Benadrly in pharmacy

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

While these drugs are helpful, they also make users feel confused, drowsy, and dizzy. This is evident from inside sticker on a bottle of Benadryl tabletswhich warns that “drowsiness may occur” and to “be careful when driving a motor vehicle”.

Another, long-term risk, however, is absent from the warning label. A large number of studies show 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 drugs to which Benadryl belongs is known as anticholinergic medicines. 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. Besides antihistamines, other anticholinergics include antidepressants and drugs used to treat overactive bladder.

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

Importantly, the risk increases with cumulative dose—meaning that patients who take more doses of an anticholinergic over time are even more likely to develop dementia.

When did this association appear?

Researchers have long noticed that the brain of an Alzheimer’s patient produces less acetylcholine than normal. In the past, medical scientists even used a particularly powerful anticholinergic called scopolamine for mimic Alzheimer’s symptoms in study participants. The same drug is notorious in Colombiawhere criminals used it to make 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 remained unchallenged until the early 2000s. At the time, Indiana University geriatrician, neuroscientist and aging research professor Malaz Boustany was working with a population of elderly black patients.

“I’ve noticed, from my own experience with one or two patients in my practice, that stopping these drugs doesn’t actually improve their brain health,” says Bustani. “So I started designing epidemiologic studies to investigate the long-term effect of anticholinergics.”

His research, although initially limited to small sample sizes, clearly shows a link between dementia and anticholinergics. And he wasn’t the only one who noticed. In the late 2000s and early 2010s, a wave of studies linked dementia to anticholinergic use in various geriatric populations.

By the time the JAMA investigation came out, it only confirmed the obvious: anticholinergics have a dangerous link.

Does genetics play a role?

Interestingly, the researchers note that the link is not driven by a person’s genetic predisposition to dementia. In fact, people who lacked the genetic material commonly associated with dementia were at even greater risk from anticholinergic use.

Read more: How the ‘Tylenol murders’ changed drug safety 40 years later

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

Twenty years after his first study on anticholinergics and dementia, Bustani is no longer interested in collecting more data on the relationship or exploring the exact mechanisms behind it. Instead, he focused on how to keep people off these potentially dangerous drugs altogether.

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

The anticholinergic blacklist

Anticholinergics are now unofficially blacklisted among neurologists and memory specialists. Although the research so far has mostly focused on people over the age of 65, Bustani says it’s better to play it safe even if you’re young and healthy.

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

“Forget about one; you have to worry about two and three,” notes Bustani.

A concerned patient could theoretically seek out a new drug on the ACB scale, but few patients or even doctors know of its existence. For Bustani, the most pressing issue now is getting people to pay attention.

“People don’t just take a new drug — they need and fall in love with the drug. The doctor also falls in love with the medicine,” he says. “So what is the best method for down-listing these drugs beyond the full mandate?”

Steering people away from anticholinergics

Bustani and his colleagues have tried different methods of what they call “depressing” anticholinergics. So far, two of them have shown promise: The first is a mobile healthcare app that weans patients off anticholinergics through motivational messages. The second involves a pharmacist working with prescribers and patients together to create a “wean-off” plan to wean the patient off anticholinergics.

Boustani is currently recruiting subjects for an experiment funded by the National Institutes of Health to test the plan’s efficacy. The results may hold the answer to weaning adult patients off a potentially dangerous drug.

In the meantime, doctors like Bustani will continue to spread the word as best they can.

Read more: The additional burden of dementia for women

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