What is the Endocannabinoid System?
The Endocannabinoid System is what allows CBD (and the other cannabinoids naturally occurring in hemp) to help return our bodies to return to homeostasis. The endocannabinoid system (aka The ECS)has some of the most prominent neurotransmitters in the body - all throughout the body - and functions somewhat like a conductor of an orchestra.
In 1964, researchers in Israel discovered the therapeutically active substances in cannabis that have come to be called cannabinoids and isolated the most popular and possibly effective cannabinoid, THC (tetrahydrocannabinol). More than 20 years later, in 1988, researchers identified the human body’s endocannabinoid system.
"By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance. We wouldn't have been able to get there if we had not looked at the plant."
- Dr. Raphael Mechoulam
Endocannabinoids are the special molecules naturally produced in the human body that are closely related to proper functioning of the immune system and nervous system and that are mimicked by the cannabinoids found in the cannabis plant. Cannabinoids contained in cannabis, referred to as phytocannabinoids, simply imitate endocannabinoids. Cannabinoids fit perfectly into specialized receptors found throughout the nervous and immune systems, serving to enhance, or improve upon, the body’s own ability to maintain homeostasis (balance) and health in what has become known as "The Entourage Effect".
The concept of the entourage effect was introduced in 1998 by Israeli scientists Dr. Shimon Ben-Shabat and Dr. Raphael Mechoulam. The theory is that cannabinoids within the cannabis plant work together through a network of coincidental relationships as part of a greater organism and affect the body in a mechanism similar to the body’s own endocannabinoid system. Basically, these compounds work better together than in isolation.
- Cannabinoids 101
- The Endocannabinoid System
- The Entourage Effect
- About Cannabidiol (CBD)
- About Cannabidiolic Acid (CBDa)
- About Cannabigerol (CBG)
- About Cannabigerolic Acid (CBGa)
- About Cannabinol (CBN)
- About Cannabichromene (CBC)
- About Tetrahydrocannabinol (THC)
- About Tetrahydrocannabivarin (THCV)
- About Terpenes & Terpenoids
The Human Endocannabinoid System
The Roles of Endocannabinoid System Receptors
"The discovery of the endocannabinoid system (ECS) is the single most important scientific medical discovery since the recognition of sterile surgical technique. As our knowledge expands, we are coming to realize that the ECS is a master control system of virtually all physiology."
- Dr. David B. Allen
The Endocannabinoid System is found in every animal (except for insects) and regulates a broad range of biological functions. The ECS is a biochemical control system of neuromodulatory lipids (molecules that include fats, waxes, sterols and fat-soluble vitamins such as vitamins A, D, E and K and others) and specialized receptors configured to accept certain cannabinoids. In general, a given receptor will accept only particular classes of compounds and will be unaffected by other compounds, just as a specific key is needed to open a lock.
Specialized receptors are located throughout the human body, including but not limited to, in the hippocampus (memory, learning), the cerebral cortex (decision-making, emotional behavior), the cerebellum (motor control, coordination), putamen (movement, learning), the hypothalamus (appetite, body temperature) and the amygdala (emotions). When a specific cannabinoid or combination of cannabinoids bind to a specialized receptor, an event or a series of events, is triggered in the cell, resulting in a change in the cell’s activity, its gene regulation and/or the signals that it sends to neighboring cells. This process is called “signal transduction.”
First detected in the brain, science now shows that CB1-R are also located in many other organs, connective tissues, gonads and glands. CB1 Receptors are not found in the medulla oblongata (the part of the brain stem responsible for respiratory and cardiovascular functions). CB1 receptors play an important role in the coordination of movements, spatial orientation, sensory perceptions (taste, touch, smell, hearing), cognitive performance and motivation.
The most important function of the CB1 receptors is the reduction of excessive or inadequate signaling by the neurotransmitters (messengers) in the brain. By the activation of the CB1 receptors, the hyperactivity or hypoactivity of the messengers (e.g., serotonin, dopamine) is regulated back into balance. For example, when THC binds to CB1 receptors, activity in the pain circuits is inhibited, thus resulting in reduced pain. Many other symptoms such as nausea, muscle spasticity and seizures can be alleviated or diminished with cannabinoid therapy.
CB2 receptors are primarily associated with the immune system and found outside of the brain in such places as the gut, spleen, liver, heart, kidneys, bones, blood vessels, lymph cells, endocrine glands and reproductive organs.
