The results demonstrate that the neutral antagonists such as PIMSR and AM4113 retain the therapeutic anti-addictive effects of rimonabant but without significant rimonabant-like adverse effects, which provides the first proof-of-concept evidence supporting that a purer (neutral) CB1R antagonist with little inverse agonism may have a more favorable pharmacological profile in the treatment of obesity and SUDs. Here, CNR1 is linked to obesity due to melanocortin 4 receptor deficiency.