Diphenhydramine

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Diphenhydramine is a first-generation antihistamine used to treat several conditions including allergic symptoms and itchiness, the common cold, insomnia, motion sickness, and extrapyramidal symptoms.{{cite web |title=Diphenhydramine Hydrochloride Monograph |publisher=The American Society of Health-System Pharmacists |work=Drugs.com |url=https://www.drugs.com/monograph/diphenhydramine-hydrochloride.html |url-status=live |archive-url=https://web.archive.org/web/20110615135322/http://www.drugs.com/monograph/diphenhydramine-hydrochloride.html |archive-date=15 June 2011}}{{cite journal |vauthors=Brown HE, Stoklosa J, Freudenreich O |title=How to stabilize an acutely psychotic patient |journal=Current Psychiatary |volume=11 |issue=12 |pages=10–16 |date=December 2012 |url=http://stg.currentpsychiatry.com/pdf/1112/1112CP_Freudenreich.pdf |url-status=dead |archive-url=https://web.archive.org/web/20130514183445/http://stg.currentpsychiatry.com/pdf/1112/1112CP_Freudenreich.pdf |archive-date=14 May 2013}} Diphenhydramine also has local anesthetic properties, and has been used as such in people allergic to common local anesthetics such as lidocaine.{{cite journal |vauthors=Smith DW, Peterson MR, DeBerard SC |title=Local anesthesia. Topical application, local infiltration, and field block |journal=Postgraduate Medicine |volume=106 |issue=2 |pages=57–60, 64–6 |date=August 1999 |pmid=10456039 |doi=10.3810/pgm.1999.08.650}}

Diphenhydramine is effective in the treatment of allergies.{{cite web |author1=American Society of Health-System Pharmacists |title=Diphenhydramine Hydrochloride |website=Drugs.com |url=https://www.drugs.com/monograph/diphenhydramine-hydrochloride.html |access-date=2 August 2016 |url-status=live |archive-url=https://web.archive.org/web/20160915002404/https://www.drugs.com/monograph/diphenhydramine-hydrochloride.html |archive-date=15 September 2016}} {{As of|2007}}, it was the most commonly used antihistamine for acute allergic reactions in the emergency department.{{cite journal |vauthors=Banerji A, Long AA, Camargo CA |title=Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: a literature review |journal=Allergy and Asthma Proceedings |volume=28 |issue=4 |pages=418–26 |date=2007 |pmid=17883909 |doi=10.2500/aap.2007.28.3015 |s2cid=7596980}}

By injection, it is often used in addition to epinephrine for anaphylaxis,{{cite book |veditors=Humphries RL, Stone CK |title=CURRENT Diagnosis and Treatment Emergency Medicine |edition=Seventh |series=LANGE CURRENT Series |publisher=McGraw–Hill Professional |year=2011 |isbn=978-0-07-170107-5 |chapter=Chapter 11: Shock |vauthors=Young WF}} although {{as of|2007|lc=y}} its use for this purpose had not been properly studied.{{cite journal |vauthors=Sheikh A, ten Broek VM, Brown SG, Simons FE |title=H1-antihistamines for the treatment of anaphylaxis with and without shock |journal=The Cochrane Database of Systematic Reviews |issue=1 |pages=CD006160 |date=January 2007 |volume=2007 |pmid=17253584 |doi=10.1002/14651858.CD006160.pub2 |pmc=6517288}} Its use is only recommended once acute symptoms have improved.

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Topical formulations of diphenhydramine are available, including creams, lotions, gels, sprays, and eye drops. These are used to relieve itching and have the advantage of causing fewer systemic effects (e.g., drowsiness) than oral forms.{{cite web |title=Diphenhydramine Topical |website=MedlinePlus |url=https://medlineplus.gov/druginfo/meds/a601044.html |access-date=9 October 2020 |url-status=live |archive-url=https://web.archive.org/web/20201010221833/https://medlineplus.gov/druginfo/meds/a601044.html |archive-date=10 October 2020}}

Diphenhydramine is used to treat akathisia and parkinsonism caused by antipsychotics.{{cite book |veditors=Katzung B, Masters S, Trevor A |title=Basic & Clinical Pharmacology |edition=12th |year=2012 |publisher=The McGraw-Hill Companies, Inc. |isbn=978-0-07-176401-8 |pages=483–500 |vauthors=Aminoff MJ |chapter=Chapter 28. Pharmacologic Management of Parkinsonism & Other Movement Disorders}} It is also used to treat acute dystonia including torticollis and oculogyric crisis caused by typical antipsychotics.

Because of its sedative properties, diphenhydramine is widely used in nonprescription sleep aids for insomnia. The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as paracetamol (acetaminophen) in Tylenol PM and ibuprofen in Advil PM. Diphenhydramine can cause minor psychological dependence.{{cite web |title=Benadryl Addiction |publisher=eMedTV |vauthors=Monson K, Schoenstadt A |date=8 September 2013 |url=http://allergies.emedtv.com/benadryl/benadryl-addiction.html |url-status=usurped |archive-url=https://web.archive.org/web/20140104053402/http://allergies.emedtv.com/benadryl/benadryl-addiction.html |archive-date=4 January 2014}} Diphenhydramine has also been used as an anxiolytic.{{cite journal |vauthors=Dinndorf PA, McCabe MA, Friedrich S |title=Risk of abuse of diphenhydramine in children and adolescents with chronic illnesses |journal=The Journal of Pediatrics |volume=133 |issue=2 |pages=293–5 |date=August 1998 |pmid=9709726 |doi=10.1016/S0022-3476(98)70240-9}}

