## Acute effects of delta-9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype

Matthijs G. Bossong, Hendrika H. van Hell, Chris D. Schubart, Wesley van Saane, Tabitha A. Iseger, Gerry Jager, Matthias J.P. van Osch, J. Martijn Jansma, René S. Kahn, Marco P. Boks, Nick F. Ramsey

European Neuropsychopharmacology, 2019, 13, 56, 1–11

https://doi.org/10.1016/j.euroneuro.2019.03.010

### Abstract

Cannabis produces a broad range of acute, dose-dependent psychotropic effects. Only a limited number of neuroimaging studies have mapped these effects by examining the impact of cannabis on resting state brain neurophysiology. Moreover, how genetic variation influences the acute effects of cannabis on resting state brain function is unknown. Here we investigated the acute effects of 9-tetrahydro-cannabinol (THC), the main psychoactive constituent of cannabis, on resting state brain neuro-physiology, and their modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Thirty-nine healthy volunteers participated in a pharmacological MRI study, where we applied Arterial Spin Labelling (ASL) to measure perfusion and functional MRI to assess resting state connectivity. THC increased perfusion in bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus. This latter brain area showed significantly decreased connectivity with the precuneus after THC administration. THC effects on perfusion in the left insula were significantly related to subjective changes in perception and relaxation. These findings indicate that THC enhances metabolism and thus neural activity in the salience network. Furthermore, results suggest that recruitment of brain areas within this network is involved in the acute effects of THC. Resting state perfusion was modulated by COMT genotype, indicated by a significant interaction effect between drug and genotype on perfusion in the executive network, with increased perfusion after THC in Val/Met heterozygotes only. This finding suggests that prefrontal dopamine levels are involved in the susceptibility to acute effects of cannabis.

KEYWORDS : Delta9-tetrahydrocannabinol (THC); Cannabis; Arterial spin labelling; Resting state
connectivity; Catechol-methyltransferase (COMT); Salience

### 1. Introduction

With an estimate between 128 million and 238 million users, cannabis is the most widely used illicit substance in the world ( United Nations Office on Drugs and Crime, 2017 ). It produces a broad range of acute, dose-dependent psychotropic effects, such as ‘feeling high’, relaxation and euphoria, which are regarded as the main reasons why people use cannabis ( Green et al., 2004; Manéet al., 2015 ). In addition, cannabis has been shown to acutely induce increased heart rate, perceptual alterations and psychotic symptoms ( Ashton, 2001; Hall and Degenhardt, 2009; Sherif et al., 2016 ), and to impair cognitive functions such as learning and memory ( Bossong et al., 2014a; Broyd et al., 2016 ). Finally, epidemiological studies indicate that the use of cannabis increases the risk for developing schizophrenia ( Marconi et al., 2016; Moore et al., 2007; Vaucher et al., 2017 ). These effects are primarily produced through action of 9-tetrahydrocannabinol (THC), the main psychoactive ingredient of cannabis, on the cannabinoid 1 (CB1) receptor ( Huestis et al., 2001 ; Ledent, 1999 ).

