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Drug eases cravings in stressed alcoholics

February 14, 2008 By Heidi H Ledford This article courtesy of Nature News.

Changing how the brain responds to stress may help overcome addiction.

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Researchers have found a drug that reduces responses to stress in some recovering alcoholics, and eases their cravings to have a drink.

The results, published online today in Science1, were obtained from a small clinical study of 50 recovering alcoholics, all of whom reported high levels of anxiety at the start of the study. The 25 randomly selected to be given the drug reported fewer cravings than those assigned to receive a placebo, and they had a lessened response to stressful situations.

The drug, called LY686017, might also provide relief from addiction to other drugs, including nicotine and heroin, says study author Markus Heilig, of the National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland. “It’s speculation, but it’s very possible,” he says.

Three drugs are available to treat alcoholism. One, called disulfiram, acts as a deterrent: after a dose of disulfiram, a drink of alcohol can cause vomiting and headaches. Two others drugs, naltrexone and acamprosate, are both meant to ease cravings, but naltrexone does not work in some patients, and whether acamprosate works at all has been debated.

Substance P

LY686017 acts by blocking a signalling molecule called substance P. Substance P has been linked to anxiety, pain, inflammation and depression, and is found in regions of the brain associated with stress responses and drug reward. When substance P signalling is blocked in rodents, they administer themselves less morphine.

But drugs that target this system have disappointed pharmaceutical companies. Once hailed as the next new class of pain relievers, then antidepressants, they failed clinical testing, and only one has made it to the market: aprepitant, which is used to treat nausea and vomiting in patients undergoing chemotherapy.

Meanwhile, Heilig was studying the heightened response to stress by some alcoholics. This anxiety can be the trigger that brings addicts back to the bottle. Heilig and his colleagues decided to test whether blocking substance P signalling could reduce these stress-induced cravings.

The researchers studied mice that were engineered to lack a critical component of the substance P pathway, and found that those mice drank less alcohol than normal mice. They then tested LY686017 in recovering alcoholics who had high levels of anxiety according to a standardized questionnaire.

Stress test

The alcoholics who received LY686017 reported fewer spontaneous cravings for alcohol than did those who received the placebo. But the patients were kept in a hospital, away from the behavioural triggers such as social stress that are present in the outside world. “They may get into a fight with their spouse or at work, and after that they may abstain for some period of time, but then they go past the bar where they used to drink,” says Heilig. “We wanted to mimic that in the lab.”

To create a stressful situation, the researchers led the patients into a room and told them that they had to give a five-minute improvized talk to a committee of people in white coats, as if they were interviewing for their dream job. “No one made it beyond 1.5 minutes. Everyone dried up after that,” says Heilig. “We had stern-looking people on the committee say ‘Your time is not yet up’.” Patients were then allowed to smell alcohol.

Patients who had received LY686017 produced less of the stress hormone cortisol in response to this challenge did than those on placebo. In addition, brain-imaging studies showed that those who received the drug were less disturbed by unpleasant images. Alcoholics normally overreact to such images.

Anxious drinkers

“This might be an approach that could be used for people who drink to relieve stress in their lives, or have anxiety disorders,” says Raymond Anton, director of the Center for Drug & Alcohol Programs at the Medical University of South Carolina in Charleston. But, he adds, there is no evidence to suggest that the treatment would work for those who drink for reasons other than stress.

A larger, multi-centre trial is being planned, says Heilig, which will address whether LY686017 is also effective in alcoholics with lower stress levels.

Regardless, focusing on a particular group of alcoholics may be beneficial, says Anton. “There are many reasons why they start drinking, and many reasons why they keep drinking," he says. "I think the general theme going forward will be one where we try to subtype people rather than thinking that one medication will be useful for everybody."

References

  1. George, D. T. et al. Science 10.1126/science.1153813 (2008).

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