Cannabinoid Pharmacology

Mechanism of action of cannabinoids

The human body endogenously produces a class of cannabinoids called endocannabinoids. These interact with the endocannabinoid system to regulate a variety of physiological processes including synaptic plasticity, appetite, pain, mood, memory, among others.

The endocannabinoid system includes two components: 1) neuromodulatory lipids, and 2) their receptors in the brain.

  • Neuromodulatory endocannabinoid lipids include the endogenous arachidonate-based lipids anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG).
  • The enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase(MAGL) are responsible for the degradation of AEA and 2-AG, respectively.
  • Generally, endocannabinoids interact with cannabinoid receptors (CB1 and CB2) present in the central and peripheral nervous systems.

Similar to endocannabinoids, phytocannabinoids can bind to the CB1 and CB2 receptors of the endocannabinoid system to exert various physiological effects. CB1 and CB2 receptors are G-protein coupled receptors that are important modulators of neurotransmission. This modulatory role is generally inhibitory in nature through the inhibition of adenylyl cyclase thereby reducing signalling by cAMP-binding proteins in the cell. As ligands to these CB receptors, phytocannabinoids interact with many neuroendocrine and neurochemical systems, including but not limited to the glutamatergic, GABAergic, serotonergic, and dopaminergic systems. Cannabinoids can be reversible agonists, partial agonists, or antagonist or inverse agonists; this depends on the cannabinoid in question, the target receptor, and its concentration.

In addition to binding to CB1 and CB2, cannabinoids can also interact with other receptors such as serotonin receptors, melatonin receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), and other G-protein coupled receptors, to further regulate physiological processes of pharmaceutical interest.

Distribution of cannabinoid receptors and the general mechanism of action are shown in Figures 3-5.

Cannabinoid receptor distribution in the human body