Diphenhydramine has also been used off-label by parents in an attempt to make their children sleep and to sedate them on long-distance flights.{{cite news |title=Is it wrong to drug your children so they sleep on a flight? |vauthors=Crier F |website=The Telegraph |date=2 August 2017 |url=https://www.telegraph.co.uk/travel/family-holidays/is-it-ok-drug-babies-toddlers-children-sleep-flight-antihistamines/ |url-access=subscription |access-date=13 April 2020 |url-status=live |archive-url=https://ghostarchive.org/archive/20220111/https://www.telegraph.co.uk/travel/family-holidays/is-it-ok-drug-babies-toddlers-children-sleep-flight-antihistamines/ |archive-date=11 January 2022}}{{cbignore}} 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,{{cite news |vauthors=Morris R |title=Should parents drug babies on long flights? |date=3 April 2013 |work=BBC News |url=https://www.bbc.com/news/magazine-21977785 |access-date=13 April 2020 |url-status=live |archive-url=https://web.archive.org/web/20210308034544/https://www.bbc.com/news/magazine-21977785 |archive-date=8 March 2021}} and because the drug's side effects, especially the chance of a paradoxical reaction, may make some users hyperactive. Addressing such use, the Seattle Children's Hospital argued, in a 2009 article, "Using a medication for your convenience is never an indication for medication in a child."{{cite web |vauthors=Swanson WS |date=25 November 2009 |title=If It Were My Child: No Benadryl for the Plane |publisher=Seattle Children's |url=https://seattlemamadoc.seattlechildrens.org/if-it-were-my-child-no-benadryl-for-the-plane/ |access-date=13 April 2020 |url-status=dead |archive-url=https://web.archive.org/web/20210225070641/https://seattlemamadoc.seattlechildrens.org/if-it-were-my-child-no-benadryl-for-the-plane/ |archive-date=25 February 2021}}

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.{{cite journal |vauthors=Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL |title=Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline |journal=J Clin Sleep Med |volume=13 |issue=2 |pages=307–349 |date=February 2017 |pmid=27998379 |doi=10.5664/jcsm.6470 |pmc=5263087}} A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found little evidence to inform the use of diphenhydramine for insomnia.{{cite journal |vauthors=De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A |title=Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis |journal=Lancet |volume=400 |issue=10347 |pages=170–184 |date=July 2022 |pmid=35843245 |doi=10.1016/S0140-6736(22)00878-9 |doi-access=free |hdl=11380/1288245 |hdl-access=free |s2cid=250536370}}

Diphenhydramine also has antiemetic properties, which make it useful in treating the nausea that occurs in vertigo and motion sickness. However, when taken above recommended doses, it can cause nausea (especially above 200 mg).{{cite journal |vauthors=Flake ZA, Scalley RD, Bailey AG |title=Practical selection of antiemetics |journal=American Family Physician |volume=69 |issue=5 |pages=1169–74 |date=March 2004 |pmid=15023018 |url=https://www.aafp.org/pubs/afp/issues/2004/0301/p1169.html |access-date=10 March 2016 |url-status=live |archive-url=https://web.archive.org/web/20160324141234/http://www.aafp.org/afp/2004/0301/p1169.html |archive-date=24 March 2016}}

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. Diphenhydramine is not approved by the US Food and Drug Administration (FDA) for treating anxiety. On the other hand, hydroxyzine, a first-generation antihistamine that lacks significant anticholinergic effects may be used to treat anxiety, although benzodiazepines and antidepressants are considered more effective by most clinicians. "Hydroxyzine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 21 November 2018. The mild anxiolytic effects of hydroxyzine are mostly due to its weak but significant activity as an antagonist of the 5-HT_2A receptor, a common target of most antidepressant drugs (as well as certain other antihistamines like cyproheptadine and promethazine). Diphenhydramine is not known to bind to the 5-HT_2A receptor, though it is a weak antagonist of the related 5-HT_2C receptor, which is another target of antidepressant drugs and has a significant role in mood and anxiety.{{cite journal | vauthors = Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH | title = Serotonin 5-HT(2C) receptors regulate anxiety-like behavior | journal = Genes, Brain and Behavior | volume = 6 | issue = 5 | pages = 491–496 | date = July 2007 | pmid = 17451451 | doi = 10.1111/j.1601-183X.2007.00316.x | doi-access = free }}{{cite journal | vauthors = Guaiana G, Gupta S, Chiodo D, Davies SJ, Haederle K, Koesters M | title = Agomelatine versus other antidepressive agents for major depression | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD008851 | date = December 2013 | pmid = 24343836 | doi = 10.1002/14651858.CD008851.pub2 | pmc = 11289707 }}

Diphenhydramine is contraindicated in premature infants and neonates, as well as people who are breastfeeding. It is a pregnancy Category B drug. Diphenhydramine has additive effects with alcohol and other depressants. Monoamine oxidase inhibitors (MAOIs) prolong and intensify the anticholinergic effect of antihistamines.{{cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK526010/ |title=StatPearls |vauthors=Sicari V, Zabbo CP |date=2021 |publisher=StatPearls Publishing |place=Treasure Island (FL) |chapter=Diphenhydramine |pmid=30252266 |access-date=27 December 2021 |archive-url=https://web.archive.org/web/20220528171459/https://www.ncbi.nlm.nih.gov/books/NBK526010/ |archive-date=28 May 2022 |url-status=live}}

The most prominent side effects are dizziness and sleepiness.

