학술논문
Signaling-specific inhibition of the CB1receptor for cannabis use disorder: phase 1 and phase 2a randomized trials
Document Type
Article
Author
Haney, Margaret; Vallée, Monique; Fabre, Sandy; Collins Reed, Stephanie; Zanese, Marion; Campistron, Ghislaine; Arout, Caroline A.; Foltin, Richard W.; Cooper, Ziva D.; Kearney-Ramos, Tonisha; Metna, Mathilde; Justinova, Zuzana; Schindler, Charles; Hebert-Chatelain, Etienne; Bellocchio, Luigi; Cathala, Adeline; Bari, Andrea; Serrat, Roman; Finlay, David B.; Caraci, Filippo; Redon, Bastien; Martín-García, Elena; Busquets-Garcia, Arnau; Matias, Isabelle; Levin, Frances R.; Felpin, François-Xavier; Simon, Nicolas; Cota, Daniela; Spampinato, Umberto; Maldonado, Rafael; Shaham, Yavin; Glass, Michelle; Thomsen, Lars Lykke; Mengel, Helle; Marsicano, Giovanni; Monlezun, Stéphanie; Revest, Jean-Michel; Piazza, Pier Vincenzo
Source
Nature Medicine; 20230101, Issue: Preprints p1-13, 13p
Subject
Language
ISSN
10788956; 1546170X
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.