By ALEXIS MADRIGAL
Dec. 28, 2007

In what sounds like a dream for millions of tired coffee drinkers, Darpa-funded scientists might have found a drug that will eliminate sleepiness.

A nasal spray containing a naturally occurring brain hormone called orexin A reversed the effects of sleep deprivation in monkeys, allowing them to perform like well-rested monkeys on cognitive tests. The discovery's first application will probably be in treatment of the severe sleep disorder narcolepsy.

The treatment is "a totally new route for increasing arousal, and the new study shows it to be relatively benign," said Jerome Siegel, a professor of psychiatry at UCLA and a co-author of the paper. "It reduces sleepiness without causing edginess."


Orexin A is a promising candidate to become a "sleep replacement" drug. For decades, stimulants have been used to combat sleepiness, but they can be addictive and often have side effects, including raising blood pressure or causing mood swings. The military, for example, administers amphetamines to pilots flying long distances, and has funded research into new drugs like the stimulant modafinil and orexin A in an effort to help troops stay awake with the fewest side effects.

The monkeys were deprived of sleep for 30 to 36 hours and then given either orexin A or a saline placebo before taking standard cognitive tests. The monkeys given orexin A in a nasal spray scored about the same as alert monkeys, while the saline-control group was severely impaired.

The study, published in the Dec. 26 edition of The Journal of Neuroscience, found orexin A not only restored monkeys' cognitive abilities but made their brains look "awake" in PET scans.

Siegel said that orexin A is unique in that it only had an impact on sleepy monkeys, not alert ones, and that it is "specific in reversing the effects of sleepiness" without other impacts on the brain.

Such a product could be widely desired by the more than 70 percent of Americans who the National Sleep Foundation estimates get less than the generally recommended eight hours of sleep per night.


The research follows the discovery by Siegel that the absence of orexin A appears to cause narcolepsy. That finding pointed to a major role for the peptide's absence in causing sleepiness. It stood to reason that if the deficit of orexin A makes people sleepy, adding it back into the brain would reduce the effects, said Siegel.

"What we've been doing so far is increasing arousal without dealing with the underlying problem," he said. "If the underlying deficit is a loss of orexin, and it clearly is, then the best treatment would be orexin."

Dr. Michael Twery, director of the National Center on Sleep Disorders Research, said that while research into drugs for sleepiness is "very interesting," he cautioned that the long-term consequences of not sleeping were not well-known.


Both Twery and Siegel noted that it is unclear whether or not treating the brain chemistry behind sleepiness would alleviate the other problems associated with sleep deprivation.

"New research indicates that not getting enough sleep is associated with increased risk of cardiovascular disease and metabolic disorders," said Twery.

Still, Siegel said that Americans already recognize that sleepiness is a problem and have long treated it with a variety of stimulants.

"We have to realize that we are already living in a society where we are already self-medicating with caffeine," he said.

He also said that modafinil, which is marketed as Provigil by Cephalon and Alertec in Canada, has become widely used by healthy individuals for managing sleepiness.

"We have these other precedents, and it's not clear that you can't use orexin A temporarily to reduce sleep," said Siegel. "On the other hand, you'd have to be a fool to advocate taking this and reducing sleep as much as possible."

Sleep advocates probably won't have to worry about orexin A reaching drugstore shelves for many years. Any commercial treatment using the substance would need approval from the Food and Drug Administration, which can take more than a decade.