Review
A systematic review of the antipsychotic properties of cannabidiol in humans

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Abstract

Despite extensive study over the past decades, available treatments for schizophrenia are only modestly effective and cause serious metabolic and neurological side effects. Therefore, there is an urgent need for novel therapeutic targets for the treatment of schizophrenia. A highly promising new pharmacological target in the context of schizophrenia is the endocannabinoid system. Modulation of this system by the main psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), induces acute psychotic effects and cognitive impairment. However, the non-psychotropic, plant-derived cannabinoid agent cannabidiol (CBD) may have antipsychotic properties, and thus may be a promising new agent in the treatment of schizophrenia. Here we review studies that investigated the antipsychotic properties of CBD in human subjects. Results show the ability of CBD to counteract psychotic symptoms and cognitive impairment associated with cannabis use as well as with acute THC administration. In addition, CBD may lower the risk for developing psychosis that is related to cannabis use. These effects are possibly mediated by opposite effects of CBD and THC on brain activity patterns in key regions implicated in the pathophysiology of schizophrenia, such as the striatum, hippocampus and prefrontal cortex. The first small-scale clinical studies with CBD treatment of patients with psychotic symptoms further confirm the potential of CBD as an effective, safe and well-tolerated antipsychotic compound, although large randomised clinical trials will be needed before this novel therapy can be introduced into clinical practice.

Introduction

Schizophrenia is a chronic mental disorder that typically presents in early adulthood or late adolescence. Although the incidence of schizophrenia is relatively low (10–22 per 100 000), its prevalence is relatively high (0.3–0.7 per 100) due to the chronic nature of the illness (McGrath et al., 2008). It is characterized by a wide range of symptoms, including disturbances of thought, perception, volition, and cognition (see for reviews Tandon et al., 2009, van Os and Kapur, 2009). Because of the pervasiveness of associated impairments and frequently life-long course, it is among the top ten leading causes of disease-related disability in the world. Although extensive research has been performed, its aetiology and pathophysiology remain relatively unclear, and available treatments are only modestly effective and cause serious metabolic and neurological adverse effects (Tandon et al., 2008).

A promising new pharmacological target in the context of schizophrenia is the endocannabinoid system. This neurotransmitter system consists of at least two types of receptors (CB1 and CB2) and endogenous ligands that bind to these receptors (Kano et al., 2009, Katona and Freund, 2012). Whereas CB2 receptors are more pronounced in peripheral regions, CB1 receptors are found throughout the central nervous system, with the highest concentrations demonstrated in the basal ganglia, cerebellum, hippocampus and cortex (Herkenham et al., 1991, Glass et al., 1997, Wong et al., 2010). The two most important endogenous cannabinoid ligands are anandamide and 2-arachidonoyl glycerol (2-AG). They act as retrograde messengers, which means that they are synthesised and released postsynaptically and bind to presynaptic receptors, thereby regulating the release of both inhibitory and excitatory neurotransmitters (Kano et al., 2009, Katona and Freund, 2012). The endocannabinoid system is thought to be involved in many brain functions such as mood, memory and reward processing (Hill et al., 2009, Zanettini et al., 2011, Bossong et al., 2014a, Bossong et al., 2014b).

Evidence is accumulating for a role of the endocannabinoid system in the pathophysiology of schizophrenia (Leweke and Koethe, 2008, Bossong and Niesink, 2010). For example, epidemiological studies indicate that the use of cannabis increases the risk for developing schizophrenia (Arseneault et al., 2004, Moore et al., 2007) and lowers the age of onset of the illness (Veen et al., 2004). In patients, cannabis use has been related to higher relapse rates, poor treatment outcome, and increased severity of symptoms (Linszen et al., 1994, D'Souza et al., 2005, Foti et al., 2010), as well as accelerated loss of grey matter volume (Rais et al., 2008). In addition, schizophrenia patients show increased levels of endogenous cannabinoids in cerebrospinal fluid (Leweke et al., 1999, Giuffrida et al., 2004). Autoradiography studies with post-mortem brain tissue showed enhanced CB1 receptor densities in schizophrenia patients, with significant increases demonstrated in the dorsolateral prefrontal cortex (Dean et al., 2001, Dalton et al., 2011, Jenko et al., 2012), anterior cingulate cortex (Zavitsanou et al., 2004) and posterior cingulate cortex (Newell et al., 2006). Neuroimaging studies measuring in vivo CB1 receptor availability in schizophrenia patients reported a widespread increase in levels of CB1 receptors, including the nucleus accumbens, insula, cingulate cortex, inferior frontal cortex, parietal cortex, mediotemporal lobe and pons (Wong et al., 2010, Ceccarini et al., 2013).

