Role of the endocannabinoid system in depression: From preclinical to clinical evidence

Abstract

The endogenous cannabinoid system (ECS) works as pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiological conditions, which include cognitive, emotional and motivational processes. It is composed of two G protein-coupled receptors (the cannabinoid receptors types 1 and 2 [CB1 and CB2] for marijuana’s psychoactive ingredient Δ9-tetrahydrocannabinol [Δ9-THC]), their endogenous small lipid ligands (anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and deactivation. Data from preclinical and clinical studies have reported that a hypofunction of the endocannabinoid signaling could induce a depressive-like phenotype; consequently, enhancement of endocannabinoid signaling could be a novel therapeutic avenue for the treatment of depression. To this aim there have been proposed cannabinoid receptor agonists or synthetic molecules that inhibit endocannabinoid degradation. The latter ones do not induce the psychotropic side effects by direct CB1 receptor activation, but rather elicit antidepressant-like effects by enhancing the monoaminergic neurotransmission, promoting hippocampal neurogenesis and normalizing the hyperactivity of hypothalamic-pituitary-adrenal axis, similarly as the standard antidepressants. The dysfunction of elements belonging to the ECS and the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in depression is discussed in this chapter.