2. Academic Validation
  3. Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials

Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials

  • Nat Med. 2023 Jun;29(6):1487-1499. doi: 10.1038/s41591-023-02381-w.
Margaret Haney # 1,  Monique Vallée # 2,  Sandy Fabre # 3,  Stephanie Collins Reed 1,  Marion Zanese 3,  Ghislaine Campistron 3,  Caroline A Arout 1,  Richard W Foltin 1,  Ziva D Cooper 1 4,  Tonisha Kearney-Ramos 1,  Mathilde Metna 3,  Zuzana Justinova 5,  Charles Schindler 5,  Etienne Hebert-Chatelain 6,  Luigi Bellocchio 2,  Adeline Cathala 2,  Andrea Bari 3,  Roman Serrat 3,  David B Finlay 7,  Filippo Caraci 2 8,  Bastien Redon 2 9,  Elena Martín-García 10,  Arnau Busquets-Garcia 2 11,  Isabelle Matias 2,  Frances R Levin 1,  François-Xavier Felpin 12,  Nicolas Simon 13,  Daniela Cota 2,  Umberto Spampinato 2,  Rafael Maldonado 10,  Yavin Shaham 5,  Michelle Glass 7,  Lars Lykke Thomsen 3,  Helle Mengel 3,  Giovanni Marsicano 2,  Stéphanie Monlezun 3,  Jean-Michel Revest 2,  Pier Vincenzo Piazza 14
Affiliations

Affiliations

  • 1 Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA.
  • 2 University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France.
  • 3 Aelis Farma, Bordeaux, France.
  • 4 University of California, Los Angeles, Los Angeles, CA, USA.
  • 5 Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
  • 6 Department of Biology, University of Moncton, Moncton, NB, Canada.
  • 7 Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
  • 8 Department of Drug and Health Sciences, University of Catania, Italy, and Oasi Research Institute-IRCCS, Unit of Translational Neuropharmacology, Troina, Italy.
  • 9 Basic Neuroscience Department, Université de Genève, Genève, Switzerland.
  • 10 Laboratory of Neuropharmacology, Department of Medicine and Life Sciences, University Pompeu Fabra, Barcelona, Spain.
  • 11 Cell-Type Mechanisms in Normal and Pathological Behavior Research Group, Neuroscience Programme, IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain.
  • 12 Nantes Université, CNRS, CEISAM, UMR 6230, Nantes, France.
  • 13 Aix Marseille Univ, APHM, INSERM, IRD, SESSTIM, Hop Sainte Marguerite, Service de Pharmacologie Clinique, Marseille, France.
  • 14 Aelis Farma, Bordeaux, France. pv.piazza@aelisfarma.com.
  • # Contributed equally.
PMID: 37291212 DOI: 10.1038/s41591-023-02381-w
Abstract

Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the Cannabinoid Receptor 1 (CB1-SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ9-tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing significant adverse effects. In single-ascending-dose (0.2 mg, 0.6 mg, 2 mg and 6 mg; n = 40) and multiple-ascending-dose (0.6 mg, 2 mg and 6 mg; n = 24) phase 1 trials, healthy volunteers were randomized to ascending-dose cohorts (n = 8 per cohort; 6:2 AEF0117 to placebo randomization). In both studies, AEF0117 was safe and well tolerated (primary outcome measurements). In a double-blind, placebo-controlled, crossover phase 2a trial, volunteers with CUD were randomized to two ascending-dose cohorts (0.06 mg, n = 14; 1 mg, n = 15). AEF0117 significantly reduced cannabis' positive subjective effects (primary outcome measurement, assessed by visual analog scales) by 19% (0.06 mg) and 38% (1 mg) compared to placebo (P < 0.04). AEF0117 (1 mg) also reduced cannabis self-administration (P < 0.05). In volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efficacious treatment for CUD.ClinicalTrials.gov identifiers: NCT03325595 , NCT03443895 and NCT03717272 .

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