Diphenhydramine — the active ingredient in Benadryl and dozens of over-the-counter sleep aids and allergy medications — is drawing serious concern from doctors and researchers who say its long-term use may increase the risk of dementia. A landmark 2015 study from the University of Washington, published in JAMA Internal Medicine, followed 3,434 older adults and found that the highest cumulative users of anticholinergic drugs like diphenhydramine had a 54% increased risk of developing dementia compared to non-users. That finding, confirmed by a hazard ratio of 1.54, set off a wave of research that has only deepened the worry. In 2025, allergy experts from Johns Hopkins University and the University of California, San Diego published a paper in PMC titled “Diphenhydramine: It is time to say a final goodbye,” calling for the drug to be removed from both over-the-counter and prescription markets entirely. This is not a fringe position. The concern centers on diphenhydramine’s anticholinergic properties — it blocks acetylcholine, a neurotransmitter essential for memory and learning.
For someone caring for a loved one with dementia, or anyone trying to protect their own brain health, the implications are unsettling. Millions of Americans reach for this drug casually, whether for seasonal allergies, a bee sting, or a night of poor sleep, without knowing it may carry a neurological cost that accumulates over years. Consider an older adult who takes an over-the-counter sleep aid containing diphenhydramine three or four nights a week. Over a decade, that seemingly harmless habit could place them in the highest risk category identified by researchers. This article examines what the research actually says, how the drug affects the brain, who faces the greatest risk, what the manufacturer has said in response, and which safer alternatives doctors recommend. Whether you are a caregiver, a patient, or simply someone who keeps Benadryl in the medicine cabinet, the evidence deserves your attention.
Table of Contents
- What Is Diphenhydramine and Why Are Doctors Worried About Long-Term Anticholinergic Use?
- What the Major Studies Found — And Where the Evidence Has Limits
- How Diphenhydramine Affects the Aging Brain Differently
- Safer Alternatives That Doctors Actually Recommend
- The Manufacturer’s Position and Why the Drug Remains on Shelves
- Anticholinergic Burden Is Cumulative — Check All Medications
- Where the Research Is Heading
- Conclusion
- Frequently Asked Questions
What Is Diphenhydramine and Why Are Doctors Worried About Long-Term Anticholinergic Use?
Diphenhydramine is a first-generation antihistamine developed in the 1940s. It works by blocking histamine receptors to reduce allergy symptoms, but it also blocks acetylcholine — and that is where the trouble begins. Acetylcholine plays a central role in attention, learning, and memory formation. When you block it, cognitive function takes a hit. In younger adults, this might show up as grogginess or brain fog the next morning. In older adults, the consequences appear to be far more severe and potentially lasting. According to Dartmouth Health, diphenhydramine can stay in the body for up to 18 hours in older adults, causing prolonged sleepiness, disorientation, and increased fall risk — a dangerous combination for anyone already navigating age-related cognitive changes. The research linking anticholinergic drugs to dementia is now substantial.
A 2019 nested case-control study published in JAMA Internal Medicine found a clear dose-response relationship: the more anticholinergic drugs a person was exposed to, the higher their dementia risk. A separate analysis of dose-response data published in PMC found that exposure to one anticholinergic medication was associated with a 1.6 times increased risk of dementia or Alzheimer’s disease. Two medications raised the risk to 2.1 times. Three pushed it to 2.6 times. That kind of stacking effect matters, because diphenhydramine is not the only anticholinergic drug a person might be taking — certain antidepressants, bladder medications, and muscle relaxants also have anticholinergic properties. A systematic review examining 25 studies on anticholinergic drugs and dementia, summarized by the National Center for Health Research, concluded that a link likely exists, though the authors acknowledged some studies had limitations and inconsistent results. This is not a settled, absolute conclusion, but the weight of evidence is moving firmly in one direction. As the Johns Hopkins and UC San Diego researchers argued, diphenhydramine is “outdated, dangerous, and eclipsed by safer alternatives.” When safer options exist and the potential downside is dementia, many physicians believe the risk calculation is straightforward.
