diphenhydramine

General Information

Diphenhydramine (brand Benadryl) is a first-generation antihistamine used OTC for allergy symptoms and commonly used as an OTC sleep aid.

It is strongly Anticholinergic as well as sedating. In psychiatry, that combination can make it appealing for short-term insomnia or acute distress, but it also increases delirium, constipation, and urinary retention risk—especially in older adults and in polypharmacy (Beers / clinical).

Evidence for chronic insomnia benefit is limited, and the AASM guideline recommends against routine diphenhydramine use for chronic insomnia (weak recommendation). Treat it as a time-limited adjunct while addressing underlying drivers (mood episodes, substances, pain, sleep apnea, circadian disruption).

Next-day impairment is a key limiter: driving impairment, falls, and cognitive slowing can occur, particularly with higher doses or when combined with other sedatives (clinical).

The diphenhydramine compare view, evidence feed, and print page support shared decision-making around OTC sleep aids and safer alternatives.

Diphenhydramine is inexpensive and widely accessible, which can lead to “refill momentum” as a nightly sleep aid. In older adults, Beers Criteria guidance generally supports avoiding chronic first-generation antihistamine use because anticholinergic harms often outweigh benefits.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

H1 antagonism reduces histamine signaling and produces sedation (central H1 blockade).

Antimuscarinic (anticholinergic) activity contributes to dry mouth, constipation, urinary retention, blurred vision, and delirium risk.

Sedation can feel helpful for sleep onset, but it does not treat the underlying insomnia system; tolerance and diminished benefit can occur with repeated nightly use (clinical).

• H1 receptor antagonist (sedation).
• Antimuscarinic (anticholinergic) activity.

Metabolism and Pharmacokinetics

• Substantial first-pass hepatic metabolism; CYP2D6 is a major pathway (StatPearls).
• Terminal half-life is ~9 hours in adults; only ~2% is excreted unchanged in urine (StatPearls).
• Duration can be long enough to produce next-day grogginess, especially in older adults and with higher doses (clinical).

Dosing and Administration

• Allergy symptom dosing varies by product; one common pattern is 25–50 mg every 4–6 hours with a daily maximum (label varies).
• Sleep aid dosing in OTC products is commonly a single bedtime dose (often 25–50 mg). Use the lowest effective dose and avoid escalating when next-day impairment appears (clinical).
• Avoid open-ended nightly use for chronic insomnia; prioritize CBT-I and treat comorbid contributors rather than stacking sedatives (AASM / clinical).
• Avoid combining multiple “PM” products or separate sleep aids that contain diphenhydramine because duplicate dosing is common.

Monitoring & Labs

• Sedation and next-day impairment (falls risk, driving safety).
• Anticholinergic effects (constipation, urinary retention, blurred vision).
• Confusion or delirium risk in older adults and polypharmacy (Beers).
• Duplicate diphenhydramine exposure from “PM” combination products.

Adverse Effects

Interactions

• Additive CNS/respiratory depression with alcohol, opioids, benzodiazepines, sedating antipsychotics, and other hypnotics; avoid stacking sedatives when possible (clinical).
• Additive anticholinergic burden with tricyclic antidepressants, low-potency antipsychotics, bladder antimuscarinics, and some antiemetics; increases delirium and urinary retention risk (clinical).
• CYP2D6-modulating medications can alter exposure; reassess if side effects emerge after regimen changes (StatPearls/clinical).

Other Useful Information

• For chronic insomnia, AASM guidelines prioritize CBT-I and recommend against routine diphenhydramine use; treat OTC antihistamine sleep aids as time-limited adjuncts rather than default long-term strategies.
• In older adults and in patients with high fall risk or cognitive vulnerability, first-generation antihistamines are often avoided when possible (Beers).
• If insomnia persists, consider evidence-backed options (e.g., DORAs, ramelteon, low-dose doxepin) and reassess for sleep apnea, substance use, and untreated mood symptoms.

References

1. Benadryl (diphenhydramine) tablets (OTC) label — DailyMed (2026)
2. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline — Journal of Clinical Sleep Medicine (2017)
3. 2023 American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults — Journal of the American Geriatrics Society (2023)
4. Diphenhydramine (StatPearls) — StatPearls Publishing (NCBI Bookshelf) (2025)