Hydroxyzine and dementia risk: what the long term evidence shows

Hydroxyzine comes up a lot in my practice. It is prescribed for anxiety, for itching, and sometimes before procedures to take the edge off. It works quickly, it is not a controlled substance, and many people like it precisely because it feels gentler than the alternatives. Then a patient reads something online about anticholinergic medications and dementia, sees hydroxyzine on a list, and asks whether the medication they take at night is quietly harming their brain. That is a fair question, and it deserves a careful answer rather than a reassuring one.

Start with what the medication actually does. Hydroxyzine is a first generation antihistamine. In addition to blocking histamine, it blocks muscarinic acetylcholine receptors, which gives it its anticholinergic effects. Dry mouth, constipation, urinary hesitancy, and next day grogginess all come from that second action. Acetylcholine is also a messenger the brain relies on for attention, encoding of new memories, and focus. When a medication blocks it, thinking can get cloudy, which is why highly anticholinergic drugs are a well known cause of short term confusion and delirium in older adults. The question researchers began asking about twenty years ago is whether years of that blockade could add up to something lasting.

To study that question, researchers needed a way to measure how much anticholinergic exposure a person had accumulated across all of their medications. That led to anticholinergic burden scales. The best known is the Anticholinergic Cognitive Burden scale, which assigns each medication a score. A score of 1 means possible anticholinergic activity. A score of 2 means moderate activity. A score of 3 means definite anticholinergic activity, supported by evidence of clinically relevant cognitive effects. The scores are added across everything a person takes, and a total of 3 or more is considered significant. Hydroxyzine carries a score of 3, which places it in the top tier alongside medications like amitriptyline and oxybutynin. I should note that roughly sixteen such scales exist and they do not always agree on every drug, so the scores are clinical tools, not laboratory measurements.

The strongest evidence comes from large observational studies that tracked cumulative exposure over years. In 2015, researchers following 3,434 adults aged 65 and older in the Adult Changes in Thought study used pharmacy records to calculate total anticholinergic exposure over a ten year window. People with the highest cumulative exposure, roughly equivalent to taking a standard dose of a strong anticholinergic every day for more than three years, had about a 54 percent higher risk of developing dementia than people with no exposure. This was the first study to show a clear dose response relationship, and the elevated risk persisted even years after people stopped the medications.

A 2018 study in the United Kingdom made the case stronger and harder to dismiss. Using general practice records for 40,770 patients with dementia and 283,933 matched controls, researchers examined anticholinergic prescriptions filled 4 to 20 years before diagnosis, a long lag designed to rule out the possibility that early dementia symptoms were driving the prescriptions. Drugs with an Anticholinergic Cognitive Burden score of 3 were associated with about an 11 percent higher odds of dementia, and the association held even for exposure 15 to 20 years before diagnosis. The signal was concentrated in specific classes: antidepressants, bladder medications, and antiparkinson drugs.

A 2019 nested case control study added scale and detail. With 58,769 dementia cases and 225,574 controls from English primary care records, it found that the highest total exposure, more than 1,095 standardized daily doses, was associated with about 49 percent higher odds of dementia. Significant associations appeared for anticholinergic antidepressants, antiparkinson drugs, antipsychotics, bladder antimuscarinics, and antiepileptic drugs. Here is the honest part that matters for this article. Antihistamines as a class did not show a statistically significant increase in dementia risk in this study, and the 2018 British study did not single out antihistamines either. Hydroxyzine has not been studied in isolation in any large cohort I am aware of. So the evidence on hydroxyzine specifically is thin. What we know is that it shares the pharmacology of the medications these studies flagged, and it sits at the top of the burden scale.

All of this comes with real caveats. These are observational studies, and observational studies show association, not causation. Confounding by indication is a genuine concern: the conditions these drugs treat, from depression to overactive bladder, may themselves be linked to dementia risk, and no statistical adjustment captures everything. The long exposure windows in the British studies make reverse causation less likely, since prescriptions written 15 to 20 years before diagnosis are hard to explain as treatment of early dementia symptoms, but they do not eliminate it. Short term cognitive effects of anticholinergics are well established. The long term dementia link is plausible and consistent across studies, but it is not proven.

How should a person think about this? Context matters enormously. These studies enrolled people 65 and older and measured cumulative exposure over years. A younger adult using hydroxyzine occasionally for anxiety or itching is not the population these studies describe, and occasional use looks very different from daily use over years. Age is also a factor because the aging brain has less cholinergic reserve, which is why these findings matter most for older adults. If you or a loved one takes hydroxyzine daily, the reasonable step is a medication review with your prescriber or pharmacist, looking at total anticholinergic burden across everything you take, not just this one medication. Do not stop any medication abruptly on the basis of an article.

This article is educational only and is not medical advice. Medication decisions belong in a conversation with your own prescriber, who can weigh your personal history, your total medication list, and the reasons you were prescribed hydroxyzine in the first place.

Anthony

Sources: Gray SL et al., JAMA Internal Medicine (2015), cumulative use of strong anticholinergics and incident dementia, a prospective cohort study, PMID 25621434. Richardson K et al., BMJ (2018), anticholinergic drugs and risk of dementia, case control study, PMID 29695481. Coupland CAC et al., JAMA Internal Medicine (2019), anticholinergic drug exposure and the risk of dementia, a nested case control study, PMID 31233095. Campbell N et al., Clinical Interventions in Aging (2009), the cognitive impact of anticholinergics, a clinical review, PMID 19554093. Boustani MA et al., Aging Health (2008), impact of anticholinergics on the aging brain, a review and practical application, the Anticholinergic Cognitive Burden scale listing hydroxyzine at score 3.