There is a general consensus in the scientific community that psychosis is a complex disorder and that its causes cannot be discovered by focusing only on one aspect. Several genes of small effect together with environmental exposure such as drug abuse are known to be important risk factors. Cannabis is the most popular recreational drug in the world and it is estimated that 40% of young people have tried cannabis sativa at least once in their life. This study examines the role of common variations within the cannabinoid receptor 1 (CNR1) gene and the catechol-o-methyl transferase COMT gene and their interaction with cannabis use in the aetiology of psychosis. Specifically, it analyses the main effect of 15 SNPs, namely rs10485171, rs806365, rs806366, rs12189668, rs1049353, rs806369, rs806371, rs806374, rs12195101, rs806375, rs806377, rs806378, rs2023239, rs1535355, rs6454672 and the AATn microsatellite within the CNR1 gene on psychosis and their relationship and interaction with cannabis use. Furthermore, this study analysed the main effect of 7 SNPs, namely rs737865, rs6269, rs4633, rs4818, rs165599, rs4680 and rs2075507 within the COMT gene (4 of which form the LPS haplotype) and the LPS haplotype on psychosis and the relationship of rs4680 and the LPS haplotype with cannabis use, frequency of use and self reported experiences upon use. Samples under investigation are part of two large studies of first episode of psychosis: the Psychosis Incident Cohort Outcome Study (PICOS) and the Genetics and Psychosis study (GAP). The GAP Study sample consisted of 2 populations, Caucasian European and Black African/Black Caribbean populations, analysed separately. The GAP Caucasian sample included 174 psychotic patients and 45 healthy subjects; the GAP Black group included 113 psychotic patients and 93 healthy individuals. The PICOS Study is based in Verona, Italy and consisted of 347 first episode psychosis patients and 307 healthy volunteers. Results showed that rs1049353 and rs806378 within the CNR1 gene were associated with psychosis in the GAP Caucasian sample (adjusted p-value=0.03) and (adjusted p-value=0.05). Subjects with 2 copies of the LPS haplotype experienced more perception abnormalities. This however did not retain significance after Bonferroni correction for multiple testing (adjusted p-value=0.08 and p-value= 0.16 respectively). Subjects using cannabis more than 3 times per week were more likely to respond with anxiety and or paranoia to the drug (adjusted p-value=0.004).