The over-the-counter medicine scientists say may raise your dementia risk

If you’re among the one in three adults who struggles with seasonal allergies, the one in 10 dealing with some form of insomnia, or are among the millions dealing with the occasional cold or cough, chances are you’ve got drugs containing diphenhydramine in your medicine cabinet. But what you may not realize is that for years doctors have been steadily warning against taking too much of the stuff.

Diphenhydramine is the active ingredient in countless over-the-counter medications. Originally approved to prevent and treat allergy symptoms, the drug has since become popular for its ability to also treat a range of other issues that include motion sickness, anxiety, cold symptoms, nausea, insomnia, and even Parkinson’s disease.

Though diphenhydramine certainly has proven benefits, a preponderance of data shows there are reasons to exercise caution when taking it—especially with newer and safer alternatives available.

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“Taking diphenhydramine is not without risk, especially as the duration of use increases,” says Sayantani Sindher, a pediatrician, allergist, and immunologist at Stanford Health Care. Some of these risks include weight gain, diminished cognitive function, memory impairment, and poor sleep quality. Mounting research also suggests it is linked to higher odds of developing neurodegenerative diseases like dementia. 

Despite such adverse effects, Sindher calls diphenhydramine “one of the most commonly abused medications in the United States.” She says this is, in part, because it’s so prevalent in many over-the-counter formulations that treat countless everyday ailments that “consumers can unknowingly take larger doses than needed.” 

A spokesperson for the Consumer Healthcare Products Association—an organization that represents the over-the-counter medicine industry—told National Geographic that “it’s important to underscore that these products are not intended for long-term use.” Like all medicines, the spokesperson added, “responsible use is essential.”

What is diphenhydramine and how does it work? 

Developed mid-century by American chemist George Rieveschl and first approved by the U.S. Food and Drug Administration (FDA) in 1946, diphenhydramine is what’s considered a first-generation antihistamine.

Histamine is a chemical the body’s immune system produces as a way of neutralizing allergens and fighting off pathogens. While some histamine is useful, too much can cause unwanted symptoms such as watery eyes, sneezing, coughing, or itchy skin. Antihistamines help prevent this by blocking the effects of histamine—though some antihistamines do so more thoroughly than others. 

(Here’s how different cold and flu drugs work.)

For example, newer antihistamines—known as second-generation antihistamines—usually block histamine receptors everywhere in the body except the brain and central nervous system. But first-generation antihistamines like diphenhydramine do the same while also blocking histamine receptors in the brain and central nervous system. 

When diphenhydramine crosses the blood-brain barrier this way, research shows it affects the body’s natural sleep-wake cycle and can trigger feelings of sleepiness. This makes the drug a popular go-to for treating insomnia. Crossing the blood-brain barrier also allows the drug to suppress the medullary region of the brain that’s responsible for coordinating the cough reflex—making diphenhydramine also helpful for treating cold symptoms.

But this crossing of the blood-brain barrier also blocks another neurotransmitter, called acetylcholine. “Acetylcholine is key to memory, attention, and muscle movements,” says Harita Shah, a pediatrician and clinical assistant professor of medicine at the University of Chicago Medicine. This is why diphenhydramine is also considered an anticholinergic—a class of drugs used to treat movement disorders. 

Such upsides comes with downsides though as taking even recommended doses of diphenhydramine can cause “side effects like drowsiness, confusion, dry mouth, constipation, and trouble urinating,” says Shah. Blurred vision and delirium can also occur, though not as frequently. (The spokesperson for the Consumer Healthcare Products Association acknowledged that the common side effects of taking diphenhydramine “such as drowsiness or dry mouth” are “well-established.”) 

Other less common side effects include “increased appetite, weight gain, dizziness, postural hypotension, and possible cardiac arrhythmia,” says Gordon Sussman, a professor of medicine at the University of Toronto. 

Cognitive impairment 

But what really worries scientists more are some of the more serious emerging risks associated with the drug.

