Dual-action drugs targeting cannabinoid and PPAR receptors reduced binge eating in rats | Research

The takeaway

In female rats with binge eating behavior, two dual-target drugs acting on CB1 cannabinoid and PPAR receptors successfully reduced compulsive palatable food consumption and restored disrupted hormonal and brain signaling.

Researchers and readers interested in the endocannabinoid system's role in appetite and eating disorders.

Two dual-target drugs reduced binge eating while restoring disrupted hypothalamic signaling

What the researchers found

OLHHA (CB1 antagonist/PPAR-alpha agonist) at 0.3 mg/kg and OLS (PPAR-alpha/TRPV1 agonist) at 6 mg/kg reduced aberrant palatable food consumption during binge eating tests. These treatments also partly restored disrupted leptin, opioid, and cannabinoid signaling in the hypothalamus and normalized POMC/AgRP/NPY pathways.

Why it matters

Binge eating disorder lacks effective pharmacological treatments. This study shows that drugs targeting both the endocannabinoid system and PPAR receptors can reduce binge eating behavior while correcting underlying neurochemical disruptions, suggesting a promising dual-target approach.

The numbers in context

OLHHA at 0.3 mg/kg and OLS at 6 mg/kg significantly reduced palatable food consumption during binge tests. Binge eating rats showed altered hypothalamus-pituitary axis activation with changes in leptin, opioid, and cannabinoid signaling and disrupted POMC/AgRP/NPY pathways.

How the study worked

Female rats underwent intermittent cycles of food restriction and frustration stress to induce binge eating behavior. Researchers measured plasma hormones, biochemical mediators, and gene/protein expression in the hypothalamus. Three dual-target drugs were tested: NF10-360 (dual PPAR-alpha/gamma agonist), OLS (PPAR-alpha/TRPV1 agonist), and OLHHA (CB1 antagonist/PPAR-alpha agonist).

What this study cannot tell us

This is a rat model that uses stress-induced binge eating, which may not fully capture human binge eating disorder. Only female rats were studied. The treatments were given acutely, so long-term effects and safety are unknown.

How to read the evidence

Animal study in female rats using an established binge eating model with biochemical and behavioral outcomes.

When this study was published

Published in 2025.

The bigger picture

Previous attempts to treat eating disorders by blocking CB1 receptors alone (rimonabant) failed due to psychiatric side effects. The dual-target approach, combining CB1 modulation with PPAR activation, may offer a way to get the appetite-suppressing benefits while avoiding the mood side effects that doomed single-target drugs.

Questions still open

Would these dual-target drugs avoid the psychiatric side effects that plagued rimonabant? Do the same hypothalamic disruptions occur in humans with binge eating disorder? Could these drugs work for other eating disorders beyond binge eating?

Common questions

Why target two receptor systems at once?

Blocking CB1 cannabinoid receptors alone (as rimonabant did) reduced appetite but caused serious psychiatric side effects. Combining CB1 modulation with PPAR receptor activation may provide appetite control while avoiding those problems.

What is binge eating disorder?

It is characterized by recurrent episodes of eating large amounts of palatable food in short periods, often triggered by stress, with feelings of loss of control. It affects approximately 2-3% of the population.

Read the original research

Targeting the endocannabinoid/paracannabinoid systems in binge eating behavior: Efficacy of dual ligands in a preclinical model.

Pharmacological research, 222, 108005

View on PubMed ↗Publisher’s paper ↗

Citation

de Ceglia, Marialuisa; Botticelli, Luca; Micioni Di Bonaventura, Emanuela; Vargas Fuentes, Antonio; Micioni Di Bonaventura, Maria Vittoria; Rodriguez de Fonseca, Fernando; Cifani, Carlo. (2025). Targeting the endocannabinoid/paracannabinoid systems in binge eating behavior: Efficacy of dual ligands in a preclinical model.. Pharmacological research, 222, 108005. https://doi.org/10.1016/j.phrs.2025.108005