Anticholinergics linked to dementia
April 25, 2016 8:34 AM   Subscribe

Drugs in the class "Anticholinergics", which includes Benadryl, Dramamine, and an ingredient in Tylenol PM, have been associated with increased risk of dementia or other cognitive impairment.

It's only a correlation, so e.g. it could be that those taking sleep aids are more likely to develop dementia because they often don't get enough sleep, not because they take the sleep aids.

From the CBS link:
"We know based on previous studies that as little use as 60 days, or even 90 days non-consecutively over the course of a lifetime, can be associated with these risks. It's not every night for 30 years, it's sometimes or sporadically," [Alexandra Sowa, an internist and clinical instructor at Weill Cornell Medical College] said.
Here's the damn paper (paywalled.

Last year Britain's NHS published something saying that media reports about this link are overblown.
posted by Sleeper (137 comments total) 25 users marked this as a favorite
 
Isn't one of the hallmark symptoms of Alzheimer's disordered sleeping?
posted by leotrotsky at 8:40 AM on April 25, 2016 [7 favorites]


dammit


*sadly tosses away Benedryl for seasonal allergies*
posted by Kitteh at 8:40 AM on April 25, 2016 [2 favorites]


This is exactly why I have (recently) stopped taking an anti-histamine at night to help me sleep. In any case, I don't want to take any undue risks with respect to dementia, as my father died of it.

[When I told my GP about this association, she hadn't heard about it. Hhmmmmm.]
posted by Halo in reverse at 8:43 AM on April 25, 2016


So basically drugs that help your brain calm down cause dementia? First it was the benzos and now this? Sigh.
posted by stoneweaver at 8:43 AM on April 25, 2016 [3 favorites]


If 60-90 days use of claritin/allegra/zyrtec is included then I'm already way fucked.
posted by sbutler at 8:44 AM on April 25, 2016 [13 favorites]


Welp I'm screwed
posted by Jacqueline at 8:45 AM on April 25, 2016 [2 favorites]


PRAISE BE UNTO THE WISE AND POWERFUL NETI POT!

PLEASE DO NOT FORSAKE US THAT DEPEND UPON YOUR BLESSINGS!

THE HOUR OF OUR GREATEST NEED IS UPON US!
posted by RolandOfEld at 8:46 AM on April 25, 2016 [9 favorites]


sbutler: read the full article.
posted by hippybear at 8:46 AM on April 25, 2016 [1 favorite]


It looks like Allegra isn't included, so I guess I'm switching to that.
posted by answergrape at 8:47 AM on April 25, 2016


Doh! Right at the end...

And when it comes to allergies, there are many alternatives to Benadryl, an anticholinergic and so-called first generation antihistamine. Second- and third-generation antihistamines, including brands such as Claritin, Zyrtec and Allegra, are not anticholinergics.
posted by sbutler at 8:48 AM on April 25, 2016 [10 favorites]


Mike Tringale, a spokesperson for the Consumer Healthcare Products Association, which represents over-the-counter drug makers, told CBS News, "It's important to help people understand the science without creating hysteria."

He said over-the-counter products are only approved for short-term use and that the study didn't look at how long people were taking them or the dose.

"There were some missing pieces," he said.


I know this is coming from the guy whose job it is to defend these drugs, but I think his point about science vs hysteria is a good one. I will look forward to additional, non-biased analyses of what this study does and does not say.
posted by cubby at 8:48 AM on April 25, 2016 [2 favorites]



If 60-90 days use of claritin/allegra/zyrtec is included then I'm already way fucked.

You're fine; Fexofenodine/Allegra isn't anticholinergic.
posted by Comrade_robot at 8:48 AM on April 25, 2016 [2 favorites]


*sadly tosses away Benedryl for seasonal allergies*

Here is the hazard of popular media reporting on super-specialized medical studies that are not easily summarized. (It's the old "Red wine is good for me, red wine is bad for me, red wine is good for me, red wine is bad for me!" syndrome.)

The FPP author did take pains to note it's a correlation and far from proven to be a causation. Just because people who might develop dementia take more of these drugs than others does not mean the drugs are what causes the eventual dementia.
posted by aught at 8:49 AM on April 25, 2016 [11 favorites]


If 60-90 days use of claritin/allegra/zyrtec is included then I'm already way fucked.
posted by sbutler at 8:44 AM on April 25 [+] [!]


None of those drugs are anticholinergics.
posted by Sleeper at 8:49 AM on April 25, 2016 [1 favorite]


Gravol (dimenhydrinate) seems to be on the list. Nice knowing y'all.
posted by bonobothegreat at 8:49 AM on April 25, 2016


Allegra isn't on here either, but my zyrtec is a 'maybe' ;(
posted by Reasonably Everything Happens at 8:49 AM on April 25, 2016


It's only a correlation, so e.g. it could be that those taking sleep aids are more likely to develop dementia because they often don't get enough sleep, not because they take the sleep aids.

So ... there's nothing to see here.

If 60-90 days use of claritin/allegra/zyrtec is included then I'm already way fucked.

Those are all second-generation antihistamines. They work completely differently.
posted by Sys Rq at 8:50 AM on April 25, 2016 [2 favorites]


Second- and third-generation antihistamines, including brands such as Claritin, Zyrtec and Allegra, are not anticholinergics.

::Breathes deeply into paper bag::
posted by thecaddy at 8:50 AM on April 25, 2016 [4 favorites]


PRAISE BE UNTO THE WISE AND POWERFUL NETI POT!

PLEASE DO NOT FORSAKE US THAT DEPEND UPON YOUR BLESSINGS!

THE HOUR OF OUR GREATEST NEED IS UPON US!


Do you lose the ability to hit caps-lock once the amoeba starts eating your brain?
posted by leotrotsky at 8:51 AM on April 25, 2016 [41 favorites]


From the article: "We know based on previous studies that as little use as 60 days, or even 90 days non-consecutively over the course of a lifetime, can be associated with these risks. It's not every night for 30 years, it's sometimes or sporadically," she said.

From every other article: (cnn, for instance)

A 2013 study by scientists at the Indiana University Center for Aging Research (PDF) found that drugs with a strong anticholinergic effect cause cognitive problems when taken continuously for as few as 60 days. Drugs with a weaker effect could cause impairment within 90 days.

So did scientist one read the pdf wrong? Or has my non-consecutive use of diphenhydramine (I'm a regular Benadryl Grover Cleveland) already done its damage?
posted by condour75 at 8:57 AM on April 25, 2016 [2 favorites]


::Breathes deeply into paper bag::

"This just in: paper bags probably cause death!"
posted by Celsius1414 at 8:57 AM on April 25, 2016 [20 favorites]


and from the pdf located here:

The duration of exposure was alternatively defined as the participant’s continuous use of ACs (irrespective of the number of medications and their AC burden) for at least 30, 60, or 90 days. Finally, we tallied the number of mild and severe ACs the participant took at the same time during the 1-year period before cognitive assessment.
posted by condour75 at 8:58 AM on April 25, 2016 [1 favorite]


*throws generic sleep aide into trash* that's fine I never wanted to sleep again anyway
posted by The Whelk at 8:58 AM on April 25, 2016 [11 favorites]



Allegra isn't on here either, but my zyrtec is a 'maybe' ;(
posted by Reasonably Everything Happens at 8:49 AM on April 25 [+] [!]


Hey, good link. I was thinking about going and getting a list of anticholinergics. Thanks!

It's only a correlation, so e.g. it could be that those taking sleep aids are more likely to develop dementia because they often don't get enough sleep, not because they take the sleep aids.
So ... there's nothing to see here. posted by Sys Rq at 8:50 AM on April 25 [+] [!]


