Melatonin is a

dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...

and

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

as well as

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

. As a hormone, melatonin is released by the

pineal gland The pineal gland, conarium, or epiphysis cerebri, is a small endocrine gland in the brain of most vertebrates. The pineal gland produces melatonin, a serotonin-derived hormone which modulates sleep, sleep patterns in both circadian rhythm, circ ...

and is involved in

sleep–wake cycle A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

s. As a supplement, it is often used for the short-term 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, ...

, such as from

jet lag Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. from ...

shift work Shift work is an employment practice designed to make use of, or provide service across, all 24 hours of the clock each day of the week (often abbreviated as '' 24/7''). The practice typically sees the day divided into shifts, set periods of ...

, and is typically taken orally. Evidence of its benefit for this use, however, is not strong. A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep. A

prolonged-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 ...

form of melatonin is also approved for use as a medication in

Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...

for the treatment of insomnia in certain people. Side effects from melatonin supplements are minimal at low doses for short durations (in the studies reported about equally for both melatonin and placebo). Side effects of melatonin are rare but may occur in 1 to 10 patients in 1,000. They may include

somnolence 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 ...

(sleepiness), headaches,

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 ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

, abnormal dreams, irritability, nervousness, restlessness, insomnia, anxiety,

migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

, lethargy, psychomotor hyperactivity, dizziness,

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

, abdominal pain,

heartburn Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid (gastric reflux) into the esophagus. It is the m ...

, mouth ulcers, dry mouth, hyperbilirubinaemia,

dermatitis Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can v ...

night sweats Night sweats, also referred to as nocturnal hyperhidrosis (Hyperhidrosis - a medical term for excessive sweating + nocturnal - night), is the repeated occurrence of excessive sweating during sleep. The person may or may not also perspire exces ...

pruritus Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...

, rash, dry skin, pain in the extremities, symptoms of

menopause Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

, chest pain,

glycosuria Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused ...

(sugar in the urine),

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom ma ...

(protein in the urine), abnormal liver function tests, increased weight, tiredness, mood swings, aggression and feeling hungover. Its use is not recommended 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 ca ...

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 br ...

or for those with

liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the sig ...

. Melatonin acts as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the melatonin MT₁ and MT₂ receptors, the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

s of

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

melatonin. It is thought to activate these receptors in the

suprachiasmatic nucleus The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...

of the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

in 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 v ...

to regulate the

circadian clock A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time. Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...

and sleep–wake cycles. Immediate-release melatonin has a short

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of about 20 to 50minutes. Prolonged-release melatonin used as a medication has a half-life of 3.5 to 4hours. Melatonin was discovered in 1958. It is sold

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 ...

in Canada and the United States; in the United Kingdom, it is a prescription-only medication. In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54. In the European Union, it is indicated for the treatment of insomnia in children and adolescents. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The US

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 ...

(FDA) treats melatonin as a dietary supplement and as such has not approved it for any medical uses. It was approved for medical use in the European Union in 2007. Besides melatonin, certain synthetic

melatonin receptor agonist Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The disc ...

s like

ramelteon Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. ...

tasimelteon Tasimelteon, sold under the brand name Hetlioz, is a medication approved by the U.S. Food and Drug Administration (FDA) in January 2014, for the treatment of non-24-hour sleep–wake disorder (also called non-24, N24 and N24HSWD). In June 2014, th ...

, and agomelatine are also used in medicine. In 2020, it was the 298th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Insomnia

In the European Union, prolonged-release melatonin (Circadin) is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of

in children and adolescents age 2 to 18 with

autism spectrum disorder The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...

(ASD) and

Smith–Magenis syndrome Smith–Magenis Syndrome (SMS), also known as 17p- syndrome, is a microdeletion syndrome characterized by an abnormality in the short (p) arm of chromosome 17. It has features including intellectual disability, facial abnormalities, difficulty sl ...

