Cannabinoid (CB) 1 receptor inverse agonists inhibit food intake in animals and humans, but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB₁ antagonist, AM4113, on food intake, weight gain and emesis. Neutral antagonist and binding properties were confirmed in HEK293 cells transfected with human CB₁ or CB₂ receptors. AM4113 had no effect on forskolin stimulated cAMP production at concentrations up to 630 nM. The K_i value of AM4113 (0.80±0.44nM) in competitive binding assays with the CB_1/2 agonist [³H]CP55,940 was 100-fold more selective for CB₁ over CB₂ receptors. We determined that AM4113 antagonized CB₁ receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0-20 mg kg^-1) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg kg^-1), a highly anorectic dose of AM4113 (10 mg kg^-1) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB₁ receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans they could be developed into a new class of anti-obesity agents.