Shared pathways between CBD and other GABA influencers. CBD and GABA – the Complete Guide on How They Interact – Compared to Benzos, Alcohol, and Gabapentin Cannabinoid receptor activation regulates the release of GABA, the brain’s primary inhibitory neurotransmitter, which plays a crucial role in maintaining neuronal health.
CBD and GABA – Versus Benzos, Alcohol, and Gabapentin
GABA’s one of those things most people don’t think or know much about.
Its introduction is usually abrupt and uncomfortable.
Typically, some type of intense anxiety or sleep issue is what forces a person to learn about GABA.
Sure panic attacks and seizures also share this pathway but anxiety and sleep are the two gorillas in the room (crowded).
It’s also the immediate target for arguably the most prescribed and abused class of medications out there.
Benzodiazepines. Benzos for short.
You may know the brand names (since they’re in rap songs quite a bit these days):
We’ll get into how those work (until they don’t) below but you can check out CBD versus benzos for a fascinating look at the shared pathway.
We’re going to focus on GABA directly here.
With a focus on how CBD interacts with the receptors and pathways.
We’ll look at these topics:
- What is GABA
- The GABA receptors
- Benzos and GABA receptors and function
- Alcohol and GABA receptors and function
- Gabapentin and GABA receptors and function
- CBD and GABA receptors and function
- GABA and anxiety
- GABA and sleep
- Hormones (progesterone) and GABA
- Can CBD rescue GABA receptors after benzos
- GABA supplements and ways to support healthy GABA function
What is GABA
Unlike other more complicated neurotransmitters like serotonin (see How Serotonin Works), GABA is pretty straight forward.
First, GABA is short for gamma-Aminobutyric acid.
GABA is actually produced from its main “opponent” in the nervous system. glutamate.
GABA acts as a “brake” pedal to glutamate’s “gas pedal” both systemically and at the cellular level.
Think of GABA as a wet blanket of activity within and across the brain.
Ideally, we have a tightly orchestrated balance between GABA and Glutamate with excesses when needed.
For example, GABA is critical for sleep while Glutamate is needed for focus and action.
Technically, GABA and Glutamate are amino acids and the primary source for glutamate (the precursor) is found in protein.
Separately, B6 is a critical player in the process of converting glutamate to GABA as it is needed for many transformations involving protein.
In fact, a study found that lower B6 and iron was tied to panic attacks:
We found that both Vit B6 and iron levels were significantly lower in the PA/HVA group than in the volunteer group.
Serotonin also needs this critical piece which is interesting considering its role in anxiety and sleep (see CBD and serotonin).
Interestingly, in the developing brain, GABA is excitatory but switches to inhibitory (blocks activity) as the nervous system matures.
The important piece we want to take away is this:
- Too little GABA function can lead to anxiety, insomnia, seizures, and a host of issues
- Too much GABA can lead to amnesia, drowsiness, issues with cognition
It’s the first one that’s at epidemic levels (i.e. anxiety).
We used the word “function” on purpose because the dance between glutamate and GABA is actually pretty complicated and orchestrated (hormones, proteins, DNA, RNA, transporters, etc.
Unfortunately, it can also be hit like a sledgehammer (benzos) which we’ll get into below.
First, let’s look at receptors as they’ll figure strongly later.
The GABA receptors
We usually don’t get this deep into it but its important to understand what happens via GABA receptors when we have an outside pump (benzos, GABA, Gabapentin, etc).
The contrast with how CBD works is key.
It’s estimated that 40% of the neurons in our nervous system have GABA receptors.
These neurons can govern all sorts of other pathways:
- Serotonin – the “feel right” neurotransmitter with effects on every type of behavior
- Dopamine – the “do that again” neurotransmitters
- Acetylcholine – your focus and learning tool
- Histamine- immune and allergy responder – also key to alertness
Heavy hitters of the brain and everything you feel or do.
Our immune players in the brain and nervous system also are under management from GABA.
This is critical for auto-immune and general brain landscaping.
We have two GABA receptors with many different flavors:
Simply put, these are little chemical channels into the neuron that affect the electric charge to reduce activity.
That’s all they do.
Chloride particles can go into the neuron to slow down its activity.
Glutamate, the opposing force to GABA, works the other way with sodium particles to speed up the activity.
We won’t get too deep in the woods but it’s important to understand how outside chemicals affect GABA receptors.
