Diphenhydramine: Difference between revisions

{{Short description|Antihistamine medication}}

{{Distinguish|dimenhydrinate}}

{{CS1 config|name-list-style=vanc|display-authors=6}}

{{Use dmy dates|date=May 2024}}

{{Infobox drug

| verifiedrevid = 460791686

| image = Diphenhydramine 2D skeletal.svg

| alt =

| caption =

| image2 = Diphenhydramine 3D 2aot.png

| alt2 =

| pronounce = {{IPAc-en|ˌ|d|aɪ|f|ɛ|n|ˈ|h|aɪ|d|r|ə|m|iː|n}}

| tradename = [[Benadryl]], Unisom, [[Nytol]], others

| DailyMedID = Diphenhydramine

| pregnancy_AU_comment =

| pregnancy_category =

| dependency_liability = Low<ref>{{cite book |vauthors=Hubbard JR, Martin PR |title=Substance Abuse in the Mentally and Physically Disabled |date=2001 |publisher=CRC Press |isbn=978-0-8247-4497-7 |page=26 |url=https://books.google.com/books?id=MY1kFYk98mQC&pg=PA26}}</ref><ref name="Saran2017"/>

| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection|intramuscular]], [[intravenous therapy|intravenous]], [[topical medication|topical]], [[rectal administration|rectal]]

| class = [[First-generation antihistamine]], [[antimuscarinic]], [[hallucinogen]] ([[deliriant]])

| ATC_supplemental = {{ATC|D04|AA33}}, {{ATC|R06|AA02}}

| legal_AU = S4

| legal_AU_comment = /{{nbsp}}S2 (Pharmacy Medicine) / S3 (Pharmacist Only Medicine)

| legal_CA = OTC

| legal_UK = P

| legal_UK_comment = <ref>{{cite web |title=Benylin Chesty Coughs (Original) - Summary of Product Characteristics (SmPC) |website=(emc) |date=24 February 2022 |url=https://www.medicines.org.uk/emc/product/1476/smpc |access-date=29 December 2022 |url-status=live |archive-url=https://web.archive.org/web/20221230073626/https://www.medicines.org.uk/emc/product/1476/smpc |archive-date=30 December 2022}}</ref>

| legal_US = OTC

| legal_US_comment = /{{nbsp}}Rx-only<ref>{{cite web |title=Diphenhydramine- diphenhydramine hydrochloride injection, solution |website=DailyMed |date=11 November 2019 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=921b9f64-1096-46db-866a-67f0f9ff6790 |access-date=18 May 2024}}</ref>

| legal_UN = Unscheduled

| legal_status =

| bioavailability = 40–60%<ref name="pmid2866055"/>

| protein_bound = 98–99%

| metabolism = [[Liver]] ([[CYP2D6]], others)<ref name="pmid19153052"/><ref name="DrugBank">{{cite web |title=Showing Diphenhydramine (DB01075) |publisher=DrugBank |url=http://www.drugbank.ca/drugs/DB01075 |access-date=5 September 2009 |url-status=live |archive-url=https://web.archive.org/web/20090831145953/http://drugbank.ca/drugs/DB01075 |archive-date=31 August 2009}}</ref>

| elimination_half-life = Range: 2.4–13.5&nbsp;[[hour|h]]<ref name="AHFS"/><ref name="pmid2866055"/><ref name="pmid2391399"/>

| excretion = [[Urine]]: 94%<ref name="pmid3962845">{{cite journal |vauthors=Garnett WR |title=Diphenhydramine |journal=American Pharmacy |volume=NS26 |issue=2 |pages=35–40 |date=February 1986 |pmid=3962845 |doi=10.1016/s0095-9561(16)38634-0}}</ref><br/>[[Feces]]: 6%<ref name="pmid3962845"/>

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 58-73-1

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| IUPAC_name = 2-(diphenylmethoxy)-''N'',''N''-dimethylethanamine

