Intravenous ghrelin administration increases alcohol craving in alcohol-dependent heavy drinkers: a preliminary investigation

Abstract

Background: There is a need to identify novel pharmacologic targets to treat alcoholism. Animal and human studies suggest a role for 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. Nontreatment-seeking, alcohol-dependent, heavy-drinking individuals were randomized to receive intravenous ghrelin 1 mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cue-reactivity 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 analysis of covariance 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 versus 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 = ns). No significant differences in side effects were found (p = ns).

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 pharmacologic target for treatment.

Trial registration: ClinicalTrials.gov NCT01190085.

Keywords: Alcoholism; craving; cue-reactivity; feeding peptides; ghrelin; neuroendocrinology.

Conflict of interest statement

Financial Disclosures

All authors report no biomedical financial interests or potential conflicts of interest.

Published by Elsevier Inc.

Figures

Figure 1

(A) Increase in alcohol urge by dose, expressed as its increase compared to the baseline (predrug) value of the Alcohol-Visual Analogue Scale (dA-VAS). Repeated measures ANCOVA indicated that ghrelin dose was statistically related to alcohol urge increase [F(2,40) = 3.36, p = .045], and Bonferroni-corrected pairwise comparisons revealed that alcohol urge was significantly greater for ghrelin 3 mcg/kg than placebo (p = .046). The effect size for the increase in alcohol urge for ghrelin 3 mcg/kg versus placebo was large (d = 0.94). (B) Increase in juice urge by dose, expressed as its increase compared to the baseline (pre-drug) value of the Juice-Visual Analogue Scale (dJ-VAS). Repeated measures ANCOVA indicated that ghrelin dose was not statistically related to juice urge increase [F(2,40) = 1.16, p = .32].

Figure 2

Total serum ghrelin levels in the three study groups measured at baseline (−15 min), and then after the first juice trial (+6 min), first alcohol trial (+17 min), second juice trial (+23 min), second alcohol trial (+29 min) and after the experiment (+48). There was a pronounced main effect for dose administered [F(2,39) = 88.06.7, p

Figure 3

Serum total ghrelin level was correlated with the increase in alcohol urge measured by the increase in the Alcohol-Visual Analogue Scale (dA-VAS) during both the first (p = .008; Figure 3A) and the second (p = .005; Figure 3B) alcohol cue trials. The maximum serum total ghrelin peak level across the six measurements was correlated with the increase in alcohol urge both in the first (p = .02; Figure 3C) and the second (p = .04; Figure 3D) alcohol cue trials.