AimsTo explore the clinical features of methamphetamine-induced paranoia (MIP) and associations between MIP and a genetic polymorphism in dopamine -hydroxylase (DBH-1021CT). DesignRetrospective analysis of clinical presentation and genetic association by (2) test and logistic regression analysis. SettingA Thai substance abuse treatment center. ParticipantsA total of 727 methamphetamine-dependent (MD) individuals. MeasurementsClinical: Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) and the Methamphetamine Experience Questionnaire (MEQ). Genetic: DBH-1021CT. FindingsForty per cent of individuals (289 of 727; 39.8%) with MD had MIP. Within-binge latency to MIP onset occurred more rapidly in the most recent compared with initial MIP episode (P=0.02), despite unchanging intake (P=0.89). Individuals with MIP were significantly less likely to carry lower (TT/CT) compared with higher (CC) activity genotypes (34.3 versus 43.3%; (2)(1)=5, P=0.03). DBH effects were confirmed [odds ratio (OR)=0.7, P=0.04] after controlling for associated clinical variables (MD severity, OR=3.4, P<0.001; antisocial personality disorder, OR=2.2, P<0.001; alcohol dependence, OR=1.4, P=0.05; and nicotine dependence, OR=1.4, P=0.06). TT/CT carriers were more likely to initiate cigarette smoking (OR=3.9, P=0.003) and probably less likely to be dependent on alcohol (OR=0.6, P=0.05). ConclusionsAmong methamphetamine-dependent individuals, paranoia appears to occur increasingly rapidly in the course of a session of methamphetamine use. Severity of methamphetamine dependence and antisocial personality disorder predicts methamphetamine-induced paranoia. The genetic polymorphism in dopamine -hydroxylase is associated with methamphetamine-induced paranoia and influences smoking initiation.