Diphenhydramine is a potent anticholinergic agent and potential deliriant in higher doses. 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 or feet), temporary erectile dysfunction, and excitability, and although it can be used to treat nausea, higher doses may cause vomiting.{{cite web |title=Diphenhydramine Side Effects |publisher=Drugs.com |url=https://www.drugs.com/sfx/diphenhydramine-side-effects.html |access-date=9 November 2024 |date=3 October 2024}} Diphenhydramine in overdose may occasionally result in QT prolongation.{{cite book |vauthors=Aronson JK |title=Meyler's Side Effects of Cardiovascular Drugs |date=2009 |publisher=Elsevier |isbn=978-0-08-093289-7 |page=623 |url=https://books.google.com/books?id=oeBgU3UwgZkC&dq=Diphenhydramine+QT+prolongation&pg=PA623 |access-date=4 March 2020 |url-status=live |archive-url=https://web.archive.org/web/20210308005242/https://www.google.com/books/edition/Meyler_s_Side_Effects_of_Cardiovascular/oeBgU3UwgZkC?hl=en&gbpv=1&dq=Diphenhydramine+QT+prolongation&pg=PA623 |archive-date=8 March 2021}}

Some individuals experience an allergic reaction to diphenhydramine in the form of hives.{{cite journal |vauthors=Heine A |title=Diphenhydramine: a forgotten allergen? |journal=Contact Dermatitis |volume=35 |issue=5 |pages=311–312 |date=November 1996 |pmid=9007386 |doi=10.1111/j.1600-0536.1996.tb02402.x |s2cid=32839996}}{{cite journal |vauthors=Coskey RJ |title=Contact dermatitis caused by diphenhydramine hydrochloride |journal=Journal of the American Academy of Dermatology |volume=8 |issue=2 |pages=204–206 |date=February 1983 |pmid=6219138 |doi=10.1016/S0190-9622(83)70024-1}}

Conditions such as restlessness or akathisia can worsen from increased levels of diphenhydramine, especially with recreational dosages.{{cite journal |vauthors=de Leon J, Nikoloff DM |title=Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports |journal=CNS Spectrums |volume=13 |issue=2 |pages=133–5 |date=February 2008 |pmid=18227744 |doi=10.1017/s109285290001628x |s2cid=10856872}} Normal doses of diphenhydramine, like other first-generation antihistamines, can also make symptoms of restless legs syndrome worse.{{cite web |title=Restless Legs Syndrome Fact Sheet |website=National Institute of Neurological Disorders and Stroke |url=https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/restless-legs-syndrome-fact-sheet |access-date=27 August 2019 |url-status=live |archive-url=https://web.archive.org/web/20170728021833/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Restless-Legs-Syndrome-Fact-Sheet |archive-date=28 July 2017}}

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

Anticholinergic use later in life is associated with an increased risk for cognitive decline and dementia among older people.{{cite journal |vauthors=Salahudeen MS, Duffull SB, Nishtala PS |title=Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review |journal=BMC Geriatrics |volume=15 |issue=31 |pages=31 |date=March 2015 |pmid=25879993 |doi=10.1186/s12877-015-0029-9 |doi-access=free |pmc=4377853}} Drowsiness, memory loss, confusion, dry mouth or constipation may also occur in elderly people.{{cite web |title=Does Benadryl help with or cause anxiety? |url=https://www.drugs.com/medical-answers/benadryl-help-cause-anxiety-3574583/ |publisher=Drugs.com |access-date=9 November 2024 |date=27 July 2023}}

Diphenhydramine is secreted in breast milk.{{cite journal |vauthors=Spencer JP, Gonzalez LS, Barnhart DJ |date=July 2001 |title=Medications in the breast-feeding mother |journal=American Family Physician |volume=64 |issue=1 |pages=119–26 |pmid=11456429}} It is expected that low doses of diphenhydramine taken occasionally will cause no adverse effects in breastfed infants. 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. Still, non-sedating antihistamines are preferred.{{cite journal |date=October 2020 |title=Diphenhydramine |journal=Drugs and Lactation Database (LactMed) Internet |location=Bethesda (MD) |publisher=National Library of Medicine (US) |pmid=30000938}}

Paradoxical reactions to diphenhydramine have been documented, particularly in children, and it may cause excitation instead of sedation.

Topical diphenhydramine is sometimes used especially for people in hospice. This use is without indication and topical diphenhydramine should not be used as treatment for nausea because research has not shown that this therapy is more effective than others.{{citation |author1=American Academy of Hospice and Palliative Medicine |title=Five Things Physicians and Patients Should Question |date=2013 |work=Choosing Wisely: an initiative of the ABIM Foundation |volume=45 |issue=3 |pages=595–605 |url=https://aahpm.org/uploads/about/3.6.1._AAHPM_5_Things_-_Choosing_Wisely.pdf |access-date=17 May 2024 |archive-url=https://web.archive.org/web/20130901101934/http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-hospice-palliative-medicine/ |archive-date=1 September 2013 |url-status=live |publisher=American Academy of Hospice and Palliative Medicine |doi=10.1016/j.jpainsymman.2012.12.002 |pmid=23434175 |author1-link=American Academy of Hospice and Palliative Medicine}}, which cites

• {{cite journal |vauthors=Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G |date=May 2012 |title=ABH gel is not absorbed from the skin of normal volunteers |journal=Journal of Pain and Symptom Management |volume=43 |issue=5 |pages=961–6 |doi=10.1016/j.jpainsymman.2011.05.017 |pmid=22560361 |doi-access=free}}
• {{cite journal |vauthors=Weschules DJ |date=December 2005 |title=Tolerability of the compound ABHR in hospice patients |journal=Journal of Palliative Medicine |volume=8 |issue=6 |pages=1135–43 |doi=10.1089/jpm.2005.8.1135 |pmid=16351526}}