| C = 17

| H = 21

| N = 1

| O = 1

| SMILES = O(CCN(C)C)C(c1ccccc1)c2ccccc2

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

'''Diphenhydramine''' ('''DPH''') is an [[antihistamine]] and [[sedative]] first developed by [[George Rieveschl]] and put into commercial use in 1946.<ref>{{cite book |vauthors=Dörwald FZ |title=Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds |date=2013 |publisher=John Wiley & Sons |isbn=978-3-527-64565-7 |page=225 |url=https://books.google.com/books?id=YTeY9ZEfNccC&pg=PA225 |url-status=live |archive-url=https://web.archive.org/web/20161002085621/https://books.google.ca/books?id=YTeY9ZEfNccC&pg=PA225 |archive-date=2 October 2016}}</ref><ref>{{cite web |title=Benadryl |website=Ohio History Central |url=http://ohiohistorycentral.org/w/Benadryl?rec=2591 |access-date=28 September 2016 |url-status=live |archive-url=https://web.archive.org/web/20161017192649/http://ohiohistorycentral.org/w/Benadryl?rec=2591 |archive-date=17 October 2016}}</ref> it is available as a [[generic medication]],<ref name=AHSP2016/> and also sold under the brand name '''[[Benadryl]]''', among others.<ref name=AHSP2016/> In 2021, it was the 242nd most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web |title=The Top 300 of 2021 |website=ClinCalc |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |access-date=14 January 2024 |url-status=live |archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx |archive-date=15 January 2024}}</ref><ref>{{cite web |title=Diphenhydramine - Drug Usage Statistics |website=ClinCalc |url=https://clincalc.com/DrugStats/Drugs/Diphenhydramine |access-date=14 January 2024}}</ref>

It is a [[H1 antagonist#First-generation (non-selective, classical)|first-generation H₁-antihistamine]] and it works by blocking certain effects of [[histamine]], which produces its antihistamine and sedative effects.<ref name=AHSP2016/><ref name="Saran2017"/> Diphenhydramine is also a potent [[anticholinergic]], which means it also works as a [[deliriant]] at much higher than recommended doses as a result.<ref>{{cite book |vauthors=Ayd FJ |title=Lexicon of Psychiatry, Neurology, and the Neurosciences |date=2000 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2468-5 |page=332 |url=https://books.google.com/books?id=ea_QVG2BFy8C&pg=PA332 |url-status=live |archive-url=https://web.archive.org/web/20170908214041/https://books.google.ca/books?id=ea_QVG2BFy8C&pg=PA332 |archive-date=8 September 2017}}</ref>

It is mainly used to treat [[allergy|allergies]], [[insomnia]], and symptoms of the [[common cold]]. It is also less commonly used for [[tremor]]s in [[parkinsonism]], and [[nausea]].<ref name=AHSP2016/> It is taken [[oral administration|by mouth]], [[injection into a vein|injected into a vein]], [[injection into a muscle|injected into a muscle]], or [[topical medication|applied to the skin]].<ref name=AHSP2016/> Maximal effect is typically around two hours after a dose, and effects can last for up to seven hours.<ref name=AHSP2016>{{cite web |title=Diphenhydramine Hydrochloride |website=Drugs.com |publisher=American Society of Health-System Pharmacists |date=6 September 2016 |url=https://www.drugs.com/monograph/diphenhydramine-hydrochloride.html |access-date=28 September 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}}</ref>

Common side effects include sleepiness, poor coordination, and upset stomach.<ref name=AHSP2016/> Its use is not recommended in young children or the elderly.<ref name=AHSP2016/><ref name=schroeck2016>{{cite journal |vauthors=Schroeck JL, Ford J, Conway EL, Kurtzhalts KE, Gee ME, Vollmer KA, Mergenhagen KA |title=Review of Safety and Efficacy of Sleep Medicines in Older Adults |journal=Clinical Therapeutics |volume=38 |issue=11 |pages=2340–2372 |date=November 2016 |pmid=27751669 |doi=10.1016/j.clinthera.2016.09.010 |doi-access=free}}</ref> There is no clear risk of harm when used during [[pregnancy]]; however, use during [[breastfeeding]] is not recommended.<ref>{{cite web |title=Diphenhydramine Pregnancy and Breastfeeding Warnings |website=Drugs.com |url=https://www.drugs.com/pregnancy/diphenhydramine.html |access-date=28 September 2016 |url-status=live |archive-url=https://web.archive.org/web/20161002114958/https://www.drugs.com/pregnancy/diphenhydramine.html |archive-date=2 October 2016}}</ref>

Its [[sedative]] and [[deliriant]] effects have led to some cases of [[recreational drug use|recreational use]].<ref name="Thomas2008"/><ref name="Saran2017">{{cite journal |vauthors=Saran JS, Barbano RL, Schult R, Wiegand TJ, Selioutski O |title=Chronic diphenhydramine abuse and withdrawal: A diagnostic challenge |journal=Neurology. Clinical Practice |volume=7 |issue=5 |pages=439–441 |date=October 2017 |pmid=29620065 |doi=10.1212/CPJ.0000000000000304 |pmc=5874453}}</ref>

== History ==

In 1943, diphenhydramine was discovered by chemist [[George Rieveschl]] and one of his students, Fred Huber, while they were conducting research into [[Muscle relaxant|muscle relaxants]] at the [[University of Cincinnati]].<ref name=":4">{{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}}</ref> Huber first synthesized diphenhydramine. Rieveschl then worked with [[Parke-Davis]] to test the compound, and the company licensed the patent from him.<ref name="HistDD">{{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}}</ref> In 1946, it became the first prescription antihistamine approved by the U.S. FDA.<ref name="BC">{{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}}</ref>

