First-in-Class Drug To Treat Cannabis Use Disorder Shows Great Promise in Clinical Trial

AEF0117, a first-in-class drug, has shown potential in treating cannabis use disorder (CUD) by inhibiting specific signals in cannabinoid receptors. The drug curbs the euphoria caused by THC, the key psychoactive element in cannabis, without affecting physiological functions, thereby reducing cannabis use without precipitating withdrawal symptoms.

There are no FDA-approved medications currently available for cannabis disorder or addiction.

A first-in-class drug engineered to selectively inhibit the signaling pathway of the cannabinoid receptor holds potential as a safe and efficacious treatment for cannabis use disorder (CUD). CUD is a condition in which an individual struggles to regulate their cannabis consumption, despite it causing issues in their life.

During a Phase 2a clinical trial conducted by Columbia University Irving Medical Center and Aelis Farma, a French biopharmaceutical firm, researchers found that the candidate drug, AEFO117, significantly reduced the effects of cannabis in daily cannabis smokers.

The report was recently published in the journal Nature Medicine.

AEF0117 appears to counteract the “high” associated with THC, the primary psychoactive component of cannabis, at the type 1 cannabinoid receptors—the CB1 receptors—without disrupting the receptors’ physiological and behavioral functions, which include memory and learning, emotional processing, sleep, and eating behavior.

“We have tested over a dozen potential treatment medications in our Cannabis Research Laboratory, and this is the first to decrease both the positive mood effects of cannabis and the decision to use cannabis by daily smokers,” said Margaret (Meg) Haney, Ph.D., supervisor of the phase I studies and principal investigator of the 2a proof-of-concept study, and a professor of neurobiology in the Department of Psychiatry at Columbia, where she is the director of the Cannabis Research Laboratory.

“Patients seek treatment when they have difficulty controlling their cannabis use despite the problems it is causing at work or in their personal lives. Our findings suggest AEF0117 has great potential for treating problematic cannabis use,“ added Dr. Haney, who also co-directs Columbia’s Substance Use Research Center.

Cannabis use disorder on the rise

As cannabis use becomes increasingly mainstream—with 38 states, three territories, and the District of Columbia legalizing the drug for medicinal and/or recreational use—consumption is on the rise, along with problematic use, which encompasses addiction.

Cannabis use disorder is an underappreciated risk of using cannabis that affects about 14 million individuals in the United States. Despite daily use of cannabis being at record high levels among adolescents and young adults, many are unaware that cannabis can be addictive.

To date, no medications have been approved by the Food and Drug Administration (FDA) for the treatment of cannabis use disorder—and evidenced-based behavioral therapies have shown limited benefits.

The culmination of a decade of research

AEF0117, developed by Aelis Farma, is the first of the new pharmacologic class, CB1-SSi, which is based on a unique mechanism of action that enables CB1-SSi to inhibit only the cellular signals involved in CUD. This breakthrough approach differs from previous CB1 receptor antagonists that, due to their broad blockade of all CB1 receptor activity, caused significant adverse effects preventing their clinical use.

This natural brain mechanism was discovered by the research group of Aelis Farma Chief Executive Officer Pier Vincenzo Piazza, MD, when he was the director of the Neurocentre Magendie of the French National Institute of Health and Medical Research (INSERM) in Bordeaux.

“The [Nature Medicine] article culminates more than a decade of research, from the discovery of this natural brain mechanism to our proof-of-concept clinical trial,” said Dr. Piazza. “We are delighted to contribute to the field of neuropharmacology with a class of drugs never tested in humans before.”

In the Phase 2a crossover trial that involved 29 participants with CUD who received one of two different doses of AEF0117 in one 5-day phase and placebo and in another 5-day phase in randomized order, AEF0117 significantly reduced participants’ self-reported ratings of cannabis-related positive mood effects, the primary outcome measure, by a mean of 38% while also reducing the use of cannabis. These reductions occurred without precipitating cannabis withdrawal, even for volunteers who smoked several grams of cannabis per day.

Aelis Farma is currently sponsoring a multi-site, placebo-controlled phase 2b study in collaboration with Columbia’s medical center. Frances R. Levin, MD, the Kennedy-Leavy Professor of Psychiatry and chief of the Division on Substance Use Disorders at Columbia, is running the two-year study, which is expected to enroll 330 participants with CUD to evaluate three dose levels of AEF0117 in treating cannabis addiction.

“I am so grateful for our team in the Cannabis Research Laboratory at Columbia Psychiatry for their contributions to running these studies with AEF0117, said Dr. Haney. We are also grateful to the National Institute of Drug Abuse for their support.”

Reference: “Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials” by 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 Schindler, Etienne Hebert-Chatelain, Luigi Bellocchio, Adeline Cathala, Andrea Bari, Roman Serrat, David B. Finlay, Filippo Caraci, Bastien Redon, Elena Martín-García, Arnau Busquets-Garcia, Isabelle Matias, Frances R. Levin, François-Xavier Felpin, Nicolas Simon, Daniela Cota, Umberto Spampinato, Rafael Maldonado, Yavin Shaham, Michelle Glass, Lars Lykke Thomsen, Helle Mengel, Giovanni Marsicano, Stéphanie Monlezun, Jean-Michel Revest and Pier Vincenzo Piazza, 8 June 2023, Nature Medicine.
DOI: 10.1038/s41591-023-02381-w