A CB1 receptor blocker that avoided psychiatric side effects reduced binge drinking in mice

Researchers examined the pharmacokinetics of AM4113 in mice (brain and plasma distribution) and tested its effects on binge-like ethanol consumption using a two-bottle choice drinking-in-dark paradigm in C57BL/6J mice. Specificity was assessed by measuring effects on body weight, locomotor activity, taste preferences, and ethanol metabolism. Microdialysis measured dopamine release in the nucleus accumbens during ethanol consumption.

Binge drinking causes enormous health and social harm, and effective treatments are limited. The endocannabinoid system represents a promising treatment target, but previous drugs targeting it were pulled due to psychiatric risks. This study suggests a way to retain the therapeutic benefits of CB1 blockade while potentially avoiding the dangerous side effects.

The failure of rimonabant set back endocannabinoid-targeted medicine by a decade. The distinction between inverse agonists (which cause psychiatric side effects) and neutral antagonists (which may not) reopens this therapeutic avenue not just for alcohol use disorder but potentially for obesity, nicotine addiction, and other conditions where the endocannabinoid system plays a role.

This is an animal study, and results may not translate to human binge drinking. The psychiatric safety advantage of neutral antagonists over inverse agonists needs confirmation in human trials. The drinking-in-dark model captures some but not all aspects of human binge drinking. Long-term effects were not assessed.