
Strong Link Found Between Dementia and Common Anticholinergic Drugs (2015) - objections
http://www.dddmag.com/articles/2015/04/strong-link-found-between-dementia-common-anticholinergic-drugs
======
Spare_account
My goto anti-hayfever drugs are Loratadine and Cetrizine in generic non-
branded packets for cost reasons. OP's article worried me because I regularly
take one or both of them for two months straight over summer.

The article states that Loratadine is recommended as an alternative for the
relief of allergies. The article didn't explicitly mention Cetirizine but I
have done some research and came across another article from 2012 which does
include Cetirizine in the same category as Loratadine:

[http://www.pharmacytimes.com/publications/issue/2012/april20...](http://www.pharmacytimes.com/publications/issue/2012/april2012/the-
anticholinergic-cognitive-burden-)

I believe I am safe to continue using Cetirizine and thought some of you may
have the same question. I am not an expert on these issues so if I'm mis-
understood any of this please let me know.

~~~
simonsarris
The linked study (not OP's article) only mentions first generation
antihistamines, and Cetrizine and Loratadine are both second-gen ("non-
drowsy"). _This_ study[1] alleges that Cetrizine does not have a cholinergic
response associated with it (good), but that Loratadine did show
anticholinergic activity (bad).

The OP article says:

> Those with allergies can take a second-generation antihistamine like
> loratadine (Claritin)

But perhaps Cetrizine is more safe, and we should not be taking Loratadine if
we can avoid it. Thoughts, anybody?

[1]
[https://www.ncbi.nlm.nih.gov/pubmed/15627436](https://www.ncbi.nlm.nih.gov/pubmed/15627436)

~~~
laen
The linked chart dated 2012 lists cetrizine and loratadine as "possible"
anticholinergics. It appears they will equally put you at risk. So what are
allergy sufferers alternatives? I'm dependent on loratadine and a little
dismayed to just now learn of this even if the correlation is not clear.

Guess I'll just have to start eating a bunch of honey...

[1] [http://www.agingbraincare.org/uploads/products/ACB_scale_-
_l...](http://www.agingbraincare.org/uploads/products/ACB_scale_-
_legal_size.pdf)?

~~~
mcheshier
Fexofenadine/Allegra was reviewed and not added. This is fortunate as it's the
only OTC allergy medication that actually works for me.

~~~
kbutler
Same - just took a generic fexofenadine, in fact. Of course, 5 years ago,
everybody thought diphenhydramine was safe, too.

But is there a "safe minimum frequency"? Generally, I try to avoid taking any
medication more/longer than necessary, and my bottle of diphenhydramine is
still mostly full after many years...

------
arikrak
> ...“basically any cold medications that make you sleepy might contain
> anticholinergics, so stay away from drugs that make you sleepy.” NyQuil is
> an exception, he said. It makes people sleepy, but does not contain an anti-
> cholinergic. Still, “if your solution for a sleep problem is a pill, a quick
> fix, do you want that?” Any drug taken for a long time could come with
> problems.

Over the counter sleep medicines lose their effectiveness when taken
regularly, so it people are less likely to do so (vs. taking such medicines
for allergy relief).

Also NyQuil contains doxylamine [1], which is an anticholinergic, and is
listed with the other problematic medicines [2].

