Review
A systematic review of phytocannabinoid exposure on the endocannabinoid system: Implications for psychosis

https://doi.org/10.1016/j.euroneuro.2018.12.014Get rights and content

Abstract

Cannabis, the most widely used illicit drug worldwide, produces psychoactive effects through its component cannabinoids, which act on the endocannabinoid system. Research on how cannabinoid exposure affects the endocannabinoid system is limited. Substantial evidence indicates cannabis use as a risk factor for psychosis, and the mechanism(s) by which this is occurring is/are currently unknown. Here, we conduct the first review of the effects of exogenous cannabinoids on the endocannabinoid system in humans with and without psychotic disorders. The most well established finding is the down-regulation of cannabinoid CB1 receptors (CB1R) after chronic and recent cannabis exposure, but it remains uncertain whether this effect is present in cannabis users with schizophrenia. We highlight where cannabis exposure affects the endocannabinoid system in a pattern that may mirror what is seen in psychosis, and how further research can push this field forward. In these times of changing cannabis legislation, research highlighting the biological effects of cannabinoids is greatly needed.

Introduction

Cannabis is the most widely used illicit substance worldwide (UNDOC, 2018). In light of global changes in cannabis legislation, increasing usage of cannabis among adults in the USA, and an expansion of cannabinoid pharmaceutical trials, it is vital for researchers and policy makers to have an enhanced understanding of the impact of cannabinoids on the body's endogenous cannabinoid (eCB) system (Campbell et al., 2001, Compton et al., 2016, Lynch and Ware, 2015, Zajicek et al., 2003).

Cannabinoids bind to and modify cannabinoid CB1 and CB2 receptors (CB1R and CB2R) with varying intrinsic activities. Cannabinoids consist of several structural homologies, such as the classical tricyclic dibenzopyrans, phytocannabinoid (-)-trans-Δ9-tetrahydrocannabinol (THC) and the synthetic HU-210, and non-classical bicyclic and tricyclic compounds (Pertwee, 2006a). Other structural classes of cannabinoids include the aminoalkylindole R-(+ )-WIN55212 and the eicosanoids, which consist of the endogenous arachidonylethanolamine (anandamide/AEA) and 2-arachidonylglycerol (2-AG) (Pertwee, 2006a).

Cannabis contains more than 100 phytocannabinoids, with the most abundant and most studied being THC and cannabidiol (CBD) (ElSohly et al., 2016, Pertwee, 2006a). THC is largely responsible for producing the psychoactive effects of cannabis, including cognitive impairments, which may be counteracted by CBD if present in sufficient quantities (Boggs et al., 2017, Curran et al., 2002, Huestis et al., 2001, 2007). In Europe, the concentration of THC in cannabis increased between 2006 and 2013, and has reached an average concentration of 9–13% (EMCDDA, 2018). Between 1995 and 2014 in the USA, the concentration of THC in cannabis increased from ∼4 to 12%, with the THC/CBD ratio increasing from 14 to 80 (ElSohly et al., 2016). Despite the increasing potency of cannabis, its use among US adults increased from 10.4 to 13.3%, and the percentage of the population who perceives great risk of harm from using cannabis once or twice per week decreased from 50.4 to 33.3%, between 2002 and 2014 (Compton et al., 2016). This change in perception was accompanied by increasing usage and policy change in the US, specifically the legalization of medical marijuana in 12 states by 2007 (Compton et al., 2016). This discrepancy between increasing potency and decreasing perception of risk is alarming given that cannabis use elevates the risk of adverse mental health outcomes, especially in those who are more vulnerable (Moore et al., 2007). Of particular concern is the association of cannabis use with elevated risk for psychotic disorders, when initiating cannabis use during adolesence (Andreasson et al., 1987, Arseneault et al., 2002, Di Forti et al., 2015, Marconi et al., 2016, Moore et al., 2007). The increasing concentration of THC in cannabis is of concern because THC can cause positive psychotic symptoms, cognitive impairments, and perceptual alterations in a dose-dependent manner in healthy volunteers, and exacerbate symptoms in schizophrenia patients (Curran et al., 2002, D'Souza et al., 2005, 2004).

