*1.1. Cannabinoid Receptors*

The effects associated with the endo and exocannabinoid compounds are primarily related to their interaction with the CB1 and CB2 receptors, discovered some decades ago [8–10] and characterized based on their neurobiology signaling [11]. Their involvement in many physiological and pathological events justifies the central role that they play as a possible therapeutic key for many diseases. CB receptors can be stimulated or antagonized by different ligands and can also be modulated through the inhibition of the enzymes responsible for the degradation of their endogenous ligands [12]. Unfortunately, the interaction of exocannabinoids with these receptors, especially with the CB1 subtype, is also associated with the psychotropic effects of many recreational drugs, including *Cannabis*, the so-called new psychoactive substances [13], and smart drugs (SPICE and K2 . . . ) [14], or to other undesirable serious effects of synthetic agonist or antagonist drugs [15–17].

CB1 receptors are abundantly expressed in the central nervous system (CNS), particularly in the cerebral cortex, hippocampus, basal ganglia, and cerebellum. CB2 receptors, instead, are mostly expressed in the immune system, particularly in B and natural killer cells. However, CB2 receptors have been also found in some districts of the CNS [18] and the CB1 also peripherally, albeit at low levels [11]. More detailed information on the origin, structural aspects, and signaling processes mediated by CB1 and CB2 receptors are reported in [19,20].

Generally, the activation of CB receptors determines the inhibition of adenylate cyclase, with a consequent decrease in the levels of cyclic adenosine monophosphate (cAMP), a second messenger involved in numerous intracellular signaling and essential for the regulation of many cell functions. There is also evidence that the CB1 receptor, in addition to acting on adenylate cyclase, can be coupled to ion channels [21], confirming the key role of CBs in inducing activation or depression of neurotransmission [11].

Recent studies have also revealed the existence of "atypical" EC receptors, i.e., the transient receptor potential vanilloid (TRPV) channels, involved in the nociceptive signaling; the GRP55, G-protein coupled receptors responsible for some independent CB1 and CB2 responses; the peroxisome proliferator-activated receptor gamma (PPAR-γ) receptors, which are physiologically involved in glucose metabolism and insulin signaling, and also in inflammation and pain; and the dopamine, adenosine, opioid, and 5-HT1A receptors [22].
