How CBD interacts with the endocannabinoid system?

Keys and locks

Let’s begin with reminding the basic mechanism of how the cannabinoids work in the body (and not only in human one). Cannabinoids are the name for the whole class of substances that act on the endocannabinoid system. Receptors of this system are scattered all over the body, and the parts of the body with the highest concentration of those receptors are also the places most affected by cannabinoids. Receptors of this system (the most important ones being CB1 and CB2) are best compared to the locks – they are designed to be opened by the particular key. The default keys (or “natural” ones, if you will) are the endocannabinoids – cannabinoids synthesized by the body itself. The best-known endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG).
Before we examine closer the different receptors and different ways they can work, we have to complete the picture by mentioning the “picklocks”. Those are substances which, though not produced by the body, do actually fit into the endocannabinoid system’s “locks”. In case of the endocannabinoid such “picklocks” are of course the plant-derived cannabinoids (“phytocannabinoids” – substances such as THC or CBD), but also controversial synthetic cannabinoids. It is worth remembering that the ability of substances of the exogenous origin to connect to body receptors is not at all a unique feature – this is exactly how we get affected by (and sometimes addicted to) ginger, ginkgo biloba, coffee, opiates… Some “picklocks” are indeed crafted so perfectly, that the receptors “prefer” them over the original, innate triggers – and this is, among many other factors, the reason why substances such as opiates can be dangerous. In the case of cannabinoids, we do not have this problem, which does not change the fact that the plant cannabinoids can affect our body in many different ways.

Agonists and antagonist

Before getting to CBD we should also discuss what does it mean that a substance “activates” the receptor. In the most simple terms join compound x attaches itself to the end of the synapse to stimulate it and help it to transmit the electrical signal. A substance that does that is called an agonist. The agonist causing a certain action is the simplest form of substance(ligand)-receptor interaction and corresponds to the key metaphor used in the previous paragraph.
If there is an agonist, there must be some antagonist – a substance causing the opposite effect, thus blocking the receptor. For this reason, the antagonists are sometimes referred to as blockers. Similar is the way the inverse agonists work – as one might imagine, these are compounds which although operate as agonists (they bind to receptors in the same manner and at the same site as agonists do), but their effect is reversed.
You should know that for many substances the threshold between agonistic and antagonistic action is fluid and depends on the dose of the substance.
Finally, you need to mention another type of interaction with the receptors. This is the allosteric modulation – a process in which the substance modifies the way the receptor works, though not stimulating it directly. After a positive modulation of the receptor, it will respond more vigorously to stimuli and transmit signals faster and “more eagerly”, in the case of the negative modulation it works the other way around. In this type of regulation, the ligands bind to the receptors in other sites – while in the case of “regular” agonistic and antagonistic effect the binding site is the “standard port” (orthosteric site), in the case of allosteric modulation substance connects to – you guessed it – the allosteric site. So much terminology, let’s finally get to CBD.

CBD and the endocannabinoid system

Finally, we got to the effects of the CBD. As we shall see – the way it impacts the endocannabinoid system is complex – and by no means obvious. The first surprise may be the fact that the CBD has a rather low affinity for endocannabinoid receptors. This means that for the receptors the CBD is not a “first choice” compound, they definitely “prefer” wither the innate anandamide, or psychoactive THC (if so happens that the CBD and THC are present in the system in the same time).
As for the CB1 receptor, for a long time, it was believed that the CBD is his weak antagonist. The research from 2015 has shown, however, that in addition to it being a weak antagonistic of this particular receptor, CBD also binds with it in a little different place and in a different way. It turned out that the CBD is also a strong negative allosteric modulator of the CB1 receptor. The most spectacular effects of these features can be observed in the presence of THC. It was known for quite some time that CBD significantly reduces the psychotic potential of its “evil twin” – THC. Now it is proven that the property is the result of modifying the way THC works on the CB1 receptor.
Let’s move on. The second major endocannabinoid receptor is the CB2 receptor. Among many other functions, it is responsible for the emergence of inflammation. In the case of CB2, we are dealing again with the opposite effect of THC and CBD. While the former is responsible for receptor stimulation, CBD is an inverse agonist of the CB2 receptor, thus it weakens its efficiency. The anti-inflammatory properties of the CBD can be attributed to this very mechanism, yet but it is worth noting that it has been shown that cannabidiol is actually a quite weak inverse agonist of CB2, so its impact on the receptor is negligible.
So where does the rich beneficial potential of cannabidiol come from if CBD works on one receptor indirectly (e.g. inhibiting the action of THC, and remember we are talking here about the effects of hemp’s cannabidiol, where there is no THC) and with the other receptor it interacts only marginally? Well, the effects of CBD stem from both its indirect effects on the endocannabinoid system, as well as from its pleiotropy – that is, its potential to influence a wide range of various other systems. As this second point, though extremely interesting, is also quite complex, we will look at it some other time. The last part of this article will explain the first of the abovementioned factors – the indirect impact of the CBD on the endocannabinoid system.