The task of addressing the public's growing misconceptions of the harmlessness of cannabis is made more difficult given how little is known about how acute or chronic cannabis use alters the eCB system, or how this could be involved in the pathophysiology of psychiatric disorders such as schizophrenia (Radhakrishnan et al., 2014). Although alterations of the eCB system have been observed in schizophrenia (Giuffrida et al., 2004, Ranganathan et al., 2016), the impact that phytocannabinoids have on this system remains unclear, especially within psychosis. A better understanding of the effects of cannabinoid exposure on the eCB system is of pressing importance, given the high rates of cannabis use in the general population and the high prevalence of cannabis use disorder (CUD) among individuals with schizophrenia (Koskinen et al., 2010).

Here, we systematically review the effects of exposure to cannabis and its constituent cannabinoids on the eCB system in healthy individuals including those with CUD, and individuals with schizophrenia. It should be noted that the literature regarding phytocannabinoid exposure in humans typically focuses on cannabis use.

Section snippets

Cannabinoids, the endocannabinoid system and psychosis – in brief

The eCB system is one of the most ubiquitously expressed neurotransmitter systems in the brain (Katona and Freund, 2008) and is involved in regulating a wide array of processes including feeding behaviour, memory, anxiety, and stress response (Di Marzo et al., 1998, Matias et al., 2006, Ruehle et al., 2012). The eCB system is composed of the eCB neurotransmitters, their receptors, and metabolizing enzymes (Fig. 1). The eCB system is unique in its retrograde signalling, whereby endocannabinoids

Search strategy and selection criteria

We searched PubMed for articles published until May 29, 2017. To our knowledge, no review on this specific topic has been completed before, and therefore we implemented no publication date cut-off for the earliest studies. References of the identified papers were also reviewed to identify additional relevant studies.

The following search query was used in PubMed:

(Cannabis OR marijuana OR synthetic cannabinoid OR phytocannabinoid OR “cannabis use” OR THC OR tetrahydrocannabinol OR “cannabinoid

Results

The search yielded 24 papers that met inclusion criteria (Fig. 2). This includes 13 studies in healthy volunteers exposed to phytocannabinoids, including individuals with CUD, and 11 studies in schizophrenia that reported cannabinoid exposure. Two studies investigated the effects of acute THC administration in healthy volunteers, one study examined the effects of CBD on the eCB system in schizophrenia, and the remaining studies measured the eCB system after chronic cannabis exposure. The

Post-mortem findings: effects of cannabis on cannabinoid receptors

A number of post-mortem studies have measured CB1R density in relation to cannabis exposure. Daily cannabis users exhibited lower CB1R protein and mRNA levels throughout the basal ganglia, dopaminergic midbrain nuclei, and hippocampus versus controls (Table 1; Villares, 2007). In contrast, Dean et al. (2001) found higher CB1R protein levels in combined schizophrenia patients and controls with THC metabolites in blood versus those without (Table 1). Other post-mortem reports of CB1R in

Limitations

One major limitation when comparing multiple studies is the inconsistent criteria applied by different studies to qualify cannabis users. Another factor contributing to the variable results between studies is the unknown ratio of THC/CBD and potency of cannabis used by participants. Further limitations with regard to cannabis exposure among studies is the dependence on participants’ self-report, and inconsistent time of cannabis abstinence at the time of study. Considering that abstinence leads

Conclusion

We have reviewed the current literature on the effects of cannabinoids on the central and peripheral eCB system in humans with and without a psychotic disorder. The most supported finding is the down-regulation of CB1R after chronic and recent cannabis exposure (Ceccarini et al., 2015, D'Souza et al., 2016, Hirvonen et al., 2012), but it remains uncertain whether this effect is replicated in schizophrenia patients who recently or chronically used cannabis (Ceccarini et al., 2013). There is

Acknowledgment

We thank JW, IB and JT for contributing their insight to the manuscript. This work has been supported by the CAMH Foundation. Dr. Mizrahi is funded by a grant from the National Institute of Mental Health (5R21MH103717), which had no involvement in preparation of this review.

Conflict of interest

Dr. Mizrahi reports and discloses to have received speaker and consultant from Otsuka-Lundbeck Canada. All other authors declare they have no conflict of interest.

Contributors

RM conceived the study and reviewed the manuscript, MJ prepared the manuscript, and JW, IB and JT provided input towards the manuscript.

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