MEDICAL CANNABIS OVERVIEW
For the last two decades, the number of clinical studies providing evidence demonstrating the therapeutic benefits of cannabis have been increasing. Cannabis-derived medicine brings renewed hope to patients suffering with diseases such as chronic neuropathic pain, cancer, epilepsy, chronic obstructive pulmonary disease (COPD), acquired immune deficiency syndrome (AIDS) and diabetes(3). Furthermore, with the current opioid crisis affecting North America, medical cannabis has been a promising alternative to opioid pain medications(1). Specifically, in the USA in 2017, the hospitalization rate for opioid painkiller dependence/abuse and for opioid overdoses declined on average by 23% and 13% respectively in states where marijuana was permitted for medicinal purposes(2).
Due to emerging research and anecdotal reports, we believe that cannabis therapies are the future of medicine. As such, it is imperative that we promote access to education and awareness on the results of such research.
THE ENDOCANNABINOID SYSTEM
The endocannabinoid system is a signaling pathway that occupies the central nervous system (CNS; brain and spinal cord), peripheral nervous system (PNS) and immune pathways (3, 4). This network is comprised of two major receptors: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). The binding of cannabinoids to these receptors affect the release of neurotransmitters and cytokine signalling molecules, causing a cascade that influences a number of physiological processes such as immune response, pain sensation, cardiovascular function, bone development, digestion, metabolism, wake/sleep cycles, learning, pain response, and regulation of stress and appetite (3-5).
Cannabinoid ligands are categorized into three groups based on their origin:
1. Endocannabinoids are produced endogenously within the human body and include compounds such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG).
2. Phyto-cannabinoids are produced in the vegetative matter of plants, specifically cannabis and hemp, and include two of the most widely studied cannabinoids THC and CBD.
3. Synthetic cannabinoids are developed chemically within a laboratory setting to mimic those naturally created (5, 6).
Figure 1: Location of CB1 and CB2 Receptors(7)
SIGNALLING THROUGH CANNABINOID AND OTHER RECEPTORS
- CBD cannabidiol
- CBDV cannabidivarin
- CBG cannabigerol
- CBG cannabigerovarin
- THC tetrahydrocannabinol
- THCV Δ9-tetrahydrocannabivarin
CB1 and CB2 receptors are expressed throughout the body (Figure 1). CB1 is found primarily in the CNS while CB2 receptors exist predominantly in the peripheral tissues including the immune system and related organs. A number of cannabinoids, including endogenous AEA and exogenous THC, have a high affinity for CB1(8). Interactions with this receptor affect signal transmission (Figure 2), leading to the physical and psychotropic effects brought on by whole-plant cannabis use, as well as sensations including euphoria (3, 4). THC has a weaker attraction to CB2 receptors that, unlike CB1 receptors, do not elicit psychoactive effects, but rather elicit a range of therapeutic benefits including relief from pain and symptoms of neurodegenerative diseases including multiple sclerosis (MS)(9) and Huntington’s disease (HD)(10).
Figure 2. Endocannabinoids and nerve signal transmission (10, 11).
When the presynaptic terminal releases neurotransmitters, this causes an influx of Calcium (orange dots) into the postsynaptic terminal. This stimulates the synthesis and release of endocannabinoids (2-AG), which binds to CB1 receptors that inhibitsfurther release of neurotransmitters and stops signal transmission.
- 2-arachidonolglycerol (2-AG)
- Diacylglycerol lipase-α (DAGLα)
- Anandamide (AEA)
- N-acyl-phosphatidylethanolamine (NAPE)
- NAPE-specific phospholipase D (NAPE-PLD)
- Neurotransmitter (NT)
- Arachidonic acid (AA)
- Monoacylglycerol lipase (MAGL)
- Fatty acid amide hydrolase (FAAH)
- Ethanolamine (EtNH2)
Thin arrows indicate enzymatic process; thick arrows indicate translocation; blunted arrow indicates inhibition.
Cannabinoids such as CBD affect CB1 and CB2 indirectly by preventing the breakdown of certain cannabinoids (ex. THC) allowing for their accumulation and subsequent method of action. Furthermore, CBD activates several non-cannabinoid receptors including serotonin receptors (5-HT) and glutamate receptors (NMDA) that are responsible for mood, sleep, pain and memory (4, 6, 12), and are the target of many pharmaceutical drugs involved in depression, pain, and neuroprotective effects. There are in fact many cannabinoids, both endogenous and phyto-derived, that have demonstrated interactions with receptors other than CB1 and CB2(8, 13) including cannabinoids AEA, 2-AG, THC, CBD, THCV, CBG, CBGV, and CBDV thathave been shown to interact with receptors involved in thermal sensations, (8, 13), (14), (15),(16), pain and motor skills (17), and cell function(18, 19).