How Does CBD Boost GABA for Anxiety

by Indigo Naturals April 20, 2019

We're written extensively on how CBD works with Anxiety and one key component keeps popping up over and over.

GABA.

Even though one of the most popular classes of anti-anxiety medications affects the serotonin pathways, GABA really is THE key lever for anxiety.

The other main class of medications, benzodiazepines, hits this lever way too well.

They have an immediate and powerful effect on anxiety but nasty side effects:

Very serious potential for addiction
Impaired thinking
Normalization (need more and more for the same effect)
Only useful for short term use
Anxiety and depression withdrawals

You can learn all about CBD versus Benzos here.

Benzo's not only hammered GABA levels in one direction but they cause a powerful rush of dopamine (our reward neurotransmitter).

That's the addiction side!

Research shows that GABA really is the key target for anxiety so that begs the question…

Can we improve its signaling without the terrible side effects of benzos?

What a great introduction to CBD.

CBD has shown a powerful anti-anxiety (called anxiolytic) effect.

You can read all about it at our comprehensive guide to CBD's benefits for anxiety here.

Let's focus on GABA and how CBD might directly impact its circuit in the brain.

We'll cover these topics:

How GABA works (or doesn't work) for anxiety
Issues that can affect GABA levels with anxiety
How CBD affects GABA levels for anxiety
What type of CBD to use to boost GABA for anxiety
How much CBD to boost GABA for anxiety

Let's get started.

How GABA works (or doesn't work) for anxiety

GABA is a powerful neurotransmitter in the brain.

In fact, GABA receptors are the most common type in our brains. It's a key messenger in our brain.

It's short for Gamma Butyric Acid (thank goodness!)

It's the primary inhibitory chemical in our nervous system.

"Inhibitory" just means that it slows down activity between and within neurons in our brain.

It essentially blocks activity.

Let's think of it as the "brake pedal" of our brain function.

In the brain or body, if there's a brake pedal, there must be a gas pedal!

Hello Glutamate!

Glutamate is our brain's primary excitatory neurotransmitter.

Interestingly enough, GABA is made from glutamate when its levels get too high.

These two chemicals are in a tug-of-war which, in a healthy brain, should find balance more times than not.

In tandem with the excitatory neurotransmitter glutamate, GABA modulates the inhibitory-excitatory balance necessary for proper brain function in mature brains

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231020/

There are times we need more GABA (sleep for example) and times where we need more Glutamate (final exams).

The issue is when one is chronically excessive.

Too much Glutamate and not enough GABA is implicated in mania, ADD, autism, OCD, and….anxiety.

GABA is primarily synthesized via the GAD gene.

Vitamin B6, Magnesium, and Melatonin are positive "upregulators" of GABA production via the GAD gene.

GABA has many other important roles outside of just being inhibitory:

GABA drives production of brain immune responders called oligodendrocytes
GABA drives the production of myelin which protects nerves throughout the brain
GABA is neuroprotective under stress and inflammation
GABA interacts with progesterone for stress response and anti-anxiety effects (hint hint ladies!)
GABA increases levels of human growth hormone

In terms of anxiety (our focus here), the relationship is very clear:

The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303399/

If you read our summary of CBD's benefits for anxiety, you'll see that the Amygdala (our seat of the fear and emotional response) is central to what's going on.

Most importantly, we know that benzos are extremely powerful in reducing anxiety and their activity is directly dependent on the GABA receptor.

Benzodiazepines (BZs) produce most, if not all, of their pharmacological actions by specifically enhancing the effects of endogenous and exogenous GABA that are mediated by GABAA receptors.

https://www.ncbi.nlm.nih.gov/pubmed/6147796

So GABA is where it's at in terms of the IMMEDIATE lever of anxiety.

A few interesting items on GABA levels:

Meditation has been shown to increase its levels
A single yoga session can boost GABA up to 27%
Specific types of gut bacteria can synthesize GABA

Let's look at one more level up before diving into CBD's effect on GABA.

The endocannabinoid system!

The endocannabinoid system and GABA for anxiety

We all have this system.

By "all", we mean all living animals down to the sea urchin.

It's been around about 600 million years now.

Researchers have really only started to explore how it works for the last 20 years.

GABA was discovered back in the '50s so this tells you how new the endocannabinoid system is.

Research is showing that it's tasked with balancing other key systems in the body:

Nervous system including neurotransmitters like GABA and Glutamate
Endocrine system including hormones like progesterone, estrogen, and cortisol
Immune system including inflammatory response and histamine

The intersection of these three systems accounts for much of what ails us.

