits women at a much higher clip than men. 

And in terms of Autism, another study found that GPR55 stimulation helped with "social deficits"...basically social skills in people with autism (in addition to seizures): 



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Again, this is early days but clearly, GPR55 has far-reaching effects we need to figure out.


We spent hours studying how CBD and neuroinflammation conspire with anxiety here.


The microglia, our brain's immune defender, figured prominently when it's overactive.


Researchers found that GPR55 calms this microglia response and is neuroprotective after brain lesions: 

The G protein-coupled receptor 55 ligand l-α-lysophosphatidylinositol exerts microglia-dependent neuroprotection after excitotoxic lesion. 



Check out the CBD, brain inflammation, and anxiety article...it's pretty fascinating (and you may have something else you can blame on your mother!).


Also, the CBD and probiotics for anxiety article (immune starts in the gut!).


Back to GPR55 for anxiety.


Another study applied different kinds of stressors to mice: 

  • Restraint (just like it sounds)
  • Forced swimming


They then studied anxiety-like responses in different tests.


We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. 



O-1602 (again, not a robot) increases GPR55 activity.


When they blocked the GPR55 receptor activity, the anti-anxiety effect went away!


We used lentiviral shRNA to selectively knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O-1602. 


The best part of this experiment is that it actually drilled down into how this effect has occurred.


Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice




GluA1 and GluN2A are robots!


Just kidding, they're genes for glutamate.


See our article on glutamate and mental health.


If you've read our CBD and anxiety or CBD and general anxiety disorder, you'll be familiar with glutamate.


It's the "Gas pedal" of our brain and it's directly opposed to GABA.


GABA is the primary (maybe only) lever that benzos push for anxiety.


Check out CBD versus benzos for anxiety here.


Net net is this...GPR55 takes the foot off the gas so we don't burn out our brake.


This has a direct effect on anxiety, sleep issues, and more.


Now, we're getting somewhere!


And yes, we humans both have GluA1 and GluN2A genes which do the same thing.


Okay...to summarize.


We have two interesting pathways (that we know about) for GPR55 and anxiety: 

  • Neuroinflammation via microglia activation 
  • Glutamate - GABA balance in the brain
  • Brain area connectivity in the anxiety circuit (prefrontal cortex and hippocampus).


See our artilce on can CBD stimulate the hippocampus neurogenesis for anxiety. 


So...what about CBD and GPR55?

Can CBD help with GPR pathway for anxiety 

We've gone through the effects of CBD on anxiety in-depth.


You can start at our CBD benefits for anxiety and then go from there.


New research is pointing to this GPR55 pathways as part of the equation for its effects.


First, does CBD even affect GPR55?: 

Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor also showed activity at GPR55.  



As we mentioned in the beginning, CBD actually has a more potent effect on GPR55 than on the traditional CB1 and CB2 receptors everyone is touting.


Check out the graph here: 



Let's focus down on the brain for anxiety.


What does CBD do there?


Like all good endocannabinoids, it depends on where you are in the brain and the current state.


Remember how women with childhood stress had more activation in the hippocampus?


Here, CBD (1 μM) suppressed the physiological activation of the GPR55 receptors, which restricted excitatory output from pyramidal cells.  



So, in the hippocampus, CBD appears to slow down GPR55 activity.


They originally studied this specific effect for epilepsy (think of too much gas pedal...glutamate): 

CBD shows a good affinity for GPR55 and the antagonistic effects reported would be consistent with an attenuation of synaptic transmission which could be antiepileptic.  



So there, we have too much activity (glutamate) and CBD actually reduced GPR55 which is part of its antiepileptic effect.


Remember the connection: 

Activation of GPR55 by a variety of ligands, including lysophosphatidylinositol, can release calcium from intracellular stores [201] and can boost the release of neurotransmitters, such as glutamate at synapses 


That's where eGPR55 can boost activity in certain parts of the brain. 


We're still in the early days of understanding this entire class of proteins such as GPR55 (there are 100's of them).


Clearly, there's a connection between CBD's effects and GPR55 so we'll keep an eye out as new studies tease out the effects.


Stay tuned!


Check out:


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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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