The endocannabinoid system (ECS) refers to the human body’s ability to produce its own natural cannabinoids (called endocannabinoids). Other mammals have endocannabinoid systems too. The ECS was not discovered until the lates 80s/early 90s, and we had no clue of its importance. Now, we know that the ECS is extremely important to keep the body’s most essential functions (e.g. the sleep-wake cycle, appetite regulation, immune system function) in balance. In fact, the discovery of the ECS could be one of the most important in medicine over the last 30 or so years. Cannabinoids are chemicals which impact the body. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are examples of cannabinoids, which are different chemical components that can be found in the marijuana plant. The cannabis plant contains over 150 different types of cannabinoids! Cannabinoids are in more than just marijuana, though. They’re found naturally in many foods you eat and even produced naturally in your own body. THC and CBD are the two most common cannabinoids. Even if you haven’t done any research on medical marijuana, you’ve probably heard of them. If you’ve spent a little time looking into the subject, you probably know that THC can give you a “high” feeling and CBD gives you a “relaxed” feeling. But why is that? Leafwell will help you answer this question by taking a look at the endocannabinoid system (ECS) and how it works. Check out our glossary if there are any scientific terms you do not understand. Download Our Introductory Guide To the ECS Table of Contents What is the Role of the Endocannabinoid System (ECS)? The Basics of the Endocannabinoid System (ECS) CB1 Receptors CB2 Receptors Endocannabinoids Cannabinoid Degrading Enzymes Do Our Bodies Produce Their Own Cannabinoids? What is Anandamide (C22H37NO2)? What is 2-AG, 2-Arachidonoylglycerol (C23H38O4)? What Are the Differences Between Endocannabinoids and Phytocannabinoids? How Does Cannabidiol (CBD) Affect the Endocannabinoid System? How Does THC Affect the Endocannabinoid System? CBD vs. THC: It’s Not Necessarily a Fight. What is the Entourage Effect? What is Clinical Endocannabinoid Deficiency (CED) and What Causes It? How Do You Heal the Endocannabinoid System? What Foods Contain Cannabinoids? How Does Long-term Use of Cannabis Affect the Endocannabinoid System? How Long Does It Take for Cannabinoid Receptors to Return to Normal? The Endocannabinoid System – More Research is Needed What is the Role of the Endocannabinoid System (ECS)? The ECS is intimately involved in homeostasis – keeping the body’s physiological processes stable and in balance. The ECS is involved in regulating many of life’s most essential physiological and cognitive processes, including: Fertility Pregnancy, during pre- and postnatal development Inflammatory responses and immune system functions The pleasurable effects of exercise Appetite Pain-sensation Mood Memory Mediating the pharmacological effects of cannabis. In short, the ECS does a lot more than you might think. Let’s explore the basics of the ECS and what they do. The Basics of the Endocannabinoid System (ECS) As mentioned above, the endocannabinoid system (ECS) refers to the mammalian body’s ability to produce its own natural cannabinoids (called endocannabinoids). The most essential components of the ECS are the CB1 receptors, CB2 receptors, our own naturally-occuring endocannabinoids (anandamide and 2-AG), and the enzymes that break cannabinoids down (e.g. FAAH). Cannabinoid receptors are found in every cell in the human body, meaning every cell can receive an instruction via the ECS. This means the ECS acts as a sort of mainframe for the central and peripheral nervous systems (CNS and PNS). Cannabinoids can therefore be used to communicate directly or indirectly with a wide range of receptors, including CB1 receptors, CB2 receptors, GPR55 receptors, opioid receptors, dopamine receptors, serotonin receptors and much more besides! CB1 Receptors CB1 receptors are expressed most densely in the brain. CB1 receptors are largely responsible for mediating the effects of cannabinoid binding in the brain. To put it simply, compounds like THC bind to CB1 receptors and can cause psychoactive effects. Cannabinoids that bind to CB1 receptors can decrease the release of glutamate or GABA (gamma-aminobutyric acid). Glutamate stimulates or excites the