Cocaine is rapidly metabolized to major metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), and minor metabolites, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. This IRB-approved study examined cocaine and metabolite plasma concentrations in 18 healthy humans who provided written informed consent to receive low (75 mg/70 kg) and high (150 mg/70 kg) subcutaneous cocaine hydrochloride doses. Plasma specimens, collected prior to and up to 48 h after dosing, were analyzed by gas chromatography-mass spectrometry (2.5 ng/mL limits of quantification). Cocaine was detected within 5 min, with mean+/-SE peak concentrations of 300.4+/-24.6 ng/mL (low) and 639.1+/-56.8 ng/mL (high) 30-40 min after dosing. BE and EME generally were first detected in plasma 5-15 min post-dose; 2-4 h after dosing, BE and EME reached mean maximum concentrations of 321.3+/-18.4 (low) and 614.7+/-46.0 ng/mL (high) and 47.4+/-3.0 (low) and 124.4+/-18.2 ng/mL (high), respectively. Times of last detection were BE>EME>cocaine. Minor metabolites were detected much less frequently for up to 32 h, with peak concentrations<or=18 ng/mL for all analytes except pOHBE (up to 57.7 ng/mL). These data improve our knowledge of the pharmacokinetics of cocaine and its major and minor metabolites in plasma following controlled subcutaneous cocaine administration.