Methylecgonidine is formed from cocaine base when smoked and has been identified in biological fluids of crack smokers. Ecgonidine, a metabolite of methylecgonidine formed via esterase activity, also has been identified in similar samples collected from crack smokers. Methylecgonidine and ecgonidine can be used as biomarkers to differentiate smoking from cocaine use via other routes of administration. We determined the pharmacokinetic properties of methylecgonidine and ecgonidine in sheep after intravenous administration of methylecgonidine at doses of 3.0, 5.6, and 10.0 mg/kg using gas chromatography-mass spectrometric assays. Methylecgonidine clears quickly from blood with a half-life of 18 to 21 min, whereas ecgonidine has a longer half-life of 94 to 137 min. Because ecgonidine clears more slowly, it may be a more effective biomarker of cocaine smoking. The cardiovascular stimulant effects of cocaine contrast with reported in vitro muscarinic agonist effects of methylecgonidine, decreasing contractility and stimulating nitric oxide production in cardiac cells and tissues. To test the hypothesis that methylecgonidine produces cardiovascular effects in vivo consistent with muscarinic agonism, methylecgonidine was administered to sheep intravenously (0.1-3.0 mg/kg) while monitoring heart rate and blood pressure. Significant hypotension and tachycardia occurred in all three sheep. Two of the three sheep demonstrated mild bradycardia 3 to 5 min after methylecgonidine injection. Intravenous pretreatment with atropine methyl bromide (15 microg/kg) antagonized methylecgonidine-induced hypotension in all three sheep, supporting the hypothesis that methylecgonidine acts as a muscarinic agonist in vivo.