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Diphenhydramine (DPH) is an
antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provide ...
and
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...
mainly used to treat
allergies Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
,
insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...
, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
. It is taken
by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
, injected into a vein, injected into a muscle, or applied to the skin. Maximal effect is typically around two hours after a dose, and effects can last for up to seven hours. Common side effects include sleepiness, poor coordination and an upset stomach. Its use is not recommended in young children or the elderly. There is no clear risk of harm when used during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
; however, use during
breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...
is not recommended. It is a first generation H1-antihistamine and ethanolamine and works by blocking certain effects of
histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
, which produces its antihistamine and sedative effects. Diphenhydramine is also a potent
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous syste ...
, which means it also works as a deliriant at higher than recommended doses as a result. Its sedative and deliriant effects have led to some cases of recreational use and
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...
. Diphenhydramine was first made by
George Rieveschl George Rieveschl (January 9, 1916 – September 27, 2007) was an American chemist and professor. He was the inventor of the popular antihistamine diphenhydramine (Benadryl), which he first made during a search for synthetic alternatives to scopol ...
and came into commercial use in 1946. It is available as a generic medication. It is sold under the brand name Benadryl, among others. In 2020, it was the 192nd most commonly prescribed medication in the United States, with more than 2million prescriptions.


Medical uses

Diphenhydramine is a first-generation antihistamine used to treat a number of conditions including allergic symptoms and itchiness, the common cold,
insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...
, motion sickness, and
extrapyramidal symptoms Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...
. Diphenhydramine also has
local anesthetic A local anesthetic (LA) is a medication that causes absence of pain sensation. In the context of surgery, a local anesthetic creates an absence of pain in a specific location of the body without a loss of consciousness, as opposed to a general an ...
properties, and has been used as such in people allergic to common
local anesthetics A local anesthetic (LA) is a medication that causes absence of pain sensation. In the context of surgery, a local anesthetic creates an absence of pain in a specific location of the body without a loss of consciousness, as opposed to a general a ...
such as
lidocaine Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, li ...
.


Allergies

Diphenhydramine is effective in treatment of allergies. , it was the most commonly used antihistamine for acute allergic reactions in the emergency department. By injection it is often used in addition to
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
for
anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...
, although its use for this purpose had not been properly studied. Its use is only recommended once acute symptoms have improved. Topical formulations of diphenhydramine are available, including creams, lotions, gels, and sprays. These are used to relieve itching and have the advantage of causing fewer systemic effects (''e.g.'', drowsiness) than oral forms.


Movement disorders

Diphenhydramine is used to treat akathisia and Parkinson's disease–like
extrapyramidal symptoms Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...
caused by
antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range o ...
s. It is also used to treat acute dystonia including
torticollis Torticollis, also known as wry neck, is a dystonic condition defined by an abnormal, asymmetrical head or neck position, which may be due to a variety of causes. The term ''torticollis'' is derived from the Latin words ''tortus, meaning "twisted ...
and oculogyric crisis caused by first generation antipsychotics.


Sleep

Because of its
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...
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 or
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus ...
in Advil PM. Diphenhydramine can cause minor psychological dependence. Diphenhydramine has also been used as an anxiolytic. Diphenhydramine has also been used off prescription by parents in an attempt to make their children sleep or remain sedated on long-distance flights. This has been met with criticism, both by doctors and members of the airline industry, as sedating young passengers may put them at risk if the flight encounters an emergency and they are unable to react to the situation efficiently, and the drug's side effects, especially the chance of a paradoxical reaction, may result in some individuals becoming hyperactive rather than sedated. The ethics of this use have also been challenged, with the
Seattle Children's hospital Seattle Children's, formerly Children's Hospital and Regional Medical Center, formerly Children's Orthopedic Hospital, is a children's hospital in the Laurelhurst neighborhood of Seattle, Washington. The hospital specializes in the care of infa ...
arguing in a 2009 article that "Using a medication for your convenience is never an indication for medication in a child." The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of diphenhydramine in the treatment of insomnia due to poor effectiveness and low quality of evidence. A major
systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...
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.


Nausea

Diphenhydramine also has
antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. The ...
properties, which make it useful in treating the nausea that occurs in
vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties ...
and motion sickness. However, when taken above recommended doses, it can cause nausea (especially above 200 mg).


