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The Endocannabinoid System
The endocannabinoid system is a biological system which plays many important roles in the human body. It is also responsible for the physical and psychological effects of cannabis.
Scientists first discovered the system while trying to understand the effects of cannabis, and named it the endocannabinoid system for this reason.
Endo stands for endogenous, which means originating within the body. Cannabinoid refers to the group of compounds that activate this system.
The endocannabinoid system is a major target of medical research because of its widespread effects and therapeutic potential. While scientists have sorted out the basics of this fascinating system, much more remains to be uncovered.
What are Cannabinoids?
Cannabinoids are the chemical messengers for the endocannabinoid system. While many different cannabinoids exist, they all fall under two categories: endogenous or exogenous.
Endogenous means originating inside the body. Also known as endocannabinoids, these compounds are produced naturally by the human body. They interact with cannabinoid receptors to regulate basic functions including mood, memory, appetite, pain, sleep, and many more.
Exogenous means originating outside the body. The cannabinoids found in cannabis (marijuana and hemp), such as tetrahydrocannabinol (THC) and cannabidiol (CBD), are considered exogenous. When consumed, they also interact with cannabinoid receptors to produce physical and psychological effects in the body.
What are Cannabinoid Receptors?
You may be wondering, what exactly are receptors? As their name suggests, receptors are message receivers. Messages come in the form of chemical messengers binding to the receptor. These messages produce a characteristic effect within the body.
The endocannabinoid system has two receptors: CB1 and CB2. Each receptor responds to different cannabinoids, but some cannabinoids can interact with both.
The distribution of CB1 and CB2 receptors within the body and brain explains why cannabinoids have certain effects.
CB1 receptors are foundthroughout the body, but are mostly present in the brain and spinal cord. They are concentrated in brain regions associated with the behaviors they influence.
For example, there are CB1 receptors in the hypothalamus, which is involved with appetite regulation, and the amygdala, which plays a role in memory and emotional processing. CB1 receptors are also found in nerve endings where they act to reduce sensations of pain.
CB2 receptors tend to be found in the peripheral nervous system. They are especially concentrated in immune cells. When CB2 receptors are activated, they work to reduce inflammation. Inflammation is an immune response which is believed to play a role in many diseases and conditions.
CBD does not bind directly to cannabinoid receptors. Instead, CBD works by inhibiting an enzyme called FAAH, which is responsible for the breakdown of anandamide — the most important endocannabinoid in the body. When FAAH is inhibited, it cannot break down anandamide at its normal rate. This leads to a buildup of anandamide in the brain.
What are Endocannabinoids?
Endocannabinoids are cannabinoids produced naturally within the human body. 2-AG and anandamideare the two major endocannabinoids that scientists know of.
Anandamide was the first endocannabinoid to be identified by scientists. Discovered in 1992, its name comes from the Sanskrit word ananda meaning bliss, referring to its unique effects on the mind and body. In 1995, scientists discovered a second endocannabinoid and named it 2-AG (2-arachidonoyl glycerol).
2-AG is found at higher concentrations in the brain, while anandamide is found at higher concentrations in other areas of the body. Both are capable of binding to CB1 and CB2 receptors, but differ in their affinities for these receptors (i.e. how likely they are to bind to and activate each receptor).
Endocannabinoids are “short-order” neurotransmitters, meaning they are synthesized on demand. In other words, endocannabinoids are only produced when the body signals that they are needed, and their presence is transient. These endocannabinoids are made from fat-like molecules within cell membranes, and are synthesized on-demand. This means that they get made and used exactly when they’re needed, rather than packaged and stored for later use like many other biological molecules.
After being released, endocannabinoids are quickly broken down by enzymes, which include FAAH (fatty acid amide hydrolase) and MAGL (monoacylglycerol lipase).
By contrast, when you consume marijuana, large amounts of cannabinoids enter the body and stick around. This means that the endocannabinoid system is activated more strongly and for longer than it would usually be.
There are other endocannabinoids currently under study, including noladin ether, virodhamine, and N-arachidonyl dopamine (NADA). However, their role in the body is not fully understood.
Functions of the Endocannabinoid System
The endocannabinoid system is involved with regulating many basic functions of the human body, including:
- Appetite
- Metabolism
- Pain
- Sleep
- Mood
- Movement
- Temperature
- Memory and learning
- Immune function
- Inflammation
- Neural development
- Neuroprotection
- Cardiovascular function
- Digestion
- Reproduction
Besides maintaining basic functions, the endocannabinoid system also acts in response to illness.
For example, tumor cells have been shown to express more cannabinoid receptors than healthy cells. Studies also show a rise in endocannabinoid levels in patients with various disorders, such as Parkinson’s disease, anxiety, chronic pain and arthritis.
As a result, some scientists believe the overall function of the endocannabinoid system is to regulate homeostasis.
Homeostasis is a key element in the biology of all living things. It is best described as the ability to maintain stable internal conditions that are necessary for survival. Homeostasis is the concept that most biological systems are actively regulated to maintain conditions within a narrow range. Our body doesn’t want its temperature to be too hot or too cold, blood sugar levels too high or too low, and so on. Conditions need to be just right for our cells to maintain optimum performance, and exquisite mechanisms have evolved to draw them back into the desired zone if they move out. The body’s endocannabinoid system (ECS) is a vital molecular system for helping maintain homeostasis.
