Cannabis use is exceedingly common Bahorik et al and overwhe

Cannabis use is exceedingly common ((Bahorik et al., 2014) 8%) and overwhelming evidence suggests that, especially during adolescence, it represents a major risk factor for psychosis (Gage et al., 2016), associated with earlier onset and more pronounced symptoms (Arseneault et al., 2002, 2004). Moreover, delta-9-tetrahydrocannabinol (THC), the main active 680C91 sale in cannabis, can induce transient psychotic-like experiences (D\'Souza et al., 2004). Animal and human studies further indicate that acute exposure to exogenous cannabinoids indirectly activates D2 receptors and dopaminergic transmission in the striatum and mesolimbic areas, while prolonged exposure results in a reduction of the dopamine in the prefrontal cortex (Maria Pelayo-Teran et al., 2012), thus providing a biological rationale for the clinical and epidemiological data. In line with this, an interaction model with COMT genetic variation has been proposed. The COMT gene, initially investigated for its possible role in the susceptibility for the disease, is one of the most extensively examined gene in the neurocognition of schizophrenia (Barnes et al., 2006; Degenhardt and Hall, 2006). The COMT gene encodes an enzyme responsible for degrading the majority of prefrontal cortical dopamine. The COMT Val158Met functional polymorphism regulates the enzymatic activity, with the Val allele leading to increased prefrontal dopamine catabolism and thus lower extracellular dopamine levels (Bosia et al., 2015). 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).