Could cannabidiol be used as an alternative to antipsychotics ?, Marc Fakhoury, 2016

Could cannabidiol be used as an alternative to antipsychotics ?

Marc Fakhoury

Journal of Psychiatric Research · May 2016

Doi : 10.1016/j.jpsychires.2016.05.013



Schizophrenia is a mental disorder that affects close to 1% of the population. Individuals with this disorder often present signs such as hallucination, anxiety, reduced attention, and social withdrawal. Although antipsychotic drugs remain the cornerstone of schizophrenia treatment, they are associated with severe side effects. Recently, the endocannabinoid system (ECS) has emerged as a potential therapeutic target for pharmacotherapy that is involved in a wide range of disorders, including schizophrenia. Since its discovery, a lot of effort has been devoted to the study of compounds that can modulate its activity for therapeutic purposes. Among them, cannabidiol (CBD), a non-psychoactive component of cannabis, shows great promise for the treatment of psychosis, and is associated with fewer extrapyramidal side effects than conventional antipsychotic drugs. The overarching goal of this review is to provide current available knowledge on the roles of the dopamine system and the ECS in schizophrenia, and to discuss key findings from animal studies and clinical trials investigating the antipsychotic potential of CBD.

Keywords : antipsychotics; cannabidiol; endocannabinoid system; psychosis; schizophrenia


1. Introduction

Schizophrenia is a complex mental health disorder that poses serious complications to the individual and to the society in terms of health care costs. This disease typically leads to low quality of life, long term disability, and reduced ability to work (Makinen et al., 2008). The median lifetime prevalence and incidence of schizophrenia are estimated at 0.72% and 15.2 per 100 000 individuals a year respectively (McGrath et al., 2008). However, the relative risk of this disease varies greatly across different locations and ethnicity, and has been shown to be particularly elevated among migrant group (Bhugra, 2004; Bhugra and Becker, 2005). Symptoms of schizophrenia usually emerge during adolescence and early adulthood, and are clustered into tree main categories; negative, positive, and cognitive. Negative symptoms, which are some of the most difficult to diagnose, refer to reduced emotional and behavioral response (Patel et al., 2014). Among them, blunted affect and anhedonia are the most strongly manifested in schizophrenic patients, but other symptoms such as reduced motivation and social interaction are also commonly observed (Makinen et al., 2008). In contrast to negative symptoms, positive symptoms are generally more easily identified. They are characterized by hallucinations, delusion, disorganized thinking and movement disturbances (Patel et al., 2014). Finally, cognitive deficits in schizophrenia include reduced episodic memory, poor executive functioning, low processing speed and disorganized speech, ultimately impairing the ability of the individual to properly think and communicate (Patel et al., 2014; Sheffield et al., 2014).

One of the most studied and recognized model of schizophrenia is the dopamine hypothesis (Howes and Kapur, 2009). This model attributes the symptoms of the disease to a hyperfunction of dopaminergic signaling in the mesolimbic system. It draws evidence from the observation that a large number of antipsychotics have the ability to block dopamine D2 receptors (Seeman and Lee, 1975; Howes and Kapur, 2009). Antipsychotics are divided into two classes: the typical (or first generation) and the atypical (or second generation). Although being efficient in managing some symptoms of schizophrenia, treatment with typical antipsychotics usually results in extrapyramidal side effects such as spasticity and tardive dyskinesia (Tandon and Jibson, 2002), whereas treatment with atypical antipsychotics leads to severe complications including weight gain, sedation and hyperlipidemia (Ucok and Gaebel, 2008).

Besides the dopamine hypothesis, evidence also support the notion that a dysregulation of the endocannabinoid system (ECS) may be linked to the pathophysiology of schizophrenia. The ECS is a signalling system that is mainly composed of the cannabinoid receptors types 1 (CB1) and type 2 (CB2), the endogeneous ligands N-arachidonoylethanolamine (AEA) and 2- arachidonoylglycerol (2-AG), as well as the hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) (Parsons and Hurd, 2015). Evidence supporting the role of the ECS in schizophrenia comes in part from post-mortem, imaging, and neurochemical studies showing abnormal brain levels of cannabinoid receptors and endocannabinoid ligands during the course of schizophrenia (Vigano et al., 2009; Dalton et al., 2011; Muguruza et al., 2013). Namely, some studies have shown that patients with schizophrenia-like symptoms have increased endocannabinoid signaling as a result of higher cannabinoid receptor density in certain brain areas (Dalton et al., 2011; Jenko et al., 2012). In addition, chronic administration of delta-9-tetrahydrocannabinol (THC), which acts as an agonist to cannabinoid receptor, was shown to precipitate the occurrence of schizophrenia-like symptoms in healthy subjects (D’Souza et al., 2004), and exacerbate the core psychotic and cognitive deficits in antipsychotic-treated schizophrenic patients (D’Souza et al., 2005). These findings led to the formulation of the “cannabinoid hypothesis of schizophrenia”, which speculates that a hyperactivity of the ECS may contribute to the development of schizophrenialike symptoms. As such, the use of compounds that modulate its activity could have a tremendous potential for therapeutic interventions. One such compound is cannabidiol (CBD), a non-psychotropic component of cannabis. CBD was recently suggested as a promising antipsychotic agent because of its ability to prevent the actions of THC, the main constituent of cannabis (Niesink and van Laar, 2013). However, despite recent advances in research, the antipsychotic effects of CBD are not fully understood, and there are still debates as to whether this compound should be used as a treatment for schizophrenic patients.

The aim of this review is to provide a better understanding of the current treatment approaches used for schizophrenia, and to discuss whether CBD could be used as an effective line of treatment for this debilitating disease. This review first starts by describing evidences supporting a role for dopamine and endocannabinoids in schizophrenia, and provides an overview of the most commonly encountered side effects associated with currently used antipsychotics. This paper also draws on findings of animal studies and clinical trials exploring the therapeutic profile of CBD in schizophrenia, and discusses whether this compound could be used as an alternative to antipsychotics.