A clinical trial of the ghrelin receptor blocker PF-5190457 in 42 people with alcohol use disorder found no reduction in alcohol craving, but participants selected fewer calories in a virtual food environment.
P=0.04 for calorie reductionThe only significant finding — GHSR blockade reduced virtual calorie selection, while alcohol craving and brain activation were unaffected
What the researchers found
In this Phase IIa randomized, double-blind, placebo-controlled, within-subject crossover study of 42 individuals with alcohol use disorder (29 completers):
- PF-5190457 (100 mg twice daily) did NOT reduce cue-elicited alcohol craving during a bar-like laboratory experiment
- PF-5190457 did NOT influence neural activation during a cue-reactivity task in the fMRI subset (n=12)
- PF-5190457 DID reduce virtual calories selected in a cafeteria-like virtual reality environment (P=0.04)
The primary hypothesis — that blocking the ghrelin receptor would reduce alcohol craving — was not supported. However, the food-related finding provides human evidence that GHSR blockade influences caloric intake decisions.
Why it matters
Alcohol use disorder is a major public health problem with limited pharmacological treatments. The ghrelin system has been a promising therapeutic target based on strong animal evidence. While this trial's negative result for alcohol craving is disappointing, it provides crucial human data that narrows the path forward — either the ghrelin system's role in human alcohol behavior differs from animal models, or different approaches to targeting it may be needed. The positive food-related finding also highlights the ghrelin-appetite connection as a viable therapeutic direction.
How the study worked
This was a randomized, double-blind, placebo-controlled, within-subject crossover study. Forty-two individuals with alcohol use disorder received PF-5190457 100 mg twice daily or placebo in two counterbalanced stages. Assessments included: (1) an alcohol cue-reactivity experiment in a bar-like laboratory setting measuring craving; (2) a virtual food choice experiment in a cafeteria-like virtual reality environment measuring calorie selection; and (3) for a subset of 12 participants, a cue-reactivity task during functional MRI to measure brain activation patterns. The trial was registered on ClinicalTrials.gov (NCT02707055).
What this study cannot tell us
The sample size was modest (42 enrolled, only 29 completers), limiting statistical power to detect smaller effects. The within-subject crossover design, while reducing individual variability, may introduce carryover effects. The fMRI subset was very small (n=12). Cue-reactivity in a laboratory setting may not reflect real-world alcohol craving or consumption. The study measured craving rather than actual drinking behavior. PF-5190457 is an inverse agonist/competitive antagonist — different ghrelin receptor targeting strategies might yield different results.
How to read the evidence
This is a Phase IIa randomized, double-blind, placebo-controlled clinical trial — a rigorous study design. However, the small sample size (29 completers), surrogate endpoints (craving and virtual food choice rather than drinking behavior), and primarily negative results limit the clinical impact. The evidence is early-phase clinical, with moderate methodological quality.
When this study was published
Published in 2024, this is one of the most recent clinical studies targeting the ghrelin system for alcohol use disorder. It represents the current frontier of translating ghrelin research from animal models to human therapeutics.
The bigger picture
Ghrelin is a 28-amino-acid peptide hormone that links appetite, reward, and metabolic regulation. While animal studies consistently show that blocking ghrelin signaling reduces alcohol consumption, this is one of the first rigorous human trials testing this approach — and the results suggest the translation from animal models to humans may not be straightforward for alcohol outcomes. The food-related finding adds to the evidence supporting ghrelin system targeting for obesity and eating-related disorders, an area where GLP-1 agonists have already achieved clinical success.
Questions still open
- Would a longer treatment period with GHSR blockade show effects on actual alcohol consumption rather than just cue-elicited craving?
- Could combining ghrelin receptor blockade with other pharmacotherapies for alcohol use disorder produce synergistic effects?
- Does the calorie reduction finding support developing GHSR blockers as appetite-modifying drugs for obesity?
Common questions
What is ghrelin and why might it affect alcohol behavior?
Why did the drug affect food choices but not alcohol craving?
Read the original research
A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder.
JCI insight, 9(24)
Citation
Faulkner, Monica L; Farokhnia, Mehdi; Lee, Mary R; Farinelli, Lisa; Browning, Brittney D; Abshire, Kelly; Daurio, Allison M; Munjal, Vikas; Deschaine, Sara L; Boukabara, Selim R; Fortney, Christopher; Sherman, Garrick; Schwandt, Melanie; Akhlaghi, Fatemeh; Momenan, Reza; Ross, Thomas J; Persky, Susan; Leggio, Lorenzo. (2024). A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder.. JCI insight, 9(24). https://doi.org/10.1172/jci.insight.182331