Special populations

Diphenhydramine is not recommended for people older than 60 or children under the age of six, unless a physician is consulted. These populations should be treated with second-generation antihistamines such as loratadine,
desloratadine Desloratadine (trade names Clarinex and Aerius) is a tricyclic H1 inverse agonist that is used to treat allergies. It is an active metabolite of loratadine. It was patented in 1984 and came into medical use in 2001. Medical uses Desloratad ...
, fexofenadine, cetirizine, levocetirizine, and azelastine. Due to its strong
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous syste ...
effects, diphenhydramine is on the Beers list of drugs to avoid in the elderly. Diphenhydramine is category B in the FDA Classification of Drug Safety During Pregnancy. It is also excreted in breast milk. It is expected that low doses of diphenhydramine taken occasionally will not cause any adverse effects on breastfed infants. Large doses or 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 any harmful effects of the medication on the baby and on the milk supply. Still, non-sedating antihistamines are the preferred alternative. Paradoxical reactions to diphenhydramine have been documented, in particular among children, and it may cause excitation instead of sedation. Topical diphenhydramine is sometimes used especially for people in hospice. This use is without indication and topical diphenhydramine should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives., which cites * * There were no documented cases of clinically apparent acute liver injury caused by normal doses of diphenhydramine.


Adverse effects

The most prominent side effect is sedation. A typical dose creates driving impairment equivalent to a blood-alcohol level of 0.10, which is higher than the 0.08 limit of most drunk-driving laws. Diphenhydramine is a potent
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous syste ...
agent and potential deliriant in higher doses. This activity is responsible for the side effects of dry mouth and throat, increased heart rate, pupil dilation,
urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of blad ...
, constipation, and, at high doses, hallucinations or
delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...
. Other side effects include motor impairment (
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of t ...
), flushed skin, blurred vision at nearpoint owing to lack of accommodation ( cycloplegia), abnormal sensitivity to bright light (
photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
),
sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ethe ...
, difficulty concentrating, short-term memory loss, visual disturbances, irregular breathing,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical ...
, irritability, itchy skin,
confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"
, increased body temperature (in general, in the hands and/or feet), temporary
erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of ma ...
, and excitability, and although it can be used to treat nausea, higher doses may cause vomiting. Diphenhydramine in overdose may occasionally result in QT prolongation. Some individuals experience an
allergic reaction Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
to diphenhydramine in the form of
hives Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
. Conditions such as restlessness or akathisia can worsen from increased levels of diphenhydramine, especially with recreational dosages. Normal doses of diphenhydramine, like other first generation antihistamines, can also make symptoms of restless legs syndrome worse. As diphenhydramine is extensively metabolized by the
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
, 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.


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 CNS depressants. Monoamine Oxidase inhibitors prolong and intensify the anticholinergic effect of antihistamines.


Overdose

Diphenhydramine is one of the most commonly misused over-the-counter drugs in the United States. In cases of extreme overdose, if not treated in time, acute diphenhydramine poisoning may have serious and potentially fatal consequences. Overdose symptoms may include: *
Euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and dan ...
or dysphoria *
Hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...
s (auditory, visual, tactile, etc.) * Heart palpitations * Extreme drowsiness * Severe dizziness * Abnormal speech (inaudibility, forced speech, etc.) * Flushed skin * Severe mouth and throat dryness * Tremors *
Seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
* Muscle spasms * Inability to urinate *
Vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...
* Acute
megacolon Megacolon is an abnormal dilation of the colon (also called the large intestine). This leads to hypertrophy of the colon. The dilation is often accompanied by a paralysis of the peristaltic movements of the bowel. In more extreme cases, the f ...
* Motor disturbances *
Anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil Turmoil may refer to: * ''Turmoil'' (1984 video game), a 1984 video game released by Bug-Byte * ''Turmoil'' (2016 video game), a 2016 indie oil tycoon video ...
/nervousness * Disorientation *
Disassociation Dissociation, as a concept that has been developed over time, is a wide array of experiences, ranging from a mild emotional detachment from the immediate surroundings, to a more severe disconnection from physical and emotional experiences. The ...
* Abdominal pain *
Delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...
* Coma * Death Acute poisoning can be fatal, leading to cardiovascular collapse and death in 2–18 hours, and in general is treated using a symptomatic and supportive approach. Diagnosis of toxicity is based on history and clinical presentation, and in general specific levels are not useful. 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 arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the Cardiac cycle, heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per mi ...
s such as ''
torsades de pointes ''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia ...
''. No specific
antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...
for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia. Benzodiazepines may be administered to decrease the likelihood of
psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
, agitation, and
seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
in people who are prone to these symptoms.


Interactions

Alcohol may increase the drowsiness caused by diphenhydramine.


Pharmacology


Pharmacodynamics

Diphenhydramine, while traditionally known as an antagonist, acts primarily as an inverse agonist of the
histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
H1 receptor. It is a member of the ethanolamine class of antihistaminergic agents. By reversing the effects of histamine on the
capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
, it can reduce the intensity of allergic symptoms. It also crosses the blood–brain barrier and inversely agonizes the H1 receptors centrally. Its effects on central H1 receptors cause drowsiness. Like many other first-generation antihistamines, diphenhydramine is also a potent
antimuscarinic A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of th ...
(a competitive antagonist of
muscarinic acetylcholine receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several r ...
s) and, as such, at high doses can cause anticholinergic syndrome. The utility of diphenhydramine as an
antiparkinson In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutri ...
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 A local anesthetic (LA) is a medication that causes absence of pain sensation. In the context of surgery, a local anesthetic creates an absence of pain in a specific location of the body without a loss of consciousness, as opposed to a general an ...
. Diphenhydramine has also been shown to inhibit the reuptake of serotonin. It has been shown to be a potentiator of
analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...
induced by
morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. Ther ...
, but not by endogenous opioids, in rats. The drug has also been found to act as an
inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...
of histamine N-methyltransferase (HNMT).


