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  • Our results on the acute effects of THC on


    Our results on the acute effects of THC on resting state Cdk2/Cyclin Inhibitory Peptide I function are in line with previous neuroimaging findings. Increased perfusion after THC administration in insular and prefrontal regions has previously been reported in smaller samples (Mathew et al., 1997, Mathew et al., 2002, van Hell et al., 2011a). Although the perfusion data of the current study are an extension of the data set reported by van Hell et al. (2011a), we did not demonstrate any decreases in perfusion after THC administration in contrast to reduced CBF in the right postcentral gyrus and bilateral occipital gyrus as reported in the original study. Possible explanations for these discrepant results may be found in the larger sample size or the more stringent multiple comparison corrections that were applied in the current study. Our connectivity findings are consistent with those of Klumpers et al. (2012), who also found reduced functional connectivity with the default mode network, in particular between the posterior cingulate cortex and a network of brain regions collectively referred to as the left dorsal visual stream, which is thought to be involved in attentional processes. In the present study, subjective ratings of ‘perception’ and ‘dysphoria’ were increased, whereas those of ‘relaxation’ were reduced after THC administration. To our best knowledge, this is the first time that the effects of THC on these novel subscales, as recently described by Kleinloog et al. (2014), are reported. Demonstrated acute effects of THC on feeling high and perception (‘perception’), psychotic experiences (‘dysphoria’) and mental aspects of sedation (‘relaxation’) are consistent with previously reported subjective effects after THC administration (Bossong et al., 2012, Klumpers et al., 2012, van Hell et al., 2011b, Zuurman et al., 2008). To our best knowledge, we are the first to demonstrate that variation in COMT Val158Met genotype modulated acute THC effects on brain function. This is consistent with previous studies that showed a modulating role of COMT in the effects of cannabis (Caspi et al., 2005, Costas et al., 2011, Estrada et al., 2011, Henquet et al., 2006, Henquet et al., 2009, Tunbridge et al., 2015, Vinkers et al., 2013). However, whereas other experimental studies showed strongest acute cannabis effects in Val/Val genotypes (Henquet et al., 2006, Tunbridge et al., 2015), our findings suggest an augmenting effect on activity in the executive network of Val/Met heterozygotes. Possible explanations for these discrepant findings may be found in study population and design. Previous studies examined vulnerable and/or patient groups and investigated the impact of COMT genotype on the acute symptom and/or cognitive effects of cannabis (Henquet et al., 2006, Tunbridge et al., 2015). We demonstrate in the current study that variation in COMT genotype modulates acute THC effects on resting state brain function in healthy volunteers with limited exposure to cannabis or other drugs of abuse. Because it is thought that Val/Met heterozygotes have optimal dopamine levels resulting in maximum prefrontal cortex efficiency (Dickinson and Elvevag, 2009), our findings may suggest that only optimal executive brain function, such as with intermediate COMT activity, is susceptible to the acute effects of THC. This is further supported by a recent resting-state electroencephalography (EEG) study, which showed that brain activity in response to acute nicotine was modulated by COMT genotype, with significant increases in frontal regions in individuals with the Val/Met genotype only (Bowers et al., 2015). Our results may have implications for understanding the relationship between cannabis use and the development of brain disorders such as schizophrenia or addiction. It is thought that patients inappropriately attribute incentive salience to otherwise relatively neutral environmental cues, which may result in the formation of psychotic symptoms (Heinz, 2002, Kapur, 2003) or the development of addictive behaviour (Berridge, 2012, Flagel et al., 2009). Emerging evidence suggests that reduced engagement of the salience network, and in particular the insula, is a feature of many brain disorders, including schizophrenia and addiction. Insular dysfunction may diminish the capacity of the brain to discriminate between self-generated and external information, thereby contributing to psychotic or addictive behaviour through impaired salience attribution (Wylie and Tregellas, 2010, Droutman et al., 2015, Uddin, 2015). Because we demonstrated increased perfusion after THC administration in the salience network including the bilateral insula, one possibility is that frequent cannabis use may result in desensitisation of the salience network, which may ultimately lead to the development of brain disorders such as schizophrenia or addiction (Hall and Degenhardt, 2009, Marconi et al., 2016, Moore et al., 2007, Vaucher et al., 2017).