Some consume cannabis for its mind-altering effects while others seek symptom relief. Cannabis wouldn’t have any of these effects if our bodies didn’t contain a biological system capable of interacting with plant cannabinoids like THC.
Our endocannabinoid system (ECS) does just that. But it isn’t there for the purpose of enabling the effects of cannabis. It‘s an ancient biological system which evolved long before human beings walked the Earth or cultivated marijuana. The ECS serves a vital purpose for our health and well-being because it regulates core aspects of biology.
What is it doing and how does it work? Let’s cover the basics of the ECS–what it is, its key components, and major biological functions. We will also explore how the ECS works within specific physiological systems of the body, as well as how plant cannabinoids influence it.
What is the endocannabinoid system and what does it do?
The endocannabinoid system (ECS) is a biological system first discovered in the late 1980s and early ’90s. It is largely composed of endogenous cannabinoid molecules (endocannabinoids) together with the receptors they interact with and enzymes that regulate their levels in the body. This simply means that the body produces native molecules which are similar in certain ways to plant cannabinoids like THC and play an important role in our normal biology.
The different pieces of the ECS “work together” to modulate everything from sleep to mood, memory, appetite, reproduction, and pain sensation. Scientists still have plenty of questions about the human endocannabinoid system and how it functions, but there is an overarching principle that the ECS seems to embody within the bodily tissues it helps regulate.
Homeostasis: Staying in the Goldilocks zone
To understand the endocannabinoid system (ECS), it’s helpful to know a little about one of the most fundamental concepts in biology: homeostasis. A good way to understand homeostasis is to think of the story of “Goldilocks and the Three Bears.”
The classic fairy tale illustrates the idea that the best outcome often lies somewhere in the middle, between two extremes. We don’t want things too hot or too cold, but just right.
Homeostasis is the concept that most biological systems are actively regulated to maintain conditions within a narrow range. Our bodies don’t want 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 to the Goldilocks zone if they move out.
The body’s endocannabinoid system (ECS) is a vital molecular system for helping maintain homeostasis—it helps our cells stay in their biological Goldilocks zone.
Because of its crucial role in homeostasis, the ECS is widespread throughout the animal kingdom. Its key pieces evolved millions of years ago and the ECS can be found in all vertebrate species.
The three key components of the endocannabinoid system are:
- Cannabinoid receptors found on the surface of cells, which sense the presence of endocannabinoids;
- Endocannabinoids, small molecules that activate cannabinoid receptors;
- Metabolic enzymes that quickly break down endocannabinoids after they are deployed.
Key pieces of the endocannabinoid system (ECS)
Because of its crucial role in homeostasis, the ECS is widespread throughout the animal kingdom. Its key pieces evolved a long time ago, and the ECS can be found in all vertebrate species.
The three key components of the human endocannabinoid system are:
- Cannabinoid receptors found on the surface of cells
- Endocannabinoids, small molecules that activate cannabinoid receptors
- Metabolic enzymes that break down endocannabinoids after they are used
What Are Cannabinoid Receptors?
Cannabinoid receptors sit on the surface of cells and “listen” to conditions outside the cell. They transmit information about changing conditions to the inside, kick-starting the appropriate cellular response. There are two major cannabinoid receptors: CB1 and CB2. These aren’t the only cannabinoid receptors, but they were the first ones discovered and remain the best-studied.
- CB1 receptors are one of the most abundant receptors in the brain. These are the receptors that interact with THC to enable the classic psychoactive effects of cannabis.
- CB2 receptors are more abundant outside of the nervous system, in places like the immune system. CB2 receptors are a major reason why cannabinoids, including THC and CBD, often have anti-inflammatory effects.
CB1 and CB2 receptors are key players in the endocannabinoid system (ECS). They are located on the surface of many different types of cells in the body. Both receptors are found throughout the body, but CB1 receptors are more abundant in the central nervous system, including on neurons in the brain. In contrast, CB2 receptors are more abundant outside of the nervous system, including cells of the immune system.
Dr. Matthew Hill, a professor of cell biology at the University of Calgary, explained more about the two major endocannabinoid receptors in this conversation:
Endocannabinoids are molecules that bind to and activate cannabinoid receptors. However, unlike plant cannabinoids, endocannabinoids are produced naturally by cells in the body (“endo” means “within”).
There are two major endocannabinoids: anandamide and 2-AG. These endocannabinoids are made from fatty 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.
Anandamide. Derived from the Sanskrit word “ananda,” which translates to “joy,” “bliss,” or “delight,” anandamide is sometimes called “the bliss molecule.” This fatty acid neurotransmitter was first identified and named in 1992 by Dr. Raphael Mechoulam. It plays a role in many physiological processes of the body, including the nervous system, metabolism, and embryonic development.
