In the past few months TikTok videos about the over-the-counter antihistamine Benadryl have gone viral because of research suggesting that long-term use of the popular drug is associated with an increased risk of developing dementia. And similar effects on memory and cognition have also been suggested for dozens of other common medications.
Benadryl is a brand-name medication that contains diphenhydramine, the active ingredient in many allergy, cold and anti-itch drugs. It can cause significant drowsiness and is also found in several sleep aids. Diphenhydramine has anticholinergic effects, meaning it blocks the action of a neurotransmitter called acetylcholine. Medical uses of anticholinergics go beyond allergy relief; drugs in this class have long been used as prescription tricyclic antidepressants and incontinence treatments, as well as over-the-counter sleep aids. But experts have been finding evidence that links anticholinergics to increased dementia risks. “That’s now clear, and we have plenty of data to back it up,” says Malaz Boustani, a geriatrician and neuroscientist at the Indiana University School of Medicine. He and other researchers are now trying to determine whether anticholinergics really are contributing to dementia development in any way—and if so, what exactly is happening in the brains of vulnerable adults.
Anticholinergics inhibit the parasympathetic nervous system, which regulates rest and stress responses. The drugs do this by binding to brain cell receptors and blocking acetylcholine, a neurotransmitter that plays a part in many bodily systems, including heart regulation, muscle contractions, urination and digestion. Acetylcholine also affects attention and memory—and a lack of the neurotransmitter in the brain has been linked to Alzheimer’s disease. When bound to receptors, anticholinergics prevent acetylcholine from acting on the parasympathetic nervous system, often causing effects such as dry mouth. These medications can also make people groggy by blocking histamine receptors, which are involved in alertness as well as allergies. Side effects should fade once the drug is out of someone’s system (which in Benadryl’s case would be within a couple of days). But Boustani says less is known about the effects of regular or heavy use.
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A 2015 paper in JAMA Internal Medicine offered some striking insight into possible long-term effects. The hallmark study—which became the basis for the recent viral TikToks—observed adults 65 years or older who had been taking various kinds and amounts of anticholinergic drugs for 10 years. The group reporting the highest amount of such use had a 54 percent increased risk of developing dementia. Since the study, a steady stream of new research has corroborated this link.
The studies show an association between dementia risk and the quantity and frequency of anticholinergic use. One capsule of Benadryl to relieve an allergy every once in a while probably won’t affect someone all that much, but repeated doses of anticholinergic drugs over months or years pose a greater risk, Boustani says. Taking multiple anticholinergics for multiple conditions may also increase your exposure and could raise the risk further, he adds. Another consideration is that some of these drugs have more potent effects than others. Boustani’s team created the Anticholinergic Cognitive Burden (ACB) Scale, a list of drugs with scores based on their potential negative effects on the brain. The scale goes from 1 (possibly an anticholinergic burden) to 3 (definitely a strong anticholinergic burden), Boustani says. For example, someone taking three anticholinergic drugs, all with a score of 1, will have a total anticholinergic cognitive burden score of 3. Boustani says that person may see roughly the same cumulative effects as someone who just takes one anticholinergic with a score of 3. There are currently no protocols or recommendations for doctors and pharmacists to consider a person’s ACB score when prescribing drugs. But the American Geriatrics Society maintains a list of drugs older people should avoid, and it does include many anticholinergic medications.
Researchers are still digging into the specific brain mechanisms that may be involved in elevated dementia risk from these drugs, Boustani says. A leading hypothesis suggests this might be related to how the drugs interact with neurotransmitter receptors. Long-term anticholinergic use might leave acetylcholine receptors perpetually blocked, triggering a series of reactions that either leads to the production of beta-amyloid—a toxic protein thought to be a main cause of dementia—or prevents the brain from clearing this protein out. Researchers have suggested these drugs might affect inflammation and blood flow in the brain, which may result in memory loss and weakened cognition. But so far this research is inconclusive.
Some experts are skeptical that anticholinergics play a role in developing dementia; they suspect the drugs may instead worsen underlying cognitive issues. Ariel Gildengers, a psychiatrist at the University of Pittsburgh, led a 2023 study that did not show a link between anticholinergics and developing dementia. But it did show a link between the drugs and mild cognitive impairment (MCI), a condition in which people have worse cognitive function than expected at their age but do not meet the criteria for dementia. And MCI does have a noticeable chance of turning into dementia. About 10 to 15 percent of people living with MCI develop dementia each year, according to the Alzheimer’s Association. “If you are in the earliest stages of dementia, then anticholinergics may kind of make the dementia more apparent without actually causing the dementia,” Gildengers says.
Research in this area has several major caveats, says Shelly Gray, a pharmacy professor at the University of Washington, who was the first author of the 2015 JAMA paper. “We cannot determine that anticholinergics actually cause dementia” because the 2015 study and others on the relationship have been observational, she says. Clinical trials are needed to confirm causation. Most of these studies are also done in adults aged 65 and older, who are more likely to develop dementia than younger adults and more likely to face medical conditions such as insomnia, which are often treated with anticholinergics. Gray, Boustani and Gildengers say that they keep these possible confounding factors in mind when they design and analyze their studies.
Because research has focused mostly on older adults, there is less evidence on whether younger people who take anticholinergics have increased risk of dementia later in life. Gray says it’s generally a good idea to avoid anticholinergics, however, especially if you’re older. “A big reason why we're seeing anticholinergic medications used by older adults is because they are available over the counter,” Gray says. Many readily available medications have anticholinergic active ingredients, including Benadryl, as well as the antihistamine Dimetapp (which contains the drug brompheniramine), the motion sickness medication Dramamine (dimenhydrinate) and the sleep aid Unisom (doxylamine).
Many anticholinergics can be swapped with other options, Gray says. For example, studies show that cognitive behavioral therapy is often effective for insomnia. "Second-generation antihistamines,” such as those in Claritin and Zyrtec, along with steroid-based nasal sprays such as Flonase, will counteract allergy symptoms without targeting acetylcholine receptors—says Jyothi Tirumalasetty, a clinical assistant professor of medicine at Stanford University, who specializes in allergy and immunology.
The Food and Drug Administration first approved Benadryl as a prescription antihistamine in 1946 and for over-the-counter sales in 1980s. Given the research on potential risks, Tirumalasetty says the FDA might evaluate the drug’s safety differently today and may consider making it available only through prescription. The FDA did not respond to a request for comment by the time of publication. In an e-mail to Scientific American, Kenvue (formerly a division of Johnson & Johnson and Benadryl’s current proprietor) wrote, “We are not aware of any studies that show a causal link between labeled use of diphenhydramine, and an increased risk of developing dementia. Diphenhydramine is an ingredient which is generally recognized as safe and effective by the FDA for [over-the-counter] use.”
Researchers are continuing to investigate anticholinergics and their possible long-term effects on brain health, hoping to help with future clinical and regulation guidance. Boustani says many questions persist, such as how the timing of taking or discontinuing these drugs affects the development of future memory problems.
For now, Boustani is focused on empowering his patients, especially older adults, with the ability to understand their medications and any attendant risks. He says people taking or considering an anticholinergic at any age should ask themselves a few questions: “Are there any alternatives? What symptoms am I addressing, and is alleviating them worth this risk? What is the smallest dose and time period I can take this medication for?”
“The brain is a precious organ,” Boustani says. “There is no health without brain health.”