Semaglutide shows potential to curb cocaine addiction behaviors

A new study published in European Neuropsychopharmacology suggests that semaglutide, a drug already used to treat type 2 diabetes and obesity, may also help reduce cocaine use, drug-seeking behavior, and relapse in preclinical models. The research found that semaglutide lowered both the motivation to consume cocaine and the amount taken by rats, while also dampening the brain’s response to cocaine. These findings indicate that semaglutide may be a potential candidate for future clinical trials targeting cocaine use disorder, a condition for which no approved medication currently exists.

Cocaine use disorder is a chronic condition marked by strong cravings, loss of control over drug use, and a tendency to relapse after periods of abstinence. Despite its severe public health impact, there are no approved medications specifically designed to treat it. Psychosocial therapies often yield limited success, which has led scientists to explore pharmaceutical alternatives.

One area of interest involves a class of drugs known as glucagon-like peptide-1 receptor agonists. These compounds were originally developed to regulate blood sugar levels in people with type 2 diabetes. More recently, research has shown that they may also influence the brain’s reward systems, which are heavily involved in addiction. One such compound, exendin-4, has been shown to reduce drug-seeking behavior in rodents. However, it has not demonstrated effectiveness in humans, possibly due to its short duration of action and relatively weak binding to its target receptors.

Semaglutide, sold under brand names such as Ozempic, is a longer-acting and more potent version of these drugs. It has become widely known for its use in treating type 2 diabetes and for promoting weight loss. Importantly, earlier studies found that semaglutide reduces alcohol consumption in both animals and people diagnosed with alcohol use disorder. These findings raised the possibility that semaglutide might also reduce other forms of addictive behavior. The present study aimed to investigate whether that potential extends to cocaine use.

“There are currently no treatments for cocaine use disorder, raising the need for new treatments,” said study author Elisabet Jerlhag, a professor of pharmacology at the University of Gothenburg. “Previous studies have shown that GLP-1 receptor agonists like exenatide reduce cocaine responses in animals, but to a low extent. We recently showed that semaglutide, a GLP-1 receptor agonist with higher potency, reduces alcohol-related responses with a high magnitude, and these data were verified in a human clinical trial where semaglutide reduced alcohol drinking in humans with alcohol use disorder. We therefore wanted to investigate if semaglutide reduces cocaine responses with a higher magnitude.”

The researchers conducted a series of experiments in male rats and mice to examine how semaglutide affects cocaine-related behaviors. First, they used a self-administration model in rats, where the animals were trained to press a lever to receive doses of cocaine. After the behavior was well established, rats were given different doses of semaglutide to see whether it would reduce cocaine intake.

Two of the three doses tested (0.026 and 0.039 milligrams per kilogram) significantly lowered the number of lever presses for cocaine. The lowest dose (0.013 milligrams per kilogram) did not have a noticeable effect. The reduction in cocaine-taking was not due to sedation or reduced movement, as overall activity levels remained stable in most cases. Food and water intake did decrease with semaglutide, but these changes were expected and did not indicate nausea, based on a specific test involving kaolin consumption.

The researchers also examined how semaglutide influenced motivation to consume cocaine by using a progressive-ratio schedule, which gradually increases the number of lever presses required to receive each cocaine dose. Both effective doses of semaglutide reduced the animals’ willingness to work for the drug, suggesting a drop in motivation.

Next, the team tested semaglutide’s effect on relapse-like behavior. In this part of the study, rats first learned to self-administer cocaine, then underwent extinction training where cocaine was no longer available. Later, after a single dose of cocaine was given to trigger a craving, the rats were tested to see if they would resume lever pressing. Semaglutide significantly reduced this reinstatement of drug-seeking behavior at the higher doses. Again, the lowest dose had no measurable effect.

In a separate line of experiments, the researchers looked at how semaglutide affected dopamine signaling in the brain. Dopamine is a key neurotransmitter involved in the brain’s reward system and is strongly activated by cocaine use. In both mice and rats, semaglutide reduced the spike in dopamine typically seen after cocaine administration. These reductions were observed using techniques that measure chemical levels in real time within the nucleus accumbens, a region linked to drug reward and reinforcement.

Additional tests in mice showed that semaglutide also blunted the increase in locomotor activity caused by cocaine, a behavior often used as a proxy for the drug’s stimulant effects. Notably, semaglutide by itself did not change baseline dopamine levels or locomotor activity, suggesting that it specifically interferes with the effects of cocaine rather than broadly dulling brain activity or causing fatigue.

To rule out the possibility that semaglutide was simply making the animals feel sick or disoriented, the researchers measured intake of kaolin clay, a behavior in rodents that reflects nausea. Across all experiments, semaglutide did not increase kaolin intake, suggesting that the behavioral changes observed were not caused by malaise.

“We found that semaglutide reduces cocaine intake, motivation to consume cocaine, relapse to cocaine taking behaviors possibly by blocking the cocaine induced reward,” Jerlhag told PsyPost. In particular, there was a “26% reduction in cocaine intake, 52% reduction in motivation to consume cocaine, and 62% reduction in relapse to cocaine taking behaviors.”

While these findings are promising, the researchers emphasize that the study has limitations. Most notably, the behavioral experiments were conducted only in male rats. Although semaglutide has been shown to reduce alcohol and food intake in both male and female rodents, further work is needed to confirm whether the same effects apply to females in the context of cocaine use.

Another limitation is that the exact mechanisms behind semaglutide’s effects on cocaine behavior are not fully understood. Although the reduction in dopamine response provides one clue, the brain’s reward and motivation systems are complex and involve multiple interacting circuits. Future research may explore how semaglutide interacts with these systems, particularly the gut-brain axis, where it is believed to have multiple signaling roles.

There is also a need to determine whether these results translate to humans. Prior studies with similar drugs have shown mixed outcomes in clinical settings, likely due to differences in potency, treatment schedules, and individual variation in patients. Given semaglutide’s longer duration of action and stronger receptor affinity, it may overcome some of the limitations observed with earlier compounds.

Finally, the authors point out that while semaglutide caused some reductions in food and water intake, these effects did not seem to produce significant discomfort in the animals. Even so, understanding how the drug affects patients who are already underweight or have other health complications will be important for evaluating its clinical potential.

The study, “Semaglutide suppresses cocaine taking, seeking, and cocaine-evoked dopamine levels in the nucleus accumbens,” was authored by Cajsa Aranäs, Antonia Caffrey, Christian E. Edvardsson, Heath D. Schmidt, and Elisabet Jerlhag.