TY - JOUR
T1 - Signaling-specific inhibition of the CB1 receptor for cannabis use disorder
T2 - phase 1 and phase 2a randomized trials
AU - Haney, Margaret
AU - Vallée, Monique
AU - Fabre, Sandy
AU - Collins Reed, Stephanie
AU - Zanese, Marion
AU - Campistron, Ghislaine
AU - Arout, Caroline A.
AU - Foltin, Richard W.
AU - Cooper, Ziva D.
AU - Kearney-Ramos, Tonisha
AU - Metna, Mathilde
AU - Justinova, Zuzana
AU - Schindler, Charles
AU - Hebert-Chatelain, Etienne
AU - Bellocchio, Luigi
AU - Cathala, Adeline
AU - Bari, Andrea
AU - Serrat, Roman
AU - Finlay, David B.
AU - Caraci, Filippo
AU - Redon, Bastien
AU - Martín-García, Elena
AU - Busquets-Garcia, Arnau
AU - Matias, Isabelle
AU - Levin, Frances R.
AU - Felpin, François Xavier
AU - Simon, Nicolas
AU - Cota, Daniela
AU - Spampinato, Umberto
AU - Maldonado, Rafael
AU - Shaham, Yavin
AU - Glass, Michelle
AU - Thomsen, Lars Lykke
AU - Mengel, Helle
AU - Marsicano, Giovanni
AU - Monlezun, Stéphanie
AU - Revest, Jean Michel
AU - Piazza, Pier Vincenzo
N1 - Funding Information:
We gratefully acknowledge V. Roullot-Lacarrière, V. Lalanne, A. Grel and M. Mondésir for technical help; M. Dobrow for supervising the phase 1 studies; J. Puig for performing phase 2a statistical analysis; and D. Grassi for insightful comments on the manuscript. The work benefited from the support of the Animal Breeding and Housing facility (S. Laumond) of the Magendie Neurocentre and of the Biochemistry and Biophysics Facility of the Bordeaux Neurocampus. We are grateful to the US National Institute on Drug Abuse (NIDA) for supplying the cannabis cigarettes for the phase 2a study and for expert data collection from E. Corcoran, R. K. Denson, G. Fazilov and M. Connaughton. The following agencies and sources are gratefully acknowledged for their financial support: NIDA grant R01 DA038875-01 (M.H.); NIDA grant 5U54DA037842 (F.R.L.) (supplementary funding for the phase 2a study); Labex Brain (ANR-10-LABX-43) (P.V.P.); Mission interministérielle de lutte contre les drogues et les conduites addictives (MILDECA) (P.V.P.); Conseil Régional Nouvelle Aquitaine (CRNA) (P.V.P.); Banque Publique d’investissement Française (BpiFrance) (P.V.P.); NIDA Intramural Research Program (Z.J. and Y.S.); and Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas PNSD-2021I076 (R.M.) and PNSD-2019I006 (E.M.-G.). Finally, we would like to acknowledge the support from Aelis Farma SA, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS) and Université de Bordeaux.
PY - 2023/6
Y1 - 2023/6
N2 - 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 .
AB - 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 .
KW - Animals
KW - Cannabis
KW - Double-Blind Method
KW - Dronabinol/adverse effects
KW - Hallucinogens/therapeutic use
KW - Marijuana Abuse
KW - Mice
KW - Randomized Controlled Trials as Topic
KW - Substance Withdrawal Syndrome/drug therapy
UR - https://www.scopus.com/pages/publications/85161454156
U2 - 10.1038/s41591-023-02381-w
DO - 10.1038/s41591-023-02381-w
M3 - Article
C2 - 37291212
AN - SCOPUS:85161454156
SN - 1078-8956
VL - 29
SP - 1487
EP - 1499
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -
ODG 3 – Bona salut i benestar