What is the Endocannabinoid System, and What Does it Do?
The endocannabinoid system (ECS) is a biological organism. First found in the late ’80s and early ’90s much remains undetermined about the system today. The ECS contains endocannabinoids, receptors, and enzymes thought to help control a range of functions in humans. Functions including sleep, mood, memory, appetite, reproduction, and pain sensation. Scientists still have many questions about the human endocannabinoid system and how it works.
Significant Parts of the Endocannabinoid System (ECS)
Because of its essential job in homeostasis, the ECS is standard throughout the animal kingdom. Its key pieces developed a long time ago, and the ECS is in all vertebrate species.
The three critical components of the human endocannabinoid system are:
- Cannabinoid receptors found on the exterior surface of cells
- Endocannabinoids are tiny molecules that trigger cannabinoid receptors
- Metabolic enzymes that decompose endocannabinoids
What are Cannabinoid Receptors, and Why Do We Have Them?
Cannabinoid receptors lie on the surface of cells and “hear” conditions outside the cell. They communicate information about shifting conditions to the inside of the cell, kick-starting the proper cellular response.
There are a couple of crucial cannabinoid receptors: CB1 and CB2. These aren’t the only cannabinoid receptors, but scientists first discovered them and they remain the most well-known. CB1 receptors are one of the most popular receptor types in the brain. These are the receptors that work with THC to cause intoxication. CB2 receptors are more profuse outside of the nervous system, in places like the immune system. However, both receptors are throughout the body.
What are Endocannabinoids?
Endocannabinoids are molecules that, like the plant cannabinoid THC, bind to and trigger cannabinoid receptors. However, unlike THC, the human body creates endocannabinoids naturally by cells in the human body (“endo” means “within,” as in within the body).
There are two main endocannabinoids: anandamide and 2-AG. These endocannabinoids come from fat-like molecules within cell membranes and synthesize at request. The body creates and uses the endocannabinoids when needed rather than packed and saved later, like many other biological molecules.
Anandamide. Derived from the Sanskrit word “ananda,” which translates to “joy” and “bliss,” anandamide’s nickname is the bliss molecule. More technically known as N-arachidonoylethanolamine (AEA), this fatty acid neurotransmitter is the topic of several scientific research studies that try to establish its effects on humans. First recognized and named in 1992 by Raphael Mechoulam, anandamide influences working memory and early-stage embryo growth.
2-AG. 2-ArachidonoylGlycerol (2-AG) was first labeled in 1994-1995 by Raphael Mechoulam and his student Shimon Ben-Shabat. While it was earlier a recognized chemical compound, scientists first became aware of its attraction to cannabinoid receptors. 2-ArachidonoylGlycerol (2-AG) is in maternal bovine as well as human milk.
How Do We Use Metabolic Enzymes?
The third part of the endocannabinoid triad contains the metabolic enzymes. These enzymes rapidly destroy endocannabinoids within the ECS. The two large enzymes are FAAH, which decomposes anandamide, and MAGL, which decomposes 2-AG. These enzymes use endocannabinoids when needed, but not for longer than needed. This process differentiates endocannabinoids from many other molecular indicators in the body. Indicators such as hormones or traditional neurotransmitters, which can endure for many seconds or minutes or get packed and stored for later use.
You can find these three crucial components of the endocannabinoid system inside nearly every body’s primary system. The parts of the ECS are often called upon to bring things back, therefore maintaining homeostasis.
The ECS is busy only when and where it’s needed. “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).” – Dr. Vincenzo Di Marzo, Research Director at the Institute of Biomolecular Chemistry in Italy. In layman’s terms, the endocannabinoid system aids in bringing things back to the biological ‘Just right’ zone.
Endocannabinoid regulation of brain cell firing
Brain cells (neurons) talk by sending electrochemical gestures to each other. Each neuron must heed to its partners to choose whether it will fire off its signal at any time. However, neurons don’t like to be overwhelmed. If they get overloaded by signals, it can be poisonous.
