What is the endocannabinoid system?
The endocannabinoid system (ECS) is a neuromodulatory system that is found throughout the human body. The ECS plays a role in numerous biological processes such as brain development, learning and memory, and maintenance of homeostasis. The system is composed of cannabinoid receptors, endocannabinoids and enzymes that are responsible for endocannabinoid synthesis and degradation.
Endocannabinoids signal via two types of G-protein coupled receptors – cannabinoid receptor 1 (CB1 receptor) and cannabinoid receptor 2 (CB2 receptor). These receptors are widely distributed throughout the body.
Figure 1: location of the CB1 and CB2 receptors in the body.
Additional functions of the ECS:
|CNS||Role in neurogenesis and neuroprotection, sleep patterns and the sensations of olfaction and hearing|
|Cardiovascular system||Cardiovascular injury and inflammation promotion via CB1 receptors, and attenuation via CB2 receptors|
|Gastrointestinal tract||Gut motility and food intake regulation, intestinal inflammation reduction and intestinal barrier permeability enhancement|
|Liver||Cannabinoid receptor expression increases under pathophysiological conditions. Promotion of steatosis, fibrogenesis, hepatic apoptosis and hepatocyte proliferation via CB1 and inhibition via CB2|
|Immune cells||Modulation of immune cell functional activities, predominantly via CB2 receptors|
|Muscle||Regulation of energy metabolism in skeletal muscle and formation of new muscle fibres|
|Bone||Regulation of bone elongation and remodelling|
|Reproductive system||Regulation of multiple stages of pregnancy. Involvement in male fertility via preservation of sperm function|
|Skin||Regulation of skin cell proliferation, differentiation, cell survival, immune responses and cutaneous inflammation suppression|
Any deficiencies in the ECS may result in abnormal or suboptimal function. It has been proposed that endocannabinoid deficiency may be implicated in conditions such as migraines, irritable bowel syndrome, fibromyalgia, multiple sclerosis, Huntington’s disease and Parkinson’s disease.
Where does cannabis fit in?
The cannabis plant contains more than 750 chemicals, of which approximately 104 are phytocannabinoids. Its principal phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The THC:CBD ratio varies between different plant strains.
THC acts as a partial agonist at CB1 and CB2 receptors, exhibiting a higher binding affinity at the former. CBD has little binding affinity for these receptors but is capable of modulating them in the presence of THC. CBD can also reduce the efficacy and potency of anandamide by behaving as a non-competitive negative allosteric modulator at the CB1 receptor.
The level of receptor expression varies between these different tissues. In the central nervous system (CNS), CB1 receptors are expressed at high levels whereas CB2 receptors are expressed to a much lower extent; they in contrast, predominate within the immune system.5 This has implications for the therapeutic impact of cannabinoids on different organ systems throughout the body.
Cannabinoids are a class of chemicals that act on these cannabinoid receptors. Cannabinoids are derived from three sources:
- Endocannabinoids, or endogenous cannabinoids, are neurotransmitters produced in the body
- Phytocannabinoids are cannabinoids produced by plants such as the cannabis plant
- Synthetic cannabinoids are synthesised to be structurally analogous to endocannabinoids or phytocannabinoids and act by similar biological mechanisms
While many questions regarding the mechanisms and functions of the ECS still exist, some facts are known. The ECS is recognised as having a critical role in the fine-tune maintenance of homeostasis. This is due to its wide distribution, its negative feedback regulation, and the rapid synthesis and degradation of endocannabinoids, which ensures that they are not present in the body in high amounts for a long time.2 The most extensively studied endocannabinoids are N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG).
It is known that depolarisation or activation of certain G protein-coupled receptors (GPCRs) triggers the on-demand synthesis of 2-AG, mainly from 2-arachidonoyl-containing phospholipids, which are present in lipid membranes. 2-AG is then released into the extracellular space and acts as a full agonist with high efficacy on both the CB1 and CB2 receptors. Rapid degradation of 2-AG then occurs through numerous different pathways.
Anandamide, another extensively studied endocannabinoid, is synthesised predominantly from N-arachidonoyl phosphatidyl ethanol (NAPE) and released into the extracellular space when triggered by external stimuli. Anandamide acts as a partial agonist at both CB1 and CB2 receptors, although it exhibits very low efficacy at the latter. Similar to 2-AG, anandamide is also rapidly degraded.
Activation of CB1 and CB2 GPCRs results in the activation of many well-established metabolic signalling pathways, including the mitogen-activated protein kinase pathway (MAPK), phosphoinositide 3-kinase pathway (PI3K), cyclooxygenase-2 pathway (COX-2), and modulation of protein kinase B (Akt), as well as several ion channels. In addition, it has also been shown that some cannabinoid receptor agonists or antagonists can bind to, and potentially modulate, other non-cannabinoid GPCRs, including opioid, adenosine, 5-HT, angiotensin, prostanoid, dopamine, melatonin, and tachykinin receptors.
What are the functions of the ECS?
Binding of endocannabinoids to cannabinoid receptors, and subsequent receptor stimulation, causes subsequent downstream signalling, resulting in a variety of biological processes to occur. Principal functions of the ECS includes brain development, regulation of nausea, appetite and pain, seizure susceptibility inhibition, mood elevation, anxiolytic effects and facilitation of learning and memory processing, including the avoidance of aversive situation learning.