Antihistamines like diphenhydramine — the active ingredient in Benadryl, Tylenol PM and many cold medicines — are prescribed and sold over the counter to combat allergic reactions, dry up congestion and aid sleep.

While these drugs are useful, they also leave users feeling confused, sleepy and dizzy. This much is apparent from the inside sticker on a bottle of Benadryl tablets, which warns that “drowsiness may occur” and to “be careful when driving a motor vehicle.”

However, another, longer-term risk is absent from the warning label. A significant body of research has shown that diphenhydramine and other similar drugs increase the risk of developing Alzheimer’s disease and other types of dementia.

What Are Anticholinergic Drugs?

Among pharmacologists, the class of medicines that Benadryl belongs to are known as anticholinergic drugs. These compounds suppress the activity of a neurotransmitter called acetylcholine, which is involved in memory and cognition, as well as muscle function elsewhere in the body. Aside from antihistamines, other anticholinergics include antidepressants and medications used to treat an overactive bladder.

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In 2015, an investigation in JAMA Internal Medicine analyzed the risk of anticholinergics in 3,434 people over the age of 65 in Seattle over the course of a decade, the largest and longest study to date. The research clearly showed that participants taking anticholinergic drugs developed dementia and Alzheimer’s more often.

Importantly, risk increased along with cumulative dose — meaning that patients that took more doses of an anticholinergic over time were even more likely to develop dementia.

When Did This Association Emerge?

Researchers have long observed that the brains of a patient with Alzheimer’s disease produce less acetylcholine than is normal. In the past, medical scientists have even used a particularly powerful anticholinergic, called scopolamine, to mimic the symptoms of Alzheimer’s in study participants. The same drug is infamous in Colombia, where criminals have used it to render victims docile, confused or unconscious.

For a long time, pharmacologists thought that the delirious side-effects of drugs like scopolamine or benadryl were benign and short-lived. This belief went unchallenged until the early 2000s. Around that time, Indiana University geriatrician, neuroscientist and professor of aging research Malaz Boustani was working with a population of elderly Black patients.

“I noticed, from my own experience with one or two patients in my practice, that stopping these medications didn’t actually improve their brain health,” Boustani says. “So I started to design epidemiological studies to investigate the long-term effect of anticholinergics.”

His research, though confined to small sample sizes at first, clearly showed an association between dementia and anticholinergics. And he wasn’t the only one to notice. Throughout the late 2000s and early 2010s, a flurry of studies linked dementia to anticholinergic use in various geriatric populations.

By the time the JAMA investigation came out, it merely confirmed the obvious: anticholinergics had a dangerous association.

Do Genetics Play a Role?

Interestingly, researchers observed that the relationship was not driven by a person’s genetic predisposition for dementia. In fact, people who lacked the genetic material typically associated with dementia were put at an even greater risk by using anticholinergics.

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“We were like, ‘Oh my god. This is a reversible risk factor for people who are otherwise not vulnerable,” Boustani says.

Twenty years after his first study on anticholinergics and dementia, Boustani is no longer interested in gathering more data on the association or investigating the precise mechanisms behind it. Instead, he’s focused on how to keep people off of these potentially dangerous drugs entirely.

“About five or six years ago, we switched from an observational epidemiological approach to being interventionist,” Boustani adds.

The Anticholinergic Blacklist

Among neuroscientists and memory specialists, anticholinergics are already on an unofficial blacklist. Even though the research has mostly focused on people over the age of 65 so far, Boustani says it’s better to play it safe even if you’re young and healthy.

In 2008, Boustani developed the anticholinergic burden scale (ACB), which has since become widely-used by researchers. The scale rates drugs zero to three based on the strength of their anticholinergic properties.

“Forget about one; it’s two and three you have to worry about,” Boustani notes.

A concerned patient could theoretically look up a new medication on the ACB scale, yet few patients, or even doctors, are aware of its existence. For Boustani, the most pressing problem now is getting people to pay attention.

“People don’t take a new medication just like that — they have a need and they fall in love with a medication. Doctor’s fall in love with the medication too,” he says. “So, what’s the best method of deprescribing these medications outside of an all-out mandate?”

Steering People Away from Anticholinergics

Boustani and his colleagues have tried various methods for what they call “deprescribing” anticholinergics. So far, two of them have shown promise: The first is a mobile health care application that nudges patients away from anticholinergics through motivational messaging. The second involves a pharmacist that works with prescribers and patients together to create a “deprescription” plan to wean a patient off anticholinergics.

Right now, Boustani is recruiting subjects for an experiment funded by the National Institutes of Health to test the efficacy of the plan. The results may hold the answer to getting elderly patients off a potentially dangerous drug.

In the meantime, physicians like Boustani will keep spreading the word as best as they can.

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