[1]
[https://www.google.com/search?q=nyquil%20active%20ingredient...](https://www.google.com/search?q=nyquil%20active%20ingredients)
[2] [http://www.agingbraincare.org/uploads/products/ACB_scale_-
_l...](http://www.agingbraincare.org/uploads/products/ACB_scale_-
_legal_size.pdf)

~~~
daodedickinson
I wonder why NyQuil is outside of quotes. Did a professor of medicine really
make such an unbelievable mistake?

Let us not forget that this class of drugs (which includes diphenhydramine
(Benadryl), scopolamine, and datura is called "deliriant".

From Wikipedia: " The term was introduced by David F. Duncan and Robert S.
Gold to distinguish these drugs from psychedelics and dissociatives, such as
LSD and ketamine respectively, due to their primary effect of causing
delirium, as opposed to the more lucid states produced by other hallucinogens
(psychedelics and dissociatives)... The delirium produced is characterized by
stupor, confusion, confabulation, and regression to "phantom" behaviors such
as disrobing and plucking.[2] Other commonly reported behaviors include
holding full conversations with imagined people, finishing a complex, multi-
stage action (such as getting dressed) and then suddenly discovering one had
not even begun yet, and being unable to recognize one's own reflection in a
mirror."

This is the expected behavior for someone who consumes about 500-700mg of
diphenhydramine at once (the dose suggested on the package is usually 50mg).
Benadryl is probably the most powerful hallucinogen known; it distorts the
senses far more than even some of the most notorious illegal drugs and the
reasons for its continued over-the-counter legality might make for an
interesting book. Obviously it has healthy uses, and many deliriants have
long-established religious uses in North America. The Serpent and the Rainbow
and Passage of Darkness: The Ethnobiology of the Haitian Zombie are two books
that explain how anticholinergic drugs are what create real-life zombies.

~~~
pflats
>I wonder why NyQuil is outside of quotes. Did a professor of medicine really
make such an unbelievable mistake?

It's more likely the professor either talked about NyQuil in a follow-up
question where the direct quote did not flow nicely, or expounded on it in
much longer length than the author wanted to quote directly.

------
itchyouch
As a narcoleptic, I have no trouble falling asleep, the trouble is with
staying asleep and getting deep rest during my sleeping periods. I've found
that some nutritional strategies work tremendously well.

[http://main.poliquingroup.com/ArticlesMultimedia/Articles/Ar...](http://main.poliquingroup.com/ArticlesMultimedia/Articles/Article/1041/Ten_Excellent_Nutrition_Tips_for_Better_Sleep.aspx)

Personally, I only supplement 4 nutrients and it has been a tremendous sleep
quality improvement.

Vitamin D3 in the AM Taurine & Magnesium Glycinate prior to sleep. L-Theanine
is also added depending on whether I took caffeine during the day.

For my wife who also has sleep problems, she takes Ambien, but Ambien +
Taurine will knock her out, while she can still wake up on Ambien alone.

~~~
ggchappell
From your linked article:

> #1: Eat More Protein During the Day & Select Carbs at Night

> ... eating a meal of carbohydrates in the evening can help you go to sleep
> quickly.

This is curious. I've run across this advice before. I have also found, from
repeated experiments, that eating starchy foods just before bed makes it
harder for me to go to sleep. Maybe I have some weird body chemistry ....

------
cloverich
Firstly, the article is open why not simply link it? Second -- people take
these medications to help them sleep. Difficulty sleeping is a comorbidiy of
dementia. I haven't made it through the paper yet -- but pointing out anything
other than association seems awfully premature.

Link:
[http://archinte.jamanetwork.com/article.aspx?articleid=20917...](http://archinte.jamanetwork.com/article.aspx?articleid=2091745&)

~~~
elcritch
Not necessarily. If they were able to sufficiently test for confounding
variables, it'd be a reasonable conclusion. The news article specifically
states they were able to control and remove overlap with existing dementia
cases. Question is how well it's done, and I don't have time to examine the
OP. Post if you notice anything?

~~~
joveian
Here is a comment from the authors about residual confounding:
[https://archinte.jamanetwork.com/article.aspx?articleID=2428...](https://archinte.jamanetwork.com/article.aspx?articleID=2428897)

------
soylentcola
Poked around a bit and ran across at least one article [1] that advises
caution but also points out that these results are seen in fairly
high/frequent doses, are still being studied, and that anyone prescribed or
currently taking an anticholinergic medication should check with their doctor
before just stopping the drug. The way I see it, not everyone is necessarily
at risk and as with many things, the outcome of not taking the medication
could be worse than the potentially higher risk of negative outcomes from
taking the medication.

Either way, something to consider.

[1] [http://www.nhs.uk/news/2015/01January/Pages/media-
dementia-s...](http://www.nhs.uk/news/2015/01January/Pages/media-dementia-
scare-about-common-drugs.aspx)

------
wheaties
Can we have the data to see if their statistics are good and that they applied
the right techniques to clean their data? I don't trust any medical study much
anymore because next week one will come out refuting this claim.

