Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia: Implications for Pharmacological Intervention

The term schizophrenia describes a group of multifaceted psychiatric conditions causing significant impairment of the quality of life of affected patients. Although multiple pharmacological treatment options exist, e.g. first- or second-generation antipsychotics, these therapeutics often cause disturbing side effects, such as extrapyramidal symptoms, prolactin increase, sexual dysfunction and/or metabolic syndrome. Furthermore, cognitive impairments and negative symptoms, two factors significantly influencing the course and outcome, are not sufficiently addressed by the available antipsychotics. Since its discovery, multiple clinical and preclinical studies have linked the endocannabinoid system to schizophrenia. Both the endocannabinoid anandamide and the cannabinoid CB1 receptor are deeply linked to underlying disease processes. Based hereon, clinical trials in schizophrenia have explored cannabidiol, a primary component of Cannabis sativa, and rimonabant, a partial antagonist to the CB1 receptor. While the latter did not reveal positive results, cannabidiol significantly ameliorated psychotic symptoms, which was associated with an increase in anandamide serum levels. However, the exact mechanisms of the antipsychotic effects of cannabidiol are not fully understood, and, furthermore, only a limited number of clinical trials in humans have been concluded to date. Thus, the level of proof of safety and efficacy required to approve the therapeutic use of cannabidiol in schizophrenia is currently lacking. However, cannabidiol is a promising candidate as an effective and mechanistically different antipsychotic treatment with a favourable side-effect profile. We therefore conclude that further studies are urgently needed to clarify the antipsychotic effects and safety profile of cannabidiol, and to fully explore its potential antipsychotic mechanism.