Endocannabinoid System

Interworking's of the Endocannabinoid System

Interworking's of the Endocannabinoid System

Ashley Shafer

American College of Healthcare Sciences



The endocannabinoid system is a complex regulatory system that primarily maintains homeostasis within the body. The who, what, where, when, why, and how questions are answered in this literature review to give the reader a beginner understanding of this newest system discovery. The endocannabinoid system is explained using scholarly scientific articles and the latest research so people can be aware and educate themselves on this central operating system in the human body to possibly live an stress-less life. Taking it back to health and science class, the endocannabinoid system is a health modulator that significantly affects overall well-being in cognitive and psychological processes.


Considered to be the master conductor of all biological systems, the endocannabinoid system (ECS) is a complex regulatory mechanism designed to achieve homeostasis within all vertebrae species. Homeostasis, a stable balance in which every system is working efficiently, is vital because when something is off-kilter, the ECS recognizes this imbalance and helps work to correct it (Furrer, 2018). Every physiological system studied is positively modulated by the ECS and is inherent to proper human functioning (Marcu, 2015). Overseeing memory, emotional processing, sleep, digestion, motor function, immune response and inflammation, appetite, pain, blood pressure, bone growth, and the protection of neural tissues by the ECS are rigorously being researched with a more profound understanding of the interrelationships yet to be uncovered. 

The ECS regulates and controls our critical bodily functions by sending chemical messages, thus triggering biological actions to maintain normal brain and body function. Comprised of three principal elements: endocannabinoid receptors, specialized molecules called endocannabinoids that interact with those receptors, and enzymes that either synthesize or metabolize these endocannabinoids. The two primary cannabinoid receptors (a molecule inside or on the surface of a cell that binds to a specific substance and causes a particular effect in the cell (Marieb and Hoehn, 2019) are called CB1 and CB2 receptors. These receptors are distributed throughout the central nervous and immune systems and within many other tissues, including the brain, gastrointestinal system, reproductive and urinary tracts, spleen, endocrine system, heart, and circulatory system (Backes et al., 2014). This research review paper will examine the endocannabinoid systems' psychological functions and interactions with stress and mood within the central nervous system. The ECS is fundamental to living a stress-less life and improving mood because it oversees all other operating systems in the human body to achieve homeostasis involving the central nervous system. 


Sources for this integrative literature review of the interworking of the endocannabinoid system were gathered from multiple databases accessed through the American College of Healthcare Sciences (ACHS) Library Launchpad. Databases included ProQuest Central, ProQuest RefWorks, Library and Information Resources Network (LIRN), and PubMed. Key search terms were "endocannabinoid system," "endocannabinoids and human health," "endocannabinoid system history," "endocannabinoid system and brain," and "endocannabinoid system and endocannabinoid deficiency syndrome." 

Initial search criteria included "peer-review" and "full-text" documents within the past five years. From these criteria and search words, solid secondary sources were found. After scanning system reviews and meta-analysis reports, primary sources were uncovered from the secondary sources reference list. Other resources include the Integrative Cannabis Specialist 101 course materials Dr. Glen Nagel provided and books on hand from my library. 


Emotional homeostasis or equilibrium and cognitive brain function are fundamental purposes of the endocannabinoid system as it acts as a neuromodulatory pathway. Neuromodulation is where a neuron uses one or more chemicals to regulate diverse populations of neurons (Marieb and Hoehn, 2019). In the case of the ECS, the two G-protein coupled receptors (GPCRs) are cannabinoid receptors 1 and 2 (CB1 and CB2), which inhibit both intracellular and extracellular signaling (Borgan et al., 2020). These signals, inside and outside the cells, modulate synaptic transmission, the communication process from a neuron to a target (Lu and Mackie, 2021). 

IMAGE: https://sonapharmacy.com/what-is-the-endocannabinoid-system/

CB1 receptors are mainly found throughout the brain, particularly in the cerebral cortex, hippocampus, basal ganglia, and cerebellum (Ye et al., 2019; Zou et al., 2018). To break that down, the cerebral cortex is where our conscious mind is found, where we are aware of ourselves and our sensations to communicate, remember, understand, and initiate voluntary movements. The hippocampus is an area of the brain where our emotions override our logic, memories are stored, and why reason can stop us from expressing our feelings inappropriately. The basal ganglia control movement and the cerebellum adjusts motor output, ensuring coordination and balance (Marieb and Hoehn, 2019). These are areas of the brain where the ECS receptors are predominately found within the central nervous system.