~~~
oliwarner
Ask the author. The paper says they had full access to their data. They might
be able to pass an anonymised version of that along. They might even be
willing.

The process of scientific discussion (that you "don't trust") is just how
science works.

I suspect what you actually dislike is the way these papers are cross-
reported. It's one thing to be featured in a relevant journal, it's another to
be syndicated as "THE CURE FOR DEMENTIA" by a much higher-level journal (or
heavens forbid, a newspaper... or worse).

You can blame the sponsors and drug companies for that. Neither of which
really seem to be involved here.

~~~
pc2g4d
> The process of scientific discussion (that you "don't trust") is just how
> science works.

The invisibility of the data upon which papers rely is one of the key
weaknesses of science as currently practiced, as it makes verification of
analysis impossible. I don't think it has to be "how science works", and in
fact I hope that science moves away from such opacity to requiring data to be
published alongside papers.

------
DenisM
Complete list (more or less) of affected drugs:

[http://www.virginiageriatrics.org/consult/medications/medsLi...](http://www.virginiageriatrics.org/consult/medications/medsList.html)

~~~
stordoff
Thanks for the link. This is somewhat concerning as I currently take two drugs
on that list (promethazine, amitriptyline), though TBH given the improve they
provide to daily life I think it is an acceptable, unfortunate risk.

------
im3w1l
I've seen many people claim choline has nootropic effects (i.e. that
supplementing it is good for cognition), so this doesn't seem surprising.

Note: I am not a doctor, and this is not medical advice.

~~~
enkephalin
but at the same time it exhibits depressogenic effects in a lot of people.
especially in higher dosages. so it's not really that clear cut.

------
hvidgaard
While not a new result, it is very scary none-the-less. Some of those drugs
are a daily goto for many people to handle various issues. I hope medical
professionals will take this result into account before recommending them for
any longterm treatment.

~~~
viper161616
Most of this stuff is available over the counter - so medical professionals
don't even need to be consulted. I hope they pull it behind the counter if the
results are corroborated. It would make handling allergies a pain though.

~~~
im3w1l
In the article they recommend using loratadine (Claritin). Is that
insufficient as a replacement?

~~~
a3n
Claritin makes me feel weird, sort of light headed.

Back in the eighties in Seattle I would take a Benadryl every morning, because
I was allergic to just about everything (I was poke tested). Eventually I
downgraded to chlor-trimaton. So I guess I'm potentially doomed.

Here in Denver I rarely have allergy issues.

~~~
elcritch
You could try looking into factors to actively reduce your risk. Exercise,
eating healthy, and drink lots and lots of coffee. E.g. It's all poker and
you're down on the pot but it just means you need to learn to play a different
better hand. At least it's the approach I found to be beneficial.

~~~
a3n
It's certainly the only sane approach, I agree. It's like Lyle Lovett said,
"You have to try ..."

My mention of doom is because I got the impression that the rise in risk (10%)
was associated pretty hard with long term use, which I had, and distant past
wasn't mentioned as a mitigation.

------
joveian
Here is an article that talks about possible mechanisms: [http://sci-
hub.io/http://content.iospress.com/articles/journ...](http://sci-
hub.io/http://content.iospress.com/articles/journal-of-alzheimers-
disease/jad150290)

