Diphenhydramine

• 1. Introduction

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  Diphenhydramine, sold under the brand name Benadryl, is a medicine that most people take in order to feel drowsy. In some people it does the opposite. Particularly at higher doses, it can bring agitation, anxiety, or restlessness where sleep was expected. That odd split is the first of several puzzles. Where did this compound come from? How does one molecule manage to calm itching, ease motion sickness, steady tremors, and still end up inside sleep aids? Why do sleep specialists advise against using it for insomnia? And what happens when people take far more than any label allows? The answers lead from a university laboratory to emergency rooms, forensic labs, and an African border post.

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• 2. From Lab to Shelf

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  In 1943, the chemist George Rieveschl and one of his students, Fred Huber, were at work at the University of Cincinnati. They were studying muscle relaxants, not allergy treatments. Huber was the first to synthesize diphenhydramine. Rieveschl then worked with the company Parke-Davis to test the compound, and the company licensed the patent from him. In 1946 it became the first prescription antihistamine approved by the FDA in the United States.

  A side effect of the drug opened a second line of research in the 1960s. Scientists found that diphenhydramine weakly blocked the reuptake of the neurotransmitter serotonin. That finding set off a search for antidepressants with similar structures and fewer side effects. The search ended with fluoxetine, sold as Prozac, a selective serotonin reuptake inhibitor. An earlier hunt that started from another antihistamine, brompheniramine, had already produced zimelidine, the first drug of that type.

  As late as 1975, diphenhydramine in the United States was still sold only by prescription and used under medical supervision. Today the picture is very different. McNeil Consumer Healthcare sells it as Benadryl in the United States, the United Kingdom, Canada, and South Africa. Other countries know it as Dimedrol, Daedalon, Nytol, or Vivinox, and generic versions are available. In 2023 it ranked 294th among the most commonly prescribed medications in the United States, with more than 700,000 prescriptions.

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• 3. One Molecule, Many Targets

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  A table of binding strengths lists a value of 9.6 to 16 for the histamine H1 receptor. In that table a smaller number means a tighter grip. Muscarinic receptors, which respond to the messenger acetylcholine, show values from about 30 to a few hundred. So the drug favors histamine receptors but still grips several others firmly.

  At the H1 receptor, diphenhydramine is traditionally called an antagonist. More precisely, it acts mainly as an inverse agonist, and it belongs to the ethanolamine class of antihistamines. By reversing what histamine does to the capillaries, it lowers the intensity of allergic symptoms. It also crosses the blood-brain barrier and acts on H1 receptors inside the brain. That central action is what causes drowsiness.

  The drug's second job is blocking muscarinic acetylcholine receptors, which makes it a potent antimuscarinic. Doing this in the brain explains its use against parkinsonism. At high doses the same action produces anticholinergic syndrome. A third job is blocking sodium channels inside cells, and this is the basis of its use as a local anesthetic. In rats it has also boosted pain relief from morphine, though not from the body's own opioids. It also inhibits an enzyme called histamine N-methyltransferase.

  The body handles the drug in a predictable way. Oral bioavailability runs from 40% to 60%, and the blood level peaks two to three hours after a dose. The liver does most of the work, removing two methyl groups in succession and using the enzymes CYP2D6, CYP1A2, CYP2C9, and CYP2C19. Maximal effect comes around two hours after an oral dose, and effects can last up to seven hours.

  How quickly the drug leaves depends on age. A 1990 study found elimination half-lives of 5.4 hours in children, 9.2 hours in young adults, and 13.5 hours in the elderly. A 2018 study in children and adolescents measured 8 to 9 hours.

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• 4. Allergies and Beyond

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  In emergency departments, diphenhydramine was the most commonly used antihistamine for acute allergic reactions. For anaphylaxis, it is often injected alongside epinephrine. That use has never been properly studied, and the advice is to give it only once the acute symptoms have improved.

  Creams, lotions, gels, sprays, and eye drops carry the drug to the skin and eyes. These topical forms relieve itching and cause fewer system-wide effects, such as drowsiness, than the oral forms do. The drug also numbs tissue. People allergic to common local anesthetics such as lidocaine have received it for that purpose.

  In neurology, diphenhydramine treats parkinsonism. It also treats acute dystonia, including torticollis and oculogyric crisis, the muscle spasms of the neck and eyes that typical antipsychotics can trigger.

  Nausea is another target. Diphenhydramine has antiemetic properties that help with the nausea of vertigo and motion sickness, and it is the active ingredient in Dramamine, also sold as Gravol. Above the recommended dose, especially above 200 mg, it can cause nausea instead. Topical use for nausea is sometimes seen in hospice care. That use has no formal indication, and research has not shown it to beat other treatments.

  Anxiety is where the drug runs out of support. The FDA has not approved it for that purpose. Long-term use may cause memory loss, especially in older people. Hydroxyzine, a related antihistamine without strong anticholinergic effects, is sometimes used instead. Its mild calming effect comes from weak but significant blocking of the 5-HT2A receptor. Diphenhydramine does not bind that receptor, though it weakly blocks the related 5-HT2C receptor, which plays a significant role in mood and anxiety.

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• 5. The Sleep Aid Question

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  In 2017, the American Academy of Sleep Medicine issued clinical practice guidelines that recommended against diphenhydramine for insomnia. The reasons were poor effectiveness and low-quality evidence. A major systematic review and network meta-analysis of insomnia drugs, published in 2022, found little evidence to guide its use for that purpose.