It’s key to the difference between CBD and many of the chemicals we use to affect GABA function (benzos, barbiturates, Gabapentin, Alcohol, etc).
The key result is tolerance.
Tolerance is when the brain adjusts the other way to an increase in a key neurotransmitter.
In this case, GABA.
Anything that creates withdrawal symptoms can safely be said to create tolerance.
More and more of a substance is needed to create the same effect.
When a person uses a benzo to pump up GABA, the brain panics (a bit) and tries to offset this boost.
After all, balance is the key.
It can do this in a few ways and they mainly deal with the receptors:
- The brain can reduce the sensitivity of GABA receptors
- The brain can reduce the numbers of the GABA receptor
- The brain can rate-limit the pathways (such as the enzyme needed to convert glutamate to GABA)
The net effect of this?
When the medication wears off, the GABA level is even lower than before!
Long term use can send this process into a spiral where withdrawal symptoms are excruciating.
In fact, it’s hard to tell if the anxiety or insomnia is due to the original state or from the loss of the benzos, alcohol, etc.
Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepine binding sites, and in preclinical models lead to cell death.
Here’s the key point for this article.
CBD has not shown an ability to build up a tolerance. Which means there aren’t withdrawal effects.
Let’s walk through how these various players interact with GABA.
- Benzos and GABA receptors and function
- Alcohol and GABA receptors and function
- Gabapentin and GABA receptors and function
- CBD and GABA receptors and function
We’ll leave out GABA supplements directly since it’s been shown that they can’t cross the blood-brain barrier (which is where we need it for nervous system function).
Initial studies from the fifties reported GABA’s inability to cross the BBB (Van Gelder and Elliott, 1958). Since then, several research groups have replicated this finding.
Only at very high doses and injected was there conflicting research at best.
The placebo effect may be king there.
Back to the big four.
Benzos and GABA receptors and function
On a given neuron, you have different types of landing pads including:
- GABA receptor site
- Barbiturate receptor site
- Benzodiazepine receptor site
When benzos hit their site, they literally open the flood gate (chlorine in this case) to juice up the GABA flow.
To be technical:
This alteration, in turn, induces a conformational change in the GABA-A receptor’s chloride channel that hyperpolarizes the cell and accounts for GABA’s inhibitory effect throughout the central nervous system.3
To translate, benzos attach to a site that then acts as a turbo boost to GABA function.
The withdrawal and tolerance side is much more complex.
There’s a detailed look at the link below but good luck:
The takeaway is an orchestrated reaction by the nervous system to offset the juicing of GABA levels by benzos:
- Reduced sensitivity to GABA
- Changes in brain area size
- Increases sensitivity in the opposing Glutamate system
- Knock on effects with widespread consequences
Look. GABA is the most prevalent neurotransmitter in the nervous system with direct action on every other neurotransmitter.
Let’s tease out just one pathway, albeit it, a powerful one.
Here’s where it gets interesting.
Many drugs that show an addictive quality also affect our brain’s ability to change.
This makes perfect sense. why is it so hard to “learn new tricks” and change behaviors?
Benzos have stacked the deck against you by reducing the brain’s fertilizer. BDNF.
Check out CBD and BDNF for a deeper dive but this is critical.
We demonstrate that 9 weeks of social isolation induces a deficit in motivational behavior with increased anxiety as well as impairment in hippocampal neurogenesis. This was parallelled by reduced BDNF levels in the hippocampus.
Basically, they found that benzos offset the effects of SSRIs on neurogenesis.
Look. if you read our article on exactly how do SSRIs work, you’ll see it all comes down to neurogenesis and BDNF!
Stay with us here. it’s very interesting.
There’s a direct tie between BDNF and GABA:
One of the key molecules regulating the GABAergic synaptic transmission is the brain-derived neurotrophic factor (BDNF)
BDNF (and the other neurotrophins as they’re called) are the landscapers and construction crew.
Benzos show up on the scene and they’re opening the floodgates of GABA.
The brain responds by trying to offset this artificial “push” on the system.
It uses BDNF to re-route pathways including both GABA and Glutamate.
And we get.
Glutamatergic and GABAergic synapses reacted differently to postsynaptic BDNF: glutamatergic input increased, whereas GABAergic input decreased.
As a result. BDNF drops to counter this effect as we saw above.
But wait a minute. BDNF is key to a dynamic and healthy brain.
It’s literally at the heart of addiction and mental health (see BDNF here).