"Another implication of the ability of cholinergic antagonists to promote
dementing diseases is that sufficient choline needs to be provided so that
adequate PC production can continue. This might most effectively be done by
administering the choline as a component of a nutrient mixture that contains
all three of the PC precursors which limit PC’s rate of synthesis: uridine as
its monophosphate; DHA or EPA; and choline [24]. This mixture has been shown
to diminish Aβ formation in experimental animals [32], and could have the
added benefit of partially restoring the deficient brain synapses."

~~~
mirimir
I'm reminded that health freaks have recommended supplements containing
phosphatidylcholine and precursors _for many years_. It does make sense, in
that phosphatidylcholine is a bipolar lipid, and plays important roles in cell
membranes.

------
onetwotree
This is consistent with the Cholinergic hypothesis[1] of Alzheimer's disease.
Also, note that the various hypotheses for Alzheimer's are not really
"competing", so this doesn't mean that the more recent lines of research are
any more or less valid.

Alarming stuff! I've no problem giving up Benydryl, but my partner takes
Disiprimine,and it's the only drug she's found that works well for her
depression :-(

[1]
[https://en.wikipedia.org/wiki/Alzheimer%27s_disease#Choliner...](https://en.wikipedia.org/wiki/Alzheimer%27s_disease#Cholinergic_hypothesis)

------
bowenfreddy
From the source [1]: "study participants 65 years or older were sampled
randomly from Seattle-area GH members. Participants with dementia were
excluded. The original cohort of 2581 participants was enrolled from 1994
through 1996. An additional 811 participants were enrolled from 2000 through
2003. In 2004, the study began continuous enrollment to replace those who died
or dropped out."

[1]
[http://archinte.jamanetwork.com/article.aspx?articleid=20917...](http://archinte.jamanetwork.com/article.aspx?articleid=2091745#Methods)

------
m0llusk
This result echoes previous research into links between cognitive decay and
use of paracetemol:

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921468/](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921468/)

The suggested mechanism is that coal tar derived medicines trigger a self
sustaining inflammation reaction which causes generation and accumulation of
amyloid plaques.

------
tP5n
Most peoples anti-hayfever drugs will be 'second generation' antihistamines,
like loratadine and cetirizine, which are not problematic.

More worrying to me is the fact that OTC antiemetic (motion sickness) drugs
like Gravol/Dramamine/Vomex/Dramina are made of dimenhydrinate, which is 50%
diphenhydramine, which in turn is what the mentioned 'first generation'
antihistamines are made of.

------
wslh
What is the difference between a branded drug like Tylenol and paracetamol?

~~~
oliwarner
Standard Tylenol is paracetamol (aka acetaminophen)... But the article here is
talking about Tylenol _PM_ , which is a different formulation. From Drugs.com:

> What is Tylenol PM (acetaminophen and diphenhydramine)? Acetaminophen is a
> pain reliever and a fever reducer. Diphenhydramine is an antihistamine that
> reduces the natural chemical histamine in the body.

It's explicitly the anticholinergic diphenhydramine that's being looked at in
things like Tylenol PM. Standard paracetamol isn't being questioned, I don't
think.

~~~
Spare_account
FWIW this was my understanding as well.

------
w23j
Does anybody know if this also concerns drugs taken with an inhaler? I use an
inhaler for allergic asthma and am not sure if the drug is "anticholinergic".

~~~
daveguy
I am not a doctor. Consult your doctor. That said, my non-medical grain-of-
salt advice.

 _Find out the mechanism of action._

1) If the allergy medicine is "anticholinergic" \-- same mechanism of action
but not the same drug -- then it may or may not have the same side effects.

2) If it is "diphenhydramine" then it likely does have the same side effects
(even if different delivery).

3) If it is a different mechanism of action then it likely will not have the
same side effect.

If 1 monitor the research, if 3 you probably don't need to worry at all. If 2:
talk to your doctor about alternatives. Keep in mind this is just a single
study and new evidence may overturn current evidence. But the side
significance and magnitude of the effect I would say is cause for concern
(again just one study I expect there will be many more).

~~~
hga
_2) If it is "diphenhydramine" then it likely does have the same side effects
(even if different delivery)._

Dose dependency was mentioned, and I'm presuming/hoping taking it by inhaler
results in a relatively low dose to the brain....

~~~
GFK_of_xmaspast
Presumably one takes it by an inhaler so that it goes directly to the
trachea/lungs/etc instead of having to get absorbed through digestion, get
distributed in the bloodstream, survive the liver, and finally make it to the
needed areas.

------
ajuc
Great, I took berodual for years because of asthma :/

~~~
hga
That was with an inhaler?

The study says the effect was dose dependent, so with any luck your brain
wasn't getting all that much....

~~~
simonster
Yes, from the WP article
([https://en.wikipedia.org/wiki/Ipratropium_bromide](https://en.wikipedia.org/wiki/Ipratropium_bromide)),
the anticholinergic in Berodual does not diffuse into the blood and also does
not cross the blood-brain barrier, so it seems like you're safe.

