Effects of repeated-dose isradipine on the abuse liability of cocaine.

Despite preclinical studies suggesting that isradipine may antagonize the abuse liability of cocaine, pretreatment with sustained-release isradipine did not reduce euphoric mood in cocaine-using volunteers. This double-blind, within-subject, crossover laboratory study determined whether maximal dose-loading with isradipine could antagonize effects of cocaine in 12 cocaine-dependent research volunteers administered intravenous cocaine doses (0, 0.325, and 0.65 mg/kg) on different days after 5 days of treatment with isradipine or placebo. Isradipine dose was 30 mg sustained release nightly plus 15 mg immediate release 2 hr before cocaine infusion. Cocaine produced dose-related increases in cocaine's subjective effects and a behavioral measure of reinforcement. Isradipine enhanced, rather than antagonized, subjective effects, indicating that isradipine does not antagonize cocaine's abuse liability in dependent research volunteers.

Acute intravenous low- and high-dose cocaine reduces quantitative global and regional cerebral blood flow in recently abstinent subjects with cocaine use disorder.

Cocaine-induced hypoperfusion, a risk factor for ischemic stroke, has not been fully characterized during experimental drug-taking among individuals with cocaine use disorder. We sought to examine cocaine's dose-dependent, time-related effects on cerebral blood flow. In a double-blind, randomized human laboratory study with a counterbalanced order of drug administration, 31 male and female subjects with cocaine use disorder were divided into two groups receiving either (a) low-dose cocaine (0.325 mg/kg intravenously) or placebo (N=15) or (b) high-dose cocaine (0.650 mg/kg intravenously) or placebo (N=16). The different dose conditions were administered on test days separated by a rest period of >or=48 h. Cerebral blood flow was assessed quantitatively using H(2)O(15) positron emission tomography. Experimentally administered low- and high-dose cocaine conditions versus their corresponding placebo conditions were associated with global and regional hypoperfusion. The trend for high- versus low-dose cocaine to be associated with greater hypoperfusion achieved statistical significance only for the dopamine-rich sublobar and midbrain regions. Cocaine's hypoperfusion effects were maximal at 8 mins after infusion (i.e., at about the expected peak of intravenous cocaine levels) and had mostly dissipated by 32 mins after infusion. Although hypoperfusion occurred throughout the brain, the left hemispheric dopamine-rich sublobar region was the most severely affected. Cocaine-induced cerebral hypoperfusion is associated with the time course of its pharmacological effects, and dopamine-rich areas, particularly in the left hemisphere, may be most vulnerable. Increasingly larger doses of cocaine may be associated with greater risk for ischemic stroke.

Effects of isradipine on cocaine-induced subjective mood.

We hypothesized that in humans, as in animals, isradipine, a dihydropyridine-class calcium channel antagonist, would antagonize cocaine's rewarding effects, based on preclinical evidence that isradipine inhibits cocaine-mediated increases in mesolimbic dopamine (DA), thereby reducing cocaine's abuse liability. Confirmation of our hypothesis would make isradipine a promising medication for treating cocaine dependence. Eighteen male and female volunteers (mean age, 32.6 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for cocaine dependence participated in a double-blind, placebo-controlled, crossover study. Subjects received placebo or sustained-release (SR) low-dose or high-dose isradipine (15 or 30 mg), plus placebo or low-dose or high-dose cocaine HCl (0.325 or 0.650 mg/kg), for 9 treatment sessions separated by a 2-day interval. Standardized assessments of abuse liability, including a choice procedure to determine preference for cocaine with and without isradipine over monetary incentives, were conducted at scheduled intervals. Cocaine administration produced dose-related prototypic increases in stimulant-related effects, including euphoria, and drug preference over monetary incentives. Isradipine lacked any stimulant or abuse liability effects or the propensity to elicit craving, and it did not antagonize any of cocaine's stimulant-related effects associated with its abuse liability. In conclusion, SR isradipine (up to 30 mg) does not antagonize cocaine's rewarding effects in cocaine-dependent individuals. While higher isradipine doses may have been more effective at antagonizing cocaine reward, we could not test such doses due to the risk of serious adverse events. Also, isradipine-mediated inhibition of mesolimbic DA release may be an ineffective treatment of cocaine dependence.