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

• Published in: Nature Medicine Vol. 29; no. 6; pp. 1487 - 1499
• Main Authors: 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
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group 01.06.2023; Nature Publishing Group US
• Subjects: Cannabinoid CB1 receptors; Cannabinoids; Cannabis; Clinical trials; Drug addiction; Drug therapy; Inhibitors; Life Sciences; Marijuana; Placebos; Randomization; Receptors; Self-administration; Signaling; Tetrahydrocannabinol; THC
• ISSN: 1078-8956; 1546-170X; 1744-7933
• 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 (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 .