Background There is a need to identify novel pharmacological targets to treat alcoholism. Animal and human studies suggest a role of ghrelin in the neurobiology of alcohol dependence and craving. Here, we were the first to test the hypothesis that intravenous administration of exogenous ghrelin acutely increases alcohol craving. Methods This was a double-blind placebo-controlled human laboratory proof-of-concept study. Non-treatment seeking alcohol-dependent heavy drinking individuals were randomized to receive intravenous ghrelin 1mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cuereactivity procedure, during which participants were exposed to neutral (juice) and alcohol cues. The primary outcome variable was the increase in alcohol craving (also called “urge”) for alcohol, assessed by the Alcohol Visual Analogue Scale. Results Out of 103 screenings, 45 individuals received the study drug. Repeated measures of ANCOVA revealed a group effect across ghrelin doses in increasing alcohol craving (p < .05). A dose-specific examination revealed a significant effect of ghrelin 3 mcg/kg vs. placebo in increasing alcohol craving (p < .05) with a large effect size (d = .94). By contrast, no significant ghrelin effect was found in increasing either urge to drink juice or food craving (p: n.s.). No significant differences in side effects were found (p: n.s.). Conclusions Intravenous administration of exogenous ghrelin increased alcohol craving in alcohol-dependent heavy drinking individuals. Although the small sample requires confirmatory studies, these findings provide preliminary evidence that ghrelin may play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacological target for treatment.
Preclinical and clinical studies show that the GABAB receptor agonist baclofen may represent a pharmacotherapy for alcohol dependence (AD). However, the mechanisms by which baclofen affects drinking are not well characterized; thus this pilot study investigated possible baclofen’s biobehavioral mechanisms. The design was a double-blind controlled randomized human laboratory pilot study. Fourteen non-treatment seeking alcohol-dependent heavy drinking subjects received either baclofen 10 mg t.i.d. or an active placebo (cyproheptadine 2 mg t.i.d., to control for sedation) for a 7-day period. At day 8, participants performed an alcohol cue-reactivity (CR) followed by an alcohol self-administration (ASA). Additionally, we explored possible moderators that might guide future larger studies, i.e. anxiety, family history and onset of alcoholism, and D4 dopamine receptor (DRD4) and 5-HTTLPR polymorphisms. The main results were a significant effect of baclofen for increasing stimulation (p=.001) and sedation (p<.01). Furthermore, when drinking during the ASA and the 2 days before was analyzed as a composite variable, there was a significant effect of baclofen to reduce alcohol consumption (p<.01). As for the exploratory analyses, baclofen’s effects to increase alcohol sedation and to reduce alcohol consumption were limited to those individuals with DRD4 ≥7 repeats (DRD4L). Yet, baclofen’s effects on alcohol consumption were also moderated by 5-HTTLPR LL genotype. In conclusion, baclofen’s ability to reduce alcohol drinking may be related to its effects on the biphasic effects of alcohol, but larger studies are needed to confirm these preliminary findings.
Background One hypothesis suggests that the differential response to ondansetron and serotonin specific re-uptake inhibitors (SSRIs) may be due to a functional polymorphism of the 5′-HTTLPR promoter region in SLC6A4, the gene that codes for the serotonin transporter (5-HTT). The LL 5′-HTTLPR genotype is postulated to be specifically sensitive to the effects of ondansetron with SS/SL 5′-HTTLPR genotypes sensitive to SSRIs. This study tests this hypothesis by matching non-treatment seeking alcohol dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mis-matching them assessing naturalistic and bar-laboratory alcohol drinking. Methods Seventy-seven AD individuals were randomized to one of two counterbalanced arms to receive sertraline 200mg/day or ondansetron 0.5 mg/day for three weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for three weeks followed by a second ASAE. Individuals then received the alternate drug for three weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in SDUs) for 7 days prior to each ASAE and milliliters consumed during each ASAE were the primary outcomes. Results Fifty-five participants completed the study. The genotype x order interaction was significant [F(1,47) = 8.42, p = .006] for DDD. Three ANCOVAs were conducted for DDD during the week before each ASAE. Ondansetron compared to sertraline resulted in a significant reduction in DDD during the week before the first [F(1,47) = 7.64, p = .008] but not the third ASAE. There was no difference in milliliters consumed during each ASAE. Conclusion This study modestly supports the hypothesis that ondansetron may reduce DDD in AD individuals with the LL genotype as measured naturalistically. By contrast there was no support that ondansetron reduces drinking during the ASAEs or that sertraline reduces alcohol use in individuals who have SS/SL genotypes. We provide limited support that ondansetron may reduce drinking in non-treatment seeking individuals with the LL genotype.
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