In the 1960s, diphenhydramine was found to weakly inhibit [[reuptake]] of the [[neurotransmitter]] [[serotonin]].<ref name="Domino_1999"/> This discovery led to a search for viable [[antidepressant]]s with similar structures and fewer side effects, culminating in the invention of [[fluoxetine]] (Prozac), a [[selective serotonin reuptake inhibitor]] (SSRI).<ref name="Domino_1999">{{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}}</ref><ref name="url_Adawi_Awdish">{{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}}</ref> A similar search had previously led to the synthesis of the first SSRI, [[zimelidine]], from [[brompheniramine]], also an antihistamine.<ref name="Barondes">{{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}}</ref>

In 1975, diphenhydramine was still available only by prescription in the U.S. and required medical supervision.<ref>{{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}}</ref>

[[File:Benadryl tablets (4438315926).jpg|thumb|left|Diphenhydramine tablets]]

Diphenhydramine is a first-generation antihistamine used to treat a number of conditions including [[allergic]] symptoms and [[pruritus|itchiness]], the [[common cold]], [[insomnia]], [[motion sickness]], and [[extrapyramidal symptoms]].<ref name="AHFS_monograph">{{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}}</ref><ref name="Brown_2012">{{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}}</ref> Diphenhydramine also has [[local anesthetic]] properties, and has been used as such in people allergic to common [[local anesthetic]]s such as [[lidocaine]].<ref name="pmid10456039">{{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}}</ref>

===Allergies===

Diphenhydramine is effective in treatment of allergies.<ref name=AHSF2016>{{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}}</ref> {{As of|2007}}, it was the most commonly used antihistamine for acute allergic reactions in the emergency department.<ref name=2007rev>{{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}}</ref>

By injection it is often used in addition to [[epinephrine (medication)|epinephrine]] for [[anaphylaxis]],<ref name="Current EM">{{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}}</ref> although {{as of|2007|lc=y}} its use for this purpose had not been properly studied.<ref name=Cochrane2007rev>{{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}}</ref> Its use is only recommended once acute symptoms have improved.<ref name=AHSF2016/>

[[File:Benadryl Itch Stopping Gel (4600729217).jpg|thumb|left|A bottle of topical "Itch-Stopping Gel" diphenhydramine]]

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.<ref>{{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}}</ref>

===Movement disorders===

Diphenhydramine is used to treat [[akathisia]] and [[parkinsonism]] caused by [[antipsychotic]]s.<ref name="Katzung Basic Ch28">{{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}}</ref> It is also used to treat acute [[dystonia]] including [[torticollis]] and [[oculogyric crisis]] caused by [[Typical antipsychotic|typical antipsychotics]].

===Sleep===

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 [[acetaminophen]] (paracetamol) in [[Tylenol PM]] and [[ibuprofen]] in [[Advil PM]]. Diphenhydramine can cause minor psychological dependence.<ref>{{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}}</ref> Diphenhydramine has also been used as an [[anxiolytic]].<ref name="Dinndroff_1998">{{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}}</ref>

Diphenhydramine has also been used off-prescription by parents in an attempt to make their children sleep and to sedate them on long-distance flights.<ref>{{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}}</ref> 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,<ref>{{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}}</ref> 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|Seattle Children's hospital]] argued, in a 2009 article, "Using a medication for your convenience is never an indication for medication in a child."<ref>{{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}}</ref>

The [[American Academy of Sleep Medicine]]'s 2017 [[clinical practice guideline]]s recommended against the use of diphenhydramine in the treatment of insomnia, because of poor effectiveness and low [[quality of evidence]].<ref name="pmid27998379">{{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}}</ref> 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.<ref name="pmid35843245">{{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}}</ref>

===Nausea===

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&nbsp;mg).<ref>{{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}}</ref>

===Special populations===

Diphenhydramine is not recommended for people older than 60 and children younger than six, unless a physician is consulted.<ref name=AHSP2016/><ref name=schroeck2016/><ref name="Physicians Desk">{{cite book |author=Medical Economics |title=Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 2000 |edition=21st |publisher=Medical Economics Company |location=Montvale, NJ |year=2000 |isbn=978-1-56363-341-6}}</ref> These people should be treated with second-generation antihistamines, such as [[loratadine]], [[desloratadine]], [[fexofenadine]], [[cetirizine]], [[levocetirizine]], and [[azelastine]].<ref name="Goodman"/> Because of its strong [[anticholinergic]] effects, diphenhydramine is on the [[Beers Criteria|Beers list]] of drugs to avoid in the elderly.<ref name="urlwww.ncqa.org">{{cite web |title=High risk medications as specified by NCQA's HEDIS Measure: Use of High Risk Medications in the Elderly |publisher=National Committee for Quality Assurance (NCQA) |url=http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf |url-status=dead |archive-url=https://web.archive.org/web/20100201113909/http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf |archive-date=1 February 2010}}</ref><ref>{{cite web |title=2012 AGS Beers List |website=The American Geriatrics Society |url=http://www.americangeriatrics.org/files/documents/beers/2012AGSBeersCriteriaCitations.pdf |access-date=27 November 2015 |url-status=dead |archive-url=https://web.archive.org/web/20120812232804/http://www.americangeriatrics.org/files/documents/beers/2012AGSBeersCriteriaCitations.pdf |archive-date=12 August 2012}}</ref>