When the benzo goes away, how do we rebuild back the pathways to “normal” GABA function?
THAT….is why it’s so hard and long for the GABA system to normalize after long term benzo use.
The construction crew’s on break. When it does back on, it tends to boost glutamate.
That must feel terrible!! In the opposite direction, we want to go.
The very gene (GAD) that dictates how much glutamate gets turned into GABA is partially governed by none other than….BDNF:
Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity.
We just went down a rabbit’s hole of ONE pathway but for a good reason.
It shows the mechanics of how our brain suppresses GABA function with benzo use.
What about our oldest hammer on GABA….alcohol?
Alcohol and GABA receptors
We stumbled on this effect with our CBD versus Alcohol review due to perimenopause.
There’s a reason it’s the default self-medication mode until a GP prescribes benzos or SSRIs.
First, alcohol causes a boost to estrogen which is naturally leaving the system at that time.
Equally powerful is its effect on GABA.
In functional studies, alcohol has been reported to potentiate GABA receptor-mediated 36CI-flux in microsacs, neuro synaptosomes, and cultured spinal cord neurons at pharmacologically relevant concentrations.
To translate, alcohol primes the GABA system to flow!
Interestingly, they even pinpointed where it operates and were able to block the effects when by blocking GABA activity there:
The potentiating effect of alcohol is blocked by GABA antagonists and the inverse agonists of the benzodiazepine receptor site.
Hmmmm….the benzo receptor site from above.
On a side note, alcohol also calms the stress response by blunting our key stress signaling hormone. CRF – Corticotropin-Releasing Factor.
This is the same one that spikes in the first few weeks of SSRI treatment thus causing an increase in anxiety/depression.
Without fail, most doctors will prescribe benzos during this time to “give the SSRI time to work”.
Alcohol interacts in such a way as to acutely reduce CRF levels in the brain; chronic alcoholism does the opposite.
Of course, the same issue with tolerance and addiction apply with alcohol:
When a person over drinks, there is depleted GABA function in the brain and also, possibly, a hyper-excitable glutamate system.
This is why you can feel anxious and frazzled with a handover.
Although alcohol’s effect is different and more universal than benzos, their shared similarities are found both in site activity, GABA, and effects (both positive and negative).
Let’s look at a new addition to the GABA party.
Gabapentin and GABA receptors
G abapentin was discovered in the ’70s and is currently sold as Neurontin.
It’s easiest to think of gabapentin as a synthetic GABA.
The same as how progestin is a synthetic progesterone.
It’s really only approved for seizures and neuropathic pain by the FDA but the vast majority is given for so-called “off label” uses like anxiety and insomnia.
Gabapentin does not directly interact with the GABA receptors to work.
Gabapentin functions by modulating enzymes involved in GABA synthesis.
It boosts the raw material for the production of more GABA.
Since there’s no free ride in the universe in artificially boosting GABA, do we see the same effects with gabapentin?
We’ll look at two pieces:
- Side effect profile
- Tolerance and withdrawal
The side effect profile is a good place to start.
Here are the more common ones for neurontin:
- memory loss,
- lack of coordination,
- difficulty speaking,
- viral infections,
- double vision,
- unusual eye movements, and
- jerky movements.
We love this little addendum:
Other side effects of Neurontin include mood or behavior changes, depression, or anxiety.
Tucked away in that “behavior changes” are sexual dysfunction, suicidal thoughts, and suspicious feelings.
What. Just from GABA boosting?
The list sounds awfully similar to SSRIs, especially the sexual dysfunction (inability to reach orgasm) and suicidal thoughts.
Any connection there?
6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions.
There are even anecdotal studies of people who develop Serotonin Syndrome via gabapentin (albeit, usually with other medications).
The net effect:
On account of these results, we speculate that gabapentin modulates the release of serotonin from blood platelets.
Now. serotonin is a WHOLE different animal than just GABA (simple inhibitory or brake pedal effect).
Messing with that system is tricky at best. Just check out the research on CBD versus SSRIs.
It also leads to our next section. tolerance.
Gabapentin and tolerance and withdrawal
Does the brain have a knee-jerk (not sure where the brain’s knee would be) to gabapentin’s effect?
Does it push back?
Our review, and other non-abuse reports falling outside the scope of this study (73–79), identified that gabapentin, too, produces these effects (i.e., tolerance, physical dependence, and withdrawal) thereby warranting reevaluation of its abuse potential.
