Safer sleeping pills keep brain alert to danger

Clinical Trials & Research
Most sleeping pills are so strong that the sound of a fire alarm is unlikely to wake those who take them. However, a new study, published in the journal Frontiers in Behavioral Neuroscience, proposes a safer alternative to these drugs.
woman's hands taking sleeping pills
New research proposes a safer alternative to existing sleeping pills.

One-third of adults in the United States do not get enough sleep on a regular basis, according to the Centers for Disease Control and Prevention (CDC).

Between 50 and 70 million individuals in the country either have sleep disorders such as insomnia or live with sleep deprivation.

The CDC also report that about 4 percent of the U.S. population over the age of 20 take sleeping pills and that this figure tends to increase with age and education.

According to the same source, 1 in 8 adults in the country who have sleeping problems take sleeping aids.

But how safe are these drugs? Researchers have linked various adverse health effects with the prolonged use of sleeping aids, and the risk of addiction is well-known.

New research points to another safety hazard that sleeping pills may pose. Professor Tomoyuki Kuwaki, Ph.D., of Kagoshima University in Japan, and colleagues note in their paper that retaining “the ability to wake from sleep in response to dangerous situations is an ideal characteristic of safe hypnotics.”

But most sleeping pills do not have this characteristic. In a trial of widely used hypnotics quoted by the researchers, half of the participants who took the drugs did not wake up at the sound of a fire alarm.

However, Prof. Kuwaki and the team may have found a solution to this problem. The researchers tested a novel hypnotic drug in mice and found that the rodents woke up as quickly as their drug-free counterparts when confronted with a danger signal. They were also able to fall back asleep just as quickly when the threat was gone.

Studying a safer alternative to sleeping pills

Prof. Kuwaki, who is the senior author of the study, explains how most sleeping pills work. Benzodiazepines, the most widely used type of sleeping aid, suppress our brain’s ability to respond to the sensory information it processes during sleep.

These pills “stimulate the widespread brain receptor GABA-A,” explains the researcher, “which makes us sleepy but also suppresses off-target brain areas — including the ‘gatekeeper’ that decides which sensory inputs to process.”

Prof. Kuwaki and his colleagues hypothesized that a new class of hypnotics, called dual orexin receptor antagonists (DORAs), may enable the brain to stay alert to danger signals, providing a safer alternative to existing sleeping pills.

To test their hypothesis, the researchers administered DORAs to one group of mice, gave another group a benzodiazepine called triazolam, and administered a placebo to the third group.

“DORA-22 and triazolam had similar sleep-promoting effects, extending the duration of deep sleep by 30–40% compared to placebo,” says Prof. Kuwaki.

Within 1–4 hours of giving the mice the sleeping pills, the researchers presented them with various danger signals: the smell of a fox, an alarming sound, or a trembling of their cages, which mimicked an earthquake.

How DORAs affect sleep and wakefulness

“As expected, arousal in response to these threatening stimuli was delayed significantly in the triazolam treatment, but not in the DORA-22 treatment, compared to placebo,” reports the senior author.

Importantly, the sleep-inducing effects of DORA-22 continued after the threat had passed.

“Even though the DORA-22-treated mice were quickly woken by a threat, they subsequently fell back asleep as quickly as with triazolam, and significantly faster than with placebo,” says Prof. Kuwaki.

DORAs are also less likely to induce drowsiness the next day and affect one’s ability to drive vehicles. Human clinical trials are needed to further test the benefits and safety of DORAs, but the researchers are hopeful that the benefits will translate to humans.

Although it remains to be seen whether DORAs have the same properties when used in humans, our study provides important and promising insight into the safety of these hypnotics.”

Professor Tomoyuki Kuwaki

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