What the Major Studies Found — And Where the Evidence Has Limits
The 2015 University of Washington study remains the most frequently cited piece of this puzzle. Researchers tracked 3,434 participants aged 65 and older over several years, using pharmacy records to calculate cumulative anticholinergic exposure. Those with the highest cumulative doses faced a 54% increased risk of dementia, with a 95% confidence interval of 1.21 to 1.96. This was not a small, preliminary trial — it was a well-powered prospective cohort study published in one of medicine’s most respected journals. The dose-response pattern was particularly concerning: more exposure meant more risk, which is exactly what you would expect if the drug were genuinely causing harm rather than simply correlating with it. The 2019 JAMA Internal Medicine study reinforced this picture with a different methodology — a nested case-control design — and still found a dose-response relationship between anticholinergic exposure and dementia risk. Then in 2024, a study published in the Journal of Allergy and Clinical Immunology: In Practice looked specifically at patients with allergic rhinitis and found that those taking first-generation antihistamines faced escalating dementia risk with increasing cumulative dosage.
Importantly, first-generation antihistamines like diphenhydramine showed a higher risk profile than second-generation alternatives. However, it is important to be honest about the limits of this evidence. A 2023 study found no conclusive link between anticholinergics and dementia, though it did find a significant association with mild cognitive impairment — a condition that often precedes dementia. some researchers have raised the possibility of reverse causation: people in the early, undetected stages of dementia may have sleep problems or other symptoms that lead them to use more diphenhydramine, rather than the drug causing the dementia. Others point out that observational studies, no matter how well-designed, cannot prove causation the way randomized controlled trials can. These are legitimate caveats. But given that a randomized trial deliberately exposing people to a suspected dementia risk factor for years would be unethical, observational data is likely the best evidence we will ever get — and it consistently points toward concern.
How Diphenhydramine Affects the Aging Brain Differently
One of the reasons this issue is so pressing for older adults and dementia caregivers is that aging fundamentally changes how the body handles diphenhydramine. The drug is metabolized by the liver and cleared by the kidneys, both of which slow down with age. As Dartmouth Health has noted, diphenhydramine can linger in an older adult’s system for up to 18 hours — compared to roughly four to six hours in a younger person. That means a dose taken at bedtime can still be impairing cognition, balance, and judgment well into the following afternoon. This extended duration of action compounds the anticholinergic burden. Acetylcholine levels naturally decline with age, so blocking what remains has a proportionally larger impact.
Think of it this way: a 30-year-old taking diphenhydramine is reducing their acetylcholine activity from a high baseline. A 75-year-old is reducing it from an already diminished baseline, potentially pushing their brain below the threshold needed for normal memory function. For someone who already has mild cognitive impairment or early-stage dementia, the effect can be dramatic — sudden confusion, inability to recognize family members, or dangerous nighttime wandering, all triggered by a pill that is supposed to help them sleep. The cardiac risks add another layer of concern. Diphenhydramine can cause dangerous cardiac effects, particularly at higher doses or in people with existing heart conditions. CNN reported in August 2025 that experts now say the drug’s risks outweigh its usefulness across the board. For caregivers managing a loved one’s medications, this means diphenhydramine — whether it appears as Benadryl, ZzzQuil, Tylenol PM, or a generic store-brand sleep aid — should be a red flag during any medication review.
Safer Alternatives That Doctors Actually Recommend
If diphenhydramine carries these risks, the natural question is what to use instead. The good news is that second-generation antihistamines are widely available, affordable, and considered significantly safer for brain health. These include loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec). According to Harvard Health, second-generation antihistamines have lower anticholinergic activity and are less likely to cross the blood-brain barrier, which is the key distinction. If a drug cannot easily reach the brain, it cannot easily impair cognition. For allergy sufferers, the switch is relatively straightforward. Loratadine and fexofenadine are non-sedating, meaning they control allergy symptoms without the drowsiness that many people actually seek from Benadryl. Cetirizine can cause mild drowsiness in some users, but its anticholinergic burden is still far lower than diphenhydramine’s.
