Serotonin is important for regulating pain, mood, cognition, and more. Here is why the serotonergic system is important for certain effects of THC and CBD.
The endocannabinoid system (ECS) is highly intertwined with the monoamine neurotransmitters, which include dopamine, norepinephrine, and serotonin.
In fact, many of the effects of THC and CBD would not exist without these systems. I have already covered 5 Effects of THC That Are Due To Dopamine. Below, you will learn about the importance of the serotonergic system for both THC and CBD.
The Serotonergic System
Neurons which produce serotonin originate in the brain stem in several areas which make up the raphe nuclei. These neurons extend along many different pathways that can be categorized as ascending or descending.
Ascending pathways project to higher brain regions, such as the cortex, limbic system, and hypothalamus. They regulate perception, cognition, memory, and mood.
Descending pathways project to the brain stem, cerebellum, and spinal cord. They regulate movement, body temperature, and pain.
Upon stimulation of serotonergic neurons, serotonin is released into the neuronal synapse, where it can activate serotonin receptors. There are 14 different serotonin receptors, each of which regulates distinct effects of serotonin.
Serotonin is subsequently removed from the synapse by the serotonin transporter (SERT). Intracellular serotonin levels can also be regulated by the degrading enzyme monoamine oxidase A (MAO-A).
Mechanisms of How THC/CBD Can Interact With Serotonin
You may read that THC is capable of inhibiting both serotonin-metabolizing MAO activity (2010 study) and serotonin reuptake activity (2007 study). However, it does both of these so weakly that it is not likely to be clinically relevant. Here are 3 ways that THC and CBD can interact with the serotonin system that are likely to be important:
CB1 activation enhances serotonergic neuron firing
CB1 receptors are expressed directly in some serotonergic neurons, but also in GABAergic and glutamatergic neurons that regulate the activation of serotonergic neurons. Both endocannabinoids and THC were shown to increase serotonergic neuron firing in animals.
However, studies of serotonin levels in different brain regions after treatment with cannabinoids have produced conflicting results. This may be due to biphasic effects, where cannabinoids can increase serotonin under some conditions, but decrease them under others. But overall, it appears that CB1 activation tends to increase serotonin release.
CB1 can interact with the 5-HT2A receptor
The CB1 receptor is capable of directly binding to other receptors to form what is called a heterodimer or heteromer. This is one way that the ECS can interact with other neurotransmitter systems.
A 2015 study demonstrated that CB1 receptor can form a heteromer with the 5-HT2A receptor. This heteromer exists in brain areas such as the hippocampus, dorsal striatum and cortex and mediates some of the memory-impairing and anti-anxiety effects of THC.
CBD can directly activate the 5-HT1A receptor
CBD is an agonist of the 5-HT1A receptor, which underlies some of its anxiolytic, antidepressant, neuroprotective, antiemetic, and antinociceptive properties.
Effects of THC & CBD That Depend Serotonin Receptors
Here are the top 6 cannabinoid effects that are mediated through serotonin receptors. Remember that these studies were performed in animals and that in many cases these effects have not yet been confirmed to be clinically meaningful in humans.
Although CB1 receptor agonists (such as THC) can reduce pain through several different mechanisms, one may involve serotonin. A 2010 study showed that CB1 agonists reduced acute pain through activation of descending spinal serotonin pathways and subsequent activation of 5-HT2A and 5-HT7 receptors in the spinal cord.
There are also serotonergic mechanisms for reducing neuropathic pain with CBD. For example, a 2019 study showed that inducing neuropathic pain in mice reduced serotonergic firing of the spinal pathway. CBD reversed these changes and improved neuropathic pain partially through the 5-HT1A receptor.
Both THC and FAAH inhibitors, which raise levels of anandamide, can improve animal models of depression. The antidepressant effects of these molecules went away when animals were depleted of serotonin (2016 study, 2018 study), indicating that they are working at least partially through increasing serotonin release.
In addition, the antidepressant effect of CBD in animal models depended on activation of the 5-HT1A receptor (2016 study). Read more about the effects of cannabinoids in depression.
Low dose THC and FAAH inhibitors can have anti-anxiety effects. A 2007 study showed that anti-anxiety effects of THC depended on the 5-HT1A receptor, although a 2015 study demonstrated a dependence on the 5-HT2A receptor.
CBD also has an anti-anxiety effect that is mediated by activating the 5-HT1A receptor in some experimental models. However CBD treatment of chronically stressed mice had an anti-anxiety effect mediated through cannabinoid instead of serotonin receptors (2018 study).
4. Memory Impairment
As mentioned earlier, memory impairments caused by THC depended on formation of a heteromer between the CB1 receptor and the 5-HT2A receptor. A 2018 study confirmed that this heteromer exists in humans and its levels, which were increased in cannabis users, inversely correlated with working memory.
CBD is reported to reverse some memory impairments of THC, and it may do this through activation of 5-HT1A receptors (2019 study).
Anti-nausea effects of CBD in animal models were mediated by agonism of 5-HT1A receptors in the brainstem (2012 study).
6. Body Temperature
Hypothermia, or lowered body temperature, is an effect of THC that many people may not even know about. This effect also involves 5-HT1A receptors in the brainstem (2001 study).
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