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Ketamine disrupts memories to help heavy drinkers cut back

Fighting addiction means navigating a minefield of memories. A drive past an old hangout, an encounter with a drinking buddy, or a glimpse of a TV commercial can call up strong, positive associations that draw someone back into smoking, drinking, or drug use.

Now, researchers have used the anesthetic ketamine to try to dismantle these associations. The result: Heavy drinkers reduced their alcohol consumption for at least 9 months.

Long-term memories rely on the strength of connections between networks of neurons. Incorporating new information into a memory—for example, updating your understanding of traffic laws to drive in a foreign country—requires a brief upheaval at the junctions between neurons, called synapses, where cells transmit their chemical signals. During that disturbance, some of the proteins at the synapse that help receive and interpret these signals get broken down and recycled.

To edit and restabilize the memory, researchers have found that one type of receptor protein, called the N-methyl-D-aspartate (NMDA) receptor, is especially important. It can set off processes inside a neuron to make new synaptic proteins that in turn influence the strength of the connection between a neuron and its neighbor.

That’s where ketamine comes in. The popular recreational drug has long been used in anesthesia and a form of ketamine was approved this year in the United States to treat severe depression. Researchers are studying its potential to treat several other conditions, including addiction and post-traumatic stress disorder. Although scientists don’t understand all of ketamine’s mechanisms, one of its central features is especially interesting to addiction researchers: its ability to block NMDA receptors—and thus potentially keep the brain from restabilizing a memory.

To see whether this approach could help people reduce drinking, Ravi Das, a psychopharmacologist at University College London, and colleagues recruited 90 “harmful drinkers.” The volunteers consumed, on average, about 30 pints of beer a week and wanted to cut down, but they had not been diagnosed with addiction.

In one visit to the lab, 30 participants sat in front of a glass of beer and observed a sequence of four onscreen photos of beer along with a few pictures of nonalcoholic beverages. They rated their urge to drink the beer and how much they thought they would enjoy it. Then the screen prompted them to pick up the beer and drink it. On the next visit, they saw the four beer images again, but after the prompt to pick up the beer, the screen cut off. No beer today, after all. Minutes later, they got a single high dose of intravenous ketamine.

In essence, the researchers were trying to create a surprise that would prompt the brain to update some of its alcohol-related memories, and then use ketamine to prevent the memories from restabilizing. That process, they hoped, would interfere with the associations in the brain between drinking and reward that drive cravings.

In addition to this “retrieval plus ketamine” group that got the beer-related surprise, the study also included two control groups: 30 people who went through the beer-anticipation task but got a placebo injection instead of ketamine, and 30 more who got ketamine after a different “surprise” task where the available beverage and the onscreen images were orange juice, not beer.

Ten days after the experiment, the retrieval plus ketamine group was the only one of the three groups to report a significant decrease in their urge to drink a beer placed in front of them. They also reported liking the beer less and having less of an urge to drink more beer after that first one.

In the days and months after the experiment, all three groups managed to reduce their drinking, but the retrieval plus ketamine group, which happened to have slightly higher drinking levels at the start of the study, showed the most dramatic reduction. Ten days after the experiment, this group reported drinking about 10 fewer pints a week than before the experiment. By 9 months, they had cut their weekly beer consumption roughly in half, the researchers report today in Nature Communications. Not all these benefits are necessarily due to the memory disruption, though: Both control groups showed roughly a 35% reduction in drinking at 9 months.

“To actually get changes in [participants’] behavior when they go home and they’re not in the lab is a big deal,” says Mary Torregrossa, a neuroscientist who studies addiction at the University of Pittsburgh in Pennsylvania. But without any brain imaging data, “we don’t know exactly what happened to the memory,” she says. A single encounter with a glass of beer and a few photos clearly didn’t totally upend the participants understanding of what a beer is or what it’s like to drink one. But it could have subtly changed subconscious processes that drive the emotional reaction to alcohol, she says.

Ketamine may well affect the brain in other ways that can influence alcohol consumption, Torregrossa adds. But because it’s an approved drug with a good safety record, “it’s a pretty obvious direction to go” in developing treatment.

If evoking and disrupting memories before ketamine use boosts its effects, as this study’s comparison to the orange juice group suggests, it’s a pretty simple activity to add to a treatment, Das says. His group is now planning to analyze electroencephalography data taken during these experiments to looks for possible predictors of a good response.