Diphenhydramine is excreted in breast milk.<ref name="pmid11456429">{{cite journal |vauthors=Spencer JP, Gonzalez LS, Barnhart DJ |title=Medications in the breast-feeding mother |journal=American Family Physician |volume=64 |issue=1 |pages=119–26 |date=July 2001 |pmid=11456429}}</ref> 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 drug]]s, such as pseudoephedrine, or before the establishment of lactation. A single bedtime dose after the last feeding of the day may minimize harmful effects of the medication on the baby and on the milk supply. Still, non-sedating antihistamines are preferred.<ref name="pmid30000938">{{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}}</ref>

[[Paradoxical reaction]]s to diphenhydramine have been documented, particularly in children, and it may cause excitation instead of sedation.<ref name="pmid18227744"/>

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.<ref name="AAHPMfive">{{citation |author1=American Academy of Hospice and Palliative Medicine |author1-link=American Academy of Hospice and Palliative Medicine |title=Five Things Physicians and Patients Should Question |publisher=[[American Academy of Hospice and Palliative Medicine]] |work=[[Choosing Wisely]]: an initiative of the [[ABIM Foundation]] |date=2013 |volume=45 |issue=3 |pages=595–605 |pmid=23434175 |doi=10.1016/j.jpainsymman.2012.12.002 |url=https://aahpm.org/uploads/about/3.6.1._AAHPM_5_Things_-_Choosing_Wisely.pdf |access-date=17 May 2024 |url-status=live |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}}, which cites

* {{cite journal |vauthors=Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G |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 |date=May 2012 |pmid=22560361 |doi=10.1016/j.jpainsymman.2011.05.017 |doi-access=free}}

* {{cite journal |vauthors=Weschules DJ |title=Tolerability of the compound ABHR in hospice patients |journal=Journal of Palliative Medicine |volume=8 |issue=6 |pages=1135–43 |date=December 2005 |pmid=16351526 |doi=10.1089/jpm.2005.8.1135}}</ref>

There were no documented cases of clinically apparent acute liver injury caused by normal doses of diphenhydramine.<ref name="pmid31643789">{{cite book |chapter=Diphenhydramine |title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. |year=2012 |location=Bethesda (MD) |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |pmid=31643789 |url=https://www.ncbi.nlm.nih.gov/books/NBK548470/ |access-date=21 June 2021 |url-status=live |archive-url=https://web.archive.org/web/20210729103723/https://www.ncbi.nlm.nih.gov/books/NBK548470/ |archive-date=29 July 2021}}</ref>

===Anxiety===

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.<ref name=drugs/> Benadryl is not approved by the US [[Food and Drug Administration]] for treating anxiety.<ref name=drugs/>

==Adverse effects==

The most prominent side effects are dizziness and sleepiness.<ref name="diph effects"/> A typical dose creates driving impairment equivalent to a [[blood alcohol content|blood-alcohol level]] of 0.10, which is higher than the 0.08 limit of most drunk-driving laws.<ref name=2007rev/>

Diphenhydramine is a potent [[anticholinergic]] agent and potential [[deliriant]] in higher doses. This activity is responsible for the [[adverse drug reaction|side effects]] of dry mouth and throat, [[tachycardia|increased heart rate]], [[mydriasis|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, [[amnesia|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.<ref name="diph effects">{{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}}</ref> Diphenhydramine in overdose may occasionally result in [[QT prolongation]].<ref>{{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}}</ref>

Some individuals experience an [[allergic reaction]] to diphenhydramine in the form of [[hives]].<ref name="pmid9007386">{{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}}</ref><ref name="pmid6219138">{{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}}</ref>

Conditions such as [[psychomotor agitation|restlessness]] or [[akathisia]] can worsen from increased levels of diphenhydramine, especially with recreational dosages.<ref name="pmid18227744">{{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}}</ref> Normal doses of diphenhydramine, like other [[H1 antagonist#First-generation (non-selective)|first generation antihistamines]], can also make symptoms of [[restless legs syndrome]] worse.<ref>{{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}}</ref>

