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.

(MORE: Can’t Sleep? Losing Belly Fat Might Help)

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.

(MORE: Sleeping It Off: How Alcohol Affects Sleep Quality)

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.

(MORE: Study: Sleeping Pills Linked with Early Death)

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.

(MORE: Are You Happy? You Might Have Hypocretin to Thank)

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.

44 comments
baxter
baxter

It sounds very promising.... My doctor recently prescribed a pill called intermezzo for me and it's been working really well. It's a tablet that melts under your tongue and you immediately fall asleep. It's really fast acting (they instruct you to already be in bed before taking the pill!) and you get no grogginess in the morning. It's supposed to be taken when you wake up in the middle of the night and can't go back to bed but I've also had success taking it in the beginning of the night. It's like ambien without the side effects. 

mahamiou
mahamiou

@OraElAlaoui j'ai lu j'attendrais que d'autres cobayes essayent les 10 premières années avant :)

NiMiXus
NiMiXus

@TIME Interesting report. Clonazepam and the like also work as sleeping remedy but have grogginess. Old World remedies are the best.

EvelynConnaway
EvelynConnaway

We once had a great sleeping pill, PLACIDYL, manufactured by Abbott , with no after effects.  My first time to use it was, after the death of a loved one, when sleeping is really hard, as you dream and can't really sleep well.  My doctor wrote me a prescription and it was wonderful, sleep with no bad dreams and you wake up with no after effects!  I have never found out why they quit making the drug.  Drug companies quit making a lot of good drugs, for no real reason that I have found out - maybe they weren't making enough money on them.

hotandbothered
hotandbothered

I have chronic pain with a disruptive sleep pattern, RA, Lupus, 4 other auto-immune diseases, 7 degenerative discs and spinal stenosis. I never stop hurting. Stress is a large part of my life - dad has dementia, my health's very poor, etc - and it's not easily dismissed by a 'cup of tea' or 'breath exercises' or 'just let the stress go and learn to relax..." Life is a challenge for me but I'm doing my best. My dr prescribed a pill for me last year and it's been such a help. It's a sleeping pill. It works. It's not overpowering, you drift off to sleep quite nicely. I've never woken up feeling tired or have that 'druggy feeling' even if I'm wakened after only 3 hours of sleep for emergency visits to the hospital to care for my dad or when my pain wakes me up. I don't have any side effects. I don't feel addicted to it. I go a week sometimes before I have a long, hard night where sleep won't come and even though it's 2 or 3 in the morning I can take it and still get some good sleep before having to rise in the morning. I don't know if it's okay to mention the pill. I'll name it and maybe it can help someone else. Temazepam

Caroline Khalil
Caroline Khalil

A message to the governments of the world Save the Copts of Egypt, we are suffering from a religious distinction deliberately by the Islamist government led by Mohamed Morsi, the Egyptian president was killed the day before yesterday 8 Copts in the Mar Girgis Church in particular area in Cairo in front of the police and the distress center of the Egyptian army, who refused to intervene Save the Copts of Egypt from the Islamic oppression

BorisIII
BorisIII

If scientist want to study peoples dreams they should give them Ambien.  Listened to my mom talk to us about the dreams she was having while awake.  And of course she was sleep walking while trying to get some food out of the kitchen. 

cocosyder
cocosyder

Please let me know when Duke gets this for aclinical trial. I will be first in line

Nicki McAleer
Nicki McAleer

As someone who has been attempting to fix sleep problems for about 15 years, I'd be grateful for a low-risk prescription sleep aid...if it worked. The biggest problem with medications is that you have no idea how they'll affect you, even if they've been widely proven to work well. For me, getting to sleep is hard enough, but completing the two or three REM cycles needed per night is near impossible, and always seems to lead to an all-day hangover.

Emmie Moore
Emmie Moore

Instead of always drinking coffee flaved water,teas sports water try some old fashion home made fruit n vagtable drinks there is a cure that! What they want to think. Wake up amerieca!!!!!!! It' not a joke stores are fully bad foods in packges don't buy them.

Emmie Moore
Emmie Moore

Why don't they tell the truth! it in some of the food we eat, keep all electronic devices far from your bed and start using and taking care of yourself wit. Old time remedies if you can at least try the new are distroying our health a long with sport,n health drinkiks we don't need all these med's that we are given use comoncese, use wisdom ask your gramama!

Andy Pratt
Andy Pratt

No such thing as a cure all. Best to deal with things in stride.

Christy Virgil
Christy Virgil

Just what this country needs! More drugs...not!!

Rita Sor
Rita Sor

Id also have a sleep disorder:(

DunneDunnej33
DunneDunnej33

@TIME sleeping pills saves lives --i believe it saves mine---saves me from feeling totally frustrated

KarlGra
KarlGra

@TIME Sometimes or very often the side effects are tragic. Better option: warm milk & cinnamon, reading & positive thinking.

kujakupoet
kujakupoet

@TIME Agh. We need need medicines that do the opposite of that to treat narcolepsy.

usedtobgop
usedtobgop

@TIME Or people could just get off their behinds in the evening and do something that makes them tired enough to sleep.

CaloriesProper
CaloriesProper

Our 24-7 overstressed lifestyle probably causes crappy sleep, and we can't afford to be groggy or forgetful for half the day.  This may be the second best thing to a chill pill.  And if your metabolic health is anything but pristine, you can't afford crappy sleep either - eg, http://caloriesproper.com/?p=1228.


purpleenergy
purpleenergy

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rpearlston
rpearlston

@KarlGra @TIME And that doesn't always work.  

Even as an infant, I was a poor sleeper.  I tried warm milk, and it did nothing for me.  Then I tried a small drink, and it helped a bit.  (I never was a big drinker, so one drink would be enough).  Sleeping pills work for me, but I when I was still in school, and then when I was still working, I had to wait to use them until a Friday or Saturday night, so that I could sleep them off.  

Reading and positive thinking isn't always enough.  The tragic results tend to happen when people don't take their meds or don't take them seriously.  As usual, it's about personal responsibility.  And on that point, while your solution may work for you, it's not really responsible to be telling people, carte blanche, that sleeping pills have tragic side effects when you have no idea why or how someone else may be taking them.

cocosyder
cocosyder

Physical activity in the evening is just what not to do.  Exercise earlier

rpearlston
rpearlston

@usedtobgop @TIME That's arrogant.  Not everyone sleeps as easily as you believe.  For many such people, the usual "sleep hygiene" advice (the stuff that you trumpet so loudly) simply does not and cannot work.

rlm_11
rlm_11

While I agree that 1.) we shouldn't be so quick to medicate people the way we do and 2.) a good stretch session before bed does me wonders, serious sleep problems aren't as easily fixed with just stretching, drinking tea, and relaxing.

rpearlston
rpearlston

@purpleenergy And where are the testimonials from all of the people for whom this concoction does not work?  That's one of the problems with testimonials - only the positive ones are ever used.  So, there could be two positives and ten negatives, but you'll never see/hear about the negatives.

That's aside from the fact that 1) natural does not mean safe, and 2) I strongly suspect that you are advertising a product here.  For that, you have been reported.

purpleenergy
purpleenergy

@rpearlston @purpleenergy vedic research and innovation is a no profit organisation working towards the development of natural pain relievers as it is being felt all over the world that pain killers had been doing more harm to the human body.These plates were developed by eip, usa and swiss tesla plates but their prices were too high for the lay men.We came along with a purple plate for $5.00 in 2007. Yes and we wanted to tell more and more people worldwide about this so that they can benefit.You did what you felt was right for you and it for the readers to decide whats right n wrong.