Endocannabinoid System (ECS)
The Endocannabinoid System (ECS) is a vast biological system expressed throughout the vertebrate central nervous system, peripheral nervous system and peripheral organs. While being named after cannabis, the only plant known to potently modulate the ECS and which led to its discovery, studies have shown the ECS plays a major homeostatic role in a wide variety of bodily and mental functions, including:
Neurological function, motor function, brain plasticity, learning and memory, sleep, thermoregulation, inflammation, appetite, digestion, sensation and pain, cellular growth and proliferation, immune function, regulation of stress and emotions, psychological function, addiction, metabolism, energy balance, the autonomous nervous system, the reproductive system, and others. [1-6]
Cannabinoid Receptor expression in some organs and body systems. 
The ECS is composed of:
The two main G-protein-coupled receptors (GPCRs) of the ECS are known as cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). The initial discovery of the receptors then led to the discovery of the endogenous ligands that activate them (endocannabinoids). The CB1 and CB2 receptors are categorized under the Class A rhodopsin GPCR family .
Scientists had been searching for decades to understand the mechanism by which THC and the other phytocannabinoids exerted their effects. In the 1970’s it was hypothesized the effects of phytocannabinoids was simply caused by their ability to disorder membrane lipids, due to their marked lipophilicity . The first real hint came in the mid-1980’s when phytocannabinoids demonstrated the ability to inhibit signaling molecules at GPCRs . Then, with the development of potent radiolabelled ligands for receptor discovery, the CB1 receptor was officially identified and cloned in 1990, and the CB2 receptor was subsequently identified and cloned in 1993 .
CB1 receptors are predominantly, but not exclusively, expressed at central and peripheral nerve terminals where they affect inhibition of neurotransmitter release [8, 11]. CB1 receptors are expressed at high levels in brain regions expected from the psychoactive effects of THC, like the cerebral cortex and hippocampus. However, CB1 expression is quite low in other brain areas, such as the respiratory centers and medulla . Overall, CB1 receptor expression in the brain is more abundant than most other GPCRs, with expression nearly equivalent to that of glutamate and GABA receptors . More recent studies have also found CB1 expression in the spleen, tonsils, gastrointestinal tract, uterus, prostate, vascular smooth muscle cells, and adrenal glands .
The CB2 receptor was initially labeled the “peripheral CB receptor”, as it was considered to be primarily expressed in the immune system . But more recently it has been demonstrated that CB2, while normally having low expression in the central nervous system (CNS) under “homeostatic conditions”, displays significant increases of CNS expression in “non-homeostatic” situations such as neuroinflammation, neurodegeneration and in gliomas . One in vitro study demonstrated a 200-fold CB2 up-regulation in an encephalomyelitis model .
Besides these main CB1 and CB2 receptors of the ECS, there are several other GPCRs that interact with both endocannabinoids and phytocannabinoids. These include GPR55, GPR18 and GPR119 [6, 14]. Endocannabinoids and phytocannabinoids also interact with transient receptor potential channels (TRPA and TRPV) of various types, and with peroxisome proliferator-activated receptor gamma (PPARγ) [6, 15]. Endocannabinoid and phytocannabinoid interactions with the 5-HT families of serotonin receptors are also widely evidenced [14, 15], as are their interactions with the opioid, muscarinic, dopamine and adenosine receptor families .
Additionally, the CB1 and CB2 receptors are known to form dimers or complexes of higher order. These include heterodimers with serotonin, angiotensin, opioid, GPR55, dopamine and adenosine receptors, among others, including CB1-CB2 heterodimers. Homodimers of CB1-CB1 and CB2-CB2 have also been reported. 
Artistic depiction of THC molecules binding with CB1 receptors.
Once the CB1 and CB2 receptors of the ECS were discovered, work was begun to establish if mammalian physiologies produce endogenous CB receptor ligands (receptor-activating compounds), or whether CB receptors are only targets for phytochemicals and other exogenous compounds (made outside the body).
In 1992, William “Bill” Devane and his team, key researchers in the discovery of CB receptors, isolated a lipophilic compound from animal brain that was found to be a significant CB1 agonist. Upon synthesis and analysis, the compound was identified as N-arachidonoyl ethanolamide (AEA), nicknamed “anandamide” (since “ananda” is the Sanskrit and Pali term for “bliss” or “joy”, in honor of the THC effects that inspired the entire scientific endeavor). Hence, the first “endocannabinoid” was discovered. 