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.<ref>{{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}}</ref> Drowsiness, memory loss, confusion, dry mouth or constipation may also occur in elderly people.<ref name="drugs">{{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}}</ref>

==Contraindications==

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

==Overdose==

Diphenhydramine is one of the most commonly misused over-the-counter drugs in the United States.<ref name="pmid32491510">{{cite book |vauthors=Huynh DA, Abbas M, Dabaja A |title=Diphenhydramine Toxicity |year=2021 |pmid=32491510}}</ref> In cases of extreme overdose, if not treated in time, acute diphenhydramine poisoning may have serious and potentially fatal consequences. Overdose symptoms may include:<ref name="urlDiphenhydramine overdose: MedlinePlus Medical Encyclopedia">{{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}}</ref>

{{div col|colwidth=18em}}

* Abdominal pain

* Abnormal speech (inaudibility, forced speech, etc.)

* Acute [[megacolon]]

* [[Anxiety]]/nervousness

* Coma

* [[Delirium]]

* [[Disorientation]]

* [[Dissociation (psychology)|Dissociation]]

* [[Euphoria]] or [[dysphoria]]

* Extreme drowsiness

* Flushed skin

* [[Hallucination]]s (auditory, visual, tactile, etc.)

* Heart palpitations

* Inability to urinate

* Motor disturbances

* Muscle spasms

* [[Seizures]]

* Severe dizziness

* Severe [[Xerostomia|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.<ref name="Goodman"/> 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.<ref name="Poisoning&Overdoses">{{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}}</ref> Several levels of evidence strongly indicate diphenhydramine (similar to [[chlorpheniramine]]) can block the [[voltage-gated potassium channel|delayed rectifier]] [[potassium channel]] and, as a consequence, prolong the [[QT interval]], leading to [[cardiac arrhythmia]]s such as ''[[torsades de pointes]]''.<ref>{{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 |pmid=9918600}}</ref>

No specific [[antidote]] for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated with [[physostigmine]] for severe delirium or tachycardia.<ref name="Poisoning&Overdoses"/> [[Benzodiazepine]]s may be administered to decrease the likelihood of [[psychosis]], [[psychomotor agitation|agitation]], and [[seizure]]s in people who are prone to these symptoms.<ref>{{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}}</ref>

==Interactions==

[[Ethanol|Alcohol]] may increase the drowsiness caused by diphenhydramine.<ref name="urlDiphenhydramine and Alcohol / Food Interactions - Drugs.com">{{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}}</ref><ref name="pmid10344773">{{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}}</ref>

==Pharmacology==

===Pharmacodynamics===

{| class="wikitable floatright" style="font-size:small;"

|+ <br/>Diphenhydramine<ref name="PDSP">{{cite web |title=PDSP K_i Database |work=Psychoactive Drug Screening Program (PDSP) |vauthors=Roth BL, Driscol J |author1-link=Bryan Roth |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |url=https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=diphenhydramine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query |access-date=14 August 2017 |url-status=live |archive-url=https://web.archive.org/web/20190420130325/https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=diphenhydramine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query |archive-date=20 April 2019}}</ref>

|-

! Site !! K_i (nM) !! Species !! Ref

|-

| {{abbrlink|SERT|Serotonin transporter}} || ≥3,800 || Human || <ref name="pmid9537821">{{cite journal |vauthors=Tatsumi M, Groshan K, Blakely RD, Richelson E |title=Pharmacological profile of antidepressants and related compounds at human monoamine transporters |journal=European Journal of Pharmacology |volume=340 |issue=2–3 |pages=249–58 |date=December 1997 |pmid=9537821 |doi=10.1016/s0014-2999(97)01393-9}}</ref><ref name="pmid23357028">{{cite journal |vauthors=Krystal AD, Richelson E, Roth T |title=Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications |journal=Sleep Medicine Reviews |volume=17 |issue=4 |pages=263–72 |date=August 2013 |pmid=23357028 |doi=10.1016/j.smrv.2012.08.001}}</ref>

|-

| {{abbrlink|NET|Norepinephrine transporter}} || 960–2,400 || Human || <ref name="pmid9537821"/><ref name="pmid23357028"/>

|-

| {{abbrlink|DAT|Dopamine transporter}} || 1,100–2,200 || Human || <ref name="pmid9537821"/><ref name="pmid23357028"/>

|-

| [[5-HT2C receptor|5-HT_2C]] || 780 || Human || <ref name="pmid23357028"/>

|-

| [[Alpha-1B adrenergic receptor|α_1B]] || 1,300 || Human || <ref name="pmid23357028"/>

|-

| [[Alpha-2A adrenergic receptor|α_2A]] || 2,900 || Human || <ref name="pmid23357028"/>

|-

| [[Alpha-2B adrenergic receptor|α_2B]] || 1,600 || Human || <ref name="pmid23357028"/>