Not necessarily. The causation VS correlation question is present in almost every study of medicine.
posted by Sleeper at 8:58 AM on April 25, 2016 [1 favorite]


It's also worth noting that the expert doctor quoted by CBS News in their article is not one of the authors of the actual study, though in my opinion the way CBS wrote the piece implies it. Be wary whenever reading about medical studies in the mainstream media, particularly online. They will seriously jerk us around in the fierce battle for pageviews.
posted by aught at 8:59 AM on April 25, 2016 [3 favorites]


Christ, I'm certain I hit 90 days during childhood. And, back in those days at least, it was considered totally fine and safe to knock out your fussy baby with a little Benadryl.
posted by mubba at 9:01 AM on April 25, 2016 [5 favorites]


and from the pdf located here:

Which is interesting, and possibly makes a stronger case for the link, but should be noted is not the article in the FPP, in case anyone is confused.
posted by aught at 9:03 AM on April 25, 2016


*throws generic sleep aide into trash* that's fine I never wanted to sleep again anyway

Yeah I've gone through a couple of periods of this so.. bleh.
posted by curious nu at 9:03 AM on April 25, 2016


Christ, I'm certain I hit 90 days during childhood.

I'm surprised / impressed the researchers found enough people, for a control, who *hadn't* taken more than the study's threshold number of doses of the antihistamines in question. Though that also makes me wonder what other factors there were that might not have been controlled for, in a population of people who had taken these common medications.
posted by aught at 9:06 AM on April 25, 2016 [8 favorites]


yeah, no. this study looked at people who were taking the drugs at the time of the study, which i presume means daily. The prior study was people who had taken it daily for 60 or 90 days consecutively in the past. So you don't get 60 benadryls for life before it starts screwing you up.
posted by condour75 at 9:07 AM on April 25, 2016 [4 favorites]


If fucked-up sleep causes dementia I'm probably already senile. I've never taken any of this stuff, though, so I've got that going for me.
posted by The Card Cheat at 9:08 AM on April 25, 2016 [1 favorite]


well, mother of fuck

see you all at the Tranquil Acres Care Facility For People Who Just Wanted To Be Able To Breathe Through Their Goddamn Nose And Get Some Goddamn Sleep, then
posted by prize bull octorok at 9:12 AM on April 25, 2016 [67 favorites]


Do you lose the ability to hit caps-lock once the amoeba starts eating your brain?

Gawddamnit, this old hat again? It is not at all hard to use water from the cold tap, heated in a kettle, and remove the vast majority of the vestiges of risk in putting simple salt water in your nose. Or use distilled if you're really, really, really, tinfoil hat level paranoid.
posted by RolandOfEld at 9:17 AM on April 25, 2016 [3 favorites]


Benzos cause dementia ?
posted by sio42 at 9:17 AM on April 25, 2016 [4 favorites]


Promethazine is anticholinergic, which is significant for me as it's the main thing that's relieved my headache/nausea for a few years now. Fortunately, I just found a new treatment, so I hope any negative effects from the promethazine are reversible. I've definitely felt clouded from the promethazine, and for more than just the dosage period.

I have been feeling a little sharper lately, so here's hoping.
posted by amtho at 9:23 AM on April 25, 2016


Imimprimine and Psuedophedrine HCL are on the "definite" list of Anticholinergics. This is a biiiiiig category of drugs, many for chronic conditions.
posted by Slap*Happy at 9:24 AM on April 25, 2016 [2 favorites]


That newer stuff doesn't work as well as Benedryl on me, though. Goddammit.
posted by emjaybee at 9:26 AM on April 25, 2016 [3 favorites]


Alternatives for sleep: suvorexant (if you can afford it), low dose doxepin (it's been argued that antimuscarinic effects are limited at 3-6 mg), mirtazepine (off-label, side effects galore--hardcore insomniacs only). Z-drugs are similar enough to benzos that they probably have comparable effects on cognition. If someone tries to give you quetiapine for sleep kindly tell them to fuck off.
posted by dephlogisticated at 9:29 AM on April 25, 2016 [4 favorites]


Fortunately, I never use Benadryl anyway, since it already has a negative reputation of drowsiness-inducing.
posted by Apocryphon at 9:31 AM on April 25, 2016 [1 favorite]


From my quick skim of the study, it looked like this is more of an issue for older people (70+) which has already been known about (as far as Benedryl is concerned).

For me, you can pry my Benedryl from my cold dead hands. Only thing that works to get me to sleep. (Ambien put me in the hospital, Klonopin did nothing, Seroquel also did nothing (even at 600mg).)
posted by sperose at 9:33 AM on April 25, 2016 [4 favorites]


It's a no-brainer, for me, at least. I have not been able to ever take antihistamines, muscle relaxants, narcotics, Nyquil, none of these things. I also found that ibuprofen over time will cause neural deficits. The effects of allergy medicines on me far outweigh any benefits from them, and this has been for my whole life.

The fact that they put fentanyl patches on the elderly for pain, especially those with a dementia diagnosis already, is criminal. Drugging people is drugging people. Fortunes are made drugging people, and the payout is for deliberately sketchy research as to the efficacy of these "medications." The big sell, you must have a medicine for every little thing. When you add them all together it is a huge thing.
posted by Oyéah at 9:33 AM on April 25, 2016 [1 favorite]


Imimprimine and Psuedophedrine HCL are on the "definite" list of Anticholinergics.

So Claritin-D would put it back in the risk column, because of the pseudoephedrine?
posted by sbutler at 9:36 AM on April 25, 2016 [1 favorite]


Frankly, I can't remember if I've ever taken Benedryl for more than 90 days in my life.
posted by TheWhiteSkull at 9:37 AM on April 25, 2016 [9 favorites]


I don't see the active ingredient from my Visine A.C. allergy eye drops (Tetrahydrozoline) on either list. Does anyone know if that one is a worry? Looks like the other allergy med I take occasionally, Advil Allergy & Congestion Relief, was included in the study, ugh.
posted by JenMarie at 9:38 AM on April 25, 2016


TheWhiteSkull: I see what you did there.
posted by hippybear at 9:38 AM on April 25, 2016 [3 favorites]


The 2015 Gray-Anderson et al. "Cumulative Use of Strong Anticholinergics and Incident Dementia A Prospective Cohort Study" did fine "Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time." This study is the basis for this list of anticholinergics that may have cognitive effects.
posted by the man of twists and turns at 9:40 AM on April 25, 2016 [2 favorites]


looks like I chose the wrong day to stop drinking rubbing alcohol
posted by grumpybear69 at 9:42 AM on April 25, 2016 [9 favorites]


Gravol and some of the stronger drowsy-inducing antihistamines make me trip the hell out so maybe it's good that I avoid it anyway. They put me in a sort of half-sleep state where I sometimes confuse real life with being in a dream and wind up saying shit that makes no sense. I am not sure if I ever took them for 90 days though so yay me I guess.
posted by Hoopo at 9:44 AM on April 25, 2016 [1 favorite]


Okay, I'm hoping naproxen doesn't come up with some sort of horrible side effect. I usually don't have trouble sleeping, but when I do, that's my go-to. I don't know if the soporific effect is some kind of unusual side effect, or if it just keeps little twinges and aches from waking me up when I'm drifting off, but it works great.
posted by tavella at 9:51 AM on April 25, 2016 [3 favorites]


So Claritin-D would put it back in the risk column, because of the pseudoephedrine?

Unknown. They did a study that linked the use of some Antichlorogenics to an increased risk for dementia. Pseudophedrine HCL wasn't one of the drugs listed in the study.

Also, the study dealt with patients 65 and older.
posted by Slap*Happy at 9:53 AM on April 25, 2016


Here's the actual paper. One thing that jumped out to me: The incidence of depression among anticholinergic users in the study was about 2.5 times that of the non-users.

Also, heads-up to fellow Wellbutrin (bupropion) users that it's an anticholinergic drug.
posted by compartment at 9:55 AM on April 25, 2016 [5 favorites]


Also, heads-up to fellow Wellbutrin (bupropion) users that it's an anticholinergic drug.

Nah, it's good:
Results of other studies have shown that bupropion and its metabolites do not have appreciable affinity for postsynaptic receptors including histamine, α- or β-adrenergic, serotonin, dopamine, or acetylcholine receptors.
posted by dephlogisticated at 10:04 AM on April 25, 2016 [4 favorites]


Okay, I'm hoping naproxen doesn't come up with some sort of horrible side effect.

