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
  • 1. Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada. [email protected].
  • 2. Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada. [email protected].
  • 3. Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. [email protected].
  • 4. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. [email protected].
  • 5. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. [email protected].
  • 6. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. [email protected].
  • 7. Campbell Family Mental Health Research Institute, Toronto, ON, Canada. [email protected].
  • 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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