A restful night’s sleep might make a cup of coffee less of a desperate need first thing in the morning. But pharmaceutical companies are looking into whether the latest pills to promise sound, natural sleep could also play an active role in overcoming even the most powerful addictions.

The new sleep aids block the activity of brain peptides called orexins. These tiny proteins keep us wide awake and attentive during the day, and they also govern some stimulating effects of addictive drugs. Orexins do not cause addiction or relapse directly, but neither happens without the peptides’ participation.

The intriguing connection between sleep and addiction has long been observed in people who suffer from narcolepsy—a disorder that causes sudden-onset sleep. Although narcoleptics were sometimes treated with potent amphetamines to help them stay awake, they never became addicted to the drugs. By 1998 genetic detective work had traced the cause of narcolepsy to mutations in the genes for orexins or their receptors—discoveries that revealed both the peptides’ existence and their critical role in keeping the brain awake. Efforts to turn those insights into novel insomnia treatments have led to several compounds that are now in late-stage clinical trials.

The same companies developing these sleep aids are also investigat-ing orexins’ role in addiction through research in animals. In a recent study Davide Quarta and his co-workers at Glaxo­SmithKline Medicines Research Center in Verona, Italy, confirmed that when the company’s experimental orexin blocker SB-334867 was admin­istered to rats along with amphetamine their brains released less dopamine and they became less sensitized to the stimulant than controls did, even with repeated doses. Sensitized neurons grow extra receptors for the craved drug, demanding more of it to achieve stimulation, thereby fueling a cycle that leads to addiction.

John J. Renger and his colleagues at Merck also showed that a different experimental orexin blocker, administered with amphetamine to rats, prevented sensitization. In the same study, the company’s dual orexin-receptor antagonist (DORA), administered along with nicotine to rats that were previously addicted to nicotine, prevented the animals from relapsing.

“What we showed was not that orexins are a target of amphetamine,” Renger explains, “because we know amphetamine targets dopamine.” The brain’s release of orexins in response to the stimulants, however, enhances dopamine’s downstream activities that lead to sensitization and addiction. “Orexin sets the tone,” Renger says, that enables those brain changes to occur.

As narcolepsy illustrates in the extreme, a lack of orexin removes a barrier to sleep. For that reason, the new orexin-blocking sleep aids may facilitate more natural slumber than current sleeping pills, which depress brain activity generally and therefore have to fight “wake” signals, including orexin.

Stimulant drugs may produce a similarly unnatural imitation of normal stimuli, Renger speculates, which could explain why orexins play a role in facilitating the dopamine-driven learning and reward processes that lead to addiction. The animal studies indicate that administering orexin blockers with a stimulant drug could facilitate unlearning the addiction, too.

The companies have not announced plans to develop orexin blockers for substance abuse treatment, but Renger notes that once the sleep aids reach the market, they may help toward that end just by facilitating a good night’s sleep. “There’s evidence out there that one of the major reasons for alcoholics to relapse is insomnia,” he explains, “because they relied on it to help them get to sleep.” The orexin-blocking sleeping pills might provide a better-quality sleep than alcohol-induced unconsciousness. Whether they are the first sleeping pills guaranteed not to be addictive remains to be seen.