If I remember correctly, naproxen puts you at risk for liver damage.
posted by drezdn at 10:08 AM on April 25, 2016 [1 favorite]


I take a pile of pseudoephedrine because I like to be able to breathe. And my other option (steroids are bad news for me for other reason) is nose surgery, specifically turbinate reduction. So, I can get empty nose syndrome or dementia. And be depressed either way.

Or.... perhaps I could assume that it's the underlying condition that increases my risk for depression/dementia etc? And that not breathing is actually a *worse* plan than dropping a drug that apparently works well for me otherwise?
posted by nat at 10:08 AM on April 25, 2016


In another perspective-- every possible response to a physical symptom, including not treating it, comes with risks.
At the worst case, this should reweight the risk calculus, and I don't even see evidence for that (until you can prove to me that the group that took drugs for 30/60/90 days is equivalent in every way to the group that didn't.)
posted by nat at 10:10 AM on April 25, 2016 [8 favorites]


Huh. Anticholinergics cause dementia? Looks like constantly shooting up atropine in order to deal with constantly huffing nerve gas might be a bad idea.
posted by qcubed at 10:10 AM on April 25, 2016 [2 favorites]


I am currently fighting a cart/horse battle with Klonapin -- trying to slowly withdraw from it over a period of months. When I take enough to sleep, I'm groggy all day. When I back off enough to not feel groggy, well, I don't know, I feel groggy because I sleep for shit.

I do NOT like what it's doing to my short-term memory though, which is noticeably worse than it was 10 years ago. So I think I'm gonna go with insomnia & see if I can solve for that by other means.

Never was a Benadryl/Tylenol PM fan. That stuff wipes me out for days when I take it.
posted by Devils Rancher at 10:12 AM on April 25, 2016


I am totally screwed. And every time I use neti pots/Neil Med/whatever I get a giant sinus infection. My only consolation is that the climate change will probably get us all anyway before I have a chance to develop dementia.
posted by holborne at 10:25 AM on April 25, 2016



The FPP author did take pains to note it's a correlation and far from proven to be a causation. Just because people who might develop dementia take more of these drugs than others does not mean the drugs are what causes the eventual dementia.


This scared the shit out of me because I have debilitating allergies and have definitely used benadryl to cope. You're absolutely right, though.

Even if it was causative, it might only be a weak risk factor. It reminds me of the panic that some people who sequence their genomes experience. They get a look at their genetics, cleanly displayed for ease of browsing, and find all these increased prevalence for x genes. An 8% increased risk of testicular cancer, considering that the incidence in the overall population is still 5.7 per 100,000 in America, is still not that bad. It's not assured. And you can easily compensate for it by avoiding other risk factors.

Same applies here.
posted by constantinescharity at 10:33 AM on April 25, 2016 [2 favorites]


I'm allergic. Doesn't matter what, if it isn't food but its outside - I'm probably allergic to it. Also, if it has fur, I'm likely mildly allergic to it as well. Oh, and if it is mostly dead skin - probably allergic to it as well. So, knowing this now, I figure I've course corrected myself towards a great deal of early onset dementia.

The thing is, I don't care. I can't care. The reality is this, when your nose basically drains constantly, and your head is swollen and thick from blowing your nose / sneezing so much that you are considering a career change requiring becoming an equestrian and terrorizing some guy named Icabod in New York with firey pumpkins... well.. lets just say I may eventually be demented, but at least I'll be able to function today, and tomorrow - as long as I take the damn antihistamine.

And yes, I neti pot too.
posted by Nanukthedog at 10:37 AM on April 25, 2016 [5 favorites]


I took Benadryl nightly for a good long time because of insomnia, stopping only because I was warned by a PA that it wasn't a good thing for me, at all. I can say that since I stopped I am not only sleeping a little bit better, but I'm also clearer-headed in general and not so. damned. tired. in the morning.

Dementia tho? Come fucking on. Sigha.
posted by nevercalm at 10:42 AM on April 25, 2016


Imimprimine and Pseudophedrine HCL are on the "definite" list of Anticholinergics.
Great, the only decongestant that isn't a placebo could be cooking my brain. I've probably taken 30-90 doses in a month. Oh well, still worth it.
posted by rodlymight at 10:48 AM on April 25, 2016


Metafilter: Isn't a placebo; could be cooking my brain.
posted by hippybear at 10:50 AM on April 25, 2016 [4 favorites]


Well I've spent the last 32 years breathing.

Maybe that was enough.
posted by Ray Walston, Luck Dragon at 10:50 AM on April 25, 2016 [5 favorites]


If I remember correctly, naproxen puts you at risk for liver damage.

I think you're thinking of paracetamol/acetaminophen/tylenol here. Which is usually fine in occasional use, and increases in risk if taken more often.

Naproxen can be relatively safe compared to other drugs, but should be used in moderation.
posted by ovvl at 10:56 AM on April 25, 2016


As somebody who works at an Alzheimer's Society, can I just pop in to say to take a deep breath about this? I'm not saying to ignore it, but in all honesty, the research on risk factors into the causes of dementia is so all over the place right now that it is very hard to know what to take away from any of these studies. And a new one comes out about once a week. Today, for example, I have articles in my inbox about the fact that dementia may cause diabetes (where we usually have been talking about diabetes being a potential risk factor for developing dementia) and one on how deficits in certain mitochondrial proteins are a factor. A couple of weeks ago I was fielding questions about maple syrup being the new superfood in prevention. And so on.

Speaking broadly, there are non-modifiable and modifiable risk factors at play. The non-modifiable stuff includes genetics (there are 20ish genes implicated in sporadic dementia at this point, about 3 in the familial form (which only makes up about 3% of the cases)), age, gender, and some other health conditions. Modifiable - which is more interesting, because there might be things we can do about it - include things like diet, exercise, levels of education and cognitive activity, smoking, etc. The FINGER study is probably the biggest/best attempt at capturing these so far. But the basic takeaway is that (unless you have the familial form) there are a whole lot of risk factors/protective factors at play and we don't yet have any good understanding of how much they contribute and how they might work with or against each other.

Anti-cholinergics have been muttered about for some time, and their side effects include things that look like symptoms of dementia; just last week I saw something going out from a medical association to doctors warning (again) not to prescribe them to people with dementia, because they make things worse. But I have heard before the theory that using them can contribute to dementia; this might be the first large scale study to look at it that I'm aware of. What is left unanswered for me:

-they are seeing changes in the brain scans. What kind of changes? The formation of the protein plaques and tangles characteristic of Alzheimer's can't be detected in scans of living brain tissue at this point. So what are they seeing?

-is this a correlation/causation thing? Remember, some years back, we were on about aluminium being a risk for causing dementia. Now, we don't talk about it much, because further research revealed that the changes that occur in the brain of someone with Alzheimer's or a related dementia causes aluminium to more readily leech into the brain tissue and form deposits - the aluminum wasn't causing the dementia, the deposits are symptomatic of it.

-what levels of dosage were being taken, and for how long, etc.

Anyways, I'll see if I can dig up the full study and link it back here if possible. It might answer some of these. But right now, everything we can get our hands on is showing that there is a lot of different things going on, and it isn't going to be a simple as it coming down to one thing that we should do/should not do that is going to be the determining factor.

At the end of it all, age is still your number one risk factor; past that diet and exercise seem to be the things you can do that have the most chance of a positive benefit. Beyond that, I can't say much except it is your health, and you will need to make informed decisions about what you take and do that impact your health in a great many ways, beyond dementia.
posted by nubs at 10:59 AM on April 25, 2016 [50 favorites]


Here's another list of anticholinergics [pdf], which I found earlier on IU's own announcement about this paper. Zyrtec *is* on there, but I don't understand the classifications. Could someone with some more medical knowledge shed some light on this?
posted by gusandrews at 11:02 AM on April 25, 2016


Dramamine for 90 days and I don't need to develop dementia because I will be a human puddle. When I hit the Zyquil after a protracted struggle with sleep so I can get just one good night I end up sleeping through the next day even though I am up and moving around with my eyes open.
posted by srboisvert at 11:04 AM on April 25, 2016


I saw the people's pharmacy list of anticholinergics. And well, I'm fucked. Benedryl and pseudephedrine basically daily from a young age (thanks allergies!) I don't as much anymore except in the spring. But in addition, I take cyclobenzaprine, baclofen and am weaning off diazepam after two years of nightly alprazolam - which I wanted to get off of due to the benzo-dementia connection.

