Cannabis Addiction
Is a Drug to Treat Cannabis Addiction Finally Within Reach?
BORDEAUX, France — Could AEF0117, a drug that has a novel mechanism of action in the brain, be the drug to fight cannabis addiction? Results from a phase 2a clinical trial that examined the efficacy of AEF0117 in patients with cannabis use disorder have created quite a stir. The study was published in Nature Medicine. Not only did AEF0117 weaken the effects of cannabis, but it also decreased a person's desire to use it, all without causing withdrawal symptoms. These findings have generated a significant buzz in the scientific and medical community.
"In the past, 8% of cannabis users would develop an addiction — today, this figure is 15%. Addiction to cannabis has become the main reason for seeking treatment at specialist drug clinics," said Pier Vincenzo Piazza, MD, PhD, psychiatrist, neurobiologist, and general director of Aelis Farma, the biopharmaceutical company that developed AEF0117.
This rise in cases can be explained by the increase in THC content in cannabis over the years. THC content increased from 5% in the 1970s to 30% today. Although cannabis is still less addictive than tobacco (33% of users become addicted), cocaine, heroin, or alcohol (25% of users become addicted), the number of cannabis users is increasing. Currently, 14.2 million in the United States and more than half a million in France use cannabis.
CB1 Receptor Inhibition
Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge
AEF0117 is the first signaling-specific inhibitor of the CB1 receptor. THC acts in the brain via CB1 cannabinoid receptors located on neurons. The total inhibition of CB1 receptors has long been an avenue of research, but the adverse effects caused by CB1 receptor antagonists are incompatible with a therapeutic approach.
"We thought that it would be impossible to modulate part of a receptor by a molecule. But in 2014, we discovered this unexpected natural mechanism precisely at the level of the CB1 cannabinoid receptors," Piazza told Medscape French Edition. At the time, he was the director of the Magendie Neurology Center (Inserm ― the French National Institute of Health and Medical Research) in Bordeaux, France. Along with his colleagues, he demonstrated that in response to high doses of THC, a hormone, pregnenolone, is synthesized and becomes bound to CB1 receptors, which reduces some of the effects of THC. The discovery of this new mechanism was published in Science in 2014.
"It then took 2 years to create a synthetic molecule that could mimic the effects of pregnenolone on the CB1 receptors," Piazza continued. Unlike pregnenolone, the new molecule needed to to be fully absorbable, stable, and not transformable into other steroids.
Triple Action
AEF0117 was assessed as part of a placebo-controlled, double-blind, phase 2a study. The participants were volunteers who had a cannabis addiction. In the treated group, the volunteers received either 0.06 mg (n = 14) or 1 mg (n = 15) of the investigational drug. Use of AEF0117 was associated with a significant reduction in the positive subjective effects of cannabis (19% for the 0.06-mg dose and 38% for the 1-mg dose; P < .04). The investigators showed an association with reduced cannabis use, as measured by self-administration (P < .05). No adverse events were linked to the treatment in comparison with placebo. Furthermore, there were no withdrawal symptoms, even among healthy volunteers who would smoke several grams of cannabis a day.
"I call this triple action: reduced positive effects of cannabis, reduced desire to use it, and a lack of withdrawal symptoms linked to the partial receptor inhibition," said Piazza.
Commenting on the study for Medscape, Guillaume Davido, MD, a psychiatrist who specializes in addiction studies at Bichat Hospital in Paris, said, "Patients really miss the psychoactive anxiolytic effect of cannabis when they stop using it. This is what makes stopping so difficult. Getting rid of this 'honeymoon' effect with the product is a considerable step forward." Davido is sure AEF0117 will be approved for prescription use. It should be used in conjunction with appropriate psychotherapeutic care, as is the case with the treatment of alcohol addiction, which combines medication with cognitive-behavioral therapy (CBT). Currently, CBT is the only recommended treatment for cannabis use disorder.
Currently, no treatments are approved for cannabis use disorder, said Davido. "At the moment, we can only provide medicinal products to treat cannabis withdrawal symptoms, such as irritability, sleep disorders, and anxiety."
New Trial Recruiting
A phase 2b trial has been launched in the United States. It is in the process of recruiting 330 participants with cannabis addiction at 11 sites. Recruitment is scheduled to be completed by October. The three doses to be assessed in this new trial, which is being conducted in collaboration with Columbia University Irving Medical Center in New York, will be around 1 mg. "We tested two very different doses (0.06 mg and 1 mg) of AEF0117, because in animals, very low doses block some of the effects of cannabis," said Piazza. "But it became apparent that we would need a much higher dose to stop the desire for cannabis use completely."
The results should be available by mid-2024. "And if its therapeutic efficacy is confirmed, a whole new pharmacology of receptors is opened up to us," said Piazza.
Piazza is the general director of Aelis Farma, the biopharmaceutical company developing AEF0117.
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