Alcohol use disorder (AUD) remains a major public health problem, affecting an estimated 400 million individuals over age 15 worldwide, yet fewer than 3% of those with AUD receive medication-assisted treatment. Repurposing drugs already approved by regulatory authorities is a pragmatic strategy to accelerate development of novel pharmacotherapies for AUD. The nicotinic partial agonist varenicline, approved for smoking cessation, has clinical evidence for reducing alcohol craving and producing modest reductions in alcohol consumption. The muscarinic M1/M4-preferring agonist xanomeline, recently approved for schizophrenia when combined with the peripherally restricted muscarinic antagonist trospium (Cobenfy™), has shown the ability to attenuate cocaine self-administration in preclinical models. Given xanomeline’s central M1/M4 stimulation, it was hypothesized that xanomeline might reduce alcohol drinking, but peripherally mediated adverse effects could limit dosing.
The study used six adult male cynomolgus monkeys (Macaca fascicularis) with approximately three years of prior ethanol self-administration experience. Animals had access to ethanol 22 hours per day, five days per week. Food pellets were available under the same self-administration contingencies during the first five hours of the daily session. The abstract reports that ethanol intakes were stabilized prior to pharmacological interventions, but it does not provide baseline intake values, individual subject data, or detailed behavioral metrics in the abstract.
Three pharmacological conditions were tested using intramuscular (IM) administration twice daily:
The abstract specifies these dose ranges and the twice-daily IM route but does not report dose–response curves, plasma concentrations, or exact dosing schedules across study phases.
Administration of varenicline reduced ethanol intake in one of the six monkeys without producing moderate-to-severe adverse effects in that animal. The abstract does not report the magnitude or statistical significance of the reduction, the dose at which the effect occurred, or whether any animals experienced tolerability issues with varenicline at the tested doses.
When administered alone, xanomeline reduced ethanol intake in one of six monkeys and did so without moderate-to-severe adverse effects in that individual. As with varenicline, the abstract does not provide quantitative reductions, responder characteristics, or details on side effects observed at specific xanomeline doses within the 0.3–1.0 mg/kg range.
Co-administration of xanomeline with the peripherally restricted muscarinic antagonist trospium allowed administration of higher xanomeline doses (0.56–1.7 mg/kg) without the adverse effects that limited dosing when xanomeline was given alone. Under the xanomeline-plus-trospium condition, ethanol intake decreased in three of four monkeys tested. The abstract indicates that trospium mitigated peripherally mediated adverse effects and thereby improved tolerability and therapeutic opportunity for xanomeline, but it does not enumerate the specific adverse effects that were prevented nor provide detailed safety data or statistical analyses.
The results suggest that stimulation of acetylcholine receptors can reduce ethanol self-administration in a subset of subjects with long-term ethanol drinking history. The partial nicotinic agonist varenicline and the muscarinic-preferring agonist xanomeline each produced reductions in ethanol intake in some animals, but broader efficacy at tolerable doses was limited by peripherally mediated adverse effects for xanomeline. Combining xanomeline with the peripherally acting muscarinic antagonist trospium permitted higher central xanomeline dosing and was associated with ethanol intake decreases in a larger proportion of animals tested under that regimen. These findings support further exploration of acetylcholine receptor–targeting agents for AUD, particularly strategies that preserve central efficacy while minimizing peripheral side effects.
The abstract reports group sizes, dose ranges, administration route, and broad outcomes but omits several details important for clinical translation and full evaluation:
Because the full text is available via the journal link, readers interested in detailed methods, full safety data, and quantitative efficacy outcomes should consult the complete article for comprehensive results and analyses.
In this nonhuman primate model of chronic ethanol self-administration, acetylcholine receptor agonists demonstrated the capacity to reduce drinking in some subjects. The combination of xanomeline with the peripheral muscarinic antagonist trospium improved tolerability and increased the proportion of animals showing reduced ethanol intake. These preclinical data identify muscarinic agonists and dual strategies to limit peripheral adverse effects as promising directions for AUD pharmacotherapy development, while underscoring the need for detailed safety, dose–response, and translational studies.