2-AG. 2-ArachidonoylGlycerol (2-AG) was first described in the 1990s by Raphael Mechoulam and his student Shimon Ben-Shabat. While it was previously a known chemical compound, this is when scientists first became aware of its affinity for cannabinoid receptors. It is present at high levels in the central nervous system and, like anandamide, 2-AG is involved in a variety of physiological processes.
Cannabinoids are a class of molecules characterized by their ability to activate cannabinoid receptors like CB1 and CB2. Anandamide and 2-AG are the two major endocannabinoids produced naturally in the body. THC is the psychoactive plant cannabinoid produced by cannabis. All three of these cannabinoids can activate CB1 and CB2 receptors, although each one has a different potency at each receptor.
I previously spoke to cannabinoid scientist Dr. Saoirse O’Sullivan in more detail about endocannabinoids and the diverse roles they play in tissue systems throughout the body:
What Are Endocannabinoid Enzymes?
The third piece of the endocannabinoid system includes the metabolic enzymes that quickly destroy endocannabinoids once they are used. The two main enzymes are FAAH, which breaks down anandamide, and MAGL, which breaks down 2-AG.
These enzymes ensure that endocannabinoids get used when they’re needed, but not for longer than necessary. This process distinguishes endocannabinoids from many other molecular signals in the body, such as hormones or other neurotransmitters, which persist for longer periods of time or get packaged and stored for later use.
Enzymes are molecules that accelerate chemical reactions in the body, often for breaking down molecules. FAAH and MAGL are key players in the ECS because they quickly break down endocannabinoids. FAAH breaks down anandamide, while MAGL breaks down 2-AG. These enzymes break down endocannabinoids very quickly, but are not effective at breaking down plant cannabinoids like THC.
Endocannabinoid System: Maintaining Balance?
These three key components of the endocannabinoid system can be found within almost all major tissues of the body. When something brings a cell out of its “Goldilocks zone,” these three components of the ECS are often called upon to bring things back, thus maintaining homeostasis.
Because of its role in helping bring things back to their physiological Goldilocks zone, the ECS is often engaged only when and where it’s needed. Dr. Vincenzo Di Marzo, Research Director at the Institute of Biomolecular Chemistry in Italy, put it this way:
“With the ‘pro-homeostatic action of the ECS’ we mean that this system of chemical signals gets temporarily activated following deviations from cellular homeostasis. When such deviations are non-physiological, the temporarily activated ECS attempts, in a space- and time-selective manner, to restore the previous physiological situation (homeostasis).”
In other words, the endocannabinoid system helps bring things back to the biological Goldilocks zone.
Below we will consider examples of how the ECS helps maintain homeostasis in different parts of the body.
Nervous System & Brain
Brain cells (neurons) communicate by sending electrochemical signals to one another. Each neuron must listen to its partners to decide whether it will fire off its own signal at any given moment. However, neurons don’t like to get too much input—there’s a Goldilocks zone. If they get overloaded by signals, it can be toxic.
That’s where endocannabinoids come in.
Consider a simplified scenario with one neuron listening to two others.
One of the two outputting neurons might become overactive and send too many signals to the neuron that’s listening. When that happens, the neuron that’s listening will produce endocannabinoids specifically where it’s connected to the overactive neuron. Those endocannabinoids will travel back to the “loud” neuron where they bind to CB1 receptors, transmitting a signal that instructs it to quiet down. This brings things back to the Goldilocks zone, maintaining homeostasis.
As the example above illustrates, endocannabinoids travel backward, which is why they’re known as retrograde signals. Most of the time, information flow between neurons is strictly in one direction, from sender neurons that release neurotransmitter signals to receiver neurons that listen to those signals. Endocannabinoids allow receiver neurons to regulate how much input they’re getting, and they do this by sending retrograde signals (endocannabinoids) back to overactive sender neurons.
But the brain isn’t the only organ that needs to maintain homeostasis. Every other system of the body needs this kind of regulation to help ensure survival, including many aspects of our digestive system and metabolism.
Diet, Feeding Behavior & Metabolism
Even though the CB1 receptor is found in highest abundance within the brain, it is also found throughout the body. This includes organs important for energy homeostasis, such as the gastrointestinal tract, pancreas, muscle, and fat cells. And within the nervous system, CB1 receptors are often concentrated in brain areas critical for regulating energy expenditure and metabolism, as well as sensory organs important for finding food (e.g. the nose and tongue).
Most cannabis consumers will tell you that THC promotes hunger and enhances the taste and smell of food. This common experiential report is consistent with what is generally observed in scientific studies. For example, activating CB1 receptors in “taste cells” or “smell cells” in animals tends to increase the perception and attractiveness of odors and foods.
