[30] This has been met with criticism, both by doctors and by members of the airline industry, because sedating passengers may put them at risk if they cannot react efficiently to emergencies,[31] and because the drug's side effects, especially the chance of a paradoxical reaction, may make some users hyperactive.

"[32] The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of diphenhydramine in the treatment of insomnia, because of poor effectiveness and low quality of evidence.

Large doses and long-term use may affect the baby or reduce breast milk supply, especially when combined with sympathomimetic drugs, such as pseudoephedrine, or before the establishment of lactation.

A single bedtime dose after the last feeding of the day may minimize the harmful effects of the medication on the baby and the milk supply.

[39] Diphenhydramine (as Benadryl) is not typically used to treat anxiety because its long-term use may cause adverse effects, such as memory loss, especially in the elderly.

[41] The mild anxiolytic effects of hydroxyzine are mostly due to its weak but significant activity as an antagonist of the 5-HT2A receptor, a common target of most antidepressant drugs (as well as certain other antihistamines like cyproheptadine and promethazine).

This activity is responsible for the side effects of dry mouth and throat, increased heart rate, pupil dilation, urinary retention, constipation, and, at high doses, hallucinations or delirium.

Other side effects include motor impairment (ataxia), flushed skin, blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), sedation, difficulty concentrating, short-term memory loss, visual disturbances, irregular breathing, dizziness, irritability, itchy skin, confusion, increased body temperature (in general, in the hands and/or feet), temporary erectile dysfunction, and excitability, and although it can be used to treat nausea, higher doses may cause vomiting.

[48] As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment.

[51] Overdose symptoms may include [52] Acute poisoning can be fatal, leading to cardiovascular collapse and death in 2–18 hours, and in general, is treated using a symptomatic and supportive approach.

[54] Several levels of evidence strongly indicate diphenhydramine (similar to chlorpheniramine) can block the delayed rectifier potassium channel and, as a consequence, prolong the QT interval, leading to cardiac arrhythmias such as torsades de pointes.

Diphenhydramine is a potent antimuscarinic (a competitive antagonist of muscarinic acetylcholine receptors) and, as such, at high doses can cause anticholinergic syndrome.

[71] The utility of diphenhydramine as an antiparkinson agent is the result of its blocking properties on the muscarinic acetylcholine receptors in the brain.

[5] Diphenhydramine, available in various salt forms,[76] such as citrate,[77][78] hydrochloride,[79] and salicylate,[80] exhibits distinct molecular weights and pharmacokinetic properties.

[86] Gas chromatography with mass spectrometry (GC-MS) can be used with electron ionization on full scan mode as a screening test.

[86] Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for people having ingested diphenhydramine.

[87] Quantification can be used to monitor therapy, confirm a diagnosis of poisoning in people who are hospitalized, provide evidence in an impaired driving arrest, or assist in a death investigation.

[86] In 1943, diphenhydramine was discovered by chemist George Rieveschl and one of his students, Fred Huber, while they were conducting research into muscle relaxants at the University of Cincinnati.

[72] This discovery led to a search for viable antidepressants with similar structures and fewer side effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI).

[93] Diphenhydramine is sold under the brand name Benadryl by McNeil Consumer Healthcare in the US, UK, Canada, and South Africa.

[97] In some jurisdictions, diphenhydramine is often present in postmortem specimens collected during investigation of sudden infant deaths; the drug may play a role in these events.

Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing diphenhydramine.

[101] Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases of abuse and addiction have been documented.

[102] People with mental health problems—especially those with schizophrenia—are also prone to abuse the drug, which is self-administered in large doses to treat extrapyramidal symptoms caused by the use of antipsychotics.