The GABA-B agonist baclofen significantly increased blood levels of ghrelin, GLP-1, amylin, and leptin in alcohol-dependent individuals, revealing connections between GABAergic signaling and peptide hormone regulation — though it did not reduce drinking.
4 peptide hormones significantly changedBaclofen simultaneously increased ghrelin (P=0.01), leptin (P=0.01), amylin (P=0.004), and GLP-1 (P=0.02) in alcohol-dependent individuals over one week
What the researchers found
In 34 alcohol-dependent individuals receiving baclofen 30 mg/day vs. placebo for one week in a double-blind crossover:
Outpatient phase (1 week of treatment):
- Acyl-ghrelin significantly increased (P=0.01)
- Leptin significantly increased (P=0.01)
- Amylin significantly increased (P=0.004)
- GLP-1 significantly increased (P=0.02)
Laboratory experiment (alcohol cue-reactivity + self-administration):
- Significant drug × time-point interactions for amylin (P=0.001) and insulin (P=0.03)
- Trend-level interactions for GLP-1 (P=0.06) and ACTH (P=0.10)
- No significant effect on alcohol drinking behavior (P≥0.05)
Prolactin, TSH, growth hormone, cortisol, and ACTH were also measured but showed less consistent changes.
Why it matters
Understanding how the brain's GABA system controls metabolic peptide hormones has implications for both addiction and obesity treatment. The finding that GABA-B activation simultaneously raises ghrelin (appetite-promoting), GLP-1, amylin, and leptin (appetite-suppressing hormones) reveals a complex neuroendocrine response that may explain why some alcoholism treatments affect eating behavior. These shared pathways between alcohol and food reward could inform the development of drugs that treat both conditions simultaneously.
How the study worked
This was a randomized, double-blind, placebo-controlled study. Thirty-four alcohol-dependent individuals received baclofen 30 mg/day or placebo for one week in a naturalistic outpatient setting. They then completed a controlled laboratory experiment including alcohol cue-reactivity, fixed-dose alcohol priming, and self-administration procedures. Blood samples were collected at multiple time points and analyzed for 10 neuroendocrine markers: ghrelin, leptin, amylin, GLP-1, insulin, prolactin, TSH, growth hormone, cortisol, and ACTH.
What this study cannot tell us
The sample size (34) is modest. Baclofen dose (30 mg/day) is on the lower end of doses used in clinical practice, and higher doses might produce different neuroendocrine effects. The one-week treatment period is short. The negative drinking outcome means baclofen's effects on peptide hormones did not translate into reduced alcohol consumption in this study. The simultaneous increase of both appetite-promoting (ghrelin) and appetite-suppressing (GLP-1, amylin, leptin) hormones is paradoxical and difficult to interpret. Causation versus correlation for the peptide changes cannot be established.
How to read the evidence
This is a well-designed randomized, double-blind, placebo-controlled clinical study with 34 participants. The neuroendocrine findings are robust with multiple significant results. However, the primary clinical outcome (drinking behavior) was negative, and the sample size is moderate. Evidence level is moderate for mechanistic insights in a human clinical study.
When this study was published
Published in 2018, this study continues to be relevant for understanding the intersection of GABAergic pharmacology, peptide hormones, and addiction neuroscience.
The bigger picture
This study comes from Lorenzo Leggio's research group at NIH, which has been at the forefront of investigating gut-brain peptide interactions in alcohol use disorder. The same group conducted the ghrelin receptor blocker trial (PF-5190457) also in this database. Together, these studies map out how the brain's reward, stress, and feeding systems are interconnected through peptide hormones — and how pharmacological manipulation of one system (GABA) cascades into changes across multiple peptide pathways. This integrative approach may eventually lead to treatments that simultaneously address addiction, overeating, and stress disorders.
Questions still open
- Why does GABA-B activation simultaneously increase both hunger-promoting (ghrelin) and satiety-promoting (GLP-1, amylin) hormones?
- Would higher baclofen doses or longer treatment duration show effects on both peptide hormones and alcohol consumption?
- Could the neuroendocrine changes caused by baclofen explain weight gain sometimes reported as a side effect of the drug?
Common questions
What is baclofen and why was it tested in alcohol dependence?
Why is it significant that baclofen changed gut hormone levels?
Read the original research
Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment.
Neuropharmacology, 137, 230-239
Citation
Farokhnia, Mehdi; Sheskier, Mikela B; Lee, Mary R; Le, April N; Singley, Erick; Bouhlal, Sofia; Ton, Timmy; Zhao, Zhen; Leggio, Lorenzo. (2018). Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment.. Neuropharmacology, 137, 230-239. https://doi.org/10.1016/j.neuropharm.2018.04.011