Cannabis and the Serotonin Receptor Pathway
by Tamir Bresler, Assistant Editor of Terpenes and Testing Magazine
Consumption of cannabis can affect us in a various ways. This is due, in part, to the gigantic number of biologically-active molecules that are present in cannabis plants. It’s also due to the astounding number of ways in which cannabinoids seem to interact with the macromolecules and cells of our bodies—ways that we are continuing to discover. Many of these interactions are mediated by the endocannabinoid system (ECS) spread throughout our tissue. But another pathway of effect that is not nearly as appreciated is via its antagonism, or inhibition, of the serotonin receptor type 3.
Serotonin, also known by its chemical nomenclature 5-hydroxytryptamine, is a major stakeholder in the mammalian neurotransmitter deck of cards, which also includes dopamine, glycine, acetylcholine, and gamma-aminobutyric acid (GABA). Like the other neurotransmitters, serotonin is a rather simple molecule, featuring a histamine-like moiety attached to a phenol ring. Rather than getting it from our diet, our neurons make serotonin from the essential amino acid tryptophan. They then store it in vesicles at the end of nerve cells, called axon terminals, where they await some signal to “become activated”, the vesicle fusing with the axon membrane and spewing the serotonin out into the space between two axons, or the synapse.
Figure 1. In some ways, the neurotransmitters dopamine and serotonin provide complementary pathways in human and mammalian cognition, as highlighted by the image above. Serotonin, in particular, is implicated in mood, memory, sleep, and (not mentioned above) bowel function.
There are currently estimated to be 14 types of serotonin (5-HT) receptors, each involved with different functions and present in different parts of the body.  They are responsible for passing on such important messages as the constricting of blood vessels (5-HT1B) , urinary bladder contraction (5-HT2A) , memory consolidation (5-HT5A) , and many more.
The 5-HT receptors also modulate the release of the other important neurotransmitters from their respective vesicles.  For example, 5-HT2C regulates mood and anxiety by inhibiting the release of dopamine and norepinephrine in certain areas of the brain.  Decreasing the activity of this receptor is what causes increased dopamine release in response to “reinforcing” drugs that make us happy and create cravings. These include caffeine, nicotine, morphine, cocaine, and more. 
The odd receptor that stands out from this family, 5-HT3, is responsible for passing along the gastric feeling of an upset stomach, particularly the symptoms of nausea and emesis (vomiting). The message of having these symptoms seems to be sent out from the stomach via activation of these receptors in the axons of the nerve cells that innervate the gastro-intestinal system. Therefore, theoretically speaking, it makes logical sense that shutting these receptors off, or turning their intensity down, would knock the signal of having these symptoms down. And that’s exactly what happens.
Figure 2. There are many things that can contribute to the vomiting reflex. From the gastro-intestinal system, the 5-HT3 receptor is a key effector.
It turns out that 5-HT3 receptor antagonists, both specially-developed pharmacology agents as well as cannabis and cannabinoid derivatives themselves, work extremely well in reducing or eliminating the symptoms of nausea and vomiting.  The first such agent, Ondansetron, was developed by the pharmaceutical giant GlaxoSmithKline (GSK) in 1984 and went to market with FDA approval in 1991. 
Amazingly, the cannabis treatments that have been approved by the FDA don’t just work on the everyday upset stomach—they work on medication-resistant, chemotherapy-induced nausea and emesis. For some patients, cannabis products or isolated cannabinoid derivatives are the only agents that actually work to reduce their symptoms, even more so than pharmaceutical preparations. Not only that, but cannabis is the only antiemetic that also increases appetite.  Clearly, some heavy antagonism of this receptor by cannabinoids is going on.
The big breakthrough in cannabinoid science was discovering the mammalian endocannabinoids that interact with the ECS receptors CB1 and CB2, which are the same receptors through which THC exerts its effects on the human body.  But the activity of THC on these receptors alone couldn’t explain all of the physiological outcomes. There also seemed to be a missing piece when it was discovered that CBD doesn’t directly activate or modulate the cannabinoid receptors. 
The exact mechanism by which cannabinoids inhibit 5-HT3 is yet unknown. However, evidence has shown that CBD and THC inhibit the 5-HT3 receptor in a dose-dependent manner, independent of the concentration of serotonin.  In other words, the inhibition that was observed was the same regardless of how much serotonin is present. This suggests that the cannabinoids function as noncompetitive inhibitors.
Experimental data suggests that the inhibition of 5-HT3 may specifically occur as a result of “desensitization” of the receptor.  That means that exposure to the cannabinoids over time increases the threshold of activation, making the receptor less sensitive. This desensitization seems to directly contribute to the magnitude of inhibition being observed.
It’s worth pointing out that in addition to modulation of 5-HT3, cannabis was also shown to have activity against other serotonin receptors.  Particularly, the anti-anxiety (anxiolytic) activity of CBD, as well as its countering of oxidative stress and inflammation, seems to be at least partly mediated by 5-HT1A on the receiving neuron.
There’s a lot of science to unpack in this article. The most important things to note are that serotonin, which is an integral part of our nervous system’s messaging transmission, has lots of different receptors, and cannabinoids seem to interact with them in diverse ways that are still being discovered and explored. It’s through these interactions that some of the most robust and unique benefits of cannabinoids can be achieved. As time goes by, research will pull back the curtain even further on what goes down in 5-HT3 town.
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Image Credit: Natural Living Ideas