For people who find themselves unable to control their cannabis consumption, treatment options are limited. The Food and Drug Administration has not approved any medications for cannabis use disorder, even as legal reforms are steadily making the substance more widely available. But a new drug that aims to safely stem cravings is being developed by a French biopharmaceutical company and shows promise in animal and initial human trials.
In the trials, the new drug effectively reduced the perceived pleasant effects, or high, from marijuana, helping users gain control of their intake without triggering withdrawal symptoms—even in human volunteers who reported smoking several grams every day. (The study on human users focused on cannabis smoking and other inhalation methods, including vaping. Edible products have not yet been tested.) Study participants were also less likely to purchase and self-administer the cannabis that the researchers made available at the lab’s dispensary. The findings were published earlier this month in Nature Medicine.
Approximately 14.2 million people aged 12 years or older in the U.S. were diagnosed with cannabis use disorder in 2020—and “those numbers are increasing,” says the study’s senior author Pier Vincenzo Piazza, a physician and neurobiologist, who is also CEO of Aelis Farma, the company behind the new drug. “Smoking cannabis once in a while is not a problem, like drinking one glass of wine with your friends is not a problem,” Piazza says. “But some of these people with cannabis use disorder smoke between five to 10 joints a day. In that case, you have several problems that appear.”
People who consume large amounts of marijuana and are unable to cut back can experience problems with motivation and socialization, along with significant cognitive impairment—especially in adolescents—Piazza says. Those who begin using marijuana at or before age 18 have a higher risk of developing cannabis use disorder, according to the U.S. Centers for Disease Control and Prevention. “Once cannabis use disorder is developed, it is very difficult to treat,” Piazza adds.
He and his team focused on targeting the pathways initiated by cannabinoid receptor 1, or CB1—a receptor that is found on nerve cells throughout the brain and is critical in regulating mood, pleasure, appetite and sleep. CB1 is also one of two binding sites of the psychoactive ingredient of cannabis, delta-9-tetrahydrocannabinol (THC). When bound, THC overstimulates CB1. This activates several intracellular pathways, causing people to feel high or intoxicated, Piazza explains. Drugs that fully block CB1 may prevent THC from binding—but they also block molecules called endocannabinoids, which the body naturally produces to control CB1 receptors’ activity. When these fully blocking drugs hinder natural endocannabinoids from binding to CB1, that can cause withdrawal symptoms.
“This receptor plays such a critical role in physiological function that you can’t just block it, and if you do, there are all sorts of serious adverse events,” says co-lead study author Margaret Haney, director of the Cannabis Research Laboratory at Columbia University. “People have suicidal ideation; their mood is disrupted.” They may experience anxiety and depression, as well as weight changes and problems with sleep, she says.
The new compound, called AEF0117, works differently: it is a signaling inhibitor, which means it blocks only “a pocket” of the CB1 receptor, Haney explains. Blocking that pocket specifically inhibits the pathway responsible for the habit-forming psychoactive effects of cannabis. The body’s endocannabinoids can still bind to the receptor normally, but when THC slots in, that signaling pathway is blocked.
“In doing so, when people smoke cannabis, they aren’t getting the same effect that they are used to getting. It doesn’t produce the same ‘good effect high’ that it normally would,” Haney says. “We hypothesize if it’s going to not feel as good, they’re not going to be motivated to smoke to the same degree. That could allow them to then gain control of their use.”
Safety tests of AEF0117 in animals, including mice, rats and dogs, showed no adverse effects or toxicity, and trials in rodents and squirrel monkeys inhibited cannabis effects and THC-seeking behavior. In one of the new study’s human trials, groups of daily cannabis users took the medication at various doses and self-reported their experiences. The perceived pleasant effects of marijuana were reduced by 19 percent in participants who took a capsule containing 0.06 milligram of the drug, in comparison with those who took a placebo, while the effects were reduced by 38 percent in those who took 1 mg of the drug.
Additionally, the researchers examined whether participants would feel compelled to buy and smoke cannabis after taking AEF0117. “What this medication did was shifted that all down, and they chose not to spend their actual money in the lab,” Haney says. And because the CB1 receptors are still free to bind with the body’s own endocannabinoids, participants didn’t report withdrawal symptoms.
That recent human trial was small, involving 29 volunteers—mostly male individuals—with cannabis use disorder. Aelis Farma is now in the middle of a larger three-month clinical trial with 300 participants at several clinical centers in the U.S. The results of that study are expected by 2024, Piazza says. “If everything goes well, we should be able to submit a new drug application for market approval by the end of 2027 or 2028,” he adds.
Although the compound still needs to pass the next set of trials before FDA approval, the initial results are “promising,” says Jane Metrik, a behavioral and social sciences professor at Brown University. “In animals, and in humans in particular, the study demonstrated a good safety profile and that [the drug] was well tolerated,” Metrik says. “What’s really important: it was shown to reduce self-administration of cannabis, of THC, without any kind of precipitated withdrawal.”
Currently patients suffering from cannabis use disorder can only turn to psychosocial treatments such as cognitive-behavioral therapy or motivational enhancement therapy. Both require working with trained clinicians who can help develop behavioral strategies to reduce cannabis use.
“As wonderful as behavioral treatments are, unfortunately, because of the way our health care is operating right now, it’s not accessible to many people, and there are inequities because of that,” says Metrik, who is also a licensed clinical psychologist who treats patients with substance use disorders, including those involving cannabis. “Practically speaking, if you have an effective medication that can be more easily distributed to patients who need it, it would lead to a lot of improvement in people’s lives.”
Haney suggests that other options, such as using a combination of medication and therapy, may help more people. And not everyone with cannabis use disorder wants to stop use completely, Piazza notes. He contends that AEF0117 could help people take back control over their use to any desired level.
“The new therapy could bring someone who has excess cannabis use back to [a] recreational use [level]. They would go to the point that everyone starts at,” Piazza says. “If some of them want to stop completely, the drug may help them to do that as well.”