Diphenhydramine

Diphenhydramine, also sold as Benadryl and known chemically as Diphenylhydramine, is a first-generation H1-antihistamine that also acts as a sedative. It blocks histamine and has strong anticholinergic effects. While it typically causes drowsiness, some people—especially at higher doses—experience a paradoxical reaction of agitation, anxiety, or restlessness instead of sedation. The drug is taken by mouth, injected into a vein or muscle, or applied to the skin. After an oral dose, its peak effect occurs around two hours later, and the effects can last up to seven hours.

Common side effects include sleepiness, poor coordination, and an upset stomach. There is no clear evidence of harm during pregnancy, but it is not recommended while breastfeeding. Developed by George Rieveschl, it entered commercial use in 1946 and is available as a generic. In 2023, it was the 294th most prescribed medication in the United States, with over 700,000 prescriptions. Its sedative and deliriant properties have led to some recreational use.

Medically, diphenhydramine is used for allergic symptoms and itching, the common cold, insomnia, motion sickness, and extrapyramidal symptoms. It also has local anesthetic properties and is used in people allergic to common anesthetics like lidocaine. For allergies, it is effective and was the most common antihistamine for acute allergic reactions in emergency departments as of 2007. By injection, it is often given alongside epinephrine for anaphylaxis, though its use for this purpose had not been properly studied as of 2007 and is only recommended after acute symptoms improve. Topical forms—creams, lotions, gels, sprays, and eye drops—relieve itching with fewer systemic effects like drowsiness.

For movement disorders, it treats parkinsonism and acute dystonia, including torticollis and oculogyric crisis caused by typical antipsychotics. As a sleep aid, it is widely used in nonprescription products for insomnia, though it can cause minor psychological dependence. It has also been used as an anxiolytic. Some parents have used it off-label to sedate children on long flights, but this practice has been criticized by doctors and airline staff because sedation may impair emergency reactions and because paradoxical hyperactivity is possible. The Seattle Children’s Hospital argued in 2009 that using medication for convenience is never an indication for children. The American Academy of Sleep Medicine’s 2017 guidelines recommended against diphenhydramine for insomnia due to poor effectiveness and low-quality evidence, and a 2022 systematic review found little evidence to support its use for this condition.

Diphenhydramine has antiemetic properties, useful for nausea from vertigo and motion sickness, though doses above 200 mg can cause nausea. It is the active ingredient in Dramamine (also known as Gravol). It is not typically used for anxiety because long-term use may cause adverse effects like memory loss, especially in the elderly, and it is not FDA-approved for that purpose. Unlike hydroxyzine, which has mild anxiolytic effects due to weak 5-HT2A receptor antagonism, diphenhydramine does not bind to that receptor, though it weakly antagonizes the related 5-HT2C receptor, which plays a role in mood and anxiety. For akathisia, doses of 50–100 mg may be used.

Diphenhydramine is contraindicated in premature infants, neonates, and breastfeeding individuals. It is a pregnancy Category B drug. It has additive effects with alcohol and other depressants, and monoamine oxidase inhibitors (MAOIs) prolong and intensify its anticholinergic effects. The most prominent side effects are dizziness and sleepiness. As a potent anticholinergic, it can cause 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).