Cannabinoids and the Brain: The GABAergic Neurotransmission System

First it was in Bob Marley songs. Now, cannabis is a popular topic across the spectrum media and popular culture. 

You may have come across articles or blogs discussing compounds called cannabinoids that are present in cannabis plants and their effects on the neurotransmitter GABA. In this article, you’ll learn more about cannabinoids and their effects on mental health, especially in relation to the GABA system. Let's get started!

What is GABA and How Does it Affect Us?

GABA, or gamma-aminobutyric acid, is an inhibitory neurotransmitter that is known for its major significance in the central nervous system, especially the brain. GABA is produced by glutamate decarboxylase, an enzyme that converts glutamate to GABA with vitamin B6 (pyridoxine) as a cofactor. When an action potential (rapid changes in membrane voltage) reaches the presynaptic cell, voltage-gated calcium channels open and trigger the release of GABA into the synaptic cleft. GABA then binds to its receptors, leading to changes in conductance brought about by the influx of ions such as potassium and chloride. These cause a reduction in neuronal excitability by impeding nerve transmission in which said ions are involved [1].

In short, GABA induces calm. This specific effect of GABA gave rise to different studies that examined its effect and correlation to different psychiatric disorders such as schizophrenia, depression, post-traumatic stress disorder, and more [2].

How is this possible? It’s all thanks to a complex network of neurons and structures that are involved in the utilization (i.e., binding and releasing) of GABA called the “GABAergic Neurotransmission System.” They are found throughout the central nervous system and play a crucial role in many physiological processes including sleep and different motor controls. This is why dysfunction in this system has been linked to different psychological disorders similar to those mentioned earlier [3].

You can read more about GABA in our in-depth guide here, or if you're already familiar with it, take a look at Tro Calm which uses compounds that modulate the GABA system!

The GABAergic Neurotransmission System

Some of the most notable structures involved in this system are the GABA receptors. The two most important receptors that play a role in the utilization of GABA are called GABAA and GABAB. GABA binds to each receptor upon its release into the postsynaptic nerve terminal, producing a different response.

• GABAA is a ligand-gated ion channel or ionotropic receptor that is known for its structural complexity. These receptors mediate fast synaptic inhibition due to their direct activation of the chloride pore that allows chlorine ions to move across the cell. This causes hyperpolarization of the cell membrane due to the increase in negative ions, making it harder for the neuron to depolarize and fire an action potential [4].
• GABAB is a metabotropic receptor that belongs to the family of G-protein-coupled receptors. They have limited structural diversity and mediate slow synaptic inhibition. Both disrupt cell polarization, which reduces the probability of an action potential to be fired [5].

The action potential reduction through the inhibitory effects of GABA binding to either of the receptors is what induces relaxation of the mind and body. Additionally, GABA receptors are susceptible to modulators, which are substances that influence their activity such as positive and negative allosteric modulators. Allosteric modulators bind to a specific site of the receptor, known as an allosteric site. This induces the increase or decrease of the receptor's affinity towards its agonist, a substance that initiates a response when bound with a receptor [1].

Negative allosteric modulators decrease the activity of GABA receptors by either lowering their affinity towards GABA or by inhibiting the opening of ion channels in response to GABA. Some examples of this are bicuculine, picrotoxin, and flumazenil, which are mostly used for research purposes and to reverse the effects of positive allosteric modulators [6].

Positive allosteric modulators, on the other hand, have the opposite effect. They enhance the activity of GABA receptors by either increasing their affinity towards GABA or by potentiating the opening of ion channels in response to GABA. Some examples of this are benzodiazepines, zolpidem, and barbiturates, which are widely used in clinical practice due to their sedative, anticonvulsant, anxiolytic, and muscle-relaxant effects [6].

Given all that, why can't we just synthesize GABA for oral consumption or find commodities that innately contain GABA such as tea or some fruits and vegetables? The problem now presents itself as GABA has long been known to have low permeability across the blood-brain barrier, a system of microvascular endothelial cells that protects the brain from toxic substances [7]. This impedes the GABA that we would ingest and absorb in our bloodstream from reaching our brains.

Then how? Is there something we can do to make GABA more accessible to our brains so that we can experience this relaxation effect? Lucky for us, science always finds a way to solve our problems. The answer? Cannabinoids!

Cannabinoids and their Role in our Mental Health

Cannabinoids are a group of compounds known for their psychoactive properties and potential therapeutic benefits that are still being studied up to this day. The two most studied types of cannabinoids are endocannabinoids and phytocannabinoids.

