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

Abstract

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 CB 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 CB 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.

Cannabidiol as a potential treatment for psychosis

“…Accumulating evidence implicates the endocannabinoid system in the pathophysiology of psychosis. 6,7 A recent meta-analysis concluded that patients with psychosis have significantly higher levels of the endocannabinoid anandamide both in cerebrospinal fluid and in blood, and higher expression of the main central cannabinoid 1 receptor (CB1) on peripheral immune cells. 8 This elevated endocannabinoid tone was observed at all stages of illness, from the prodrome to chronic psychosis.…”

Cannabis Vapour Exposure Alters Neural Circuit Oscillatory Activity In A Neurodevelopmental Model Of Schizophrenia: Exploring The Differential Impact Of Cannabis Constituents

“…Additionally, the widespread impact of cannabinoid exposure in schizophrenia may be due in part to the involvement of the endocannabinoid system (eCB) in the etiology of the disorder. Patients with schizophrenia have altered eCB functioning, evidenced by elevated levels of anandamide and post-mortem CB1R expression in patients 61, 62 . Exposure to exogenous cannabinoids may shift the homeostatic norm in patients such that it acutely restores system function in some regions to levels associated with typical functioning, while concurrently exacerbating dysfunctions in other regions.…”

Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities

“…While tetrahydrocannabinol (THC), the major component of cannabis, is pro-psychotic, the potential antipsychotic and precognitive properties of cannabidiol for schizophrenia and its efficacy for other neuropsychiatric disorders are actively being pursued. [43][44][45] In an exploratory 6-week, double-blind study, patients with schizophrenia were randomized to cannabidiol (n = 43) or placebo (n = 45) added to preexisting antipsychotics. 46 Although no differences between cannabidiol and placebo emerged regarding the Positive and Negative Syndrome Scale (PANSS) total or negative and general scale scores, cannabidiol had significantly lower PANSS positive scores at week 6.…”