The ECS is composed of eCBs and enzymes (for the synthesis and breakdown of eCBs), as well as the cannabinoid receptors, CB1 and CB2, which are widely distributed throughout the body. Cannabinoid receptors are activated by different ligands that are either endogenous, such as eCBs, or exogenous, such as marijuana derivatives and synthetic compounds.

The term cannabinoid includes compounds of different origin: endogenous cannabinoids (i.e., the eCBs), cannabinoids from vegetable origin or phytocannannabinoids, and cannabinoids from synthetic origin, either agonists or antagonists to the cannabinoid receptors (Fig. 1). (shown as cover photo)

Based on their chemical structure, cannabinoids are divided into 4 groups: classical, nonclassical, aminoalkylindoles, and eicosanoids. Classical cannabinoids are dibenzopyran derivatives, such as 9-tetrahydrocannabinol (9-THC) and HU-210; nonclassical cannabinoids contains bicyclic and tricyclic analogs of 9-THC that lack a pyran ring like CP 55,940; aminoalkylindoles have structures that differ markedly from those of both classical and nonclassical cannabinoids and are well represented by WIN 55,212-2, a derivative of pravadoline; and eicosanoids have structures quite unlike those previously mentioned, with N-arachidonoylethanolamine (anandamide [AEA]) and 2-arachidonoylglycerol (2-AG) being the main ones [2].

Approximately 60 phytocannabinoids are synthesized by Cannabis sativa [3,4]; of these, Δ-9-THC (THC) is the main psychoactive compound [5]. Other cannabinoids found in cannabis are Δ-8-THC, cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC) [6], among others. Furthermore, other organisms also produce their own cannabinoids, i.e., eCBs, derived from arachidonic acid, such as AEA and 2-AG, O-arachidonyl ethanolamine (virodhamine), 2-arachidonylglycerylether (noladin ether), N-arachidonoyl dopamine (NADA), and oleamide. There are cannabinoid-related molecules called N-acylethanolamides, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), that do not activate the CB1 receptor but instead interact with the peroxisome proliferator-activated receptor (PPAR)α, mediating anti-inflammatory processes [7,8].

There are a large number of cannabinoids of synthetic origin, differing in their affinity to one or both cannabinoid receptors; in addition, there are also agonists or antagonists which have been useful in the experimental study of the ECS.

eCBs can be defined as endogenous lipids, derivatives of amides, esters, and ethers, and comprise long-chain polyunsaturated fatty acids, mainly arachidonic acid. eCBs are located in lipid membranes, synthesized on demand in a Ca+2-dependent fashion in response to either physiological or pathological stimuli [9] and, in the case of AEA, accumulation and breakdown in liposomes [10]. AEA and 2-AG are the most studied eCBs and, despite being arachidonic acid derivatives, they can be synthesized by several pathways; however, the enzymes required are not the same in all instances. The enzymes required for AEA synthesis are N-acyltransferase (NAT) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). For 2-AG synthesis, the enzymes phospholipase C (PLC) and diacylglycerol lipase (DGL) are required, among others. Breakdown enzymes also differ between AEA and 2-AG; fatty acid amide hydrolase (FAAH) is responsible for AEA hydrolysis whereas monoacylglycerol lipase (MGL) is required in the case of 2-AG [9] (Fig. 1; [11]).

In addition to CB1 and CB2, the existence of a third cannabinoid receptor (CB3) has been suggested [12], and there are also 2 orphan G protein-coupled receptors (GPCRs) which overlap with CB1 and CB2, namely, GPR18 and GPR55 [13]. CB1 and CB2 are associated with the G proteins of the Gi/o family (Gi1-3 and Go1 and 2) via the intracellular loops of the protein. Both cannabinoid receptors inhibit adenylyl cyclase via Gi and stimulate MAPK activity. By inhibiting adenylate cyclase, the reduction of the second messenger cAMP leads to the opening of rectifying potassium channels. CB1 also mediates the inhibition of N-type and P/Q-type calcium currents [14,15].

The cannabinoid receptors are widely distributed; CB1 is expressed mainly in the central nervous system (CNS), particularly in the cerebral cortex, olfactory bulb, cerebellum, and spinal cord [16]. It can also be located in peripheral tissues such as the adrenal glands, thymus, tonsils, lungs, heart, bone marrow, prostate, uterus, ovaries, and testes [17]. Although CB1 mRNA levels represent only 1-10% of the CB2 content in immune tissues, they are expressed (from the highest to the lowest expression level) in B lymphocytes, NK cells, polymorphonuclear neutrophils, CD8 T cells, and CD4 T cells [1]. CB2, on the other hand, is also expressed in the CNS but is most highly expressed in immune tissues such as the spleen and thymus [1,18] as well as in blood cell subpopulations such as CD4 and CD8 lymphocytes, neutrophils, monocytes, NK cells, and B lymphocytes [1].