Endocannabinoid Regulation of Inflammation
Swelling is a natural protective response the immune system has in reaction to infection or physical harm. The purpose of inflammation is to remove germs or damaged tissue. The inflamed part creates fluid and immune cells move into the area. Their goal is to work and return things to normal conditions.
It’s critical that inflammation restricts the location of harm and doesn’t continue longer than needed, which can cause damage. Chronic inflammation and autoimmune diseases are instances of the immune system getting triggered improperly. When that happens, the inflammatory reaction lasts too long. This causes chronic inflammation or gets guided toward healthy cells, which is known as autoimmunity.
What are Cannabinoid Receptors?
Cannabidiol (CBD), a non-intoxicating part of the cannabis plant, has created significant attention among scientists and physicians recently—but how CBD expels its therapeutic impact on a molecular level is under study. Cannabidiol is a pleiotropic drug in that it creates many effects through many molecular pathways. Scientific research has identified more than 65 molecular targets of CBD.
Even though CBD has little binding affinity for both cannabinoid receptors (CB1 and CB2), cannabidiol modulates multiple non-cannabinoid receptors and ion channels. CBD also moves through various receptor-independent pathways by slowing the “reuptake” of endogenous neurotransmitters (such as anandamide and adenosine) and increasing or prohibiting the binding action of specific G-protein coupled receptors. Here are some of the ways that CBD presents its various therapeutic effects.
CBD directly triggers the 5-HT1A (hydroxytryptamine) serotonin receptor at heavy concentrations, thereby creating an anti-anxiety effect. This G-coupled protein receptor is involved in a range of biological and neurological processes, including anxiety, addiction, appetite, sleep, pain perception, nausea, and vomiting.
5-HT1A is a part of the group of 5-HT receptors, which the neurotransmitter serotonin triggers. These receptors live in both the central and peripheral nervous systems. 5-HT receptors activate multiple intracellular cascades of chemical messages to create either an excitatory or inhibitory response, depending on the message’s chemical context.
CBDA [Cannabidiolic acid], the raw, unheated version of CBD present in the cannabis plant, also has a strong affinity for the 5-HT1A receptor (even more so than CBD). Preclinical studies indicate that CBDA is a potent anti-emetic, more robust than either CBD or THC, which also have anti-nausea properties.
CBD directly interacts with various ion channels to confer a therapeutic effect. CBD, for example, binds to TRPV1 receptors, which also function as ion channels. TRPV1 is known to mediate pain perception, inflammation, and body temperature.
TRPV is the technical abbreviation for “transient receptor potential cation channel subfamily V.” TRPV1 is one of several dozen TRP (pronounced “trip”) receptor variants or subfamilies that mediate the effects of a wide range of medicinal herbs.
Scientists also refer to TRPV1 as a “vanilloid receptor,” named after the flavorful vanilla bean. Vanilla contains eugenol, an essential oil with antiseptic and analgesic properties; it also helps unclog blood vessels. Historically, the vanilla bean is a folk cure for headaches. CBD binds to TRPV1, which can influence pain perception. Capsaicin—the pungent compound in hot chili peppers—activates the TRPV1 receptor. Anandamide, the endogenous cannabinoid, is also a TRPV1 agonist.
Whereas cannabidiol directly activates the 5-HT1A serotonin receptor and several TRPV ion channels, some studies indicate that CBD functions as an antagonist that blocks or deactivates another G protein-coupled receptor known as GPR55.
GPR55 is an “orphan receptor” because scientists are still unsure if it belongs to a more prominent receptors family. GPR55 lives in the brain, especially in the cerebellum. It is involved in modulating blood pressure and bone density, among other physiological processes.
GPR55 promotes osteoclast cell function, which facilitates bone reabsorption. Overactive GPR55 receptor signaling is associated with osteoporosis.
GPR55, when activated, also promotes cancer cell proliferation, according to a 2010 study by researchers at the Chinese Academy of Sciences in Shanghai.
