---
title: "Acetylcholine Receptor Agonists Reduce Ethanol Self-Administration in Cynomolgus Monkeys: Varenicl"
id: "pubmed-42562046"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42562046"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42562046/"
doi: "10.1016/j.ejphar.2026.179199"
published_at: "2026-09-10T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Acetylcholine Receptor Agonists Reduce Ethanol Self-Administration in Cynomolgus Monkeys: Varenicl
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42562046
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42562046/)
- **DOI:** [10.1016/j.ejphar.2026.179199](https://doi.org/10.1016%2Fj.ejphar.2026.179199)
- **Published At:** 2026-09-10T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Alcohol use disorder (AUD) affects an estimated 400 million people over age 15 worldwide, yet fewer than 3% receive medication-assisted treatment, motivating exploration of repurposed drugs. - The nicotinic partial agonist **varenicline** has prior clinical evidence for reducing alcohol craving and moderately decreasing drinking; the muscarinic M1/M4-preferring agonist **xanomeline** is approved with trospium for schizophrenia and reduces cocaine self-administration in animals. - Six adult male **cynomolgus monkeys** with ~3 years of ethanol self-administration were tested; ethanol access was 22 h/day, 5 days/week, with food pellets available during the first 5 h. - Drugs were given IM twice daily: varenicline (0.03–0.3 mg/kg), xanomeline (0.3–1.0 mg/kg), and xanomeline co-administered with trospium (xanomeline 0.56–1.7 mg/kg plus 0.3 mg/kg trospium). - **Varenicline** and xanomeline alone reduced ethanol intake in only 1 of 6 monkeys without causing moderate-to-severe adverse effects in that animal. - Co-administration of xanomeline with the peripheral muscarinic antagonist **trospium** enabled higher xanomeline doses to be tolerated and decreased ethanol intake in 3 of 4 monkeys tested under that condition. - The findings indicate that **muscarinic agonists** like xanomeline have potential as AUD pharmacotherapies, but peripheral adverse effects limit dosing unless mitigated. - The study supports further investigation of acetylcholine receptor agonists for AUD, with attention to managing peripherally mediated side effects; details about specific adverse effects, statistical outcomes, and individual subject data were not reported in the abstract.
## Clinical Analysis & Structured Key Points
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Epub 2026 Aug 6. # Effects of chronic treatment with acetylcholine receptor agonists on ethanol self-administration in male cynomolgus monkeys [Emily A Cronin](https://pubmed.ncbi.nlm.nih.gov/?term=Cronin+EA&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#full-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Lindsey K Galbo-Thomma](https://pubmed.ncbi.nlm.nih.gov/?term=Galbo-Thomma+LK&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#full-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Phillip M Epperly](https://pubmed.ncbi.nlm.nih.gov/?term=Epperly+PM&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#full-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Bruce E Blough](https://pubmed.ncbi.nlm.nih.gov/?term=Blough+BE&cauthor_id=42562046)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#full-view-affiliation-2 "Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA."), [Antonio Landavazo](https://pubmed.ncbi.nlm.nih.gov/?term=Landavazo+A&cauthor_id=42562046)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#full-view-affiliation-2 "Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA."), [Robert W Gould](https://pubmed.ncbi.nlm.nih.gov/?term=Gould+RW&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#full-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Paul W Czoty](https://pubmed.ncbi.nlm.nih.gov/?term=Czoty+PW&cauthor_id=42562046)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#full-view-affiliation-3 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA. Electronic address: Paul.Czoty@wfusm.edu.") Affiliations Expand ### Affiliations * 1 Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA. * 2 Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA. * 3 Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA. Electronic address: Paul.Czoty@wfusm.edu. * PMID: **42562046** * DOI: [ 10.1016/j.ejphar.2026.179199 ](https://doi.org/10.1016/j.ejphar.2026.179199) Free article Item in Clipboard # Effects of chronic treatment with acetylcholine receptor agonists on ethanol self-administration in male cynomolgus monkeys Emily A Cronin et al. Eur J Pharmacol. 2026. Free article Show details Display options Display options Format Abstract PubMed PMID Eur J Pharmacol Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Eur+J+Pharmacol%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Eur+J+Pharmacol%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) . 2026 Sep 10:1032:179199. doi: 10.1016/j.ejphar.2026.179199. Epub 2026 Aug 6. ### Authors [Emily A Cronin](https://pubmed.ncbi.nlm.nih.gov/?term=Cronin+EA&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#short-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Lindsey K Galbo-Thomma](https://pubmed.ncbi.nlm.nih.gov/?term=Galbo-Thomma+LK&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#short-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Phillip M Epperly](https://pubmed.ncbi.nlm.nih.gov/?term=Epperly+PM&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#short-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Bruce E Blough](https://pubmed.ncbi.nlm.nih.gov/?term=Blough+BE&cauthor_id=42562046)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#short-view-affiliation-2 "Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA."), [Antonio Landavazo](https://pubmed.ncbi.nlm.nih.gov/?term=Landavazo+A&cauthor_id=42562046)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#short-view-affiliation-2 "Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA."), [Robert W Gould](https://pubmed.ncbi.nlm.nih.gov/?term=Gould+RW&cauthor_id=42562046)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#short-view-affiliation-1 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA."), [Paul W Czoty](https://pubmed.ncbi.nlm.nih.gov/?term=Czoty+PW&cauthor_id=42562046)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42562046/#short-view-affiliation-3 "Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA. Electronic