I recently received a question from a friend. They asked if there was any truth to Benadryl causing dementia. They linked to this online video:
“I keep seeing this come up,” he wrote. Come up where? In peer-reviewed literature? In well-done, controlled studies? Or just on social media? Because social media algorithms are designed to keep you engaged. So, if you have an interest in dementia, the algorithm is going to learn this over time and direct just about every wild theory at you. In this case, the “association” between diphenhydramine (the active ingredient in Benadryl in the United States) and dementia comes from observational studies looking at long-term anticholinergic use.
Long-term, in case you missed it when I wrote it just now.
What did the study do? The researchers took 3,434 participants over the age of 65 without dementia and followed them for 2 to 18 years. They then looked at the prescribed medications (anticholinergics) and how long they took them, then compared the cumulative exposure to the outcome of dementia. Here’s the deal, though… It wasn’t just diphenhydramine. The papers states: “The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics.” Furthermore, they were dealing with a population already at higher risk for dementia, those 65 and older. And, as the discussion section states:
“We should note a few potential limitations of our study. Several methods exist for estimating anticholinergic burden, with no single criterion standard. We focused on high-potency anticholinergics based on pharmacologic properties, and our list is in alignment with what is endorsed by the American Geriatrics Society. Misclassification of exposure is possible because several first-generation antihistamines are available as over-the-counter medications. However, GH members often purchase over-the-counter medications at health care plan pharmacies, and these purchases are recorded in the computerized pharmacy database, improving data capture. As in any observational study, unmeasured or residual confounding could introduce bias in our estimates. However, we controlled for a number of factors not typically found in studies restricted to administrative data (eg, self-rated health, depressive symptoms). Our exposure measure relied on prescription fills and did not guarantee that the medication was consumed. Finally, the generalizability is unknown, and our findings will need replication in other samples with greater numbers of minority participants.”
Gray SL, Anderson ML, Dublin S, et al. Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study. JAMA Intern Med. 2015;175(3):401–407. doi:10.1001/jamainternmed.2014.7663
Did you catch it? Here: “We focused on high-potency anticholinergics based on pharmacologic properties, and our list is in alignment with what is endorsed by the American Geriatrics Society.” I’m no pharmacist, but Benadryl for seasonal allergies once in a while during allergy season is probably not high-potency long-term, right? Maybe?
In case you missed it, I also wrote that diphenhydramine is the active ingredient in Benadryl in the United States. This is because the brand name has different antihistamines in different parts of the world: “Benadryl may contain different antihistamines. In Vancouver, it is diphenhydramine; in London, United Kingdom, it is cetirizine; in Cophenhagen, Denmark, it is acrivastine.”
My biggest concern here is the statement of “I keep seeing this come up.” I asked my friend where he had been seeing this, and he told me it was on his social media, just like I expected. Their algorithm is probably now feeding him one thing after another about health and healthcare, and the algorithm is probably also missing the mark… As algorithms tend to do.
When we try to learn and grow, one of the hardest things to do is to let go of our preconceived notions and find points of view that are different from our own. This is tricky with science because an “opposing” or “different” point of view may very well be a point of view that is anti-scientific and just plain wrong. Still, we need to seek out those alternative reasons for the things we are seeing. We don’t want to be deceived by the things we think are true when they are not true. Us epidemiologists use biostatistics for this, making sure that the math checks out on our observations and that what we have seen has nothing to do with chance and everything to do with a true association.
My friend doesn’t seem to be interested in listening to alternative reasons behind the observation that the active ingredient in American Benadryl is associated with dementia. When I pointed out to him these other points of view, he lashed out and said that he was convinced the medication was causing him to lose his mental acuity. It could not possibly be because he is getting older and has smoked weed regularly for going on 20 years now. Nope, it must be the seasonal allergy medicine.
This is how life is in this new era of technology, when people will trust random people on the internet more than they’ll trust friends with fancy letters like “MPH” after their names or “biostatistician” in their job titles. After all, what do we know? We just work all the time to defend Big Bad Voodoo Pharma after all, right?
Right.
The Poxes Blog 
At a glance, the study looks to be one of the finest studies in confounders.
And likely, one that would find very similar results with anticholinergic drugs, largely due to cohort selection.
Still, better to study and actually look than to proceed under assumptions of conventional wisdom that’s not only not right, but worse, not even wrong.
As for antisocial media, I actively avoid it for reading selections. Otherwise, I’m loading up on diphenhydramine to counter my BS allergy.