CBD is a GPR55 antagonist, as University of Aberdeen scientist Ruth Ross disclosed at the 2010 conference of the International Cannabinoid Research Society in Lund, Sweden. By blocking GPR55 signaling, CBD may act to decrease both bone reabsorption and cancer cell proliferation.
PPARS – NUCLEAR RECEPTORS
Activation of the receptor known as PPAR-gamma has an anti-proliferative effect and an ability to induce tumor regression in human lung cancer cell lines. PPAR-gamma activation degrades amyloid-beta plaque, a key molecule linked to the development of Alzheimer’s disease. This why cannabidiol, a PPAR-gamma agonist, may be a helpful remedy for Alzheimer’s patients.
PPAR receptors also regulate genes involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions. People with diabetes, accordingly, may benefit from a CBD-rich treatment regimen.
What are phytocannabinoids?
There are three general categories of cannabinoids:
- Phytocannabinoids: Cannabinoids produced by plants.
- Endogenous cannabinoids (endocannabinoids): Cannabinoids produced naturally by living animals (humans included) that interact with the body’s endogenous cannabinoid (endocannabinoid) system.
- Synthetic cannabinoids: Cannabinoids developed by humans in a laboratory.
While many people have heard about compounds found in cannabis – such as THC and CBD –many are surprised to learn that certain cannabinoids can be found naturally in our bodies. These are endocannabinoids. As a pivotal component of the endocannabinoid system, endocannabinoids help us operate at our best. When our endocannabinoid system functions appropriately, our bodies maintain homeostasis – the optimal state for our cells and tissues to function.
Unfortunately, the body does not always function the way nature intended. An autoimmune disease, for example, occurs when the immune system attacks healthy organs and tissues instead of attacking bacteria, viruses, or other sources of infection. Similarly, in some cases, the body lacks the average level of endocannabinoids for proper functionality. When this happens, it may be beneficial to get cannabinoids from an outside source.
Phytocannabinoids are naturally-occurring cannabinoids found in the Cannabis Sativa plant. As it stands, over 100 of them exist. These cannabinoids exist in other plants as well, such as the Echinacea Purpure. However, 113 compounds are unique to the Cannabis plant. These natural, plant-derived cannabinoids can help create proper homeostasis within the body by promoting balance in the endocannabinoid system.
A lesser-known fact is that scientists found phytocannabinoids in the ECS in mammals. Current studies focus on how these plant molecules aid in medicine, both on their own and through synthetic formats.
The most common and well-known plant-based compounds are tetrahydrocannabinol (THC) and cannabidiol (CBD). They are popular because of their potential therapeutic benefits. THC alleviates chronic pain, muscle spasms, and inflammation, while CBD has shown to help with various mental and physiological ailments in mammals.
HOW ARE PHYTOCANNABINOIDS DIFFERENT?
Phytocannabinoids are found in plants, while endocannabinoids live within mammal bodies. The prefix “Phyto” signifies that they are plant-derived in the former, while “endo” reveals the latter’s endogenous nature.
Recently, phytocannabinoids exist in several plant species different from cannabis, including Echinacea purpurea, Echinacea Angustifolia, Echinacea pallida, Acmella oleracea, Helichrysum umbraculigerum, and Radula marginata. According to the definition, these molecules are phytocannabinoids show binding affinity at cannabinoid receptors, but they show chemical structures far different from THCs.
All of the plants within the cannabis genus contain “phytocannabinoids,” and there are dozens of different ones. The most well-known are THC and CBD. THC is the only one that gets you “high.”
The leaves and flowers of marijuana plants make joints and edibles because they typically contain 15-20% THC. CBD oils come from the hemp plants, which includes, at most, 0.3% THC. That’s why CBD oils don’t get you high.
