Blocking CB1 receptors in the gut reduces alcohol drinking through a ghrelin-hunger hormone pathway | Research

The takeaway

A peripheral CB1 receptor blocker reduced alcohol drinking in mice by suppressing the hunger hormone ghrelin in stomach cells, working through vagal nerve signals from gut to brain rather than acting directly in the brain.

People interested in alcohol addiction treatment, gut-brain axis research, and peripheral cannabinoid receptor pharmacology.

Peripheral CB1 blocker reduced alcohol drinking via gut ghrelin pathway, not brain

What the researchers found

The peripheral CB1R inverse agonist JD5037 reduced ethanol drinking in wild-type mice but not in mice lacking CB1R, ghrelin, or the ghrelin receptor. JD5037 inhibited formation of active ghrelin without affecting its inactive precursor. Blocking gastric vagal afferents eliminated the effect.

Why it matters

Previous CB1 receptor blockers (like rimonabant) failed because they acted in the brain and caused psychiatric side effects. This study shows a peripheral-only CB1 blocker can reduce alcohol drinking through a gut-brain pathway, potentially avoiding brain-related side effects entirely.

The numbers in context

JD5037 reduced ethanol drinking in wild-type but not CB1R-/-, ghrelin-/-, or GHS-R1A-/- mice. The drug reduced octanoyl-ghrelin (active form) without affecting desacyl-ghrelin (inactive precursor). Effect eliminated by blocking gastric vagal afferents.

How the study worked

Pharmacological study in multiple mouse strains (wild-type and knockout models lacking CB1R, ghrelin peptide, or GHS-R1A) testing the peripheral CB1R inverse agonist JD5037 on ethanol drinking, with mechanistic investigation of ghrelin production in stomach cells and vagal nerve signaling.

What this study cannot tell us

Mouse model; alcohol drinking behavior in mice may not fully represent human alcoholism. JD5037 has not been tested in humans for this purpose. The relative contribution of this peripheral pathway versus central mechanisms in human alcohol seeking is unknown.

How to read the evidence

Preliminary: elegant mechanistic mouse study with multiple knockout controls, but no human data.

When this study was published

Published in 2019 in Cell Metabolism.

The bigger picture

The gut-brain axis is increasingly recognized as a driver of behavior, and this study provides a specific mechanism: CB1 receptors in stomach cells control active ghrelin production, which signals alcohol-seeking via the vagus nerve. Targeting this pathway could yield alcoholism treatments without the psychiatric risks of brain-penetrating drugs.

Questions still open

Would peripheral CB1 blockers reduce alcohol consumption in humans through this same ghrelin pathway? Could targeting ghrelin directly be simpler than targeting CB1? Does this pathway also apply to other substances or just alcohol?

Common questions

How does the gut affect alcohol cravings?

This study found CB1 receptors in stomach cells control production of active ghrelin (the hunger hormone), which signals alcohol-seeking behavior through the vagus nerve connecting gut to brain. Blocking this pathway in mice reduced drinking.

Could this lead to a new alcoholism treatment?

Potentially. A peripheral-only CB1 blocker could reduce alcohol drinking through the gut without the psychiatric side effects that derailed brain-penetrating drugs like rimonabant. But human trials are needed.

Read the original research

Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.

Cell metabolism, 29(6), 1320-1333.e8

View on PubMed ↗Publisher’s paper ↗

Citation

Godlewski, Grzegorz; Cinar, Resat; Coffey, Nathan J; Liu, Jie; Jourdan, Tony; Mukhopadhyay, Bani; Chedester, Lee; Liu, Ziyi; Osei-Hyiaman, Douglas; Iyer, Malliga R; Park, Joshua K; Smith, Roy G; Iwakura, Hiroshi; Kunos, George. (2019). Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.. Cell metabolism, 29(6), 1320-1333.e8. https://doi.org/10.1016/j.cmet.2019.04.012