nervous system, GABA calms it down. When glutamate levels are high, GABA levels are often low, and vice-versa. Glutamate = go, GABA = stop. THC inhibits the production of GABA. This means that fewer “stop” signals are transmitted to dopamine neurons. This leads to a buildup of the “go” signal, glutamate, which can increase the amount of dopamine available in the body, causing a “high”. Limiting glutamate release reduces neuronal excitation. Limiting GABA release suppresses inhibition, a common form of short-term plasticity. Activating CB1 receptors also changes our internal clocks and sense of time. Our internal clocks speed up, which makes external time appear to slow down. This is thought to be due to altered blood flow to the cerebellum when using THC. Activating CB1 receptors also increases our appetite and desire for food. Other effects of activating CB1 receptors include: having a painkilling or pain-distracting effect; an antiemetic (anti-nausea) effect; and either an “up”, excited psychoactive effect (that high doses of THCV can provide) or a more “down”, relaxed effect associated with THC. Blue – CB1 receptor structure. Green – CB2 receptor structure. Author: Esculapio at it.wikipedia. CC BY-SA 3.0. https://commons.wikimedia.org/wiki/File:Cb1_cb2_structure.png CB2 Receptors Expressed most densely in the immune system, but also found expressed on neurons in more limited amounts in the brain, gastrointestinal system and peripheral nervous system (PNS). CB2 receptors have been implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis (cell death), and induction of cell migration (cell movement & development). CB2 receptor agonists (compounds that turn on CB2 receptors) may have significant anti-inflammatory properties. This can help treat pain and inflammation. Targeting CB2 receptors have been particularly useful for the treatment of autoimmune disorders and arthritis. Endocannabinoids These are the body’s own naturally occurring cannabinoids, which bind to CB1 & CB2 receptors. Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) are the two primary endocannabinoids. Cannabinoid Degrading Enzymes Such as fatty acid amide hydrolase (FAAH), which breaks down anandamide and THC; and monoaglycerol lipase (MAGL), which breaks down 2-AG. These enzymes break down both endocannabinoids and plant-derived cannabinoids (phytocannabinoids), and prevent dangerous levels of endo- and phyto- cannabinoids from building up in the human body. The Endocannabinoid System (ECS). Synaptic signaling of THC across the presynapse and postsynapse. Download Our Introductory Guide To the ECS Do Our Bodies Produce Their Own Cannabinoids? Yes. There are two main endocannabinoids produced naturally by the body: Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG). What is Anandamide (C22H37NO2)? Anandamide is derived from the Sanskrit word ananda, meaning “joy, bliss, delight.” Anandamide is degraded by the enzyme fatty acid amide hydrolase (FAAH), which is an enzyme that breaks down THC and anandamide. Anandamide is a weak partial agonist of CB1 receptors and weak agonist of CB2 receptors, meaning that it has some euphoric and anti-inflammatory effects. THC inhibits FAAH, which leads to elevated anandamide levels, which alongside the increase in dopamine is where cannabis’ psychoactive and analgesic effects come from. Anandamide plays a role in the regulation of feeding behavior, and the neural generation of motivation and pleasure. Acetaminophen/paracetamol/tylenol also inhibits FAAH, but doesn’t have psychoactive effects, and is not as potent an FAAH inhibitor as THC. Anandamide (C22H37NO2). Picture from: https://commons.wikimedia.org/wiki/File:Anandamide_skeletal.svg What is 2-AG, 2-Arachidonoylglycerol (C23H38O4)? 2AG is a full agonist of both the CB1 and CB2 receptors. This means that 2AG fits into the CB1 and CB2 receptors fully (called an agonist), and can have both pain-killing and anti-inflammatory effects. 2-AG is present at relatively high levels in the central nervous system (CNS). 2AG is involved in several essential physiological functions. These include cell division, energy metabolism, and inflammation. 2AG production has been associated with pain relief, suppression of vomiting, stimulation of appetite, and the inhibition of tumor growth. 