BEHIND THE SCIENCE
THE ENDOCANNABINOID SYSTEM: CBD and THC EXPLAINED PART II
The endocannabinoid system is a highly precise system that reacts to the environment and initiates a response. Endocannabinoids are released at the right time and in the right place in response to environmental stimuli such as stress, sport, time of day, hunger and others. For example, when stressed, endocannabinoid levels rise and initiate a stress response to relieve the stress, and in the case of pain – when injured, endocannabinoids initiate a pain-relieving effect. In this way, endocannabinoids help bring the body back into balance.
BEHIND THE SCIENCE
THE ENDOCANNABINOID SYSTEM: CBD and THC EXPLAINED PART II
The endocannabinoid system is a highly precise system that reacts to the environment and initiates a response. Endocannabinoids are released at the right time and in the right place in response to environmental stimuli such as stress, sport, time of day, hunger and others. For example, when stressed, endocannabinoid levels rise and initiate a stress response to relieve the stress, and in the case of pain – when injured, endocannabinoids initiate a pain-relieving effect. In this way, endocannabinoids help bring the body back into balance.
How does the endocannabinoid system work?
Endocannabinoids are called retrograde signals that move in reverse order. Normally, information travels in one direction between neurons – from the ‘sender’ who sends the signal to the ‘receiver’ who receives the signal. In contrast, endocannabinoids work from the ‘receiver’ neuron and send the signal to the ‘sender’ neuron, on which the receptors are located (Mechoulam and Parker, 2013).
Neurotransmitters are chemical compounds that carry a nerve impulse between neurons through a special connection called a synapse. Neurotransmitters travel from one end of a neuron (the ‘sender’) to the other (the ‘receiver’) via the synapse, and once they reach the final neuron (the ‘receiver’) they bind to receptors that transmit a signal to initiate a response. This binding activates the production of endocannabinoids as 2-AG in the ‘recipient’ neuron. The 2-AG then travels across the synapse to the original neuron (the ‘sender’ neuron), which contains the cannabinoid receptor CB1. The endocannabinoid in the 2-AG binds to the CB1 receptor, which inhibits the release of the neurotransmitters, thereby reducing the response to the stimulus (Zou and Kumar, 2018) (see Figure 1). This whole signalling system is highly controlled, with endocannabinoids being produced and broken down by enzymes on demand, as they are not stored in our body like other neurotransmitters (Pagotto et al., 2006).
Why do we need an endocannabinoid system?
Figure 1: A simplified endocannabinoid signalling system. 1 – The neurotransmitter glutamate approaches the end of the ‘sender’ neuron and spills into the synapse. 2 – Glutamate binds to the NMDAR receptor in the ‘recipient’ neuron. 3 – Binding of glutamate to the receptor triggers calcium efflux, which in turn activates the production of the endocannabinoid AEA by the enzyme NAPE-PLD. 4 – The endocannabinoid AEA travels across the synapse back to the ‘sender’ neuron and binds to the CB1 receptor. 5 – This endocannabinoid-receptor fusion inhibits glutamate flow (Pamplona, n.d.).
How does cannabis affect the endocannabinoid system?
As we mentioned in this post (Link), cannabis produces a wide range of cannabinoids, but the most studied are cannabidiol (abbreviated CBD) and delta-9-tetrahydrocannabinol (abbreviated THC).
CBD acts as a receptor antagonist – it binds to the CB1 receptor but does not activate it. Therefore, other molecules such as THC cannot bind to the receptor, which is how CBD reduces the effects of THC (Klumpers and Thacker, 2019). As CBD does not directly act on the CB1 receptor, it interacts with other enzymes, receptors and other parts of the cell as ion channels. For example, CBD blocks the activity of the enzyme fatty acid amide hydrolase (FAAH for short), which is responsible for the degradation of the endocannabinoid AEA. As AEA cannot be degraded, larger amounts accumulate, allowing more of the endocannabinoid to interact with the CB1 receptor – a stronger response to the stimulus (McPartland et al., 2015). This is just one of the mechanisms by which CBD affects our endocannabinoid system.
THC, meanwhile, acts as a receptor partial agonist – it binds to CB1 and CB2 receptors, activating them for further signal transmission. When THC interacts with the CB1 receptor in our brains, it produces a feeling of “high”. In addition, our bodies are adapted to fine-tune endocannabinoids by activating enzymes like FAAH, and THC is unfamiliar to our bodies, so it is not broken down as quickly by enzymes and lingers in the system longer (Klumpers and Thacker, 2019).
