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  • In recent years neuroimaging studies have increasingly demon


    In recent years, neuroimaging studies have increasingly demonstrated acute effects of THC on CX5461 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 perception (Mathew et al., 1989, Mathew et al., 1992, Mathew et al., 1997, Mathew et al., 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 dorsal 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 cortex, 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 compared to Met homozygotes (Chen et al., 2004, Tunbridge et al., 2006). Epidemiological studies have demonstrated the COMT Val158Met genotype as a moderator of the association between cannabis use and the later development of psychotic symptoms or schizophrenia (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 consistent 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 function, with the Val allele associated with poorer performance (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 psychotic effects and cognitive impairments in individuals with increased COMT activity, particularly in people with a (genetic risk for a) psychotic disorder (Henquet et al., 2006, Henquet et al., 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 impact of acute THC on working memory performance but not on psychotic experiences in participants vulnerable to paranoia. However, it is unknown how COMT genotype modulates acute THC effects on resting state brain function.