Doxylamine, sold under the brand name Unisom among others, 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 provid ...

medication which is used in the treatment of

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

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 dermat ...

. In combination with pyridoxine ( vitamin B₆), it is also used to treat morning sickness in pregnant women. Doxylamine is available

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...

, and is used in nighttime

cold medicine Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ...

s, such as NyQuil, as well as in pain medications containing acetaminophen and codeine, to help with

sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a de ...

. The medication 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 ...

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of doxylamine include

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 c ...

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

grogginess Sleep inertia is a physiological state of impaired cognitive and sensory-motor performance that is present immediately after awakening. It persists during the transition of sleep to wakefulness, where an individual will experience feelings of drows ...

, and

dry mouth Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause. This symptom is very common and is often seen as a side eff ...

, among others. Doxylamine is an

—specifically 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 ...

H₁ receptor—and to a lesser extent 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 sys ...

—specifically an antagonist of the muscarinic acetylcholine receptors M₁ through M₅. It is a first-generation antihistamine and crosses the blood–brain barrier into the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

, thereby producing centrally mediated sedative and hypnotic effects. Doxylamine was first described in 1948 or 1949. Several of the first-generation antihistamines, including doxylamine, are the most widely used sleep medications in the world.

Medical uses

Doxylamine is an antihistamine used to treat

sneezing A sneeze (also known as sternutation) is a semi-autonomous, convulsive expulsion of air from the lungs through the nose and mouth, usually caused by foreign particles irritating the nasal mucosa. A sneeze expels air forcibly from the mouth and ...

, runny nose, watery eyes, hives,

skin rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...

itching Itch (also known as pruritus) is a Wikt:sensation, sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of Sensory system, sensory experience. Itch has many similarities to pain, ...

, and other

cold Cold is the presence of low temperature, especially in the atmosphere. In common usage, cold is often a subjective perception. A lower bound to temperature is absolute zero, defined as 0.00K on the Kelvin scale, an absolute thermodynamic ...

allergy 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 ...

symptoms. It is also used as a short-term treatment for insomnia.

Insomnia

The first-generation sedating antihistamines

diphenhydramine Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into ...

, doxepin, doxylamine, and pyrilamine are the most widely used medications in the world for preventing and treating insomnia. As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia. As of 2008 and 2017, over-the-counter antihistamines were not recommended by the American Academy of Sleep Medicine for treatment of chronic insomnia "due to the relative lack of efficacy and safety data". Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed. A 2015 systematic review of over-the-counter sleep aids including doxylamine found little evidence to inform the use of doxylamine for treatment of insomnia. A major systematic review and

network meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...

of medications for the treatment of insomnia published in 2022 found that doxylamine had an

effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...

( standardized mean difference (SMD)) against

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

for treatment of insomnia at 4weeks of 0.47 (95% 0.06 to 0.89). The certainty of evidence was rated as moderate. No data were available for doxylamine in terms of longer-term treatment (3months). For comparison, the other sedating antihistamines assessed, doxepin and trimipramine, had effect sizes (SMD) at 4weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence), respectively. Doses of doxylamine that have been used for sleep range from 5 to 50mg, with 25mg being the typical dose.

Morning sickness

Doxylamine is used in the

combination drug A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC prod ...

pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy). It is the only medication approved by the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

for the treatment of morning sickness.

Available forms

Doxylamine is used medically as doxylamine succinate, the

succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...

of doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination with pyridoxine (a form of vitamin B₆) (brand names Bendectin, Bonjesta, Diclegis). Doxylamine is available alone as

immediate-release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or or ...

tablets containing 25mg doxylamine succinate. Oral tablets containing 12.5mg doxylamine succinate as well as oral capsules containing 25mg doxylamine succinate were also previously available but were discontinued. The combination of doxylamine and pyridoxine is available in the form of extended- and delayed-release oral tablets containing 10 to 20mg doxylamine succinate and 10 to 20mg pyridoxine hydrochloride. Doxylamine alone is available

, whereas doxylamine in combination with pyridoxine is a prescription-only medication. Doxylamine is also available in over-the-counter nighttime

products such as NyQuil Cold & Flu (contains acetaminophen, doxylamine succinate 6.25 to 12.5mg, and dextromethorphan hydrobromide), where it serves as the sedating component.

Contraindications

The

fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

safety rating of doxylamine is "A" (no evidence of risk).

Side effects

s of doxylamine include

, and

, among others. Doxylamine is a potent

and has a side-effect profile common to such drugs, including blurred vision, dry mouth,

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

, muscle incoordination,

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 bladd ...

mental confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"

, and delirium. Because of its relatively long elimination half-life (10–12hours), doxylamine is associated with next-day effects including sedation,

, and tiredness when used as a hypnotic. This may be described as a " hangover effect". The shorter elimination half-life of diphenhydramine (4–8hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard. Antihistamines like doxylamine are sedating initially but tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation. Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine. This is in contrast to diphenhydramine. Studies of doxylamine's

carcinogenicity A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...

in mice and rats have produced positive results for both

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 ...

and

thyroid cancer Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. C ...