Diphenhydramine is one of the most commonly misused over-the-counter drugs in the United States.{{cite book |vauthors=Huynh DA, Abbas M, Dabaja A |title=Diphenhydramine Toxicity |year=2021 |pmid=32491510}} Overdose symptoms may include {{cite encyclopedia |title=Diphenhydramine overdose |encyclopedia=MedlinePlus Medical Encyclopedia |publisher=U.S. National Library of Medicine |url=https://www.nlm.nih.gov/medlineplus/ency/article/002636.htm |url-status=live |archive-url=https://web.archive.org/web/20130530074604/http://www.nlm.nih.gov/medlineplus/ency/article/002636.htm |archive-date=30 May 2013}}

{{div col|colwidth=18em}}

• Abdominal pain
• Abnormal speech (inaudibility, forced speech, etc.)
• Acute megacolon
• Anxiety/nervousness
• Coma
• Delirium
• Disorientation
• Dissociation
• Dysphoria
• Extreme drowsiness
• Flushed skin
• Hallucinations (auditory, visual, tactile, etc.)
• Heart palpitations
• Inability to urinate
• Motor disturbances
• Muscle spasms
• Seizures
• Severe dizziness
• Severe mouth and throat dryness
• Tremors
• Vomiting

{{div col end}}

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. Diagnosis of toxicity is based on history and clinical presentation, and in general precise plasma levels do not appear to provide useful relevant clinical information.{{cite book |vauthors=Manning B |veditors=Olson K |title=Poisoning & Drug Overdose |edition=6th |year=2012 |publisher=McGraw-Hill |isbn=978-0-07-166833-0 |chapter=Chapter 18. Antihistamines |chapter-url=http://www.accessmedicine.com/content.aspx?aID=55974020. |access-date=19 March 2013}} 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.{{cite journal |vauthors=Khalifa M, Drolet B, Daleau P, Lefez C, Gilbert M, Plante S, O'Hara GE, Gleeton O, Hamelin BA, Turgeon J |title=Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=288 |issue=2 |pages=858–65 |date=February 1999 |doi=10.1016/S0022-3565(24)38031-0 |pmid=9918600}}

No specific antidote for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia. Benzodiazepines may be administered to decrease the likelihood of psychosis, agitation, and seizures in people who are prone to these symptoms.{{cite journal |vauthors=Cole JB, Stellpflug SJ, Gross EA, Smith SW |title=Wide complex tachycardia in a pediatric diphenhydramine overdose treated with sodium bicarbonate |journal=Pediatric Emergency Care |volume=27 |issue=12 |pages=1175–7 |date=December 2011 |pmid=22158278 |doi=10.1097/PEC.0b013e31823b0e47 |s2cid=5602304}}

Alcohol may increase the drowsiness caused by diphenhydramine.{{cite web |title=Diphenhydramine and Alcohol / Food Interactions |publisher=Drugs.com |url=https://www.drugs.com/food-interactions/diphenhydramine.html |url-status=live |archive-url=https://web.archive.org/web/20130217152320/http://www.drugs.com/food-interactions/diphenhydramine.html |archive-date=17 February 2013}}{{cite journal |vauthors=Zimatkin SM, Anichtchik OV |title=Alcohol-histamine interactions |journal=Alcohol and Alcoholism |volume=34 |issue=2 |pages=141–7 |year=1999 |pmid=10344773 |doi=10.1093/alcalc/34.2.141 |doi-access=free}}

Diphenhydramine, while traditionally known as an antagonist, acts primarily as an inverse agonist of the histamine H₁ receptor.{{cite journal |vauthors=Khilnani G, Khilnani AK |title=Inverse agonism and its therapeutic significance |journal=Indian Journal of Pharmacology |volume=43 |issue=5 |pages=492–501 |date=September 2011 |pmid=22021988 |doi=10.4103/0253-7613.84947 |doi-access=free |pmc=3195115}} It is a member of the ethanolamine class of antihistaminergic agents.{{cite book |vauthors=Brunton L, Chabner B, Knollmann B |veditors=Brunton L |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=12e |year=2011 |publisher=McGraw Hill |isbn=978-0-07-162442-8 |pages=242–245 |chapter=Chapter 32. Histamine, Bradykinin, and Their Antagonists}} By reversing the effects of histamine on the capillaries, it can reduce the intensity of allergic symptoms. It also crosses the blood–brain barrier and inversely agonizes the H₁ receptors centrally. Its effects on central H₁ receptors cause drowsiness.

Diphenhydramine is a potent antimuscarinic (a competitive antagonist of muscarinic acetylcholine receptors) and, as such, at high doses can cause anticholinergic syndrome.{{cite web |vauthors=Lopez AM |title=Antihistamine Toxicity |publisher=WebMD LLC |work=Medscape Reference |date=10 May 2010 |url=http://emedicine.medscape.com/article/812828-overview |url-status=live |archive-url=https://web.archive.org/web/20101013230957/http://emedicine.medscape.com/article/812828-overview |archive-date=13 October 2010}} The utility of diphenhydramine as an antiparkinson agent is the result of its blocking properties on the muscarinic acetylcholine receptors in the brain.

