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    Science Digest – The Endocannabinoid System Explained

    The human body is an amazing, brilliantly designed machine. Conventional medicine has long recognised 11 systems in our body that are said to manage all its essential functions. 

    Dr Alton Oshner (1896 – 1981) was an internationally recognised surgeon and medical researcher, best known for being the first to propose that cigarette smoking is the primary cause of lung cancer. In a letter to his son, he elegantly describes how each of these systems, when one of them becomes out of tune, will work together to restore the body to a state of balance, also known as homeostasis.

    Not surprisingly, Dr Oshner did not include the endocannabinoid system in his description. Mostly because concrete scientific evidence of its existence came in the 1980s. What is surprising is that, given its importance, it is still not widely known by the medical profession. According to a survey from 2013, only 13% of US medical schools included the endocannabinoid system in their teaching programs.

    What is the Endocannabinoid System?

    The Endocannabinoid system (ECS) is a complex biological system present in nearly all animals. That includes vertebrates (mammals, birds, reptiles, and fish) and invertebrates (sea urchins, leeches, mussels, nematodes, and others), but not insects. In the human body, the ECS regulates nearly all other systems to keep them in balance and in doing so affects a vast range of biological functions, such as sleep, mood, pain and pleasure perception, appetite, to name but a few.

    When we talk about the ECS things can get complicated really fast! So let’s try to take small steps to understand what this fascinating system actually is. There are a lot of scientific names you need to get familiar with so we will highlight them for you. 

    Cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are activated exclusively by cannabinoids.

    By now you must have heard of cannabinoids. These are compounds found in the cannabis plant such as the widely known THC and CBD, although in reality there are more than one hundred of them. Sometimes you can find these referred to as phytocannabinoids (phyto = of a plant). Cannabinoids exert some of their effects by binding to and activating certain receptors in our body. The receptors that are exclusively activated by cannabinoids are referred to as cannabinoid receptors. There are two of these receptors, the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2). There are other receptors that can be activated by cannabinoids, but for the sake of simplicity, we will only mention CB1 and CB2.


    Fact: In the brain, we have more of these receptors (CB1 and CB2) than all of the other types of receptors put together.


    Ok, so now we know that we have receptors in our body that are activated by THC and other cannabinoids. For example, THC gets you “high” because it activates the CB1 receptor. These receptors can be found in cells of practically every organ of our bodies. According to the latest data from the Gene database, at the National Center for Biotechnology Information (NCBI) website, CB1 receptors are mostly located in the cells of the brain, while CB2 receptors are mostly found in cells involved with the immune system, lymph node and spleen (see figures below). It’s because of their distribution in the human body that the activation of CB1 or CB2 receptors by different cannabinoids (such as THC and CBD) can have different outcomes on our overall health.

    Distribution of CB1 receptors in the human body (source):

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4

    Distribution of CB2 receptors in the human body (source):

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4

    After the discovery of THC and the cannabinoid receptors, scientists asked: “Why would our bodies have such receptors?”. For sure mother nature didn’t put them there in the off chance that if we ever consumed this plant it would make you “stoned”.  If we have these receptors, then we must have a molecule in our bodies that naturally activates them. So the search for what we call endocannabinoids began.

    Endocannabinoids are naturally occurring molecules produced in the body that activate the cannabinoid receptors.

    Most cells of our body have the capacity to produce endocannabinoids so they are produced locally, on-demand, and since these molecules are not water-soluble and therefore cannot travel far in our bodies, they also act locally.

    We now know of several molecules that bind to the cannabinoid receptors. Again, for the sake of keeping things as simple as possible, we will cover only the two most studied, These are arachidonoylethanolamine (also known as Anandamide or AEA) and 2-arachidonoylglycerol (2-AG)

    Anandamide was the first endocannabinoid to be discovered. It activates the CB1 receptors, the same receptor as THC does. It can also activate the CB2 receptor, but it prefers the CB1 (higher affinity for CB1). Ananda literally means “bliss”, so many call it the “bliss molecule”. On the other hand, 2-AG will bind to either CB1 or CB2 without preference.


    Fact: Chocolate contains naturally occurring anandamide, the first discovered endocannabinoid.


    So far we have as part of our ECS

    – Two receptors: CB1 and CB2

    – Two molecules that activate these receptors: Anandamide (AEA) and 2-AG

    At this point, it can be helpful to understand that usually, the higher the number of receptors the higher the effect seen after activating them. Similarly, more endocannabinoids surrounding the receptors means that more receptors get activated. Therefore, the enzymes that produce (i.e. synthesise) and breakdown (i.e. metabolise) the endocannabinoids are also considered to be part of the ECS. In practice, it means that the regulation of these enzymes determines how many molecules are free to activate the receptors, that is to say, to stimulate or inhibit the ECS.

    Anandamide is produced mainly by an enzyme called N-arachidonoyl phosphatidylethanolamine phospholipase D (NAPE-PLD). 

    NAPE-PLD uses N-arachidonoyl phosphatidylethanolamine (NAPE) as substrate (a substance that an enzyme acts on to produce a chemical reaction) to produce anandamide (AEA). 

    2-AG is produced by an enzyme called diacylglycerol lipase (DAGL).

    DAGL uses diacylglycerol (DAG) to produce 2-AG

    As soon as a cell generates anandamide (AEA) and 2-AG, it releases them into the space between the cells where it is free to bind to the CB1 or CB2 receptors.

    To regulate the amount of endocannabinoids that are free to activate the cannabinoid receptors, our cells are also equipped with enzymes that break down these molecules into other compounds.

    Once inside the cell, AEA is broken down to arachidonic acid (AA) and ethanolamine (ETA) mainly by an enzyme called fatty acid amide hydrolase (FAAH). 

    Even though FAAH can also break down 2-AG to arachidonic acid (AA) and glycerol the main enzyme responsible for 2-AG metabolism is called monoacylglycerol lipase (MAGL). 

    Now we have that the ECS is composed of

    – Two cannabinoid receptors: CB1 and CB2

    – Two endocannabinoids that activate these receptors: Anandamide (AEA) and 2-AG

    – Two enzymes that produce endocannabinoids: NAPE-PLD and DAGL

    – Two enzymes that breakdown endocannabinoids: FAAH and MAGL 

    These are only the core components of what constitutes the ECS. As research in the field progresses more enzymes are found to be involved in regulating the effect of these or other endocannabinoids, and more receptors are found to be activated by them.  

    Not too long ago, a theory was put forward by Dr Ethan Russo that a clinical endocannabinoid deficiency (CECD), whether congenital or acquired, may help to explain the pathophysiology of conditions such as migraine, fibromyalgia, irritable bowel syndrome, and others, which are commonly alleviated by clinical cannabis. He also explains why trying to control the levels of endocannabinoids is a complicated task. Until more research is done, he suggests the use of CBD as “a clinical agent that modifies endocannabinoid function”. 

    CARINA PINTO KOZMUS
    Author

    ŽELJKO PERDIJA M.D.
    Reviewer


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