  The shelves tell a different story. Because the drug sedates, it is widely used in nonprescription sleep aids. Procter & Gamble markets an over-the-counter formulation under the brand ZzzQuil. Prestige Brands sells another in the United States under the name Sominex. The drug can also cause minor psychological dependence.

  Some parents have used it off-label to make their children sleep or to sedate them on long-distance flights. Doctors and members of the airline industry have both criticized the practice. A sedated passenger may be unable to react efficiently in an emergency. The side effects can also leave some users hyperactive.

  In a 2009 article, Seattle Children's Hospital put the objection in one line: "Using a medication for your convenience is never an indication for medication in a child."

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• 6. Side Effects and Cautions

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  Dry mouth and throat, a faster heartbeat, widened pupils, urinary retention, and constipation all trace back to the drug's anticholinergic action. At high doses the same action can produce hallucinations or delirium. The most prominent everyday side effects are dizziness and sleepiness.

  The longer list includes poor coordination, flushed skin, and blurred vision at close range. It also includes abnormal sensitivity to bright light, trouble concentrating, short-term memory loss, irritability, and confusion. Some people develop hives as an allergic reaction. Higher doses may cause vomiting. In overdose, the drug may occasionally prolong the heart's QT interval.

  Restlessness and akathisia can worsen as diphenhydramine levels rise, especially at recreational doses. Even normal doses, like other first-generation antihistamines, can aggravate restless legs syndrome. The liver metabolizes the drug extensively, so people with hepatic impairment need caution.

  Older adults face a slower road. Anticholinergic use later in life is associated with a higher risk of cognitive decline and dementia. Drowsiness, memory loss, confusion, dry mouth, and constipation can also appear.

  Pregnancy carries no clear risk of harm, and the drug sits in pregnancy Category B. Premature infants, newborns, and breastfeeding mothers are another matter. The drug is contraindicated for them. It passes into breast milk, and occasional low doses are expected to cause no harm to a nursing baby. Large doses and long-term use may affect the baby or reduce milk supply, particularly when combined with a decongestant such as pseudoephedrine. A single bedtime dose after the day's last feeding may limit the harm, though non-sedating antihistamines are preferred.

  Alcohol adds to the drowsiness. Monoamine oxidase inhibitors prolong and intensify the drug's anticholinergic effect.

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• 7. Overdose and the Laboratory

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  Diphenhydramine is one of the most commonly misused over-the-counter drugs in the United States. In overdose, the list of possible symptoms is long. It includes abdominal pain, acute megacolon, tremors, muscle spasms, and an inability to urinate. It also includes delirium, dissociation, and dysphoria. Hallucinations can be auditory, visual, or tactile. Seizures and coma are possible.

  Acute poisoning can be fatal. Cardiovascular collapse and death can follow within 2-18 hours. Several lines of evidence indicate that the drug, like chlorpheniramine, can block the delayed rectifier potassium channel in heart cells. That block prolongs the QT interval and can lead to arrhythmias such as torsades de pointes.

  No specific antidote is known. Treatment is symptomatic and supportive. For severe delirium or a racing heart, doctors have used physostigmine to treat the anticholinergic syndrome. Benzodiazepines may be given to lower the chance of psychosis, agitation, and seizures in people prone to them. Diagnosis rests on the patient's history and clinical picture, because precise plasma levels do not appear to give useful clinical information.

  Laboratories can still measure the drug in blood, plasma, or serum. Gas chromatography with mass spectrometry works as a screening test, and either that method or GC-NDP can quantify it. Measurements can monitor therapy, confirm poisoning in hospitalized people, supply evidence in an impaired driving arrest, or assist a death investigation. Rapid urine screens based on competitive binding can show a false positive for methadone in someone who took diphenhydramine.

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• 8. Misuse, Law, and Myth

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  In the Republic of Zambia, diphenhydramine is among the prohibited and controlled substances, and travelers are told not to bring it in. Several Americans have been detained by the Zambian Drug Enforcement Commission for carrying Benadryl and other over-the-counter medicines containing it.

  The United States treats it quite differently. It is not a controlled substance, because its serious side-effect profile and limited euphoric effects give it limited abuse potential. Since 2002, the FDA has required special labeling that warns against using several diphenhydramine products at once. In some jurisdictions the drug often turns up in postmortem specimens collected during investigations of sudden infant deaths, and it may play a role in those events.

  Still, cases of abuse and addiction are documented. The drug is cheap and sold over the counter in most countries, so adolescents who cannot get more sought-after drugs are particularly at risk. People with mental health problems, especially schizophrenia, may also take large doses to treat movement symptoms caused by antipsychotics. Users report calming effects, mild euphoria, and hallucinations. Research has suggested that antimuscarinic agents, including diphenhydramine, "may have antidepressant and mood-elevating properties".

  One study gave a 400 mg dose to adult men with a history of sedative abuse. They reported wanting the drug again, even while reporting trouble concentrating, confusion, tremors, and blurred vision.

  In 2020 the social media platform TikTok carried a trend called the Benadryl challenge. Participants swallowed dangerous amounts of the drug and filmed the psychoactive results. The challenge has been implicated in several hospitalisations and at least two deaths.

  A stranger legacy lives on in folklore. People under the drug's influence have reported seeing a shadow figure known as the Hat Man, who has since become an internet meme and an urban legend.

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