My first thought reading the above thread was that maybe if they're used for sleep, it was a correlation that had to do with lack of sleep. There was that study a few years back how one of the functions of sleep was clearing toxins (real not woo) from the brain.

Which also makes me wonder which is worse for you in regards to dementia- chronic sleep problems or the meds that help with sleep? The answer, I suppose is figuring out how to fix your sleep problems without medication. I'm certainly trying, but no amount of sleep hygiene is going to fix the fact that my legs want to do their own river dance when my head hits the pillow.
posted by [insert clever name here] at 11:18 AM on April 25, 2016 [3 favorites]


dephlogisticated: "Alternatives for sleep: suvorexant (if you can afford it)"

Yeah, no. Suvorexant works by blocking orexin receptors. Orexin is neuroprotective, and is one of the first cell types lost in a lot of neurodegenerative diseases. My colleagues and I have proposed several research grants looking at orexin loss as a potential mediator of neurodegeneration - not that orexin loss causes degeneration, more that once you lose the protection, you put your brain at greater risk of insult.

That, and the thrilling fact that low orexin tone is associated with increased obesity - and too little orexin results in narcolepsy. I'm not your doctor, but if you have any other alternatives, I'd stay away from suvorexant.
posted by caution live frogs at 11:30 AM on April 25, 2016 [7 favorites]


You know what else is linked to increased risk of dementia?

Insufficient sleep.
posted by Anticipation Of A New Lover's Arrival, The at 11:31 AM on April 25, 2016 [7 favorites]


OK, I have my filthy hands on the paper itself. A couple of things to note from a quick read through:

-The AC+ group - ie, those taking anticholinergic drugs - was 60 people in total of the pool of about 500.
-of those, it looks like only 52 got actual imaging;
-The AC+ folks had poorer cognitive function scores, reduced cortical volume, and reduced temporal lobe thickness along with reduced glucose metabolism.
-To be in the AC+ group, the medication had to be taken for a minimum of 1 month.
-AC drugs had to be "medium to high" in terms of effect (and I can't seem to get at the supplement on which drugs were identified in the medium to high ranges).
-Looks like they controlled well for all the other conditions medically that might contribute (vascular issues, cardiac issues, hypertension, diabetes, anxiety/depression, etc).

So, certainly something interesting here that deserves some follow-up, if anyone wants a copy of the study maybe just drop me a note
posted by nubs at 11:33 AM on April 25, 2016 [10 favorites]


nope, don't care, just do not care, i dont caaaaaare. literally every single thing i need to take to actually be able to live is bad for me unto death anyway, bring on the butter coated salt encrusted benadryls
posted by poffin boffin at 11:38 AM on April 25, 2016 [22 favorites]


Here's a breakdown into risk categories - don't know if it was the same division used here.
posted by atoxyl at 11:45 AM on April 25, 2016


dephlogisticated : If someone tries to give you quetiapine for sleep kindly tell them to fuck off.


Care to elaborate? I've been prescribed quetiapine for sleep.
posted by zug at 11:49 AM on April 25, 2016


Also Zantac is on the list. Blech.
posted by blahblahblah at 12:05 PM on April 25, 2016 [1 favorite]


My mother was a Benadryl addict (probably to potentiate opioids she was also using) - she would open the little capsules and melt down the powder with hot water, then inject the mixture into her legs. She did this for years, and she developed what I'd consider to be early-onset dementia in her 60's, with no family history of dementia. I know it's just anecdotal, but this study certainly makes me think.
posted by averageamateur at 12:19 PM on April 25, 2016 [2 favorites]


Also Zantac is on the list. Blech.

Yeah, I guess if you've got serious gastro reflux issues you have to pick your poison. The anticholinergics put you at risk for dementia while the proton pump inhibitors put you at risk for kidney failure.

Good times, good times.
posted by Justinian at 12:28 PM on April 25, 2016 [1 favorite]


Between Zyrtec, Zantac, and Sudafed I'm way over my 30 day limit! So I guess I'll just keep on keeping on guys. I mean... the number of people who have taken 30+ days worth of any combination of the drugs on the list must be truly massive.
posted by Justinian at 12:36 PM on April 25, 2016 [1 favorite]


Well, either I am going to either stop aging, become an immortal cyborg or get my head cryogenically frozen, depending on what my health insurance covers
posted by y2karl at 12:41 PM on April 25, 2016 [3 favorites]


My mother was a Benadryl addict (probably to potentiate opioids she was also using) - she would open the little capsules and melt down the powder with hot water, then inject the mixture into her legs. She did this for years, and she developed what I'd consider to be early-onset dementia in her 60's, with no family history of dementia. I know it's just anecdotal, but this study certainly makes me think.

I was just thinking I've barely ever taken Benedryl on purpose but it is a known cutting agent for drugs that I did use for a while. Maybe an inversion of priorities...
posted by atoxyl at 12:47 PM on April 25, 2016


A couple of weeks ago I was fielding questions about maple syrup being the new superfood in prevention.


Do Canadians have a significantly lower incidence of dementia?
posted by TheWhiteSkull at 12:48 PM on April 25, 2016 [2 favorites]


I've come to the conclusion that there are two kinds of medication.

1) Medication for which we have identified potentially serious long term side effects.
2) Medication for which we have not yet identified the potentially serious long term side effects, but for which they exist.

That's not snark. Any medication you take is interfering in same way with your system and that's going to have potentially serious consequences. So unless the side effects are "may cause sudden death" or "likely to cause your skin to slough off" I just kind of shrug and take the pills. Also not snark.
posted by Justinian at 12:48 PM on April 25, 2016 [7 favorites]


OK, I have my filthy hands on the paper itself. A couple of things to note from a quick read through:

-The AC+ group - ie, those taking anticholinergic drugs - was 60 people in total of the pool of about 500.
-of those, it looks like only 52 got actual imaging;
-The AC+ folks had poorer cognitive function scores, reduced cortical volume, and reduced temporal lobe thickness along with reduced glucose metabolism.
-To be in the AC+ group, the medication had to be taken for a minimum of 1 month.
-AC drugs had to be "medium to high" in terms of effect (and I can't seem to get at the supplement on which drugs were identified in the medium to high ranges).
-Looks like they controlled well for all the other conditions medically that might contribute (vascular issues, cardiac issues, hypertension, diabetes, anxiety/depression, etc).


This is probably a dumb question, but did they test the AC+ group after a cessation of AC drugs? If I take benadryl the day before I do a battery of cognition-measuring tests, I'm not going to do my best, probably.
posted by clockzero at 12:58 PM on April 25, 2016 [3 favorites]


I used to work at a nursing home and saw what it was like for people with dementia and for their families. I empathized with the families and I guess I sympathized with the patients but apparently my unconscious was protecting me from the idea that it might be *me* with dementia some day. But this post has unlocked that terrifying idea for me. So thanks.
posted by bleep at 1:08 PM on April 25, 2016


Between Zyrtec, Zantac, and Sudafed I'm way over my 30 day limit

The article says Zyrtec is not an anticholinergic, so you're OK on this particular front there. (yay).