Okay. let’s look at CBD now.
CBD and GABA receptors function
So what’s behind door #4 since the other three doors potentially open to addiction, tolerance, and withdrawal.
What about CBD and GABA function?
Let’s cut to the chase. CBD has shown no tolerance, addiction, or withdrawal effects in countless studies.
Does it even affect GABA function then?
Let’s walk through some studies and don’t worry. we’ll translate!
First, a study on schizophrenia (see CBD and schizophrenia) where GABA/Glutamate imbalance is a key marker:
Overall, these findings show that CBD can restore cannabinoid/GABAergic signaling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure.
Let’s break it down because it’s really interesting.
There’s a whole re-evaluation of the effects of early exposure to viral infection and mental health issues later in life.
We did a massive review on CBD and early trauma or CBD and the immune system for mental health.
Front and center is schizophrenia.
In that study, they exposed mice to infection which causes an immune response to overact and damage the balance between glutamate and GABA.
Too much glutamate in the brain is actually toxic and the effect of this can lead to symptoms of schizophrenia.
What they found was that CBD normalized this glutamate/GABA balance!
Think of how revolutionary this is.
The other chemicals above are pumping GABA in one direction regardless of how much (hence the sedation and other effects. too much GABA).
CBD is working in a different way which we desribe below (endocannabinoid system).
What about CBD on GABA levels directly.
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 EC5 evoked current.
Remember that GABA is a system to change the voltage of a given neuron. This is electricity folks.
CBD and our most prominent endocannabinoid (2-AG) in the brain were able to upregulate the effects of GABA on calming the neuron’s activity.
This piece is important:
The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site.
It did not work on the benzo site like benzos and alcohol.
Hmmm. Okay. further down the rabbit hole.
We find that although CBD has no direct effect on excitatory transmission, it does inhibit two forms of endogenous cannabinoid-mediated retrograde synaptic plasticity: depolarization-induced suppression of excitation and metabotropic suppression of excitation, while not affecting signaling via GABA-B receptors.
To translate from Klingon….
CBD is affecting the naturally occurring endocannabinoid system which has multiple means to balance GABA and Glutamate systems (electrical, chemical, etc).
It’s doing without directly pumping the GABA receptor (important. so the brain doesn’t push back by dropping baseline GABA function).
So. do we actually FEEL this result or is it just fancy science and jargon.
Let’s look at three key players with GABA dysfunction (too low):
First, Anxiety and GABA:
In contrast to the effects of delta 9-THC, 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.
Did you catch the reference drug they were comparing CBD to?
Diazepam. You know. Valium. Benzo .
The full study found:
Finally, the anxiolytic effects of systemic CBD partially depended on GABAA receptor activation.
What about seizures?
This is how CBD initially gained popularity on the world stage.
The differential effects of CBD suggest that the cannabinoid acts to inhibit seizure spread in the CNS by action on GABA, but not glycine, mechanisms.
There have since been many studies on this avenue and remember that we can talk about GABA without considering glutamate. Two sides of the same coin.
As for sleep….let’s combine anxiety and sleep together:
The final sample consisted of 72 adults presenting with primary concerns of anxiety (n = 47) or poor sleep (n = 25). Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time.
Interestingly, woman have to really look at hormones for sleep as we found out the hard way with perimenopause (story is here).
There’s no getting around estradiol and progesterone (see CBD and perimenopause sleep issues).
We’re going to wrap up this study because it’s very exciting.
Researchers wanted to look at the effects of CBD on brain excitation (GABA/Glutamate) between people with autism and those without.
First. their results:
Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant.
Let’s explain why we’re ending with this one.
Okay. so it boosted GABA across the brain….except in the prefrontal cortex (DMPFC) for people with autism.
It turns out that imbalance between GABA/Glutamate in this area is part of the symptomology of autism:
Imbalance between excitation and inhibition and increased excitatory-inhibitory (E-I) ratio is a common mechanism in autism spectrum disorders (ASD) that is responsible for the learning and memory, cognitive, sensory, motor deficits, and seizures occurring in these disorders.
CBD had a completely different effect depending on the state (or need) of the system!
We see this all the time across different pathways.
For example with cancer:
- Health cell with low inflammation – CBD does not reduce inflammation
- Healthy cell with high inflammation – CBD reduces inflammation
- Cancerous cell – CBD INCREASES inflammation
This may seem strange until you understand that a spike in inflammation is how the body naturally kills cancerous cells.
