A New Potential Therapeutic Approach for Alcoholism: MCH11

A study evaluated the new selective MAGL inhibitor (monoacylglycerol lipase inhibitor) MCH11 in mice, showing that the compound reduces ethanol consumption and motivation to drink, in addition to exhibiting anxiolytic effects similar to those of antidepressants. The results highlight a crucial point for treatment development: the efficacy of MCH11 revealed marked sex-dependent differences, indicating that sex is a fundamental biological variable in therapeutic response.

Alcohol Use Disorder (AUD) is a condition that affects approximately 2.6 million people worldwide each year and has relapse rates of around 70% within the first year, even with pharmacological treatment.¹ ² In this context of limited effectiveness of current treatment options, the endocannabinoid system (ECS) has been explored as a target for new interventions.³

The study in focus evaluated MCH11 in mice—a novel MAGL inhibitor, the main enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG).⁴ Regarding alcohol use, MCH11 reduced both voluntary ethanol consumption and motivation to drink, but with pronounced differences between males and females. In males, all doses tested (10, 20, and 40 mg/kg) dose-dependently reduced ethanol intake and preference over 29 days, with a faster effect at the 40 mg/kg dose. In females, the initial doses were insufficient, and only after increasing the dose to 60 mg/kg (from day 20 onward) was a significant reduction in consumption observed—possibly in part due to higher baseline ethanol intake (8–9 g/kg in females versus 5–6 g/kg in males).

From a behavioral perspective, MCH11 showed an antidepressant-like profile in males. Importantly, acute treatment did not impair locomotion or performance in cognitive tasks, suggesting the absence of relevant sedation or cognitive impairment.

The study also explored the combination of MCH11 with topiramate (MCH11 + TOP), a drug already used in AUD. In males, the combined therapy reduced ethanol consumption more robustly than either drug alone. In females, topiramate alone and the combination were more effective than MCH11 alone, with the additional benefit of the combination being more modest than in males.

At the molecular level, the study showed that chronic ethanol consumption induced sex-dependent changes in the expression of genes related to the dopaminergic, opioid, and endocannabinoid systems (Th, Oprm1, Cnr1, Cnr2) in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). MCH11 reversed most of these changes in males at lower doses, whereas in females only the highest dose (60 mg/kg) was partially effective and did not fully normalize genes such as Oprm1 and Cnr2. In contrast, the MCH11 + TOP combination increased Cnr2 gene expression in the NAc in both sexes, with an approximately twofold greater effect in females, suggesting this gene as a possible key mediator of the combined action.

Taken together, these preclinical findings support MAGL inhibition via MCH11 as a promising strategy to reduce alcohol consumption and motivation to drink, with additional effects on mood and impulsivity. At the same time, they demonstrate that treatment sensitivity, effective doses, and molecular mechanisms differ significantly between males and females. The study reinforces the need to systematically incorporate sex as a fundamental biological variable in the development of future therapies for alcoholism, especially in approaches targeting the endocannabinoid system.

References

1. P. Bach, J. Franck, J. Hallgren, H. Widing, M. Gissler, J. Westman, Pharmacological treatments in alcohol use disorder and risk of Alcohol-Related hospitalizations: a register study, Acta Psychiatr. Scand. (2025), https://doi.org/10.1111/ acps.13802.
2. P. Le, J.J. Rich, E.Y. Bernstein, J. Glass, H. Gasoyan, S.E. Back, et al., Disparities in treatment for alcohol use disorder among all of us participants, Am. J. Psychiatry 181 (11) (2024) 973–987, https://doi.org/10.1176/appi.ajp.20230730.
3. M.S. Garcia-Gutierrez, F. Navarrete, A. Gasparyan, D. Navarro, A. Morcuende,T. Femenia, et al., Role of cannabinoid CB2 receptor in alcohol use disorders: from animal to human studies, Int J. Mol. Sci. 23 (11) (2022), https://doi.org/10.3390/ ijms23115908.
4. Torregrosa, A. B., García-Gutiérrez, M. S., Navarro, D., Navarrete, F., & Manzanares, J. (2025). MCH11, a new monoacylglycerol lipase inhibitor, reduces ethanol consumption and motivation to drink in mice, with sex-dependent differences. Biomedicine & pharmacotherapy, 192, 118662. https://doi.org/10.1016/j.biopha.2025.118662