In recent years, neuroimaging studies have increasingly demonstrated acute effects of THC on brain function, the vast majority of them involving a cognitive challenge ( Bossong et al., 2014b ). For example, without affecting performance accuracy, THC caused reductions in activity during encoding of information in temporal and prefrontal areas, but increases in activity during recall, which suggests neural compensation to meet the cognitive demands of a task ( Bhattacharyya et al., 2009; Bossong et al., 2012 ). However, state-of-the-art research on the acute impact of THC on resting state brain function, thereby mapping its psychotropic effects, is limited. An initial series of studies by Mathew and colleagues using Positron Emission Tomography (PET) showed increased perfusion after THC in prefrontal, insular and anterior cingulate regions, which was associated with reported intoxication levels and changed time per- ception ( Mathew et al., 1989, 1992, 1997, 2002 ). Van Hell et al. (2011a) confirmed these findings by demonstrating increased perfusion measured with Arterial Spin Labelling (ALS), and increased amplitude of fluctuations in resting state functional Magnetic Resonance Imaging (MRI) signal in the frontal cortex and bilateral insula after THC administration ( van Hell et al., 2011a ). In these studies, altered perfusion is measured as changes in regional cerebral blood flow (CBF), which is directly correlated with the level of local neural activity ( Attwell et al., 2010; Dukart et al., 2018 ). The few studies that investigated acute effects of THC on resting state functional connectivity showed THC-induced connectivity changes within both the sensorimotor and dor- sal visual stream networks, including the cerebellum and dorsal frontal cortical regions ( Klumpers et al., 2012 ), and significant reductions in functional connectivity between the ventral striatum and the limbic lobe, prefrontal cor- tex, striatum and thalamus ( Ramaekers et al., 2016 ). Grimm et al. (2018) did not show any significant effects of oral THC administration on striatal functional connectivity measures.

Importantly, there is marked inter-individual variability in the susceptibility to the effects of cannabis ( Atakan et al., 2013 ). One possibility is that inter-individual differences in the impact of cannabis are explained by genetic variation. In this context, an extensively studied vulnerability gene is catechol-methyl-transferase (COMT), which encodes the main catecholamine degrading enzyme COMT. A functional nucleotide polymorphism (SNP) in the COMT gene (rs4680) results in a valine-to-methionine mutation at position 158 (Val158Met). Variation of the COMT Val158Met is associated with dopamine turnover in the prefrontal cortex. Individuals with the COMT Val/Val allele show increased COMT enzyme activity and, consequently, reduced dopamine levels com- pared to Met homozygotes ( Chen et al., 2004; Tunbridge et al., 2006 ). Epidemiological studies have demonstrated the COMT Val158Met genotype as a modera- tor of the association between cannabis use and the later development of psychotic symptoms or schizophre- nia ( Caspi et al., 2005; Costas et al., 2011; Estrada et al., 2011; Nieman et al., 2016; Vinkers et al., 2013 ), although not all studies demonstrated consis- tent findings ( de Sousa et al., 2013; van Winkel, 2011; Zammit et al., 2011 ). In cannabis users, the COMT Val158Met genotype was shown to moderate executive func- tion, with the Val allele associated with poorer perfor- mance ( Verdejo-Garcia et al., 2013 ). Experimental studies on COMT modulation of the impact of cannabis showed stronger responses to cannabis or THC in terms of acute psy- chotic effects and cognitive impairments in individuals with increased COMT activity, particularly in people with a (ge- netic risk for a) psychotic disorder ( Henquet et al., 2006, 2009 ). A study by Spronk et al. (2016) in healthy volunteers failed to demonstrate a moderating role of COMT genotype on cannabis-induced effects on reversal learning. Tunbridge et al. (2015) showed that COMT genotype affects the im- pact of acute THC on working memory performance but not on psychotic experiences in participants vulnerable to para- noia. However, it is unknown how COMT genotype modulates acute THC effects on resting state brain function.

The aim of the present study was to investigate the acute effects of THC on resting state brain neuro-physiology, and to examine the impact of COMT genotype on these effects. Thirty-nine healthy volunteers participated in a randomised, placebo-controlled, crossover pharmacologi- cal MRI study. Acute effects of THC were assessed on rest- ing state perfusion measured with ASL and on resting state connectivity measured with functional MRI. Consistent with previous neuroimaging studies (Mathew et al., 1997, 2002; van Hell et al., 2011a ), we anticipated increased perfusion after THC administration in the insula and frontal cortex. Given the particular role of COMT in prefrontal dopamine degradation (Chen et al., 2004; Tunbridge et al., 2006 ), we further hypothesised that COMT genotype would modulate perfusion in the executive network, which includes the dor- solateral prefrontal cortex.

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