, especially in the mouse. The carcinogenicity of the drug in humans is not well-studied, and the

International Agency for Research on Cancer The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations. Its role is to conduct and ...

lists the drug as "not classifiable as to its carcinogenicity to humans". Continuous and/or cumulative use of

medications, including first-generation antihistamines, is associated with a higher risk of cognitive decline and dementia in older people.

Overdose

Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600mg/day for 6months have been given to adults 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 wit ...

, with little

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

encountered. The median lethal dose () is estimated to be ~500mg/kg in humans. Symptoms of

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended.

may include

, dilated pupils,

, night terrors, euphoria,

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 ...

seizure 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 l ...

s, rhabdomyolysis, and death. Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and

cardiorespiratory arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...

. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000mg doxylamine succinate. Rarely, an overdose results in rhabdomyolysis and

acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both. Causes of AKI are c ...

Pharmacology

Pharmacodynamics

Doxylamine acts primarily as an antagonist or inverse agonist of the

H₁ receptor. This action is responsible for its

and sedative properties. To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors, an action responsible for its

and (at high doses)

deliriant Deliriants are a subclass of hallucinogen. The term was coined in the early 1980s to distinguish these drugs from psychedelics and dissociatives such as LSD and ketamine, respectively, due to their primary effect of causing delirium, as oppose ...

effects.

Pharmacokinetics

The

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of doxylamine is 24.7% for

oral administration 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 ...

and 70.8% for intranasal administration. The T_max of doxylamine is 1.5 to 2.5 hours. Its elimination half-life is 10 to 12hours (range 7 to 15hours). Doxylamine is metabolized in the

primarily 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 co ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

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. CYP2D ...

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

, and

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

. The main metabolites are ''N''-desmethyldoxylamine, ''N'',''N''-didesmethyldoxylamine, and doxylamine ''N''-oxide. Doxylamine is eliminated 60% in the

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

and 40% in feces. Doxylamine levels after a single 25 mg oral dose of doxylamine

Chemistry

Doxylamine is a member of the ethanolamine class of antihistamines. Other antihistamines from this group include bromodiphenhydramine, carbinoxamine, clemastine,

dimenhydrinate Dimenhydrinate, sold under the brand name Dramamine, among others, is an over-the-counter drug used to treat motion sickness and nausea. Dimenhydrinate is a theoclate salt composed of diphenhydramine, an ethanolamine derivative, and 8-chloroth ...

, orphenadrine, and phenyltoloxamine.

History

Doxylamine is a first-generation

and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949. It has been the antihistamine component of

NyQuil Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including a ...

since 1966. Bendectin, a combination of doxylamine, pyridoxine (vitamin B₆), and

dicyclomine Dicycloverine, also known as dicyclomine, sold under the brand name Bentyl in the US, is a medication that is used to treat spasms of the intestines such as occur in irritable bowel syndrome. It is taken by mouth or by injection into a muscl ...

(an

antispasmodic An antispasmodic (synonym: spasmolytic) is a pharmaceutical drug or other agent that suppresses muscle spasms. Smooth muscle spasm One type of antispasmodics is used for smooth muscle relaxation, especially in tubular organs of the gastrointest ...

agent), was marketed for treatment of morning sickness in 1956. This product was reformulated in 1976 to remove dicyclomine. The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association with congenital limb defects. However, these concerns have not been supported by studies. In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis. The combination was not removed from the market in Canada, where it had been marketed since 1979.

Society and culture

Formulations

Doxylamine is primarily used as the

succinic acid Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...

, doxylamine succinate. * It is the sedating ingredient of

(generally in combination with

dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...

and acetaminophen). * In Commonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with paracetamol (acetaminophen) and codeine under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment for

tension headache Tension headache, also known as stress headache, or tension-type headache (TTH), is the most common type of primary headache. The pain can radiate from the lower back of the head, the neck, eyes or other muscle groups in the body typically affect ...

and other types of pain. * Doxylamine succinate is used in general

sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), Sleep Aid (generic, Australia) and Dorminox (Poland). * In the United States: ** Doxylamine succinate is the active ingredient in many over-the-counter sleep-aids branded under various names. ** Doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 becoming the only drug approved for morning sickness with a class A safety rating for pregnancy (no evidence of risk). * In

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

: ** Doxylamine succinate and pyridoxine ( vitamin B₆) are the ingredients of Diclectin, which is used to prevent morning sickness. ** It is also available in combination with vitamin B₆ and

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

under the brand name Evanorm (marketed by Ion Healthcare). * In

India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...

** Doxylamine preparations are available typically in combination with Pyridoxine that may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.

References

{{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 ...

, titlestyle = background:#ccccff , list1 = {{Histamine receptor modulators {{Muscarinic acetylcholine receptor modulators Antiemetics Antihistamines Ethers H1 receptor antagonists Hypnotics Muscarinic antagonists 2-Pyridyl compounds Sedatives