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Published On November 14, 2018

CLINICAL RESEARCH

Your Brain on Drugs, Revisited

People with drug addictions produce more of a certain brain chemical—and research may point to new ways to block it.

The Department of Health and Human Services spent more than $1 billion in September to combat the opioid crisis, and in October, Congress passed a sweeping bill to put another $8.5 billion to the same purpose. Yet a weak spot for the national response has always been treatment, which is still made available to only 1 in 10 people who have opioid use disorder.

Part of the problem is a dearth of effective medications. The gold standard would be a medication that could tame the cravings that addiction etches into the brain, and a new treatment now beginning clinical trials may offer some hope of meeting this goal. It owes its discovery, curiously, to the study of narcolepsy.

Narcolepsy is a condition that causes daytime sleepiness and cataplexy, which involves episodes of muscle weakness brought on by strong emotions. These symptoms arise as a result of the loss of certain cells in the hypothalamus that produce a protein important for staying awake and alert.

Because it was isolated simultaneously by two groups of scientists, this single protein goes by two names—orexin and hypocretin. It has been the subject of intense scrutiny by narcolepsy researchers, including Jerry Siegel from the Department of Psychiatry and Brain Research Institute at the University of California, Los Angeles.

Twelve years ago, Siegel was looking for control tissue—slices of normal brains that he could compare with brain tissue from people with narcolepsy, whose brains lack hypocretin-producing cells. A colleague in Siegel’s lab told him that a control brain Siegel had recently acquired had 50% more of those types of cells than normal. This individual had died of cancer. Then came the surprise that led to a possible link to addiction. The scientists discovered that the donor of the brain in question had been addicted to heroin, although he had stopped using it prior to his death.

Over the next several years, the UCLA-led team obtained four additional brains from people who had died of opiate overdoses. Each of those brains also had a higher-than-usual number of hypocretin-producing cells. The researchers then found that they could similarly produce additional hypocretin cells in mice by giving them morphine. The number of hypocretin-producing cells in the mice brains returned to normal levels after four weeks without morphine.

Based on those results, in fall 2018 researchers at the 7th International Symposium on Narcolepsy discussed the controversial notion of giving opioid drugs to people with narcolepsy to see if that could boost their numbers of hypocretin-producing cells and alleviate their symptoms. A few case reports support the idea that this would be effective, but several scientists said that the risk of addiction and other side effects was too great for it to become a viable treatment for narcolepsy.

Siegel suggested a different approach—looking at those addicted to opioids who have an excess of hypocretin-producing cells. Before Siegel’s discovery of the excess cells in these patients, other researchers had looked at the curious role hypocretin may play in addiction. “We look at orexin [or hypocretin] as a molecule for translating motivation into action,” says Gary Aston-Jones, director of the Brain Health Institute at Rutgers University in Piscataway, N.J. He and his colleagues recently published a paper in Biological Psychiatry showing an increase in the number of hypocretin-producing neurons in the brains of rats exposed to cocaine, resembling Siegel’s observations of the effect of opioids on humans.

Two drugs prone to abuse, heroin and cocaine, act on the brain chemically in different ways but both provoke persistent increases in hypocretin-producing neurons. This suggests that the cells may play a role in addiction itself, according to Stephanie Borgland, a researcher at the Hotchkiss Brain Institute at the University of Calgary in Canada.

If having extra hypocretin-producing cells possibly contributes to addiction, the next logical step in this line of research might be to study the effects of selectively pruning those cells. That’s not possible with current technology, but several labs have been able to explore the effect of temporarily blocking hypocretin’s signals, and Aston-Jones’ group found that doing so can blunt the enthusiasm with which rats seek cocaine.

In fact, there are already medications that block hypocretin receptors. Searching for a blockbuster sleep aid, pharmaceutical companies explored the impact of such compounds under the premise that inducing a temporary state echoing narcolepsy might help people to sleep at night. One of the compounds, suvorexant, was developed by Merck and marketed as Belsomra, which would be approved by the Food and Drug Administration in 2014.

While many medications, such as methadone, have been used to reduce opioid drug cravings, there is no approved drug for people with cocaine or amphetamine problems, and finding a long-term treatment is paramount because of the prevalence of the addiction. A pilot study of the use of suvorexant in people being treated for opioid use and insomnia is currently being started in a residential facility at Penn State University, and a similar study at University of Texas Health Science Center in Houston involving cocaine users just wrapped up.

Siegel and other teams studying the hypocretin-producing cells are, for their part, excited by the prospect of finding an avenue to help with the opioid crisis. “We should have a role in fixing this,” Siegel says.