Studies on neuropathological changes in substance-related and addictive disorders (SRADs) suggest that substance abuse or pathological gambling induces persistent abnormalities in the brain reward system that compromise emotional, decision making, and stress responses. Moreover, the enhancement of cortisol secretion resulting from long-term hyperactivation of the stress response is thought to impair the self-regulating system that controls emotion and executive function. In contrast, oxytocin induces prosocial behavior, attenuates the stress response, and reduces addictive behaviors in laboratory animals and humans. Prosocial behavior, a major coping response for stress in humans, is believed to be related to reward system function. Cognitive-behavioral therapy (CBT) is reported to lessen some symptoms of SRADs by affecting the function of the prefrontal cortex. Taken together these findings suggest that abnormalities of the reward system trigger the psycho-behavioral spiral of disturbances in prosocial behavior, the stress response, and self-regulation that are associated with SRADs. It is proposed that CBT in combination with drugs known to modulate prosocial behavior and the stress response could be of therapeutic value in the treatment of SRADs.