193 Impact of oral Cannabis on driving skills and genetic vulnerability to psychotic symptoms Christian Giroud, Chin B. Eap, Bernard Favrat, Frank Sporkert, Marc Augsburger, Bertrand Rochat, Jonathan Paz Montoya, Vincent Castella and Patrice Mangin Abstract In a previous study designed to assess the effects of an oral intake of cannabis or dron- abinol on driving capability, 2 out of 8 healthy male subjects, all of them occasional cannabis smokers, over-reacted to medium doses of ∆ 9 -tetrahydrocannabinol by developing transient psy- chotic symptoms. Since some candidate genes associated with vulnerability to drug side-effects have been suggested, a pilot study involving genetic investigations was carried out. Genetic poly- morphisms of CYP2C9 and 2C19 were analyzed. One volunteer who experienced psychotic symptoms was the only one to display a CYP2C9 *2/*2 genotype suggesting a poor metabolizer phenotype. The THC/11-OH-THC concentration ratio was slightly higher than those calculated for the other volunteers. Because very few is known about the identity of the UGT enzymes involved in THCCOOH glucuronidation, in vitro experiments were performed allowing to identify UGT1A3 and 1A1 as the main enzymes catalyzing this reaction. The same volunteer was found to have a Val/Val COMT polymorphism suggesting an increased dopamine metabolism and a dop- amine receptor D2 A1/A2 polymorphism possibly causing a brain hypodopaminergic state. Alteration of dopaminergic neurotransmission has been reported to increase the risk of psychiatric disorders after drug exposure. In conclusion, our findings suggest that the contribution of genetic polymorphisms in cannabis vulnerability and THC metabolism warrants further investigations. 1. Introduction In a previous study that was designed to evaluate the effects of ingestion of cannabis on car-driving capability, we have observed two cases of "cannabis acute psychosis" whose cause has not yet been clearly established (Favrat et al 2005; Menetrey et al 2005). These unwanted side effects occurred during a double blind controlled administration study with placebo. The 8 male subjects who were recruited for this study were occasional cannabis smokers without known psychi- atric history. Two of them developed transient psychotic symptoms (depersonal- ization, paranoid feelings and derealization) following oral administration of a cannabis milk decoction containing a medium dose of THC (15.8 mg) or dronabi- nol (20 mg). The participants reported a strong feeling of intoxication. Their willingness to drive was more or less diminished according to the importance and emotional load of the fictive job entrusted to them. Their tracking ability assessed with a driving simulator was also strongly diminished. Some genetic and envi- ronmental conditions may differentially predispose individuals to drug adverse