Diphenhydramine

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Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particularly at higher doses. This may manifest as agitation, anxiety, or restlessness rather than sedation.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Dead linkTemplate:Cbignore</ref><ref>Template:Cite journal</ref> It is a 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.<ref>Template:Cite book</ref> It is mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremors in parkinsonism, and nausea.<ref name=AHSP2016/> It is taken by mouth, injected into a vein, injected into a muscle, or 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include sleepiness, poor coordination, and an upset stomach.<ref name=AHSP2016/> There is no clear risk of harm when used during pregnancy; however, use during breastfeeding is not recommended.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

It was developed by George Rieveschl and put into commercial use in 1946.<ref>Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is available as a generic medication.<ref name=AHSP2016/> In 2022, it was the 258th most commonly prescribed medication in the United States, with more than 1Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Its sedative and deliriant effects have led to some cases of recreational use.<ref name="Thomas2008"/><ref name="Saran2017">Template:Cite journal</ref>

Medical uses

File:Benadryl tablets (4438315926).jpg

Diphenhydramine tablets

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.<ref name="AHFS_monograph">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Brown_2012">Template:Cite journal</ref> Diphenhydramine also has local anesthetic properties, and has been used as such in people allergic to common local anesthetics such as lidocaine.<ref name="pmid10456039">Template:Cite journal</ref>

Allergies

Diphenhydramine is effective in the treatment of allergies.<ref name=AHSF2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:As of, it was the most commonly used antihistamine for acute allergic reactions in the emergency department.<ref name=2007rev>Template:Cite journal</ref>

By injection, it is often used in addition to epinephrine for anaphylaxis,<ref name="Current EM">Template:Cite book</ref> although Template:As of its use for this purpose had not been properly studied.<ref name=Cochrane2007rev>Template:Cite journal</ref> Its use is only recommended once acute symptoms have improved.<ref name=AHSF2016/>

File:Benadryl Itch Stopping Gel (4600729217).jpg

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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Movement disorders

Diphenhydramine is used to treat akathisia and parkinsonism caused by antipsychotics.<ref name="Katzung Basic Ch28">Template:Cite book</ref> It is also used to treat acute dystonia, including torticollis and oculogyric crisis caused by 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 paracetamol (acetaminophen) in Tylenol PM and ibuprofen in Advil PM. Diphenhydramine can cause minor psychological dependence.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Diphenhydramine has also been used as an anxiolytic.<ref name="Dinndroff_1998">Template:Cite journal</ref>

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.<ref>Template:Cite newsTemplate: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>Template:Cite news</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 Hospital argued, in a 2009 article, "Using a medication for your convenience is never an indication for medication in a child."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="pmid27998379">Template:Cite journal</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">Template:Cite journal</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 the recommended doses, it can cause nausea (especially above 200 mg).<ref>Template:Cite journal</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" /> Diphenhydramine is not approved by the US Food and Drug Administration (FDA) for treating anxiety.<ref name="drugs" /> 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.<ref> "Hydroxyzine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 21 November 2018. </ref> 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.<ref name="pmid17451451">Template:Cite journal</ref><ref name="Gua2013">Template:Cite journal</ref>

Contraindications

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.<ref>Template:Cite book</ref>

Adverse effects

The most prominent side effects are dizziness and sleepiness.<ref name="diph effects" />

Diphenhydramine is a potent anticholinergic agent and a 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.<ref name="diph effects">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Diphenhydramine in overdose may occasionally result in QT prolongation.<ref>Template:Cite book</ref>

Some individuals experience an allergic reaction to diphenhydramine in the form of hives.<ref name="pmid9007386">Template:Cite journal</ref><ref name="pmid6219138">Template:Cite journal</ref>

Conditions such as restlessness or akathisia can worsen from increased levels of diphenhydramine, especially with recreational dosages.<ref name="pmid18227744">Template:Cite journal</ref> Normal doses of diphenhydramine, like other first-generation antihistamines, can also make symptoms of restless legs syndrome worse.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref> Drowsiness, memory loss, confusion, dry mouth or constipation may also occur in elderly people.<ref name="drugs">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Special populations

Diphenhydramine is secreted in breast milk.<ref name="pmid11456429">Template:Cite journal</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 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.<ref name="pmid30000938">Template:Cite journal</ref>

Paradoxical reactions 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">Template:Citation, which cites

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Overdose

Diphenhydramine is one of the most commonly misused over-the-counter drugs in the United States.<ref name="pmid32491510">Template:Cite book</ref> Overdose symptoms may include<ref name="urlDiphenhydramine overdose: MedlinePlus Medical Encyclopedia">Template:Cite encyclopedia</ref>

• 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

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">Template:Cite book</ref> 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.<ref>Template:Cite journal</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"/> Benzodiazepines may be administered to decrease the likelihood of psychosis, agitation, and seizures in people who are prone to these symptoms.<ref>Template:Cite journal</ref>

