What is the Endocannabinoid System - an update

What is the Endocannabinoid System?  An Update

** updated from blog post. 9/28/2020



The endocannabinoid system is built into our bodies and, although newly discovered, has been pursued scientifically for many years. It has been far more supported in research than cannabis plants themselves, but even this system has been difficult to research as thoroughly as its important role demands because of the restriction of research on cannabis, the stealth nature of the endocannabinoid system, the need to develop new research tools, and its extreme complexity. Yet it is critical to understand the breadth and complexity of the system that allows medical cannabis to have its effects on the body. This update to a previous blog has been added because it is important to understand that the knowledge of this system is always evolving, based on the best current scientific evidence.  These posts are also aimed at helping physicians and other health providers to better understand medical cannabis and how the plant-based phytocannabinoid system interacts with the built-in endocannabinoid system.


When a natural substance influences the body, it is because it either uses or bypasses a system built into the body. The opium poppy works for pain because it uses our built-in endorphin system. Desiccated thyroid replaces and bypasses the body’s failing thyroid hormone production system. St. John’s-wort works for depression because it enhances the chemistry of the brain’s mood-regulating system. Curcumin works on the body’s immune system to decrease inflammation. Medical cannabis is effective for a wide variety of conditions because it enhances the body’s extensive endocannabinoid system.


Researchers discovered some of the active ingredients in cannabis almost 50 years before they could figure out where and how these substances worked.   The first part of the endocannabinoid system to be discovered was the cannabinoid-1 receptor (CB-1) in the 1980s.  Soon after came discovery of the cannabinoid-2 receptor (CB-2).  Several years later an Israeli research team, headed by Raphael Mechoulam discovered the neurotransmitter N-arachidonoylethanolamine (AEA).  They named it anandamide from the Sanskrit word ananda for happiness or bliss and the scientific word amide for the amide chain located at the end of this molecule.


Later, a second endocannabinoid neurotransmitter was discovered, 2-arachidonoyl glycerol (2-AG).  Later still, the enzymes responsible for assembly, breakdown, and inactivation of AEA and 2-AG were determined to be part of the endocannabinoid system. AEA and 2-AG turned out to have properties that go well beyond neurotransmission. We still do not understand the full magnitude of this system, but slowly have begun to elucidate it. It is responsible for a broad range of stabilizing and destabilizing activities in the body. A 2013 review by Pacher and Kunos states “modulating Endocannabinoid System activity may have therapeutic potential in almost all diseases affecting humans, including obesity/metabolic syndrome, diabetes and diabetic complication, neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal, skin diseases, pain, psychiatric disorders, cachexia, cancer, chemotherapy induced nausea and vomiting, among others.”   


We now know of a system of immense importance, built into each of us, that is newly discovered but responds to a plant with over 5,000 years of medical use. The current understanding of this system is that there are two cannabinoid receptors (CB-1 and CB-2), two endocannabinoid (eCB) neurotransmitters, and signaling agents (anandamide or AEA and 2-AG), and five enzymes that either synthesize 2-AG (DAGL-α, and DAGL-β), and AEA (NAPE selective phospholipase-D) or break down 2-AG (MAGL) and AEA (FAAH).   It also appears two or three other enzymatic and chemical substrates construct AEA.


Regardless of which processes are involved in synthesis of AEA and 2-AG, they are only made in response to an increase of CB-1 or CB-2 receptors in local areas due to injury or disease. This occurs when imbalances develop and results in this system being pinpoint in nature rather than systemic throughout the body. There is also increasing evidence that endocannabinoids modify other systems, which modify the endocannabinoid system in turn. The full impact and importance of the endocannabinoid system is only coming into focus in the last decade, with an explosive focus on research in the last five years. Clinical research remains far behind pharmacological and animal research, mostly due to the politically motivated restrictions that make studying clinical effects of plant cannabinoids too difficult.  However, cataloguing and studying the endocannabinoid system is quickly revealing something far more complex than the plant, something that seems to constantly rebalance most of the body’s essential systems for controlling pain, mood, inflammation, energy, wellness, and illness.


A picture is emerging of a system that polices the body’s buildup and breakdown functions, trying to balance them.  When disease or injury intrude, the same endocannabinoid system intervenes to restore balance.  The importance of the endocannabinoid system is still only partially understood, but is becoming clear at a breathtaking pace, with over 8000 articles in PubMed on this system.  The complexity of the interplay of this system with other body and brain systems includes interactions of the endocannabinoids with endorphins, hormones, cytokines, growth factors, pleasure molecules, immune cells, connective tissue system, bone metabolism, nerve and glial cell inflammation, cell regeneration, and cell death (apoptosis).  We are only in the early stages in understanding the rich complexities at play here.  The story has not even significantly filtered into standard medical practice or medical school curricula. 


When a system as extensive as the endocannabinoid system succumbs to illnesses such as chronic mood disturbances, persistent pain, osteoporosis, or even cancer, figuring out how to rebalance it has great potential.  To accomplish this, we need a more complete understanding of that system.  The major components of the endocannabinoid system include receptors, stimulators of those receptors, enzymes, in combinations and variations that allow it to fine-tune physical function in exquisite detail.










Dr. Allison Kendrick

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