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.

An Overview of the Heterogeneity of Major Depressive Disorder: Current Knowledge and Future Prospective

“…In this line, pharmacological agents were developed, and thus the first generation antidepressants, monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants (TCA) came into use in the 1950s. Due to their limitations including low tolerance and toxicity, subsequently, SSRI, SNRI and atypical antidepressants were developed for better clinical application [ 71 , 72 ].…”

“…A reduction in the ECS along with biochemical and genetic changes in ECS members (the cannabinoid receptors types 1 and 2 (CB1 and CB2), endocannabinoids anandamide (N- arachidonoyl-ethanolamine, AEA) and 2- arachidonoylglycerol (2-AG) and enzymes for their degradation, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) could underlie the depressive disorder. In particular, reduced CB1R-mediated ECS reduces drive toward reward, increases anxiety and decreases extinction of aversive memories; therefore pharmacological blockade of CB1R signaling is reported to predispose humans to depression, particularly those with previous depressive episodes [ 72 ]. The neuronal subpopulations also express the CB1 receptors, such as the dorsal raphe nucleus [ 103 ], the locus coeruleus [ 104 ], GABAergic interneurons (high CB1 receptor levels) and glutamatergic neurons (relatively low CB1 receptor levels) [ 105 ] and may be associated with the psychotropic and non- psychotropic effects of CB1 receptor activation.…”

“…Moreover, increased ECS is hypothesized to mimic the effects of conventional antidepressants to enhance serotonergic and noradrenergic signaling, maintain hedonia during chronic stress, suppress HPA axis hyperactivity and increase hippocampal BDNF expression and neurogenesis. Further, acute or chronic treatment with pharmacological agents that modulate cannabinoid receptors, endogenous cannabinoids, synthetic nonspecific CB1/CB2 receptor agonists, selective CB1 receptor agonists and agents that inhibit endocannabinoids deactivation or cellular reuptake are reported to elicit antidepressant-like effects [ 72 , 102 ]. Notably, CB1 receptor ligands may cause unwanted psychotropic effects while CB2 receptor activation may be safer, yet the evidences are controversial to commend application.…”

Cannabidiol Drugs Clinical Trial Outcomes and Adverse Effects

“…CBD is one of more than 120 naturally occurring cannabinoids found in Cannabis sativa L. (ElSohly and Slade, 2005;Brenneisen, 2007;Radwan et al, 2009;Fischedick et al, 2010;Andre et al, 2016;Park et al, 2019) Various CBD formulations have been tested in pre-clinical studies to have diverse medicinal properties, such as anti-nausea, anti-emetic, anti-tumor, anti-inflammatory, antidepressant, anti-psychotic, and anti-anxiolytic; however, the variance in drug formulations used and limited sample sizes reduce the applicability of these studies in clinical applications (Costa, B, et al, 2006;Parker et al, 2011;Micale et al, 2013;Kucerova et al, 2014;Micale et al, 2015;Bogdanović, 2017;Rock and Parker, 2017;Sumanasekera et al, 2018;Fonseca, 2018;Stark et al, 2019). Epidiolex (GWP42003-P) is a colorless to yellow strawberry-flavored tincture that contains 100 mg/ml of plant-derived CBD and less than 0.3% of THC(A) (Guy et al, 2014).…”

Translational research of antidepressants with an example of cannabidiol effect

“…Although not all symptoms of human depression can be achieved in animals, the translational animal models of depression used are still useful to fi nd new drugs with potential antidepressant activity and also to improve our knowledge on the neurobiology of this psychiatric disorder [2][3][4][5][6][7]. reduced levels of endocannabinoids [16].…”