Search

Aripiprazole blocks psychostimulant seeking in a rat model of relapse. However, in humans, it may increase ongoing use. We tested aripiprazole specifically for relapse prevention. Methadone-maintained outpatients who were abstinent from cocaine in weeks 11-12 were randomized to double-blind aripiprazole (15 mg daily) or placebo in weeks 13-27 after 12 weeks of contingency management. Participants reported craving through ecological momentary assessment. We stopped the trial because very few (18/41) participants fulfilled the abstinence criterion. The results suggested that aripiprazole delayed lapse [hazard ratio (HR)=0.45, 95% confidence interval (CI)=0.14-1.42, P=0.17] and relapse (HR=0.31, 95% CI=0.07-1.27, P=0.10), but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group (Fisher's exact P=0.026), although the frequency of craving was similar in the aripiprazole and placebo groups (1.89 vs. 1.16%, reffect=0.43, 95% CI=-0.08-0.76). The results suggest that in recently abstinent cocaine users, aripiprazole might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle.

Seven cocaine-abusing volunteers were trained to discriminate 50 mg oral cocaine vs placebo across 50 2-h sessions. Discriminative, subjective and autonomic effects were assessed with a procedure developed for precise characterization of their acute time-course. Subjective effects of oral cocaine began 10-15 min post-drug, peaked at 40-50 min and took up to 100 min post-drug to return nearly to baseline. Autonomic effects also began 10-15 min post-drug, peaked at 40-50 min and typically returned to baseline by 120 min post-drug; for most participants, peak heart rate and blood pressure remained within the range seen with placebo. Six out of seven participants acquired the discrimination (although this typically required 15-30 sessions, and there were some intriguing dissociations between the ability to discriminate oral cocaine from placebo and the ability to identify it as a stimulant). In most participants, oral cocaine produced increases in ratings of 'liking', 'alertness' and 'good effects', and in motor performance. Overall, the results support the sensitivity of the behavioral-testing procedure used, and show that 50 mg oral cocaine can serve as a discriminative stimulus in adult humans.

Kappa-opioid agonists produce neurobiological and behavioral effects opposite to those of cocaine and may be useful for the treatment of cocaine dependence. To evaluate the kappa- and mu-agonist effects of cyclazocine and to test whether cyclazocine pretreatment would attenuate the effects of cocaine, healthy, male and female, experienced opiate and cocaine users (n = 13) were enrolled in a two-phase study. In Phase 1, placebo, cyclazocine (0.2, 0.4 and 0.8 mg) and the mu-agonist hydromorphone (5 and 15 mg) were administered orally in six 4.5-hour sessions separated by at least 72 h. In Phase 2, cocaine (100 mg intranasal) was given 2 h after oral pretreatment with cyclazocine (0, 0.1, 0.2, 0.4, 0.8 and 0 mg, in that order) in each of six sessions conducted daily Monday to Friday and the following Monday. Physiological, subjective and behavioral measures were collected in each session. Nine participants completed Phase 1; eight completed Phase 2. Hydromorphone (15 mg) produced prototypic mu-agonist effects. Cyclazocine exhibited only modest kappa-like effects. Cyclazocine also had only modest, non-dose-related effects on response to cocaine. However, cocaine effects were consistently lower on the last administration (cyclazocine 0 mg pretreatment) following 4 days of cyclazocine pretreatment, compared to the first administration (0 mg pretreatment). This finding is unlikely to be fully attributable to cocaine tolerance and is not accounted for by pharmacokinetic changes; plasma concentrations of cocaine were not altered by cyclazocine. This study is suggestive but not strongly supportive for the use of kappa-opiate drugs to diminish acute effects of cocaine administration or for the use of these kappa agonists in drug abuse treatment applications.