|-

| [[Alpha-2C adrenergic receptor|α_2C]] || 2,100 || Human || <ref name="pmid23357028"/>

|-

| [[D2 receptor|D₂]] || 20,000 || Rat || <ref name="pmid1361536">{{cite journal |vauthors=Tsuchihashi H, Sasaki T, Kojima S, Nagatomo T |title=Binding of [3H]haloperidol to dopamine D2 receptors in the rat striatum |journal=J. Pharm. Pharmacol. |volume=44 |issue=11 |pages=911–4 |year=1992 |pmid=1361536 |doi=10.1111/j.2042-7158.1992.tb03235.x |s2cid=19420332}}</ref>

|-

| [[Histamine H1 receptor|H₁]] || 9.6–16 || Human || <ref name="pmid">{{cite journal |vauthors=Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG |title=Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes |journal=Bioorganic & Medicinal Chemistry |volume=14 |issue=19 |pages=6640–58 |date=October 2006 |pmid=16782354 |doi=10.1016/j.bmc.2006.05.077}}</ref><ref name="pmid23357028"/>

|-

| [[Histamine H2 receptor|H₂]] || >100,000 || Canine || <ref name="pmid1703298">{{cite journal |vauthors=Gantz I, Schäffer M, DelValle J, Logsdon C, Campbell V, Uhler M, Yamada T |title=Molecular cloning of a gene encoding the histamine H2 receptor |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue=2 |pages=429–33 |year=1991 |bibcode=1991PNAS...88..429G |pmid=1703298 |doi=10.1073/pnas.88.2.429 |doi-access=free |pmc=50824}}</ref>

|-

|[[Histamine H3 receptor|H₃]] || >10,000 || Human || <ref name="pmid23357028"/><ref name="pmid10347254">{{cite journal |vauthors=Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG |title=Cloning and functional expression of the human histamine H3 receptor |journal=Molecular Pharmacology |volume=55 |issue=6 |pages=1101–7 |date=June 1999 |pmid=10347254 |doi=10.1124/mol.55.6.1101 |s2cid=25542667}}</ref><ref name="pmid11179434">{{cite journal |vauthors=Liu C, Ma X, Jiang X, Wilson SJ, Hofstra CL, Blevitt J, Pyati J, Li X, Chai W, Carruthers N, Lovenberg TW |title=Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow |journal=Molecular Pharmacology |volume=59 |issue=3 |pages=420–6 |date=March 2001 |pmid=11179434 |doi=10.1124/mol.59.3.420 |s2cid=123619}}</ref>

|-

| [[Histamine H4 receptor|H₄]] || >10,000 || Human || <ref name="pmid11179434"/>

|-

| [[Muscarinic acetylcholine receptor M1|M₁]] || 80–100 || Human || <ref name="pmid1346637">{{cite journal |vauthors=Bolden C, Cusack B, Richelson E |title=Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=260 |issue=2 |pages=576–80 |date=February 1992 |pmid=1346637}}</ref><ref name="pmid23357028"/>

|-

| [[Muscarinic acetylcholine receptor M2|M₂]] || 120–490 || Human || <ref name="pmid1346637"/><ref name="pmid23357028"/>

|-

| [[Muscarinic acetylcholine receptor M3|M₃]] || 84–229 || Human || <ref name="pmid1346637"/><ref name="pmid23357028"/>

|-

| [[Muscarinic acetylcholine receptor M4|M₄]] || 53–112 || Human || <ref name="pmid1346637"/><ref name="pmid23357028"/>

|-

| [[Muscarinic acetylcholine receptor M5|M₅]] || 30–260 || Human || <ref name="pmid1346637"/><ref name="pmid23357028"/>

|-

| {{abbrlink|VGSC|Voltage-dependent sodium channel}} || 48,000–86,000 || Rat || <ref name="pmid11036158"/>

|-

| {{abbrlink|hERG|Human Ether-à-go-go-Related Gene}} || 27,100 ({{abbrlink|IC₅₀|Half-maximal inhibitory concentration}}) || Human || <ref name="pmid8641472">{{cite journal |vauthors=Suessbrich H, Waldegger S, Lang F, Busch AE |title=Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole |journal=FEBS Letters |volume=385 |issue=1–2 |pages=77–80 |date=April 1996 |bibcode=1996FEBSL.385...77S |pmid=8641472 |doi=10.1016/0014-5793(96)00355-9 |doi-access=free |s2cid=40355762}}</ref>

|- class="sortbottom"

| colspan="4" style="width: 1px;" |Values are K_i (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

