Diphenhydramine

Don't use diphenhydramine or other antihistamine sleep aids as a regular sleep aid. From age 65, the standard guidance for older adults says to avoid them; below 65 there is no evidence-based cut-off, but they still work poorly.

What it is

Diphenhydramine is a first-generation antihistamine: one of the older allergy drugs, whose main side effect is drowsiness. That side effect is why it is sold as a sleep aid without a prescription. It is also strongly anticholinergic — it blocks acetylcholine, a chemical nerves use to signal — which adds effects on thinking to the drowsiness.

The drowsiness wears off within days

In a small randomised crossover trial, fifteen healthy men took diphenhydramine or a placebo twice a day for four days. They were measurably drowsier on diphenhydramine on day one, and indistinguishable from placebo by day four.^[1]

That trial measured daytime drowsiness rather than sleep, and it was small. But it is the clearest direct test, and both the American and European sleep guidelines advise against antihistamines for insomnia.^{[2] [3]} Even a reader not worried about dementia has little reason to take it night after night.

The dementia signal

Among 3,434 adults aged 65 and over followed for about seven years, the heaviest cumulative use of anticholinergic drugs — the equivalent of a standard daily dose for more than three years, accumulated over a decade — carried a 54% higher risk of dementia than no use. The risk rose step by step across the four levels of exposure.^[4]

That study covered anticholinergic drugs as a whole, not diphenhydramine alone, and it was observational: early dementia may itself drive sleep problems and antihistamine use. The step-by-step rise makes the link hard to dismiss.

Later work has softened the size, though not the direction. A study roughly seventeen times larger, in the same journal, broke the signal down by drug class,^[5] and pooling 26 studies of more than 600,000 people put the class-level association at a more modest level.^[6] A Swedish study of nearly 200,000 people with dementia pointed the same way: it found the odds rising with the cumulative dose of strong anticholinergics, up to about 66% higher after three or more years' worth of standard daily doses, and the association showed up notably for antihistamines and bladder drugs, not only for psychiatric drugs. It too is observational.^[7] For antihistamines specifically, the size of the risk is less certain than a single 54% figure suggests.

Older adults: the guidance says avoid

The American Geriatrics Society Beers Criteria — the standard reference for drugs usually best avoided in older people — list first-generation antihistamines from age 65.^[8] Below 65 there is no age threshold in the evidence; the reason to skip it earlier is that it works poorly, not that a cut-off exists.

The same caution applies to doxepin above the very low dose (3–6 mg) used for sleep: at higher doses it is among the anticholinergics in the dementia research. See Treating chronic insomnia.

What to do

1. Don't take it nightly. It stops sedating within days, and the harms build with cumulative use.
2. From 65, avoid it and other first-generation antihistamines as sleep aids.
3. For chronic insomnia, start with cognitive behavioural therapy for insomnia (CBT-I), which outlasts any pill.
4. If you do need a pill, a prescription option chosen with a doctor is a better bet; see Treating chronic insomnia.

Further reading

• Richardson GS et al. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002.^[9]
• Gray SL et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 2015.^[10]
• 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2023.^[11]
• Riemann D et al. The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023. J Sleep Res 2023.^[12]