The Endocannabinoid System
This endocannabinoid system is a central regulatory system that affects a wide range of biological processes. It is believed to be one of the most important and widespread receptor systems involved in establishing and maintaining human health. For thousands of years, people all over the world have known the effects of cannabis, yet it was not until the early 1990s that research scientists discussed and identified “the endocannabinoid system.”
This system consists of a group of molecules known as cannabinoids, as well as the cannabinoid receptors to which they bind; in essence, our bodies have a network of lock-and-key chemical receptors that respond to the signals of cannabinoids.
Endocannabinoids and their receptors are found in the brain, central nervous system, organs, connective tissues, glands, and immune cells.
What Does The Endocannabinoid System Do?
In each tissue, the cannabinoid system performs different tasks, but the goal is always to maintain homeostasis, or a stable internal environment despite fluctuations in the external environment. Homeostasis is a key element in the biology of all living things and is best described as the ability to maintain stable internal conditions that are necessary for survival. Disease is simply a result of some aspect of failure in achieving homeostasis, making the endocannabinoid system a unique target for medical applications. This system appears to regulate many important physiologic pathways in the human body, including gastrointestinal activity, cardiovascular activity, pain perception, maintenance of bone mass, protection of neurons, hormonal regulation, metabolism control, immune function, inflammatory reactions, and inhibition of tumors cells.
Two Different Types of Receptors
In 1990, cannabinoid receptor type 1 (CB1) it was located at the synapses of the central nervous system and the peripheral terminals of sensory neurones. CB1 receptors, which help to mediate inhibition of neurotransmitter release, are some of the most widely expressed G protein-coupled receptors in the brain and are found at the terminals of central and peripheral neurons and areas of the brain that control movement and postural control, pain and sensory perception, memory, cognition, emotion, autonomic and endocrine functions. CB1 receptors are also found in other parts of the body including the heart, uterus, testis, small intestine and peripheral cells. They are also found in appetite regulating areas such as the hypothalamus as well as reward centres such as the lymbic system and have therefore been implicated in food intake. Most recently, CB1 has been isolated in tissues that are important for energy metabolism such as the liver, adipose (fat) tissue and skeletal muscle.
A second receptor called CB2, which is predominantly expressed in the cells of the immune system both within and outside the central nervous system such as the spleen, T-cells, B-cells and macrophages, was identified in 1993 through homology cloning. CB2 works to modulate modulate cytokine release and immune cell migration in a manner that seems to reduce inflammation and certain kinds of pain.
Cannabinoid receptors act as binding sites for endogenous cannabinoids as well as cannabinoids found in marijuana. When cannabinoids bind to CB1 or CB2 receptors, they act to change the way the body functions. Cannabinoids exert their effects by interacting with cannabinoid receptors present on the surface of cells in different parts of the central nervous system.
These two receptors only share 48% amino acid sequence identity, are distributed in different tissues and also have different signalling mechanisms. They also differ in their sensitivity to agonists and antagonists. Evidence suggests that additional cannabinoid receptor types may exist.
What Binds to The Receptors?
The discovery of the cannabinoid receptors CB! and CB2 led to the discovery of the body’s own natural cannabinoids (endocannabinoids), the most important of which are arachidonoyl-ethanolamide (anandamide or AEA), 2-arachidonoyl glycerol (2-AG) and arachidonyl glyceryl ether (noladin ether). These naturally endogenous ligands or cannabinoids bind to the CB1 and CB2 receptors. The first such endogenous compound called AEA functions as a CB1 receptor partial agonist. Many other endocannabinoids that can activate CB receptors, such 2-AG, have since been discovered. Evidence has emerged that the endocannabinoid ligands are synthesized on demand rather than stored; the endocannabinoid system is transiently activated under certain stressful conditions to restore homeostasis.
Three Different Types of Cannabinoids
Delta-9-tetrahydrocannabinol (Δ9-THC or THC) and other identified cannabinoids Cannabidiol (CBD), Cannabinol (CBN), Cannabigerol (CBG), Cannabichromene (CBC) and dozens more, are phytocannabinoids produced through photosynthesis in hair-like trichomes on the surface of the cannabis plants during flowering phase. THC has analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties. CBD has anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects.
As an annual, cannabis plants follow a solar cycle consisting of two basic stages often referred to as vegetative, and bloom. Cannabinoids are created in the bloom phase. In general, there are three different types of endocannabinoids:
- Endocannabinoids which are produced by the body
- Synthetic Cannabinoids which are synthetically produced
- Phytocannabinoids which are produced by the cannabis plant
Lock and Key System
The cannabinoids interact with the receptors, much like a lock and key. The receptor is the lock and the cannabinoid molecule is the key – when the cannabinoid “key” attaches to the receptor “lock”, which is on the cell wall, a reaction is triggered resulting in an effect on the brain and body. Furthermore, under certain scenarios, cannabinoids are able to induce certain effects even when the cannabinoid receptors have been blocked with an antagonist; this would suggest the existence of non-CB receptor targets for these receptor molecules such as transient receptor potential channels (TRPV1 and TRPM8), the peroxisome proliferator activated receptors (PPAR alpha and gamma), G protein-coupled orphan receptors (GRP55), certain ion channels (e.g. calcium channels), transmitter-gated ion channels (e.g. glycine receptors) and finally established non-cannabinoid G protein-coupled receptors (e.g. acetylcholine muscarinic receptors).
Studies show that activation of the cannabinoid receptors leads to inhibition of adenylate cyclase, which stops the conversion of ATP to cyclic AMP (cAMP).
For more information, Ken-Mackie has an excellent presentation on the science of Cannabis. A few of his supporting slides from the linked presentation are listed below.