Let's zoom in on the neurotransmitters since we're talking about GABA specifically.

Is the endocannabinoid system even involved with GABA production?

The answer is yes.

2-AG (the most prominent endocannabinoid in the brain) is directly involved:

The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABAA receptors at low concentrations of GABA

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207709/

This speaks to the endocannabinoid system for "balance".

Notice how this happens at "low concentrations".

It's a back-up support system to GABA.

Too little GABA triggers 2-AG to boost its levels.

Think of 2-AG as back-up power for GABA production when it gets too low.

Later in that same article, it was shown that 2-AG boosted the effects of diazepam (common benzo). Maybe you know it as Valium.

The benzos are known to primarily act by boosting GABA levels.

That's 2-AG.

What about Anandamide, the 2nd most prominent endocannabinoid in the brain?

We have new insight on this which is extraordinary.

There's a new study which shows that a woman who does not feel pain and anxiety has a specific mutation which causes her situation.

The mutation in question was for FAAH.

Guess what FAAH does….

It breaks down Anandamide.

In Jo Cameron's situation, her FAAH isn't clearing out Anandamide and she doesn't feel pain or anxiety.

FAAH is an endocannabinoid. Anandamide is an endocannabinoid.

Skew the levels of each and you have no anxiety. Or pain!

There's a full review of the (fascinating) connection between CBD and the woman who can't feel pain or anxiety:

https://indigonaturals.net/blogs/news/the-amazing-connections-between-cbd-and-the-woman-who-never-felt-pain-or-anxiety

Those are just the levels of endocannabinoids and GABA.

Other factors can affect GABA levels which are influenced by endocannabinoids.

For one, stress has been shown to eat up GABA in the brain:

Stress and fl-Carbolines Decrease the Density of Low-Affinity GABA Binding Sites

Research here

Psychological stress has also displayed a powerful effect to reduce levels of GABA in important areas of the brain for anxiety:

Prefrontal GABA decreased by approximately 18% in the threat-of-shock condition relative to the safe condition.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107037/

This may partially be due to the inflammatory response in the body on the levels of GABA.

GABA has been shown to calm immune response, and equally, inflammation can reduce GABA levels.

Cytokines and glial cells are the main weapons in our inflammatory response:

Inflammatory cytokines are known to modulate GABAA receptor-mediated responses and glial overexpression of certain cytokines lead to spontaneous seizures and decrease in GABAergic cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231020/

You can learn all about CBD, inflammation, and anxiety here.

Let's finally jump into CBD's effect on GABA.

How CBD affects GABA levels for anxiety

You can learn all about CBD and anxiety directly here or CBD and general anxiety disorder here.

Let's speak specifically about CBD and GABA levels here since we've established the direct effect it has on anxiety.

We'll start with the endocannabinoids above which affect GABA levels.

2-AG is a strong determinant.

Both CBD and 2-AG were shown to increase the levels of GABA production:

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

https://www.ncbi.nlm.nih.gov/pubmed/28249817

Interestingly, it didn't have this effect through the benzodiazepine receptors on the GABA neuron.

Based on the information above for anxiety:

We want to boost anandamide
We want to boost 2-AG
We want block FAAH

These are all anti-anxiety moves involving the GABA pathway.

So...what does research show for CBD and drivers of GABA for anxiety?

It was found that CBD inhibits both AEA hydrolysis by FAAH-containing membrane preparations (Watanabe et al., 1996), and AEA uptake by RBL

This basically means that CBD blocks the FAAH breaking down of anandamide!

That's two of the three above!

In fact, CBD was the only cannabinoid to block FAAH:

CBD was the only compound to inhibit FAAH

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165957/

The net effect of this on GABA…

Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant

This was a study focusing on Autism (the ASD group).

Interestingly, CBD increased GABA across different areas but actually decreased it in people with autism, especially in the prefrontal cortex.

This may speak to a different balancing required for people with autism (not enough activity in the prefrontal cortex, therefore less boost to GABA which is inhibitory).

Learn all about CBD and autism here.

For the control group, a net increase in GABA signaling across brain regions.

https://www.ncbi.nlm.nih.gov/pubmed/30758329

Another study on mice showed a similar anti-anxiety effect from CBD and diazepam (benzo):

mice treated with cannabidiol and nabilone spent a greater amount of time in the open arm of the maze, an effect similar to that produced by diazepam, the reference anxiolytic agent.

https://www.ncbi.nlm.nih.gov/pubmed/2162942/

Finally, the anxiolytic effects of systemic CBD partially depended on GABAA receptor activation in the EPM model

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604171/

We discussed how stress eats up GABA in the brain.