Chemo and radiation. spike in inflammation!
This isn’t some magic trick of CBD though. It’s the underlying system it bolsters. the endocannabinoid system.
Remember 2-AG, our most prominent endocannabinoid naturally?
The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABAA receptors at low concentrations of GABA.
The most important three words in this entire article in that sentence…
2-AG boosts GABA levels when they run low.
You could argue that anxiety, sleep issues, seizures are more a failure of the endocannabinoid system than the GABA/Glutamate systems.
This speaks to why CBD doesn’t show tolerance, addiction, or withdrawals.
It doesn’t push in one direction!
Let’s look at specific issues when the GABA function is imbalanced.
GABA and anxiety
GABA is a big player in terms of anxiety as should be obvious from the effects (albeit temporary) with benzos.
That being said, there are higher-level brain connectivity and pathways at play.
Check out our CBD and the mechanisms of anxiety to get a 30,000-foot view of the different pathways.
Without question, one lever of anxiety is definitely reduced GABA.
This lever is especially pronounced in one area of the brain key to the anxiety circuit. the amygdala.
This small, almond-shaped area of the brain is key to emotional and fear processing.
When it’s too active (versus the opposing prefrontal cortex), anxiety can occur.
What can possibly calm its activity?
Hopefully, it’s obvious by now. GABA!
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.
In fact, researchers show that benzos have this very effect (but knock-on effects across other brain areas):
In humans, administration of benzodiazepines attenuates the activation of the amygdala in the presence of negative emotional stimuli.
This specificity for amygdala activity is likely the difference between anti-anxiety versus sedation.
Speaking of which.
GABA and sleep
GABA is a powerful regulator of sleep quality, duration, and ease.
As researchers put it:
Gamma-aminobutyric acid (GABA) is likewise a strong sleep regulator that may activate GABA receptors as well as inhibitors of waking processes.
When researchers looked at patients with insomnia, there was a clear connection:
Average brain GABA levels were nearly 30% lower in patients with PI (.18 +/− .06) compared to controls (.25 +/− .11).
PI is short for primary insomnia.
Interestingly, many doctors will prescribe benzos (used to be barbituates) for sleep.
They do cause sedation but at the expense of quality of sleep:
The first and second generation of hypnotics (barbiturates and benzodiazepines respectively) decrease waking, increase slow-wave sleep and enhance the intermediate stage situated between slow-wave sleep and paradoxical sleep, at the expense of this last sleep stage.
People. this is crucial.
Scientists now know that its this phase when the brain basically removes the toxins and waste that accumulate during the day.
cellular waste byproducts that may have accumulated in the interstitial space and in the brain cells are thoroughly removed.
This is one of the reasons that brain scans from sleep deprivation look like scans from people with extreme anxiety.
The net takeaway:
Benzodiazepines are known to reduce stage 3–4 sleep.
What about CBD and the sleep-wake cycle? Does it interfere there?
Different from anxiolytic and antidepressant drugs such as benzodiazepines and selective serotonin reuptake inhibitors, acute administration of an anxiolytic dose of CBD does not seem to interfere with the sleep cycle of healthy volunteers.
See how SSRIs were thrown in there as well (See CBD versus SSRIs).
Again, this is a question of balancing GABA function versus pumping GABA levels.
Very different effects for a neurotransmitter that’s intimately woven into almost every system of our nervous system.
Let’s look at hormones (especially for our ladies out there).
Hormones (progesterone) and GABA
A brutal perimenopause (that story is here) is what led us to CBD originally.
The more we researched, the more we understood both the power and misinformation on the hormones estradiol and progesterone.
Progesterone is a critical player in the GABA story and it’s dropping for women starting around mid-’30s.
It’s at 50% of peak levels by age 40 and there’s cliff around age 46-48 with perimenopause when the monthly cycle starts to wind down.
Why does this matter for GABA?
By both means of administration, progesterone significantly enhanced inhibitory responses of Purkinje cells to GABA and suppressed glutamate excitation within 3-10 min post-steroid.
So. progesterone basically promotes GABA activity and calms Glutamate activity.
Wait a minute. isn’t that everything we’ve been talking about above?
What’s the effect of this?
These results are consistent with the anxiolytic actions of the steroid.
Anxiolytic just means anti-anxiety effects.
Sleep is no different .
