Kishorchandra Gonsai

d-Cycloserine attenuates reactivity to smoking cues in nicotine dependent smokers: A pilot investigation

Increasing evidence indicates that smoking cues contribute to nicotine self-administration and attenuating conditioned reactivity to smoking cues may aid abstinence of smoking and prevention of smoking relapse in individuals with nicotine dependence. Based on prior studies showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitates extinction of learned fear during behavioral exposure therapy in humans and facilitates extinction of cocaine-induced conditioned place preference in animals, we evaluated whether DCS would have potential for reducing reactivity to smoking cues when combined with cue exposure treatment in humans with nicotine dependence. In this double-blind placebo-controlled pilot laboratory study, 25 smokers were recruited from the general community and randomized to DCS or placebo, plus cue exposure therapy. DCS significantly attenuated smoking cue reactivity in response to in-vivo smoking cues based on physiological reactivity and subjective urge-to-smoke ratings and led to a significantly smaller expired carbon monoxide (CO) level at the one-week follow-up compared to placebo, although exploratory analyses indicated no effect on smoking behavior overall. These findings provide promising support for DCS combined with cue exposure therapy in attenuating conditioned reactivity to smoking cues.

Randomized, double blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients.

UNLABELLED This study examined the dose-related efficacy of disulfiram for treating cocaine dependence in methadone-stabilized cocaine dependent participants. DESIGN One hundred and sixty-one cocaine- and opioid-dependent volunteers were entered into a 14-week, double blind, randomized, placebo-controlled clinical trial at two sites. METHODS Participants were stabilized on methadone during weeks 1-2 and received disulfiram at 0, 62.5, 125 or 250 mg/day during weeks 3-14. All participants also received weekly cognitive behavioral therapy. Thrice-weekly urine samples and weekly self-reported drug use assessments were obtained. RESULTS Baseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid-positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p < 0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p = 0.04). CONCLUSIONS Disulfiram may be contraindicated for cocaine dependence at doses <250 mg/day. Whether disulfiram at higher doses is efficacious in reducing cocaine use in dually cocaine and opioid dependent individuals needs to be determined.

The safety and efficacy of varenicline in cocaine using smokers maintained on methadone: a pilot study.

In this double-blind, placebo-controlled trial, we compared varenicline (2 mg) to placebo for treatment for cocaine and tobacco dependence in 31 methadone-maintained subjects. Subjects received weekly counseling during the 12-week study participation. Our results indicate that varenicline is safe to give to this subject population, as there were no adverse events related to medication during this study. Varenicline was no more effective than placebo for abstinence from cocaine. Treatment with varenicline was associated with a reduced number of cigarettes smoked per day, even though subjects received only a brief education for smoking cessation. The self-report reduction in smoking was corroborated by CO levels and the Fagerström Test of Nicotine Dependence. However, self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group, although this appears to be due to randomization differences related to lifetime depression diagnosis. These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone.

Progesterone effects on cocaine use in male cocaine users maintained on methadone: a randomized, double-blind, pilot study.

Previously, the authors reported that progesterone treatment attenuated reports of cocaine-induced high in male and female cocaine users. In this pilot clinical trial, the authors tested the safety and efficacy of oral progesterone as a treatment for cocaine dependence in methadone-stabilized male cocaine users. This was a 10-week, randomized, double-blind, placebo-controlled trial. Forty-five male methadone-stabilized cocaine users were randomized to receive placebo (n=15) or progesterone (n=30) for 9 weeks. The progesterone dose was gradually increased from 100 mg to 300 mg twice daily by Week 4 and maintained through Week 10. Treatment retention for the clinical trial was 80%, without significant group differences (log rank=2.4, p=.12). Hierarchical linear modeling estimates of obtaining a cocaine positive urine result across 10 weeks showed a very slight reduction in cocaine use for the progesterone group (Z=-2.89, p<.004). The placebo group showed a slight increase in cocaine use from Week 1 to Week 10 (Z=2.72, p<.007). These slopes significantly differed from each other (Z=-3.83, p<.0001). Overall, the placebo group showed significantly lower probability of having a cocaine positive urine result at treatments end (Weeks 9 and 10) compared with the progesterone group (0.60 vs. 0.73; U=4837, p<.04). These preliminary findings do not support the efficacy of progesterone in male cocaine users. The efficacy of progesterone in female cocaine users remains to be determined in future studies.