Curious if there are good alternatives to Dramamine (I don't use it, but its a necessity for my wife on long car trips).
posted by thefoxgod at 1:11 PM on April 25, 2016


For all of you wondering what to do for sleep now that you can't have Benadryl, here's one of a zillion YouTube videos consisting entirely of 8-10 hours of the sound of cats and kittens purring:

https://www.youtube.com/watch?v=CY7t8ow2gOM
posted by girl Mark at 1:13 PM on April 25, 2016 [6 favorites]


This is me crossing my fingers for correlation not causation. I've got a kid with a food allergy (diphenhydramine is the first line of defense in case of exposure) and a pretty harsh dust mite allergy (ditto). I'm not about to throw away our supply of benadryl given it could save my son's life.
posted by that's candlepin at 1:13 PM on April 25, 2016


Slightly OT but I really, really wish we had better drugs for insomnia (especially the early-waking kind that becomes more common in elderly people). I was holding my breath for suvorexant but unfortunately it doesn't look like it does much for sleep maintenance at safe dosages. If improved sleep could actually reduce the risk of Alzheimer's in addition to the other benefits of sleep (with of course the usual caveats about interpreting causality), it seems to me like that would be an amazing public health win.
posted by en forme de poire at 1:45 PM on April 25, 2016


Slightly OT but I really, really wish we had better drugs for insomnia (especially the early-waking kind that becomes more common in elderly people). I was holding my breath for suvorexant but unfortunately it doesn't look like it does much for sleep maintenance at safe dosages. If improved sleep could actually reduce the risk of Alzheimer's in addition to the other benefits of sleep (with of course the usual caveats about interpreting causality), it seems to me like that would be an amazing public health win.

One is also inclined to wonder how intimately the existence of sleep disorders is tied to the crushingly unavoidable regime of the Business Day. Maybe if people could sleep whenever they normally feel sleepy, without worrying about having to wake up at an arbitrary time to do almost every job out there, insomnia wouldn't be nearly as big of a problem.
posted by clockzero at 2:01 PM on April 25, 2016 [11 favorites]


dephlogisticated : If someone tries to give you quetiapine for sleep kindly tell them to fuck off.
Care to elaborate? I've been prescribed quetiapine for sleep.


Don't know about dephlogisticated, but I told my psychiatrist to fuck off with it because 1 seroquel gave me a 3 day simulation of something not altogether unlike dementia.
posted by rodlymight at 2:04 PM on April 25, 2016


Mm, I think that's a little bit of it on a social level; definitely people trying to conform their clocks to the business day has some public health costs. But I think it's also undeniable that insomnia is a big problem for many retirees who don't have to be anywhere in particular at any given time.
posted by en forme de poire at 2:05 PM on April 25, 2016 [1 favorite]


Maybe if people could sleep whenever they normally feel sleepy, without worrying about having to wake up at an arbitrary time to do almost every job out there, insomnia wouldn't be nearly as big of a problem.

I'm a housewife/hermit who can sleep whenever and I get insomnia as in I desperately need/want to sleep but can't.

Like right now: I've been awake ~30 hours, my short-term memory is shot, and I'm completely miserable, but every time I try to go to bed I can't get comfortable or sleepy.
posted by Jacqueline at 2:07 PM on April 25, 2016 [3 favorites]


This is why FSM invented cannabis.
posted by spitbull at 2:20 PM on April 25, 2016 [3 favorites]


I have always, like for as long as I can remember, had a hard time getting to sleep. Usually it takes me on the order of 30-60 minutes to fall asleep, and I can be 90% of the way there and if something disturbs me - a pulled sheet, a cough, a sudden discomfort - I am back at square one. Some nights, the bad ones, it takes a couple of hours. Normally I can counteract this by sleeping on the couch under a down comforter or heavy blanket, but sometimes even that doesn't work.

For a decent period of time I used Benadryl to ameliorate this issue. I couldn't tell you if I took it 1092 times but probably? Because I used it for allergies before I made the connection that it was an effective sleeping aid. Anyhow it was for a long time a godsend re: my relatively minor insomnia.

The only time I didn't need it was for a period of around 3 months during which I was undergoing an intense fitness routine which included 3x per week at the gym and daily interval training on the treadmill. I was, however, drinking milk and taking an ibuprofen before going to sleep.

And re: cannabis, I tried that - it was also very effective but started freaking me out at night, so I stopped.

The best thing ever was cyclobenzaprine, which was like cannabis but never freaky. The only upside to throwing my back out during softball.

Anyhow, it's a tough call when you can't sleep because it is both distressing and bad for your health, which can tip the scales re: the calculus of risk. I've mostly sworn off diphenhydramine and I'm not quite 40 so hopefully, if there really is a high risk factor related to cumulative absorption, there is also a benefit to stopping. But who knows.
posted by grumpybear69 at 2:24 PM on April 25, 2016 [1 favorite]


It seems most anti-depressants are anticholinergic. So, now what? I went without for several months; it was not attractive. I'm on a low dose, so maybe I'll just lose *some* of my cogni-whatever-stuff.
posted by theora55 at 2:26 PM on April 25, 2016 [3 favorites]


"Like right now: I've been awake ~30 hours, my short-term memory is shot, and I'm completely miserable, but every time I try to go to bed I can't get comfortable or sleepy."

Turkey sandwich, warm milk...and insist to yourself you will sleep. Don't take no for an answer.

Regarding the subject of this FPP, it took from the end of a May, until the end of a December to shake the effects of general anesthesia with opiates. That long to restore crystal clear memory and crisp function.
posted by Oyéah at 2:34 PM on April 25, 2016


Maybe if people could sleep whenever they normally feel sleepy, without worrying about having to wake up at an arbitrary time to do almost every job out there, insomnia wouldn't be nearly as big of a problem.

posted by clockzero


Eponyappropriate. I'm a lucky person who has this sort of job and think of myself as not having insomnia. But on the rare occasion when I do have to be up early (e.g. this morning) - yup, suddenly I 'can't sleep'.

BTW I found the paper and supplemental material; neither Sudafed (definitely AC) nor Zyrtec (possibly?) were actually on the lists in the study, maybe because the number of participants wasn't high enough or... ? I'm not this kind of scientist so I don't know. Does one of you?

(nubs - if you or anyone else wants the supplemental material lemme know, I got a PDF of it here).
(Sigh-- open access! research paid for by public money should be public! Even if we lay people have no idea how to interpret!)

Oh and in other news, I at first had trouble finding the paper- because in the April 2016 issue of Neurology JAMA, there is another paper entitled "Association of Proton Pump Inhibitors With Risk of Dementia". I am kind of curious how many Neuro JAMA articles have a title with the words "Association" as well as "Dementia" or "Brain Atrophy" or etc.
posted by nat at 2:38 PM on April 25, 2016 [1 favorite]


This is why FSM invented cannabis.

While cannabis has many fine properties, inducing sleepiness has never been one for me. Quite the opposite, in fact.
posted by thefoxgod at 2:39 PM on April 25, 2016 [1 favorite]


Care to elaborate? I've been prescribed quetiapine for sleep.

I don’t want to make this too much of a derail, but I’ll give you the quick version of my soapbox rant. The antipsychotics as a class have some really problematic side effects—e.g., metabolic disturbances (hyperlipidemia, hyperglycemia, weight gain), extrapyramidal symptoms, QT prolongation, increased mortality in some populations, etc. They’re indispensable drugs for some conditions, namely schizophrenia and bipolar, but my personal opinion is that the risk/benefit calculation doesn't generally justify their use as first-line monotherapy for conditions in which psychosis or mania are absent (plenty of people disagree, so take that with a grain of salt). Quetiapine hits a bunch of receptors, but the sedation is likely due to its antihistamine properties more than anything else. Arguably the antipsychotic properties of the drug aren’t buying you that much additional mileage, they’re just adding a ton of side effects. In other words, it's like using a cluster bomb to hammer a nail. Unless there are psychiatric comorbidities that would justify an antipsychotic, it doesn’t make a lot of sense.
posted by dephlogisticated at 2:40 PM on April 25, 2016 [4 favorites]


> Don't take no for an answer

Insomnia isn't a matter of moral fortitude.
posted by The corpse in the library at 2:56 PM on April 25, 2016 [14 favorites]


Results of other studies have shown that bupropion and its metabolites do not have appreciable affinity for postsynaptic receptors including histamine, α- or β-adrenergic, serotonin, dopamine, or acetylcholine receptors.

There's some nuance to the situation. I think at least one of those cites might refer to a study that examined binding affinity only for muscarinic cholinergic receptors. Bupropion does bind to nicotinic cholinergic receptors. (Hence its usefulness as a smoking cessation aid, I guess.)

