Melatonin

A reference work, not a recommendation to use: this profile describes mechanism and evidence and does not replace medical advice. The claims come from marketing and forums and are tested here, not endorsed.

Claims checked

• Fall asleep faster

  Small benefit

  Sleep · Patients: primary sleep disorders · Human, randomised

  Meta-analysis of 19 RCTs: time to fall asleep about 7 minutes shorter ^[8]. In adults with chronic insomnia, no significant effect in a later meta-analysis, but in children ^[9]; the AASM guideline advises against in adults ^[10].

• Less jet lag

  Proven benefit

  Sleep · healthy · Human, randomised

  Cochrane review: in nine of ten RCTs less jet lag after flights across five or more time zones, NNT 2; benefit depends on timing ^[11]. The review dates from 2002.

• Sleep longer and better

  Small benefit

  Sleep · Patients: primary sleep disorders · Human, randomised

  About 8 minutes more total sleep and slightly better sleep quality (SMD 0.22) ^[8]; in adults with chronic insomnia, sleep duration and sleep efficiency not significantly improved ^[9].

Mechanism of action

Melatonin is produced at night in the pineal gland and activates two high-affinity G protein-coupled receptors, MT1 and MT2, through which it influences sleep and circadian rhythms; the synthetic agonists ramelteon, tasimelteon and agomelatin are also built on these receptors ^[1]. In humans, ingested melatonin shifts the internal clock according to a phase response curve that is almost the opposite of that of light: given in the morning, it delays rhythms, in the afternoon or early evening it advances them ^[2]. Melatonin is thus primarily a timing signal, not a classic sleeping pill.

After oral administration, peak concentration is reached after about 50 minutes, and the half-life is about 45 minutes; bioavailability in a systematic review was 9 to 33%, on average about 15%, and was influenced by age, caffeine, smoking, oral contraceptives, food intake and fluvoxamine ^[3]. In a study of 12 healthy men comparing oral and intravenous melatonin, absolute oral bioavailability was even only about 3%, which points to pronounced first-pass breakdown ^[4]. In 5 healthy people, fluvoxamine raised the peak concentration of oral melatonin on average 17-fold because it inhibits its breakdown ^[5]. For other routes, a systematic review describes higher plasma levels via the oral mucosa than after swallowing, as well as slow, variable absorption through the skin with deposition in the skin ^[6]. In a crossover study of 10 healthy women, transdermal melatonin reached its peak only after about 21 hours at a bioavailability of about 10%, rectal about 36% ^[7].

A meta-analysis of 19 placebo-controlled studies with 1683 participants with primary sleep disorders found a time to fall asleep about 7 minutes shorter, 8 minutes more total sleep and slightly better sleep quality ^[8]. A later meta-analysis on chronic insomnia found no significant effect on sleep onset latency, sleep duration or sleep efficiency in adults without comorbidities, but did in children and adolescents ^[9]. The guideline of the American Academy of Sleep Medicine therefore advises against (weak recommendation) the use of melatonin in chronic insomnia in adults ^[10]. The data are clearer for jet lag: in a Cochrane review, melatonin reduced jet lag in nine of ten studies after flights across five or more time zones (NNT 2), with greater benefit after eastward flights; taken at the wrong time of day, however, it caused tiredness and delayed adaptation ^[11].

Product quality is a problem of its own. Of 31 analyzed products, over 71% deviated by more than 10% from the stated content, the range extended from −83% to +478%, and eight products contained serotonin ^[12]. In the US, melatonin ingestions by children and adolescents reported to poison control centers rose by 530% between 2012 and 2021; five children had to be ventilated, two died ^[13]. A safety review describes, for short-term use, only mild side effects such as dizziness, headache, nausea and drowsiness, but considers long-term safety in children unresolved and advises against use in pregnancy and breastfeeding for lack of data ^[14]. In the EU, classification as a medicinal product or food supplement depends on the amount per unit, according to a current review ^[15].

Targets

Effect profile

Which signaling systems the compound affects according to current data. ↑ enhanced, ↓ dampened, ≈ modulated, ○ no effect; dots = evidence level.

