Endocannabinoid System Science

CBD and the Serotonin System

What is 5-HT1a?

Although CBD is potentially the most biologically active cannabinoid, it exerts very little effect on cannabinoid receptors. It does bind with relatively high affinity to several other receptors in the brain and body. One of the receptors through which a lot of CBD’s activity is mediated is the serotonin 5-HT1a receptor (5-hydroxytryptamine type 1a).  This is one of the most abundant protein receptors in the human body.  It is present in neurons in the brain and in muscle and gland cells throughout the body.

What activates 5-HT1a?

Serotonin is one of the primary inhibitory neurotransmitters in mammalian brains, and it is the primary endogenous (-from within the body) agonist of 5-HT1a receptors.  One of its most fundamental functions is the inhibition of fear and anxiety.  In addition, it mediates the production of several hormones including oxytocin (associated with love and affection) and HGH (human growth hormone), and the inhibition of other neurotransmitters such as cortisol, which is positively correlated with stress.  Furthermore, chronic overexposure to cortisol levels desensitizes 5-HT1a autoreceptors in the corticolimbic system, which is the center of pleasure, reward, and drive.  In the body, serotonin controls blood pressure through vasodilation of peripheral blood vessels.

How does it work?

In general, a brain is able to do what a brain does because it is made up of billions and billions of neurons which communicate with one another via chemicals that produce a specific response, in a specific kind of neuron, for a specific purpose.  This allows for an enormous magnitude of specialization of neurons and neuronal pathways.

Two neurons that communicate with one another do so through something called a synapse.  A synapse is the small space, around 20-40 nanometers (billionths of a meter) wide, separating the two neurons.  Neuron A, the neuron sending the signal, is called the presynaptic neuron.  Neuron B, the neuron receiving the signal, is called the postsynaptic neuron.

In general, neuron A releases neurotransmitters such as serotonin or dopamine into the synapse, and from there they bind with their specific receptor on neuron B and thereby exhibit their effect.  When a receptor is located on the postsynaptic neuron, it is called a postsynaptic receptor.

However, the serotonergic system is different from many other neurotransmitter systems in that there are also 5-HT1a receptors located on neuron A, called autoreceptors.  The function of autoreceptors is to complete a negative feedback circuit of serotonin production.

This is to ensure that just the right amount of serotonin ends up in the synapse, and the system has been calibrated over millions of years of evolution.  When there is an excess of serotonin in the synapse, it binds with the autoreceptors of neuron A, which inhibits the production of serotonin and stops the neuron from firing.

What is CBD’s effect on 5-HT1a?

CBD is a known agonist of  5-HT1a receptors, just like serotonin.  This means that it binds with the receptor, causing the receptor to produce its effect on the cell.  In the case of most neurons, activation of this receptor causes a reduction in the activity of two key enzymes for cellular activity and metabolism.

With these enzymes suppressed by an agonized 5-HT1a receptor, the overall activity of the cell, including synaptic signalling, is lowered.  In the amygdala, this produces an inhibition of fear and anxiety, and when there is a lack of serotonin, generalized anxiety disorder can result after prolonged stasis in that condition.

By agonizing serotonin receptors, CBD has the same effect as actual serotonin molecules.  This is understood to be one of the main mechanisms of action of CBD’s anti-anxiety and antidepressant effects.

Additionally, CBD also upregulates (increases) the synthesis and release of serotonin.  Because CBD only acts on the external serotonin receptor but not the internal systems of the serotonergic system, activation of the receptor by CBD doesn’t result in a negative feedback response of serotonin synthesis, but by an alternative mechanism, actually increases synthesis and release of serotonin.

Most of the  brain’s serotonin is produced in the raphe nuclei, which is located at the base of the brain near the spinal cord.  From there it is transported through various pathways to the forebrain and limbic systems.  This process is mediated by the endocannabinoid system at least partially, and CBD administration increases the flow of serotonin toward the higher-thought parts of the brain.  This is the third of its subtle actions on the serotonergic system with respect to the relief of anxiety and depression.