The Endocannabinoid System:
A Pharmacists' Guide to the ECS
The human body is a complex system with trillions of cells and hundreds of systems that all work together to maintain life and consciousness. In order for these systems to remain functional and healthy, there must be a system that facilitates regulation and homeostasis in all the different parts of the body, much like nuts and bolts hold together the diverse parts of a car, from the gears in the transmission to the wiper blades or air vents.
The system responsible for this balance and homeostasis is the endocannabinoid system.
The endocannabinoid system includes several Gi/o protein-coupled receptors, their endogenous arachidonyl ligands, and the enzymes that synthesize and metabolize those ligands.
To illustrate the prevalence and importance of the ECS, consider the fact that 58% of all membrane receptors in the human body are CB endocannabinoid receptors; they are more numerous and abundant than all other transmembrane receptors…COMBINED.
ECS Neurotransmitters
Endogenous cannabinoids, or endocannabinoids, are neurotransmitters naturally produced by the body. They bind to cannabinoid receptors, specifically CB1 and CB2 receptors, located throughout the brain, immune system, and elsewhere. Examples include anandamide, 2-arachidonoylglycerol (2-AG), n-arachidonoyl dopamine (NADA), and virodhamine (OAE).
Endocannabinoids are created and perform in the reverse of more well-known neurotransmitters like serotonin, dopamine, and norepinephrine.
For example, dopamine is produced in advance, stored, and then released from the presynaptic cell in response to stimuli. The dopamine crosses a synapse to reach and activate the postsynaptic cell, which then causes you to feel happy, motivated, and focused. (Dopamine plays a role in several other neurological and motor functions, but is most often associated with your brain’s reward system.)
Endocannabinoids, on the other hand, are key components of cellular membranes the body is able to manufacture on demand, not in advance, and they travel backward: endocannabinoids first leave the postsynaptic cell and end their journey in the presynaptic cell. This process allows the postsynaptic cell to regulate the flow of neurotransmitters coming from the presynaptic cell.
While all endocannabinoids play an important role in regulating pre- and postsynaptic activity, one of the best researched is anandamide, perhaps for its reputation as the “bliss molecule.”
ECS Receptors
Not only do humans produce their own cannabinoids, but they also have cannabinoid receptors designed specifically to recognize and respond to them. These receptors are called CB1 and CB2.
CB1 receptors exist in full numbers on your brain’s nerve cells, or neurons, especially those in the hypothalamus, hippocampus, and amygdala, which are primarily responsible for regulating hormones, memory, and emotion, respectively. CB1 receptors are also found in the central nervous system (CNS), intestines, muscles, thyroid gland, and various other organs and glands.
Poorly functioning CB1 receptors can lead to a number of consequences, including:
- Decreased brain energy and function.
- Age-related decline in cognitive faculties
- Irregular hormone production in the thyroid gland, which controls metabolism, digestion, and heart rate.
- Fatty liver disease.
- Irregular food intake.
CB2 receptors (first discovered in 1993) occur most commonly in the spleen, tonsils, thymus, and immune cells; only a small number exist in the brain. CB2 receptors are best known for their role in regulating immune function through their ability to trigger and stop immune responses, including inflammation.
Changes in CB2 receptor function plays a role in human disease; whether cardiovascular, gastrointestinal, neurodegenerative, psychiatric, autoimmune, or cancerous, virtually any ailment of the body or mind is linked to abnormal CB2 function.
Together, the body’s endocannabinoids and the CB1 and CB2 receptors that bind with them form the endocannabinoid system.
ECS Enzymes
The human body is a complex system with trillions of cells and hundreds of systems that all work together to maintain life and consciousness. In order for these systems to remain functional and healthy, there must be a system that facilitates regulation and homeostasis in all the different parts of the body, much like nuts and bolts hold together the diverse parts of a car, from the gears in the transmission to the wiper blades or air vents.
The system responsible for this balance and homeostasis is the endocannabinoid system.
The endocannabinoid system includes several Gi/o protein-coupled receptors, their endogenous arachidonyl ligands, and the enzymes that synthesize and metabolize those ligands.
To illustrate the prevalence and importance of the ECS, consider the fact that 58% of all membrane receptors in the human body are CB endocannabinoid receptors; they are more numerous and abundant than all other transmembrane receptors…COMBINED.
The ECS and Homeostasis
Homeostasis refers to the underlying set of conditions required by the various systems of the human body in order to remain healthy. This includes things like electrolyte levels, blood pH, mitochondrial output, etc.
It makes sense that a system present ubiquitously throughout the human body would be involved in maintaining homeostasis. That system – in conjunction with a few others – is the endocannabinoid system (ECS). As endocannabinoid researcher and former Senior Medical Advisor to GW Pharmaceuticals, Dr. Ethan Russo, puts it, “The endocannabinoid system ‘regulates regulation’ throughout the human body.”
Without going down the rabbit hole of molecular biology, endocannabinoid receptors are essentially dampers of cellular activity. When a CB receptor is activated in a cell, that cell’s activity is reduced. It doesn’t matter what kind of cell it is CB receptors reduce cellular output.