The star of this show is actually a metabolite of progesterone. allopregnanolone.
It’s the basis for the new blockbuster postpartum depression medication at $25K.
But our health delivery system is fine!
We have a whole review of pregnenolone here since it’s so important as we get older to support all our steroidal hormones.
Men and women have similar levels of pregnenolone, the mother of all hormones including estrogen and testosterone and they’re declining as we get older.
Check the review above if your aging. If you’re not, what’s the secret (besides metformin and fisetin).
Let’s look at a critical question for people whose GABA system is impaired.
Can CBD rescue GABA receptors after benzos
We’re going to do a deep dive into the long term effects of benzos on GABA function.
Basically, the body will suppress the actual DNA production of the proteins needed to make GABA receptors (there are 5 proteins that form the “gate”).
This can occur within weeks. That’s why there’s a black box warning on benzos.
After benzos leave the system, it can take weeks, months, or even years for the body to bring that production back online when it gets signals that the excess GABA juicing is gone.
CBD can definitely help with the rebound issues from benzo withdrawal.
Can it support or speed the receptor rescue?
Let’s look at a study that considered cannabis (a mixture of THC and CBD) for benzo withdrawal.
They actually broke out the CBD levels which is important since THC can actually have very different effects (see CBD versus THC for anxiety).
First, the summary level results:
At the final follow-up period after three medical cannabis prescription courses, 66 total patients (45.2%) had discontinued benzodiazepine use, showing a stable cessation rate over an average of 6 months.
We want to avoid THC when it comes to GABA:
Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group.
THC pushes another pathway too hard called anandamide (mimics it at CB1 receptor).
They even reference the net effects of this in the study above:
Previous studies have reported associations of high THC/low CBD content with an increased risk of anxiety.18 CBD and THC have proposed conflicting effects on anxiety.
Let’s look at the CBD side…
There’s a great chart here that shows benzo use depending on levels of THC and CBD.
To recap, at the higher CBD levels, the percentage of people who were able to stop benzos was higher.
This flipped, as we go down in CBD.for significant percentages.
That’s a top-level view and we definitely need more research.
We know that CBD does not have display tolerance or normalization with use which is critical to returning the GABA pathway to a healthy functioning.
GABA supplements and ways to support healthy GABA function
GABA supplements are a big item these days.
For those not self-medicating with alcohol, there’s a slew of supplements out there with varying amounts of research.
The most popular:
- Pharma GABA
- Valerian root
- Amino acids – Glycine, Tryptophan, L-Theanine (from Green Tea)
Of these, Silexan has the best research with Germany leading the way.
For the oral GABA supplement, there’s really not great research that it can cross the blood-brain barrier in any significant amount.
That isn’t to say that a strong placebo effect isn’t present of that changes in the gut can “migrate” and instruct the nervous system.
The PharmaGABA is a product of fermentation so the gut microbiome is a possible connection (see CBD and probiotics for anxiety).
We don’t have that research since it’s nearly impossible to measure GABA levels in the brain.
KAVA has potential health issues.
Then there are the amino acids.
Glycine is really interesting since it has an inhibitory role in the nervous system similar to GABA.
Most inhibitory neurons in the brain and spinal cord use either γ-aminobutyric acid (GABA) or glycine as a neurotransmitter.
Remember that GABA IS an amino acid.
We covered Tryptophan as a stress buffer with social anxiety here. This really speaks to serotonin function. which CBD supports just like GABA!
Collagen is a great source for all the core amino acids.
That’s a wrap on GABA. As we get new research, we’ll make sure to add it.
CBD and benzo addiction
CBD versus alcohol
CBD versus benzos
The benzo brainwave issue
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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Taking It Slow With GABA
As you can see in my daughter’s favorite cartoon based on Aesop’s “Tortoise and the Hare,” the race goes to the slow and steady. That cadence fits for GABA as well. And while GABA is not one of the sexy neurotransmitters you see in the popular press, it should be.
Not as specialized as the more well-known messenger molecules like serotonin, oxytocin or dopamine, GABA is the brain’s primary inhibitory neurotransmitter.
It is the turtle of your neurons, the blinking red light of your synapses, your brain’s signal to calm down its firing. Formally known as γ-Aminobutyric acid, GABA ’s chief job in the central nervous system consists of reducing neuronal excitability.
