This study aimed to determine whether the second-generation cannabinoid receptor subtype 1 (CB1) antagonist, monlunabant - designed to treat obesity by targeting peripheral receptors - might actually exert its effects through CB1 receptors in the central nervous system. In adult male mice, both monlunabant and rimonabant reduced appetite and antagonized CB1 agonist-induced hypothermia. Monlunabant was consistently less potent than rimonabant in both appetite suppression and blocking hypothermia. The cannabinoid agonist HU-210 produced profound hypothermia, which was significantly attenuated by 10 mg/kg of either drug and by 3 mg/kg of rimonabant. Similarly, both drugs reduced appetite in food-deprived mice with limited access to preferred food at the same doses that were effective in the hypothermia assay. Lower doses of monlunabant, which likely saturated peripheral receptors, had no effect on appetite. These findings suggest that monlunabant suppresses appetite mainly through antagonism of central CB1 receptors. Consequently, monlunabant and other second-generation CB1 antagonists being developed for obesity may carry a similar risk of adverse psychiatric effects, as previously observed with rimonabant.