## Cannabidiol as a potential treatment for psychosis

C.D. Schubart, I.E.C. Sommer, P. Fusar-Poli, L. de Witte, R.S. Kahn, M.P.M. Boks

European Neuropsychopharmacology, 2014, 24 ,(1), 51–64.

http://dx.doi.org/10.1016/j.euroneuro.2013.11.002

### Abstract

Although cannabis use is associated with an increased risk of developing psychosis, the cannabis
constituent cannabidiol (CBD) may have antipsychotic properties. This review concisely describes the role of the endocannabinoid system in the development of psychosis and provides an overview of currently available animal, human experimental, imaging, epidemiological and clinical studies that investigated the antipsychotic properties of CBD. In this targeted literature review we performed a search for English articles using Medline and EMBASE. Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved the use of CBD as intervention. Evidence from several research domains suggests that CBD shows potential for antipsychotic treatment.

KEYWORDS : Cannabidiol; Schizophrenia; Psychosis; Treatment; Cannabis; Antipsychotics

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 52
1.1. Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 52
1.2. Outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2. Experimental procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3. Endocannabinoid system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 52
3.1. Endocannabinoid system and psychotic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.1.1. The role of cannabinoids in psychotic disorders . . . . . . . . . . . . . . .  . . . . . . . . . . . . 53
3.1.2. The role of cannabinoid receptors in psychotic disorders . . . . . . . . .. . . . . . . . . . . 54
4. Cannabidiol and the endocannabinoid system . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 55
5. Cannabidiol and the immune response . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6. Cannabidiol as an antipsychotic agent . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6.1. Evidence from animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6.2. Evidence from human experimental studies. . . . . .  . . . . . . . . . . . . . . .. . . . . . . . . . . 56
7. Evidence from imaging studies. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 57
8. Evidence from epidemiological studies. . . . . . . . . . .  . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
9. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
10. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . 58
11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . 59

### 1. Introduction

1.1. Background

Since the introduction of new generation atypical antipsychotics in the 1990s, few clinically meaningful new treatment options for schizophrenia have emerged despite a persistent need. Schizophrenia remains a highly invalidating disorder (van Os and Kapur, 2009) with a lifetime prevalence of 0.3–0.6% (McGrath et al., 2008).

Several lines of etiological research implicate cannabis use as a, probably modest, risk factor for psychotic illness in general and schizophrenia in particular (Myles et al., 2012; Grech et al., 2005; Rapp et al., 2012; Zammit et al., 2002; van Os et al., 2002; Manrique-Garcia et al., 2012). Delta-9- tetrahydrocannabinol (THC) is one of the 70 phytocannabinoids (Mechoulam et al., 2007) that can be found in the Cannabis sativa plant and is thought to be the main psychotropic agent of the cannabis (Pertwee et al., 2007). THC is dose dependently associated to psychiatric symptoms such as psychotic like experiences in several studies (Schubart et al., 2010; Moore et al., 2007).

In contrast, in 1974 the cannabis plant constituent cannabidiol (CBD), was reported to interfere with the
psychomimetic actions of THC (Karniol et al., 1974) providing a first indication that CBD may have potential as an antipsychotic agent as later suggested by Bhattacharyya et al. (2010).

1.2. Outline

This paper first provides a brief overview of the endocannabinoid system (ECS) and a concise description of the role of the ECS in the neuropathology of psychotic disorders. Then we will review currently available animal, human experimental, imaging, epidemiological and finally clinical studies that investigated the antipsychotic properties of CBD. Reviews are available focusing on the effects of cannabidiol on psychosis (Zuardi et al., 2012), on the relationship with neuroimaging findings (Batalla et al., 2013; Bhattacharyya et al., 2012a, 2012c) and the potential neuroprotective effects of cannabidiol in the context of neuro-imaging studies (Hermann and Schneider, 2012). This review stands out by providing an overview of neuropathological background including the endocannabinoid system and neuro-immune response.

2. Experimental procedures

To assess the evidence on the use of cannabidiol in the treatment of psychotic disorders, we performed a search for English articles using Medline and EMBASE. Search items included “cannabidiol and treatment”, “cannabidiol and psychosis” and “cannabidiol and schizophrenia”. Each citation was evaluated by reading title and abstract and determining relevance and eligibility. Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved CBD as intervention. Additional studies were identified by searching reference lists of previously identified studies. Studies of other ligands of cannabinoid receptors were not selected. In total 66 studies on the CBD and psychosis (models) were selected. Additionally several studies on the role of the ECS in psychosis were also reviewed.

3. Endocannabinoid system

CBD is one of the phytocannabinoids that interacts with the ECS. The ECS consists of cannabinoid receptors, endogenous cannabinoids and several enzymes controlling activation and availability of these endocennabinoids (Pertwee, 2008). The ECS has a role in several physiological processes such as memory (Hampson and Deadwyler, 1999), appetite (Di Marzo et al., 2001) and stress responses (Hill et al., 2010).

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