The role of the endocannabinoid system in the pathophysiology of mood disorders

Il ruolo del sistema endocannabinoide nella fisiopatologia dei disturbi dell'umore

G. Serra***, V. Bogliolo**, A. Garzia**, F. Zazzara*, A. Koukopoulos*, F. Demontis**, G. Serra**

** Dipartimento di Scienze del Farmaco, Università di Sassari; * Centro "Lucio Bini", Roma, *** Ospedale Sant'Andrea, Dipartimento di Neuroscienze, Salute Mentale e Funzioni Sensoriali, Sapienza Università di Roma


To review the available preclinical and clinical evidence suggesting a possible role of endocannabinoid system in the neurobiology of mood disorders.


Critically review the most recent data of the literature and of the authors publications on the role of endocannabinoid system in the neurobiology of mood disorders.


The term “endocannabinoid system” refers to the recently discovered neuromodulator system comprising cannabinoid receptors (which bind tetrahydrocannabinol (THC), the major active component of cannabis) and their endogenous ligands. At least two types of cannabinoid receptors have been identified, CB1 and CB2 receptors. The CB1 receptor is widely distributed in neuronal terminals, while the CB2 receptor is extensively expressed throughout the immune system, but are present also in the brain. The main endogenous ligands (endocannabinoids) of cannabinoid receptors are anandamide and 2-AG (2-arachidonoylglycerol). Following the release of endocannabinoids, these compounds exert an action on cannabinoid receptors and are rapidly inactivated by uptake and degradation.

The degradation of endocannabinoids is achieved by means of two specific enzymes, the fatty acid amide hydrolase (FAAH) and the monoacylglyceride lipase (MAGL) enzymes. FAAH degrades anandamide, whereas the MAGL degrades 2-AG. This article, after a brief description of the clinical picture of mood disorders and after detailing the current hypotheses on the pathophysiology of depression and mania, critically reviews the available preclinical and clinical evidence suggesting a possible role of the endocannabinoid system in the neurobiology of mood disorders. Many animal studies suggest that the direct or indirect (i.e., endocannabinoid reuptake inhibition or reduced enzymatic degradation) stimulation of cannabinoid CB1 receptors exerts an antidepressant-like action. On the other hand, several animal models of depression seem to be associated to a decreased activity of the endocannabinoid system. On the contrary, we have recently demonstrated that the supposed antidepressantlike activity of the CB1 receptor antagonist, Rimonabant, is a “false positive” effect, thus providing an experimental support to explain the obvious contradiction of a drug claimed to be antidepressant in animals, but withdrawn from the market after few years of clinical use due to its depression-inducing potential.


The hypothesis that the stimulation of cannabinoid CB1 receptors may result in an antidepressant effect is consistent with the clinical experience with cannabis use in humans. Thus, the direct agonists of CB1 receptors, as well as endocannabinoid reuptake and degradation inhibitors should be considered as potential antidepressant drugs.

These observations led us to speculate that these compounds could share with classical antidepressants not only the therapeutic effect but also the ability to induce mania/hypomania and worsen the course of manic-depressive disorders. In fact, as it has been suggested for classical antidepressants, cannabis use, even more than classical antidepressants, appear to be associated with early onset of bipolar disorders, worsening of its course and impaired mood stabilization.

Therefore, we suggest that the use of cannabinoid CB1 receptor agonists should be used with caution in the treatment of depression, and preferably in treatment resistant patients.

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