Aim of this paper is to investigate the psychobiological reactions to experimentally induced negative emotional states in active marijuana-dependent smokers and whether changes in emotional reactivity were reversed by prolonged abstinence. Twenty-eight patients were randomly included into group A (fourteen active marijuana-dependent smokers) or group B (fourteen abstinent marijuana-dependent subjects). Emotional response evaluation of group B subjects was assessed after 6 months of abstinence. Fourteen healthy volunteers, matched for age and sex, were used as controls. Psychometric and emotional response evaluations were performed by administering Symptoms Check List-90 and State-Trait Anxiety Inventory Y-1 (STAI). Neutral and unpleasant set of pictures selected from the international affective picture system and the Self-Assesment Manikin procedure (SAM) have been used to determine ratings of pleasure and arousal. Before and after the experimental session, blood samples were collected to determine ACTH and cortisol plasma levels. Active cannabis users displayed significantly higher levels of pleasantness SAM scores and lower levels of arousal SAM scores compared to abstinent cannabis users and controls in response to emotional task. In a close parallel with psychological data, hormonal findings indicate a persistent hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis in cannabis users, particularly among active marijuana smokers, and an impaired hormonal reaction to negative emotions, in comparison with healthy subjects. The capacity of the HPA axis to respond to stressful stimuli/negative emotions seems to be only partially recovered after 6 months of abstinence. Ours findings, although obtained in a small number of subjects, suggest an association between active cannabis use, subjective reduced sensitivity to negative emotions and threat and HPA axis dysfunction.