Not only receptors. The indirect effects of CBD on the endocannabinoid system

CBD affects the endocannabinoid system also in two other important ways – by modifying the activity of this system’s enzymes and transport proteins, and thus – the concentration of anandamide – the “default” endocannabinoid.
Let’s begin with enzymes. When it comes to systems of the body, it is often forgotten that the system consists not only of the receptors and the “dedicated” neurotransmitters but also of the enzymes which regulate the whole mechanism. In the case of the endocannabinoid system, the one key enzyme is the fatty acid amide hydrolase (FAAH). FAAH is responsible for the breaking down (degradation) of anandamide, a process of which CBD is an inhibitor. In other words – cannabidiol makes the enzyme that should break down anandamide not work as efficiently as it should, which leads to an increased concentration of anandamide in the system, therefore its increased impact. As we see, the CBD does not work here directly, instead, it enhances the effects of the natural element of the system in question. However, it has also been discovered that CBD is actually a quite weak inhibitor of FAAH – so the cannabidiol effects cannot be attributed wholly (or even largely) to its interaction with enzymes.
Another part of the system, which shows how broad the effects of cannabidiol are is the FABP – fatty acid-binding protein. As the name suggests, these proteins are responsible for binding – in this case, they bind to already present in the synapse anandamide in order to transport it outside the synapse, where it is broken down by the abovementioned hydrolase FAAH. Similarly, as in the other case, here the CBD effectively competes for the FABP “attention”, effectively taking its place in the deadly embrace of FABP. This heroic sacrifice of CBD causes less anandamide to be metabolised, therefore it remains longer in the system and its effect enhances.
“Cleaning” synapses from the excess neurotransmitter (by FABP in this case) is called reuptake, and slowing this process down is the way how many different drugs and psychoactive substances work We can, therefore, say that the CBD is anandamide reuptake inhibitor. It sounds great, but as we have seen above it is only a part of the mechanism of how CBD works.

One substance – many possibilities

We have outlined the CBD impact on the endocannabinoid system. As we mentioned – CBD also affects many other systems and these interactions result with the broad spectrum of CBD’s beneficial effects. Now, let’s summarize briefly what we already know about the effects of CBD on the endocannabinoid system:
• CBD is a weak antagonist of CB1 receptors (which may be associated with its effect on pain sensation)
• CBD is a strong negative allosteric modulator of the CB1 receptor (CBD attenuates the psychotropic effects of THC – of course, in the situation which they are administered together, but generally this property might be linked to antipsychotic and sedative effects of cannabidiol)
• CBD is a weak inverse agonist of the CB2 receptor (which is associated with its anti-inflammatory properties),
• CBD is an inhibitor of fatty acid amides hydrolase (slowing down the decomposition of anandamide)
• CBD is an anandamide reuptake inhibitor (keeps its concentration in the synapses at a high level)
As can be seen, the broad scope of CBD effects can be explained by its nuances effect on endocannabinoid system – to a certain extent. Generally, we find that CBD’s action is mainly indirect – that its main role in enhancing the effects of anandamide – the native neurotransmitter of the endocannabinoid system.
At the same time, we see that in order to fully understand the rich spectrum of cannabidiol’s effects we will need to go beyond the endocannabinoid system and look at the effect of CBD on other systems. We will do so in the next article.

References:
1. Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signalling in the nervous system. Chem Rev. 2008;108(5):1687-1707. doi:10.1021/cr0782067
2. Bennett G.: Does the CBD Bind at the CB1 receptor? Yes and No
3. Chung H, Fierro A, Pessoa-Mahana CD. Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study. PLoS One. 2019;14(7):e0220025. Published 2019 Jul 23. doi:10.1371/journal.pone.0220025
4. Jacobs DS, Stephen BA, Kohut J, Jiang S., Nikas SP, Makriyannis A., Bergman J. Acute and chronic effects of cannabidiol on Δ9-tetrahydrocannabinol (Δ9-THC)-induced disruption in stop signal task performance. Exp Clin Psychopharmacol. 2016 Oct; 24(5): 320–330.
5. Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi:10.1007/978-3-319-45541-9_4
6. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35:764–774
7. How CBD Works
8. THC & CBD – Promiscuous Partners With Receptors Many
9. Turned on by Cannabinoids – CB1 receptor Pharmacology

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