Chronic stress and inflammation are being tied directly to anxiety.

The effects of stress on GABA levels are well documented. A few quick takeaways:

Chronic stress impairs GABAergic control of the amygdala through suppressing the tonic GABAA receptor currents.

https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=24758222

This just means that chronic stress interferes with GABA signaling in the key area for anxiety...the Amygdala.

Interestingly, when they then introduced an anti-inflammatory, the GABA production returned after the stress:

Wang GY demonstrated that chronic or acute administration of dexamethasone (DEX) upregulates GABA release and GABAergic neuronal spiking in the amygdala

https://www.frontiersin.org/articles/10.3389/fnins.2018.00562/full

So why does this matter for CBD?

CBD is a powerful anti-inflammatory and most importantly, is a powerful ally against neuroinflammation:

Cannabidiol (CBD) has emerged as a promising strategy to treat the inflammation that results from microglial hyperactivation [78], with no psychotropic side effects. Moreover, CBD has been shown to attenuate oxidative and nitrosative stress in several human disease models

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386505/

The microglia note above speaks to CBD's ability to calm the inflammatory and immune response in the brain as well.

This is just a smattering of dozens of studies regarding GABA/Glutamate balancing and CBD.

You get more information here:

CBD, histamines, and anxiety
CBD and anxiety
CBD, anxiety, and inflammation
Compare CBD and antianxiety medications (such as benzos which increase GABA)
CBD versus benzos for GABA and anxiety

There's an important concern when picking the right CBD for anxiety and GABA levels

Let's look at that now.

What type of CBD to use for boosting GABA with anxiety

This is very important.

Remember that GABA is inhibitory (the brake) and Glutamate is excitatory (the gas pedal) in the brain.

Too little brake in the emotional circuit can cause anxiety.

It also helps if we take our foot off the gas pedal (glutamate, stress, and….histamine!)

Histamine is a powerful excitatory neurotransmitter in the brain.

Most of us know histamine from its induced allergic response.

In the body and brain, it is very excitatory and part of our immune/inflammatory response:

These results suggest that in rats acute stress increases colonic mast cell histamine content. This effect is mediated by the release in cascade in the brain first of IL-1 and secondly of CRF.

https://www.ncbi.nlm.nih.gov/pubmed/14555722

IL-1 is a cytokine (inflammatory agent) directly tied to anxiety above.

CRF is even more interesting. You can learn all about it at our CBD for Social Anxiety for CBD for corticotropin-releasing factor for anxiety

It is a circuit between the brain and body for stress response and...anxiety!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2343625/

That's why allergies and histamine release can feel like anxiety!

That's also why antihistamines can reduce anxiety (see a comparison of anti-anxiety meds and CBD) and a known side effect is drowsiness (similar to benzos).

Most importantly for this article is that an increase of histamine will eat up GABA.

The two represent another push-pull relationship that governs our wake/sleep cycles and other key balancing acts.

Here's the deal...everyone is pushing "full-spectrum" or "broad spectrum" CBD oil out there.

Everyone!

The biggest brands.

Full-spectrum just means CBD is added back to hemp oil or has other cannabinoids.

All that plant material is likely to trigger histamine responses for 40-60% of the population.

On top of this, they may have THC up to .3% which can actually cause anxiety.

Check out why in our CBD versus THC for anxiety article for lots of research.

On both accounts, that's going the wrong way.

Especially since the dozens of NIH studies, we have listed are based on CBD by itself!

CBD Isolate.

We literally crafted IndigoNaturals CBD based on this research and for anxiety (see our story here).

Learn why CBD Isolate is best for anxiety here.

Now...how much CBD for anxiety and GABA level support.

How much CBD to boost GABA for anxiety

Here's where it gets interesting.

Studies actually show that the anti-anxiety effects of CBD are on a bell curve.

This just means that they increase as we go up in dosage until a certain point where they start to level out.

The research is showing that at a higher level, CBD may trigger other systems (PPAR, etc).

A study looked at anxiety relief for humans and found that 300 mg of CBD presented a significant antianxiety effect.

https://www.ncbi.nlm.nih.gov/pubmed/30328956

This is especially true for the effect of CBD on long term anxiety.

The secret star there is called BDNF...our brain's fertilizer!

The effect was much less at 150 mg or 600 mg.

Now, it makes sense to start low and test your effects.

We see lots of clients who get relief at 40-50mg up to 100 mg.

It really depends on your particular situation.

We have an entire article on how much CBD to take for anxiety here.

Anxiety is a great test since we can tell right away when we're getting relief.

Let us know what works for you!