The cannabinoid controversy: Cannabinoid agonists and antagonists as potential novel therapies for mood disorders

Abstract

The last twenty years have been characterized by a huge progress in the field of cannabinoids. Metabotropic (CB1 and CB2) and ionotropic (TRPV1) receptors for cannabinoids were discovered and their endogenous ligands (endocannabinoids) were isolated. Cannabinoid research has evolved from studying the effects of exogenous cannabinoid substances to unraveling the functional role of the endocannabinoid system. Potent and selective cannabinoid agonists and antagonists, as well as endocannabinoid inhibitors, have been and are synthesized and characterized for their therapeutic potential. Since cannabis preparations have historically been abused for their psychotropic and mood-altering properties, many research efforts focused on endocannabinoids, regulation of affect, and mood disorders. Interesting but also apparently discordant results and hypothesis have thus emanated. In this chapter we will first review the link between cannabinoids and affective disorders as evidenced by clinical studies on cannabis users or abusers, as well as by genetic, postmortem, and biomarker studies in relevant populations. We will critically discuss the current neurobiological hypotheses of affective disorders and the functional role of the endocannabinoid system in the regulation and dysregulation of neuronal networks mediating emotional responses. We will finally examine the potential value of endocannabinoid targets in the search for novel and improved medications, in particular preclinical behavioral results with CB1 receptor antagonists, and with indirect cannabinoid agonists/endocannabinoid catabolism inhibitors, as well as recent findings from clinical studies with Rimonabant.