Cocaine cues elicit craving and physiological responses. The cerebral circuits involved in these are poorly understood. The purpose of this study was to assess the relation between regional brain activation and cocaine cue elicited responses. Thirteen right-handed cocaine abusers were scanned with positron emission tomography (PET) and [F-18] fluorodeoxyglucose (FDG) twice; during an interactive interview about neutral themes and during an interactive interview about cocaine themes designed to elicit cocaine craving. In parallel the behavioral (rated from 0: felt nothing to 10: felt extreme) and cardiovascular responses were recorded. During the cocaine theme interview subjects reported higher self reports for cocaine craving (+2.5+/-3.3, p < or = 0.02) and had higher heart rates (+4.7+/-7.2%, p < or = 0.001), systolic (+4+/-4%, p < or = 0.0001), and diastolic blood pressures (+2.6+/-3.8%, p < or = 0.003) than during the neutral interview. Absolute and relative metabolic values in the orbitofrontal (+16.4+/-17.1%, p < or = 0.005; +11.3+/-14.3%, p < or = 0.008) and left insular cortex (+21.6+/-19.6%, p < or = 0.002; +16.7+/-19.7%, p < or = 0.01) and relative values in cerebellum (+17.9+/-14.8%, p < or = 0.0008) were higher during the cocaine theme than during the neutral theme interview. Relative metabolic values in the right insular region (p < or = 0.0008) were significantly correlated with self reports of cocaine craving. Activation of the temporal insula, a brain region involved with autonomic control, and of the orbitofrontal cortex, a brain region involved with expectancy and reinforcing salience of stimuli, during the cocaine theme support their involvement with craving in cocaine addicted subjects.