Benadryl & the Brain: What the Research Says About Dementia Risk

Beyond the Prescription — Episode 3

Benadryl is one of those medications that hardly feels like a medication anymore. It sits in bathroom cabinets, purses, travel bags, and bedside drawers. People take it for allergies, itching, colds, and sometimes simply because it makes them sleepy. Its generic name is diphenhydramine, and it has been available over the counter for decades.

But there is another side to diphenhydramine that receives far less attention: Benadryl is a strong anticholinergic drug. That matters because acetylcholine, a neurotransmitter whose activity Benadryl blocks at certain receptors, is deeply involved in memory, attention, learning, and normal brain function. When researchers began looking at what happens with repeated exposure to strongly anticholinergic medications over years, they found something worth paying attention to.

Benadryl Doesn't Just Block Histamine

Most people know Benadryl as an antihistamine. Histamine participates in allergic reactions, so blocking histamine receptors can reduce symptoms such as itching, sneezing, and runny nose. But diphenhydramine doesn't act only on histamine receptors. It also blocks other receptors, giving it strong anticholinergic activity.

Acetylcholine is one of the brain's major neurotransmitters. It plays an important role in attention, learning, memory formation, and signaling throughout both the central and peripheral nervous systems. This helps explain some familiar effects of Benadryl: sleepiness, slowed thinking, difficulty concentrating, and confusion. Those aren't completely unrelated side effects. They are clues to what the drug is doing neurologically.

Why Acetylcholine Matters So Much to Memory

The connection between acetylcholine and cognition is not theoretical. One of the characteristic changes seen in Alzheimer's disease is deterioration of cholinergic neurons and reduced cholinergic signaling. In fact, several medications used to treat symptoms of Alzheimer's disease work in essentially the opposite direction from anticholinergic drugs: they inhibit the enzyme that breaks down acetylcholine, allowing more acetylcholine to remain available for signaling.

That creates an interesting pharmacological contrast. On one side, we have medications intended to preserve acetylcholine signaling in people with cognitive impairment. On the other, we have common medications that block acetylcholine receptors—and some of them are available without a prescription. 

Why Age Changes the Equation

The American Geriatrics Society includes oral diphenhydramine on its Beers Criteria, a widely used list of medications considered potentially inappropriate for many adults 65 and older. The concern isn't simply that Benadryl makes older people sleepy.

The 2023 criteria specifically warns to consider total anticholinergic burden because cumulative exposure has been associated with delirium, falls, and dementia. Clearance of these medications can also decrease with advancing age. That means the same little pink tablet someone took without much thought at 35 may deserve a very different conversation at 65 or 75.

The Dementia Study That Raised a Bigger Question

One of the most important studies appeared in JAMA Internal Medicine in 2015. Researchers followed 3,434 adults age 65 and older who did not have dementia when they entered the study. Instead of simply asking whether someone had ever taken an anticholinergic drug, the researchers examined pharmacy records and calculated cumulative exposure during the previous ten years. The participants were then followed for an average of 7.3 years, during which 797 developed dementia.

The researchers found a dose-response relationship: the greater the cumulative exposure to strong anticholinergic medications, the greater the observed risk of dementia. People in the highest cumulative exposure category had a 54% higher adjusted risk of dementia compared with nonusers. Among the most commonly used strong anticholinergic medications in the study were first-generation antihistamines—the drug class that includes diphenhydramine.

That doesn't prove that Benadryl causes dementia. This was an observational study, and observational research cannot establish cause and effect. But it raises a much more practical question: How much anticholinergic exposure are we accumulating over a lifetime without realizing it?

It's the Cumulative Burden That Gets Interesting

This is where the subject becomes much larger than Benadryl. A person may take diphenhydramine for allergies or sleep. Another medication may be prescribed for bladder symptoms. Another may be prescribed for depression, nausea, dizziness, or another condition. Individually, each medication may have a reason. Biologically, however, the brain experiences their combined anticholinergic activity.

This is known as anticholinergic burden, and many people may have no idea how large that burden has become. The American Geriatrics Society's list of drugs; some are prescription drugs, some are sitting on the shelf at the drugstore. The body doesn't make that distinction.

What About Occasional Benadryl?

The research does not show that taking Benadryl once for an allergic reaction causes dementia, nor does the association between long-term anticholinergic exposure and dementia tell us that every person taking one of these medications will develop cognitive impairment. What the research does give us is a reason to look differently at repeated and cumulative exposure, particularly as we get older.

That is a very different question from whether a drug works. Benadryl works. It blocks histamine. It can reduce allergic symptoms and make people sleepy. The more useful long-term question is: What else is it doing when we use it repeatedly?

The Sleep Issue Deserves Special Attention

Benadryl is also commonly used as a sleep aid precisely because it causes sedation. But sedation isn't the same biological process as restorative sleep, and using an anticholinergic medication night after night means the exposure is no longer occasional.

A dose here or there may not look significant. Repeated hundreds or thousands of times over years, however, it becomes something entirely different: cumulative exposure. 

This is exactly the kind of medication history that can disappear when healthcare is organized around individual prescriptions and individual symptoms rather than the total biological picture.

This Is What Deprescribing Addresses

Deprescribing doesn't simply mean stopping medications. It means periodically asking whether a medication is still necessary, whether the original reason for taking it still exists, whether the dose is still appropriate, whether another option could accomplish the same goal with less risk, and what the combined burden of all medications may be doing.

Over-the-counter drugs belong in that review too, perhaps especially drugs like Benadryl because their familiarity can make them almost invisible. If you've taken the same OTC medication for ten or twenty years, it may never occur to you to put it on the list when someone asks what medications you take. But your nervous system knows it's there.

The Bigger Question

The point of this series isn't to tell people that every medication is bad. It's to ask a question that often gets lost once a prescription, or an OTC habit, becomes routine: Does this medication still make biological sense for this person, at this age, after this many years of exposure?

With Benadryl, we have a drug that enters the brain, strongly interferes with acetylcholine signaling, can impair cognition in the short term, and belongs to a broader group of medications whose cumulative exposure has been associated with increased dementia risk. Asking the question is where deprescribing begins.

Previous Episodes in Beyond the Prescription

Episode 1 — Statins & the Energy System
Watch the video on YouTube.

Episode 2 — Proton Pump Inhibitors
Read the PPI article.

References

Gray SL, Anderson ML, Dublin S, et al. Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study. JAMA Internal Medicine. 2015;175(3):401–407.

Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Internal Medicine. 2019;179(8):1084–1093.

American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2023;71:2052–2081.

Agostini JV, Leo-Summers LS, Inouye SK. Cognitive and Other Adverse Effects of Diphenhydramine Use in Hospitalized Older Patients. Archives of Internal Medicine. 2001;161(17):2091–2097.

This article is for educational purposes and is not a recommendation to change or discontinue a medication without discussing your individual circumstances with an appropriate healthcare professional.