Drugs that activate CB1 receptors (including THC) stimulate hunger and food consumption, but there is often more nuance to this than many people appreciate. For example, THC doesn’t just stimulate feeding in rodents, but alters the type of foods they prefer depending on whether they are already hungry or satiated. Hungry rats given THC show an increased preference for high-fat food compared to high-carbohydrate food, while satiated rats given THC show the opposite trend. Thus, THC can influence what types of food you most want to eat based on your body’s current metabolic state.
The distribution of CB1 receptors across all of these tissues suggests that the ECS has an important role to play in regulating metabolism broadly. That, together with many observations related to how the ECS affects food-seeking behavior, has led some scientists to suggest that a major reason the ECS evolved in animals may be to coordinate behavior, metabolism, and sensory perception for the purposes of long-term energy storage and survival.
The presence of the ECS in tissue systems related to general metabolic function may be why there are hints from animal research that certain plant cannabinoids, such as CBD and THCV, may have therapeutic effects for certain forms of metabolic dysfunction, such as diabetes. But research has been slow in this area. As Dr. Saoirse O’Sullivan told me: “Historically, cannabinoid research is very central nervous system biased.” Nonetheless, a fair amount of work has been done on THC’s effects on feeding and weight loss, which I discussed with Dr. O’Sullivan in more detail:
Immune System & Inflammation
Inflammation is a natural protective reaction of the immune system in response to infection or physical insult. The purpose of inflammation is to remove pathogens (germs) or damaged tissue. The inflamed area is produced by fluid and immune cells moving in to do the dirty work of removing the problem so things can return to their Goldilocks zone (homeostasis).
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 autoimmune 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 autoimmunity.
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, told me how tweaking the endocannabinoid system 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, then stop. This prevents excessive inflammation, allowing cells, and thus the body, to return to the Goldilocks zone.
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.
The ability to regulate the body’s inflammatory response may be why cannabinoids show promise for treating not only chronic inflammatory conditions–everything from autoimmune disease to gut inflammation–but also for having potential neuroprotective effects in the context of traumatic brain injury or protecting blood-brain-barrier integrity. I discussed these things in more detail with cannabinoid scientist Dr. Saorise O’Sullivan:
Other Areas of Biology & Medicine
The ECS is involved in so many aspects of biology that it’s impossible to cover them all. We have covered many other aspects of ECS biology in more detail in other articles and I have spoken with a variety of experts about many ECS-related topics. Here’s a list of ECS topics and resources for you to learn more:
- Chronic pain & Opioid Addiction:
- Stress & Post-Traumatic Stress Disorder (PTSD):
- Schizophrenia & Psychosis:
- Sex & Prenatal Development:
- Human Cognition:
- Plant Medicine & the Entourage Effect:
- Sleep, Dreaming & Insomnia:
Other treatment potential of cannabinoids
While much remains to be discovered about the endocannabinoid system and the various medical uses and treatment potential of cannabinoids, certain conditions have been identified as key areas of research potential. In particular, cannabinoids may be used to treat:
- Acute and chronic kidney disease
- Alzheimer’s & Neurodegenerative disease
- Autoimmune diseases
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. For example, THC gets you high because it activates the CB1 receptor within the brain. Endocannabinoids like anandamide also activate CB1.
So why aren’t we constantly high?
A couple big reasons. First, THC doesn’t interact with CB1 receptors in exactly the same fashion as the body’s natural endocannabinoids. Second, the metabolic enzymes that quickly break down endocannabinoids like anandamide don’t work on THC, so THC lingers around for much longer.
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 properties may come from its ability to inhibit this enzyme and thereby increase endocannabinoid tone.
The endocannabinoid system (ECS), composed 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 Goldilocks zone, 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 Goldilocks principle (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.
- Cardiovascular disease
- Skin Health
- Motor Control
With increased research, this list is likely to grow significantly. What’s clear is that there is virtually no aspect of our biology that is not affected in some way by our endocannabinoid system. I discussed some of the latest clinical research efforts related to cannabinoid-based medicines with Dr. Ziva Cooper of the the UCLA Cannabis Research Initiative:
How do plant cannabinoids like THC and CBD interact with 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. For example, THC gets you high because it activates the CB1 receptor within the brain. Endocannabinoids like anandamide also activate CB1.
So why aren’t we constantly high?
A couple big reasons. First, THC doesn’t interact with CB1 receptors in exactly the same fashion as the body’s natural endocannabinoids. Second, the metabolic enzymes that quickly break down endocannabinoids like anandamide don’t work on THC, so THC lingers around for much longer.
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 properties may come from its ability to inhibit this enzyme and thereby increase endocannabinoid tone.
Endocannabinoid system 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 Goldilocks zone, 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 Goldilocks principle (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.