Endocannabinoids are those produced by our own body such as 2-arachidonoyl glycerol (2-AG) and anandamide (AEA, also known as the “bliss” hormone). The release and increase of these compounds are found to be associated with decreased anxiety, lower symptom severity for schizophrenia and depression, and improved sleep [8].

So why can't we just induce the increase of these endocannabinoids in our body whenever we need to feel the need to calm and relax ourselves? Unfortunately, studies have shown that increasing AEA would lead to the activation of TRPV1, a non-cannabinoid receptor that increases anxiety, and that elevation of 2-AG would cause a protective shutdown resulting in a downregulation to CB1, one of the receptors needed to produce a desired response [9].

It’s a good thing we have phytocannabinoids! Phytocannabinoids, as the name suggests, are a group of compounds that are naturally produced by the cannabis plant (Cannabis sativa) where its name originated. They are also psychoactive compounds that generate similar effects. The following section lists some of the most studied phytocannabinoids and how they interact with the GABAergic neurotransmission system [10].

Examples of Phytocannabinoids

1. Cannabidiol (CBD) is one of the two most well-known phytocannabinoids.  CBD can interact with the GABAergic neurotransmission system in several ways. One of them is its capability to enhance the activity of GABAA receptors by acting as a positive allosteric modulator, a mechanism that is also being utilized by one of the endocannabinoids (namely AEA). The binding of CBD to GABAA receptors increases its response towards its agonist (GABA) and more GABA receptor interaction means a much faster and more potent calming effect.

   Another interaction is its ability to increase the availability of GABA in the brain. This is due to CBD's ability to impede the reuptake of GABA, increasing the readily available concentration of GABA in the synapse between neurons. This has been demonstrated in a previous study wherein treatment with CBD was found to decrease anxiety-like behavior in adult male Wistar rats [11].

   Although mostly positive, the effects of CBD on the GABAergic neurotransmission system and the body at large is still being investigated. Studies have also shown that CBD has a complex interaction with the GABAergic neurotransmission system depending on dosage. This suggests that CBD may have biphasic effects on GABA, which means that GABA's activity may increase or decrease depending on the dose and context of CBD usage [11].

2. Tetrahydrocannabinol (THC) is the other well-known phytocannabinoid that is at the center of studies and experiments currently being done on cannabis plants. Its interaction with the GABAergic neurotransmission system is through its binding and activation of CB1 in the brain. The activation of CB1 receptors located on GABAergic interneurons can lead to a decrease in GABA release and therefore an increase in neuronal excitability. This causes the psychoactive effect of THC, which includes the feeling of being high and changes in mood and cognition [12].

   Similar to CBD, THC also has a complex relationship with the GABAergic neurotransmission system as studies have shown that its effect may also be dependent on its dose, route of administration, and context of use. Additionally, the GABAergic system is not the only system that THC interacts with. It is also linked with other neurotransmission systems in the brain such as serotonergic, dopaminergic, and glutamatergic systems [13].

3. Cannabinol (CBN) is considered a minor compound with lesser studies compared to CBD, but this doesn't diminish its possible benefits. Being the main degradation product of THC, CBN also functions as an agonist of CB1 but with 10 times lower affinity. This means that CBN doesn't have as much potency as THC, but does have sleep-inducing and anti-inflammatory properties. These effects are found to be more effective when administered as a mixture of either CBD or THC [14].

4. Tetrahydrocannabivarin (THCV) is another minor phytocannabinoid that deserves a spotlight due to its promising biological activities. It is a homologue of THC with a propyl side chain (in place of the pentyl side chain that exists in THC) that acts as a CB1 antagonist rather than an agonist. Since CB1 receptors are involved in the transmission of physiological processes that lead to pain, inflammation, and cognitive behaviors, the inhibition of CB1 by THCV could lead to a decrease in these. It could also reduce anxiety and depression since CB1 is also known to be involved in mood changes and emotions. Just like CBN, THCV also has varied effects on the GABAergic neurotransmission system when combined with other cannabinoids and at different concentrations [15].

Conclusion

The world of cannabinoids is still far from being fully unraveled. There is still more information to be discovered about their interactions with not only the GABAergic system but also with other neurotransmission systems. What we do know is that there are a lot of possible health benefits, some of which include a reduction in pain, inflammation, depression, and anxiety, and even an increase in the calmness and relaxation. Do your research. Choose wisely for you. And go slow, no matter which cannabinoid you decide to try! 

