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 Justinova, Charles W. Schindler, Etienne Hebert-Chatelain, Luigi Bellocchio, Adeline Cathala, Andrea Bari, Roman Serrat, David B Finlay, Filippo Caraci, Bastien Redon, Elena Martín-García, Arnau Busquets-García, Isabelle Matias, Frances R. Levin, François-Xavier Felpin, Nicolas Simon, Daniela Cota, Umberto Spampinato, Rafaël Maldonado, Yavin Shaham, Michelle Glass, Lars Lykke Thomsen, Helle Mengel, Giovanni Marsicano, Stéphanie Monlezun, Jean-Michel Revest, Pier-Vincenzo Piazza
Nature Medicine June 2023 DOI: 10.1038/s41591-023-02381-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Phase 1 single- and multiple-ascending-dose trials plus a phase 2a randomized, double-blind, placebo-controlled crossover trial Peer reviewed |
|---|---|
| Sample size | 93 |
| Population | Healthy volunteers (phase 1) and volunteers with cannabis use disorder (phase 2a) |
| Intervention | AEF0117 |
| Dose | 0.2 mg, 0.6 mg, 2 mg and 6 mg (single ascending dose); 0.6 mg, 2 mg and 6 mg (multiple ascending dose); 0.06 mg and 1 mg (phase 2a) |
| Measures | visual analog scales |
| Topics | Cannabis |
| Registration | NCT03325595 NCT03443895 NCT03717272 |
| Key findings | AEF0117, a CB1 signaling-specific inhibitor, was safe and well tolerated in healthy volunteers and, in people with cannabis use disorder, reduced cannabis's positive subjective effects by 19% at 0.06 mg and 38% at 1 mg versus placebo, with 1 mg also reducing cannabis self-administration. The authors suggest it is a safe and potentially efficacious treatment for cannabis use disorder. |
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.ClinicalTrials.gov identifiers: NCT03325595 , NCT03443895 and NCT03717272 .
Comparable studies
Other randomized controlled trials on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Healthy participants | 2012 | Randomized controlled trial | n = 48 |
| Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing Healthy, English-native, right-handed men who had used cannabis 15 times or less in... | 2009 | Double-blind, randomized, placebo-controlled crossover trial | n = 15 |
| Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers Healthy male subjects | 2012 | Randomized controlled trial | n = 16 |
| Modulation of Mediotemporal and Ventrostriatal Function in Humans by Δ9-Tetrahydrocannabinol Healthy, native English-speaking, right-handed men of white race/ethnicity who had used... | 2009 | Randomized controlled trial | n = 15 |
| Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition Healthy volunteers with a history of light cannabis use | 2019 | Randomized, double-blind, within-subjects crossover | n = 14 |
Citations in the library
Cited by 4
- Emerging medications and pharmacological treatment approaches for substance use disorders. Pharmacology, Biochemistry, and Behavior March 1, 2025
- Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex. Brain, Behavior, and Immunity May 1, 2026
- Advances in the study of pharmacotherapy for addiction to naturally-derived psychoactive substances. Chinese journal of natural medicines August 2025
- The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses. Psychological Medicine November 2023
Cites 2
- Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone Nature Neuroscience September 11, 2019
- Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best practice & research. Clinical endocrinology & metabolism February 2009