The Endocannabinoid System (ECS)

The endocannabinoid system (ECS) consists of receptors, their ligands and enzymes that are responsible for the synthesis and the degradation of ligands. The ECS regulates the mental-physical homeostasis on various levels. Next to the most well-known cannabinoid receptors CB1 und CB2 recently also GPR55 has been discussed as potential CB3 receptor. The most well-known endocannabinoids are anandamide and 2-AG. They are released postsynaptically and modulate the GABAA (inhibitory neurotransmission) and the release of glutamate (excitatory neurotransmission). A lack of endocannabinoids that leads to various physical and psychological diseases can be balanced with plant-based cannabinoids.

The endocannabinoid system (ECS) is defined as a conglomerate of receptors (cannabinoid receptors), their endogenous ligands (endocannabinoids) and enzymes that are responsible for the synthesis and degradation of the endocannabinoids. In fact, the endocannabinoid system received its name from the plant cannabis, while the psychotropic substance in cannabis (the cannabinoid Δ9-THC) was already isolated in the 1960s1, the first endogenous receptor (where Δ9-THC binds) was cloned in the 1990s2 and was termed accordingly. The ECS primarily is a neuromodulatory system that, inter alia, engages in the development of the central nervous system and later in neural plasticity (relevant for learning and memory). Furthermore, the ECS supports the body to react appropriately to endogenous (e.g. inflammatory) or exogenous (e.g. trauma, pollutants) influences. In some publications the function of the ECS is summarized as follows: It regulates the mental-physical homoeostasis by “relaxing, eating, sleeping, forgetting and protecting.3

Hence, today scientists metaphorically describe the ECS as a “microcosm of psychoneuroimmunology or as body-and-mind-medicine, respectively”.3

The most prevalent cannabinoid receptors are CB1 and CB2. Both receptors consist of seven transmembrane domains, are coupled to G-inhibitory proteins and linked to signal cascades such as adenylyl cyclase and cAMP, mitogen-activated protein (MAP) kinase and the regulation of intracellular calcium.4 Furthermore, some cannabinoids show binding affinity to transient receptor potential vanniloid channels (TRPVs) and peroxisome proliferator-activated receptors (PPARs).

The highest CB1 receptor density is found in the basal ganglia of the mesencephalon (substatia nigra pars reticulata and globus pallidus), in the hippocampus and the cerebellum, which is not surprising considering the known impact of the endocannabinoid system on cognition and motion/coordination. On the other hand, the very low CB1 receptor density in the brain stem, which controls basal vital functions like respiration, may explain why there is virtually no fatal overdose for Δ9-THC. CB2 is primarily associated with the immune system and is expressed on immune cells, including microglia cells in the nervous system.5 Recently, GPR55, another G-protein coupled receptor, was found to have binding affinity to different endo- and phytocannabinoids; today this receptor is being discussed as potential CB3 receptor of the ECS. Different from CB1 and CB2 though, GPR55 is not coupled to inhibitory G-proteins but to G-alpha proteins.

The best studied endogenous cannabinoids are the lipids 2-arachidonoglycerol (2-AG) and arachidonoylethanolamide (AEA), also known as Anandamide (from ananda, Sanskrit for: bliss). Anandamide is the ethanolamine derivate of arachidonic acid, a fourfold unsaturated fatty acid, that is particularly prevalent in the central nervous system.4 Endocannabinoids are released postsynaptically and modulate neurotransmission by binding to presynaptic CB1 receptors. Hence, they act as retrograde signals in the sense of a feedback loop. 2-AG is the major agonist of CB1 in the brain where it is found in micromolar concentrations. Physiological and pharmacological studies indicate that the ECS is involved in the regulation of GABAA (inhibitory neurotransmission) and the release of glutamate (excitatory neurotransmission). Apparently, 2-AG even binds – like many sedating and anxiolytic pharmaceuticals – to the GABAa receptor itself and is capable of modulating its binding affinity to neurosteroids allosterically.5 Anandamide (AEA), amongst others, affects serotonergic neurotransmission by multiplying the 5-HT1A receptor signal and by inhibiting the 5-HT2A receptor signal. It is being hypothesized that an “endocannabinoid-deficiency-syndrome” may contribute to the etiology of migraine, fibromyalgia, irritable bowel syndrome, psychological disorders and other diseases.6  A lack of endogenous endocannabinoids can be balanced pharmaceutically by the uptake of exogenous phyto-cannabinoids. In addition, in 2014 McPartland et al. summarized complementary therapeutic approaches that have tonic effects on the ECS (i.e. change of diet, relaxation methods) in a review.3

AEA is mainly catabolized by the enzyme fatty acid amide hydrolase 1 (FAAH1), whereas 2-AG is degraded by monoacylglycerol lipase (MAGL) and to a lesser extent by α,β-hydrolase-6 (ABHD-6), cyclooxygenase 2 (COX2) und FAAH1.3 Hence, a change in function of these enzymes (e.g. by mutations) as a consequence leads to altered AEA and 2-AG levels in the body.

[1] Y. Gaoni, R. Mechoulam: Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. In: Journal of the American Chemical Society. 86, 1964, S. 1646, doi:10.1021/ja01062a046

[2] Marx J. Marijuana receptor gene cloned. Science. 1990;249(4969):624-626. doi:10.1126/SCIENCE.2166339 (kein pdf)

[3] McPartland JM, Guy GW, Di Marzo V. Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System. Romanovsky AA, ed. PLoS One. 2014;9(3):e89566. doi:10.1371/journal.pone.0089566

[4] Cabral GA, Rogers TJ, Lichtman AH. Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function. J Neuroimmune Pharmacol. 2015;10(2):193-203. doi:10.1007/s11481-015-9615-z

[5] Sigel E, Baur R, Rácz I, et al. The major central endocannabinoid directly acts at GABA A receptors. doi:10.1073/pnas.1113444108

[6] Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2008;29(2):192-200. Accessed July 31, 2018.