Blocking CB1 receptors in the gut reduces alcohol drinking through a ghrelin-hunger hormone pathway
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Peripheral CB1 blocker reduced alcohol drinking via gut ghrelin pathway, not brain
- Evidence Grade:
- Preliminary: elegant mechanistic mouse study with multiple knockout controls, but no human data.
- Study Age:
- Published in 2019 in Cell Metabolism.
- Original Title:
- Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.
- Published In:
- Cell metabolism, 29(6), 1320-1333.e8 (2019)
- Authors:
- Godlewski, Grzegorz, Cinar, Resat(3), Coffey, Nathan J(2), 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
- Database ID:
- RTHC-02049
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked 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.
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Cite This Study
https://rethinkthc.com/research/RTHC-02049APA
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
MLA
Godlewski, Grzegorz, et al. "Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.." Cell metabolism, 2019. https://doi.org/10.1016/j.cmet.2019.04.012
RethinkTHC
RethinkTHC Research Database. "Targeting Peripheral CB1 Receptors Reduces Ethanol Intake vi..." RTHC-02049. Retrieved from https://rethinkthc.com/research/godlewski-2019-targeting-peripheral-cb1-receptors
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.