Medical Cannabis

Human cells often communicate through the attachment of signalling molecules to receptors embedded in the cell's surface membrane. One kind of these receptors are the G-Protein Coupled Receptors (GPCRs) and among the different kinds of GPCRs are the cannabinoid receptors. There are two types of cannabinoid receptors: CB1 and CB2. They are central to the endocannabinoid system (ECS), which is a relatively new signalling network that was first discovered in the 1980s and we are learning is conserved among vertebrates and is important in many physiologic functions.

CB1 receptors are found primarily on central and peripheral neurons and are thought to primarily modulate neurotransmitter release.

CB2 receptors exist primarily in immune system cells. They are believed to modulate cytokine release.

Signaling through the ECS has been implicated in a wide range of physiological functions and diseases that include:

• Anxiety
• Appetite
• Autonomic functions
• Bladder function
• Cancer control
• Energy balance
• Female reproductive function
• GI function
• Homeostasis
• Inflammation
• Memory
• Metabolic functions
• Cell growth and proliferation
• Motor control
• Neurogenesis
• Neuroprotection
• Neuroplasticity
• Neurotransmission
• Regulation of pain
• Sleep
• Stress response
• Thermoregulation

The endocannabinoids are molecules that naturally bind to the cannabinoid receptors. They are arachidonic acid derivatives and include arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol (2-AG), and 2-arachidonyl glyceryl ether. Deficiency or imbalance of these molecules is hypothesized to be a mechanism of disease.

CB1 and CB2 are also the primary receptors of exogenous cannabinoids (such as the phytocannabinoids from cannabis), which become bioavailable by inhaling or ingesting cannabis products.

Some cannabinoids bind to additional receptors (to varying degrees). These include vanilloid receptor 1 and transient receptor potential ankyrin 1. The effect of signalling through these receptors is hypothesized to result in additional pharmacologic effects of cannabinoids, such as analgesia.

References:
Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):101-21. doi: 10.1054/plef.2001.0341. PMID: 12052030.

In contrast to endocannabinoids that are produced by human cells, the phytocannabinoids are naturally occurring molecules found in plants of the Cannabis genus, including Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Although there are hundreds of phytocannabinoids that have been isolated and identified, there are six main phytocannabinoids present (in varying amounts) in today's medical cannabis products. These phytocannabinoids are cannabichromene (CBC), cannabidiol (CBD), cannabidivarin (CBDV), cannabigerol (CBG), cannabinol (CBN), and tetrahydrocannabinol (THC).

The pharmacology of cannabinoids is an area of active research. The table below summarizes our current understanding of their effects on the human body.

Additional phytocannabinoids of interest for their potential in treating seizure disorders include cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), and cannabigerovarinic acid (CBGVA).

Phytocannabinoids have precursor forms that may have distinct characteristics or medicinal value. An example is CBDA, which is converted to CBD and CBC through exposure to heat and light. CBDA is a candidate COX-2 enzyme inhibitor, making it a potential anti-inflammatory drug.

Some phytocannabinoids can be converted to others. For example, when THC is exposed to heat and light, the much less psychoactive phytocannabinoid CBN is formed. Similarly, when CBG is exposed to heat and light, THC and CBD are formed.

References:

Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy. Br J Pharmacol. 2021 Dec;178(24):4826-4841. doi: 10.1111/bph.15661. Epub 2021 Sep 30. PMID: 34384142; PMCID: PMC9292928.

Cannabis-Based Products for the Treatment of Skin Inflammatory Diseases: A Timely Review. Pharmaceuticals (Basel). 2022 Feb 9;15(2):210. doi: 10.3390/ph15020210. Erratum in: Pharmaceuticals (Basel). 2022 Jul 11;15(7): PMID: 35215320; PMCID: PMC8878527.

Terpenes are naturally occuring, aromatic compounds contained in the cannabis flower and they contribute to both the fragrance of cannabis and the drug effects of the cannabinoids. The interaction between cannabinoids and terpinoids is often referred to as the "entourage effect". Over 100 terpenes have been identified so far and the extent of their ability to modulate the effects of cannabinoids is another area of active research.