Disease is largely a result of a failure in achieving homeostasis. Thus, the endocannabinoid system’s role in maintaining homeostasis makes it a unique and promising target in medicine.
The Endocannabinoid System in Medicine
Due to its widespread effects in the human body, the endocannabinoid system is believed to hold promise in treating many diseases and conditions. In recent years, scientists have been exploring various ways of targeting this system.
CBD is one of the most common ways of targeting the endocannabinoid system to treat various conditions. CBD, is known to produce therapeutic effects by interacting with the endocannabinoid system.
CBD has demonstrated relief for a wide variety of conditions including chronic pain, nausea, multiple sclerosis, and epilepsy.
In sum, the endocannabinoid system is truly a treasure trove for scientists and medical professionals. It is extremely complex, plays important roles in many vital processes, and holds promise as a treatment target for many debilitating conditions.
Endocannabinoid Regulation of Inflammation
Inflammation is a natural protective reaction the immune system has in response to infection or physical damage. The purpose of inflammation is to remove pathogens (germs) or damaged tissue. The inflamed area is produced by fluid and immune cells moving into the area to do the dirty work and eliminate the infection.
It’s important that inflammation be limited to the location of damage and doesn’t persist longer than needed, which can cause harm. Chronic inflammation and auto-immune diseases are examples of the immune system getting activated inappropriately. When that happens, the inflammatory response lasts too long (which results in chronic inflammation) or gets directed toward healthy cells (which is known as auto-immunity).
In general, endocannabinoids seem to suppress or limit the immune system’s inflammatory signals. Professor Prakash Nagarkatti, Vice President for Research at the University of South Carolina whose laboratory studies endocannabinoid regulation of immune responses, talks about how tweaking the ECS might be a good way to treat inflammatory diseases.
“Most of our research demonstrates that endocannabinoids are produced upon activation of immune cells and may help regulate the immune response by acting as anti-inflammatory agents. Thus, interventions that manipulate the metabolism or production of endocannabinoids may serve as a novel treatment modality against a wide range of inflammatory disease.”
Consider a normal immune response triggered by a bacterial infection. First, immune cells detect the presence of bacteria and release pro-inflammatory molecules that tell other immune cells to come and join the fight.
Endocannabinoids get released as well which also signal to other immune cells for assistance and likely help limit the inflammatory response so it isn’t excessive. By tightly regulating inflammation, the immune system can destroy germs or remove damaged tissue, and then stop. This prevents excessive inflammation, allowing cells, and thus the body, to return to homeostasis.
Under normal conditions (top-left), cells of the immune system patrol the body, on alert for any intruders, such as bacteria. During a bacterial infection (top-right), immune cells detect the presence of bacteria and then release a variety of molecules to help mount a defensive attack (bottom). These signals include pro-inflammatory molecules (small circles) that help recruit more immune cells to the site of infection. Endocannabinoids (small diamonds) also get released, and likely help regulate the magnitude and extent of this inflammatory response.
Plant Cannabinoids and the Endocannabinoid system
The reason that plant cannabinoids have psychoactive and medicinal effects within the body is, in large part, because we have an endocannabinoid system (ECS) that they can interact with.
It’s important to remember that molecules like cannabinoids and other neurotransmitters rarely interact with only one receptor type; they often interact with many. The plant-based cannabinoid CBD illustrates this nicely, as it interacts with numerous receptor types in the brain. So, while plant cannabinoids may activate the same cannabinoid receptors as endocannabinoids, they will likely interact with several other receptors and therefore have distinct effects.
CBD is also interesting because it can affect overall levels of endocannabinoids in the brain, referred to as “endocannabinoid tone.” CBD inhibits the FAAH enzyme, which breaks down anandamide. Thus, CBD can increase anandamide levels by preventing FAAH from breaking it down. Inhibiting the FAAH enzyme has been shown to be a useful strategy for treating anxiety disorders, and some of CBD’s anti-anxiety propertiesmay come from its ability to inhibit this enzyme and thereby increase endocannabinoid tone.
Summary
The endocannabinoid system (ECS), comprised of cannabinoid receptors, endocannabinoid molecules, and their metabolic enzymes, is a crucial molecular system that the body uses to help maintain homeostasis. Because of its vital role in making sure that cells and systems remain in their physiological homeostasis, the ECS is tightly regulated; it gets deployed exactly when and where it’s needed. However, this doesn’t mean that activating the ECS, through consumption of cannabis or by any other means, will always make things just right.
Like any other complex biological system, the ECS can go awry. “If deviation from physiological homeostasis is prolonged, due to either external factors or chronic pathological conditions, the eCS can lose its time- and space-selective mode of action and start affecting inappropriate cells,” Dr. Di Marzo explained. “In these cases, the ECS, instead of being beneficial, may actually contribute to disease progression.”
It’s important to remember that activating the ECS, through cannabis consumption or by any other means, isn’t a cure-all. Like most of biology, it’s complicated.
By understanding the biological principle of homeostasis, and how the ECS illustrates this at the cellular level, we can more deeply appreciate why we have an ECS to begin with, and how a variety of cannabis-based therapies might actually work. The presence and critical function of the ECS across many systems of the body, including the nervous and immune systems, explains why such a wide variety of ailments and disease states are responsive to cannabis-based interventions.
References:
https://www.leafly.com/news/science-tech/what-is-the-endocannabinoid-system
https://www.leafscience.com/2017/03/17/the-endocannabinoid-system-a-beginners-guide/
