> The brain’s waste-removal process is “like turning on the dishwasher,” a neurologist says, but common sleep medications may harm it"
> The team then tested the impact of Zolpidem (a common sleep medication also known as Ambien or Zolpimist) on this system, and found that the norepinephrine waves during sleep decreased by 50 percent and fluid transport into the brain decreased by around 30 percent in zolpidem-treated mice. These results suggest that sleeping aids that impact norepinephrine production—which includes most sleeping aids—might harm the brain’s waste-removal system.
Anecdata (size = 1): I was going through a phase of terrible sleep, and one day decided to take some CBD. I woke up feeling terrible in the head. I had slept like a log, but it felt in my brain as if I hadn't slept at all!
You say you were going through a phase of terrible sleep. Would you say that particular night of sleep was worse than your average night of sleep during that phase?
Basically, it felt like the body had gone through the motions of sleeping, but the brain felt even more tired than usual. It felt very confusing, as all measures seemed to indicate that I had slept for a solid 8+ hours, but I felt less rested than when I'd gone to sleep. It's like someone hit the "pause" button on the brain processing cycle, and sleep never happened for the brain.
More like a movie theater ? By the end of the day your shoes stick to the floor and there's a crunch under every step and ideally you'd just hit it all with a firehose.
they discovered the brain's waste removal during NREM sleep (the glymphatic system) is driven by rhythmic norepinephrine pulses controlling coordinated blood vessel movements.
*Zolpidem (Ambien) suppresses this cleaning process by interfering with norepinephrine pulses*
This has implications for Alzheimer's and dementia.
> This has implications for Alzheimer's and dementia.
Long term use of drugs that interact with the GABA-A receptor have been known to be associated with dementia risk for a very long time.
Zolpidem (Ambien) isn't indicated for long-term use, but there are some doctors who ignore this and prescribe long-term. It's rare, though.
I think some people are drawing narrow conclusions from the use of Zolpidem in this study. They're not saying Zolpidem uniquely causes this problem, they're just showing that Zolpidem was one way to trigger this. It's like a property of many sedative hypnotics and quite possibly other types of sleep aids, too. Demonizing Zolpidem isn't the point of this study.
Went to look up Ambien's company's stock. Google Gemini is hallucinating like crazy:
> Cosette Pharmaceuticals is permanently closed, so there is no stock for the company.
> Cosette Pharmaceuticals was a pharmaceutical company that manufactured topical creams, ointments, oral liquids, and suppositories. They had facilities in New Jersey and North Carolina.
No, Google. They're just a private company.
Thanks, Google.
Beyond this, I can't imagine this drug will be something people will want to continue taking. It was already posited to not be good for Alzheimer's, and now they have a smoking gun for a plausible mechanism.
It's one study, on mice. This is the beginning of a long chain where more studies are done -> a consensus is formed -> doctors start to hear about the consensus and take it into account prescribing it
It could plausibly be 20 years before that plays out
Ambien has been generic for a very long time. It's not an expensive drug.
It's also not even indicated for long-term nightly use. You can find stories online of people who get continuous prescriptions from their doctor, but doing so is a rare practice. Most doctors are nervous to prescribe any drug of this class right now. When they do, it's only for short-term or occasional use.
I don't think this is really a pitchforks-out moment against drug companies.
Michael Edward Johnson has an interesting theory called vasocomputation with the core hypothesis:
> vasomuscular tension stabilizes local neural patterns. A sustained thought is a pattern of vascular clenching that reduces dynamic range in nearby neurons. The thought (congealed pattern) persists until the muscle relaxes.
This person is part of a group that seemingly posts to twitter and cites twitter as statement against academic institution and traditional scholarship. Some members of the group are academics themselves. Maybe some things can only be posted there, and so your intuition is correct. But I think you misunderstand why specifically you are seeing twitter links so prominently used. My sense is it's attacking the politics of citation.
If that's true, that might also be part of why dreams exist. If the glymphatic cleanout during sleep is a rhythmic constriction wave across the brain, then whatever the brain is doing at the time the wave crosses it becomes a sustained thought as a side effect.
Maybe that's why sleep, in the sense of becoming immobile, is a thing. The brain disconnects a lot of the motor control so that the hallucination caused by sustained randomness from cleanout waves don't make us flail all over the place and hurt ourselves.
It's interesting because I just started taking Qelbree\Viloxazine (a selective norepinephrine reuptake inhibitor), and even though I feel great I have a ton of trouble staying asleep. It seems to be a common complaint among folks talking it.
Before this, I took Strattera\Atomoxetine (which has the same method of action) for at least five years. And while falling asleep has long been difficult for me, staying asleep hasn't been.