2-Arachidonoylglycerol (2-AG) chemical formula. C23H38O4. Both anandamide and 2AG target GPR18/GPR55 and TRP receptors as well, which is one reason why cannabinoids have analgesic, anti-inflammatory and antiemetic (nausea-beating) properties. GPR stands for G Protein-Coupled Receptor, which is a large group of receptors responsible for the detection of light (vision), smell and taste, and the regulation of mood, the immune system and water balance. The GPR receptor, GPR55, is sometimes considered a CBD3 receptor. Cannabinoids can be used to dampen an overactive immune system, which can be very useful for autoimmune disorders or other instances where inflammation is out-of-control. TRP stands for Transient Receptor Potential (TRP). TRP channels mediate a variety of sensations such as pain, temperature, different kinds of tastes, pressure, and vision. Some TRP channels are thought to behave like microscopic internal thermometers in animals that can sense hot or cold. What Are the Differences Between Endocannabinoids and Phytocannabinoids? Endocannabinoids are produced naturally by the body. Phytocannabinoids are cannabinoids produced by plants, with the cannabis plant being the most abundant producer of phytocannabinoids that we know of. Endocannabinoids have a range of effects on the ECS, from full antagonism (turn off the cannabinoid receptors) to full agonism (turn on the cannabinoid receptors). Phytocannabinoids, meanwhile, are more often than not partial antagonists or agonists. Phytocannabinoids also tend to have weak affinity for CB receptors, meaning that they do not bind very tightly to them. This means that phytocannabinoids can mimic endocannabinoids, but not completely. How Does Cannabidiol (CBD) Affect the Endocannabinoid System? You can read more about how CBD works here. CBD (C21H30O2) is an indirect antagonist of the body’s cannabinoid receptors CB1 and CB2, a 5-HT1A (a serotonin receptor) partial agonist, meaning it can help regulate mood; a TRPV1 (vanilloid receptor) agonist, meaning it can help treat pain; and an allosteric modulator – a substance that changes how a receptor responds to a compound – of the μ- and σ-opioid receptors. CBD may be particularly useful as an anti-inflammatory, mood stabilizer, and antispasmodic. This can make CBD useful for treating chronic pain, anxiety and depression, multiple sclerosis and epilepsy. If you are looking for a good-quality CBD product from a dispensary to treat such conditions, then get a medical marijuana card from us here at Leafwell! CBD molecular structure. C21H30O2. How Does THC Affect the Endocannabinoid System? You can read more about how THC works here. THC (C21H30O2) is a partial agonist of both CB1 and CB2 receptors. THC can increase dopamine production in the short-term, whereas using THC regularly in the long-term can blunt the dopamine receptors. Low doses of THC can increase serotonin levels. THC is an effective painkiller, and could also be useful as an anti-inflammatory, treatment of spasticity, antiemetic (nausea/vomiting prevention), appetite stimulant, and a treatment for an overactive bladder. From: https://www.needpix.com/photo/1557766/tetrahydrocannabinol-cannabis-marijuana-medicine-medical-alternative-herb-plant-nature. Author: Erzebethh, Pixabay. THC (tetrahydrocannabinol). C21H30O2. CBD vs. THC: It’s Not Necessarily a Fight. What is the Entourage Effect? Well, we say “not necessarily,” because CBD can buffer THC when in equal doses. Cannabinoids can be said to “fight” one another, but they also work in tandem with one another in what is called the “entourage effect” – the combination of cannabinoids, terpenes (smell) and flavonoids (taste) that give cannabis its unique therapeutic effects. Both THC and CBD have cancer-beating properties, and both can improve each other’s therapeutic potential. Many have a belief that CBD is the medical component of cannabis, but this is not true. Sure, CBD has its uses, but combining it with THC (even small, non-psychoactive amounts of around 1-2 mg) makes CBD more effective. Some people may get some benefits from using just CBD, but this may not be the case for everyone. Scientists such as Professor Roger Pertwee have refered to the cannabinoids in the cannabis plant as “fight-o-cannabinoids”, as they compete with each other to some extent to impart various effects on CB1 and CB2 receptors. However, this is not always the case, and cannabinoids also work