References

[1] Ghit, A., Assal, D., Al-Shami, A. S., & Hussein, D. E. (2021). GABAA receptors: Structure, function,  pharmacology, and related disorders. Journal of Genetic Engineering and Biotechnology, 19(1).  https://doi.org/10.1186/s43141-021-00224-0

[2] Schür, R. R., Draisma, L. W. R., Wijnen, J. P., Boks, M. P., Koevoets, M. G. J. C., Joëls, M., Klomp,  D. W., Kahn, R. S., & Vinkers, C. H. (2016). Brain Gaba levels across psychiatric disorders: A  systematic literature review and meta-analysis of 1H-mrs studies. Human Brain Mapping, 37(9),  3337–3352. https://doi.org/10.1002/hbm.23244

[3] Skilbeck, K. J., Johnston, G. A., & Hinton, T. (2010). Stress and gabaareceptors. Journal of  Neurochemistry, 112(5), 1115–1130. https://doi.org/10.1111/j.1471-4159.2009.06539.x

[4] Ochoa-de la Paz, L. D., Gulias-Cañizo, R., D´Abril Ruíz-Leyja, E., Sánchez-Castillo, H., & Parodí, J.  (2021). The role of GABA neurotransmitter in the Human Central Nervous System, physiology, and  pathophysiology. Revista Mexicana De Neurociencia, 22(2). https://doi.org/10.24875/rmn.20000050

[5] Padgett, C. L., & Slesinger, P. A. (2010). GABAB receptor coupling to G-proteins and ion channels.  GABABReceptor Pharmacology - A Tribute to Norman Bowery, 123–147.  https://doi.org/10.1016/s1054-3589(10)58006-2

[6] Olsen, R. W. (2018). Gabaa receptor: Positive and negative allosteric modulators.  Neuropharmacology, 136, 10–22. https://doi.org/10.1016/j.neuropharm.2018.01.036

[7] Hepsomali, P., Groeger, J. A., Nishihira, J., & Scholey, A. (2020). Effects of oral gamma-aminobutyric  acid (GABA) administration on stress and sleep in humans: A systematic review. Frontiers in  Neuroscience, 14. https://doi.org/10.3389/fnins.2020.00923

[8] Garani, R., Watts, J. J., & Mizrahi, R. (2021). The endocannabinoid system in psychotic and mood  disorders, a review of human studies. Progress in Neuro-Psychopharmacology and Biological  Psychiatry, 106, 110096. https://doi.org/10.1016/j.pnpbp.2020.110096

[9] Alger B. E. (2013). Getting high on the endocannabinoid system. Cerebrum: The Dana forum on  brain science, 2013, 14.

[10] Cifelli, P., Ruffolo, G., De Felice, E., Alfano, V., van Vliet, E. A., Aronica, E., & Palma, E. (2020).  Phytocannabinoids in neurological diseases: Could they restore a physiological GABAergic  transmission? International Journal of Molecular Sciences, 21(3), 723.  https://doi.org/10.3390/ijms21030723

[11] De Gregorio, D., McLaughlin, R. J., Posa, L., Ochoa-Sanchez, R., Enns, J., Lopez-Canul, M., Aboud,  M., Maione, S., Comai, S., & Gobbi, G. (2019). Cannabidiol modulates serotonergic transmission and  reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain, 160(1), 136– 150. https://doi.org/10.1097/j.pain.0000000000001386

[12] Laaris, N., Good, C. H., & Lupica, C. R. (2010). Δ9-tetrahydrocannabinol is a full agonist at CB1  receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology, 59(1-2), 121– 127. https://doi.org/10.1016/j.neuropharm.2010.04.013

[13] Ortiz, Y. T., McMahon, L. R., & Wilkerson, J. L. (2022). Medicinal cannabis and central nervous  system disorders. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.881810

[14] Maioli, C., Mattoteia, D., Amin, H. I., Minassi, A., & Caprioglio, D. (2022). Cannabinol: History,  syntheses, and biological profile of the greatest “Minor” cannabinoid. Plants, 11(21), 2896.  https://doi.org/10.3390/plants11212896

[15] McPartland, J. M., Duncan, M., Di Marzo, V., & Pertwee, R. G. (2015). Are cannabidiol and Δ9- tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.  British Journal of Pharmacology, 172(3), 737–753. https://doi.org/10.1111/bph.12944