Reports of the death of CB1 antagonists have been greatly exaggerated: recent preclinical findings predict improved safety in the treatment of obesity.

CB1 antagonists, including rimonabant (SR 141716A), hold considerable therapeutic potential in the reduction of appetite and lipogenesis and in improving the metabolic profile of obese individuals and those with diabetes. However, rimonabant has not been approved in the USA because of its numerous side-effects, including depression and anxiety. Because of this, it is expected that fewer attempts will be made to introduce CB1 antagonists into the market. However, a 'second generation' of compounds has produced promising results in animal models in terms of these side-effects, and may pave the way toward new development and clinical testing of compounds that lack the side-effects of rimonabant. This new generation includes neutral CB1 antagonists, which likely have less intrinsic activity than clinically tested drugs, and peripherally restricted compounds. The current paper reviews the behavioral profile of rimonabant and related compounds, including a similarity in hypophagic effects with putative neutral antagonists and peripherally restricted antagonists. Emerging evidence of a lack of effects in models of nausea, anxiety, and depression is discussed. It is concluded that, with increasing emphasis on modeling the more troublesome side-effects of CB1 antagonists, safe, efficacious therapeutic targets may emerge. Further rigorous preclinical testing should be carried out.