Subsequently, several other fatty acid derivatives were discovered as endogenous cannabinoids of the ECS, including the major endocannabinoid 2-arachidonoyl glycerol (2-AG) in 1995 [16, 17], together with endocannabinoid-like compounds palmitoyl ethanolamide (PEA), oleoyl ethanolamine (OEA), and others .
While AEA and 2-AG are both derived from arachidonic acid and share similar structure and general function, they have large differences in biochemical synthesis pathways, receptor affinities and breakdown pathways. Both AEA and 2-AG are characterized as agonists at the CB1 receptor, producing the characteristic behavioral effects associated with CB1 agonists like THC. But CB1 is preferentially activated by 2-AG compared with AEA [7, 19]. 2-AG is a full agonist at CB2, having significantly greater functional activity than AEA there, while AEA is a CB2 partial agonist and antagonizes 2-AG there [19, 20]. Interestingly, 2-AG has been found at concentrations 170 times higher than AEA in the brain .
Of importance to ECS function are the enzymes that synthesize and degrade AEA and 2-AG, significantly affecting their levels in body tissues (referred to as “endocannabinoid tone”), which influences all the key physiological and psychological functions these endocannabinoids help regulate. 
AEA originates from a phospholipid precursor, N‐arachidonoyl phosphatidyl‐ethanolamine (NArPE), that is transformed into AEA via four alternative enzymatic pathways. 2-AG is almost exclusively synthesized by alpha and beta diacylglycerol lipases (DAGLs). 
AEA is primarily degraded by fatty acid amide hydrolase (FAAH), but also by N-acylethanolamine-hydrolyzing acid amidase (NAAA), breaking AEA apart into arachidonic acid (AA) and ethanolamide [4, 6]. 2-AG is primarily degraded by monoacylglycerol lipase (MAGL), but is also degraded by FAAH and the alpha beta hydrolase domain proteins ABHD6 and ABHD12, breaking 2-AG apart into AA and glycerol [4, 22].
Since the regulatory effects of AEA and 2-AG on the ECS have been prolonged or intensified by the application of compounds inhibiting their degradation (increasing endocannabinoid tone), methods for influencing the degradation and cellular reuptake of AEA and 2-AG are of significant therapeutic interest [6, 22].
Artistic depiction of synaptic orchestra with neurotransmitters and receptors.
Symphony of Action
While the vast and complex structure and function of the ECS is just starting to be uncovered by science, we already know a fair bit about how the cannabinoid receptors, endocannabinoids and enzymes work in concert to regulate the multiple physiological and psychological functions the ECS is involved in.
It appears the primary site of action for the ECS is at and around the neuronal synapses enervating the many organs and systems the ECS helps regulate [4, 6, 12]. In general, both AEA and 2-AG work within neuronal synapses as retrograde signaling molecules, moving from post- to presynaptic neurons [3, 4, 6, 12]. They are produced at the postsynaptic terminal by endocannabinoid-synthesizing enzymes described above, moving to the presynaptic terminal either by passive diffusion or active transport mechanisms .
Once at the presynaptic neuron terminal, AEA and 2-AG bind with CB1 or CB2 receptors depending on the synaptic CB receptor expression profile, inhibiting the release of other neurotransmitters [4, 12]. This can suppress release of the major excitatory neurotransmitter glutamate and of the major inhibitory neurotransmitter GABA, modulate levels of the major second messenger cAMP, and affect levels of calcium and potassium ions fundamental to neuronal activity [4, 12]. Upon their release, AEA and 2-AG can also bind at pre- and postsynaptic terminals or intracellularly to the GPCR, TRP, PPARγ, and other receptors they also modulate to influence their regulatory functions as well [3, 4, 12].
Once their work is over, AEA and 2-AG are broken down by the endocannabinoid-degrading enzymes described above, making way for fresh waves of endocannabinoids and phytocannabinoids to keep the ECS symphony playing! [3, 4, 12]
All in all, the intricacy of the ECS and its deep interactions within multiple core physiological systems is a very exciting development in biology and medicine, with significant promise for powerful therapies to emerge as novel methods of modulating the ECS are discovered and safely implemented. [4-6]
Role of Phytocannabinoids
The phytocannabinoids in Hemp have unique abilities to modulate the CB1 and CB2 receptors of the ECS, while also inhibiting the enzymatic degradation and cellular reuptake of the endocannabinoids, thereby increasing endocannabinoid tone via multiple pathways (detailed in our Phytocannabinoids science section). These phytocannabinoid effects on the ECS may be more pronounced when using full spectrum preparations compared with single cannabinoid isolates (details in our Full Spectrum Hemp Oil science section).
CANNACEA is honored to provide science-based full spectrum hemp oils to supplement your Endocannabinoid System!
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