|}

Diphenhydramine, available in various salt forms,<ref>{{cite journal | vauthors = Wang C, Paul S, Wang K, Hu S, Sun CC |title=Relationships among Crystal Structures, Mechanical Properties, and Tableting Performance Probed Using Four Salts of Diphenhydramine |date=2017 |journal=Crystal Growth & Design |volume=17 |issue=11 |pages=6030–6040 |doi=10.1021/acs.cgd.7b01153}}</ref> such as citrate,<ref>{{cite journal | vauthors = Rao DD, Venkat Rao P, Sait SS, Mukkanti K, Chakole D |title=Simultaneous Determination of Ibuprofen and Diphenhydramine Citrate in Tablets by Validated LC |date=2009 |journal=Chromatographia |volume=69 |issue=9–10 |pages=1133–1136 |doi=10.1365/s10337-009-0977-3 |s2cid=97766056}}</ref><ref>{{cite journal | vauthors = Rao DD, Sait SS, Mukkanti K | 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 | date = April 2011 | pmid = 21439118 | doi = 10.1093/chrsci/49.4.281 }}</ref> hydrochloride,<ref>{{cite journal | vauthors = Chan CY, Wallander KA | title = Diphenhydramine toxicity in three children with varicella-zoster infection | journal = DICP| volume = 25 | issue = 2 | pages = 130–132 | date = February 1991 | pmid = 2058184 | doi = 10.1177/106002809102500204 | s2cid = 45456788 }}</ref> and salicylate,<ref>{{cite journal | vauthors = Kamijo Y, Soma K, Sato C, Kurihara K | 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 | date = November 2008 | pmid = 18608279 | doi = 10.1080/15563650802116151 | s2cid = 43642257 }}</ref> exhibits distinct molecular weights and pharmacokinetic properties. Specifically, diphenhydramine hydrochloride and diphenhydramine citrate possess molecular weights of {{val|291.8|u=g/mol}}<ref name="pubchem8980">{{cite web |title=Diphenhydramine Hydrochloride |work=PubChem |publisher=U.S. National Library of Medicine |url=https://pubchem.ncbi.nlm.nih.gov/compound/8980}}</ref> and {{val|447.5|u=g/mol}},<ref name="pubchem174697">{{cite web |title=Diphenhydramine citrate |work=PubChem |publisher=U.S. National Library of Medicine |url=https://pubchem.ncbi.nlm.nih.gov/compound/174697}}</ref> respectively. These variations in molecular weight influence the dissolution rates and absorption characteristics of each salt form. Consequently, a dose of 25 mg diphenhydramine hydrochloride is therapeutically equivalent to 38 mg of diphenhydramine citrate. As such, dosage adjustments are necessary to account for these differences when switching between salt forms.<ref name="salts-drugs-com">{{cite web | vauthors = Pope C |date=28 August 2023 |title=Diphenhydramine Hydrochloride vs Citrate: What's the difference? |work=drugs.com |url=https://www.drugs.com/medical-answers/difference-between-diphenhydramine-hydrochloride-3510045/}}</ref>

Diphenhydramine, while traditionally known as an [[receptor antagonist|antagonist]], acts primarily as an [[inverse agonist]] of the [[histamine]] [[histamine H1 receptor|H₁ receptor]].<ref name="pmid22021988">{{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}}</ref> It is a member of the [[ethanolamine]] class of antihistaminergic agents.<ref name="Goodman">{{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}}</ref> By reversing the effects of histamine on the [[capillary|capillaries]], it can reduce the intensity of [[Allergy|allergic symptoms]]. It also crosses the [[blood–brain barrier]] and [[inverse agonist|inversely agonizes]] the H₁ receptors [[central nervous system|centrally]].<ref name="pmid22021988"/> Its effects on central H₁ receptors cause drowsiness.

Diphenhydramine is a potent [[muscarinic antagonist|antimuscarinic]] (a [[competitive antagonist]] of [[muscarinic acetylcholine receptor]]s) and, as such, at high doses can cause [[anticholinergic syndrome]].<ref name="urlAntihistamine Toxicity">{{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}}</ref> The utility of diphenhydramine as an [[management of Parkinson's disease#Medication|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]].<ref name="pmid11036158">{{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}}</ref> Diphenhydramine has also been shown to inhibit the reuptake of [[serotonin]].<ref name="Domino_1999"/> It has been shown to be a [[potentiator]] of [[analgesia]] induced by [[morphine]], but not by [[endogenous opioid]]s, in rats.<ref name="pmid2860599">{{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}}</ref> The drug has also been found to act as an [[enzyme inhibitor|inhibitor]] of [[histamine N-methyltransferase]] (HNMT).<ref name="pmid16168438">{{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}}</ref><ref name="pmid4402747">{{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 |pmid=4402747}}</ref>