Not quite sure how my experience relates, but makes me wonder if either too much norepinephrine also adversely impacts sleep or if I'm sleeping more "efficiently," so to speak, which is why I wake up feeling rested.
I don't remember any sort of similar experience when taking Effexor about a year ago, but I don't believe I ever reached a high enough dosage for the norepinephrine reuptake to take effect.
“Mediating alertness”, as in more available norepinephrine increases or deceases how alert you are?
From my experience while awake, I would assume decreases. While it’s yet to have a huge impact on my ADHD, it’s has had a noticeable impact on reducing my self-doubt and hesitance to speak up. But I’m not sure how to unify that with it reducing the quality of my sleep.
Maybe, since I’m taking it in the AM it’s wearing off at night, and thus my level of alertness in the middle of the night is being heightened. That would line up with antidotal reports I’ve read of people saying they had less sleep disruptions when they took it at night. Something I’m planning to try moving to.
It’s also possible it takes take to reach a steady state (I’ve only been taking it two weeks)
Maybe a receptor resistance build up? Seems to be a common pattern that medication needs to be dosed up to work- and blunts the receptors for the "normal" amount the body produces, if it does not cease to produce it at all.
I was wondering the same thing. I couldn't find any research on what increased baseline norepinephrine does to the pulses. I can see it being detrimental (pulses don't work as well) or neutral (brain adjusts to the new baseline).
note its not just sleep meds that harm the process....
taking caffeine several hours before sleep does as well as caffeine co-competes with adenosine...adenosine serves to close the hetodimer dopamine receptors...i.e. the dopamine receptors that are tied to locomotion and other things are closed due to the action of adenosine during sleep.
Glymphatic system: Waste clearance system in the brain. More active during sleep.
Slow vasomotion: Squeezing and relaxing motion that pumps fluid through glymphatic system
Norepinephrine-mediated: Norepinephrine is a signaling chemical. They discovered that norepinephrine is key to the signaling chain that drives slow vasomotion in the glymphatic system during sleep.
In short, they found that norepinephrine signaling pulses in a specific system trigger a pumping motion that helps with waste clearance from the brain in sleep. They also found that a sleep medication suppresses that norepinephrine signaling, reducing waste clearance during sleep.
As always, be careful interpreting these studies. The amount of medications used in these studies tends to be very high to elicit the desired effect, so we don't know if doses used medicinally in humans cause the same effect or if that effect is significant.
As a Gen Xer, the relatively recent discoveries around the purpose of sleep are pretty fascinating to me. Throughout most of my life, we basically didn't know why we need sleep. It's very clear we (and essentially all vertebrates) do need sleep, but we really didn't know why.
Now we basically do: sleep is when you clear out waste products in your brain. As someone who definitely doesn't understand all the details, it's when "channels" it your brain get opened up so these waste products can be swept away. This study (based on the title) claims to show the mechanism for doing that:
1. Norepinephrine-mediated: norepinephrine is a neurotransmitter, so this is saying it's responsible for the mechanism of action.
2. slow vasomotion - you can Google what vasomotion means, but it's essentially a rhythmic change it the walls of blood vessels - this is essentially the "sweeping away" part I mentioned above.
3. glymphatic clearance - the glymphatic system in the brain is that network of fluid filled spaces in the brain, and it's what clears away brain waste products, so glymphatic clearance means allowing the glymphatic system to "wash away" those waste products.
So, this study claims to explain the mechanism by which waste products get cleared from the brain during sleep, and the larger context is that it is indeed why we need sleep in the first place.
I'm also squarely GenX. While studying mechanical engineering, one of my roommates was in psychology. He said "we" didn't need sleep. He said one of his professors told them that. I said, "But we ALL do it." He said it was just a convenience thing.
To his credit, he decided to test his theory. By not sleeping. During FINALS WEEK. He said, by the third day, he saw Tom Sawyer and Huck Finn walk across the pages of the book he was reading, and decided it was time to take a nap.
But, hey, I tried smoking banana peel, ala the Anarchist's Cookbook, so I don't have any room to talk.
Even before I went to college I knew that Race Across America winners would sleep only a couple hours a night, timed to wake at sunrise to trick their brains into thinking they’d gotten more sleep. They’d be hallucinating by the end, which did not sound like fun.
I think the longest I ever made it was 70 hours. Maybe 80. I had two finals on consecutive days so I stayed up to cram for the second. Fibbed to my parents about when I was available to come home for the holidays, so I went to the computer lab to binge games with a couple friends, never made it to sleep that night.
I went to bed when the blue background on the computer terminal started to swim. That’s enough internet for me today.
