Antihistamines and Dementia Risk: What You Need to Know About Long-Term Use

For decades, diphenhydramine - the active ingredient in Benadryl - has been a go-to remedy for allergies, colds, and especially sleep trouble in older adults. It’s cheap, easy to find, and works fast. But what if using it every night for years could quietly increase your risk of memory problems? The science is messy, but the warning signs are real. And for people over 65, the choice between a good night’s sleep and long-term brain health isn’t as simple as it seems.

Why Some Antihistamines Are Different

Not all antihistamines are the same. There are two main types: first-generation and second-generation. First-generation ones - like diphenhydramine, doxylamine, and chlorpheniramine - cross the blood-brain barrier. Once inside, they block acetylcholine, a chemical your brain needs to form memories and stay sharp. This is called anticholinergic activity. It’s why these drugs make you drowsy. But that same effect can interfere with brain function over time.

Second-generation antihistamines - like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) - were designed differently. They don’t cross into the brain easily. Thanks to special transporters that push them out, their anticholinergic effect is 100 to 1,000 times weaker. They work just as well for allergies, but they don’t fog your brain. If you’re over 65 and taking an antihistamine regularly, this difference matters more than you think.

The Research: Mixed Signals, But a Clear Pattern

The big 2015 study from JAMA Internal Medicine shook things up. Researchers tracked over 3,400 people aged 65 and older for a decade. They found that those who took anticholinergic drugs - including first-gen antihistamines - for the longest time had a higher chance of developing dementia. That study led to major guidelines, including the American Geriatrics Society’s 2023 Beers Criteria, which now says: avoid first-generation antihistamines in older adults. That’s a Level A recommendation - the strongest possible warning.

But here’s where it gets complicated. A 2022 study of nearly 9,000 older adults found no statistically significant link between dementia and first-gen antihistamine use. The same was true for second-gen drugs. Another 2019 study looked specifically at antihistamines and found no increased dementia risk - unlike antidepressants or bladder medications, which clearly showed higher risk. So why the contradiction?

The answer might be in what’s being measured. Some studies group all anticholinergic drugs together. Others isolate specific ones. Some track daily doses, others total years of use. One 2020 review found that studies varied so much in method that results couldn’t be reliably compared - the data was all over the place. That’s why the European Medicines Agency says the evidence is inconsistent.

What the Experts Really Think

Dr. Shelley Gray, who led the landmark 2015 study, doesn’t believe all anticholinergics are equally dangerous. She says the strongest links are with antidepressants and bladder meds - not antihistamines. But Dr. Malaz Boustani, who helped create the Anticholinergic Cognitive Burden Scale, warns that even small amounts of brain-blocking drugs can pile up. He’s seen older patients taking multiple medications - a sleep aid, a painkiller, an allergy pill - each with mild anticholinergic effects. Together, they add up.

The American Geriatrics Society doesn’t take chances. Their 2023 guidelines are blunt: don’t use diphenhydramine or doxylamine in people over 65. Why? Because the potential harm outweighs the benefit. Even if the risk is small for each person, when you’re talking about millions of older adults taking these pills nightly, even a 5% increase could mean tens of thousands of extra dementia cases.

Real People, Real Choices

On Reddit, a geriatric care manager with over 2,000 karma wrote that 83% of her clients over 70 were using Benadryl every night to sleep - and didn’t know it could hurt their brain. A 2022 survey by the National Council on Aging found that 42% of adults 65+ use over-the-counter antihistamines for sleep. And 78% of them had no idea these drugs have anticholinergic properties.

One woman on AgingCare.com shared her story: her mother took Benadryl for years to sleep. Now she has dementia. She doesn’t blame the drug outright - but she can’t stop wondering. That’s the emotional weight behind the data. People aren’t just looking for facts. They’re looking for permission to stop something they’ve been told is safe.

What to Do Instead

If you’re using diphenhydramine for sleep, there are better options. Cognitive Behavioral Therapy for Insomnia (CBT-I) is the gold standard. Studies show it works for 70 to 80% of older adults. It teaches you how to sleep better without pills. The problem? There aren’t enough therapists. Wait times average over eight weeks. And Medicare only pays $85 to $120 per session - not enough to keep many providers in business.

Prescription alternatives exist too. Low-dose doxepin (Silenor) is approved for insomnia and has minimal anticholinergic effects. It’s not cheap, but it’s safer than Benadryl. For allergies, switch to loratadine or cetirizine. They work just as well. And if you’re using antihistamines for nighttime itching or a runny nose, talk to your doctor about non-drug fixes - humidifiers, nasal saline rinses, or allergy-proof bedding.

What’s Changing Now

The market is shifting. Sales of first-gen antihistamines dropped 24% between 2015 and 2022. Second-gen ones grew by nearly 20%. More drug labels now mention cognitive risks - though the FDA still only requires “may cause drowsiness” on OTC bottles. The European Medicines Agency has been ahead of the curve, requiring leaflets to warn about long-term cognitive effects since 2022.

A new study called ABCO, launched in early 2023 with $4.2 million in NIH funding, is tracking 5,000 people for 10 years. It’s the most detailed look yet at how anticholinergics affect the brain over time. Early results from the UK Biobank suggest that when you control for underlying sleep disorders, antihistamine use doesn’t raise dementia risk. That’s huge - it might mean the real culprit isn’t the drug, but the poor sleep it’s meant to fix.

The American Geriatrics Society’s 2024 update is coming. It’s expected to refine the rules even further, maybe even giving different risk levels for different drugs. For now, the message is clear: if you’re over 65 and taking diphenhydramine regularly, it’s time to talk to your doctor - not just about your sleep, but about your brain.

How to Check Your Medications

You don’t need a PhD to understand your risk. Here’s how to take action:

1. Look at the active ingredient on your bottle. If it’s diphenhydramine, doxylamine, or chlorpheniramine, you’re on a first-gen antihistamine.
2. Check the Anticholinergic Cognitive Burden Scale (ACB). Diphenhydramine is a Level 3 - highest risk. Loratadine and cetirizine are Level 0 - no risk.
3. Ask your pharmacist or doctor: “Is this drug on the Beers Criteria list for older adults?”
4. Review all your meds - even OTC ones - every six months. Many people take five or more drugs that add up.
5. If you’re using it for sleep, ask about CBT-I. It’s not magic, but it’s the safest long-term solution.

There’s no need to panic. Stopping one pill won’t reverse damage. But switching to a safer alternative - and addressing the root cause of your symptoms - could protect your brain for years to come.