A novel CB1 receptor neutral antagonist (AM4113) suppressed binge-like alcohol drinking and reduced alcohol-triggered dopamine release in mice without causing the depression and anxiety linked to previous CB1 blockers.
Read this if you are interested in how the endocannabinoid system relates to alcohol use and potential new treatments for binge drinking.
Reduced binge drinking without affecting body weight, activity, or taste preferences
What the researchers found
Previous CB1 receptor blockers like rimonabant were effective against obesity and nicotine addiction but were withdrawn because they caused depression and suicidal ideation. Researchers tested AM4113, a "neutral antagonist" that blocks the CB1 receptor without producing the inverse agonist effects believed to cause psychiatric side effects.
AM4113 suppressed binge-like alcohol consumption in mice using a drinking-in-the-dark model. Importantly, it did so without affecting body weight, general activity levels, or preference for sweet and bitter tastes, indicating the reduction was specific to alcohol rather than a general appetite or motivation suppression.
The compound also reduced alcohol-induced dopamine release in the nucleus accumbens, a brain region central to reward and addiction. This suggests the endocannabinoid system plays a direct role in regulating how alcohol activates the brain's reward circuitry, and that blocking this pathway can reduce binge drinking without the dangerous psychiatric side effects of earlier compounds.
Why it matters
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 numbers in context
AM4113 had slower brain elimination than plasma elimination. Suppressed ethanol consumption and preference. No significant effects on body weight, ambulatory activity, saccharin/quinine preference, or ethanol metabolism. Reduced ethanol-induced dopamine release in nucleus accumbens.
How the study worked
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.
What this study cannot tell us
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.
How to read the evidence
This is an animal pharmacology study providing preliminary evidence for a new therapeutic approach to binge drinking through the endocannabinoid system.
When this study was published
Published in 2018. Neutral CB1 antagonists continue to be explored for addiction applications.
The bigger picture
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.
Questions still open
- Will neutral CB1 antagonists prove safe in human psychiatric terms where inverse agonists did not? Could this approach be combined with other addiction treatments? Does the endocannabinoid system play a similar role in binge drinking across different populations?
Common questions
How does the endocannabinoid system relate to alcohol?
Why not just use the old CB1 blockers?
Read the original research
Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling.
Neuropharmacology, 131, 200-208
Citation
Balla, Andrea; Dong, Bin; Shilpa, Borehalli M; Vemuri, Kiran; Makriyannis, Alexandros; Pandey, Subhash C; Sershen, Henry; Suckow, Raymond F; Vinod, K Yaragudri. (2018). Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling.. Neuropharmacology, 131, 200-208. https://doi.org/10.1016/j.neuropharm.2017.10.040
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