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Cannabidiol Popularity Raises Questions for Clinicians

September 04, 2019

By Andrew Penn, RN, MS, NP, CNS, APRN-BC
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Like more well-known systems such as serotonin, the endocannabinoid system is comprised of neurotransmitters (ligands) synthesizing enzymes for these neurotransmitters, receptors, and degrading enzymes. The CB1 receptor is the most widely distributed G protein-coupled receptor in the central nervous system. As is often the case in the history of receptor pharmacology, the discovery of the cannabinoid receptor sparked interest in discovering the endogenous ligand for this receptor. The two primary endocannabinoid neurotransmitters are anandamide (Sanskrit for “bliss,” abbreviated AEA) and 2-Arachidonoylglycerol (2-AG). AEA and 2-AG are synthesized in response to increased intracellular calcium at the postsynaptic terminal. AEA is synthesized by N-arachidonoylphosphatidylethanolamine (NAPE) and 2-AG by diacylglycerol (DAG).6

It is important to understand that these neurotransmitters are not stored in vesicles like monoamines, but rather, are made on demand and released across the synaptic cleft towards the CB1 receptors that are expressed on the presynaptic membrane. The CB1 receptor has both an orthosteric site (which is the target for AEA, 2-AG, and THC) and an allosteric site (which is the target for CBD). CB2 receptors are mostly located on immune cells7 and may modulate inflammation but are not the focus of this presentation.


The cannabis plant is a complex manufacturer of more than 500 different compounds, of which more than 100 are cannabinoids. The remainder are terpenes (which not only give cannabis its distinctive odor, but also may contribute to the psychoactivity of cannabinoids by influencing the permeability of the blood-brain barrier), phenolic compounds, steroids, and enzymes. It is important to know that these compounds often work in concert with the endocannabinoid system and with each other, known as “the entourage effect.”8,9 While THC was the first cannabinoid to be extensively studied, the increasing interest around CBD will be the focus of my presentation.

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CBD is often described as the “nonpsychoactive” cannabinoid (to distinguish it from the decidedly active THC) but a more accurate description would be “nonintoxicating,” as it is quite clear that while CBD is without the euphoriant or stimulus-distorting qualities of its THC kin, it appears to have potential benefits in the treatment of anxiety, depression, and psychosis, if early studies prove to be replicable.10,11,12

The endogenous ligands for the CB1 receptor, AEA and 2-AG, are partial agonists at this site, which is to say they partially activate the G protein-coupled receptor. THC is also a partial agonist at the orthosteric site of the CB1 receptor (some of the synthetic cannabinoids known as “spice” are full CB1 agonists, accounting for their significantly greater potency and intoxicating effects). In the absence of CBD, this receptor, partially activated, is responsible for the subjective effects of THC. Interestingly, CBD acts as a positive allosteric modulator at the CB1 receptor, so when CBD is bound to the allosteric site13 the confirmation of the orthosteric site changes, attenuating the ability of THC to activate the CB1 receptor. Subjectively, this results in a modulation of the intoxication and reduction of paranoia occasioned by THC.14 Cannabis users report that strains with a high amount of CBD (especially if the quantity of THC is low) will be less intoxicating than a strain with low concentration of CBD and high concentrations of THC.

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