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  • Caspi et al first identified that


    Caspi et al. (2005) first identified that the COMT polymorphism moderated the influence of adolescent cannabis use on developing adult psychosis (Caspi et al., 2005). In particular, compared to Met carriers, subjects with the Val/Val genotype were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis (Caspi et al., 2005). It has been hypothesized that the Val allele increases the risk of psychosis via depleting prefrontal dopamine availability and thus increasing mesolimbic dopaminergic activity in a feedback loop. In turn, THC enhances mesolimbic dopaminergic activity, further contributing to the development of psychosis (Misiak et al., 2017). Thus, individuals carrying the Val/Val genotype are more likely to experience THC-psychosis, because their dopamine systems are already “primed” (Luzi et al., 2008). However, contrasting findings have also been reported. In details, Costas and colleagues observed higher lifetime prevalence of cannabis use in schizophrenic subjects homozygous for the Met allele in comparison to Val homozygous (Costas et al., 2011). In sum, results on the interaction between cannabis and COMT Val158Met polymorphism when studying psychotic symptoms or psychotic disorders are still debated. While some data supported the hypothesis of Val/Val as the risk genotype, other studies identified Met as the risk allele, leading a recent meta-analysis to conclude that currently there is no evidence for a significative interaction (Vaessen et al., 2018). Concerning cognitive functioning, there has been a wide range of studies investigating the COMT polymorphism modulation of cognitive functions, including executive functions, working memory and attention (Fossella et al., 2002; Kondo et al., 2015; Mattay et al., 2003), overall reports indicating worse performance of Val/Val homozygous among healthy individuals, patients with schizophrenia and their unaffected relatives. Similarly, in functional neuroimaging studies, the COMT polymorphism has also been associated to ion channel processing efficiency during cognitive tasks (Egan et al., 2001; Heinz and Smolka, 2006). Moreover, this polymorphism has been suggested to predict cognitive outcome in patients treated with cognitive remediation therapy (Bosia et al., 2007; Bosia et al., 2015; Lindenmayer et al., 2015). While the role of COMT on cognition is widely ascertained, contrasting evidence has been reported for cannabis, especially in patients with psychosis. On the one hand studies in the general population showed that acute cannabis intoxication causes impairment in several cognitive domains, including episodic memory, working memory and attention and similar effects have been suggested also for the long-term use (Cosker et al., 2018). In line with this, regular cannabis use has been associated to structural and functional brain alterations (Lorenzetti et al., 2016; Murray et al., 2017; Nader et al., 2014). On the other hand, in patients with schizophrenia the effects of cannabis on cognition are far less clear. Ringen et al. (2010) reported worse performance in verbal memory and attention among patients who used cannabis in the last 6 months (Ringen et al., 2010), but other studies showed no differences in cognitive abilities between cannabis users and non-users (Bahorik et al., 2014; Scholes and Martin-Iverson, 2009). Conversely, better performance in working memory, executive functions, and verbal memory have been observed among patients with cannabis abuse, compared to non-users (Helle et al., 2017; Schnell et al., 2009). It is to notice that the relationship between cannabis use and cognition is also mediated by several external and individual factors, including genetic variations that may modulate the neurobiological effects of cannabis. As highlighted in a recent review (Cosker et al., 2018), the interaction with COMT gene is of particular interest for its key role in prefrontal neurocognition. In healthy cannabis users, data suggest an interaction between COMT Val158Met polymorphism and THC exposure on the main cognitive abilities, with cannabis causing impairments in Val/Val homozygous subjects (Tunbridge et al., 2015; Verdejo-Garcia et al., 2013), although negative results have also been reported (Spronk et al., 2015). Surprisingly, in patients with schizophrenia the interaction between COMT gene and cannabis use on cognition is still largely unexplored. To our knowledge, only one study was conducted in patients with psychotic disorders, exploring the effect of acute exposure and showing that Val/Val subjects were more sensitive to THC-induced memory and attention impairments (Henquet et al., 2006). A fuller understanding of the interaction between COMT and cognitive effects of cannabis could help to elucidate the mechanisms by which cannabis is linked to psychosis and further contribute to identification of the factors underlying cognitive deficits in schizophrenia.