address: Paul.Czoty@wfusm.edu.") ### Affiliations * 1 Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA. * 2 Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA. * 3 Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA. Electronic address: Paul.Czoty@wfusm.edu. * PMID: **42562046** * DOI: [ 10.1016/j.ejphar.2026.179199 ](https://doi.org/10.1016/j.ejphar.2026.179199) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Alcohol use disorder (AUD) affects 400 million individuals over age 15 worldwide but <3% of AUD patients receive medication-assisted treatment, highlighting the need for novel pharmacotherapies. Repurposing drugs already approved by the Food and Drug Administration to treat other conditions could be a productive approach. For example, the smoking cessation medication varenicline, a partial agonist at α4β2 nicotinic acetylcholine receptors, has been shown to reduce alcohol craving and moderately reduce alcohol drinking in clinical trials. Additionally, the muscarinic acetylcholine receptor agonist xanomeline, approved for managing schizophrenia when given in combination with the peripherally-restricted muscarinic acetylcholine receptor antagonist trospium (Cobenfy™), can attenuate cocaine self-administration in laboratory animals. Its mechanism of action, stimulation of M1 and M4 receptors, suggests that it could reduce alcohol drinking. Six adult male cynomolgus monkeys with 3 yrs of ethanol self-administration experience had access to ethanol 22 h/day, 5 days/week; food pellets were self-administered during the first 5 h of the session. Once ethanol intakes were stable, monkeys received varenicline (0.03-0.3 mg/kg), xanomeline (0.3-1.0 mg/kg) or a combination of xanomeline (0.56-1.7 mg/kg) plus 0.3 mg/kg trospium intramuscularly (IM) twice daily. Varenicline and xanomeline only reduced ethanol intake in the absence of moderate-to-severe adverse effects in one of six monkeys. When co-administered with the peripheral muscarinic acetylcholine receptor antagonist trospium, however, higher xanomeline doses could be administered without adverse effects and ethanol intake was decreased in three of four monkeys. Xanomeline and other acetylcholine receptor agonists have potential as alcohol use disorder pharmacotherapies but peripherally mediated adverse effects must be effectively managed. **Keywords:** Alcohol; Macaques; Trospium; Varenicline; Xanomeline. Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors have nothing to disclose. ## Similar articles * [ Cognitive-Enhancing Effects of Acetylcholine Receptor Agonists in Group-Housed Cynomolgus Monkeys Who Drink Ethanol. ](https://pubmed.ncbi.nlm.nih.gov/38135508/) Galbo-Thomma LK, Epperly PM, Blough BE, Landavazo A, Saldaña SJ, Carroll FI, Czoty PW.Galbo-Thomma LK, et al.J Pharmacol Exp Ther. 2024 May 21;389(3):258-267. doi: 10.1124/jpet.123.001854.J Pharmacol Exp Ther. 2024.PMID: 38135508Free PMC article. * [ Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats. ](https://pubmed.ncbi.nlm.nih.gov/23995301/) Thomsen M, Fulton BS, Caine SB.Thomsen M, et al.Psychopharmacology (Berl). 2014 Feb;231(3):469-79. doi: 10.1007/s00213-013-3256-9. Epub 2013 Aug 31.Psychopharmacology (Berl). 2014.PMID: 23995301Free PMC article. * [ Acetylcholine and muscarinic receptor targeting in bipolar disorder: does xanomeline-trospium chloride and other investigational muscarinic agonists hold promise as mechanistically informed treatments for manic episodes, mixed features and cognitive deficits in bipolar disorder? ](https://pubmed.ncbi.nlm.nih.gov/40531190/) McIntyre RS.McIntyre RS.Expert Opin Investig Drugs. 2025 Jun;34(6):519-526. doi: 10.1080/13543784.2025.2522885. Epub 2025 Jul 11.Expert Opin Investig Drugs. 2025.PMID: 40531190Review. * [ Xanomeline/Trospium (Cobenfy): A Novel Approach for the Treatment of Schizophrenia in Adults. ](https://pubmed.ncbi.nlm.nih.gov/41056016/) Miron AA, Ifteni PI, Nguyen T, Dima L.Miron AA, et al.Am J Ther. 2025 Nov-Dec 01;32(6):e525-e535. doi: 10.1097/MJT.0000000000002026. Epub 2025 Oct 8.Am J Ther. 2025.PMID: 41056016Review. * [ From theory to therapy: unlocking the potential of muscarinic receptor activation in schizophrenia with the dual M1/M4 muscarinic receptor agonist xanomeline and trospium chloride and insights from clinical trials. ](https://pubmed.ncbi.nlm.nih.gov/40056428/) Meyer JM, Kramer K, Vuocolo S, Kaul I, Miller AC.Meyer JM, et al.Int J Neuropsychopharmacol. 2025 Apr 11;28(4):pyaf015. doi: 10.1093/ijnp/pyaf015.Int J Neuropsychopharmacol. 2025.PMID: 40056428Free PMC article.Review. [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42562046) ## MeSH terms * Alcohol Drinking* / drug therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alcohol+Drinking%2Fdrug+therapy%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alcohol+Drinking) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Ethanol* / administration & dosage Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Ethanol%2Fadministration+and+dosage%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Ethanol) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Macaca fascicularis Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Macaca+fascicularis%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Macaca+fascicularis) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Male Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Male%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Male) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Muscarinic Agonists* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Muscarinic+Agonists%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Muscarinic+Agonists) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Nicotinic Agonists* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Nicotinic+Agonists%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Nicotinic+Agonists) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Pyridines* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Pyridines%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Pyridines) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Self Administration Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Self+Administration%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Self+Administration) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42562046/) * Thiadiazoles* / pharmacology Actions * [ Search in PubMed ](https://pubmed.n
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