Cannabinoid receptor activation regulates the release of GABA, the brain’s primary inhibitory neurotransmitter, which plays a crucial role in maintaining neuronal health. With more supplements these days than ever before, it can be confusing to figure out which supplements are compatible with one another and which have adverse effects. We often hear individuals asking, do any supplements interact with CBD oil? And while we always recommend checking with your doctor before adding any sup
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.
Should CBD Be Taken With Other Supplements?
With more supplements these days than ever before, it can be confusing to figure out which supplements are compatible with one another and which have adverse effects. We often hear individuals asking, do any supplements interact with CBD oil?
And while we always recommend checking with your doctor before adding any supplements to your wellness routine, we’ve compiled a list of trendy supplements and their known interactions with CBD oil.
MCT Oil & CBD
MCT stands for medium-chain triglyceride because it contains medium length chains of fats called triglycerides. Because of their shorter length, they are easier to digest than other longer chain fatty acids.
MCT oil is commonly extracted from coconuts because more than 50% of the fat in coconut oil comes from MCTs. However, these fats can also be extracted from other foods like palm and dairy products.
So what is the advantage of adding these MCTs to your routine? This natural, healthy fat may help support brain function, memory, and heart health – and who wouldn’t want that!
Where does CBD come into the equation? It is fat-soluble, meaning that it dissolves in oil rather than water. When we are thinking about the body, fat-soluble substances are better absorbed into the bloodstream when they are digested with fat.
For health-minded individuals, natural, healthy fats are the best option for this easier absorption. So how do you mix CBD and MCT oil for ultimate absorption? Well, you can go for a fun route, like adding MCT oil and CBD to Keto coffee, or you can go a more standard direction by opting for a CBD oil with a MCT carrier oil.
So in terms of interaction, MCT oil and CBD are a great pair, especially if you are looking for quick absorption and faster effects.
CBD + Valerian Root
If getting a good night’s sleep is your main concern, you have undoubtedly heard of all of the various aids for sleep – from meditation and supplements to tryptophan-rich foods and yoga poses. But with all of the recommendations and guarantees for sleep, it can get overwhelming.
By now, everyone has heard of the effects of CBD on sleep cycles. But perhaps Valerian Root is not so common. This ancient herb, known for its calming effects, contains a number of compounds that may help reduce stress and promote better sleep. So what about if we combined it with CBD?
While every body is different, the effects of CBD alongside valerian root has had marvelous results on restlessness and more restful sleep.
Because valerian root contains antioxidants that appear to have sedative and sleep-enhancing properties, it pairs quite nicely with CBD. And because CBD is known to influence the endocannabinoid system, which is responsible for all kinds of bodily functions (including sleep), taking CBD with valerian root may enhance the overall effects.
How? GABA is a neurotransmitter that inhibits or slows down the brain’s functions. When GABA steps in, it can present itself in the body as the feeling of relieving anxiety, reducing stress, and improving sleep. And while the brain naturally releases GABA at the end of the day to help you get to sleep, valerian root and CBD are both known to affect GABA levels and get you to dreamland even more seamlessly.
However, be sure to check with your doctor, as not all groups should take valerian root, including: individuals with liver disease, women who are pregnant or breastfeeding, and children under 3 years old. And as a disclaimer: unlike its lovely scented flowers, valerian root has a strong earthy odor, so it may be a good idea to opt for a capsule with valerian root powder to forgo the scent!
Or even better, a capsule with both CBD and valerian root for even better rest and relaxation!
CBD + L-theanine
L-theanine is a nootropic or, in other words, a supplement used commonly to enhance memory or other cognitive functions. L-theanine is believed to encourage wakeful relaxation without making you sleepy.
By influencing chemical messengers in the body like serotonin and dopamine, which influence mood, sleep, and emotion, L-theanine may help support normal stress response, focus, and memory in healthy individuals.
How does L-theanine interact with CBD and what are the benefits of taking them together? As mentioned before, it is believed that CBD helps to balance the body’s endocannabinoid system to help it naturally manage stressors like anxiety, sleeplessness and physical pain. While L-theanine is hard at work to support better mental focus, CBD can calm the mind and body, giving you the best of both worlds. For this reason, L-theanine and CBD seem to pair very well together for increased clarity and calm.
What about L-theanine, CBD, and Ashwagandha?
Now if you are wondering about L-theanine and CBD together, you may be privy to the supplement world in general and wonder: can I take L-theanine, CBD, and something like Ashwagandha together?
The easy answer: yes! However, time of day is really key to unlocking the most of these three supplements together.
Classified as an adaptogen, or an herb believed to help the body resist physical and mental stress, ashwagandha has been for centuries for helping calm the mind and body. It has also been used to help boost brain function, while promoting a sense of calm for the body and mind.
Because ashwagandha is commonly known for its help with stress response and maintaining calm, it is a good idea to take this supplement before bed to help you fall asleep. Which begs the question: when should you be taking L-theanine and CBD?
Cannabidiol (CBD) is quite versatile in its usage, as it can be taken in different dosages at all times of day. When taken in higher doses, it is believed to help with rest and sleep. When taken in lower doses, CBD can simply support a sense of calm when taking care of everyday activities, and even provide a little boost of focus. Basically, CBD can be taken whenever you need a little extra calm.
So where does L-theanine fit into the equation?
Being the nootropic it is, L-theanine is probably better suited for the morning time. Because it evokes mental clarity, you can take L-theanine alongside your morning cup of coffee and morning dose of CBD, and leave ashwagandha for later in the day (with a higher dose of CBD).
Supplement stacks like FOCL Day contain L-theanine as well as several other nootropics (and of course, CBD) to create the ultimate superfood for your brain in just one capsule!