A first-in-class drug engineered to selectively inhibit the signaling pathway of the cannabinoid receptor CB1 has shown promise as a safe and effective treatment for cannabis use disorder (CUD). Tests in animal models, together with newly reported Phase I and IIa clinical trials, showed that the drug reduces the effects of cannabis without triggering withdrawal symptoms. Data from the Phase IIa clinical trial, led by a team at Columbia University Irving Medical Center and French biopharma Aelis Farma, found that the drug candidate, AEFO117, significantly reduced the effects of cannabis in daily cannabis smokers.

“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 Haney, PhD, supervisor of the Phase I studies and principal investigator of the Phase IIa proof-of-concept study. Haney is a professor of neurobiology in the Department of Psychiatry at Columbia, where she is the director of the Cannabis Research Laboratory. Haney also co-directs Columbia’s Substance Use Research Center,

“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,” continued Haney, who is first author of the team’s published paper in Nature Medicine, titled “Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials.”

Cannabis is the most widely used illicit drug in the world, and 19.5% of those who have used cannabis develop a cannabis use disorder (CUD), the authors noted. CUD is characterized by persistent impairment, such as failing to attend to work or personal obligations, continuing to use cannabis despite problems, and an inability to cut down its use. “In the United States, 14.2 million individuals were diagnosed with CUD in 2020, and 14% of those receiving substance use disorder treatment reported cannabis as their primary drug of abuse,” the team continued. And 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. Yet while daily use of cannabis is at record high levels among adolescents and young adults, many are unaware that cannabis can be addictive. And to date there are no FDA-approved drugs  for the treatment of cannabis use disorder. Evidenced-based behavioral therapies have also shown limited benefits. “… despite an escalating need, there is no medication to facilitate CUD treatment,” the investigators continued.

Developed by Aelis Farma, AEF0117 is the first of the new pharmacologic class known as signaling-specific inhibitors of the CB1 (CB1-SSi), which is based on a unique mechanism of action that enables CB1-SSi to inhibit only the cellular signals involved in CUD. AEF0117 appears to counteract the “high” associated with THC, the primary psychoactive component of cannabis, at the type 1 cannabinoid receptors, but without disrupting the receptors’ physiological and behavioral functions, which include memory and learning, emotional processing, sleep, and eating behavior. 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. “CB1-SSi appears to be one of the few classes of compounds able to inhibit the effects of a receptor agonist without having psychoactive effects per se, which provides a considerable advantage for its potential therapeutic use and constitutes a major advance in the pharmacology of inhibitors,” the researchers pointed out.

The natural brain mechanism was discovered by the research group of Aelis Farma CEO 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. Piazza is senior and corresponding author of the newly released paper in Nature Medicine, which he commented “… culminates more than a decade of research, from discovery of this natural brain mechanism to our proof-of-concept clinical trial … We are delighted to contribute to the field of neuropharmacology with a class of drugs never tested in humans before.”

The Phase IIa randomized, double-blind, placebo-controlled crossover trial involved 29 participants, aged 29–44 years, with CUD, in non-treatment seeking male and female cannabis smokers. The participants were randomized to receive one of two different doses of AEF0117 in one five-day phase, and placebo in another five-day phase. “The main objectives of the study were to evaluate the effects of AEF0117 on the perceived ‘good effect’ of cannabis as a measure of abuse liability and on self-administration. An additional objective was to determine if AEF0117 reversed cannabis’ effects on cognitive performance, pain threshold and heart rate,” the authors explained.

The results showed that 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 or disrupting normal functions (such a mood, sleep or food intake) over a five day period, even for volunteers who smoked several grams of cannabis per day. “Overall, the absence of effects of AEF0117 on food intake or sleep (robust measures of cannabis withdrawal) and the small amplitude changes observed on certain mood ratings do not suggest that AEF0117 precipitates cannabis withdrawal or produces clinically relevant changes in mood among volunteers smoking cannabis,” the investigators stated.

Aelis Farma is currently sponsoring a multi-site, placebo-controlled Phase IIb 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 Haney. We are also grateful to the National Institute of Drug Abuse for their support.”

In conclusion, the authors noted, “AEF0117 is the first of a new pharmacological class of inhibitors, CB1-SSi, that modify the activity of their target receptor in a signaling-specific manner. Because these drugs reproduce the effects of a natural mechanism to counteract CB1 overactivation,  they can inhibit the effects of THC without altering the basal activity of the CB1. Therefore, these compounds seem to have no effect on normal behavior and physiological activity while decreasing cannabis’ abuse-related and reinforcing effects, resulting in a well-tolerated and potentially efficacious therapy for CUD.”

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