According to a recent review19, out of more than 545 metabolic constituents identified from Cannabis20, 144 have been isolated and identified as phytocannabinoids. Phytocannabinoids fall into the following 11 subclasses according to their chemical structures:
- cannabigerol (CBG, 1)
- (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC, 2)
- cannabidiol (CBD, 3)
- cannabichromene (CBC, 4)
- cannabinol (CBN, 5)
- (-)-Δ8-trans-tetrahydrocannabinol (Δ8-THC, 6)
- cannabicyclol (CBL, 7)
- cannabidiol (CBND, 8)
- cannabielsoin (CBE, 9)
- cannabitriol (CBT, 10)
- miscellaneous types
Scientists recognize the endocannabinoid system for its involvement in uterine function. Estrogen, for example, has been shown to regulate the expression of FAAH, the primary protein tasked with breaking down anandamide, the first endogenous cannabinoid compound identified in the mammalian brain.
Aberrant signaling by endocannabinoids and their molecular cousins, the prostaglandins, occurs in menstrual pain and heavy bleeding. New research from scientists in Italy, Britain, and Qatar adds to how we understand these conditions by probing the connection between endocannabinoid levels and preterm birth, meaning delivery before the 37th week of pregnancy.
The scientists measured the levels of FAAH and anandamide (AEA), along with two related lipids, called PEA and OEA, in 217 women at risk for preterm birth. Plasma AEA increases during pregnancy until labor, so the researchers hoped to find a threshold that could predict preterm birth.
They found that an AEA concentration above 1.095 nanomolar (nM) was a valuable predictor of preterm birth. The specificity (valid negative rate) was 87%, meaning they will only miss about 1-in-10 cases using this threshold. On the other hand, the sensitivity (true positive) was only 26%, meaning 3-in-4 results are false positives.
The authors conclude that using anandamide as a marker was more accurate and less invasive than current testing methods. PEA could also be a marker for preterm birth, but FAAH and OEA levels were not well correlated.
Future research should replicate this diagnostic threshold prospectively.
Another recent study suggested that AEA levels are generally around 0.6-0.8 nM in the blood, but this fluctuates to some degree throughout the day. So, blood needs to collect consistently.
Homeostasis: Staying Just Right
Understanding the human endocannabinoid system helps one of the essential theories in biology: homeostasis. And the easiest way to understand homeostasis is to think of Goldilocks and the Three Bears’ classic children’s tale. The idea is that the best result often lies somewhere in the middle, between two extremes. We don’t want things too cold or too hot, but just right in the middle.
Homeostasis is the idea that most biological systems are constantly regulated to maintain settings within a narrow range. Bodies don’t want the temperature to be too cold or too hot, blood sugar levels too low or too high, and so on. Conditions need to be just right for our cells to sustain optimal performance, and intricate mechanisms have advanced to draw them back to the Goldilocks zone if they leave.
The body’s endocannabinoid system (ECS) is a vital molecular system for helping maintain homeostasis.
The ECS is composed of 3 parts:
- Endocannabinoid Receptors
- Enzymes to digest the cannabinoids
What is homeostasis?
Homeostasis is the ability to regulate and maintain a relatively stable internal state. This state persists despite changes in the outside world. From plants to people, all organisms must keep their internal environment to process energy effectively and, ultimately, survive. If your blood pressure increases dramatically or your body temperature drops your internal systems can struggle to work effectively. These systems may eventually fail.
Why is Homeostasis Essential?
You can trace the term “homeostasis” back to the 1920s. Originally, homeostasis was an expansion of the work of the late physiologist Claude Bernard. In the 1870s, Bernard first detailed how complex organisms must maintain balance in their internal environment, or “milieu intérieur,” to survive in the world outside. Cannon expanded the concept, introducing homeostasis to the general public through his book, “The Wisdom of the Body” (The British Medical Journal, 1932).
Widely deemed a core principle of physiology, Cannon’s description of homeostasis remains in use today. The term derives from the Greek root words meaning “similar” and a state of stability. The prefix “homeo” stresses that homeostasis does not work like a thermostat or vehicle cruise control, fixed at one measurement. Instead, homeostasis maintains important physiological factors within an ideal range of values.