For people who have been using diphenhydramine primarily as a sleep aid, the conversation is more nuanced. Doctors generally recommend cognitive behavioral therapy for insomnia (CBT-I) as a first-line treatment, along with improved sleep hygiene practices. When medication is necessary, physicians may consider low-dose melatonin or prescription options that do not carry anticholinergic risk. The tradeoff is worth acknowledging plainly. Second-generation antihistamines may not feel as potent to someone accustomed to diphenhydramine’s heavy sedation. Some patients interpret that sedation as the drug “working better,” when in reality the drowsiness is a side effect, not a sign of superior allergy control. Breaking that association — helping patients understand that they can get effective relief without being knocked out — is part of the clinical challenge. But given the potential stakes, the tradeoff between a slightly less dramatic subjective effect and a substantially lower risk of cognitive decline seems clear.
The Manufacturer’s Position and Why the Drug Remains on Shelves
Despite growing alarm in the medical community, diphenhydramine remains readily available in every pharmacy and grocery store in America. Kenvue, the manufacturer of Benadryl, has stated that it is “not aware of any studies that show a causal link between labeled use of diphenhydramine and an increased risk of developing dementia.” That statement, reported by Scientific American, hinges on a precise word: causal. As discussed earlier, randomized controlled trials proving causation would be unethical to conduct. So the standard Kenvue is pointing to is one that can likely never be met — a rhetorical strategy familiar from the tobacco and opioid industries. This creates a frustrating gap between what researchers are finding and what consumers are told.
The Johns Hopkins and UC San Diego experts who called for removing diphenhydramine from the market argued that the existing evidence is sufficient to act, particularly when safer alternatives exist. Their position essentially asks: why tolerate any risk of dementia from an allergy pill when medications with better safety profiles are equally effective and equally available? The FDA, for its part, has not moved to restrict diphenhydramine’s over-the-counter status. It has, however, taken action on a related front — adding a warning about rare but severe itching (pruritus) that can occur after stopping long-term use of cetirizine (Zyrtec) or levocetirizine (Xyzal), indicating that the regulatory agency is paying attention to antihistamine safety, even if it has not yet acted on diphenhydramine specifically. For families managing dementia or cognitive decline, waiting for regulatory action is not a realistic option. The practical path forward is to work with a physician or pharmacist to identify every anticholinergic drug in a loved one’s medication regimen — not just Benadryl, but sleep aids, cold medicines, and other products that contain diphenhydramine under different brand names — and systematically replace them with safer alternatives.
Anticholinergic Burden Is Cumulative — Check All Medications
One of the most important and least understood aspects of this issue is that anticholinergic risk is cumulative. Diphenhydramine gets the headlines, but it is only one of many medications with anticholinergic properties. Certain tricyclic antidepressants, bladder control medications like oxybutynin, and even some antipsychotics carry significant anticholinergic burden. The dose-response data from the PMC analysis makes this stark: exposure to four or more anticholinergic medications was associated with a 2.6 times increased risk of dementia or Alzheimer’s disease.
A person taking diphenhydramine for allergies, oxybutynin for an overactive bladder, and amitriptyline for nerve pain could be accumulating a dangerously high anticholinergic load without any single prescriber recognizing the total picture. Caregivers and patients should ask a pharmacist to calculate the total anticholinergic burden across all medications. Tools like the Anticholinergic Cognitive Burden Scale exist specifically for this purpose. This is especially critical for older adults who see multiple specialists, each of whom may prescribe medications without full knowledge of what the others have ordered.
