50 years back, when researchers suggested that the main cause of clinical depression is “serotonin deficiency”. Although in present research studies, it turns out that the pathogenesis of depression is much more complicated than previously thought.
It is true that serotonin ( 5-HT from the proper chemical name 5-hydroxytryptamine) is a versatile compound that regulates many physiological functions in the body. In addition to being a neurotransmitter of the central nervous system responsible for mood, appetite, sleep, memory or learning. Practically 90% of serotonin is found in the cells of the digestive system, which helps to control the appropriate regulation of bowel motility.
5-HT affects the body by binding to serotonin receptors classified as 7 subgroups (5-HT1, 5-HT2 …).
The new scientific discoveries regarding serotonin have now commenced after the biochemist Maurice Rapport in the late 1940s isolated this compound and established its molecular structure. We had to wait several decades to discover that the receptors for serotonin – 5-HT1 and 5-HT2 (named 5-HT1A and 5-HT2A) were identified in the rat brain, and more recent studies have confirmed this.
Apart from serotonin, they can bind other molecules to serotonin receptors. In 2005, researchers determined that cannabidiol (CBD) receptors (CB1 and CB2) can bind to serotonin receptors. He points to a broader relationship between endocannabinoid and serotoninergic systems. After all, they are involved in similar physiological functions in the human body i.e. reducing anxiety, pain, relieving nausea and maintaining a proper body temperature.
From a pharmacological point of view, cannabinoid and serotonin receptors belong to the so-called G-protein-coupled receptors. As we have seen, this type of receptors can combine to form dimer-like complexes (a dimer is a structure made up of two receptors that merge together into one functional unit.)
A new discovery
A breakthrough discovery was made by Spanish scientists studying cerebral ischemia in newborn piglets. They showed that the neuroprotective effect was mediated by the serotonin receptor 5-HT1A connected to the CB2 cannabinoid receptor in the dimeric complex.
There are descriptions in the scientific literature that show that CBD is a weak 5-HT1A receptor agonist. Recall – an agonist is a compound that binds to the receptor and on this basis triggers its action on the body. On the contrary, acts against it as an antagonist that blocks the receptor.
CBD acts as an agonist against 5HT2A receptors
It has been shown that activation of the 5-HT1A receptor by cannabidiol lowers blood pressure, slows down the heart rate and reduces the sensation of pain. However, from an article published in the British Journal of Pharmacology, it appears that CBD prevents liver damage, reduces anxiety, pain and nausea in laboratory animals based on this mechanism of action. Interestingly, CBDA (cannabidiol acid) – the acid precursor of cannabidiol, present in large amounts in a crude cannabis plant, is a stronger 5-HT 1A agonist than CBD, and therefore very high hopes are associated with the possible use of this compound as an antiemetic.
CBD also has a link with the 5-HT2A receptor, although it is weaker compared to the 5-HT1A receptor and is mediated by antagonism. While CBD stimulates the 5-HT1A receptor, it apparently acts as an antagonist to 5-HT2A. The 5HT2A receptor is referred to as psychedelic because its strong agonists are compounds such as LSD or mescaline.
5-HT2A & CB1 Receptors
It is important to note that oral intake of a large dose of marijuana resin (called hashish) can produce effects likened to LSD. Long-term hemp researcher Dr Ethan Russo advised that THC is a hallucinogenic factor in the hash. While closely related cannabidiol (CBD) has opposite activity.
Is it possible that the compound 5-HT2A receptor effectuates the hallucinogenic properties of THC? Contrast to CBD, THC does not directly bind to 5-HT2A. However, as mentioned earlier, THC can directly activate the CB1 cannabinoid receptor, and from the article published by PLoS Biology in 2015, we know that CB1 receptors form a complex structure with 5-HT2A receptors, hence the hallucinogenic effect after ingestion of hashish.
The 5-HT3A receptor is unique among serotonin receptors because, unlike all other serotonin receptor subtypes, 5-HT3A is not a G protein-coupled receptor. Rather, 5-HT3A acts as an ion channel that regulates the flow of ions across the cell membrane and contributes to creating fast electrical signals in the brain. 5-HT3A receptors are involved in mood modulation as well as in the transmission of pain signals.
THC and CBD as potent modulators
5-HT3A receptor blockers (antagonists) are used to treat nausea and vomiting induced by chemotherapy. Both THC and CBD are potent, negative allosteric modulators of 5-HT3A receptors. This means that these compounds change the shape of the receptor so that the molecule that originally activates it (eg serotonin) is unable to bind to it. This may explain some of the antiemetic effects of THC and CBD.
Until now, the interactions between cannabinoids and other serotonin receptors (5-HT4,6,7) have not been fully identified. However, ongoing research will let us know in the near future.
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