REVIEWCannabidiol as a potential treatment for psychosis
Introduction
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).
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, Bhattacharyya et al., 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.
Section snippets
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
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).
Five endogenous cannabinoids have been identified (Devane et al., 1992) that bind to CB1
Cannabidiol and the endocannabinoid system
Although CBD has very low affinity for CB1 and CB2 receptors, Pertwee and colleagues found that CBD is capable of altering CB1R/CB2R function at relatively low concentrations by antagonizing CB1/CB2 receptor agonists such as AEA and 2-AG (Thomas et al., 2007, Pertwee, 2008). CBD could therefore also be able to interfere with the impact of THC on the ECS, providing a biological basis for the notion that the THC/CBD ratio in cannabis products might moderate the risk of cannabis associated
Cannabidiol and the immune response
Finally, as described above, cannabidiol may also have an attenuating role in immune responses associated with psychotic disorders (De Filippis et al., 2011). Various studies demonstrated that the endocannabinoid system is involved in chemotaxis and migration of immune cells, including microglia cells. CBD was shown to decrease the number of mast cells and macrophages in inflammatory bowel models (De Filippis et al., 2011). Exogenous cannabinoids, including cannabidiol (Kaplan et al., 2008),
Cannabidiol as an antipsychotic agent
The remainder of this paper will focus on different lines of evidence on the antipsychotic potential of CBD. Table 1 provides an overview of experimental human and animal studies of psychosis models.
Evidence from imaging studies
Studies investigating cannabis related changes in brain tissue composition provide markedly divergent results (Yücel et al., 2008, Matochik et al., 2005). Demirakca provided evidence for the idea that the THC/CBD ratio plays an explanatory role for these contrasting results. They found an inverse correlation between the THC/CBD ratio in hair samples of cannabis users and hippocampal volume suggesting a protective effect of cannabidiol. Differences in THC/CBD ratio between studies can
Evidence from epidemiological studies
Numerous studies show that psychotic outcomes are associated with cannabis use in a dose-dependent fashion (Moore et al., 2007, Stefanis et al., 2004, van Gastel et al., 2012, Skinner et al., 2010). The strength of this association might be influenced by cannabis potency, which can be defined in terms of the concentrations of THC and, inversely, CBD (Potter et al., 2008, Pijlman et al., 2005). Rottanburg et al. (1982) described a cohort with a relatively high (30%) percentage of psychotic
Clinical studies
Zuardi and colleagues published several reports on the therapeutic use of CBD monotherapy in patients with psychotic symptoms. In a case report, successful treatment with 1200 mg/day CBD was described in a 19 year old woman with schizophrenia (Zuardi et al., 1995). In a short report, therapy of three treatment resistant schizophrenia patients with escalating doses up to 1280 mg/day of CBD was described, of whom only one patient showed mild symptom improvement (Zuardi et al., 2006). The authors
Tolerability
Extensive in vivo and in vitro reports of CBD administration across a wide range of concentrations did not detect important side or toxic effects, and in addition, the acute administration of this cannabinoid by different routes did not induce any significant toxic effect in humans (Bergamaschi et al., 2011). With a median Lethal Dose (LD50) of 212 mg/kg in rhesus monkeys, CBD has a low toxicity (Rosenkrantz et al., 1981). Bergamaschi et al. (2011) demonstrated that CBD is well tolerable up to
Conclusion
In summary, evidence from several study domains suggests that CBD has some potential as an antipsychotic treatment.
Animal studies show that CBD is capable of reversing various THC induced psychosis like behaviors in dopaminergic but also glutamatergic animal models of psychosis (Fernandes et al., 1974, Malone et al., 2009, Zuardi et al., 1991, Long et al., 2010, Moreira and Guimaraes, 2005, Gururajan et al., 2011). In addition, these studies found that the vanilloid (TRPV1) receptor is likely
Role of funding source
This study was financially supported by a Grant from the Netherlands Organization for Scientific Research (NWO), Grant no. 91207039. The NWO had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. No other sources of external funding were used for this study.
Contributors
C. Schubart was involved in the literature search, drafting and revising the paper. I. Sommer was involved in designing the conceptual framework and revision of the paper. P. Fusar-Poli performed a literature search, was involved in designing the conceptual framework and revision of the paper. L. de Witte contributed to drafting, the conceptual framework and revision of the paper. R. Kahn revised the paper. M. Boks was involved in designing the conceptual framework, writing and revision of the
Conflicts of interest
None of the authors of the above manuscript have any conflict of interest which may arise from being named as an author on the manuscript or receive any financial support that could potentially affect the reporting of the study.
Acknowledgments
We would like to express our gratitude to the Trimbos Institute for annually providing data on cannabinoid concentrations in Dutch Coffee shops. This study was financially supported by a Grant of the NWO (Netherlands Organization for Scientific Research), Grantnumber: 91207039.
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2019, Journal of Chromatography ACitation Excerpt :A dose of 20–200 mg oral/day of CBD has to be regarded as physiological and, therefore, it should be available in pharmacies as an over-the-counter (OTC) product or a food supplement [13]. Indeed, even though an oral dose lower than 200 mg/day does not exert any relevant pharmacological activity, it is reported that starting from 20 to 200 mg/day CBD may have health-maintaining properties [15,20–24]. Finally, low CBD concentration, i.e. intake less than 20 mg/day for the average adult, should be allowed in food products without any restriction [13].
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2019, European NeuropsychopharmacologyCitation Excerpt :The finding that particularly CBD lead to increased PPFIA2 expression is noteworthy, since CBD is generally viewed as the less toxic of the cannabinoids overall human studies suggest that CBD could counteract adverse effects from THC consumption when administrate with THC simultaneously (Iseger and Bossong, 2015). CBD is also researched for efficacy in treatment of anxiety and potentially psychosis (Mcguire et al., 2018; Schubart et al., 2011a, b; Schubart et al., 2014). However the effects of CBD on psychosis treatment is not always consistent (Boggs et al., 2018).