The brain needs balance because too much excitement can be damaging. It’s one of the most important aspects of neuronal health. When the synapses fire too much and too often, they get hot like an engine with no oil. Called excitotoxicity, this occurs commonly in the major neurodegenerative diseases as well as strokes, epilepsy, traumatic brain injuries, alcohol use disorder, and the rapid withdrawal from benzodiazepines. Excitotoxicity often happens because of unhealthy levels of glutamate – the brain’s primary excitatory neurotransmitter (subject of the previous article in this series) and the yang to GABA ’s yin.
In a fitting twist of fate, GABA is synthesized from glutamate. Out of the great excitatory neurotransmitter comes the great inhibitory neurotransmitter. And working together, they both act as handmaidens that facilitate the functions of our endocannabinoid system ( ECS ).
GABA and the ECS
Do you know where the most CB1 cannabinoid receptors are located? The same CB1 receptors that THC uses to get you high? The majority of these famed CB1 receptors are embedded on your brain’s GABA -producing interneurons.
Interneurons – also known as relay neurons, connector neurons, or intermediate neurons – connect to small circuits in local regions of the brain (as well as connecting different brain regions). They act as the crucial middleman between sensory inputs coming into the body and the response of the motor signals that are transmitted back out.
As you can see in this diagram, the classic function of an interneuron is to insert itself into a circuit and, if activated, dial down the signaling. In technical language, GABA ergic interneurons “gate signal flow and determine network dynamics [and] are essential for sculpting network responses.” Via their inhibitory actions, interneurons prevent instability in the brain. And when you activate your CB1 receptor, the most likely response is the triggering of an interneuron’s release of GABA , something that carries out so much of the work done by the ECS .
While this ‘get-to-know-a-neurotransmitter’ profile focuses on GABA ’s higher-level neural processes, we shouldn’t overlook the importance of GABA ’s role in other areas such as:
- Brain development, where it regulates the stem cells, their migration and differentiation, as well as the formation of synapses
- Insulin production in the β-cells of the pancreas
- Suppression of inflammation in the immune response
- Acupuncture’s efficacy, which is partly mediated by the endocannabinoid system’s modulation of GABA
Anxiety, Benzos, and CBD
One theory about anxiety views it as a result of insufficient inhibitory control in the brain. In that context, using a benzodiazepine (like Valium or Xanax) to increase inhibition makes sense. Instead of directly activating a receptor like a key turning a lock, the mechanism of action for benzos is a “positive allosteric modulation” (signal boost) of the GABA a receptor.
Canadian researchers report that when patients received a medical cannabis prescription, half of them discontinued their benzos.
Benzos are positive modulators of GABA . So are barbiturates (the first generation of downers), the delightful Quaaludes (that a certain generation raves about), and that old human favorite, alcohol. The strengthening of GABA by these drugs leads to the dissociative and sedating effects that can be both pleasurable and terribly addictive.
Benzos aren’t big business just because of big ad budgets. As potent anxiolytic (anxiety-resolving) agents, they’re awfully effective – and possess quite the potential for danger. An overdose, either alone or combined with booze, can be fatal. And the withdrawal effects of benzos can also be lethal if stopped too quickly without tapering.
According to a 2019 Canadian study, when patients received a medical cannabis prescription, half of them discontinued their benzo prescriptions. A 2020 review article on neurological diseases reported that plant cannabinoids might help to restore a broken GABA transmission system. Plant cannabinoids, especially CBD , are notorious for their calming effect. In large part, this may be attributable to the endocannabinoid system’s control over GABA and the calming of the brain.
In rats stressed out by being restrained (they hate this), the endocannabinoid system helped to calm their racing heart via GABA – and if you blocked their CB1 cannabinoid receptor from working, their heart raced even more. In another animal study, Spanish scientists sought to explore how CBD exerts its anti-anxiety effects. They found that in mice with no CB1 receptors, CBD stopped working for anxiety. They also found that the presence of CBD decreased the levels of the CB1 receptor and the GABA a receptor in the amygdala (the fear center of the brain), while increasing CB2 receptor levels.
“It is tempting to speculate that CBD regulates, directly or indirectly, GABA a neurotransmission,” the researchers surmised. This observation concurred with previous findings of Australian investigators, who reported that CBD and the endocannabinoid 2- AG both interact with the GABA a receptor in a way that enhances the natural calming effects of GABA , the slow-down neurotransmitter.