------
KingMob
Interesting, especially the finding that the dementia is correlated with
multiple different anticholinergic drugs, but the counter-argument is simple:
people taking lots of medications are probably less healthy in general, and
therefore more likely to develop dementia.

Since there's no ethical way to do a prospective study, this is more
suggestive than anything else. They admit they don't know the mechanism yet,
so take with a grain of salt.

~~~
agentgt
_> people taking lots of medications are probably less healthy in general, and
therefore more likely to develop dementia._

I have already seen several casual confounds in other comments like this and I
have to think the scientist went to stringent lengths to eliminate as many
confounds and variables given how strong they claim the link is.

 _> They admit they don't know the mechanism yet, so take with a grain of
salt._

Just because they don't know the mechanism doesn't mean it should not be taken
seriously. We barely confident of the mechanism that causes Tobacco/Nicotine
to give cancer. Some even argue it isn't even Nicotine but rather the bacteria
that is around nicotine that produces carcinogens. And there is a good chance
like Nicotine products the cause is probably multifaceted (like coupled
vehicles etc.).

That being said I haven't read the study in detail.

~~~
KingMob
> I have to think the scientist went to stringent lengths to eliminate as many
> confounds and variables given how strong they claim the link is.

Having worked in academic science, I can assure you, every scientist tries to
make their findings sound strong.

> Just because they don't know the mechanism doesn't mean it should not be
> taken seriously.

True. There are many things for which we get good evidence before knowing the
mechanisms. But here, I'm not sure the evidence is that good, which is why I
think a suggested mechanism of action would go a long way.

------
ild
SSRIs, contrary to the article are all potent anticholinergic.

~~~
hga
That's not true; I suspect it depends on how many other receptors they hit.
One reason Lexapro/escitalopram is liked for its laser precision, in the
prescribing information it has the following aside, relevant to receptors it
doesn't hit:

" _Antagonism of muscarinic, histaminergic, and adrenergic receptors has been
hypothesized to be associated with various anticholinergic, sedative, and
cardiovascular side effects of other psychotropic drugs._ "

~~~
ild
Doesn't what you just cited mean that Lexapro is anticholinergic?

~~~
hga
It doesn't hit those receptors, so no, hence its ending with "other
psychotropic drugs", the latter explicitly excludes Lexapro from being in that
class of drugs.

~~~
ild
Yes, you are right, but your quote was not complete, so I got confused.

------
cmonsen
Got around to reading the primary source. I am surprised there isn't more
skepticism from this group, but it may have to do with not having time to read
the paper. A few reasons to be skeptical of the results (some are stronger
than others):

1) First, required reading for anyone interpreting medical studies:
[http://jama.jamanetwork.com/article.aspx?.articleid=201218](http://jama.jamanetwork.com/article.aspx?.articleid=201218)
TLDR; is that ~40% of _randomized_ (generally considered highest level of
quality) studies and maybe more are proven wrong by subsequent ones resulting
from publication bias. Consider that this would not have been published in a
high profile journal if it showed no effect, hence pub bias. In other words,
we're not seeing the similarly large analyses that show no effect because
they're not published.

2) The adjusted analyses have confidence intervals on the odds ratio that
overlap with 1.0 except for the highest dose group. There is evidence of a
dose response relationship, but there is a problem in how they measure dose
response. Cumulative dose biases towards people who have been on medications
for a long time. People who are able to take medications (ie are older) for a
long time are at greater risk for dementia.

3) It is problematic that they assume any effect on their endpoint is a class
effect (ie true of all anticholinergics). The relationship with one medication
may be driving this effect entirely. I would like to see, for example,
oxybutynin pulled out of the analysis which is never prescribed for allergies
and more often for neurological conditions, which could be an unmeasured
confounder depending on how they modeled the comorbidities.

4) Controlled analyses are difficult to do well. Most of the time it controls
for linear effects, meaning synergistic effects (which are probably involved
in development of dementia) are not captured unless explicitly modeled. I do
not see that they did this here.