The older you get the more dangerous it is to do this. You can start dying sometime between 70 and 120 hours. And the quality of whatever you’re doing is declining rapidly after 30 or so. Go to bed.
Another big learning from this is that "not all sleep is created equal." What happens during NREM isn't the same as what happens during REM.
Which surprises me because I thought we were all taught that REM is the best kind of sleep (and the hardest to induce). But also doesn't Ambien reduce the amount of time in REM and increase NREM.
I'm confused again. Someone better educated than me care to explain?
Hmm, I don't know about Ambien, but I didn't hear that REM is the best kind of sleep. On the contrary, REM sleep is the sleep level just below being awake, while what you really need is deep sleep, and when you're in really deep sleep, you're not dreaming.
> sleep is when you clear out waste products in your brain.
It's unfortunately more complicated than this: we also clear out the same waste products in our brain during wakefulness. Mostly at a higher rate, too. Perhaps there's some unique way in which this happens during sleep but this certainly isn't the "key" (if there is in fact one) to why we need to sleep.
Your questions around why we need sleep make me wonder if we could develop a drug cocktail to do that work for us while we're awake. Similar to Iain M. Banks' "Culture" book series where humans can inject themselves with their "drug glands" to improve their capabilities.
yes, but after about 30 years of this, your brain will start to create a data structure to represent the claim, and then you can sort of backfill with dictionary lookups. I can trace my entire career to reading a single paper by doing this very tediously (it gets easier; eventually, you build an embedding and every paper is really just another point in hypothesis space).
Bio papers (of this type) follow a fairly straightforward pattern:
<entity> <affects in some way> <some important system> <under these conditions>
in this case norepinephrine is the entity- it's a small molecule the brain uses to transmit information around. It literally floats from one cell to another, and the recipient acts upon it.
The effect in this case would be "slow vasomotion"- I ahdn't actually heard of this before, but apparently blood vessels oscillate, independently of normal heartbeat.
The important system- again, something I wasn't particularly aware of- is the glymphatic system. Apparently, it's used for garbage cleanup?
And the conditions are "during sleep"
So basically the garbage gets taken out at night by a little guy.
> I can trace my entire career to reading a single paper by doing this very tediously (it gets easier; eventually, you build an embedding and every paper is really just another point in hypothesis space).
Tangential, but it really annoys me how people use computational jargon to represent internal mental processes. These are absolutely terrible metaphors outside of computing and I have no clue what you're referring to. What the hell does "building an embedding" even mean with respect to humans? Yea, I'm sure I encode some embedding inside my brain. I'm also certain this is just a tiny part of the mental processes I rely on.
Please note that I've worked in both biology and CS for 30+ years. Everything I describe in this way is a simplified approximation of mental processes, and half-joking (mainly appreciated by ML nerds and cognitive neuroscientists, I admit)
To build an embedding for a human means to build an approximate map of entities within a metric space. We do this all the time, for example unsupervised clustering of related entities (for example species classification based on visible character states).
From what I can tell, the human brain basically has a number of approximate computing systems- we have associative memory (hash tables/dictionary lookups), trajectory interpolation/extrapolation (catching a ball with only a few glances), logical reasoning from a premise (theoretical math), monte carlo tree search (formulating a complex plan wiht multiple steps and some unknowns), etc, etc. I certainly don't propose that my terminology is specifically scientifically correct, it's just heuristics I apply to my own thought patterns.
> To build an embedding for a human means to build an approximate map of entities within a metric space. We do this all the time, for example unsupervised clustering of related entities (for example species classification based on visible character states).
I thought you said "for a human". These are all computational concepts that are unrelated to human cognition (at least in terms of evidence). Why are we talking about human cognition in terms of "metric space" when metric space applied to human cognition is nonsensical?
> From what I can tell, the human brain basically has a number of approximate computing systems- we have associative memory (hash tables/dictionary lookups), trajectory interpolation/extrapolation (catching a ball with only a few glances), logical reasoning from a premise (theoretical math), monte carlo tree search (formulating a complex plan wiht multiple steps and some unknowns), etc, etc. I certainly don't propose that my terminology is specifically scientifically correct, it's just heuristics I apply to my own thought patterns.
Police? This comment right here: they failed to read my comment.
I of course certainly strongly support you describing your mental cognition the way you want to! It's just not evidence that other people can be modeled with the same computational mechanics, nor that these mechanisms are sufficient. We should use meaningful terms that people can actually recognize rather than trying to forcing mental cognition to fit models that are curently in vogue.
I recognized the word "glymphatic" from recent articles about the discovery of the brain's self-cleaning system, and then understood from the headline that these authors identified that the mechanism by which this occurs is driven by norepinephrine.
