Sleeping pills probably do more harm than good

Diet and lifestyle 28. aug 2022 3 min Professor Maiken Nedergaard Written by Kristian Sjøgren

People take sleeping pills to fall asleep, to sleep well and be well rested the next day. However, new research into the effect of norepinephrine in the brain suggests that sleeping pills probably do more harm than good. The reason is that the sleeping pills affect tiny oscillations in norepinephrine in the brain, which are necessary for a good night’s sleep.

Researchers have long known that norepinephrine, a hormone, is one of the key regulators of sleep. The levels of norepinephrine rise during the day, and when levels are low, we fall asleep and then sleep.

In addition, norepinephrine plays a major role in stress and the ability to focus. It is also essential for the glymphatic system, which removes waste substances from the brain when we sleep, so that we can wake up refreshed and well rested.

A new study published in Nature Neuroscience reveals that norepinephrine not only shapes the macroscale aspects of sleep but also regulates brain activity at the microscopic level.

The study shows that the levels of norepinephrine in the neurons oscillate several times a minute during the night.

This discovery is crucial for understanding the role of norepinephrine in high-quality sleep but also has clinical significance in relation to the use of sleeping pills and the development of dementia.

“In our study, we identified a completely new sleep microarchitecture that promotes memory and whether you wake up refreshed and feel that you have had a good night’s sleep. This also means that we identified an area that requires caution in manipulating with sleeping pills, since this can affect both memory and the benefits of sleep,” explains a researcher behind the study, Maiken Nedergaard, doctor and Professor at the University of Copenhagen, Denmark and the University of Rochester, United States.

Inducing the brain to fluoresce

The researchers used an advanced technology called fibre photometry to study norepinephrine in the neurons in the brain of mice in sleep studies.

Using fibre photometry, researchers insert a small glass tube into the brain of the mice. The researchers then inject a noradrenaline biosensor into the mice, and it fluoresces according to the activity of noradrenaline in the brain.

The advantage of fibre photometry is that the researchers do not have to study the mouse brains under a microscope, which would not be optimal for studying sleep because the mice have to be restrained, and restrained animals rarely fall asleep or sleep very well.

“However, with fibre photometry we can study the activity of norepinephrine in their brains when they sleep in their own cage and feel more secure,” says Maiken Nedergaard.

Norepinephrine constantly oscillates throughout the night

This study led to interesting discoveries. To their great surprise, the researchers found that norepinephrine influences not only the macroscale patterns of sleep but also the microscopic patterns.

During non–rapid eye movement sleep, the activity of norepinephrine in the neurons oscillates about every 30 seconds, which adds up to many hundreds of oscillations during the night. This is completely new and important knowledge.

“The activity of norepinephrine oscillates for a reason. It has long been known that the beneficial effect of sleep can be measured by sleep spindles, bursts of sigma neural oscillatory activity during non–rapid eye movement sleep. These are important for both humans and animals so that we wake up rested and have improved memory the next morning. We show in the study that sleep spindles only occur during the norepinephrine oscillations. If norepinephrine does not oscillate, there are no sleep spindles and the animals remember less well. That is, they wake up and have slept poorly,” explains Maiken Nedergaard.

Norepinephrine affects memory

Maiken Nedergaard explains that sleep researchers broadly agree on the specific characteristics of good and poor sleep.

Waking up in the middle of sleep Is not good, and waking up many times during a long period of sleep is actually much worse than sleeping for a shorter time.

Poor sleep is also clearly linked to many diseases, from obesity to dementia. The quality of sleep is also crucial for memory.

The researchers therefore also investigated how the norepinephrine oscillations affected the brain’s sleep spindles and thus the mice’s memory. They manipulated the norepinephrine oscillations so that they either became longer or smoothed out. They then examined how this affected the mice’s ability to remember various objects they had seen just before falling asleep. In this context, mice tend to prefer to investigate objects they have not seen before.

Sleep medication impairs memory among older people

The mice with good oscillations in norepinephrine had improved memory. The mice with the smoothed-out oscillations in norepinephrine had severely impaired memory, and excessive oscillations in norepinephrine woke the mice up.

Maiken Nedergaard explains that these findings are clinically relevant, since sleeping pills inhibit oscillations in norepinephrine. This means that they make people fall asleep but probably negatively affect not only memory but also the brain’s ability to clear waste substances during sleep.

“Inhibiting the oscillations prevents getting the restorative sleep that you need. This can have major consequences. Many nursing home residents with dementia are given sleeping pills because they often have difficulty in sleeping continuously throughout the night. Our study indicates that this may be a bad idea because it will further impair their memory by eliminating the norepinephrine oscillations,” says Maiken Nedergaard.

Maiken Nedergaard says that the study indicates a need to develop sleeping pills that instead stabilize the oscillations in noradrenaline in the brain, since this will lead to better and more restorative sleep.

“Such sleeping aids will probably also help the brain to clear waste substances during sleep, since noradrenaline and its oscillations play a major role in the glymphatic system, which helps the brain to remove waste products during sleep,” she concludes.

Memory-enhancing properties of sleep depend on the oscillatory amplitude of norepinephrine” has been published in Nature Neuroscience. In 2014, the Novo Nordisk Foundation awarded a grant to Maiken Nedergaard and Steven A. Goldman towards establishing the Center for Translational Neuromedicine at the University of Copenhagen.

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