Furthermore, the two primary endocannabinoid neurotransmitters have distinct expression patterns. Anandamide is released tonically, or constantly, producing a baseline agonism of CB1 and CB2 receptors; let’s say on a scale of 1-10, anandamide tonic release keeps CB1 and CB2 activity at a 4. This means that that activity level can be both increased and decreased. Both anandamide and 2-AG are released on demand from the cellular membrane rather than stored in vesicles like classical neurotransmitters like dopamine.
The distinct expression patterns are as follows:
Anandamide is released tonically (constantly) by cleaving arachidonic acid (AA) – which is a primary fatty acid found in the phosopholipid bilayer of all human cell walls – from the phosphate group that makes up the hydrophilic portion of the membrane structure. AA is then bound to ethanolamide, which is also present ubiquitously throughout the human system. Anandamide is arachidonyl ethanolamide, and this two step process occurs in a microseconds-long timeframe, allowing for rapid production of anadamide.
2-AG undergoes a similar process, but it occurs only under specific conditions – phasically or transiently – rather than tonically as is the case with anandamide. In addition, 2-AG is a more potent agonist of CB1 and CB2 receptors, functioning to greatly increase CB activity, effectively halting cellular activity for a short period of time, on the order of milliseconds, which has obvious implications, regardless of cell type.
The dynamic relationship between 2-AG and anandamide gives the ECS a unique ability to influence and regulate the activity of all cells which express endocannabinoid receptors.f
Other Components of the ECS
In addition to anandamide and 2-AG, there are at least five other signaling molecules considered to be members of the endocannabinoid system. There are also several “orphan receptors” that were previously unclassified because of a lack of understanding of their function. We now know that several endocannabinoids bind to them to exert their effects. These discoveries have opened new avenues of research into novel therapeutic targets that have eluded the medical community for years.
Novel Endocannabinoid Signaling Molecules
- N-Arachidonoyl dopamine (NADA) – CB1 and TRPV1 receptor agonist
- N-Arachidonoyl Glycerol (NAGly) – GPR18 receptor agonist; FAAH enzyme inhibitor
- Oleoylethanolamide (OEA) – PPARa receptor agonist
- Palmitoylethanolamid (PEA) – PPARa, GPR55, and GPR119 receptor agonist
- 2-Arachidonyl Glyceryl Ether (2-AGE) – CB1, CB2, TRPV1, and PPARa receptor agonist
- Virodhamine – CB1 and CB2 receptor antagonist
- Lysophosphatidylinositol (LPI) – GPR55 receptor agonist
- 2-Arachidonoyl Lysophosphatidylinositol (2-ALPI) – GPR55 receptor agonist
Novel Endocannabinoid Receptors
- Orphan Receptor GPR18
- Orphan Receptor GPR55
- Orphan Receptor GPR119
- Transient Receptor Potential Vanilloid Receptor, Type 1 (TRPV1)
- Peroxisome Proliferator-Activated Receptor Alpha (PPARa)
- Peroxisome Proliferator-Activated Receptor Gamma (PPARy)
Endocannabinoid Deficiency
Like we discussed in the last section, anandamide sets a baseline activity level at CB1 & CB2 receptors. Logically, if the baseline ECS activity is altered or disrupted in some meaningful way, then the regulatory capacity of the ECS will also be impacted. Couple this with the fact that CB1 receptors are more abundant than all other receptors in the human body combined, and it becomes easy to see that a disruption of ECS activity will produce a disruption in the activity of the processes regulated by the ECS.
This list of processes is long, and includes cytokine and chemokine activity in the immune systems; GABA, glutamate, dopamine, serotonin, and endorphin activity within the brain; nociception and pain transmission within the peripheral nervous system; peristalsis and appetite regulation within the digestive system, and several other fundamental processes throughout the body. Again, this is possible thanks to the ability of the ECS to both increase and decrease its activity levels based on changes in the surrounding environment.
The following is an example of how the endocannabinoid system is involved in the regulation of a fundamental process occurring in literally hundreds of different cell types: Retrograde neurotransmission.
Depolarization of a neuron – which occurs when a neuron “fires” – causes a disruption in the postsynaptic cell wall, triggering the synthesis of 2-AG.
2-AG then diffuses backwards – in a “retrograde” direction – and binds to cannabinoid receptors on the presynaptic neuron, inhibiting release of the primary neurotransmitter.
The postsynaptic cell wall repolarizes and returns to its inactive state, thus inhibiting the production of 2-AG.
This process of retrograde neurotransmission has been thought to exist since Freud first suggested a neurological analog for the repression of memories more than a century ago. It is necessary for neuroplasticity as well as motor control and cognition, memory formation, appetite, and several other basic functions within the central nervous system. It disinhibits GABA signaling and glutamate signaling depending on different conditions, and it even controls pituitary activity and the development and differentiation of fetal brain tissue.
When any of these processes are disrupted in an idiopathic way, it is now irresponsible not to consider whether the endocannabinoid system may be involved in their pathogenesis, and therefore, if it has the potential to be a therapeutic target in their treatment.