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Article Dans Une Revue Nature Medicine Année : 2023

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

Margaret Haney
  • Fonction : Auteur
Sandy Fabre
Stephanie Collins Reed
Marion Zanese
Ghislaine Campistron
  • Fonction : Auteur
Caroline A Arout
  • Fonction : Auteur
Richard W Foltin
  • Fonction : Auteur
Ziva D Cooper
Tonisha Kearney-Ramos
  • Fonction : Auteur
Mathilde Metna
  • Fonction : Auteur
Zuzana Justinova
Charles Schindler
Etienne Hebert-Chatelain
  • Fonction : Auteur
Luigi Bellocchio
  • Fonction : Auteur
Adeline Cathala
  • Fonction : Auteur
Andrea Bari
  • Fonction : Auteur
Roman Serrat
  • Fonction : Auteur
David B Finlay
  • Fonction : Auteur
Filippo Caraci
Bastien Redon
  • Fonction : Auteur
Elena Martín-García
Arnau Busquets-Garcia
Isabelle Matias
  • Fonction : Auteur
Frances R Levin
  • Fonction : Auteur
Daniela Cota
Umberto Spampinato
  • Fonction : Auteur
Rafael Maldonado
Yavin Shaham
Michelle Glass
  • Fonction : Auteur
Lars Lykke Thomsen
Helle Mengel
  • Fonction : Auteur
Giovanni Marsicano
Stéphanie Monlezun
  • Fonction : Auteur
Jean-Michel Revest
Pier Vincenzo Piazza

Résumé

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.
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Dates et versions

hal-04235516 , version 1 (10-10-2023)

Identifiants

Citer

Margaret Haney, Monique Vallée, Sandy Fabre, Stephanie Collins Reed, Marion Zanese, et al.. Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials. Nature Medicine, 2023, 29, pp.1487 - 1499. ⟨10.1038/s41591-023-02381-w⟩. ⟨hal-04235516⟩
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