, in whom

sleep hygiene Sleep hygiene is a behavioral and environmental practice developed in the late 1970s as a method to help people with mild to moderate insomnia. Clinicians assess the sleep hygiene of people with insomnia and other conditions, such as depression, ...

measures have been insufficient. Some studies have shown melatonin to reduce the time until onset of sleep and increase sleep duration in children with

neurodevelopmental disorder Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...

s. It is also indicated for the short-term treatment of primary insomnia characterized by poor quality of sleep in people who are aged 55 or over. It is deemed to be a first-line agent for short-term treatment of insomnia in people 55 years old or older. Positions on the benefits of melatonin for insomnia are mixed. A review by the

Agency for Healthcare Research and Quality The Agency for Healthcare Research and Quality (AHRQ; pronounced "ark" by initiates and often "A-H-R-Q" by the public) is one of twelve agencies within the United States Department of Health and Human Services (HHS). The agency is headquartered i ...

(AHRQ) from 2015 stated that evidence of benefit in the general population was unclear. A review from 2017 found a modest effect on time until onset of sleep. Another review from 2017 put this decrease at six minutes to sleep onset but found no difference in total sleep time. Melatonin may improve sleep in people with

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

. Children with autism have abnormal melatonin pathways and below-average physiological levels of melatonin. Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings. However, many studies on melatonin and autism rely on self-reported levels of improvement and more rigorous research is needed. While the packaging of melatonin often warns against use in people under 18 years of age, studies suggest that melatonin is also an efficacious and safe treatment for insomnia in people with

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

, including children. However, larger and longer studies are needed to establish long-term safety and optimal dosing. The American Academy of Sleep Medicine's 2017

clinical practice guideline Clinical may refer to: Healthcare * Of or about a clinic, a healthcare facility * Of or about the practice of medicine Other uses * ''Clinical'' (film), a 2017 American horror thriller See also * * * Clinical chemistry, the analysis of bodily flu ...

s recommended against the use of melatonin in the treatment of insomnia due to poor effectiveness and very low

quality of evidence Evidence-based medicine (EBM) is "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients". The aim of EBM is to integrate the experience of the clinician, the values of t ...

. The

medication

may work as well as melatonin, at greater cost but with different adverse effects, for some sleep conditions. There is evidence to suggest that the typical advertised dose of most melatonin supplements (more than 1mg) are excessive for the treatment of insomnia and may even be detrimental to overall sleep quality. Controlled-release melatonin at a dose of 4mg has been found to cause excessive melatonin levels upon waking (>50pg/mL), possibly contributing to lethargy in the morning. By contrast, 0.4mg of controlled release melatonin was not found to cause elevated melatonin levels upon waking.

Circadian rhythm sleep disorders

Melatonin may be useful in the treatment of

delayed sleep phase syndrome Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is a delaying of a person's circadian rhythm (biological clock) compared to those of societal norms. The diso ...

. Melatonin is known to reduce

, especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation. Melatonin appears to have limited use against the sleep problems of people who work

. Tentative evidence suggests that it increases the length of time people are able to sleep.

REM sleep behavior disorder

Melatonin is a safer alternative than

clonazepam Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class ...

in the treatment of

REM sleep behavior disorder Rapid eye movement sleep behavior disorder or REM behavior disorder (RBD) is a sleep disorder in which people act out their dreams. It involves abnormal behavior during the sleep phase with rapid eye movement (REM) sleep. The major feature of ...

– a condition associated with the

synucleinopathies Synucleinopathies (also called α-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells. There are three main types of synucle ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

and

dementia with Lewy bodies Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions. Memory loss is not always an early symptom. The disease worsens over time ...

. However, clonazepam may be more effective. In any case, the quality of evidence for both treatments is very low and it is unclear whether either are definitely effective.

Dementia

A 2020

Cochrane review Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...

found no evidence that melatonin helped sleep problems in people with moderate to severe

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

due to

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect. Melatonin may, however, help with sundowning (increased confusion and restlessness at night) in people with dementia.

Available forms

2mg

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 ...

formulation of melatonin sold under the brand name Circadin is approved for use in the

European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...

in the short-term treatment of

in people age 55 and older.As PDF.
Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Melatonin is also available as an

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 ...

in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3mg to 10mg or more. It is also possible to buy raw melatonin powder by the weight. Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, or liquids. It is also available for use

sublingually Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue. The sublingual glands receive their primary ...