together. This is the more pleasing-sounding “entourage effect”. Perhaps it is best to think of cannabinoids like a family. They both get along and fight, but they all live together in the same house and are related to each other. Some of them may have clashing personalities, but they have their own unique attributes that balance each others’ weaknesses out. Crash course in terpenes by THC Design. From https://thcdesign.com/blog/its-all-about-the-terpenes/ What is Clinical Endocannabinoid Deficiency (CED) and What Causes It? CED is a theory posited by Dr. Ethan Russo, who states that, “in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes.” Essentially, many (but not necessarily all) conditions result in a shortage or dysregulation of the production, metabolism, and abundance of endocannabinoids, and change the state or condition of cannabinoid receptors. This shortage or dysregulation can arise from an injury, infection, an event that triggers long-term inflammatory responses, or a genetic dysfunction. Many conditions are thought to be associated with a CED, including fibromyalgia, migraine and irritable bowel disorders (IBDs). Chronic pain, insomnia, anxiety, and depression may all be interlinked symptoms that have ECS dysregulation at its root. Autoimmune disorders can cause widespread inflammation in the human body, and cannabinoids may help reduce this inflammation. Dravet and Lennox-Gastaut syndromes (types of epilepsy) could arise due to the lack of genetic coding for a specific cannabinoid that allows for calcium and sodium ion regulation. It is theoretically possible to have an overabundance of cannabinoids as well. In fact, a patient by the name of Jo Cameron lacked the genetic code to produce the enzyme FAAH. This resulted in an overabundance of anandamide in her system, meaning she hardly felt any pain or anxiety! So yes, the theory seems to have some observable evidence supporting it. How Do You Heal the Endocannabinoid System? Phytocannabinoids can act as mimics of the human body’s own endogenous cannabinoids. Shortages can cause health problems, so replacing them is a way of helping heal these problems. CBD, THC, CBN, CBG, CBC, THCV and so many others can help overcome these shortages. Essential fatty acids (omega-3, omega-6), chocolate, herbs, spices, and tea can naturally stimulate the ECS, as can exercise. Getting 6+ hours of sleep can also help regulate the ECS. Playing board and card games may also help stimulate the ECS through reward mechanisms – anandamide is released during exercise, as well as the satisfactory completion of a complex task. Reducing stress and alcohol consumption may be another way to help keep the ECS in balance, as these reduce inflammation. What Foods Contain Cannabinoids? Other than cannabis and hemp, the following foodstuffs contain cannabinoids: Clove Black Pepper Cinnamon Oregano Echinacea Broccoli Kale Sprouts Carrots Ginseng Sunflowers Black truffles Kava Chocolate/cacao (contains anandamide and the anandamide-like compounds N-oleoylethanolamine and N-linoleoylethanolamine) Rue Liverwort Helichrysum Black pepper contains beta-caryophyllene, which is also found in cannabis and is a cb2 receptor agonist Beta-caryophyllene is useful for the treatment of pain and anxiety. Author: Hubertl. From https://commons.wikimedia.org/wiki/File:Black_Pepper_IMG_4866_-_02.jpg, CC-BY-SA 4.0. How Can I Strengthen My Endocannabinoid System? Eat the above foods, as well as plenty of exercise (but not overtraining) and using cannabinoid-based medications whenever necessary. Getting between 7 and 9 hours of sleep per night will also help. The endocannabinoid system and the immune system are linked, so keeping your immune system functioning and balanced (i.e. neither under- nor over- reactive) will help keep your ECS in balance. How Does Long-term Use of Cannabis Affect the Endocannabinoid System? Cannabis is a complex plant, containing up to 150 cannabinoids, all with different effects. Some have psychoactive effects, but many do not. When more than one cannabinoid is in play simultaneously, they work separately, opposed to each other, or in tandem with each other (remember the entourage effect?). Long-term use of all of these different cannabinoids has not been studied. However, long-term use of cannabis or cannabinoid-based medications may have a variety of effects. Long-term use