For example, the human body regulates its internal concentrations of hydrogen, calcium, potassium, and sodium. Cells rely on these elements for standard functionality. Homeostatic processes also mitigate water, oxygen, pH, and blood sugar levels, as well as internal body temperature.
In all healthy organisms, these processes unfold constantly and automatically, according to Scientific American. A multitude of systems often works together to hold steady a singular physiological factor, like body temperature. If these internal processes flounder or fail, an organism may fall victim to disease or even death.
How Homeostasis is Maintained
Many homeostatic systems attune themselves to distress signals in the body. They do this to know when essential variables fall outside the scope of their ideal range. The nervous system picks up on these fluctuations and calls back to a control center, often based in the brain. The control center then directs muscles, organs, and glands to correct for the deviation. This continuous disturbance and correction cycle is “negative feedback.”
One example is how the human body maintains an internal temperature of about 98.6 degrees Fahrenheit (37 degrees Celsius). When too warm, sensors in the skin and brain signal a distress call. This initiates a chain reaction that directs the body to sweat. Then, once chilled, the body responds by shivering and reducing blood circulation to the skin. This process is prevalent when sodium levels increase. According to two NIH-funded studies, the body sends an alarm to the kidneys to conserve water and discharge excess salt in urine.
Organisms will also alter certain types of behavior in response to negative feedback. For example, when overheated, we may take off a layer of clothing, move our body into the shade, or seek a glass of water.
Modern Models of Homeostasis
The idea of negative feedback can be traced back to Cannon’s description of homeostasis in the 1920s. This was the first explanation of how homeostatic processes work. However, in recent years, many scientists argue that organisms are also capable of anticipating potential disturbances to our balanced internal state rather than only making adjustments retroactively.
This alternate model of homeostasis, referred to as allostasis, suggests that the acceptable set point for a variable can shift in response to changes in environmental factors, according to a 2015 article in Psychological Review. This point may change under the influence of other factors like circadian rhythms, menstrual cycles, or fluctuations in body temperature. Setpoints may also shift in response to physiological circumstances such as a fever or to adjust for multiple homeostatic processes taking place at once, according to a 2015 review in Advances in Physiology Education.
“The setpoints themselves aren’t fixed but can show adaptive plasticity,” said Art Woods, a biologist at the University of Montana in Missoula. “This model allows for anticipatory responses to upcoming potential disturbances to set points.”
For example, in anticipation of a meal, the body releases extra insulin, ghrelin, and other hormones, according to a 2007 review in appetite. This preemptive adjustment prepares the body for an incoming flood of calories rather than struggling later to control blood sugar and energy reserves.
This capacity to alter setpoints permits animals to adapt to short-term stressors. However, they may still fail in the face of more severe long-term challenges, such as climate change.
“Activating homeostatic response systems can be fine for short periods,” Woods said. However, these responses don’t last for long. “Homeostatic systems can fail if cells push them too far; so, although systems may be able to handle near-term novel climates, they may not be able to handle larger changes over longer periods.”
Keeping Information Flowing
Homeostasis may have evolved initially to assist organisms in preserving optimal function in different situations and environments. However, according to a 2013 essay in the journal Trends in Ecology & Evolution, some scientists speculate that homeostasis primarily offers a “quiet background” for cells, tissues, and organs to interact and communicate with one another. This theory suggests that homeostasis makes it easier for organisms to deduce important information from the surrounding environment and subsequently share information between body parts.
Regardless of its primary purpose, homeostasis has transformed research in the life sciences for over a century. Though most often discussed in connection with animal physiology, homeostasis also enables plants to maintain energy reserves, nourish cells, and react to environmental changes. The social sciences, computer science, cybernetics, and engineering all utilize homeostatic processes. These sciences use these processes as a guiding framework for understanding how people and machines preserve stability despite disruptions.