Recently we examined in details how CBD interacts with the endocannabinoid system.This interaction is very complex and involves different ways of cannabidiol binding to receptor as well as its indirect effects (the most important being its impact on anandamide). On this occasion we mentioned that the effect of the most important cannabinoid of hemp on the human body is far more complex and not limited to interaction with the dedicated endocannabinoid system – it includes surprising impact on such different and diverse systems as the vanilloid, adenosine, dopamine, and even opioid systems. Continuing our mini-series, today we will look into the mechanism of how CBD interacts with one of the most important and comprehensive systems regulating a whole plethora bodily functions – the serotonin system. It’s been only recently that we started to recognize, let alone understand the impact CBD has on this system (as is the case with many of the cannabinoids’ less-obvious interactions), so although many findings suggesting that serotonin plays an important role in the beneficiary and medicinal properties of cannabidiol, there is no way yet to identify the exact mechanism and extent of this beneficial impact. Along with the complex nature of the CBD’s interaction with other systems, this proves just how complex and potent the substances from the natural pharmacopoeia can be.
The very fact that we can analyze the mechanism of how CBD works on our body on so many different levels and taking into account so many different systems stems from the pleiotropy and promiscuity of the cannabinoids. In this context these terms are closely linked: pleiotropy means that the substance is more than one specific effect, and promiscuity – yup, this is an actual pharmacological term! – refers to the fact that CBD has more than one pharmacological target, that is, that it can bind at more than one type of receptor. It is thanks to this second feature – that the cannabidiol’s molecules tend to seek more than one molecular partner – we can consider CBD’s influence outside of its “dedicated” endocannabinoid system.
It is also worth noting that this pharmacological promiscuity is something typical rather for substances of natural origin and early generation of drugs. There is a simple reason for that – drug manufacturers opt for a potent and possibly most selective product (focusing on one pharmacological target also allows you to avoid potential side effects), whereas Mother Nature is more lavish. This is why substances present in their pure form in plants – such as just the cannabinoids – often demonstrate a full range of diverse beneficiary properties. From the point of view of consumers reaching for hemp products because of their overall positive effect on the body (CBD hemp oil is a prime example of such dietary supplement) such diverse effect is an invaluable advantage, yet considering potential medical uses of cannabis this pleiotropy might cause some problems. Thus, for general health-promoting purpose it is best to go with the whole-plants extracts, whereas the pharmaceutical industry will rather be interested in isolates (coexistence of multiple cannabinoids and their synergies additionally hinders the desired selectivity), or even in the “enhanced” synthetic cannabinoids.
Before we get to how the CBD affects the serotonin system, it is worth noting that the occurrence of this kind of “facultative” interaction depends on the concentration of the substance. While when administered in a smaller dose CBD will only display certain effects associated with its impact on endocannabinoid system, with increasing its concentration in the body the effects of subsequent circuits’ activation will gradually kick in.
Grossly oversimplifying – serotonin is a “hormone of happiness.” In fact, there is strong evidence of its mood-enhancing properties and ‘serotonin hypothesis’ of depression linking this condition with serotonin deficit is also strongly supported. However this neurotransmitter exhibits much more multifaceted effects. Serotonin is an essential neurotransmitter of serotonin (more correctly – serotonergic) system and in addition to regulating the central nervous system it also affects the functioning of many other neurotransmitters … as well as of the digestive system (90% of serotonin is produced in the gut!). Consequently, serotonin regulates such diverse functions of the body and behavior as aggression, learning, appetite, sleep, consciousness and the reward-seeking behaviour.
From a chemical point of view, a serotonin is 5-hydroxy tryptamine derivative (psychedelics’ aficionados will probably perk their ears here) and is often referred to as 5-HT. Serotonin binds at serotonin receptors (also called 5-HT receptors). Scientists have identified seven different types of those receptors. Except for the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors.
Most drugs and substances that affect the body via the serotonin system are either serotonin receptors’ agonists (they stimulate them) or their antagonist (thus inhibiting their work). The former group of compounds includes, among others, psychedelic agents such as LSD, mescaline ( 5-HT2A receptor agonists) the latter – antipsychotic drugs.
CBD and the serotonergic system
As has already been revealed, CBD affects the serotonin system. Of course, cannabidiol binds to serotonin receptors only in a certain concentration, but it certainly shows weak to moderate affinity to several different receptors, possibly producing different effects. This is especially intriguing as-as we described recently – CBD shows fairly weak affinity to receptors of its own endocannabinoid system!
The properties of CBD to bind at different types of receptors, as well as the important and diverse role serotonin plays in the human body can explain a wide range of effects that could be potentially attributed to CBD and serotonin special relation. Let us discuss the most important of those potential effects, bearing in mind that many of these properties are still hypothetical and had been linked with the endocannabinoid system for a long time before scientists’ attention shifted to serotonergic system.
