Cannabidiol as a potential treatment for psychosis

doi:10.1016/j.euroneuro.2013.11.002

European Neuropsychopharmacology

Volume 24, Issue 1, January 2014, Pages 51-64

https://doi.org/10.1016/j.euroneuro.2013.11.002 Get rights and content

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.

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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REVIEWCannabidiol as a potential treatment for psychosis

Abstract

Introduction

Section snippets

Experimental procedures

Endocannabinoid system

Cannabidiol and the endocannabinoid system

Cannabidiol and the immune response

Cannabidiol as an antipsychotic agent

Evidence from imaging studies

Evidence from epidemiological studies

Clinical studies

Tolerability

Conclusion

Role of funding source

Contributors

Conflicts of interest

Acknowledgments

Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study

Br. Med. J.

Causal association between cannabis and psychosis: examination of the evidence

Br. J. Psychiatry

Pharmacology, signaling and physiological relevance of the G protein-coupled receptor 55

Adv. Pharmacol.

Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis

Eur. J. Pharmacol.

Neuroimaging studies of acute effects of THC and CBD in humans and animals: a systematic review

Curr. Pharm. Des.

Does intravenous Delta9-tetrahydrocannabinol increase dopamine release? A SPET study

J. Psychopharmacol.

Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease

Immunol. Res.

Safety and side effects of cannabidiol, a Cannabis sativa constituent

Curr. Drug Saf.

The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes

J. Leukoc. Biol.

Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function

Mol. Psychiatry

Induction of psychosis by Delta9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing

Arch. Gen. Psychiatry

Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis

Arch. Gen. Psychiatry

Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology

Neuropsychopharmacology

Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies

Curr. Pharm. Des.

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Br. J. Pharmacol.

Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition

Biol. Psychiatry

Delta9-tetrahydrocannabinol induces dopamine release in the human striatum

Neuropsychopharmacology

Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia

Schizophr. Res.

Novel cannabinoid receptors

Br. J. Pharmacol.

Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation

Expert Rev. Mol. Med.

Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene×environment interaction

Biol. Psychiatry

Endocannabinoid signaling and synaptic function

Neuron

Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia

Am. J. Med. Genet .B: Neuropsychiatr. Genet.

Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex

Eur. J. Pharmacol.

Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis

Psychopharmacology (Berlin)

Cannabis and anxiety: a critical review of the evidence

Hum. Psychopharmacol.

TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists

J. Neurosci.

Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction

Biol. Psychiatry

Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Delta-9-tetrahydrocannabinol in humans

Psychopharmacology (Berlin)

Early cannabinoid exposure influences neuroendocrine and reproductive functions in mice: II. Postnatal effects

Pharmacol. Biochem. Behav.

Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex

Neuropsychopharmacology

REVIEW
Cannabidiol as a potential treatment for psychosis