, or as

transdermal patch A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medicat ...

es. The American Academy of Sleep Medicine (AASM) said that the melatonin content in unregulated (without a USP verified mark) supplements can diverge widely from the claimed amount; a study found that the melatonin content ranged from one half to four times the stated dose.

Contraindications

Contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

s of melatonin include

hypersensitivity reaction Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...

s among others. It is not recommended in people with

autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

s due to lack of data in these individuals. Prolonged-release pharmaceutical melatonin (Circadin) contains

lactose Lactose is a disaccharide sugar synthesized by galactose and glucose subunits and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from ' (gen. '), the Latin word for milk, plus the suffix '' - ...

and should not be used in people with the

lactase deficiency Lactose intolerance is a common condition caused by a decreased ability to digest lactose, a sugar found in dairy products. Those affected vary in the amount of lactose they can tolerate before symptoms develop. Symptoms may include abdominal pai ...

or glucose–galactose malabsorption. Use of melatonin is also not recommend in women who are

pregnant Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

or in people with

Adverse effects

Melatonin appears to cause very few

side effects 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 ...

as tested in the short term, up to three months, at low doses. Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials, and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and

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 (medicine), saline), sham surgery, and other procedures. In general ...

. Prolonged-release melatonin is safe with long-term use of up to 12 months. Although not recommended for long-term use beyond this, low-dose melatonin is generally safer, and a better alternative, than many prescription and over-the-counter sleep aids if a sleeping medication must be used for an extended period of time. Low doses of melatonin are usually sufficient to produce a

hypnotic Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...

effect in most people. Higher doses do not appear to result in a stronger effect but instead appear to cause drowsiness for a longer period of time. There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor. Specifically, taking exogenous melatonin shortly after a meal is correlated with impaired glucose tolerance. Therefore, Rubio-Sastre and colleagues recommend waiting at least 2 hours after the last meal before taking a melatonin supplement. Melatonin can cause

, next-day

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 irritability. In

autoimmune disorders An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation. Melatonin can lower

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...

levels. Melatonin's effects on human reproduction remain unclear. Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased

REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream viv ...

time and dream activity in people both with and without

narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...

. In 2022 the American Academy of Sleep Medicine (AASM) advised that parents should talk to a healthcare professional before giving melatonin or any supplement to children. Increased use of melatonin in the 21st century has significantly increased reports of melatonin overdose, calls to poison control centers, and related emergency department visits for children. The number of children who unintentionally ingested melatonin supplements in the US had increased 530% from 2012 to 2021. Over 4,000 reported ingestions required a hospital stay, and 287 children required intensive care. And the AASM says there is little evidence that melatonin supplementation is effective in treating insomnia in healthy children.

Overdose

Melatonin appears to be relatively safe in

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.

. It has been administered at daily doses of up to 300mg without causing clinically significant adverse reactions in the literature. The most commonly reported adverse effect of melatonin overdose is

. Upon melatonin overdose,

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 ...

may be expected and the compound should be cleared within 12hours. No special treatment is needed for melatonin overdose.

Interactions

Melatonin is

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

mainly by

CYP1A Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the ''CYP1A1'' gene. The protein is a member of the cytochrome P450 superfamily of enzymes. Function Metabolism of xenobiotics and drugs CYP1A1 ...

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. A ...

s. As such, inhibitors and

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

s of CYP1A enzymes, such as

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 ...

, can modify melatonin metabolism and exposure. As an example, the CYP1A2 and

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

inhibitor

fluvoxamine Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...

increases melatonin peak levels by 12-fold and overall exposure by 17-fold and this combination should be avoided. CYP1A2 inducers like

cigarette smoking Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is believed ...

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...

, and

rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...

may reduce melatonin exposure due to induction of CYP1A2. In those taking

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...

, some evidence suggests there may exist a potentiating interaction, increasing the

anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...

effect of warfarin and the risk of bleeding.