Diphenhydramine also acts as an intracellular sodium channel blocker, which is responsible for its actions as a local anesthetic.{{cite journal |vauthors=Kim YS, Shin YK, Lee C, Song J |title=Block of sodium currents in rat dorsal root ganglion neurons by diphenhydramine |journal=Brain Research |volume=881 |issue=2 |pages=190–8 |date=October 2000 |pmid=11036158 |doi=10.1016/S0006-8993(00)02860-2 |s2cid=18560451}} Diphenhydramine has also been shown to inhibit the reuptake of serotonin. It has been shown to be a potentiator of analgesia induced by morphine, but not by endogenous opioids, in rats.{{cite journal |vauthors=Carr KD, Hiller JM, Simon EJ |title=Diphenhydramine potentiates narcotic but not endogenous opioid analgesia |journal=Neuropeptides |volume=5 |issue=4–6 |pages=411–4 |date=February 1985 |pmid=2860599 |doi=10.1016/0143-4179(85)90041-1 |s2cid=45054719}} The drug has also been found to act as an inhibitor of histamine N-methyltransferase (HNMT).{{cite journal |vauthors=Horton JR, Sawada K, Nishibori M, Cheng X |title=Structural basis for inhibition of histamine N-methyltransferase by diverse drugs |journal=Journal of Molecular Biology |volume=353 |issue=2 |pages=334–344 |date=October 2005 |pmid=16168438 |doi=10.1016/j.jmb.2005.08.040 |pmc=4021489}}{{cite journal |vauthors=Taylor KM, Snyder SH |title=Histamine methyltransferase: inhibition and potentiation by antihistamines |journal=Molecular Pharmacology |volume=8 |issue=3 |pages=300–10 |date=May 1972 |doi=10.1016/S0026-895X(25)12747-8 |pmid=4402747}}

Oral bioavailability of diphenhydramine is in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration.{{cite journal |vauthors=Paton DM, Webster DR |title=Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines) |journal=Clinical Pharmacokinetics |volume=10 |issue=6 |pages=477–97 |year=1985 |pmid=2866055 |doi=10.2165/00003088-198510060-00002 |s2cid=33541001}} Diphenhydramine, available in various salt forms,{{cite journal |vauthors=Wang C, Paul S, Wang K, Hu S, Sun CC |date=2017 |title=Relationships among Crystal Structures, Mechanical Properties, and Tableting Performance Probed Using Four Salts of Diphenhydramine |journal=Crystal Growth & Design |volume=17 |issue=11 |pages=6030–6040 |doi=10.1021/acs.cgd.7b01153|bibcode=2017CrGrD..17.6030W }} such as citrate,{{cite journal |vauthors=Rao DD, Venkat Rao P, Sait SS, Mukkanti K, Chakole D |date=2009 |title=Simultaneous Determination of Ibuprofen and Diphenhydramine Citrate in Tablets by Validated LC |journal=Chromatographia |volume=69 |issue=9–10 |pages=1133–1136 |doi=10.1365/s10337-009-0977-3 |s2cid=97766056}}{{cite journal |vauthors=Rao DD, Sait SS, Mukkanti K |date=April 2011 |title=Development and validation of an UPLC method for rapid determination of ibuprofen and diphenhydramine citrate in the presence of impurities in combined dosage form |journal=Journal of Chromatographic Science |volume=49 |issue=4 |pages=281–286 |doi=10.1093/chrsci/49.4.281 |pmid=21439118}} hydrochloride,{{cite journal |vauthors=Chan CY, Wallander KA |date=February 1991 |title=Diphenhydramine toxicity in three children with varicella-zoster infection |journal=DICP |volume=25 |issue=2 |pages=130–132 |doi=10.1177/106002809102500204 |pmid=2058184 |s2cid=45456788}} and salicylate,{{cite journal |vauthors=Kamijo Y, Soma K, Sato C, Kurihara K |date=November 2008 |title=Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support |journal=Clinical Toxicology |volume=46 |issue=9 |pages=864–868 |doi=10.1080/15563650802116151 |pmid=18608279 |s2cid=43642257}} exhibits distinct molecular weights and pharmacokinetic properties. Specifically, diphenhydramine hydrochloride and diphenhydramine citrate possess molecular weights of {{val|291.8|u=g/mol}}{{cite web |title=Diphenhydramine Hydrochloride |url=https://pubchem.ncbi.nlm.nih.gov/compound/8980 |work=PubChem |publisher=U.S. National Library of Medicine}} and {{val|447.5|u=g/mol}},{{cite web |title=Diphenhydramine citrate |url=https://pubchem.ncbi.nlm.nih.gov/compound/174697 |work=PubChem |publisher=U.S. National Library of Medicine}} respectively. These variations in molecular weight influence the dissolution rates and absorption characteristics of each salt form.{{cite web |date=28 August 2023 |title=Diphenhydramine Hydrochloride vs Citrate: What's the difference? |url=https://www.drugs.com/medical-answers/difference-between-diphenhydramine-hydrochloride-3510045/ |work=drugs.com |vauthors=Pope C}}

The primary route of metabolism is two successive demethylations of the tertiary amine. The resulting primary amine is further oxidized to the carboxylic acid. Diphenhydramine is metabolized by the cytochrome P450 enzymes CYP2D6, CYP1A2, CYP2C9, and CYP2C19.{{cite journal |vauthors=Krystal AD |title=A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice |journal=Sleep Med Rev |volume=13 |issue=4 |pages=265–74 |date=August 2009 |pmid=19153052 |doi=10.1016/j.smrv.2008.08.001}}

