The effect of glucagon-like peptide-1 (GLP-1) receptor agonists on substance use disorder (SUD)-related behavioural effects of drugs and alcohol: A systematic review

Abstract

Glucagon-like-peptide-1 (GLP-1)-receptor agonists have been proposed as putative treatment for substance use disorders (SUD). The objective of this systematic review is to characterize the effects of GLP-1-receptor agonists on SUD-related behavioural effects of drugs, nicotine, and alcohol.The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A search was performed in PubMed and EMBASE on June 16, 2018. The inclusion criteria were primary studies investigating the use of GLP-1-receptor agonists on behavioural endpoints related to SUD.Seventeen studies were included, investigating the effect of the GLP-1-receptor agonists exendin-4, fluoro-exendin-4, liraglutide, AC3174 and GLP-1 (7-36) on SUD-related behavioural effects of ethanol, cocaine, amphetamine, and/or nicotine. All studies used rodents as subjects. Nine of the studies dealt with ethanol, six with cocaine, two with amphetamine, and two with nicotine. Most studies investigated acute treatment effects, finding a significant effect in all but one experiment. A few studies investigated more chronic effects, but only on ethanol. All the studies reported sustained effects. Eleven studies tested more than one dose, finding a dose-related response in ten out of thirteen experiments. Six studies report a central effect through intracerebral administration or by using mice in which the central GLP-1-receptors had been inactivated. In conclusion, a solid body of evidence documents acute effects of GLP-1-receptor agonist treatment on behavioural effects of alcohol, nicotine, amphetamine and cocaine. Documentation of effect of more chronic GLP-1-receptor stimulation on these behaviours is limited.

Use of GLP‐1 receptor agonists and subsequent risk of alcohol‐related events. A nationwide register‐based cohort and self‐controlled case series study

“…Data in abstract format reported that liraglutide treatment reduces alcohol intake in patients with diabetes 27 . Thus, most evidence of an effect of GLP‐1 receptor agonists on alcohol consumption is based on rodent studies 16 and studies in velvet monkeys, 28 all showing that GLP‐1 receptor agonists reduce intake of alcohol. The present study was based on the hypothesis that GLP‐1 receptor agonists attenuate the ability of alcohol to activate the mesolimbic dopamine system, and through this decreases the motivation for alcohol consumption 29,30 .…”

“…Thus, it is possible that the effect that is either only observed in the initial treatment phase, that is, 3 months or is caused by GLP‐1 receptor agonist‐related adverse events is due to unspecified factors, for example, more frequent contact to doctors, healthy life style advice or other lifestyle choices during this specific period of time. Most previous experimental studies have examined potential acute effects of GLP‐1 receptor agonists, while evidence on chronic or subchronic use of GLP‐1 receptor agonists and alcohol use is sparse 16 . It is thus possible that only acute but not chronic use of GLP‐1 receptor agonists affect alcohol consumption.…”

“…[12][13][14] To date, the GLP-1 receptor agonists liraglutide and semaglutide are approved for treating obesity. 15 Studies on the effect of GLP-1 receptor agonists on alcohol addiction have reported reduction in alcohol drinking behaviour in rodents and monkeys, 9,16 and polymorphisms in the GLP-1 receptor gene have been associated with alcohol use disorders. 17 However, to date, no published studies on humans have examined the potential association between GLP-1 receptor agonists and alcohol use disorders.…”

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

“…In support of this hypothesis, several studies have reported expression of GLP-1 receptors in brain areas associated with reward and addiction ( 6 , 9 – 16 ). Furthermore, treatment with GLP-1 receptor agonists reduce alcohol intake and decrease relapse-like alcohol drinking in nonhuman primates ( 17 ) and rodents ( 18 ). In humans, a recent study reported that the GLP-1 receptor 168Ser allele variant was associated with increased alcohol intake in humans ( 19 ).…”

Treatment of Type 2 Diabetes and Obesity on the Basis of the Incretin System: The 2021 Banting Medal for Scientific Achievement Award Lecture

“…Importantly, GLP-1 has effects on the reward system ( 67 ). If overeating in obesity is viewed as a disturbance of appetite regulation, related to other forms of abuse, the GLP-1RAs might also be useful in other forms of abuse ( 68 ), and this is currently being investigated.…”