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. The primary route of metabolism is two successive
demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...
s of the tertiary amine. The resulting primary amine is further oxidized to the
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
. Diphenhydramine is metabolized by the
cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s
CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...
, CYP1A2, CYP2C9, and CYP2C19. 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. A 1985 review of antihistamine pharmacokinetics found that the elimination half-life of diphenhydramine ranged between 3.4 and 9.3 hours across five studies, with a median elimination half-life of 4.3 hours. A subsequent 1990 study found that the elimination half-life of diphenhydramine was 5.4 hours in children, 9.2 hours in young adults, and 13.5 hours in the elderly. 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. In a 2018 study in children and adolescents, the half-life of diphenhydramine was 8 to 9 hours.


Chemistry

Diphenhydramine is a diphenylmethane
derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...
. Analogues of diphenhydramine include orphenadrine, an
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous syste ...
, nefopam, an
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
, and tofenacin, an
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...
.


Detection in body fluids

Diphenhydramine can be quantified in blood, plasma, or serum. Gas chromatography with
mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a '' mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is u ...
(GC-MS) can be used with electron ionization on full scan mode as a screening test. GC-MS or GC-NDP can be used for quantification. Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive
methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to hero ...
results for people having ingested diphenhydramine. 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.


History

Diphenhydramine was discovered in 1943 by
George Rieveschl George Rieveschl (January 9, 1916 – September 27, 2007) was an American chemist and professor. He was the inventor of the popular antihistamine diphenhydramine (Benadryl), which he first made during a search for synthetic alternatives to scopol ...
, a former professor at the
University of Cincinnati The University of Cincinnati (UC or Cincinnati) is a public research university in Cincinnati, Ohio. Founded in 1819 as Cincinnati College, it is the oldest institution of higher education in Cincinnati and has an annual enrollment of over 44,00 ...
. In 1946, it became the first prescription antihistamine approved by the U.S. FDA. In the 1960s, diphenhydramine was found to weakly inhibit
reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of trans ...
of the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
serotonin. This discovery led to a search for viable
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...
s with similar structures and fewer side effects, culminating in the invention of
fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
(Prozac), a
selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellul ...
(SSRI). A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.


Society and culture

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. 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. Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia, 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.


Recreational use

Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases of
abuse Abuse is the improper usage or treatment of a thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, crimes, or other t ...
and
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...
have been documented. 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. People with mental health problems—especially those with
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
—are also prone to abuse the drug, which is self-administered in large doses to treat
extrapyramidal symptoms Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...
caused by the use of
antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range o ...
s. Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug. Research has shown that antimuscarinic agents, including diphenhydramine, "may have antidepressant and mood-elevating properties". A study conducted on adult males with a history of
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...
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. In 2020, an Internet challenge emerged on social media platform
TikTok TikTok, known in China as Douyin (), is a short-form video hosting service owned by the Chinese company ByteDance. It hosts user-submitted videos, which can range in duration from 15 seconds to 10 minutes. TikTok is an international version ...
involving deliberately overdosing on diphenhydramine; dubbed the
Benadryl challenge The Benadryl challenge is an Internet challenge which emerged in 2020, and revolves around the deliberate consumption, excessive use and overdose of the antihistamine medicine diphenhydramine (commonly sold in the United States under the brand n ...
, 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 and at least one death.


Names

Diphenhydramine is marketed under the trade name Benadryl by McNeil Consumer Healthcare in the U.S., Canada, and South Africa. Trade names in other countries include Dimedrol, Daedalon, and Nytol. It is also available as a generic medication.
Procter & Gamble The Procter & Gamble Company (P&G) is an American multinational consumer goods corporation headquartered in Cincinnati, Ohio, founded in 1837 by William Procter and James Gamble. It specializes in a wide range of personal health/consumer he ...
markets an over-the-counter formulation of diphenhydramine as a sleep aid under the brand ZzzQuil. In 2014 this product had annual sales of over $120 million and had a 29.3% share of the $411 million sleep-aid market category.


Other organisms

Tomato The tomato is the edible berry of the plant ''Solanum lycopersicum'', commonly known as the tomato plant. The species originated in western South America, Mexico, and Central America. The Mexican Nahuatl word gave rise to the Spanish word , ...
es (''Solanum lycopersicum'') have a high uptake of diphenhydramine.


See also

* Tripelennamine


References


Further reading

* * *


External links

* {{Navboxes , title =
Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ( ...
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