The elimination half-life of diphenhydramine has not been fully elucidated, but appears to range between 2.4 and 9.3 hours in healthy adults.{{cite book |title=AHFS Drug Information |year=1990 |publisher=Published by authority of the Board of Directors of the American Society of Hospital Pharmacists |url=https://books.google.com/books?id=WR0NAQAAMAAJ |access-date=9 October 2017 |url-status=live |archive-url=https://web.archive.org/web/20230114195325/https://books.google.com/books?id=WR0NAQAAMAAJ |archive-date=14 January 2023}} A 1985 review of antihistamine pharmacokinetics found that the elimination half-life of diphenhydramine ranged between 3.4 and 9.3 hours across five studies, with a median elimination half-life of 4.3 hours. A subsequent 1990 study found that the elimination half-life of diphenhydramine was 5.4 hours in children, 9.2 hours in young adults, and 13.5 hours in the elderly.{{cite journal |vauthors=Simons KJ, Watson WT, Martin TJ, Chen XY, Simons FE |title=Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children |journal=Journal of Clinical Pharmacology |volume=30 |issue=7 |pages=665–71 |date=July 1990 |pmid=2391399 |doi=10.1002/j.1552-4604.1990.tb01871.x |s2cid=25452263}} A 1998 study found a half-life of 4.1 ± 0.3 hours in young men, 7.4 ± 3.0 hours in elderly men, 4.4 ± 0.3 hours in young women, and 4.9 ± 0.6 hours in elderly women.{{cite journal |vauthors=Scavone JM, Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI |title=Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers |journal=J Clin Pharmacol |volume=38 |issue=7 |pages=603–9 |date=July 1998 |pmid=9702844 |doi=10.1002/j.1552-4604.1998.tb04466.x |s2cid=24989721}} In a 2018 study in children and adolescents, the half-life of diphenhydramine was 8 to 9 hours.{{cite journal |vauthors=Gelotte CK, Zimmerman BA, Thompson GA |title=Single-Dose Pharmacokinetic Study of Diphenhydramine HCl in Children and Adolescents |journal=Clin Pharmacol Drug Dev |volume=7 |issue=4 |pages=400–407 |date=May 2018 |pmid=28967696 |doi=10.1002/cpdd.391 |pmc=5947143}}

Diphenhydramine can be quantified in blood, plasma, or serum.{{cite book |veditors=Smith RK, Bogusz MJ |vauthors=Pragst F |title=Forensic Science (Handbook of Analytical Separations) |edition=2nd |publisher=Elsevier Science |location=Amsterdam |year=2007 |isbn=978-0-444-52214-6 |page=471 |chapter=Chapter 13: High performance liquid chromatography in forensic toxicological analysis |volume=6}} Gas chromatography with mass spectrometry (GC-MS) can be used with electron ionization on full scan mode as a screening test. GC-MS or GC-NDP can be used for quantification. Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for people having ingested diphenhydramine.{{cite journal |vauthors=Rogers SC, Pruitt CW, Crouch DJ, Caravati EM |title=Rapid urine drug screens: diphenhydramine and methadone cross-reactivity |journal=Pediatric Emergency Care |volume=26 |issue=9 |pages=665–6 |date=September 2010 |pmid=20838187 |doi=10.1097/PEC.0b013e3181f05443 |s2cid=31581678}} 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.

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.{{cite news | vauthors = Hevesi D |date=29 September 2007 |title=George Rieveschl, 91, Allergy Reliever, Dies |url=https://www.nytimes.com/2007/09/29/business/29rieveschl.html |work=The New York Times}} Huber first synthesized diphenhydramine. Rieveschl then worked with Parke-Davis to test the compound, and the company licensed the patent from him.{{cite book |last=Sneader |first=Walter |url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA405 |title=Drug Discovery: A History |date=23 June 2005 |publisher=John Wiley & Sons |isbn=978-0-471-89979-2 |page=405}} In 1946, it became the first prescription antihistamine in the United States approved by the FDA.{{cite web |vauthors=Ritchie J |title=UC prof, Benadryl inventor dies |date=24 September 2007 |publisher=Business Courier of Cincinnati |url=http://www.bizjournals.com/cincinnati/stories/2007/09/24/daily52.html |access-date=14 October 2008 |url-status=live |archive-url=https://web.archive.org/web/20081224055505/http://www.bizjournals.com/cincinnati/stories/2007/09/24/daily52.html |archive-date=24 December 2008}}

In the 1960s, diphenhydramine was found to weakly inhibit reuptake of the neurotransmitter serotonin. 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).{{cite journal |vauthors=Domino EF |title=History of modern psychopharmacology: a personal view with an emphasis on antidepressants |journal=Psychosomatic Medicine |volume=61 |issue=5 |pages=591–8 |year=1999 |pmid=10511010 |doi=10.1097/00006842-199909000-00002}}{{cite journal |vauthors=Awdishn RA, Whitmill M, Coba V, Killu K |title=Serotonin reuptake inhibition by diphenhydramine and concomitant linezolid use can result in serotonin syndrome |journal=Chest |date=October 2008 |volume=134 |issue=4 Meeting abstracts |pages=4C |doi=10.1378/chest.134.4_MeetingAbstracts.c4002 |url=http://journal.publications.chestnet.org/article.aspx?articleid=1094281 |access-date=19 March 2013 |url-status=live |archive-url=https://web.archive.org/web/20160311054736/http://journal.publications.chestnet.org/article.aspx?articleid=1094281 |archive-date=11 March 2016}} A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.{{cite book |vauthors=Barondes SH |year=2003 |title=Better Than Prozac |pages=[https://archive.org/details/betterthanprozac00baro/page/39 39–40] |location=New York |publisher=Oxford University Press |isbn=978-0-19-515130-5 |url=https://archive.org/details/betterthanprozac00baro/page/39 |url-access=registration}}

