Endocannabinoid Signaling in the Etiology and Treatment of Major Depressive Illness

Abstract

The purpose of this review is to examine human and preclinical data that are relevant to the following hypotheses. The first hypothesis is that deficient CB1R-mediated signaling results in symptoms that mimic those seen in depression. The second hypothesis is that activation of CB1R-mediated signaling results in behavioral, endocrine and other effects that are similar to those produced by currently used antidepressants. The third hypothesis is that conventional antidepressant therapies act through enhanced CB1R mediated signaling. Together the available data indicate that activators of CB1R signaling, particularly inhibitors of fatty acid amide hydrolase, should be considered for clinical trials for the treatment of depression.

Stress regulates endocannabinoid-CB1 receptor signaling

“…Chronic stress is a significant risk factor for the development of psychopathology, and there are considerable data to suggest that loss of ECS results in symptoms of depression and anxiety [77]. Thus, deficiency of ECS can be induced by chronic stress and likely is a contributor to the negative consequences that follow.…”

Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

“…CB 1 receptors are located in key regions throughout corticolimbic brain networks, such as the prefrontal cortex (PFC) and amygdala, which functionally interact with subcortical dopamine pathways (Tan et al, 2014). As such, aberrations of the endocannabinoid system are increasingly recognized as etiological factors in several neuropsychiatric syndromes, including schizophrenia, anxiety, and mood disorders (Bossong and Niesink, 2010; D'Souza et al, 2005; Hillard and Liu, 2014; Lutz et al, 2015; Papini et al, 2015; Passie et al, 2012; Saito et al, 2013; Semple et al, 2005; Smit et al, 2004; Tan et al, 2014). These conditions may involve deficits in executive function, emotional processing and social behaviours, and/or co-morbidities with affective or addiction-related phenomena—in essence, broad deficits in behavioural processes mediated by corticolimbic circuits.…”

“…These conditions may involve deficits in executive function, emotional processing and social behaviours, and/or co-morbidities with affective or addiction-related phenomena—in essence, broad deficits in behavioural processes mediated by corticolimbic circuits. Indeed, growing evidence from clinical and preclinical research demonstrates that CB 1 receptor transmission within these networks strongly regulates the expression of cognitive and emotional behaviours (Arnold et al, 2012; Crane et al, 2013; Hajos and Freund, 2002; Hillard and Liu, 2014; Laviolette and Grace, 2006b; Lutz et al, 2015; Papini et al, 2015; Pattij et al, 2008; Tan et al, 2014)…”

Blockade of 2‐arachidonoylglycerol hydrolysis produces antidepressant‐like effects and enhances adult hippocampal neurogenesis and synaptic plasticity

“…Synthetic cannabinoid receptor (CB 1 ) agonists produce anxiolytic-and antidepressant-like effects in animals (Berrendero and Maldonado, 2002;Valjent et al, 2002;Jiang et al, 2005;Patel and Hillard, 2006). Clinical and laboratory observations over the last decade indicate that the endocannabinoid (eCB) system represents a promising target for pharmacotherapy of depression (Bambico and Gobbi, 2008;Hill et al, 2009;Hillard and Liu, 2014). The eCB system has at least two endogenous ligands, anandamide (AEA), and 2arachidonoylglycerol (2-AG) that activate CB 1 receptor (Di Marzo et al, 1998;Piomelli, 2003).…”