This is important because it links to the central nervous system (CNS). The CNS comprises the brain and spinal cord, which is thought to be the integrating and control center of the nervous system that, much like our ECS is the master controller and communicator system in our body (Marieb and Hoehn, 2019). The nervous system receives, integrates, and responds to information from the sensory output, integration, and motor output, which the CB1 and CB2 receptors facilitate to send messages to neuralgia found in the CNS. Because of where the receptors are located in the body, both in the central neural activities and disorders and in the peripheral tissues, CB1 has the promise to be used as a therapeutic strategy for pain, appetite, inflammation, obesity, learning/memory, depression, energy metabolism, cardiovascular and reproductive functions, liver and musculoskeletal disorders, epilepsy, addiction, stroke, multiple sclerosis, neurodegenerative diseases, and cancer (Ye et al., 2019; Zou and Kumar, 2018). 

The expression of CB1 differs in pathological conditions, underscoring its crucial role in a vast spectrum of biological activities. CB2 receptors take part in immune-mediated responses and play a supportive role in protecting the brain from inflammation (Ibarra-Lecue et al., 2018). Since CB2 is primarily expressed in the peripheral areas, or areas away from the center of the body, it is an attractive therapeutic target for immunomodulators, pain management, osteoporosis, and treatment of liver diseases (Ye et al., 2019). Endocannabinoids interact with CB1 and CB2 receptors as allosteric modulators, where cannabinoids produced in the body indirectly influence the effects of an agonist (turned the receptor on) or antagonists (turned it off) at the receptor sites which maintains physiological stability (Lu et al., 2021).

Since the discovery of cannabinoid receptors, chemical messages or lipid neurotransmitters have bound to the receptors to maintain internal homeostasis. These neurotransmitters are referred to as endocannabinoids. Endo means "within," ligands for cannabinoid receptors include the endocannabinoids produced naturally inside the body, making them endogenous agonists or initiators. A small molecule that binds to another molecule is called a ligand. Currently, there are six recognized endocannabinoids which are anandamide (AEA) which was the first to be found and the Sanskrit word for "bliss," 2-arachidonoyl glycerol (2-AG), N-arachidonoyl-dopamine (NADA), 2-arachidonyl glyceryl ether (noladin ether), virodhamine (OAE) as well as Lysophosphatidy inositol (LPI), (Ye et al., 2019). These ligands bind to CB1 and CB2 receptors and are synthesized or created on demand when the body calls for them (Sharafi et al., 2022; Zou and Kumar, 2018). 

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CB1 receptors are predominantly expressed in the brain, then combined with endocannabinoids to form a "circuit breaker" which modulates the release of inhibitory
and excitatory neurotransmitters across the synapse (Backes, 2014) which means they increase or decrease the likelihood the neuron will fire an action potential because of retrograde signaling. Endocannabinoids are the only neurotransmitters with "retrograde signaling," which is intracellular communication that serves as a feedback mechanism that tells other neurotransmitters to slow down if they are firing too fast (Lee, 2010). 

To make this more complex, so-called orphan receptors, or non-CB1/CB2 receptors, interact with other CB-type and related receptors and ion channels. They are called GPR55, GPR18, and GPR119 orphan receptors because their endogenous ligands (binding to larger molecules, such as receptors) have yet to be identified. These orphan receptors are linked to energy homeostasis, physiological functions, estrogen, and food intake (Backes, 2014). With the potential of over 100 orphan receptors, their responsiveness to different endogenous, photogenic, and synthetic cannabinoid agonist and antagonists need to be examined further (Ye et al., 2019). 

Metabolic enzymes make endocannabinoids when needed and are also responsible for breaking down endocannabinoids once they've carried out their function. Monoacylglycerol lipase (MAGL) is responsible for degrading 2-AG, and the fatty acid amide hydrolase (FAAH) breaks down AEA (Lu and Mackie, 2021). All endocannabinoids come from polyunsaturated fatty acids, making them not water-soluble. This causes difficulty moving efficiently through the body, so they must be biosynthesized on demand from local precursor molecules. A complex function of localized activity happens when endocannabinoids serve as primary messengers in retrograde signaling. This happens between neurons from the postsynaptic neuron back across the synapse to the presynaptic neuron, controlling the release of neurotransmitters across the synapse. This synaptic function is how endocannabinoids modulate neurotransmitter flow, keeping the nervous system running efficiently (Backes, 2014).

The brain controls most body functions, including awareness, movements, sensations, thoughts, speech, and memory. The interplay between the CNS and ECS will affect the homeostatic maintenance of cognitive, behavioral, emotional, developmental, and physiological processes. As we understand, the brain is a very complex structure, and given the functionality and expression of the ECS are not written anywhere in formal textbooks, a lot has yet to be understood. How did we miss this?