For one, studies show that “learning is impacted in young adults taking diphenhydramine,” says Anna Wolfson, an allergist and immunologist at Massachusetts General Hospital and co-author of a 2022 research paper that urges the medical community to “move on” from the drug. 

One noted clinical trial demonstrated cognitive impairment when participants who took just a 50-milligram dose of diphenhydramine experienced lower memory retention and difficulty focusing compared to individuals not taking the drug. 

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These diminished cognitive abilities can also worsen with age, says Sindher. She explains that the drug remains in older bodies longer than it does in children and adolescents—eventually for as long as 18 hours. “This relatively long half-life risks results in daytime sedation the following day and explains poor concentration and attention,” she explains.

This is one reason, “people who take diphenhydramine are more likely to get in car accidents or have more balance-related fractures and other injuries,” says Sussman.  

Increased dementia risk

Longer-term use is even more worrisome as multiple studies show that diphenhydramine may also be linked to an increased risk neurodegenerative disease development. 

This includes a prominent 2015 study published in JAMA Internal Medicine that found that people who took diphenhydramine daily for at least three years had a 54 percent higher risk of developing dementia than people who took the same dose for three months or less. Subsequent Europe-based research and a study from the University of British Columbia demonstrate similar findings. 

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Although the exact mechanism behind these increased neurodegenerative risks is “still not known,” says Shah, the long-term use of anticholinergic medicines like diphenhydramine “has been shown to permanently alter the brain’s structure, neurotransmission capabilities, and chemical pathways.” 

Toxicity concerns

Even if you’re only taking the drug for a short time, doctors say you should still be mindful of the risks of overconsumption. “Taking excessive amounts of diphenhydramine within 24 to 48 hours…can result in toxicity,” says Corey Hannah Basch, a professor of public health at William Paterson University in New Jersey. “A toxic dose can lead to serious symptoms including seizures, confusion, rapid heart rate, hallucinations, urinary retention, and ataxia.” 

Indeed, in the past five years, the FDA has twice had to warn against the “serious heart problems, seizures, coma, or even death” that can accompany taking high doses of diphenhydramine and similar drugs. It did so once in 2020 and again in 2022 in response to social media trends that encouraged people to misuse the drug. 

Compounding concerns is the fact that no one knows for sure how much diphenhydramine will be toxic. “An ‘overdose’ would be different for each person,” says Wolfson. Basch agrees, noting that “there is broad medical consensus that diphenhydramine toxicity is dose dependent,” and that “the severity of symptoms depends on the amount ingested.”

One commonly cited study shows that worrisome but moderate symptoms of toxicity can occur when taking as little as 0.3 grams of diphenhydramine, but that its most severe symptoms, “including coma and death,” Basch says, “were observed at doses of 1 gram or higher.” But this higher amount may be much smaller in children, elderly adults, and people with certain medical conditions, Sussman warns. 

Such concerns are why “several organizations, including the Global Allergy and Asthma European Network, support diphenhydramine being available only as a prescription” and not in its current over-the-counter form, says Jennifer Namazy, a clinical professor of medicine in the division of allergy and immunology at the Scripps Clinic healthcare system in California. 

Safer alternatives available 

Diphenhydramine continues to be FDA approved for certain uses—including treating short-term problems such as “acute treatment of severe allergic reaction” among older populations who are at greater risk of harmful side effects, according to safety criteria from the American Geriatrics Society.  

But for these people and most of the rest of us, “the use of diphenhydramine as a first-line treatment for allergic conditions and most other situations is no longer recommended — especially with the wide availability of second-generation antihistamines as an alternative,” says Aikaterini Anagnostou, a professor of pediatrics and director of the food allergy program at Texas Children’s Hospital & Baylor College of Medicine. 

Sindher agrees and says that second-generation antihistamines like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) “have limited, if any, ability to cross the blood brain barrier, which results in fewer anticholinergic side effects.”  

“While diphenhydramine has been trusted for decades, its impairment effects and toxicity potential make it less ideal for routine use,” echoes Basch. “It’s always wise to re-evaluate longstanding medications like diphenhydramine—especially when newer options offer similar relief with fewer risks.”