A Sleeping Pill Without The Sleepy Head?

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Current sleep remedies risk addiction and memory problems, but a new class of medications may avoid these issues.

(UPDATED) A good night’s sleep is hard to get— up to 70 million Americans have disorders that disrupt their nightly slumber and take a toll on their daily activities, according to the latest government data. Among those under age 25, 44% reported falling asleep at least once in the past month because they were sleep deprived. But medications that help us to nod off may not always be safe. Sleeping pills don’t always lead to a restful night’s sleep, and studies show they can impair memory or even become habit-forming.

But in a study published in Science Translational Medicine, researchers led by Jason Uslaner of Merck found that an experimental agent known as DORA-22 can promote sleep in both rhesus monkeys and rats, without affecting memory or reaction time.  DORA-22 is part of a class of new drugs — one of which the Food and Drug Administration is already considering for approval — known as orexin antagonists.

“It’s high quality research,” says Jerome Siegel, professor of psychiatry at University of California Los Angeles, who was not associated with the study.

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The authors compared the sleep-inducing effects of DORA-22 to those of three well-known sleeping pills: diazepam (Valium), zolpidem (Ambien) and eszopiclone (Lunesta), which work by slowing down brain activity. Immediately after giving the animals the drugs, the scientists tested the animals’ memory and reaction time. (While most people take sleeping pills before going to bed, such effects are important to document so researchers, and users, can fully understand how their brains and bodies are affected by the medications in case people don’t take the drugs as prescribed.)

“It’s very enticing because there are some clear results that show [that these drugs] differ from old hypnotic drugs in terms of affecting cognition and memory in two animal species,” says Dr. Emmanuel Mignot, director of the Stanford Center for Sleep Sciences, who wrote a commentary on the research, which was published in Science.

Rats given high enough doses to cause sleep of the three currently available drugs  had difficulty recognizing whether they had seen an object previously presented to them, while those dosed with DORA-22 did not show such compromised recall. Similarly, all of the drugs except DORA-22 reduced rhesus monkeys’ ability to react to a touch screen and correctly choose a colored square associated with a reward. In fact, even at doses 30 times higher than the lowest amount needed to affect sleep, the drug did not impair performance on this task.

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What makes this new class of drugs different? Orexins, which are also known as hypocretins, are brain chemicals that promote wakefulness. Of the brain’s billions of neurons, only tens of thousands produce orexins. People with narcolepsy who have difficulty staying awake and are prone to suddenly falling asleep without warning are missing almost all of the neurons that produce these chemicals. DORA-22 and similar drugs work by blocking orexins by essentially producing a brief and reversible bout of narcolepsy.

“DORA binds to orexin receptors in the brain, which are located in areas that control sleep and wakefulness,” says John Renger, a co-author of the study and executive director of neuroscience at Merck, which funded the research. “At night orexin levels [normally] go down. [DORA works] by  mimicking what happens in the normal system where signaling in this system goes away at night.” The drug blocks orexin receptors so any of chemical that may be circulating can’t bind to its receptors and contribute to wakefulness.

In contrast, most of the currently available sleep drugs affect GABA, which is among the most prevalent chemicals found in the brain and is associated with calming the brain. While activating GABA can induce sleep, it may also cloud thinking and memory. But these drugs can also be addictive, both because they rapidly reduce anxiety and because they affect dopamine neurons that are associated with pleasure.

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The search for a sleeping agent without these potential side effects has long been a difficult one. “There are booms and busts,” says Mignot, noting that each generation of pills has been hailed as having fewer adverse effects than the previous one, only to show similar or new problems after several years on the market.  Ambien and Lunesta, for example, may have less addictive potential than Valium and Xanax which came before them,  but the newer drugs also seem to cause more problems with memory than the older class.

But because the orexin-blockers don’t seem to loop in the pleasure centers of the brain as the existing sleep medications do, they could also have a side effect of prompted bad moods, says Siegel, although that’s not such a problem if it only lasts a few minutes before you fall asleep.

He also points out that being anxious or in pain, both conditions associated with poor sleep, are linked with lower levels of orexin. Blocking orexin receptors in these people, then, wouldn’t help to improve sleep since orexin levels are already low. “It may be ineffective in exactly the population who needs it, people who are depressed and anxious, who probably have minimal levels of [orexin] to start with,” he says.

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More research will be needed to better understand these effects, and that data may be available soon since other agents that work on the orexin system are further along in human testing than DORA-22. Merck has conducted three successful clinical trials with another compound, suvorexant, and the FDA will meet to consider those results in May. Renger says that so far, those late stage clinical findings show that suvorexant helps people get to sleep faster and increases the time that patients stay asleep, compared to placebo.*

But only after such drugs make it to the market— if they ever do— will we know if a new generation of sleeping pills will finally let us rest easy.

*Updated to correct misstatement by Renger regarding the drugs to which suvorexant has already been compared.