For example, CBD is keyed to CB2 receptors, and good evidence shows CBD is a beneficial therapeutic strategy to lessen the impact of inflammatory and neuro-inflammatory diseases. Until recently, it was believed that CB2 receptors played no role with nerve cells or bundles. However, studies now show that it also plays an important role in the signal processing of the brain.
A third receptor that gets little attention is the transient receptor potential vanilloid-type one (TRPV1). The function of TRPV1 is to detect and regulate body temperature. In addition, TRPV1 is responsible for the sensations of extreme external heat and pain and is subject to desensitization. Therefore, if continuously stimulated, the pathway will eventually slow down or even stop. This raises therapeutic possibilities for agents to effectively treat certain kinds of neuropathic pain.
Additional Components of the Endocannabinoid System
There are other components that comprise the ECS. The first of these are endogenous arachidonate-based lipids, such as anandamide (N-arachidonoylethanolamine - AEA). Naturally produced by the body, anandamide's name is taken from a Sanskrit word which means "bliss and delight". That should give you a good clue as to its function. First discovered and named in 1992 by Dr. Raphael Mechoulam, the endogenous encocannabinoid anandamide is a fatty acid neurotransmitter that impacts the central nervouse system as well as the peripheral nervous system. Anandamide has been shown to govern things in the body such as memory, feeding behavior and pleasure.
Additionally important in the ECS are the enzymes that synthesize and degrade endocannabinoids. One example of these enzymes would be the fatty acid amide hydrolase. This substance is shown to break down anandamide in humans. Because it is closely tied to the regulation of feelings like fear, pain and anxiety, it is currently the subject of considerable scientific study. Another example of these crucial enzymes is monoacylglyerol lipase.
Endocannabinoid System Clinical Research
An introduction to the endogenous cannabinoid system
The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, however CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator activated receptors (PPAR’s) are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide) are the best-studied endogenous cannabinoids. Despite similarities in chemical structure, 2-AG and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiological and pathophysiological roles to these two endocannabinoids. Because of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiological and pathophysiological roles of the ECS. This review will provide an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.
The endocannabinoid system: an overview
Upon the identification of anandamide (AEA) in the porcine brain, numerous studies contributed to the current state of knowledge regarding all elements that form the “endocannabinoid system (ECS).”How this complex system of receptors, ligands, and enzymes is integrated in helping to regulate fundamental processes at level of central nervous and peripheral systems and how its regulation and dysregulation might counteract disturbances of such functions, is nowadays still under investigation. However, the most recent advances on the physiological distribution and functional role of ECS allowed the progress of various research tools aimed at the therapeutic exploitation of endocannabinoid (eCB) signaling, as well as the development of novel drugs with pharmacological advantages. Here, we shall briefly overview the metabolic and signal transduction pathways of the main eCBs representatives, AEA, and 2-arachidonoylglycerol (2-AG), and we will discuss the therapeutic potential of new ECS-oriented drugs.
The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities
The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).
Cannabinoids and Animal Physiology
Much has been learned since the publication of the 1982 Institute of Medicine (IOM) report Marijuana and Health.* Although it was clear then that most of the effects of marijuana were due to its actions on the brain, there was little information about how THC acted on brain cells (neurons), which cells were affected by THC, or even what general areas of the brain were most affected by THC. Too little was known about cannabinoid physiology to offer any scientific insights into the harmful or therapeutic effects of marijuana. That is no longer true. During the past 16 years, there have been major advances in what basic science discloses about the potential medical benefits of cannabinoids, the group of compounds related to THC. Many variants are found in the marijuana plant, and other cannabinoids not found in the plant have been chemically synthesized. Sixteen years ago it was still a matter of debate as to whether THC acted nonspecifically by affecting the fluidity of cell membranes or whether a specific pathway of action was mediated by a receptor that responded selectively to THC.