-AC drugs had to be "medium to high" in terms of effect (and I can't seem to get at the supplement on which drugs were identified in the medium to high ranges).

Perhaps they're using this classification scheme? One of the study authors is affiliated with the organization that made this chart. For what it's worth, bupropion would be considered "low" under this scheme.
posted by compartment at 3:08 PM on April 25, 2016


The best thing ever was cyclobenzaprine, which was like cannabis but never freaky. The only upside to throwing my back out during softball.

god, IF ONLY flexeril made me sleepy. literally all it does is unlock my neck, which is actually very important because that keeps me from committing terrible crimes upon humanity, but it would be nice if it also made me a little drowsy.

at 40-50mg it makes me insanely thirsty though, and also very stupid in the "i'm standing in the kitchen but i can't quite recall why" sort of way.
posted by poffin boffin at 3:13 PM on April 25, 2016 [1 favorite]


I've been an insomniac for my entire life. It sucks, it really sucks.

I used to do Benadryl, I used to do whiskey, I used to just stay up until I fainted, but since that day in '92 when the guy down the hall said to me "Dude, just take a couple hits of reefer" that's been my go to.

Ambien terrifies me.
posted by Sphinx at 3:33 PM on April 25, 2016


Turkey sandwich, warm milk...and insist to yourself you will sleep. Don't take no for an answer.

Oh FFS. This is like "Just cheer up" to someone with depression.
posted by fiercecupcake at 3:36 PM on April 25, 2016 [28 favorites]


You know, all in all, this side effect is no worse than any meds that list off their side effects on TV.
posted by Nanukthedog at 3:45 PM on April 25, 2016


JenMarie, hold on to that Tetrahydrozaline -- it'll be worth a fortune some day... ;)
posted by litlnemo at 3:50 PM on April 25, 2016


Turkey sandwich, warm milk...and insist to yourself you will sleep. Don't take no for an answer.

You basically described my morning except the milk wasn't warm. Added some Sleepy Time tea too. Lay there for hours. Even tried masturbating. None of it worked.

At this point I've given up and am just waiting it out.
posted by Jacqueline at 3:51 PM on April 25, 2016


Turkey sandwich, warm milk...and insist to yourself you will sleep. Don't take no for an answer.

Oh FFS. This is like "Just cheer up" to someone with depression.


"Insist to yourself you will sleep" is just about the worst possible answer, actually.
posted by atoxyl at 3:55 PM on April 25, 2016 [8 favorites]


The article says Zyrtec is not an anticholinergic, so you're OK on this particular front there. (yay).

Great, so we just have probably a hundred or two days of Sudafed and Zantac! I'm sure it'll be fin... what was I saying?
posted by Justinian at 4:19 PM on April 25, 2016


concentrate REALLY HARD on sleeping, focus ALL YOUR ENERGY on unconsciousness! you MUST NOT REST until you have slept!

lol irl
posted by poffin boffin at 4:31 PM on April 25, 2016 [15 favorites]


I've decided I believe this only pertains to the elderly and magically only applies to people on or after their 65th birthday.

In any case Scooter will always be there for us.
posted by Countess Elena at 4:36 PM on April 25, 2016


If you are troubled with insomnia and haven't yet tried
1) a dawn simulator and/or timed bright light -- see cet.org about circadian timing specific to yourself, and
2) blue-blocking filters on your evening lighting starting 2 hours before bedtime
I humbly, seriously, suggest giving a couple of weeks to trying those, together, consistently.
It won't work for everyone, but it won't hurt you.

Skip the absurdly expensive LED bulbs now being hyped, they cut out only about half of the blue-green band that controls the sleep cycle. You want to apply that band to set the circadian cycle (used to be called 'bright light' before they identified the narrow band for which the receptor actually responds). And you want to omit that band from your view a few hours before bedtime. Completely.

Want cheap? Yellow bug lights work fine. 12-volt amber LEDs from auto parts stores ("marker lights") work fine. Some of the yellow-orange-amber theatrical/photographic filter gels work fine. Yellow plastic "safety glasses" that wrap completely around do OK if they don't leak light in the sides.

Don't rely on "f.lux" or Apple's software to make the visible computer/phone screen warmer. That doesn't block the band that regulates sleep, it just makes the "color temperature" warmer. But you get far more light from household "white" lights -- LEDs, fluorescents, including CFLs, and streetlights

Want to pay more? Look up "turtle safe lights" -- they're readily available. This same mechanism works in many living organisms.

There's plenty of good science available, Scholar will find it.

I tried to start a thread a couple years back recommending specifics along these lines but it was ruled inappropriate for MeFi, apparently because I recommended specific products, so don't ask.

You know how to find this stuff. Copy and paste a few words from the above into search.

Seeing how many people have trouble with insomnia -- I'm taking another shot at posting some info.
At the very least this takes out one factor -- circadian rhythm extended by artificial white light -- that's definitely working hard to keep you awake.

This has worked for most of the people I've recommended it to, ages 17 to 70s.
If you don't need it, don't worry about it.
posted by hank at 4:44 PM on April 25, 2016 [4 favorites]


The best thing ever was cyclobenzaprine, which was like cannabis but never freaky. The only upside to throwing my back out during softball.

Cyclobenzaprine also has anti-cholinergic effects.

It seems like almost every drug with a sedative effect has anti-cholinergic properties, also including marijuana (which is why you get cotton mouth from it, for example). What the fuck are we supposed to do?

Trazodone seems like a good choice. It has almost no affinity for muscarinic/acetylcholine receptors, so it should be safe by that standard, and it works pretty well as a sleep aid.

However, even if we assume that this correlation between anticholinergic drugs and reduced brain volume, cognitive and executive function, etc is exactly what we fear it is in causal terms, it's worth remembering that aerobic exercise is an extremely well-documented way to improve cognitive function, supporting neurogenesis and brain volume retention and even growth.
posted by clockzero at 4:45 PM on April 25, 2016 [1 favorite]


I think at least one of those cites might refer to a study that examined binding affinity only for muscarinic cholinergic receptors.

In the context of drug side effects, anticholinergic is often shorthand for antimuscarinic. Nicotinic activity is comparatively rare, which is just as well because some of those receptor subtypes you really don't want to mess with. Antimuscarinic activity pops up everywhere and is a big problem when it comes to geriatric populations, primarily due to the associated effects on cognition.

Notwithstanding the ubiquitous nature of antimuscarinic activity, there's a really big asterix that needs to be appended to that Anticholinergic Burden list:
For the ACB, drugs ranked as 0 have no anticholinergic effects, those ranked 1 have possible anticholinergic effects based on SAA or in vitro affinity for muscarinic receptors, and those classified as 2 or 3 are medications with established and clinically-relevant cognitive effects.
The key words here are "in vitro affinity" and "clinically-relevant". That's the difference between a drug lighting up an assay in a petri dish and a drug that has demonstrable effects in people. The distinction is important: a drug that does not penetrate the blood brain barrier, for instance, is not going to cause cognitive side effects, regardless of receptor affinity.
posted by dephlogisticated at 4:54 PM on April 25, 2016 [4 favorites]


Cite for interaction of THC with ACh? I'm not seeing a whole lot though there could be downstream effects on who knows what. This is what I've seen before about dry mouth.
posted by atoxyl at 5:10 PM on April 25, 2016


So, in my inexpert opinion, this paper is absolutely not worth the level of excitement exhibited in that news story. And really isn't worth 110 comments in 8 hours level of excitement.

Anti-cholinergic neurological side effects are well known. I'm not a neurologist and don't work with the over 60 set, but the fact that the general slowing and sedating effects of stuff like benadryl goes beyond the warning to "be careful when driving a motor vehicle or operating heavy machinery" is well accepted by most people I work with. Acute delerium worsens when someone is given benadryl and often times people who develop delerium get better when their anti-cholinergic medications are trimmed back as much as possible.