Your Beautiful Nimble Brain
GABA ’s inhibitory effects can help your brain be more nimble while trending toward the sweet spot of moderate healthy activation. In this neuronal balancing act, your pay attention to this function is just as important as stop bothering to notice that. To stop from spinning out of control from too much stimulation, it’s essential for the brain to ignore signals that are no longer perceived as dangerous or relevant.
It’s been shown that a combination of dopamine and endocannabinoids regulate the GABA -releasing synapses in a rat’s prefrontal cortex (the highest area of the brain), creating what scientists refer to as “long-term depression” or LTD . That’s shorthand for your brain’s ability to reduce the activity of a circuit after it has been activated too many times. This reduction can last for hours or longer. It’s the negative side of synaptic plasticity, the ability to downgrade a signal so that you are able to upgrade it again if needed. Otherwise, your brain would reach a maximum level of all your circuits firing all of the time.
In addition to protecting the brain from excitotoxicity, the inhibitory effects of GABA influence both learning and memory. In a mouse model of memory, the ability of certain serotonin receptors to regulate spatial memory depends on a pathway involving CB1 and GABA . In another intriguing study, the signaling of GABA accelerates the breakdown of endocannabinoids, which triggers “learning-induced metaplasticity.” This means your brain’s ability to adapt and change comes, at least partially, via your endocannabinoids and GABA .
In the olfactory bulb (the locus of your sense of smell), endocannabinoids modulate your GABA ergic synapses. And in the taste center of your insular cortex, the CB1 receptor mediates GABA ’s plasticity of your taste learning system. It’s the endocannabinoids that regulate both GABA and glutamate in the striatum, a brain area associated with habit formation and movement control. The ability of the CB1 receptor to help mice be social and exploratory depends on the delicate balance between glutamate and GABA .
The GABA Health Files
For the specific disease conditions related to GABA dysfunction, let’s take a slow, deep science stroll through the GABA garden. As always, more clinical research is needed, but for anyone with these indications or areas of concern, it’s relatively easy to start harnessing the power of GABA and the ECS to improve your health.
- ALS : In a mouse model of amyotrophic lateral sclerosis, the CB1 receptor showed an ability to exert a very fine level of control over the signal transmission of both GABA and glutamate.
- Autism: According to this brain imaging study of humans, both CBD and CBDV help with autism via the GABA and glutamate pathways.
- Circadian rhythms: In the circadian rhythm section of your brain, cannabinoid signaling causes its effects by “recruiting” astrocytes (specialized immune cells of the brain) via adenosine and GABA transmission.
- Down’s syndrome: In a mouse model of Down’s syndrome, the CB1 levels are upregulated on the GABA neurons and downregulated on the glutamate neurons.
- Eyes: In the eyes of rats, CB1 activation helped to fine-tune visual signaling via modulation of GABA .
- Exercise and food: In mice, CB1 receptors enhance exercise activity and lower the desire for food via GABA neurons.
- Huntington’s disease: In humans, Huntington’s disease alters the cannabinoid and GABA receptors. In a mouse model, the level of CB1 receptors on GABA neurons plunges.
- Pain: In a rat model of pain, a synthetic cannabinoid induced analgesia via GABA a. In mice, CBD reduced pain via inhibition of GABA action potentials in the periaqueductal gray (a midbrain region that integrates the behavioral responses to internal stressors such as pain, as well as external stressors such as threats). In mice with nerve injuries, the CB1 levels go up in the cortex and the activation of these CB1 receptors causes pain relief via GABA interneurons. In mice, females experienced more pain relief from CB1 activation than males because females possessed more GABA -producing neurons with CB1 receptors in the relevant brain area. In rats with arthritic knees, the therapy combination of stem cell injections, endurance training (little treadmills) and ozone therapy (I assume they went to LA for this) decreased pain via the CB1 and GABA receptors.
- Puberty: In mice, insulin increases GABA transmission in a neuron that releases a hormone associated with puberty via the endocannabinoid system.
- Schizophrenia: In a rat model of schizophrenia, CBD restored cannabinoid and GABA signaling deficits.
- Sleep: The CB1 receptor helps to control sleep partially via GABA .
Copyright, Project CBD . May not be reprinted without permission. Lex Pelger writes articles about psychoactives and graphic novels about the endocannabinoid system. He publishes a weekly cannabinoid science newsletter Cannabinoids & the People and conducts 1-on-1 education sessions on using CBD , PEA , THC & CBDA for serious health conditions.