Modulating the endocannabinoid system in human health and disease–successes and failures
The discovery of the endocannabinoid system, comprising the G-proteincoupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipidligands or endocannabinoids, and synthetic and metabolizing enzymes, hastriggered an avalanche of experimental studies implicating the endocanna-binoid system in a growing number of physiological/pathological functions.These studies have also suggested that modulating the activity of the en-docannabinoid system holds therapeutic promise for a broad range of dis-eases, including neurodegenerative, cardiovascular and inflammatorydisorders; obesity/metabolic syndrome; cachexia; chemotherapy-inducednausea and vomiting; and tissue injury and pain, amongst others. However,clinical trials with globally acting CB1antagonists in obesity/metabolic syn-drome, and other studies with peripherally-restricted CB1/2agonists andinhibitors of the endocannabinoid metabolizing enzyme in pain, have intro-duced unexpected complexities, suggesting that a better understanding ofthe pathophysiological role of the endocannabinoid system is required todevise clinically successful treatment strategies.
Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System
John M. McPartland, Geoffrey W. Guy, Vincenzo Di Marzo | March 12, 2014, PLoS ONE 9(3) | Full Text Article
The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system.
The endocannabinoid system as a target for the treatment of motor dysfunction
Javier Fernández-Ruiz |} March 31, 2009, British Journal of Pharmacology | Full Text Article
There is evidence that cannabinoid-based medicines that are selective for different targets in the cannabinoid signalling system (e.g. receptors, inactivation mechanism, enzymes) might be beneficial in basal ganglia disorders, namely Parkinson's disease (PD) and Huntington's disease (HD). These benefits not only include the alleviation of specific motor symptoms [e.g. choreic movements with cannabinoid receptor type 1 (CB1)/transient receptor potential vanilloid type 1 agonists in HD; bradykinesia with CB1 antagonists and tremor with CB1 agonists in PD], but also the delay of disease progression due to the neuroprotective properties demonstrated for cannabinoids (e.g. CB1 agonists reduce excitotoxicity; CB2 agonists limit the toxicity of reactive microglia; and antioxidant cannabinoids attenuate oxidative damage). In addition, extensive biochemical, anatomical, physiological and pharmacological studies have demonstrated that: (i) the different elements of the cannabinoid system are abundant in basal ganglia structures and they are affected by these disorders; (ii) the cannabinoid system plays a prominent role in basal ganglia function by modulating the neurotransmitters that operate in the basal ganglia circuits, both in healthy and pathological conditions; and (iii) the activation and/or inhibition of the cannabinoid system is associated with important motor responses that are maintained and even enhanced in conditions of malfunctioning and/or degeneration. In this article we will review the available data regarding the relationship between the cannabinoid system and basal ganglia activity, both in healthy and pathological conditions and will also try to identify future lines of research expected to increase current knowledge about the potential therapeutic benefits of targeting this system in PD, HD and other basal ganglia disorders.
The endocannabinoid system and cancer: therapeutic implication
Josée Guindon, Andrea G Hohmann | March 15, 2011, British Journal of Pharmacology | Full Text Article
The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others). The main active ingredient of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), produces its effects through activation of CB1 and CB2 receptors. CB1 receptors are expressed at high levels in the central nervous system (CNS), whereas CB2 receptors are concentrated predominantly, although not exclusively, in cells of the immune system. Endocannabinoids are endogenous lipid-signalling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids identified to date are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer. This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems. The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed. Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients. In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted.
Endocannabinoid system dysfunction in mood and related disorders
C. H. Ashton, P. B. Moore | March 9, 2011, Acta Psychiatrica Scandinavica |Full Text Article
The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders. An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids. We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1(CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement. Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.
The Endocannabinoid System, Our Universal Regulator
Chad A. Sallaberry, Laurie Astern | June 1, 2018, Journal of Young Investigators | Full Text Article
The endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role in maintaining the homeostasis of the human body, which encompasses the brain, endocrine, and immune system, to name a few. ECS is a unique system in multiple dimensions. To begin with, it is a retrograde system functioning post- to pre-synapse, allowing it to be a “master regulator” in the body. Secondly, it has a very wide scope of influence due to an abundance of cannabinoid receptors located anywhere from immune cells to neurons. Finally, cannabinoids are rapidly synthesized and degraded, so they do not stay in the body for very long in high amounts, possibly enabling cannabinoid therapy to be a safer alternative to opioids or benzodiazepines. This paper will discuss how ECS functions through the regulation of neurotransmitter function, apoptosis, mitochondrial function, and ion-gated channels. The practical applications of the ECS, as well as the avenues for diseases such as epilepsy, cancer, amyotrophic lateral sclerosis (ALS), and autism, which have no known cure as of now, will be explored.