Benadryl is still everywhere. Brain-health warnings haven’t slowed its use

Benadryl has been a medicine-cabinet staple for generations, used for allergies, itching, colds and, unofficially, as a sleep aid. But the familiar pink box is also part of a drug class that has long worried geriatricians, neurologists and pharmacists: anticholinergics.

The concern is not that a single emergency dose of Benadryl will cause Alzheimer’s disease. It is that repeated use — especially by older adults, and especially when combined with other drugs that have similar effects — may add to what doctors call “anticholinergic burden.”

That burden matters because anticholinergic drugs block acetylcholine, a neurotransmitter that helps regulate memory, attention and learning. Alzheimer’s disease itself is associated with loss of cholinergic function, which is one reason some Alzheimer’s drugs are designed to preserve acetylcholine activity. Taking a drug that blocks that system can cause short-term confusion, sedation, dizziness, dry mouth, constipation and urinary retention. In older adults, those side effects can also increase the risk of falls, delirium and medication-related harm.

A 2015 warning

The best-known warning came from a 2015 study in JAMA Internal Medicine, which followed thousands of older adults and found that higher cumulative exposure to strong anticholinergic medications was associated with a higher risk of developing dementia. The study included several drug categories, including first-generation antihistamines such as diphenhydramine, older antidepressants and bladder-control medications.

That study did not prove causation. People may take these medications because of underlying health problems that are themselves linked to dementia risk. Sleep problems, depression, urinary symptoms and chronic illness can all complicate the picture. But the dose-response pattern — more exposure, higher risk — made the findings hard to ignore.

Now researchers are trying to answer the question epidemiology alone cannot settle: are some of these drugs directly harmful to brain cells?

A 2025 study led by University of Washington researchers used human induced pluripotent stem-cell-derived neurons to test several anticholinergic medications in a lab setting. The approach allowed scientists to examine drug effects on brain-like cells without some of the confounding factors that affect population studies.

The results were nuanced. Antidepressants and bladder antimuscarinic drugs — two anticholinergic classes that have been repeatedly linked to dementia risk — were consistently toxic to the lab-grown neurons. Antihistamines and antispasmodics did not show the same overt cytotoxicity at the doses and time points tested. Some drugs also affected amyloid-beta peptides, which are involved in Alzheimer’s pathology, although the study did not find significant changes in the ratio of phosphorylated tau to total tau.

In plain English: the newer study strengthens the case that some anticholinergic drugs may have direct biological effects relevant to dementia risk, but it does not prove that Benadryl alone causes Alzheimer’s.

That distinction is important for consumers. Benadryl is widely available, inexpensive and familiar. It is also found in or alongside many nighttime products, including sleep aids and “PM” pain relievers. Consumers may not realize they are taking diphenhydramine because they are buying it under a different brand name or as part of a combination product.

The American Geriatrics Society’s Beers Criteria — a widely used guide to medications that may be inappropriate for older adults — lists oral diphenhydramine as highly anticholinergic and generally recommends avoiding it in people 65 and older. The criteria note that it may still be appropriate in limited circumstances, such as acute treatment of a severe allergic reaction, but not as a routine sleep aid or everyday allergy remedy.

Newer drugs recommended

For allergies, many clinicians recommend newer antihistamines such as loratadine, cetirizine or fexofenadine, which are less sedating and have fewer anticholinergic effects. For chronic insomnia, experts generally advise against using Benadryl as a long-term solution and recommend discussing safer approaches with a clinician.

The practical message is simple: consumers should not panic over occasional past use, but they should check labels and avoid making diphenhydramine a habit — especially older adults, people with memory concerns, and anyone already taking other anticholinergic drugs.

Drug risks often hide in plain sight. Benadryl’s familiarity may be part of the problem. Because it is sold over the counter, many people assume it is harmless. The growing body of evidence suggests a more cautious view: useful in some situations, risky when overused, and worth discussing with a doctor or pharmacist before it becomes part of a nightly routine.

What consumers can do

• Check the active ingredient on allergy, cold and sleep products. Diphenhydramine may appear under several brand names.
• Ask a pharmacist to review all prescription and over-the-counter drugs for anticholinergic burden, especially for older adults.
• Do not use Benadryl or other diphenhydramine products as a nightly sleep aid without medical advice.
• Ask about newer allergy medicines that are less likely to cause sedation or confusion.
• Seek urgent medical care for serious allergic reactions, breathing problems, swelling of the lips or throat, or symptoms of anaphylaxis.