Jose Alexandre Crippa and his colleagues at the University of Sao Paulo and King’s College London have examined in details the well-established potential of CBD in treating stress, and anxiety. They have found that sufficiently high doses of CBD have a sedative effect, not only stemming from their influence on the endocannabinoid system (CBD is an allosteric modulator of the CB1 receptors and halts reuptake of anandamide), but also – and perhaps mainly – from its binding at serotonin system’s 5HT1A receptor. Interestingly, the same study showed no direct impact of the CBD at endocannabinoid receptors CB1 and CB2. Further studies have shown that CBD can in fact be regarded as a moderate 5HT1A receptor agonist, and it is exactly this receptor that is associated with anxiety, addiction, appetite, sleep, pain and nausea. Anandamide – the native endocannabinoid produced by the body – is also an agonist of this important receptor. Taking into account the role CBD plays in enhancing anandamide’s presence in the synapses, one can safely claim that the effect of cannabidiol at the 5HT1A receptor is at least a two-pronged.
It is worth noting that CBDA – cannabidiolic acid, non-oxidized, acidic version of cannabidiol found primarily in fresh and young plants – is also strong (stronger than CBD) 5HT1A receptor agonist.
Another important pharmacological target CBD in the serotonergic system is its 5HT2A receptor. This receptor is responsible among other things for stress, anxiety, headaches, and even for the psychedelic experiences (agents such as LSD and mescaline are its powerful agonists). CBD show a weak affinity to 5HT2A, and is probably its weak antagonist – which could explain both its anti-psychotic and sedative properties as well as its ability to tone psychotic effects of THC (that is – wherever those two compounds are present together in significant amounts together – i.e., in marijuana; in case of hemp products the discussed will not be noticeable).
The third of the major pharmacological targets of CBD in the serotonergic system, the 5HT3A receptor, is interesting in that it operates on a different principle than the other six types of serotonin receptors. 5H3TA is not a G protein-coupled one, instead acts as an ion channel. This receptor is responsible for mood changes, nausea and pain signaling. 5H3TA antagonists are used to treat nausea and vomiting caused by chemotherapy. Cannabinoids such as CBD are potent negative allosteric modulators of the 5H3TA receptor.This means that cannabidiol changes the structure of the channel in such a way that the receptor is less “eager” to bind its native neurotransmitter serotonin. Anandamide – the abovementioned endogenous cannabinoid – exhibits similar properties. Given the direct effect of CBD on the 5HT3A receptor, as well as its vital role in the economy of anandamide, it will be surmised that at least part of the anti-emetic properties of cannabidiol may be associated with the serotonergic system.
It is also worth to mention the indirect impact CBD inflicts on the serotonergic system. Just as with the endocannabinoid system (although in that case the indirect effect of CBD prevails the direct one), in the case of serotonin system cannabidiol can also act by regulating its native neurotransmitter’s metabolism. This can be done in two ways. First, the endocannabinoid system mediates the activity of raphe nuclei – one of the main areas of the production of serotonin. Increased activity of the endocannabinoid system (effect of an increased anandamide supply caused, in turn, by the CBD) stimulates the production and discharge of serotonin, “boosting” the entire system even without CBD’s direct binding at its receptors. At the same time CBD can increase the serotonin supply in a second way – even though it activates the serotonin receptors, unlike serotonin it does not trigger the negative feedback loop. The serotonergic system does not “recognize” CBD as “its kind”, and thus there is no re-uptake of serotonin or stopping its production. Effectively, in the presence of cannabidiol, more serotonin remains in the synapses.
To further complicate the picture of how the CBD affects the human body, we still have to mention the interesting phenomenon of joining receptor systems. G-protein coupled receptors (even belonging to other systems) can sometimes be somewhat entangled to form dimers – A “dimer” is a chemical structure formed when two of receptors floating around join together into a functional unit. As early as in 2002, scientists from the University of Seattle have discovered the dimerization of cannabinoid CB1 receptors – they were connecting with other receptors of the same kind, thus forming homomers. Then, in 2013 a group of Spanish researchers observed 5HT1A receptors joining forces with endocannabinoid system’s CB2 receptors and creating heteromers at which CBD eagerly bonded; this peculiar effect could to some extent be connected with the neuroprotective properties of cannabidiol. However, both the very formation of endocannabinoid-serotonergic dimers, as well as the impact CBD and other cannabinoids have on them is still very poorly studied.
CBD and serotonin – the effects of the health
impact of the CBD on the serotonin system is a fact. Still, it is difficult to determine which of the healthy properties of cannabidiol are results of its interaction with the endocannabinoid system and which can be attributed to the serotonergic one. The existing body of research suggests that at least some of the antipsychotics, antidepressants, mood- and sleep-stabilising, and anti-emetic properties of hemp can be attributed to the serotonin, yet to determine the scale of this impact further studies are needed.
At the end we still need to emphasize one point. Activation of the further pharmacological targets of CBD occurs in its higher concentrations – that is, mainly in the case of administration of medicinal preparations or isolates. Given that the only form the CBD legally and widely available in Poland are its whole-plant extracts with the status of dietary supplements (therefore with a moderate content of cannabidiol) it must be stated that consumers are reaching for hemp preparations because of their general health properties will mainly experience the effects associated with the activation of the endocannabinoid system. Thus, in such cases the impact of the CBD on the serotonergic system will remain rather insignificant. As for the specific case of strictly medical use of cannabidiol, the potential practical meaning of its interaction with serotonin still requires further in-depth studies. Only then we can talk about the practical importance of the impact CBD has on the serotonergic system, an impact that will probably be relevant mostly for the patients benefiting from the medicinal-grade CBD. For the rest – that is, for those reaching for the hemp-based dietary supplements – the relation of the CBD and the serotonergic system remains rather an academic curiosity with limited practical consequences.
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