Interactions

Alcohol may increase the drowsiness caused by diphenhydramine.<ref name="urlDiphenhydramine and Alcohol / Food Interactions - Drugs.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid10344773">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

citation

CitationClass=web }}</ref>
Site	Ki (nM)	Species	Ref
Template:Abbrlink	3800+	Human	<ref name="pmid9537821">Template:Cite journal</ref><ref name="pmid23357028">Template:Cite journal</ref>
Template:Abbrlink	960–2400	Human	<ref name="pmid9537821"/><ref name="pmid23357028"/>
Template:Abbrlink	1100–2200	Human	<ref name="pmid9537821"/><ref name="pmid23357028"/>
5-HT2C	780	Human	<ref name="pmid23357028"/>
α1B	1300	Human	<ref name="pmid23357028"/>
α2A	2900	Human	<ref name="pmid23357028"/>
α2B	1600	Human	<ref name="pmid23357028"/>
α2C	2100	Human	<ref name="pmid23357028"/>
D2	20000	Rat	<ref name="pmid1361536">Template:Cite journal</ref>
H1	9.6–16	Human	<ref name="pmid">Template:Cite journal</ref><ref name="pmid23357028"/>
H2	100000+	Canine	<ref name="pmid1703298">Template:Cite journal</ref>
H3	10000+	Human	<ref name="pmid23357028"/><ref name="pmid10347254">Template:Cite journal</ref><ref name="pmid11179434">Template:Cite journal</ref>
H4	10000+	Human	<ref name="pmid11179434"/>
M1	80–100	Human	<ref name="pmid1346637">Template:Cite journal</ref><ref name="pmid23357028"/>
M2	120–490	Human	<ref name="pmid1346637"/><ref name="pmid23357028"/>
M3	84–229	Human	<ref name="pmid1346637"/><ref name="pmid23357028"/>
M4	53–112	Human	<ref name="pmid1346637"/><ref name="pmid23357028"/>
M5	30–260	Human	<ref name="pmid1346637"/><ref name="pmid23357028"/>
Template:Abbrlink	48000–86000	Rat	<ref name="pmid11036158"/>
Template:Abbrlink	27100 (Template:Abbrlink)	Human	<ref name="pmid8641472">Template:Cite journal</ref>
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Diphenhydramine, while traditionally known as an antagonist, acts primarily as an inverse agonist of the histamine H₁ receptor.<ref name="pmid22021988">Template:Cite journal</ref> It is a member of the ethanolamine class of antihistaminergic agents.<ref name="Goodman">Template:Cite book</ref> 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.<ref name="pmid22021988"/> 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.<ref name="urlAntihistamine Toxicity">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="pmid11036158">Template:Cite journal</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 opioids, in rats.<ref name="pmid2860599">Template:Cite journal</ref> The drug has also been found to act as an inhibitor of histamine N-methyltransferase (HNMT).<ref name="pmid16168438">Template:Cite journal</ref><ref name="pmid4402747">Template:Cite journal</ref>

Overview of diphenhydramine targets and effects

Biological target	Mode of action	Effect
H1 receptor	Inverse agonist	Allergy reduction; Sedation
[[Muscarinic acetylcholine receptor|Template:Abbr receptor]]s	Antagonist	Anticholinergic; Antiparkinson
Sodium channels	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">Template:Cite journal</ref> Diphenhydramine, available in various salt forms,<ref>Template:Cite journal</ref> such as citrate,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> hydrochloride,<ref>Template:Cite journal</ref> and salicylate,<ref>Template:Cite journal</ref> exhibits distinct molecular weights and pharmacokinetic properties. Specifically, diphenhydramine hydrochloride and diphenhydramine citrate possess molecular weights of Template:Val<ref name="pubchem8980">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and Template:Val,<ref name="pubchem174697">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> respectively. These variations in molecular weight influence the dissolution rates and absorption characteristics of each salt form.<ref name="salts-drugs-com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The primary route of metabolism is two successive demethylations 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 enzymes CYP2D6, CYP1A2, CYP2C9, and CYP2C19.<ref name="pmid19153052">Template:Cite journal</ref>

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.<ref name="AHFS">Template:Cite book</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">Template:Cite journal</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">Template:Cite journal</ref> In a 2018 study in children and adolescents, the half-life of diphenhydramine was 8 to 9 hours.<ref name="pmid28967696">Template:Cite journal</ref>

Chemistry

Detection in body fluids

Diphenhydramine can be quantified in blood, plasma, or serum.<ref name="Analytical Separation Handbook">Template:Cite book</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">Template:Cite journal</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"/>

History

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.<ref name=":4">Template:Cite news</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">Template:Cite book</ref> In 1946, it became the first prescription antihistamine in the United States approved by the FDA.<ref name="BC">{{#invoke:citation/CS1|citation |CitationClass=web }}</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 antidepressants with similar structures and fewer side effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI).<ref name="Domino_1999">Template:Cite journal</ref><ref name="url_Adawi_Awdish">Template:Cite journal</ref> A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.<ref name="Barondes">Template:Cite book</ref>

In 1975, diphenhydramine was still available only by prescription in the US and required medical supervision.<ref>Template:Cite news</ref>

Society and culture

Marketing

Diphenhydramine is sold under the brand name Benadryl by McNeil Consumer Healthcare in the US, UK, Canada, and South Africa.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 sleep aid under the brand ZzzQuil.<ref>Template:Cite news</ref>

Prestige Brands markets an over-the-counter formulation of diphenhydramine as a sleep aid in the US under the name Sominex.<ref>Template:Cite book</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 US FDA has required special labeling warning against the use of multiple products that contain diphenhydramine.<ref>Template:Cite journal</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">Template:Cite journal</ref><ref name="isbn0-9626523-7-7">Template:Cite book</ref>

Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Recreational use

Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases of abuse and addiction have been documented.<ref name="Thomas2008">Template:Cite journal</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">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Halpert2002">Template:Cite journal</ref>

Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug.<ref name="Halpert2002"/><ref>Template:Cite journal</ref> Research has shown that antimuscarinic agents, including diphenhydramine, "may have antidepressant and mood-elevating properties".<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and at least two deaths.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> An entity reported to have been seen by people while under the effects of diphenhydramine, known as the "Hat Man", has become an Internet meme and an urban legend.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite magazine</ref>

Further reading

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