A widely used sleep aid is linked to higher dementia risk in older adults

Diphenhydramine, the active ingredient in Benadryl and in most over-the-counter nighttime sleep aids, is one of the most familiar drugs in the medicine cabinet. It is a first-generation antihistamine, and the same chemistry that makes it drowsy-inducing also makes it a potent anticholinergic, meaning it blocks the neurotransmitter acetylcholine that the brain relies on for memory and learning. Over the past decade, large studies following older adults have repeatedly tied heavy, long-term use of strong anticholinergic drugs, diphenhydramine among them, to a higher risk of dementia. The association is consistent and shows a dose-response pattern, though it has not been proven to be a direct cause.

Why an antihistamine acts on the aging brain

Acetylcholine is central to attention and memory, and it is precisely the signaling system that erodes in Alzheimer’s disease, which is why several dementia treatments work by boosting it. Anticholinergic drugs push in the opposite direction, dampening that signaling to produce their intended effects, whether that is drying up a runny nose, calming an overactive bladder or inducing sleep. In a younger brain the disruption is temporary and easily compensated, but the aging brain has less cholinergic reserve and a more permeable barrier to such drugs. That biological backdrop gives researchers a plausible reason why repeated, cumulative exposure over years, rather than an occasional tablet, is the pattern most strongly associated with cognitive harm.

The landmark cohort that measured cumulative dose

The most influential evidence comes from the Adult Changes in Thought study, a long-running project that followed more than 3,400 older adults in Washington state and tracked their medication use through pharmacy records. Researchers reported in JAMA Internal Medicine that people with the highest cumulative anticholinergic exposure, roughly the equivalent of taking a drug like diphenhydramine daily for three years or more, had about a 54 percent higher risk of developing dementia than those with little or no use. Crucially, the study documented a dose-response relationship, meaning that more use tracked with more risk, and diphenhydramine appeared by name among the common culprits alongside older antidepressants and bladder medicines. It was also among the first to suggest the risk might persist even after the drugs were stopped.

What later studies added

The finding did not stand alone. A large nested case-control study drawing on British primary care records, also published in JAMA Internal Medicine, examined tens of thousands of dementia patients and found that heavy exposure to strong anticholinergic drugs was associated with an increased risk of dementia on a similar scale, with the effect concentrated in specific drug classes rather than every anticholinergic. Across these investigations the culprits that recur are first-generation antihistamines, tricyclic antidepressants, and antimuscarinic drugs for overactive bladder. The consistency across different populations, health systems and study designs is part of why the association has been taken seriously by geriatric specialists, even as the exact magnitude of the risk varies from one analysis to the next.

The limits of what the evidence proves

Every one of these studies is observational, and that imposes a firm ceiling on what can be concluded. People who take strong anticholinergics for years differ from those who do not, and some of the conditions treated with these drugs, such as depression, insomnia or urinary problems, can themselves be early signs of a brain already heading toward dementia. That raises the possibility of reverse causation, in which the disease drives the drug use rather than the other way around. Researchers adjust for measured differences, but they cannot eliminate every hidden factor. As the National Institute on Aging notes in summarizing this body of work, the studies establish an association and a plausible mechanism, not definitive proof that the medications cause the disease.

Safer paths to a night’s sleep

The practical implication is not panic over an occasional dose but caution about routine, long-term reliance. Guidelines for prescribing in older adults, including the widely used Beers Criteria, already flag diphenhydramine and similar drugs as generally inappropriate for this age group precisely because of their anticholinergic burden. For chronic insomnia, non-drug approaches such as cognitive behavioral therapy for insomnia have stronger evidence and none of the cognitive risk, and newer antihistamines that do not cross into the brain avoid the sedating, memory-blunting effects entirely. The message that emerges from the research is that a medicine sold without a prescription is not automatically free of consequence, and that the cumulative dose taken over years, more than any single pill, is what the studies have tied to the aging brain.

Long-term dementia risk is not the only concern for an older adult. Diphenhydramine can cause confusion, blurred vision, constipation and urinary retention soon after a dose, while sedation and impaired balance can contribute to falls. The drug also remains in the body longer as metabolism slows with age. Reviewing every prescription and over-the-counter product is important because several medicines may contribute anticholinergic effects at once, creating a cumulative burden that no single package label makes obvious.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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