Where the Research Is Heading
The scientific community has not reached the finish line on this question, but the direction of travel is clear. Research is increasingly focused on quantifying the exact threshold of exposure that elevates risk, identifying genetic factors that may make certain individuals more vulnerable, and determining whether the cognitive damage from long-term anticholinergic use is reversible once the drugs are stopped. The 2024 study in the Journal of Allergy and Clinical Immunology: In Practice, which specifically compared first- and second-generation antihistamines in allergy patients, represents the kind of granular, targeted research that will eventually clarify the clinical guidance. For now, the precautionary principle applies.
The evidence that diphenhydramine poses a cognitive risk to older adults is strong enough that waiting for absolute proof seems like a gamble not worth taking — especially when the cost of switching to a safer antihistamine is essentially zero. The Johns Hopkins and UC San Diego call to remove diphenhydramine from the market may or may not succeed, but it has already shifted the conversation. More physicians are screening for anticholinergic burden, more pharmacists are flagging diphenhydramine in older patients, and more families are learning to read labels carefully. That shift, regardless of regulatory outcomes, is the most meaningful protection currently available.
Conclusion
The evidence connecting long-term diphenhydramine use to increased dementia risk is substantial and growing. From the 2015 University of Washington study showing a 54% increased risk in the heaviest users, to the 2024 research confirming escalating risk with cumulative dosage, to the 2025 call from Johns Hopkins and UC San Diego researchers to pull the drug from the market altogether, the medical community is sending an increasingly urgent message. Diphenhydramine blocks acetylcholine — a neurotransmitter essential for memory — lingers in older bodies for up to 18 hours, and contributes to a cumulative anticholinergic burden that compounds with every additional medication in the same class.
If you are a caregiver, a patient, or simply someone who reaches for Benadryl or a PM sleep aid, the most important step you can take today is to review all medications for anticholinergic content with a pharmacist. Safer second-generation antihistamines like loratadine, fexofenadine, and cetirizine are available over the counter and do not carry the same cognitive risk profile. For sleep difficulties, talk to a doctor about non-anticholinergic options. The drug in your medicine cabinet may feel harmless because it has been there for decades, but decades of use is precisely the problem the research keeps identifying.
Frequently Asked Questions
Does taking Benadryl once or twice cause dementia?
No. The research focuses on cumulative, long-term use. A single dose for an acute allergic reaction is not what the studies are measuring. The 2015 University of Washington study tracked cumulative exposure over years, and the elevated risk appeared in the highest-use group. Occasional use is a very different risk profile than nightly use over months or years.
Is diphenhydramine the only over-the-counter drug with this risk?
No. Diphenhydramine is the most common anticholinergic antihistamine, but other first-generation antihistamines like chlorpheniramine and doxylamine (found in NyQuil and Unisom) also have anticholinergic properties. Additionally, some prescription medications for bladder control, depression, and other conditions carry anticholinergic risk. The total burden across all medications matters.
Are second-generation antihistamines completely safe for the brain?
They are considered significantly safer. Harvard Health notes they have lower anticholinergic activity and are less likely to cross the blood-brain barrier. However, “safer” is not the same as “zero risk.” The FDA has added a warning about rare severe itching after stopping long-term cetirizine or levocetirizine use, so these drugs are not without any concerns — they simply do not carry the same cognitive risk as diphenhydramine.
Can stopping diphenhydramine reverse the cognitive damage?
This remains an open question. Some research suggests that mild cognitive impairment associated with anticholinergic use may improve after the drugs are discontinued, but whether long-term damage is fully reversible has not been definitively established. The earlier someone stops unnecessary anticholinergic exposure, the better their prospects.
My doctor prescribed diphenhydramine. Should I stop taking it?
Never stop a prescribed medication without consulting your doctor. Bring the research to your next appointment and ask whether a safer alternative exists for your specific situation. Many physicians are not yet fully aware of the cumulative anticholinergic burden across a patient’s entire medication list, so raising the question is valuable.
