The cannabinoid CB 1 receptor and the endocannabinoid anandamide: possible antidepressant targets

Major depression is the most common mental disorder, but current antidepressants have limited effectiveness. Recent research suggests that drugs activating cannabinoid CB(1) receptors or enhancing endocannabinoid levels have antidepressant-like effects, while the CB(1) antagonist rimonabant increases depression and suicide risk. CB(1) agonists and fatty acid amide hydrolase (FAAH) inhibitors work similarly to existing antidepressants by boosting serotonin and norepinephrine transmission and promoting new neuron growth in the hippocampus. FAAH inhibitors cause fewer adverse cannabinoid effects and have a wider therapeutic window than direct CB(1) agonists. However, because the endocannabinoid system also affects peripheral body functions, side effects require attention.

Study at a glance

Abstract

BACKGROUND: Major depression has the highest rate of prevalence and incidence of morbidity among all mental disoders. The limited efficacies of current antidepressant treatments necessitate the development of alternative pharmacotherapies. Recent preclinical findings suggesting that cannabinoid CB(1) receptor agonists and endocannabinoid enhancers possess antidepressant-like properties, and clinical evidence that the CB(1) antagonist rimonabant increases the risk of depression and suicidality, support the notion that the endocannabinoid system represents a novel target in the treatment of mood disorders. OBJECTIVE/METHODS: To compare the mechanism of endocannabinoid enhancers and CB(1) agonists with current antidepressants and provide a rationale for a role of the endocannabinoid system in the pathology and treatment of mood disorders. RESULTS/CONCLUSION: CB(1) agonists and fatty acid amide hdyrolase (FAAH) inhibitors share mechanisms with other antidepressants: the ability to enhance central serotonergic and noradrenergic transmission and promote neurogenesis in the hippocampus. FAAH inhibitors, compared with direct CB(1) agonists, exhibit distinct pharmacological properties that quell adverse cannabinoid effects and widen the therapeutic window. Since the endocannabinoid system also plays a role in peripheral functions, side effects need to be addressed.