may build up cannabinoids in the body over time and cause different effects than those expected. For example, cannabinoid hyperemesis syndrome (CHS) is thought to be caused by long-term use of THC, where too much THC builds up and causes nausea and vomiting rather than inhibiting it. Why this happens is not precisely known, but it could be due to the overactivation of serotonin and/or the TRP channels, which eventually desensitizes these receptors. This makes regulating a consistent body temperature difficult. CHS is relatively rare, but is something to be aware of. Regular consumption of high amounts of THC is not a guarantee that you will get CHS, but some may. Those who develop CHS may take hot showers to overcome the nausea. The lack of REM sleep and dreams may be an issue for some. Although cannabis (in particular, THC) can help people get to and stay asleep, it may also detract from REM sleep. This may have a negative effect on mood and memory formation in the long-term, so care must be taken with high doses of THC. There is a lot of debate surrounding the need for REM sleep and it being needed for a refreshing sleep. THC can, however, increase the amount of time in deep sleep, which is where sleep’s restorative powers of cell and tissue repair come in. Long-term use of THC may also affect the stress response system (the hypothalamic pituitary adrenal, or HPA, axis), where serotonin, dopamine, cortisol and norepinephrine receptors are blunted. The blunting effect of cannabis on these receptors can be useful for the treatment of anxiety, PTSD and ADHD/ADD – conditions where the flight-or-fight response has gone awry. Essentially, cannabis is like any other medication, where long-term use can ultimately start to have deleterious effects. The harmful effects of psychoactive cannabinoids may be reduced by utilizing other cannabinoids and terpenes, like CBD and pinene. Source: https://www.flickr.com/photos/kargaltsev/. Author: Sasha Kargalstev. ALT Text: Hot showers are one way people get over the nausea associated with cannabinoid hyperemesis syndrome (CHS). How Long Does It Take for Cannabinoid Receptors to Return to Normal? One of the advantages of using naturally-derived cannabinoids as medicine is that the body breaks them down relatively quickly, meaning that dangerous levels are not built up and a deadly overdose is theoretical rather than a practical possibility. There are few, if any, substances that humans can ingest that have the safety profile cannabis has. Those who rarely or occasionally use cannabis will not likely suffer much, if any, long-term change to their ECS. Their ECS will likely “reset” within a day or two. Longer-term users may require longer resetting time – a week to a month. For most people, stopping cannabis use is not hugely difficult, although some may have a more difficult time of it. This ability to easily reduce and come off cannabis and cannabinoids is one reason why cannabis could be an “exit drug.” Graph displaying the acute toxicity of drugs (lethal dose) and their dependence potential. Marijuana/cannabis has moderate/low dependence potential, and is not very lethal. This can make cannabis an alternative to powerful, opioid-based painkillers. Data source: Gable, R. S. (2006). Acute toxicity of drugs versus regulatory status. In J. M. Fish (Ed.),Drugs and Society: U.S. Public Policy, pp.149-162, Lanham, MD: Rowman & Littlefield Publishers. Also published at Professor Gable’s faculty page. (archive.org mirror ). The Endocannabinoid System – More Research is Needed There is still so much that needs to be learnt about the endocannabinoid system. It has only recently been discovered (late 80s/early 90s), and research into it has been limited. This can be attributed to the fact that cannabis is illegal throughout most of the world. In fact, the ECS is not even a part of the medical curriculum yet! This means that there is a huge dearth of information, even amongst health professionals. Sadly, many medical schools state that their curriculums are too busy to include the ECS, so it is up to physicians to study this hugely important and complex receptor system that is intimately involved in homeostasis on their own time! Leafwell wants to change this … Download Our Introductory Guide To the ECS See a doctor today and get a physician’s recommendation for a medical marijuana card.