THC can either mimic our internal endocannabinoids and trigger the desired response, or it can unbalance the whole system. When THC interacts with receptors, our endocannabinoid system becomes slightly unbalanced and desensitised to protect against the excessive activity, which is harmful. The lower sensitivity of the endocannabinoid system results in lower levels of endocannabinoids being produced and fewer cannabinoid receptors being located in cells – meaning that people have to consume more THC in order to experience the same sensations as before. However, precise dosing of THC can also lead to positive results, such as a reduction in anxiety and an increase in the release of dopamine, also known as the happiness hormone. Which effect THC will have, whether calming or unbalancing, anxiety-inducing, depends on the dose and the physiology of each individual (Mechoulam and Parker, 2013).
How does cannabis affect the endocannabinoid system?
As we mentioned in this post (Link), cannabis produces a wide range of cannabinoids, but the most studied are cannabidiol (abbreviated CBD) and delta-9-tetrahydrocannabinol (abbreviated THC).
CBD acts as a receptor antagonist – it binds to the CB1 receptor but does not activate it. Therefore, other molecules such as THC cannot bind to the receptor, which is how CBD reduces the effects of THC (Klumpers and Thacker, 2019). As CBD does not directly act on the CB1 receptor, it interacts with other enzymes, receptors and other parts of the cell as ion channels. For example, CBD blocks the activity of the enzyme fatty acid amide hydrolase (FAAH for short), which is responsible for the degradation of the endocannabinoid AEA. As AEA cannot be degraded, larger amounts accumulate, allowing more of the endocannabinoid to interact with the CB1 receptor – a stronger response to the stimulus (McPartland et al., 2015). This is just one of the mechanisms by which CBD affects our endocannabinoid system.
THC, meanwhile, acts as a receptor partial agonist – it binds to CB1 and CB2 receptors, activating them for further signal transmission. When THC interacts with the CB1 receptor in our brains, it produces a feeling of “high”. In addition, our bodies are adapted to fine-tune endocannabinoids by activating enzymes like FAAH, and THC is unfamiliar to our bodies, so it is not broken down as quickly by enzymes and lingers in the system longer (Klumpers and Thacker, 2019).
THC can either mimic our internal endocannabinoids and trigger the desired response, or it can unbalance the whole system. When THC interacts with receptors, our endocannabinoid system becomes slightly unbalanced and desensitised to protect against the excessive activity, which is harmful. The lower sensitivity of the endocannabinoid system results in lower levels of endocannabinoids being produced and fewer cannabinoid receptors being located in cells – meaning that people have to consume more THC in order to experience the same sensations as before. However, precise dosing of THC can also lead to positive results, such as a reduction in anxiety and an increase in the release of dopamine, also known as the happiness hormone. Which effect THC will have, whether calming or unbalancing, anxiety-inducing, depends on the dose and the physiology of each individual (Mechoulam and Parker, 2013).
Bottom line
The endocannabinoid system is only recently discovered, so the exact mechanisms by which it is affected by other phytocannabinoids such as CBD or THC have not yet been studied. The extremely broad spectrum of action of plant phytocannabinoids makes them a promising field for the treatment of a wide range of ailments and symptom relief. Through science, cannabis products are slowly being discovered and are becoming more and more available, so that more people will be able to see for themselves the benefits of cannabis.
References
Klumpers, L.E. and Thacker, D.L. 2019. A brief background on cannabis: From plant to medical indications. Journal of AOAC International. 102(2), pp.412–420.
McPartland, J.M., Duncan, M., Di Marzo, V. and Pertwee, R.G. 2015. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. British Journal of Pharmacology. 172(3), pp.737–753.
Mechoulam, R. and Parker, L.A. 2013. The endocannabinoid system and the brain. Annual Review of Psychology. 64(1), pp.21–47.
Pagotto, U., Marsicano, G., Cota, D., Lutz, B. and Pasquali, R. 2006. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine Reviews. 27(1), pp.73–100.
Pamplona, F. n.d. Endocannabinoid signaling | Mind the Graph. [Accessed 2 June 2021]. Available from: https://mindthegraph.com/profile/fabriciopamplona1/endocannabinoid-signaling#/.
Zou, S. and Kumar, U. 2018. Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. International Journal of Molecular Sciences. 19(3), article no: 833 [no pagination].