Okay, delirium is an acute change, dementia is a permanent change. But while it's easy to link a med to such a demonstrable and dramatic short term effect like sedation (take away to bendaryl and the person becomes less sleepy/delerious!) chronic changes are lot harder to prove. None-the-less, most people I know who had an opinion felt there should be a strong suspicion that excessive use of any sedating medication, from Vodka Martinis to Phenbarbitol to Xanax to Benadryl may have permanent side effects. Some took it for granted as true that there is some level of increased risk, regardless of the lack of rigorous studies.

The relative incidence cognitive decline would be the first thing to study when establishing a link between anticholinergics and dementia, but the overlap between acute and chronic effects make tests of cognition harder to interpret. Do people do worse on tests because they take their Bentyl right before sitting down for a long period of time? Did the study control for the fact that people who take Benadryl more often are just simply going to more frequently tested within 12 hours of their last Benadryl dose? Are people with pre-symptomatic dementia who take anticholinergic meds simply diagnosed earlier because they're more likely to have an episode of forgetfulness or confusion while being on their med?

Honestly, the most outstanding thing contributed by this study is the imaging difference (I'm pretty sure I've seen differences in cognitive scores before, but those might have been smaller studies). To me, this is a slightly better measure of long term changes than cognitive scores... but honestly I'm so unfamiliar on studies involving MRI measurement of cortical thickness and ventricle volume that I wouldn't be surprised if the imaging is much less reliable than I think it is.

Otherwise, population studies , case controls, cohort studies et cetera, while an extremely useful first step, are almost never enough to change clinical practice by themselves. This is especially true of studies that use someone else's dataset, where the data collection wasn't designed specifically to answer the question your study is hoping to answer. Plenty of comments have already alluded to this fact, the various ways these studies have been proven red herrings in the past, the missing pieces of information, possible confounders, correlation/causation.

And even assuming there is some causation, what then? If the risk is relatively small, you gotta ask yourself, honestly, how big does a risk have to before its enough to rethink the value of a medication? I personally never take anti-histamines, mostly because I hate even mild sedation side effects. But if my sinus congestion was bad enough such that the mild sedation was worth it, would 50 years of improved allergies be worth 20 percent off your working memory for 10 years? Maybe.
posted by midmarch snowman at 5:14 PM on April 25, 2016 [2 favorites]


I just skimmed the article, and although it's a house built on a lot of correlations, they tell a story that's consistent. In particular, the one that stands out to me: the relative risk ratio of cognitive decline was 2.5 for those taking AC meds, but 7.7 for those with AC meds who are also amyloid beta positive. While this is still just correlational, this are correlations that hint at a plausible mechanism.

As midmarch says, it's not clear how to interpret cognitive testing in people currently using anticholinergics, however the 96 month followup including progression to MCI or Dementia suggests this is not solely a "day of test" phenomenon. If it were, then the experiment is easy: take the AC+ folks off their meds for 72 hours and retest them, and they should all bounce back to normal.

The biggest "hmm" things to me in the study are that the AC+ folks have statistically significantly higher rates of depression and anxiety and overall medication use, and also higher rates of other disease conditions that may not be statistically significant. Although the authors tried to control for these statistically, that's usually not a guarantee that these factors are weeded out.
posted by soylent00FF00 at 5:29 PM on April 25, 2016 [3 favorites]


Turkey sandwich, warm milk...and insist to yourself you will sleep. Don't take no for an answer.

Good to know you don't have severe crippling insomnia, because you wouldn't be saying BS like that if you did.
posted by Ferreous at 5:29 PM on April 25, 2016 [7 favorites]


dephlogisticated, thanks for the clarification. I really appreciate it.

Can you (or anyone else) clarify whether binding affinity at nicotinic subtypes has ever been associated with long-term cognitive issues? Or has this relationship only been observed for inhibitors of muscarinic subtypes?
posted by compartment at 6:16 PM on April 25, 2016


Cite for interaction of THC with ACh? I'm not seeing a whole lot though there could be downstream effects on who knows what. This is what I've seen before about dry mouth.

I was sort of guessing about the relationship between cotton mouth and choline receptor activity.

There is reason to suspect that marijuana modulates choline function. Here are some citations:

1. Cannabis seems to significantly modulate the turnover rate of ACh in certain brain areas, lowering turnover and increasing choline levels. This data is drawn from in vivo tests done on mice.

2. However, there is also evidence that THC has broad and underdescribed inhibitory effects on a variety of neurotransmitters, including ACh. The test subjects here were guinea pigs and in vitro brain tissue.

3. "The effects of cannabinoids on memory processes are similar to those found following administration of antimuscarinic drugs and in neurological patients suffering from deficits in limbic cholinergic functioning."

4. Cannabis reduces acetylcholine release from the neocortex, reduces ACh utilization in the brain, especially in the hippocampus. (This is probably related to how cannabis makes you feel kind of pleasantly confused)

So, I was probably misstating the case when I said that THC is an anti-cholinergic, in the sense that it doesn't seem to directly block the binding of ACh to receptors; however, it does have clinically significant interactions with the ACh system, some of which appear to effectively mimic anticholinergic drugs.

All else being equal, then, it seems like marijuana is a better choice than Benadryl as a sleep aid if you're concerned about the risks of neurological decline.
posted by clockzero at 6:20 PM on April 25, 2016


If you are troubled with insomnia and haven't yet tried
1) a dawn simulator and/or timed bright light -- see cet.org about circadian timing specific to yourself, and
2) blue-blocking filters on your evening lighting starting 2 hours before bedtime
I humbly, seriously, suggest giving a couple of weeks to trying those, together, consistently.
It won't work for everyone, but it won't hurt you.



i've been doing this since february 25th and now my new normal bedtime is 3am when it used to be 1am, and instead of getting up at 930 feeling well rested i am now getting up at 1130 feeling cranky and sore and generally furious
posted by poffin boffin at 6:26 PM on April 25, 2016 [3 favorites]


Also, this advice, although well-meaning, can't help those of us who wake up at 4:30 with an urge to review all of our sins until 30 minutes before the alarm is set, at which point unbelievable drowsiness arrives. Natural light isn't a problem; I see it when it's coming. I need something to hold me down.
posted by Countess Elena at 6:36 PM on April 25, 2016 [5 favorites]


After years of intolerable pain levels due to interstitial cystitis, Atarax is the thing that works best for me. I'll risk the dementia to be (relatively) free of the pain.
posted by MaritaCov at 7:29 PM on April 25, 2016 [2 favorites]


aerobic exercise is an extremely well-documented way to improve cognitive function

I'll just go senile, thanks
posted by Jacqueline at 7:56 PM on April 25, 2016 [8 favorites]


As someone with dermatographism, a formaldehyde resin allergy, and a recurring id reaction, I have also found Atarax to be invaluable. I took it last night. I also took some ranitidine. My husband has also found a number of other pharmaceuticals implicated here to be essential to getting through various illnesses. And it is thus that I'm sitting here squirming, in full-on breathe-through-my-nose-so-I-don't-panic mode. I really wanted to be lucid enough in 2084 to help train, if not lead, my people in the fight against the Robotrons.

P.S. Earlier I almost signed an email like so:
Best,
Best,
limeonaire
And I mistakenly ordered Dr. Bronner's diet cream soda, rather than Dr. Brown's.

As Lisa once screamed: OH MY GOD. I'M LOSING MY PERSPICACITY!!! AHHHHH!
posted by limeonaire at 7:58 PM on April 25, 2016 [2 favorites]


Any medication you take is interfering in same way with your system and that's going to have potentially serious consequences. So unless the side effects are "may cause sudden death" or "likely to cause your skin to slough off" I just kind of shrug and take the pills. Also not snark.

This. Those who have the freedom to argue otherwise (or able to fret about the long-term consequences of their pharmaceutical drug of choice), check your privilege.

FWIW, when I need to pop Benadryl, I'm neither doing it to treat allergies nor am I doing it to get to sleep. Anticholinergics have many uses, and the great thing about Benadryl is that it's both over the counter and ubiquitous. Also, if you get the children's chewable tablets, they taste like candy.
posted by steady-state strawberry at 8:02 PM on April 25, 2016


Can you (or anyone else) clarify whether binding affinity at nicotinic subtypes has ever been associated with long-term cognitive issues?

