Antihistamines: Drowsiness, Sleep and Which Are Safe for Driving

Histamine in the brain acts as a neurotransmitter that sustains wakefulness. Antihistamines block H1 receptors, and the antiallergic effect takes place at the periphery, in the nose, skin and eyes. The problem arises when the drug crosses the blood-brain barrier and blocks the same receptors in the central nervous system: drowsiness, slowed reactions and poorer concentration appear. A review of on-the-road studies notes that all antihistamines can cross the blood-brain barrier and potentially cause sedation, but the degree varies greatly and depends on the drug.

How should this be read? It is a very small trial (eight people, all men), so it is not suitable for drawing conclusions about the scale of risk in the population. It is valuable, however, because it shows something questionnaires do not capture: in the morning after an evening dose almost half of the H1 receptors in the cerebral cortex were still occupied, and the people did not feel sleepy. This gap between feeling and the actual state of the brain recurs in the further studies described below.

Two caveats worth remembering. First, the classification of generations differs between sources: in many works cetirizine, loratadine and fexofenadine are all counted as second generation, and the name 'third generation' used in this review is not universal. For the reader what matters is not the naming but the specific substance. Second, this is a review from 2004, some of the drugs mentioned there (for example terfenadine) have been withdrawn from the market, and the results concern the doses tested in those trials.

Important limitations: the study was done in a simulator, not in real traffic, with one dose of each drug and in healthy people aged 25-44. Alcohol was used here as a reference point (about 0.1%), which does not mean that diphenhydramine is 'equivalent' to a specific number of drinks; it shows only that it impaired driving at least to the same degree, and on the primary end point more. The results concern a single 50 mg dose, and the effect of repeated doses is decided partly by the developing tolerance we describe below.

What follows from this? The study concerns daytime sleepiness and performance after doses given twice a day, not sleep, so it did not directly measure whether the sleep-promoting effect fades in the same way in people who use diphenhydramine at night. The authors note, however, that it is precisely the sedative effect that underlies the use of these drugs as over-the-counter remedies for insomnia, so rapid onset of tolerance matters for this practice too. One can cautiously infer that taking such a drug 'for sleep' every day may stop giving the expected effect after a few days, but this conclusion is indirect and does not come from a study on insomnia itself.

For a driver the same tolerance is no argument for calm: the review of on-the-road studies notes that tolerance after 4-5 days does not mean complete absence of impairment for all drugs, and in the simulator even a single dose impaired driving despite no feeling of sleepiness.

The conclusion for the reader is honest, if inconvenient: diphenhydramine and other 'sleep' antihistamines are widely available and used, but the evidence for their effectiveness in occasional disturbed sleep is modest, and in the antihistamine category the review included only diphenhydramine trials, none with doxylamine. The lack of evidence of effectiveness does not mean the absence of a perceived effect in a particular person, but it does mean the benefit is uncertain, while the risk (morning drowsiness, impaired driving, anticholinergic effects) is documented. For chronic insomnia lasting a long time, the main recommended method is cognitive behavioural therapy for insomnia (CBT-I), which we discuss in a separate entry, not reaching for a pharmacy drug.

First-generation antihistamines have, besides the sedative effect, an anticholinergic effect: they block acetylcholine receptors, which can cause dry mouth, constipation, urinary retention, a faster heartbeat, vision disturbances and, in older people, disorientation and delirium. The Beers criteria (a list of potentially inappropriate medications for people aged 65 and over, developed by the American Geriatrics Society and updated in 2023) list drugs with anticholinergic action as ones usually best avoided in older people. To our knowledge, first-generation antihistamines have been on that list for years, but we do not quote the detailed entry from the full text of the criteria, so we advise an older reader or carer to check it with a doctor or pharmacist.

Honestly on the limitations: the abstract does not report a separate result for antihistamines, so the figures from this study must not be transferred to diphenhydramine or doxylamine used occasionally. The observational study concerns cumulative, years-long exposure to prescribed drugs, and the association may partly result from the disease for which the drug was prescribed (for example early symptoms of dementia may lead to taking some drugs). All that follows from this study is a general hint: the fewer drugs with strong anticholinergic action an older person takes, the better, and when reviewing medicines it is worth asking whether any of them is a 'sleeping antihistamine' bought without a prescription.

Antihistamines are an effective tool in allergy, but they are not indifferent to alertness, and the differences between products are large. A few simple rules follow from the available data: first-generation drugs (diphenhydramine and similar) are better kept for situations in which you do not have to drive or work with concentration, and for driving it is better to choose those that did not impair driving in on-the-road studies. The feeling of drowsiness is not a reliable measure. As a sleep aid diphenhydramine has modest evidence and can lower next-day performance, and in older people it is worth avoiding it in favour of talking to a doctor about the cause of insomnia.