The endocannabinoid system (ECS) is a complex cell-signaling system identified in the early 1990s by researchers exploring THC, a well-known cannabinoid compound in marijuana. The ECS is involved in regulating a range of functions and processes, including sleep, mood, appetite, memory, reproduction, and fertility.[1]

The ECS exists and is active in the body even if one does not use cannabis. It involves three core components: endocannabinoids, receptors, and enzymes. Endocannabinoids, also known as endogenous cannabinoids, are molecules made by the body. They’re similar to cannabinoids but are produced by the body. The two key endocannabinoids identified are anandamide (AEA) and 2-arachidonoylglyerol (2-AG).[1-2]

These endocannabinoids bind to receptors found throughout the body to signal that the ECS needs to take action. There are two main endocannabinoid receptors: CB1 receptors, which are mostly found in the central nervous system, and CB2 receptors, which are mostly found in the peripheral nervous system, especially immune cells. Endocannabinoids can bind to either receptor, and the resulting effects depend on where the receptor is located and which endocannabinoid it binds to.[1-2]

Finally, enzymes are responsible for breaking down endocannabinoids once they have carried out their function. The two main enzymes are fatty acid amide hydrolase, which breaks down AEA, and monoacylglycerol acid lipase, which typically breaks down 2-AG.[1-2]

The ECS plays a role in maintaining homeostasis in the body by modulating the activity of neurotransmitters and influencing a variety of metabolic pathways. It has been implicated in a variety of physiological processes including neuroprotection, immune response, inflammation, pain, and the regulation of stress and emotional state.[3-6] Dysregulation of the ECS has been associated with a variety of pathophysiological conditions, including neurodegenerative diseases, cancer, and cardiovascular diseases.[4][6]

Research into the ECS has expanded the understanding of its role in human health and disease, and it continues to be an area of active investigation for potential therapeutic targets.

References

1.An Introduction to the Endogenous Cannabinoid System.

Lu HC, Mackie K.

Biological Psychiatry. 2016;79(7):516-25. doi:10.1016/j.biopsych.2015.07.028.

The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptors are the CB1 cannabinoid receptors; however, CB2 cannabinoid receptors, transient receptor potential channels, and peroxisome proliferator activated receptors are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. The best-studied endogenous cannabinoids are 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide). Despite similarities in chemical structure, 2-arachidonoyl glycerol and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiologic and pathophysiologic roles to these two endocannabinoids. As a result of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiologic and pathophysiologic roles of the ECS. This review provides an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.

2.The Endocannabinoid System: Its General Strategy of Action, Tools for Its Pharmacological Manipulation and Potential Therapeutic Exploitation.

Di Marzo V.

Pharmacological Research. 2009;60(2):77-84. doi:10.1016/j.phrs.2009.02.010.

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The endocannabinoid signalling system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB(1) and CB(2) receptors and discovered following studies on the mechanism of action of Delta(9)-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The endocannabinoid system is quite widespread in mammalian tissues and cells and appears to play a pro-homeostatic role by being activated following transient or chronic perturbation of homeostasis, and by regulating in a local way the levels and action of other chemical signals. Compounds that selectively manipulate the action and levels of endocannabinoids at their targets have been and are being developed, and represent templates for potential new therapeutic drugs.

3.Neuroprotective and Immunomodulatory Action of the Endocannabinoid System Under Neuroinflammation.

Kasatkina LA, Rittchen S, Sturm EM.

International Journal of Molecular Sciences. 2021;22(11):5431. doi:10.3390/ijms22115431. Copyright License: CC BY

Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-╬▒ and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.

4.The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases.

Lowe H, Toyang N, Steele B, Bryant J, Ngwa W.

International Journal of Molecular Sciences. 2021;22(17):9472. doi:10.3390/ijms22179472. Copyright License: CC BY

The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems. In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development. The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases. This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of L. (hereafter referred to as ” L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.

5.Endocannabinoid System and Its Modulation of Brain, Gut, Joint and Skin Inflammation.

Osafo N, Yeboah OK, Antwi AO.

Molecular Biology Reports. 2021;48(4):3665-3680. doi:10.1007/s11033-021-06366-1.

The discovery of endogenous cannabinoid receptors CB and CB and their endogenous ligands has generated interest in the endocannabinoid system and has contributed to the understanding of the role of the endocannabinoid system. Its role in the normal physiology of the body and its implication in pathological states such as cardiovascular diseases, neoplasm, depression and pain have been subjects of scientific interest. In this review the authors focus on the endogenous cannabinoids, and the critical role of cannabinoid receptor signaling in neurodegeneration and other inflammatory responses such as gut, joint and skin inflammation. This review also discusses the potential of endocannabinoid pathways as drug targets in the amelioration of some inflammatory conditions. Though the exact role of the endocannabinoid system is not fully understood, the evidence found much clearly points to a great potential in exploiting both its central and peripheral pathways in disease management. Cannabinoid therapy has proven promising in several preclinical and clinical trials.

6.Endocannabinoid System: Role in Blood Cell Development, Neuroimmune Interactions and Associated Disorders.

Sharma DS, Paddibhatla I, Raghuwanshi S, et al.

Journal of Neuroimmunology. 2021;353:577501. doi:10.1016/j.jneuroim.2021.577501.

The endocannabinoid system (ECS) is a complex physiological network involved in creating homeostasis and maintaining human health. Studies of the last 40 years have shown that endocannabinoids (ECs), a group of bioactive lipids, together with their set of receptors, function as one of the most important physiologic systems in human body. ECs and cannabinoid receptors (CBRs) are found throughout the body: in the brain tissues, immune cells, and in the peripheral organs and tissues as well. In recent years, ECs have emerged as key modulators of affect, neurotransmitter release, immune function, and several other physiological functions. This modulatory homoeostatic system operates in the regulation of brain activity and states of physical health and disease. In several research studies and patents the ECS has been recognised with neuro-protective properties thus it might be a target in neurodegenerative diseases. Most immune cells express these bioactive lipids and their receptors, recent data also highlight the immunomodulatory effects of endocannabinoids. Interplay of immune and nervous system has been recognized in past, recent studies suggest that ECS function as a bridge between neuronal and immune system. In several ongoing clinical trial studies, the ECS has also been placed in the anti-cancer drugs spotlight. This review summarizes the literature of cannabinoid ligands and their biosynthesis, cannabinoid receptors and their distribution, and the signaling pathways initiated by the binding of cannabinoid ligands to cannabinoid receptors. Further, this review highlights the functional role of cannabinoids and ECS in blood cell development, neuroimmune interactions and associated disorders. Moreover, we highlight the current state of knowledge of cannabinoid ligands as the mediators of neuroimmune interactions, which can be therapeutically effective for neuro-immune disorders and several diseases associated with neuroinflammation.

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