In 1975, diphenhydramine was still available only by prescription in the US and required medical supervision.{{cite news |date=2 December 1975 |title=FDA Orders Sominex 2 Withdrawn From Market |work=Richmond Times-Dispatch |volume=125 |issue=336 |page=2 |via=Newspapers.com |url=https://www.newspapers.com/image/829865821/ |access-date=16 April 2024}}

Diphenhydramine is sold under the brand name Benadryl by McNeil Consumer Healthcare in the US, UK, Canada, and South Africa.{{cite web |title=Childrens Benadryl Allergy (solution) Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division |website=Drugs.com |url=https://www.drugs.com/otc/110643/childrens-benadryl-allergy.html |access-date=26 November 2019 |url-status=live |archive-url=https://web.archive.org/web/20200729221548/https://www.drugs.com/otc/110643/childrens-benadryl-allergy.html |archive-date=29 July 2020}} Trade names in other countries include Dimedrol, Daedalon, Nytol, and Vivinox. It is also available as a generic medication.

Procter & Gamble markets an over-the-counter formulation of diphenhydramine as a sleep aid under the brand ZzzQuil.{{cite news |title=Is P&G Preparing to Expand ZzzQuil? |url=https://adage.com/article/cmo-strategy/p-g-preparing-expansion-zzzquil/293998 |access-date=10 February 2017 |url-status=live |archive-url=https://web.archive.org/web/20170211081209/http://adage.com/article/cmo-strategy/p-g-preparing-expansion-zzzquil/293998/ |archive-date=11 February 2017}}

Prestige Brands markets an over-the-counter formulation of diphenhydramine as a sleep aid in the US under the name Sominex.{{cite book |date=January 2023 |title=Mother To Baby {{!}} Fact Sheets [Internet] |chapter=Diphenhydramine |publisher=National Library of Medicine |pmid=35951938 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK582675/ |access-date=16 April 2024}}

Diphenhydramine is deemed to have limited abuse potential in the United States owing to its potentially serious side-effect profile and limited euphoric effects and is not a controlled substance. Since 2002, the US FDA has required special labeling warning against the use of multiple products that contain diphenhydramine.{{cite journal |author=Food and Drug Administration, HHS |title=Labeling of diphenhydramine-containing drug products for over-the-counter human use. Final rule |journal=Federal Register |volume=67 |issue=235 |pages=72555–9 |date=December 2002 |pmid=12474879 |url=https://www.fda.gov/OHRMS/DOCKETS/98fr/120602a.htm |url-status=live |archive-url=https://web.archive.org/web/20081105004602/https://www.fda.gov/OHRMS/DOCKETS/98fr/120602a.htm |archive-date=5 November 2008}} 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.{{cite journal |vauthors=Marinetti L, Lehman L, Casto B, Harshbarger K, Kubiczek P, Davis J |title=Over-the-counter cold medications-postmortem findings in infants and the relationship to cause of death |journal=Journal of Analytical Toxicology |volume=29 |issue=7 |pages=738–43 |date=October 2005 |pmid=16419411 |doi=10.1093/jat/29.7.738 |doi-access=free}}{{cite book |vauthors=Baselt RC |title=Disposition of Toxic Drugs and Chemicals in Man |publisher=Biomedical Publications |year=2008 |pages=489–492 |isbn=978-0-9626523-7-0}}

Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia,{{cite web |format=DOC |title=List of prohibited and controlled drugs according to chapter 96 of the laws of Zambia |publisher=The Drug Enforcement Commission ZAMBIA |url=http://www.gctrips.org/documents/IllegaldrugsinZambia.docx |access-date=20 March 2013 |url-status=dead |archive-url=https://web.archive.org/web/20131116010729/http://www.gctrips.org/documents/IllegaldrugsinZambia.docx |archive-date=16 November 2013}} and travelers are advised not to bring the drug into the country. Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing diphenhydramine.{{cite web |title=Zambia |work=Country Information > Zambia |publisher=Bureau of Consular Affairs, U.S. Department of State |url=https://travel.state.gov/content/passports/english/country/zambia.html |access-date=17 July 2015 |url-status=live |archive-url=https://web.archive.org/web/20150721232323/http://travel.state.gov/content/passports/english/country/zambia.html |archive-date=21 July 2015}}

Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases of abuse and addiction have been documented.{{cite journal |vauthors=Thomas A, Nallur DG, Jones N, Deslandes PN |title=Diphenhydramine abuse and detoxification: a brief review and case report |journal=Journal of Psychopharmacology |volume=23 |issue=1 |pages=101–5 |date=January 2009 |pmid=18308811 |doi=10.1177/0269881107083809 |s2cid=45490366}} Because the drug is cheap and sold over the counter in most countries, adolescents without access to more sought-after illicit drugs are particularly at risk.{{cite web |title=Atypical Drugs of Abuse |vauthors=Forest E |date=27 July 2008 |work=Articles & Interviews |publisher=Student Doctor Network |url=https://www.studentdoctor.net/2008/07/26/atypical-drugs-of-abuse/ |url-status=live |archive-url=https://web.archive.org/web/20130527231559/http://studentdoctor.net/2008/07/atypical-drugs-of-abuse/ |archive-date=27 May 2013}} 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.{{cite journal |vauthors=Halpert AG, Olmstead MC, Beninger RJ |title=Mechanisms and abuse liability of the anti-histamine dimenhydrinate |journal=Neuroscience and Biobehavioral Reviews |volume=26 |issue=1 |pages=61–7 |date=January 2002 |pmid=11835984 |doi=10.1016/s0149-7634(01)00038-0 |s2cid=46619422 |url=http://www.queensu.ca/psychology/sites/webpublish.queensu.ca.psycwww/files/files/Faculty/Richard%20Beninger/Beninger_prp_25.pdf |access-date=23 December 2017 |url-status=dead |archive-url=https://web.archive.org/web/20200802230007/https://www.queensu.ca/psychology/sites/webpublish.queensu.ca.psycwww/files/files/Faculty/Richard%20Beninger/Beninger_prp_25.pdf |archive-date=2 August 2020}}

Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug.{{cite journal |vauthors=Gracious B, Abe N, Sundberg J |title=The importance of taking a history of over-the-counter medication use: a brief review and case illustration of "PRN" antihistamine dependence in a hospitalized adolescent |journal=Journal of Child and Adolescent Psychopharmacology |volume=20 |issue=6 |pages=521–4 |date=December 2010 |pmid=21186972 |doi=10.1089/cap.2010.0031 |pmc=3025184}} Research has shown that antimuscarinic agents, including diphenhydramine, "may have antidepressant and mood-elevating properties".{{cite journal |vauthors=Dilsaver SC |title=Antimuscarinic agents as substances of abuse: a review |journal=Journal of Clinical Psychopharmacology |volume=8 |issue=1 |pages=14–22 |date=February 1988 |pmid=3280616 |doi=10.1097/00004714-198802000-00003 |s2cid=31355546}} A study conducted on adult males with a history of sedative abuse found that subjects who were administered a high dose (400 mg) of diphenhydramine reported a desire to take the drug again, despite also reporting negative effects, such as difficulty concentrating, confusion, tremors, and blurred vision.{{cite journal |vauthors=Mumford GK, Silverman K, Griffiths RR |title=Reinforcing, subjective, and performance effects of lorazepam and diphenhydramine in humans |journal=Experimental and Clinical Psychopharmacology |date=1996 |volume=4 |issue=4 |pages=421–430 |doi=10.1037/1064-1297.4.4.421}}

In 2020, an Internet challenge emerged on the social media platform TikTok involving deliberately overdosing on diphenhydramine; dubbed the Benadryl challenge, the challenge encourages participants to consume dangerous amounts of Benadryl to film the resultant psychoactive effects and has been implicated in several hospitalisations{{cite web |title=TikTok Videos Encourage Viewers to Overdose on Benadryl |website=TikTok Videos Encourage Viewers to Overdose on Benadryl |url=https://www.checkupnewsroom.com/tiktok-videos-encourage-viewers-to-overdose-on-benadryl/ |access-date=9 October 2020 |url-status=live |archive-url=https://web.archive.org/web/20201008114600/https://www.checkupnewsroom.com/tiktok-videos-encourage-viewers-to-overdose-on-benadryl/ |archive-date=8 October 2020}} and at least two deaths.{{cite web |date=28 August 2020 |title=Dangerous 'Benadryl Challenge' on Tik Tok may be to blame for the death of Oklahoma teen |website=KFOR.com Oklahoma City |url=https://kfor.com/news/local/dangerous-benadryl-challenge-on-tik-tok-blamed-for-the-death-of-oklahoma-teen/ |access-date=9 October 2020 |url-status=live |archive-url=https://web.archive.org/web/20210802073032/https://kfor.com/news/local/dangerous-benadryl-challenge-on-tik-tok-blamed-for-the-death-of-oklahoma-teen/ |archive-date=2 August 2021}}{{cite web |date=25 September 2020 |title=Teen's Death Prompts Warning on 'Benadryl Challenge' |website=medpagetoday.com |url=https://www.medpagetoday.com/pediatrics/generalpediatrics/88816 |access-date=9 October 2020 |url-status=live |archive-url=https://web.archive.org/web/20200929121653/https://www.medpagetoday.com/pediatrics/generalpediatrics/88816 |archive-date=29 September 2020}}{{cite web |date=23 April 2023 |title=What is the Benadryl challenge? New TikTok challenge that's left 13-year-old dead |website=The Independent |url=https://www.independent.co.uk/news/long_reads/world/tiktok-benadryl-challenge-death-13-year-old-b2325133.html |access-date=23 April 2023}}

{{Reflist}}

{{Refbegin}}

• {{cite journal |vauthors=Björnsdóttir I, Einarson TR, Gudmundsson LS, Einarsdóttir RA |title=Efficacy of diphenhydramine against cough in humans: a review |journal=Pharmacy World & Science |volume=29 |issue=6 |pages=577–83 |date=December 2007 |pmid=17486423 |doi=10.1007/s11096-007-9122-2 |s2cid=8168920}}
• {{cite journal |vauthors=Cox D, Ahmed Z, McBride AJ |title=Diphenhydramine dependence |journal=Addiction |volume=96 |issue=3 |pages=516–7 |date=March 2001 |pmid=11310441}}
• {{cite journal |vauthors=Lieberman JA |title=History of the use of antidepressants in primary care |journal=Primary Care Companion J. Clinical Psychiatry |volume=5 |issue=supplement 7 |pages=6–10 |year=2003 |url=http://www.psychiatrist.com/pcc/pccpdf/v05s07/v05s0702.pdf |access-date=19 March 2013 |url-status=dead |archive-url=https://web.archive.org/web/20140611094425/http://www.psychiatrist.com/pcc/pccpdf/v05s07/v05s0702.pdf |archive-date=11 June 2014}}

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