The discovery of the ECS happened backward. First, the chemical compound identified in Cannabis Sativa, tetrahydrocannabinol (THC), was made known by an Israeli scientist, Raphael Mechoulam, in 1964 (Lee, 2010). It was not till 1990 that Lisa Matsuda and teammates from the National Institute of Mental Health (NIHM) realized that there are cannabinoid receptors in the brain and central nervous system that bonded with THC to act as subtle sensing devices, picking up biochemical cues from the body. Then, in 1992 the same scientist, Mechoulam, and collaboration research with the NIHM found the first neurotransmitter, a naturally occurring endocannabinoid AE, followed by 2-AG in 1995 (Lee, 2010). Finally, the ECS was discovered when scientists took a step back and pieced the puzzle together, seeing the bigger picture and realizing this internal signal system has been present in every vertebrae species dating back to 600 million years ago.

Humans have an endocannabinoid tone based on their AEA and 2-AG, which can dictate general well-being. If the person is not caring for themselves properly, the “tone” is not in homeostasis resulting in disease and disorder. This theory is known as Clinical Endocannabinoid Deficiency (CED), developed by Dr. Russo, a neurologist and cannabinoid scientist, in 2004 (Russo, 2016). When endocannabinoid function is not at homeostasis due to various lifestyle choices, it can derange digestion, mood, and sleep in the ECS. These deficiencies could also arise from genetic or congenital reasons, which consequently produce pathophysiological syndromes (Russo, 2016). Due to low levels of ananamide and EC stimulation could result in irritable bowel syndrome, fibermilaga, migraines, and other treatment-resistant syndromes. To avoid this, there are ways to "up-regulate" these modulators to support endocannabinoid tone. 

Evidence indicates that several classes of pharmaceuticals up-regulate the ECS system, including analgesics, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also up-regulate the ECS: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the ECS (McPartland et al., 2014). Phytocannabinoids can be consumed to up-regulate the ECS and nourish this physiological system. These phytocannabinoids can be sourced from the cannabinoid-rich plant, cannabis, or any other naturally derived plant compound.


One of the fascinating subjects to study is your own body. Breaking down the anatomy (structure) and physiology (function) of the endocannabinoid system is fascinating because there is no system in the body that the ECS does not affect. All emerging discoveries and scientific research on the endocannabinoid system are relatively recent, considering this system was around in nature over 600 million years ago. Strides, in the last 20 years, have been proving the viability and efficacy of this system and will get it written in textbooks and taught in school as the master conductor of all our operating systems. They are working as a symphony to achieve homeostasis or a dynamic state of equilibrium internally. The body naturally produces endocannabinoid compounds on a chemical level. These lipid ligand cells attach and detach to neurotransmitters or receptors that affect all our organ's functions, then get broken down and created by enzymes. 

Close interworking signals from these systems communicate via the ECS to maintain balance. A comparison to a plant's root system, when a plant needs nutrients it's not receiving through the environment, the root communication system assists the particular plant by sending the necessary nutrients through its network of roots and using microorganisms to assist. Like ECS, when the body detects a system that needs some help via chemical signals,  compounds AEA and 2-AG are created and received to support that system through its receptors through complex neurotransmitters. Much like the lock and key analogy, the lock is the receptor, and the key is the chemical compound that activates the receptor. When the body responds to stimuli or changes, it says, " Hey, need a little help over here,” which will in turn, find the right cannabinoid to fit the receptor. With the average American diet, stress factors, lack of exercise, Big Pharma, and sick care, the ECS is working on overdrive and needs some assistance to maintain balance. That is where phytocannabinoids or exogenous resources come into play and why cannabis can be revolutionary in how modern society views medicine.  

Conclusions/ Recommendations 

The endocannabinoid system's importance and role in overall health and well-being cannot be understated. The ECS's tone affects all biological functions, including eating, anxiety, learning and memory, reproduction, metabolism, growth, and development (Furrer, 2018). ECS is the master communicator in our integumentary, skeletal, muscular, lymphatic, respiratory, digestive, nervous, endocrine, cardiovascular, urinary, and reproductive systems (Lu and Mackie, 2021). As scientific research becomes readily available and understandable, it is of civic duty to reeducate the masses on the master system in the body, as people have a right to know and view the bigger picture organization of the body. From this information and understanding, people can make educated decisions about their health choices to live a balanced, stress-less life. 


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