Sameridine, a novel molecule, has both local anesthetic and partial mu-opioid receptor properties. The aim of this single, blinded, randomized, four-way cross-over study was to investigate the hypercarbic ventilatory response (HCVR) in 12 healthy volunteers. A 20-min IV infusion of two doses of sameridine 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) were compared with 0.10 mg/kg of morphine and placebo. Ventilation was studied repeatedly for 2 h by pneumotachography and inline capnography. The hypercarbic ventilatory response was measured after addition of 4% CO(2) to inspired air until steady state. A visual analog scale followed sedation. After drug infusion there was a significant rightward shift (on average 4.5 mm Hg) of the ventilatory response curve (HCVR = Delta VE/Delta ETCO(2)) in the S-Large group. There were no changes of HCVR in the other groups. On a molar basis, the S-Large dose was 6.5 times the morphine dose, and such a dose would have been expected to cause a 12 mm Hg rightward shift. This discrepancy in effect is most likely a result of the partial mu-agonist effect of sameridine. Sedation was most pronounced after S-Large and morphine infusions. The authors concluded that a large IV dose of sameridine depressed the hypercarbic ventilatory response, whereas a smaller, clinical dose did not.