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

Autor: Haney M; Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA., Vallée M; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Fabre S; Aelis Farma, Bordeaux, France., Collins Reed S; Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA., Zanese M; Aelis Farma, Bordeaux, France., Campistron G; Aelis Farma, Bordeaux, France., Arout CA; Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA., Foltin RW; Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA., Cooper ZD; Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA.; University of California, Los Angeles, Los Angeles, CA, USA., Kearney-Ramos T; Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA., Metna M; Aelis Farma, Bordeaux, France., Justinova Z; 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., Schindler C; 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., Hebert-Chatelain E; Department of Biology, University of Moncton, Moncton, NB, Canada., Bellocchio L; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Cathala A; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Bari A; Aelis Farma, Bordeaux, France., Serrat R; Aelis Farma, Bordeaux, France., Finlay DB; Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand., Caraci F; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France.; Department of Drug and Health Sciences, University of Catania, Italy, and Oasi Research Institute-IRCCS, Unit of Translational Neuropharmacology, Troina, Italy., Redon B; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France.; Basic Neuroscience Department, Université de Genève, Genève, Switzerland., Martín-García E; Laboratory of Neuropharmacology, Department of Medicine and Life Sciences, University Pompeu Fabra, Barcelona, Spain., Busquets-Garcia A; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France.; Cell-Type Mechanisms in Normal and Pathological Behavior Research Group, Neuroscience Programme, IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain., Matias I; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Levin FR; Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA., Felpin FX; Nantes Université, CNRS, CEISAM, UMR 6230, Nantes, France., Simon N; Aix Marseille Univ, APHM, INSERM, IRD, SESSTIM, Hop Sainte Marguerite, Service de Pharmacologie Clinique, Marseille, France., Cota D; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Spampinato U; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Maldonado R; Laboratory of Neuropharmacology, Department of Medicine and Life Sciences, University Pompeu Fabra, Barcelona, Spain., Shaham Y; 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., Glass M; Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand., Thomsen LL; Aelis Farma, Bordeaux, France., Mengel H; Aelis Farma, Bordeaux, France., Marsicano G; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Monlezun S; Aelis Farma, Bordeaux, France., Revest JM; University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France., Piazza PV; Aelis Farma, Bordeaux, France. pv.piazza@aelisfarma.com.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 Jun; Vol. 29 (6), pp. 1487-1499. Date of Electronic Publication: 2023 Jun 08.
DOI: 10.1038/s41591-023-02381-w
Abstrakt: 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 (CB 1 -SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ 9 -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 .
(© 2023. The Author(s).)
Databáze: MEDLINE
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