2. Academic Validation
  3. Histamine H3 Receptor as a target for alcohol use disorder: challenging the predictability of animal models for clinical translation in drug development

Histamine H3 Receptor as a target for alcohol use disorder: challenging the predictability of animal models for clinical translation in drug development

  • Transl Psychiatry. 2026 Jan 29;16(1):55. doi: 10.1038/s41398-026-03807-y.
Bernard Le Foll # 1 2 3 4 5 6 7,  Mickael Naassila # 8,  Jérôme Jeanblanc # 8,  Christian S Hendershot 9,  Jesus Chavarria 10,  Thierry Calmels 11,  Stéphane Krief 11,  Isabelle Berrebi-Bertrand 11,  Marilyne Uguen 11,  David Perrin 11,  Xavier Ligneau 11,  Isabelle Boileau 12 13 14 15,  Pablo M Rusjan 16,  Patricia Di Ciano 17 18 19,  Pamela Sabioni 20 17,  Marc Capet 10,  Philippe Robert 10,  Olivier Finance 10,  Jeanne-Marie Lecomte 21,  Jean Charles Schwartz 11 21
Affiliations

Affiliations

  • 1 Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada. Bernard.LeFoll@camh.ca.
  • 2 Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada. Bernard.LeFoll@camh.ca.
  • 3 Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. Bernard.LeFoll@camh.ca.
  • 4 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. Bernard.LeFoll@camh.ca.
  • 5 Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Bernard.LeFoll@camh.ca.
  • 6 Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Bernard.LeFoll@camh.ca.
  • 7 Campbell Family Mental Health Research Institute, Toronto, ON, Canada. Bernard.LeFoll@camh.ca.
  • 8 Université de Picardie Jules Verne, Groupe de Recherche sur l'Alcool & les Pharmacodépendances, INSERM UMR1247, Amiens, France.
  • 9 Department of Population and Public Health Sciences and Institute for Addiction Science, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 10 Department of Psychology, Western University, London, ON, Canada.
  • 11 Bioprojet-Biotech, Saint-Grégoire, France.
  • 12 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • 13 Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
  • 14 Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
  • 15 Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  • 16 The Douglas Research Centre, McGill University, Montreal, QC, Canada.
  • 17 Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  • 18 Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
  • 19 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
  • 20 Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
  • 21 Bioprojet-Pharma, Paris, France.
  • # Contributed equally.
PMID: 41611659 DOI: 10.1038/s41398-026-03807-y
Abstract

There is an important need to advance medication development for alcohol use disorder (AUD). BP1.3656B, a highly potent and selective histamine H3 receptor inverse agonist/antagonist, has been developed. Preclinical studies revealed high affinity, good pharmacokinetic profile, good brain penetration, and favorable safety. BP1.3656B reduced alcohol drinking and alcohol-seeking behavior in rodents. Phase I studies revealed good tolerability/pharmacokinetic in humans. Positron emission tomography revealed high brain occupancy in humans. Based on this favorable profile, two trials were conducted in subjects with AUD. In non-treatment seekers, BP1.3656B had no impact on intravenous alcohol self-administration (IV-ASA). A randomized clinical trial testing three doses of BP1.3656B versus placebo in treatment-seekers with AUD showed no reduction of heavy drinking days. Collective results illustrate the challenges inherent to clinical translation of AUD therapies, and reinforce the use of Phase IIa human laboratory paradigms as an important tool to de-risk translation of innovative drug targets for AUD.

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