{| class="wikitable"

|+ Overview of diphenhydramine targets and effects

|-

! Biological target !! Mode of action !! Effect

|-

| [[Histamine H1 receptor|H₁ receptor]] || [[Inverse agonist]] || [[Antihistamine|Allergy reduction]]; [[Sedative|Sedation]]

|-

| [[Muscarinic acetylcholine receptor|{{abbr|mACh|Muscarinic acetylcholine}} receptor]]s || [[Competitive antagonist|Antagonist]] || [[Anticholinergic syndrome|Anticholinergic]]; [[Management of Parkinson's disease#Medication|Antiparkinson]]

|-

| [[Voltage-gated sodium channel|Sodium channel]]s || [[Ion channel#Ion channel blockers|Blocker]] || [[Local anesthetic]]

|}

===Pharmacokinetics===

Oral [[bioavailability]] of diphenhydramine is in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration.<ref name="pmid2866055">{{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}}</ref>

The primary route of metabolism is two successive [[demethylation]]s of the [[tertiary amine]]. The resulting primary amine is further [[oxidized]] to the [[carboxylic acid]].<ref name="pmid2866055"/> Diphenhydramine is metabolized by the [[cytochrome P450]] [[enzyme]]s [[CYP2D6]], [[CYP1A2]], [[CYP2C9]], and [[CYP2C19]].<ref name="pmid19153052">{{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}}</ref>

The [[elimination half-life]] of diphenhydramine has not been fully elucidated, but appears to range between 2.4 and 9.3&nbsp;hours in healthy adults.<ref name="AHFS">{{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}}</ref> 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.<ref name="pmid2866055"/> 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.<ref name="pmid2391399">{{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}}</ref> 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.<ref name="pmid9702844">{{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}}</ref> In a 2018 study in children and adolescents, the half-life of diphenhydramine was 8 to 9&nbsp;hours.<ref name="pmid28967696">{{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}}</ref>

Diphenhydramine is a [[diphenylmethane]] [[chemical derivative|derivative]]. [[Structural analog|Analogue]]s of diphenhydramine include [[orphenadrine]], an [[anticholinergic]], [[nefopam]], an [[analgesic]], and [[tofenacin]], an [[antidepressant]].

===Detection in body fluids===

Diphenhydramine can be quantified in blood, plasma, or serum.<ref name="Analytical Separation Handbook">{{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}}</ref> [[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.<ref name="Analytical Separation Handbook"/> Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive [[methadone]] results for people having ingested diphenhydramine.<ref name="pmid20838187">{{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}}</ref> 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.<ref name="Analytical Separation Handbook"/>

== Marketing ==

Diphenhydramine is sold under the brand name [[Benadryl]] by [[McNeil Consumer Healthcare]] in the U.S., UK, Canada, and South Africa.<ref>{{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}}</ref> 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 [[hypnotic|sleep aid]] under the brand ZzzQuil.<ref>{{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}}</ref>

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

== Cultural impact ==

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 U.S. FDA has required special labeling warning against use of multiple products that contain diphenhydramine.<ref>{{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}}</ref> 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.<ref name="pmid16419411">{{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}}</ref><ref name="isbn0-9626523-7-7">{{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}}</ref>

Diphenhydramine is among prohibited and controlled substances in the [[Republic of Zambia]],<ref>{{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 <!-- original "http://www.deczambia.gov.zm/listofdrugs.html link" is dead --> |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}}</ref> 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.<ref>{{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}}</ref>

===Recreational use===

Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases of [[substance abuse|abuse]] and [[addiction]] have been documented.<ref name="Thomas2008">{{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}}</ref> 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.<ref name="urlAtypical Drugs of Abuse">{{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}}</ref> People with mental health problems—especially those with [[schizophrenia]]—are also prone to abuse the drug, which is [[self-administration|self-administered]] in large doses to treat [[extrapyramidal symptoms]] caused by the use of [[antipsychotic]]s.<ref name="Halpert2002">{{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}}</ref>

Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug.<ref name="Halpert2002"/><ref>{{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}}</ref> Research has shown that [[muscarinic antagonist|antimuscarinic agents]], including diphenhydramine, "may have antidepressant and mood-elevating properties".<ref>{{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}}</ref> A study conducted on adult males with a history of [[sedative]] abuse found that subjects who were administered a high dose (400&nbsp;mg) of diphenhydramine reported a desire to take the drug again, despite also reporting negative effects, such as difficulty concentrating, confusion, [[tremor]]s, and blurred vision.<ref>{{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}}</ref>

In 2020, an Internet challenge emerged on social media platform [[TikTok]] involving deliberately overdosing on diphenhydramine; dubbed the [[Benadryl challenge]], the challenge encourages participants to consume dangerous amounts of Benadryl for the purpose of filming the resultant psychoactive effects, and has been implicated in several hospitalisations<ref>{{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}}</ref> and at least two deaths.<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref>

==References==

{{Reflist}}

==Further reading==

{{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}}

==External links==

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