Pharmacology

Pharmacodynamics

Melatonin acts as an

of the melatonin MT₁ and MT₂ receptors, the

s of

melatonin. Endogenous melatonin is normally secreted from the

of the brain. Melatonin is thought to activated melatonin receptors in the

of the

to regulate the

and sleep–wake cycles. When used several hours before sleep according to the

phase response curve A phase response curve (PRC) illustrates the transient change (phase response) in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received. PRCs are used in various fields; examples of biolog ...

for melatonin in humans, small amounts (0.3 mg) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.

Pharmacokinetics

Absorption

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%. H ...

of melatonin is between 2.5 and 50%. Melatonin is rapidly absorbed and

distributed Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...

, reaching peak plasma concentrations after 60minutes of administration, and is then eliminated. Usual doses of exogenous melatonin of 1 to 12mg produce melatonin concentrations 10 to 100times higher than endogenous peak levels.

Distribution

The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...

of melatonin is approximately 60%. It is mainly bound to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

, α₁-acid glycoprotein, and

high-density lipoprotein High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are ty ...

. The

membrane transport protein A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembran ...

s that move melatonin across a membrane include, but are not limited to,

glucose transporter Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporter ...

s, including

GLUT1 Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the ''SLC2A1'' gene. GLUT1 facilitates the transport of glucose across ...

, and the proton-driven oligopeptide transporters PEPT1 and PEPT2.

Metabolism

Melatonin is

in the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

6-hydroxymelatonin 6-Hydroxymelatonin (6-OHM) is a naturally occurring, endogenous, major active metabolite of melatonin. Similar to melatonin, 6-OHM is a full agonist of the MT1 and MT2 receptors. It is also an antioxidant and neuroprotective, and is even more ...

Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s are conjugated with

sulfuric acid Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular formu ...

glucuronic acid Glucuronic acid (from Greek γλεῦκος "''wine, must''" and οὖρον "''urine''") is a uronic acid that was first isolated from urine (hence the name). It is found in many gums such as gum arabic (c. 18%), xanthan, and kombucha tea and ...

for

excretion Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

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 excretion, excreted from the body through the urethra. Cel ...

. Some of the metabolites formed via the reaction of melatonin with a

free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...

include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).

Elimination

In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva. Melatonin is excreted in the urine 2 to 5% as the unchanged drug. Melatonin has an

of about 20 to 60 minutes. The half-life of prolonged-release melatonin (Circadin) is 3.5 to 4hours.

Chemistry

Melatonin, also known as ''N''-acetyl-5-methoxytryptamine, is a

substituted tryptamine Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino group, amino (NH2) group ...

and a

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. F ...

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

(5-hydroxytryptamine). It is structurally related to N-acetylserotonin (normelatonin; ''N''-acetyl-5-hydroxytryptamine), which is the

chemical intermediate In chemistry, a reaction intermediate or an intermediate is a molecular entity that is formed from the reactants (or preceding intermediates) but is consumed in further reactions in stepwise chemical reactions that contain multiple elementary s ...

between serotonin and melatonin in the body. Synthetic

s used in medicine like

, agomelatine, and piromelatine (still in clinical trials) are analogues of melatonin.

History

The first

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...

for its use in circadian rhythm disorders was granted in 1987 to Roger V Short and Stuart Armstrong at

Monash University Monash University () is a public research university based in Melbourne, Victoria, Australia. Named for prominent World War I general Sir John Monash, it was founded in 1958 and is the second oldest university in the state. The university has a ...

, and the first patent for its use as a low-dose sleep aid was granted to

Richard Wurtman Richard Wurtman (March 9, 1936 – December 13, 2022) was an American neuroscientist who spent his career doing basic and translational neuroscience research at Massachusetts Institute of Technology. Early life and education Richard Wurtman earn ...

MIT The Massachusetts Institute of Technology (MIT) is a private land-grant research university in Cambridge, Massachusetts. Established in 1861, MIT has played a key role in the development of modern technology and science, and is one of the m ...

in 1995. Around the same time, the hormone got a lot of press as a possible treatment for many illnesses. ''The

New England Journal of Medicine ''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. Hist ...

'' editorialized in 2000: "With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear." It was approved for medical use in the European Union in 2007.

