Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date

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Abstract

A significant body of epidemiological evidence has linked psychotic symptoms with both acute and chronic use of cannabis. Precisely how these effects of THC are mediated at the neurochemical level is unclear. While abnormalities in multiple pathways may lead to schizophrenia, an abnormality in dopamine neurotransmission is considered to be the final common abnormality. One would thus expect cannabis use to be associated with dopamine signaling alterations. This is the first systematic review of all studies, both observational as well as experimental, examining the acute as well as chronic effect of cannabis or its main psychoactive ingredient, THC, on the dopamine system in man. We aimed to review all studies conducted in man, with any reported neurochemical outcomes related to the dopamine system after cannabis, cannabinoid or endocannabinoid administration or use. We identified 25 studies reporting outcomes on over 568 participants, of which 244 participants belonged to the cannabis/cannabinoid exposure group. In man, there is as yet little direct evidence to suggest that cannabis use affects acute striatal dopamine release or affects chronic dopamine receptor status in healthy human volunteers. However some work has suggested that acute cannabis exposure increases dopamine release in striatal and pre-frontal areas in those genetically predisposed for, or at clinical high risk of psychosis. Furthermore, recent studies are suggesting that chronic cannabis use blunts dopamine synthesis and dopamine release capacity. Further well-designed studies are required to definitively delineate the effects of cannabis use on the dopaminergic system in man.

Introduction

Cannabis is the most prevalent illicit drug of use worldwide, with use rates of 3.9% across cultures, accounting for 180.6 million users, 13.1 million of whom are dependent on the drug (Degenhardt et al., 2013, United Nations Office on Drugs and Crime, 2013). A significant body of epidemiological evidence has consistently linked psychotic symptoms with both acute and chronic use of cannabis (Andréasson et al., 1987, Moore et al., 2007, Schimmelmann et al., 2011). Cannabis use has also been implicated in the approximate doubling of the risk of development of psychotic disorders such as schizophrenia in regular cannabis users (Arseneault et al., 2004, Davis et al., 2013, Moore et al., 2007) and an increase in rates of relapse of schizophrenia in those patients with comorbid cannabis use, up to three-quarters of whom may be using the drug (Schimmelmann et al., 2011, Zammit et al., 2008). Under experimental conditions, a single dose of its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), can result in the acute induction of transient psychotic symptoms in man similar to that seen under the influence of cannabis, and these acute effects have been linked to its effects on prefrontal, medial temporal and striatal function (Bhattacharyya et al., 2009, Bhattacharyya et al., 2012a, Bhattacharyya et al., 2012b, D’Souza et al., 2008, D’Souza et al., 2004).

Precisely how these effects of THC are mediated at the neurochemical level is unclear. While abnormalities in multiple pathways may lead to schizophrenia, an abnormality in dopamine neurotransmission, particularly in striatal regions, is considered to be the final common abnormality that may explain some of the prominent symptoms of the disorder, especially psychotic symptoms (Davis et al., 1991, Howes and Kapur, 2009, Snyder, 1976). Consequently one would expect cannabis use, an environmental risk factor with strong links to psychosis, to be associated with dopamine signaling alterations. In animal models, THC has been shown to increase dopamine neuron firing rates in the ventral tegmental area in a cannabinoid 1 (CB1) receptor mediated mechanism (Cheer et al., 2000, French et al., 1997). Administration of THC also leads to an accumulation of dopamine in the nucleus accumbens which can be inhibited by CB1 and opioid receptor antagonists as well as the axonal blocking agent Tetrodotoxin (TTX) (Cheer et al., 2004, Chen et al., 1990, Tanda et al., 1997). THC administration has also been associated with increase in striatal dopamine levels with microdialysis, estimated as being of the order of 25–100% increase (Chen et al., 1990, Gardner, 2005, Ginovart et al., 2012, Tanda and Goldberg, 2003, Tanda et al., 1997). Taken together, it appears that THC acts upon CB1 receptor in the ventral tegmental area to evoke burst firing leading to dopamine increases in striatal areas and the nucleus accumbens (Kuepper et al., 2010, Lupica et al., 2004). CB1 receptor mediated modulation of dopamine levels in the pre-frontal cortex has also been demonstrated (Pistis et al., 2001).

However, since schizophrenia is a uniquely human disease, delineation in man of the neurochemical mechanisms that may underlie the increase in risk of developing schizophrenia associated with cannabis use is imperative to precisely understand and accurately model disease pathogenesis. Although, there have now been a number of studies investigating the effect of exogenous cannabinoids on dopamine signaling in man, the results of these studies are as varied as the different outcome measures, including central and peripheral markers, that have been used. The purpose of this review is to synthesize following a systematic literature search all available evidence from human studies that have investigated the acute and chronic effects of cannabis and THC on the dopaminergic system.

This review was conducted in order to review systematically the literature for the effect of cannabis and cannabinoids on the dopaminergic system in humans. We aimed to review all studies conducted in man, both interventional and observational, employing both retrospective and prospective methodologies with any reported neurochemical outcomes related to the dopamine system after cannabis, cannabinoid or endocannabinoid administration or use.

Section snippets

Inclusion/exclusion criteria

Inclusion criteria for studies were: (1) human studies, (2) investigating the acute and long-term effects of cannabinoid administration, (3) measuring molecular markers related to dopaminergic neurotransmission – including (a) biomarkers in peripheral blood, (b) in vivo (imaging) or (c) post mortem brain tissue.

Exclusion criteria were (1) studies where cannabinoid administration was not the intervention or exposure of interest and (2) studies where neurochemical outcomes were not directly

Study selection

In total 2796 records were identified, of which 2044 remained when duplicates were removed. All abstracts of the records were screened against the inclusion and exclusion criteria. A final list of 25 studies was identified for systematic analysis in this review (see Figure 1). Cumulatively, these studies reported outcomes on over 568 participants (sample size was not available for one paper (Steffens et al., 2004)) of which 244 participants belonged to the cannabis/cannabinoid exposure group.

Discussion

This is the first systematic review of all studies, both observational as well as experimental, examining the acute as well as chronic effect of cannabis or its main psychoactive ingredient, THC, on the dopamine system in man. One previous review suggested dopamine transmission alterations in cannabis use relying on largely animal models (Kuepper et al., 2010). A further previous selective review critically examined the imaging findings in humans (Ghazzaoui and Abi-Dargham, 2014) and was more

Conclusion

Despite reasonably consistent animal studies, in man, there is as yet little evidence to suggest that cannabis use affects acute striatal dopamine release or affects chronic dopamine receptor status in healthy human volunteers. However some work has suggested that there is increased dopaminergic release acutely in striatal and pre-frontal areas in those genetically predisposed or at clinical high risk of psychosis. Furthermore, recent studies are suggesting that chronic cannabis use blunts

Role of funding source

The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Contributors

Musa Sami and Sagnik Bhattacharrya conceived the study design and undertook the literature review. Musa Sami prepared the first draft. Eugenii Rabiner and Sagnik Bhattacharrya reviewed the manuscript and offered suggestions. All authors approved the final manuscript.

Conflict of interest

Sagnik Bhattacharyya has received support from the NIHR (NIHR Clinician Scientist Award; NIHR CS-11-001) and the UK MRC (MR/J012149/1) and from the NIHR Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King׳s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

The authors have no other potential conflict of interest to disclose.

Acknowledgments

We acknowledge the help of Adam Blackwell, Emma Ramstead and Karen Stringer, librarians at East Surrey Hospital.

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