Behavioral effects of gamma-hydroxybutyrate in humans.

Despite the therapeutic use and abuse potential of γ-hydroxybutyrate (GHB or Xyrem), relatively few studies have examined the behavioral effects of GHB in humans under controlled laboratory conditions. Thus, this eight-session study examined in 10 nonsubstance-abusing volunteers the behavioral effects of GHB at each of the following doses: 0, 0.32, 0.56, 0.75, 1.0, 1.8, 2.4, 3.2 g/70 kg, orally. Order of dose testing was random, except that the first two participants received active doses in ascending order and 2.4 g/70 kg was always tested before 3.2 g/70 kg. Before drug administration and at several postdrug time points, self-report, observer report, physiological, and psychomotor performance measures were obtained. Analyses based on area under the curve showed that GHB produced dose-related increases in subjective ratings of sedative-like, stimulant-like, positive mood, and dissociative effects, but no changes in psychomotor performance measures or blood pressure. Analyses based on peak effects generally showed dose-related increases in ratings indicating sedative-like, dissociative, and drug liking, although some measures showed U-shaped dose-related changes. These initial findings suggest that GHB at doses of 0.32–3.2 g/70 kg produces dissociative, sedating and some stimulant-like effects in humans without a history of sedative abuse.

Clinical Efficacy of Citalopram Alone or Augmented with Bupropion in Methadone-Stabilized Patients

Despite the success of opiate-agonist therapies such as methadone for the treatment of opiate addiction, treatment response is not complete. This study evaluates the efficacy of citalopram augmented with bupropion in the treatment of illicit opiate use in a methadone-stabilized population. We conducted a 12-week randomized, double-blind, outpatient clinical trial in which 60 subjects were randomized into one of three treatment groups: placebo, citalopram (40 mg/day) plus placebo, or citalopram (40 mg/day) plus bupropion (50 mg/day). The results indicate that neither citalopram nor citalopram augmented with bupropion were more effective than placebo in the treatment of opioid abuse.

Carvedilol does not reduce cocaine use in methadone-maintained cocaine users

INTRODUCTION The goal of this study was too test the efficacy of carvedilol (CAR), an adrenergic blocker, for reducing cocaine use in individuals with cocaine use disorder (CUD). We conducted a 17-week, double-blind, randomized controlled trial with 3 treatment arms: 25mg CAR, 50mg CAR, and placebo. METHODS One hundred and six treatment-seeking opioid and cocaine-dependent participants, who were also maintained on methadone during study participation, were randomized to placebo (n=34), 25mg/day CAR (n=37) or 50mg/day CAR (n=35). The main outcome measures were cocaine and opioid use as assessed by urine drug screening and self-reported drug use. RESULTS No significant group differences were found for treatment retention with 56% of the placebo, 76% of the 25mg and 66% of the 50mg CAR groups (p>0.05) completing treatment. The percentage (SD) of cocaine positive urines during the trial showed an overall treatment effect: 59.2 (38.9) for the placebo, 50.8 (33.8) for the 25mg and 75.1 (33.2) for the 50mg CAR group. In post hoc comparisons, neither the 25 nor 50mg CAR condition differed significantly from the placebo; however, the 25mg CAR group had a significantly lower proportion of cocaine-positive urines than the 50mg group. No significant group differences were found for the percentage of self-reported days of cocaine abstinence during the trial: 72.9 (25.3) for placebo, 72.9 (29) for CAR 25mg, and 59.3 (31.7) for CAR 50mg. Significant groups differences in the proportion of opioid positive urines submitted were not observed (p>0.05). Baseline cocaine withdrawal severity did not predict treatment response (p>0.05). CONCLUSIONS These findings did not support the efficacy of CAR for the treatment of cocaine use in cocaine and opioid dependent participants maintained on methadone. Further, CAR doses >25mg should not be used to avoid possible increases in cocaine and opioid use.