Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals.

Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg-1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen's d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.

The role of sex in daily levels of high-risk alcohol and cannabis co-use.

Background: Co-use of alcohol and cannabis is highly prevalent and may be associated with negative outcomes. The intersection between alcohol and cannabis use remains poorly understood. The present study assessed this intersection and the moderating effects of sex on the daily levels of high-risk alcohol and cannabis co-use. Methods: A secondary analysis of an experimental pharmacology study specifically designed to recruit individuals using both alcohol and cannabis was conducted. Thirty-three non-treatment seeking subjects (19 M/14F) reporting high-risk levels of alcohol and cannabis use completed a 30-day Timeline Follow-back (TLFB) assessment for alcohol and cannabis use, resulting in a total of N = 990 observations. Logistic models tested the probability of same day cannabis use as predicted by alcohol use (any use, total drinking, and binge drinking), sex, and alcohol use by sex interactions. Results: Drinking any alcohol on a given day was associated with a significant increase in the likelihood of same-day cannabis use (b = 0.61, p = 0.001) as was amount of alcohol consumed on a given day (b = 0.083, p = 0.012). These relations were significantly moderated by sex (b = 1.58, p<0.001; b = 0.14, p = 0.044). Male-identifying individuals demonstrated an increased probability of concurrent cannabis use with any alcohol use on a given day, and this relationship increased linearly as the number of drinks consumed increased. Conclusions: The present study investigated the patterns associated with co-using alcohol and cannabis in individuals reporting high-risk levels of both alcohol and cannabis use. The sex-dependent findings suggest that males are at higher risk for co-using alcohol and cannabis compared with females.