5) I am further suspicious of the way they obtained fill data. As you are
noting, many OTC anticholinergics are not "dispensed" in a way typical of
prescription anti-cholinergics. If I bought Benadryl at CVS or even if I
bought the pre-packaged bottle at the Group Health pharmacy, it's pretty clear
to me that neither of these would be reflected in the data. This skews heavily
toward prescription anti-cholinergics, which tend to be given for psych/neuro
indications which themselves have an association (though likely not a causal
one) with dementia. Again, unclear if they modeled all of these.

Overall, I share the sentiment that medical literature needs to be more open.
I think it's unfortunate that current state makes it hard to confirm analyses
like these with a great degree of certainty.

------
ekianjo
Should have 2015 in the title, it's not a new finding at all.

------
mbroshi
For those like myself that freak about this kind of stuff, and did not read
through carefully, the effect is pretty small and requires taking a lot of
benadryl:

"Three years of taking either daily Benadryl, Advil PM, Tylenol PM, or Motrin
PM, for example, is associated with about a ten percentage point increase in
the probability of experiencing dementia or Alzheimer's compared to no use."

~~~
morsch
Considering Benadryl is a medication many people take daily for several months
of the year, every year, it's not that much.

~~~
maxerickson
Is there a large group of people that prefers diphenhydramine over the newer
drugs?

I've used it occasionally for bee stings and the like, I would rather suffer
through hay fever than take Benadryl every day.

~~~
stordoff
I can't speak to the size of the group, but I would certainly fall within it.
For my condition (dermatographic urticaria), the newer drugs (loratadine,
desloratadine, cetirizine, fexofenadine) provided very little relief and
quickly lost efficacy. Diphenhydramine (and later promethazine, with also has
anti-cholinergic effects) provide significantly better relief, are well
tolerated (no noticeable drowsiness), and have retained their efficacy over a
number of months.

I don't know if this is a common experience or not, but it's not unheard of.

------
jmnicolas
As usual big pharma is poisoning us in the name of profits.

I have lost all trust in modern medicine. It doesn't mean I don't use it, but
I avoid it and find alternatives whenever I can.

~~~
adrianN
You assume malice where the simpler explanation is that until recently no link
between these drugs and Alzheimer's was known.

~~~
jmnicolas
I don't assume malice, I assume they care more about profits than my long term
health.

They have 0 incentive to look for long term consequences of the use of their
products.

~~~
ishi
That is why you have the FDA - to make sure drug companies test their products
properly.

~~~
DanBC
Hang on: FDA just makes sure the drugs are somewhat effective and don't cause
terrible side effects in the short term.

FDA regulation doesn't encourage manufacturers to look at long term effects.

EDIT: I'm wrong about this. Thanks hga.

~~~
hga
_FDA regulation doesn 't encourage manufacturers to look at long term
effects._

In granting the initial approval. There's various stuff to watch for bad long
term effects, which it must be noted also take a long time to show, and are
also known to be tied to uniquely vulnerable sub-populations who won't
necessarily be well represented in clinical trials.

Heck, for some time I took a drug what almost certainly would have never
gotten approval if anyone had realized it killed the livers of a small number
of people taking it, when the total number was large enough. The FDA black
boxed it and the original company stopped manufacturing it, but many like me
who'd passed the danger period and had no signs of liver problems continued
taking a generic version for a while.

~~~
Alex3917
> There's various stuff to watch for bad long term effects

And how many drugs have been pulled off the market after additional testing
hasn't been completed?

~~~
hga
If I understand your question, the additional testing is done in the only way
that makes sense, on the population at large (that's taking the drug, of
course). Drug companies and the FDA are _pretty_ sure they understand the
risks of the drug before the latter approves it, and I can't see it making
sense to require even larger and longer formal double blind etc. trials. The
whole process is already so expensive that it's probably at net killing people
compared to backing off some.

See GFK_of_xmaspast's link to the FDA page on Vioxx, where the drug company's
monitoring effort pulled the plug before anything else.

~~~
Alex3917
I'm saying that if the FDA orders a drug company to conduct post-approval
studies and the drug company doesn't actually conduct them, then in how many
cases has the drug been pulled off the market?

