Although a possible human application is years away, scientists have reported promising developments with a drug that could reduce marijuana addiction and relapse. A new compound increases levels of kynurenic acid in the brain, reducing the dopamine-related rewarding effects of cannabinoids, according to an animal study published online in Nature Neuroscience on Oct. 13. Two of the authors of the multi-site study explained how the drug could work in an interview with Addiction Professional in December.
Like other drugs of abuse, marijuana produces rewarding effects that reinforce drug-taking by increasing the activity of dopamine in pleasure centers in the brain, says Steven R. Goldberg, PhD, senior investigator for the National Institute on Drug Abuse (NIDA), where he is chief of the clinical pharmacology section. “Kynurenic acid is a major neuromodulator that controls dopamine,” Goldberg says. “So if you can change the levels of kynurenic acid, you can damper the influence of marijuana.”
It is likely that kynurenic acid, also known as KYNA, would work in similar ways with other drugs of abuse, says Goldberg. “We’re getting similar effects with nicotine, but not with cocaine so far,” he says, noting that cocaine produces changes in dopamine activity through a different mechanism from that of the cannabinoid receptors.
The research drug that was used to change the levels of kynurenic acid in the study, referred to only as “Ro 61-8048” in the animal study paper, increases KYNA levels in the brain.
To test it out on animals, the researchers used two straightforward behavioral procedures. In one, laboratory monkeys were given the opportunity to press a lever to inject themselves intravenously with the psychoactive ingredient of marijuana. “They do that easily,” says Goldberg. When the researchers increased the levels of KYNA, the animals reduced the amount of drug they self-injected, indicating that it was no longer as rewarding. The elevation of KYNA was also able to block relapse in the animals, says Goldberg.
Both indicators are important, because it’s one thing to get people to stop using drugs, but another to get them to avoid relapse, says Goldberg.
The KYNA “appears to be reducing the rewarding effect of THC,” says Zuzana Justinova, MD, PhD, an animal biologist who works with Goldberg at NIDA and is the lead author of the paper, titled “Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.” If the dose of tetrahydrocannabinol (THC) is increased dramatically—30-fold—then the monkeys will administer it even with elevated KYNA levels. But that kind of elevation would not occur in real life with marijuana, says Goldberg.
The KYNA elevation is blocking the behavior of self-administering the THC, which is not the same as an actual blockade effect like that of naltrexone on opioids, explains Goldberg. “Naltrexone actually binds to the receptors in the brain where opioids have their effect,” he says. “That’s not what’s going on here.”
Injecting similar to smoking
Because smoking is not practical with lab animals for a number of reasons, researchers used the injection route of administration. When the researchers first established the self-administration model in monkeys for THC, they were looking for a dose that would be similar to what humans consume, says Justinova. “We were the first lab that picked the right dose,” she says. Each lever-push is about 4 micrograms per kilogram, which is very similar to what humans get in a single puff, she says.
Researchers have tried, particularly with nicotine addiction studies, to develop monkey smoking procedures for more than 20 years, says Goldberg. “The problem is that smoking initially is an aversive event, and you have to learn that you can push past the aversiveness and get the pleasurable effect” of the nicotine, he says. When researchers could get monkeys to actually inhale cigarettes, they would continue inhaling whether or not the cigarettes had nicotine in them, making this process useless for nicotine studies.
The other challenge is that it’s difficult to administer a drug via inhaling in a dose-controlled way, Goldberg says. Anything that is smoked is getting into the brain quickly, more comparable to intravenous injection, he says, noting that the more rapid the onset after administration, the more addictive a drug is.
There are physical withdrawal symptoms for someone who is dependent on marijuana, but these aren’t as dramatic as they are for opioids, says Justinova. “But if people take marijuana every day and then stop, the physical symptoms can become severe,” she says. Withdrawal and craving lead to relapse.
Rimonabant and side effects
Why can’t researchers use antagonists of cannabinoid receptors to prevent marijuana use, the way naltrexone is an antagonist of opioid receptors and blocks any response to opioids? “That’s a good question,” says Goldberg. There was just such a drug: rimonabant, which was in clinical use for weight reduction overseas, he says. Its approval was held off in the United States because of Food and Drug Administration (FDA) concerns about potential side effects. After three years’ use in Europe, psychiatric side effects were reported, and the research was dropped.
“It wasn’t just for weight loss—it was a very promising drug for smoking cessation,” Justinova says of rimonabant. “People were using it off-label for smoking cessation.”