Preclinical studies suggested that combination of naltrexone and isradipine may be useful for the treatment of cocaine addiction. This study examined whether naltrexone and isradipine, alone or in combination, would attenuate the subjective and physiological effects of cocaine in humans. Seven cocaine users participated in a randomized, double-blind, placebo-controlled inpatient study. Before each of the seven experimental sessions, subjects were treated orally with naltrexone (50 mg or placebo), isradipine (10 mg or placebo), or naltrexone plus isradipine. Subjects then received a single dose of intranasal cocaine (4 mg or 100 mg/70 kg). Isradipine alone attenuated the systolic blood pressure response to cocaine. In contrast, isradipine plus naltrexone treatment attenuated both the systolic and diastolic blood pressure responses. Naltrexone alone did not affect the blood pressure response to cocaine. For subjective response to cocaine, isradipine, alone or in combination with naltrexone, did not have significant effects. Naltrexone treatment alone attenuated the rating of “good effects” from cocaine without affecting other subjective responses. These results suggest that isradipine alone or in combination with naltrexone attenuates some of the physiological effects of cocaine.