Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials
Margaret Haney, Monique Vallée, Sandy Fabre, Stephanie Collins Reed, Marion Zanese, Ghislaine Campistron, Caroline A. Arout, Richard W. Foltin, Ziva D. Cooper, Tonisha Kearney-Ramos, Mathilde Metna, Zuzana Justinová, Charles W. Schindler, Étienne Hébert-Chatelain, Luigi Bellocchio, Adeline Cathala, Andrea Bari, Román Serrat, David B. Finlay, Filippo Caraci, Bastien Redon, Elena Martín‐García, Arnau Busquets-García, Isabel Matias, Frances R. Levin, François‐Xavier Felpin, Nicolas Simon, Daniela Cota, Umberto Spampinato, Rafaël Maldonado, Yavin Shaham, Michelle Glass, Lars Lykke Thomsen, H. Mengel, Giovanni Marsicano, Stéphanie Monlezun, Jean‐Michel Revest, Pier Vincenzo Piazza
Abstract
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 (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 .