Background: There is no valid and accurate documentation on the combination therapy of bupropion along with naltrexone. The experimentations on these actions of combination drugs have resulted in rare success. Methods: A complex interaction occurs in the central and peripheral nervous system for reducing weight loss. It is difficult to find out the major mechanism of action of these drugs on weight reduction. Naltrexone and bupropion is the experimental combination for reducing the weight. For obesity, the combination of naltrexone/bupropion therapy’s mechanism working is still unknown. Results: The attempts for weight loss rarely have a long-term effect. It is an outcome of more likely some complex interaction between various peripheral and Central Nervous systems, and an overwhelming lack of real obesity treatment may be explained. Based on the evidence that obesity involves a change in the hypothalamic melanocortin system in addition to a brain reward system, which causes food craving and mood swings, this investigational combination therapy of NB was developed. Naltrexone and bupropion work in an interesting way. Conclusion: It affects the parts of the brain that influences food craving, food intake, eating behaviors, and loss of body weight. We will have a review on the working of naltrexone, and bupropion separately, and Vivo, current in vitro, and clinical evidence will be provided, describing how NB affects food intake and food craving. Keywords: CNS, obesity, medicine, weight lose, NB, therapy.