• ·Dopamineno data
• ·Noradrenalineno data
• ·Serotoninno data
• ·Acetylcholineno data
• ·Glutamate · AMPAno data
• ·Glutamate · NMDAno data
• ·GABAno data
• ·Histamineno data
• ·Orexinno data
• ·Adenosineno data
• ·Opioidsno data
• ↑Melatonin↑ · activates MT1 and MT2; in humans shifts the internal clock in a time-dependent manner according to a phase response curve^[1][2]
• ·Neurotrophinsno data
• ·Blood flowno data
• ·Nitric oxideno data
• ·Energy metabolismno data
• ·Insulin · glucoseno data
• ·Inflammation · oxidativeno data
• ·Stress axisno data
• ·Testosterone axisno data
• ·Endocannabinoidsno data
• ·Autophagy · senescenceno data
• ·Immune systemno data
• ·Lipid metabolismno data
• ·Coagulation · fibrinolysisno data
• ·Methylationno data

Routes of administration and bioavailability

How much of a compound reaches the blood or target tissue depends on the route into the body and on the dosage form. All routes of administration explained

• Oral (swallowed) · Tablet or capsule, immediate release

  ≈ 15% (9–33%, review); ≈ 3% in one study (human)

  Peak after about 50 minutes, half-life about 45 minutes ^[3]; pronounced first-pass breakdown ^[4]. Levels are influenced by age, caffeine, smoking, oral contraceptives, food and fluvoxamine ^[3][5].^[5]

  Human, non-randomised

• Sublingual (under the tongue) · via the oral mucosa

  According to a systematic review, higher plasma levels than after swallowing; could bypass first-pass breakdown, data small ^[6].

  Human, non-randomised

• Transdermal (through the skin) · applied to the skin

  ≈ 10% (human, n = 10)

  Very slow absorption with a peak after about 21 hours ^[7]; variable absorption and deposition in the skin ^[6]. Increased tiredness only after this route ^[7].

  Human, non-randomised

• Rectal · rectal

  ≈ 36% (human, n = 10)

  Peak after about 24 minutes in a crossover study with healthy women ^[7].

  Human, non-randomised

Human studies

• Meta-analysis of primary sleep disorders

  meta-analysis of 19 randomized, placebo-controlled studies · Patients: primary sleep disorders (adults and children) · n = 1683 · varied

  Measured: Time to fall asleep, total sleep, sleep quality

  Result: Time to fall asleep −7.06 min (95% CI 4.37–9.75), total sleep +8.25 min, sleep quality SMD 0.22.^[8]

  Human, randomised

• Meta-analysis of chronic insomnia

  systematic reviews and meta-analyses of 24 RCTs · Patients: chronic insomnia · varied

  Measured: Time to fall asleep, sleep duration, sleep efficiency, sleep quality

  Result: Adults without comorbidity: no significant effects; children and adolescents: shorter time to fall asleep and longer sleep.^[9]

  Human, randomised

• Cochrane review jet lag

  systematic review of 10 RCTs · healthy (air travelers, flight crew, military) · Travel

  Measured: Jet lag symptoms, sleep

  Result: Nine of ten studies: less jet lag at five or more time zones; NNT 2.^[11]

  Human, randomised

• Oral vs. intravenous administration

  cohort crossover study · healthy (men) · n = 12 · two study days

  Measured: Pharmacokinetics

  Result: Absolute oral bioavailability about 3%; elimination half-life 53.7 min.^[4]

  Human, non-randomised

• Alternative routes of administration

  Crossover study · healthy (women) · n = 10 · five study days

  Measured: Pharmacokinetics, sedation, side effects

  Result: Bioavailability transdermal about 10%, rectal about 36%; no change in reaction time, no serious side effects.^[7]

  Human, non-randomised

• Fluvoxamine interaction

  open interaction study · healthy (men) · n = 5 · single doses

  Measured: Serum levels of melatonin

  Result: Peak concentration on average 17-fold higher with fluvoxamine; half-life not significantly changed.^[5]

  Human, non-randomised

Risks and warnings

• Incorrectly declared content and contaminants

  In 31 analyzed products, the melatonin content deviated from the label by −83% to +478%, between batches of one product by up to 465%; eight products contained serotonin ^[12].

  Laboratory

• Ingestions by children

  In the US, reported melatonin ingestions by children and adolescents rose by 530% in 2012–2021, mainly unintentional ingestions by children up to 5 years; hospital admissions increased, five children were ventilated, two died ^[13].

  Human, non-randomised

• Mild side effects

  In the short term mainly dizziness, headache, nausea and drowsiness; in long-term RCTs comparable to placebo ^[14]. Taken at the wrong time of day, it can cause tiredness and delay adaptation to a new time zone ^[11].