Although cannabis contains more than 80 different cannabinoid compounds, the principal psychoactive component in cannabis is Δ9-tetrahydrocannabinol (THC), which exerts its effects primarily through action on the CB1 receptor (Ledent, 1999, Huestis et al., 2001). THC is thought to be responsible for the broad range of psychotropic effects of cannabis, such as ‘feeling high’, relaxation and euphoria, which are considered the main reasons for cannabis use (Green et al., 2003). In addition, THC administration has been shown to induce acute psychotic symptoms (D'Souza et al., 2004, Bhattacharyya et al., 2009, Bossong et al., 2013) and to impair cognitive functions such as learning and memory (Solowij and Michie, 2007, Bossong et al., 2014a). However, recently, another cannabinoid compound has received growing attention: cannabidiol (CBD). Although, unlike THC, CBD is devoid of any psychotropic effects, evidence is increasing that CBD has anxiolytic and antipsychotic properties (Zuardi et al., 2012, Schubart et al., 2014). Although the mode of action of CBD is not fully understood, there are indications that it acts as a cannabinoid CB1/CB2 receptor inverse agonist (Pertwee, 2008), and that it inhibits the uptake and metabolism of anandamide, thereby enhancing levels of endogenous cannabinoids (Bisogno et al., 2001, De Petrocellis et al., 2011, Leweke et al., 2012).

An increasing number of human studies have been performed to provide further insight into the antipsychotic properties of CBD. Although some of these studies have been included in excellent reviews that describe the potential of CBD as a treatment for psychosis in a broader context (Zuardi et al., 2012, Schubart et al., 2014), the aim of the current review is to provide a detailed and up-to-date systematic literature overview of studies that investigated the antipsychotic properties of CBD in human subjects. This included the effect of CBD not only on symptomatology, but also on measures that are known to be affected in schizophrenia patients, such as cognitive function, hippocampal volume or functional brain activity patterns. Papers included in this review are subdivided in the following categories: 1) studies that investigated the impact of CBD/THC ratio in cannabis on measures relevant for psychosis, 2) neuropsychological studies that examined the ability of CBD to block the acute psychotic effects of THC or ketamine in healthy volunteers, 3) neuroimaging studies with acute CBD administration to healthy volunteers, and 4) studies with CBD administration to patients with psychotic symptoms, including small-scale clinical trials with CBD. Finally, methodological issues and recommendations for future research will be discussed.

Section snippets

Search strategy

An electronic search was performed using the following criteria in the PubMed database: (“CBD” OR “cannabidiol”) AND (“schizophrenia” OR “psychosis”). Reports in English using human subjects published before September 2014 were included. In addition, references of selected papers were examined to ensure the inclusion of other relevant studies.

Results

A total of 29 studies were identified and included in the current systematic review. Twenty of these studies were found using PubMed and nine studies were

The impact of CBD/THC ratios in cannabis on measures relevant for psychosis

Eight studies have been published that examined the impact of CBD/THC ratios in cannabis on measures relevant for psychosis (Table 1). In a study using hair samples of 140 individuals to analyse levels of cannabinoids, Morgan and Curran (2008) showed that those with only THC in their hair exhibited higher levels of hallucinations and delusions than individuals with both THC and CBD, and those with no cannabinoids (Morgan and Curran, 2008). This finding of lower psychosis-like symptoms in

Neuropsychological studies with acute CBD administration to healthy volunteers

Seven neuropsychological studies have been published that investigated the ability of CBD to block the acute psychotic effects of either THC or ketamine in healthy volunteers (Table 2). In the seventies, Karniol et al. (1974) were the first to investigate this. Forty healthy volunteers were orally administered either placebo, THC (30 mg), CBD (15, 30 or 60 mg) or a combination of THC and CBD. THC administration induced strong psychological reactions and significantly impaired performance on a

Neuroimaging studies with acute CBD administration to healthy volunteers

Nine studies have been published that investigated the acute effects of CBD on brain function with neuroimaging techniques (Table 3). Three studies were performed with electroencephalography (EEG) and six with functional Magnetic Resonance Imaging (fMRI). Furthermore, one paper was published that described additional analyses of the originally reported fMRI experiments (Bhattacharyya et al., 2010).

An EEG study by Juckel et al. (2007) (N = 22) examined the effects of administration of both THC (10 

Studies with CBD administration to patients with psychotic symptoms

Five studies have been published in which patients with psychotic symptoms were treated with CBD (Table 4). In a first case report, Zuardi et al. (1995) described symptomatology of a 19-year-old female schizophrenia patient who was treated with CBD for 26 days (maximum of 1500 mg/day orally). CBD treatment resulted in the improvement of symptomatology as measured with the Brief Psychiatric Rating Scale (BPRS). This improvement was not achieved with haloperidol treatment (Zuardi et al., 1995). In

Discussion

The current review provides the first systematic literature overview of studies that investigated the antipsychotic properties of CBD in human subjects. Taken together, CBD appears to have the ability to counteract psychotic symptoms and cognitive impairment associated with cannabis use as well as with acute THC administration. In addition, it may lower the risk for developing psychosis that is related to cannabis use. These effects are possibly mediated by opposite effects of CBD and THC on

Role of the funding source

MB was supported by a Rubicon grant from the Netherlands Organisation for Scientific Research (NWO 825.11.034). The funders had no role in the literature search, decision to publish, or preparation of the manuscript.

Contributors

TA managed the literature search and wrote the first draft of the manuscript. MB contributed to the conception of the review and edited the manuscript. Both authors have approved the final manuscript.

Conflicts of interest

None.

Acknowledgements

None.

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