The shortest and most honest is that I don't know. There aren't a lot of drugs in use with significant nicotinic activity aside from the neuromuscular blockers. I'm sure there are tons of animal studies out there looking at various experimental compounds but I've more or less washed my hands of that sort of mess, so I can't speak to it with any sort of authority.

Nicotine itself seems to improve cognition and memory, which is not unrelated to its addictiveness; it gets the mesolimbic dopamine flowing, which links the behaviors of smoking to associative cues. The cholinesterase inhibitors (which nonspecifically increase cholinergic signaling) have some modest benefits for memory and hence are used for the not-terribly-effective symptomatic treatment of Alzheimer's. There's a theory that the prevalence of tobacco use among schizophrenics is in part self-medication for the cognitive deficits associated with the disease, which again comes back to dopamine gating.

I can't think offhand of any centrally-acting nicotinic antagonists that are used regularly. I don't think bupropion's a good example because its effects on monoamine signaling hopelessly complicate the picture.

After years of intolerable pain levels due to interstitial cystitis, Atarax is the thing that works best for me. I'll risk the dementia to be (relatively) free of the pain.

Good news! Hydroxyzine has a dissociation constant of >10,000 nM for muscarinic receptors, which is a fancy way of saying it ain't no thang.
posted by dephlogisticated at 8:10 PM on April 25, 2016 [2 favorites]


I started a meta on this post here. Some people there made the point that I should post my problems in the thread. After reading the paper, some points that I think need more attention are:

• This is only relevant for people taking anticholinergic medications (ACs) after they are 65.
• There is only an association between AC and dementia at the highest dosage level that was included. There was no association found otherwise.
• There was no comment on the relative benefits of using ACs vs this risk.
• Association does not mean causation.

Based on that, I really wouldn't worry too much here. And if you are worried, talk to a doctor.
posted by Ned G at 9:24 AM on April 26, 2016 [4 favorites]


"I recommend a seven-percent solution of vodka and Benadryl and Percocet. Then a sandwich and a coffee for lunch, and off to see this wonderful new artist Vivaldi at his afternoon performance!"

(Read this in your best Jeremy Brett voice for optimal performance.)
posted by jbickers at 1:07 PM on April 26, 2016 [1 favorite]


Carisoprodol, which keeps me from being in screaming pain quite often, apparently has some anticholinergic activity. Benedryl, which helps me sleep and breath during North Florida Allergy Season (April through March) is also bad. So, perhaps I can breathe and sleep less and be in excruciating back, neck, and shoulder-pain all the time, but have the benefit of remembering it all better. So, fuck.
posted by Cookiebastard at 4:06 PM on April 26, 2016


• This is only relevant for people taking anticholinergic medications (ACs) after they are 65.
• There is only an association between AC and dementia at the highest dosage level that was included. There was no association found otherwise.
• There was no comment on the relative benefits of using ACs vs this risk.
• Association does not mean causation.


Based on a very quick skim of the full paper, I have two HUGE criticisms to add to this completely accurate list:

1) I see no evidence that they corrected their significance threshold in any way for multiple comparisons (and did a huge number of comparisons). This is mandatory, super basic stuff (or if you really don't want to do the stats correction, you at the bare minimum need to verbally justify the lack of correction somehow and account for it when interpreting the results). There are also a suspiciously high number of p=0.04 values reported (for the non-scientists, that means it's just barely passing the statistical bare minimum allowing you to publish it as a "real" difference). Certainly any multiple comparisons correction whatsoever would put those p values well into the "meaningless noise" zone. Relevant xkcd for this issue, if it hasn't been linked already.

2) Furthermore, the magnitudes of all their observed effects seem incredibly tiny to me, and if differences like "2.80 mm for AC+ participants and 2.84 mm for AC− participants" do indeed have any biological significance whatsoever, this is not described or proven at all (for bonus hilarity, check out the graphs which are very misleadingly labelled with every y-axis starting as far above 0 as possible).

I'm not saying it's necessarily a complete garbage paper....but it sure smells off to me (albeit as a biomedical researcher, not a psychology/neurology researcher).
posted by randomnity at 7:20 PM on April 26, 2016 [4 favorites]


Ugh, and one more thing, though this is more a flaw of the news article than the original paper - the original study shows absolutely zero "increased risk of dementia" - they didn't look at that at all, just at various "cognitive assessments" which may or may not have any relationship whatsoever with the risk of future dementia (and again, the results may or may not even show "real" cognitive deficits in the first place).
posted by randomnity at 8:12 PM on April 26, 2016


Thanks randomnity, I didn't like the numbers much, but having your points makes me better able to articulate that fact.
posted by nubs at 7:54 AM on April 27, 2016


i use diphenhydramine regularly to help me um, help me to, uh, something or other...
posted by quonsar II: smock fishpants and the temple of foon at 1:54 PM on April 27, 2016


Ugh, and one more thing, though this is more a flaw of the news article than the original paper - the original study shows absolutely zero "increased risk of dementia" - they didn't look at that at all, just at various "cognitive assessments" which may or may not have any relationship whatsoever with the risk of future dementia (and again, the results may or may not even show "real" cognitive deficits in the first place).

The original study actually does model the risk using a Cox hazards model to determine relative risk of progression from CN (Cognitive Normal) to MCI (Mild Cognitive Impairment) or AD (Alzheimer's Disease) - see Fig. 4 on page 8.

I'm not clear where they got the diagnosis of MCI or AD, but since these are both clinical disorders with actual diagnostic rules, presumably these are based on actual clinical diagnosis.

If so, your suggest that these results aren't showing "real" cognitive deficits seems misplaced.
posted by soylent00FF00 at 3:41 PM on April 28, 2016


The original study actually does model the risk using a Cox hazards model to determine relative risk of progression from CN (Cognitive Normal) to MCI (Mild Cognitive Impairment) or AD (Alzheimer's Disease) - see Fig. 4 on page 8.

Ha, that's embarassing. You're right - I somehow managed to miss that entire figure. Skimming too fast, I guess. So erm, nevermind that comment. Sorry, and thanks for the correction!

And now that I'm looking at it, I'll mention that the numbers seem a little weird. It looks like the graph is simply showing a regular "survival" curve (where "survival" = progression, aka conversion to MCI or AD), but that would mean that about half of their AC- subjects and ~75% of their AC+ subjects developed MCI or AD by the end of the 4y followup. Seems very high to me, but possible if MCI is a very broad definition, I guess?

But...by adding up their list of the number of converters at each followup, it looks like only 14% (47/333) of the AC- and 22% (11/51) of the AC+ "converted" within those 4y (side note: 14% of 51 people would be 7 people - just 4 less than they observed). So, not anywhere near 50-75%...why? My best guess is that it's caused by a lot of people dropping out of the study early. Since it's a tiny study, every patient counts, but the mean followup time was only 32 months, with a range of 6-108 months...so most of their n=333 and n=51 study participants didn't complete the full 96-months shown on the graph. But they don't include censored subjects in their graphs or mention any other details in the text, like whether there were any differences in followup time between the two groups....so who knows how quickly that starting group of 51 dropped to an even more ludicrously low sample size. Pretty quickly, I'm guessing, since the mean followup time is one-third of the graphed followup time....which would imply that only ~15 AC+ patients actually completed the study (based on the graph showing ~75% conversion by the end, with 11 conversions listed). If so.....yikes!! Especially given the difference in sample size between groups, which increases the risk of false positives due to higher variability in the smaller group.

If so, your suggest that these results aren't showing "real" cognitive deficits seems misplaced.

This comment was just referring to the other figures, since I missed Figure 4. Based on the small effect sizes in most of the experiments and unconvincing statistics overall, I remain skeptical that Fig 1-3 demonstrate many "real" (as in both statistically distinguishable from random chance and biologically meaningful) cognitive deficits. Again though, I don't do neurology stuff, so maybe those tiny differences do actually have a meaningful effect. I wish there was more explanation in the paper of the biological significance of the observed effect sizes.
posted by randomnity at 6:39 PM on April 28, 2016 [1 favorite]


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