  Human, randomised

• Pregnancy, breastfeeding and children

  For lack of human data, use is advised against in pregnancy and breastfeeding; long-term safety in children and adolescents unresolved ^[14].

  No data

• Epilepsy

  Case reports suggest that people with epilepsy could be harmed; not studied systematically ^[11].

  Human, non-randomised

Interactions

• Fluvoxamine: Peak concentration of oral melatonin raised on average 17-fold because breakdown is inhibited (5 healthy people) ^[5].
• Warfarin: Case reports of possible harm under warfarin; interaction not studied systematically ^[11].
• Caffeine, smoking, oral contraceptives: According to a systematic review, they influence the pharmacokinetics of melatonin ^[3].

Fact check: common claims

• not supported

  “Melatonin is a strong, natural sleeping pill”

  Time to fall asleep shortens on average by only about 7 minutes ^[8]; in adults with chronic insomnia no significant effect ^[9], the AASM guideline advises against ^[10]. Melatonin acts mainly as a timing signal ^[2].

• supported

  “Melatonin helps against jet lag”

  Cochrane review with nine of ten positive RCTs and NNT 2 for flights across five or more time zones ^[11]; timing is decisive.

• refuted

  “What is on the label is also in the product”

  Over 71% of 31 products deviated by more than 10%, range −83% to +478%, partly contaminated with serotonin ^[12].

• partly supported

  “Melatonin is completely harmless, also for children”

  In the short term mostly only mild side effects ^[14]; long-term safety in children is unresolved, however ^[14], and unintentional ingestions by children led to more hospital admissions and deaths in the US ^[13].

• refuted

  “Swallowed, almost all of it arrives in the blood”

  Oral bioavailability on average about 15% according to a review ^[3] and only about 3% in a study with an intravenous comparison ^[4].

Pharmacokinetics

Absorption

Rapid orally, peak after about 50 minutes; bioavailability low and highly variable (≈ 3–15%) ^[3][4].

Half-life

About 45 minutes orally and intravenously (review) ^[3]; 53.7 minutes in a single study ^[4]; transdermally apparently much longer because of slow absorption ^[7].

Metabolism

Pronounced first-pass breakdown ^[4]; breakdown inhibited by fluvoxamine ^[5].

Entry into the brain

Not verified.

Legal status

Germany

Prescription-only as a medicinal product (AMVV Annex 1); excluded are certain products for oral use in jet lag in adults within the limits set in the AMVV for active substance content, daily amount and pack size ^[16]. Whether and under which conditions melatonin-containing food supplements are marketable has not been verified.

EU

Centrally authorized medicinal products: Circadin (EMEA/H/C/000695, since June 29, 2007) and Melatonin Neurim (EMEA/H/C/005603, since November 7, 2022) for the short-term treatment of primary insomnia characterized by poor quality of sleep in patients aged 55 and over ^[17][19]; Slenyto (EMEA/H/C/004425, since September 20, 2018) for sleep disorders in children and adolescents with autism spectrum disorder, certain neurogenetic conditions or ADHD when sleep hygiene measures are insufficient ^[18]. According to a review, products above a threshold amount are classified in the EU as medicinal products under the supervision of the European Medicines Agency, while lower-dose products are often marketed as food supplements ^[15].

USA

Regulated by the FDA as a dietary supplement and available over the counter ^[13].

Other countries

Not verified.

Authorised EU health claims

§ EU claim authorised An authorised health claim is a legal statement about the nutrient, not about this form, and not a level of evidence. The evidence for this form is reported separately under the main claim and in the human studies.

• “contributes to the reduction of time taken to fall asleep”

  Nutrient

  Melatonin

  Legal basis

  Regulation (EU) No 432/2012^[20]

  Reading

  legally permitted; for the state of the evidence, see the promise “Fall asleep faster” (small benefit, studied in people with primary sleep disorders)

• “contributes to the alleviation of subjective feelings of jet lag”

  Nutrient

  Melatonin

  Legal basis

  Regulation (EU) No 432/2012^[20]

  Reading

  legally permitted; matches the promise “Less jet lag” (proven benefit)

Open questions

• Why do the meta-analyses in adults with insomnia differ so markedly, and which subgroups benefit?
• Is the jet lag benefit confirmed in more recent, large studies with verified product quality?
• How safe is long-term use in children and adolescents?