Society and culture

Melatonin is categorized by the US

(FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada. FDA regulations applying to medications are not applicable to melatonin, though the FDA has found false claims that it cures cancer. As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin. In many countries, melatonin is recognized as a

neurohormone A neurohormone is any hormone produced and released by neuroendocrine cells (also called neurosecretory cells) into the blood. By definition of being hormones, they are secreted into the circulation for systemic effect, but they can also have a role ...

and it cannot be sold over-the-counter. According to

Harriet Hall Harriet A. Hall (born July 2, 1945) is a U.S. retired family physician, former U.S. Air Force flight surgeon and skeptic who writes about alternative medicine and quackery for ''Skeptic'' and ''Skeptical Inquirer''. She writes under the name T ...

caution is advisable, since quality control is a documented problem. 71% of products did not contain within 10% of the labelled amount of melatonin, with variations ranging from -83% to +478%, lot-to-lot variability was as high as 465%, and the discrepancies were not correlated to any manufacturer or product type. To make matters worse, 8 out of 31 products were contaminated with the neurotransmitter serotonin. Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic, which limits the risk of contamination or the means of transmitting infectious material. Melatonin is the most popular over-the-counter sleep remedy in the United States, resulting in sales in excess of US$400 million during 2017. In 2020, it was the 298th most commonly prescribed medication in the US, with more than 1million prescriptions. Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011. The FDA considered whether these food products could continue to be sold with the label "dietary supplements". On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a

food additive Food additives are substances added to food to preserve flavor or enhance taste, appearance, or other sensory qualities. Some additives have been used for centuries as part of an effort to preserve food, for example vinegar (pickling), salt (salt ...

. Bebida Beverage Company received a warning letter in 2015 for selling a melatonin-containing beverage.

Research

Psychiatry

Depression

Some research supports 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, hea ...

effect of melatonin.

Bipolar disorder

Melatonin, along with

, has been repurposed as a possible adjunctive treatment for manic episodes in

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

. However, meta-analytic evidence is somehow inconsistent and of limited interest so far, although the small samples of trials do not allow ruling out its beneficial effect. In any case, current evidence does not support the use of add-on melatonin-receptor agonists for mania.

Anxiety

Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.

Headaches

Tentative evidence shows melatonin may help reduce some types of headaches including

cluster may refer to: Science and technology Astronomy * Cluster (spacecraft), constellation of four European Space Agency spacecraft * Asteroid cluster, a small asteroid family * Cluster II (spacecraft), a European Space Agency mission to study t ...

and hypnic headaches.

Cancer

A 2013 review by the National Cancer Institute found insufficient evidence for melatonin having anti-cancer effects. A 2022 review found that melatonin supplementation had a small improvement in survival of people with cancer at one year. One review found that melatonin may alleviate chemotherapy-related side effects.

Protection from radiation

Both animal and human studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

by scavenging

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

which are generated during exposure. Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the

hydroxyl radical The hydroxyl radical is the diatomic molecule . The hydroxyl radical is very stable as a dilute gas, but it decays very rapidly in the condensed phase. It is pervasive in some situations. Most notably the hydroxyl radicals are produced from the ...

that attacks DNA, proteins, and

cellular membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (th ...

s. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without known, major side effects.

Epilepsy

A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.

Dysmenorrhea

A 2016 review suggested no strong evidence of melatonin compared to placebo for

dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in the ...

secondary to

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...

Delirium

A 2016 review suggested no clear evidence of melatonin to reduce the incidence of

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 in ...

Gastroesophageal reflux disease

A 2011 review said melatonin is effective in relieving

epigastric pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...

and

Tinnitus

A 2015 review of studies of melatonin in

tinnitus Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...

found the quality of evidence low, but not entirely without promise.

References

External links

* {{Authority control Acetamides Antidepressants Antioxidants Aromatase inhibitors Circadian rhythm Drugs acting on the nervous system Melatonin receptor agonists Methoxy compounds Mexamines Orphan drugs Treatment of bipolar disorder Tryptamine alkaloids Wikipedia medicine articles ready to translate