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Diphenhydramine and memory

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Diphenhydramine is one of the most widely taken drugs in America, and one of the most poorly understood by the people taking it.

It is sold as an allergy medicine and as a sleep aid. Most people who take it nightly do not know they are taking an antihistamine at all, because the box says "PM" rather than what is in it.

It is also the over-the-counter drug most consistently linked to problems with thinking and memory.

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Am I taking diphenhydramine?

Possibly, without knowing it. It is the active ingredient in all of these:

  • Benadryl, the allergy medicine
  • Tylenol PM and Advil PM, where the "PM" is diphenhydramine and not the pain reliever
  • ZzzQuil, Nytol, Sominex and Simply Sleep
  • Many store-brand "nighttime" and "sleep aid" products, sold as diphenhydramine hydrochloride
  • Some cold and flu night formulas

If you take something at night to help you sleep and it was not prescribed, read the active ingredients.

A closely related drug, doxylamine, is in Unisom SleepTabs and works the same way.

How much does it affect thinking?

More than most people would guess, and there is a striking trial that makes the point.

Researchers at the University of Iowa put 40 licensed drivers through a driving simulator on four separate occasions. On different weeks each person received a single dose of diphenhydramine, a dose of fexofenadine (a newer allergy drug), enough alcohol to reach a level slightly above today's US legal limit for drunk driving, or a placebo. Nobody knew which they had taken.

Driving was worst after diphenhydramine. Worse than after alcohol. Performance on fexofenadine was no different from placebo.

That is a single dose, in adults aged 25 to 44, measured the same day. It is not a statement about dementia. It is a statement about how much this drug affects attention and reaction while it is in your system, which is the thing people notice as fogginess. (Weiler JM, Bloomfield JR, Woodworth GG, et al. Annals of Internal Medicine 2000;132(5):354-363.)

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Does taking it for years matter?

This is the harder question, and the evidence is observational rather than experimental. It is also consistent.

A study followed 3,434 adults aged 65 and over for about seven years, using pharmacy records rather than asking people to remember what they took. Twenty-three percent developed dementia.

What made this study important is that it found a dose response: the more cumulative exposure someone had, the higher the risk. It also raised the possibility that risk does not simply disappear when the drug is stopped. (Gray SL, Anderson ML, Dublin S, et al. JAMA Internal Medicine 2015;175(3):401-407.)

A larger English study of nearly 59,000 people with dementia, compared against more than 225,000 without, found the same association across several anticholinergic drug classes, though antihistamines were not one of the classes where the link was clear. (Coupland CAC, Hill T, Dening T, et al. JAMA Internal Medicine 2019;179(8):1084-1093.)

Observational studies show association, not proof of cause. But when several large ones point the same way, and there is a plausible mechanism, and safer alternatives exist, the sensible response is to ask whether you still need it.

Diphenhydramine appears on the American Geriatrics Society's Beers Criteria, the list of medications best avoided in people over 65.

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What can I take instead?

This is the part most articles leave out, and it is the only part that is useful. The answer depends on what you are treating.

For allergies

Second-generation antihistamines do the same job without the same effect on thinking: loratadine (Claritin), cetirizine (Zyrtec) and fexofenadine (Allegra). In the driving study above, fexofenadine performed no differently from placebo while diphenhydramine performed worse than alcohol. For most people with ordinary hay fever, this is a straightforward swap.

For sleep

The first-line treatment recommended by the American College of Physicians for chronic insomnia is not a drug at all. It is cognitive behavioral therapy for insomnia, written CBT-I, and it works in older adults specifically. It is a short structured program about sleep timing and habits, available online and through many health systems.

That recommendation exists because sleeping tablets of every kind, including the prescription ones, carry problems in older adults that CBT-I does not.

For an overactive bladder

Here the evidence is observational and we would rather say so. Bladder anticholinergics such as oxybutynin (Ditropan) and tolterodine (Detrol) work the same way as diphenhydramine. A different class, the beta-3 agonists mirabegron (Myrbetriq) and vibegron, does not.

One large Canadian study found a higher dementia risk with anticholinergics than with beta-3 agonists. A much larger Korean study of more than 3 million people found the same, about 21% higher risk with anticholinergics. The honest summary is that beta-3 agonists avoid the anticholinergic mechanism entirely, which is a reason to ask about them, but the outcome evidence is observational.

For nerve pain, migraine or low mood

Older tricyclic antidepressants such as amitriptyline (Elavil) are prescribed at low doses for all three. Alternatives exist for each, and which one suits you depends on why it was prescribed. This is a conversation with your doctor.

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Do not stop a prescription on your own

Over-the-counter sleep aids and allergy medicines can simply be stopped, and if you have been taking one nightly for a long time you may sleep badly for a week or two while your body readjusts. That is uncomfortable, not dangerous.

Prescriptions are different. Some medicines are genuinely dangerous to stop suddenly. Take everything you take, including the things you bought yourself, to your doctor or pharmacist and ask for a review. Pharmacists can be a helpful resource and are often easier to meet.

How do you know it works?

If you stop taking something and feel sharper, it can be difficult to know whether the improvement is real or influenced by what you expected to happen.

A memory screening taken before a change, and again a few months after, gives you something to compare. Memory Exam is a 10–15 minute verbal assessment taken from home, and when taken again can compare you against your earlier result rather than only a population average.

Memory Exam is a screening tool, not a diagnosis. Results should be discussed with a qualified doctor or healthcare professional when appropriate.

Our page about medications that affect memory covers the other drug groups worth reviewing, and when memory loss can be reversed covers the non-medication causes worth ruling out at the same appointment.

Where this information comes from

  • Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance: a randomized, placebo-controlled trial in the Iowa driving simulator. Annals of Internal Medicine 2000;132(5):354-363.
  • 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, et al. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Internal Medicine 2019;179(8):1084-1093.
  • Qaseem A, Kansagara D, Forciea MA, et al. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Annals of Internal Medicine 2016.
  • Welk B, McArthur E. Increased risk of dementia among patients with overactive bladder treated with an anticholinergic medication compared to a beta-3 agonist. BJU International 2020;126(1):183-190.
  • American Geriatrics Society 2023 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.
  • Risks of dementia after treatment with an anticholinergic, beta-3 agonist, or combination of both for an overactive bladder: a Korean national cohort study. European Urology Focus, 2024. In more than 3 million people, bladder anticholinergics went with about 21% higher dementia risk than a beta-3 agonist.
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