Cannabis and Psychosis: the burden of genes
Substance Abuse

Cannabis is the most widely used illicit drug with about 10% of young adults in developed countries being regular users. Furthermore, some estimations suggest that in Europe about 1% of people consume cannabis almost daily.
In recent years it has become apparent the pathological link between cannabis use and schizophrenia-like psychotic disorders, and epidemiological evidences consistently suggest that the use of cannabis during adolescence increases the relative risk for psychotic disorders by 2-fold. Nonetheless, the majority of cannabis users do not develop psychotic disorders; why certain individuals develop psychosis when their peers, who smoke similar amounts of cannabis, remain well is unclear. It suggest that such individuals may carry some genetic susceptibility.

The active ingredient of cannabis, delta-9-tetrahydrocannabinol (delta-9-THC), is responsible for its psychotomimetic effect. Delta-9-THC inhibits, via cannanoid receptors type 1 (CBR1) activation, the release of glutamate to gamma-aminobutyric acidergic neurons that project from the nucleus accumbens to the ventral tegmental area. These neurons normally exert an inhibitory effect on the firing of dopamine neurons that project back to the nucleus accumbens. Thus, their inhibition causes increased dopamine release in the striatum and mesolimbic pathway, which is implicated in the pathogenesis of psychotic symptoms.
Moreover, it is remarkable of note that structural and functional imaging studies have shown that effects of chronic cannabis use on brain structure, such as volume reduction in the hippocampus and the amygdala, are consistent with studies showing similar alteration in patients with schizophrenia (Bhattacharyya et al. 2009) this might be due to a neurotoxic activity of chronically elevated extracellular dopamine concentration (Santiago et al. 2000).

According to that, studies on gene-environment interaction have mainly included genetic variants involved in the regulation of dopaminergic system. The most promising genetic variants in this field are COMT, AKT1, CBR1 and FAAH.

COMT

The COMT gene encodes the enzyme catechol-O-methyltransferase, which plays an important role in the degradation of dopamine in brain, and contains a functional polymorphism (COMT-Val158Met) that results in two common variants of the enzyme (Val and Met). The Val variant is associated with increased COMT activity, which results in a combination of reduced dopamine neurotransmission in the prefrontal cortex and increased levels of dopamine in mesolimbic areas.
Caspi and collegues (Caspi et al. 2005) reported that the individuals homozygous for valine 158 more likely displays psychotic symptoms after use of cannabis during adolescence, although some studies failed to replicate the original findings from Caspi, Alemany (Alemany et al. 2013) recently reported that in his sample COMT genotypes only influenced development of psychotic disorders among individuals exposed to childhood abuse, indicating that environmental exposure and genetic factors may interact in a more complex way than what expected.

AKT-1

AKT1 is a serine/treonine kinase that forms an integral part of the dopamine receptor signalling cascade in the striatum. Murine models shows that delta-9-THC activates this signalling cascade via AKT1 phosphorilation. Van Winkel and collegues (van Winkel et al. 2011) reported that subjects who carried two copies of the C allele of rs2494732 polymorphism of the AKT1 gene were especially at risk of psichotic disorders, if they used cannabis. These findings have been confirmed by Di Forti and colleagues (Di Forti et al. 2012). Nevertheless, Di Forti highlights that genome-wide association studies have shown that the relation between cannabis and psychosis seems to be polygenic; therefore it is likely that AKT1 rs2494732 contributes to susceptibility to the psychotogenic affect of cannabis together with other genetic variants.

CBR1

Cannabinoid receptor type 1 (CBR1) is the most well-characterized cannabinoid receptor, involved in the endocannabinoid system. The endocannabinoid signalling is a lipidic signalling system, which has multiple regulatory functions in the central nervous system including cognition, emotion, mood, reward-associated behaviors, feeding and pain. His main endogenous ligands are 2-arachidonoylglycerol (2-AG) and anandamide (AEA).
Endocannabinoid system also plays an important role in brain maturation during adolescence, which is a critical period for maturation of many neurotransmitter, including dopaminergic transmission (O'Donnel, 2010), Saito A. in his rewiew (Saito et al. 2013) suggest that an aberrant CBR1 signalling may hamper full-maturation of the neuronal circuit network during adolescence, which might underline the later development of psychosis.
In this respect, it is interesting that some studies have reported the role CBR1 in schizophrenia, showing an increase in canabinoid receptor binding in the dorsolateral prefrontal cortex and posterior cingulate cortex, associated with volume loss in these areas (Chavarria-Siles et al. 2008; Zavitsanou K. Et al. 2004). Thus, as previously mentioned, there might be an interaction between cannabis use and genetic factors that lead to brain morphologic changes, known to be involved in spychosis.

Nevertheless, increasing evidences shows that CBR1 mutations are related to cannabis dependence. Zhang and collegues (Zhang et al. 2004) suggested that an intronic single nucleotide polymorphism (SNP) (rs2023239) may create an alternative CBR1 transcript associated with substance abuse in general. Another study by Haughey (Haughey et al. 2008) found that the same SNP is a significant predictor of withdrawal after abstience, and a predictor of overall levels of craving in frequent cannabis users. Furthermore, Ho with his group (Ho et al. 2011) found evidence for a gene-environment interaction, showing that the CBR1 gene single nucleotide polymorphism (SNP) rs12720071 significantly interacts with cannabis. These studies suggest that genetic sensitivity to cannabis plays an important role in the development of cannabis-related problems.

FAAH

The FAAH gene codes for the fatty acid amide hydrolase (FAAH), which is the enzyme that metabolizes delta-9-THC in the brain, and that is a critical temporal regulator of endocannabinoid signalling. One SNP in FAAH (rs324420) involves a non-synonomous 385 C to A sustitution that converts a proline residue in threonine. This 385A variant encodes for a mutant FAAH anzyme characterized by reduced cellular stability compared to the wild -type (Onaivi et al. 2002). Thus, this A variant might lead to lower FAAH levels, resulting in greater endocannabinoid activity via less efficient degradation of endocannabinoids, and in turn may have an impact on withdrawal, craving and mood. According to that, Haughey (Haughey et al. 2008) reported that individuals with C/C FAAH genotype showed significantly greater craving after abstinence than did individuals with at least one copy of the A allele, demonstrating that FAAH SNPs alter the sujective effects of cannabis use and cannabis dependence.

Conclusions

Despite we are far away from fully understand the molecular mechanisms of cannabis exposure and its convergence with genetic risks in the etiology of psychotic disorders; taken together these studies support the theory that some individuals carry some genetic vulnerability to the psychotogenic effect of cannabis. The character of this vulnerability seems to be a polygenic gene-environment interaction, which may influences the initiation of substance use, the dependence and, above all, the devolpment of psychotic symptoms.
Further investigation of the relation between cannabis exposure and genetic risk factor may allow us to understand pathological processes associated with endocannabinoid system, which may in turn, shed light on the discovery of novel therapeutic intervention and prevention for cannabis-related psychotic disorders.

Ascheri Daniele
Cassardo Francesco

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