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Our library offers providers with in-depth reviews of ingredients commonly found in supplements. Each review contains information about the ingredient’s clinical applications, formulations, dosing and administration, adverse effects, and pharmacokinetics.

Melatonin

Melatonin is a hormone produced by the pineal gland and synthesized from tryptophan and serotonin. It can also be produced by enterochromaffin cells in the GI tract. (87) Melatonin is primarily involved in the regulation of sleep patterns. Endogenous melatonin increases as the retinas signal the pineal gland with diminishing light, providing crucial information in the regulation of sleep-wake cycles and core body temperatures. (10) Melatonin plays a role in circadian rhythm regulation, reproduction, mood, and immunity. It also has anti-oxidative effects and possesses properties that protect against pain, inflammation, and anxiety. (35)

Main uses

  • Headaches, migraines, and pain
  • Neurodegenerative conditions
  • Neurological conditions
  • Primary and secondary sleep disorders
  • Sleep promotion
 

Formulations

Route of administration Approximate time to achieve max plasma/serum concentrations (Cmax)

Intravenous

5 minutes

Intranasal

10 minutes

Sublingual tablets

40 minutes; higher achievable Cmax than oral tablets

Oral tablets

40 minutes

Slow-release oral tablets

2 hours and 45 minutes

Transmucosal patch

8 hours

Transdermal patch

8.5-13 hours

Transdermal nanoparticle gel

13-18 hours (35)(99)

Dosing & administration

Atopic dermatitis

General outcomes from A-level evidence

No data currently available.

Dosing & administration

3-6 mg per day, one hour before bedtime for 4-6 weeks in children

Outcomes
SCORAD index, and sleep onset latency IgE levels at higher doses (8)(86)
Class of evidence


B
Beta-blocker-induced insomnia
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
2.5 mg adjunct to atenolol 25-100 mg/day) or metoprolol (50-100 mg/day) 1 hour before bedtime for 3 weeks in adults

Outcomes
total sleep time, sleep efficiency, and Stage 2 sleep; sleep onset latency which persists upon discontinuation (72)
Class of evidence


C
Blindness-associated sleep disturbances
General outcomes from A-level evidence
No data currently available.
Dosing & administration
10 mg per day, 1 hour before bedtime until entrainment achieved and taper-reduced to 0.5 mg over 3 months in adults

Outcomes
 sleep duration time awake after 1st sleep onset, and day-time napping (31)(67)
Class of evidence


C
Dosing & administration
5 mg (slow-release) per day 1-2 hours before bedtime for 3-6 weeks in adults

Outcomes
sleep duration to a clinically relevant degree, but with no statistical significance (66)(68)
 
Class of evidence


C
Cluster headaches
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
10 mg per day in the evening for 2 weeks

Outcomes
cluster headache frequency within 3-5 days Headaches may resume upon discontinuation (45)

Class of evidence

C
Delayed sleep phase syndrome
General outcomes from A-level evidence
No data currently available.
Dosing & administration
5 mg per day, 3-4 hours before bedtime for 2-4 weeks in adults

Outcomes
sleep onset latency, wake time and total sleep time, reports of sleepiness and fatigue, and nocturnal melatonin profile onset by ~1.5 hours (12)(41)(55)
 
Class of evidence


C
Dosing & administration
5 mg per day in the evening for 4 weeks in adults with depressive symptoms

Outcomes
 CES-D and Hamilton Depression Rating Scale-17 depression scores, and sleep discontinuity (65)
 
Class of evidence


C
Dosing & administration
0.3-3 mg (slow- release) per day, 1.5-6.5 hours before dimming of light for 4 weeks in adults

Outcomes
 time to melatonin production from circadian phase, with greater efficacy the earlier the administration before dim light (54)
Class of evidence


C
Endometriosis
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
10 mg per day at bedtime for 8 weeks in adults
Outcomes
sleep quality pain and dysmenorrhea by ~40%, risk of use of other analgesics by 80%, and BNDF levels (75)
Class of evidence
C
Epilepsy
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3 mg per day, 30 minutes before bedtime adjunct to AEDs for 3 months in children

Outcomes
 seizure frequency especially at night sleep efficiency and continuity (61)(88)
Class of evidence


C
Dosing & administration
6 mg (<30 kg; 30 kg; >age of 9)(fast- or slow-release) as add-on therapy to AEDs within 1 hour of bedtime for 4-8 weeks in children

Outcomes
 GSH-Px and GSSG-Rd activities Improves attention, memory, language subscale scores in measures of QoL (29)(30)
Class of evidence


C
Fibromyalgia
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3-5 mg alone or combined with fluoxetine, or 10 mg alone or combined with amitriptyline per day for 6-8 weeks in adults

Outcomes
 pain, and Fibromyalgia Impact Score (FIQ) scores inhibitory action of the endogenous pain-modulating system (14)(37)
Class of evidence


B
Insomnia (primary)
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
0.05-0.15 mg/kg, or 5 mg per day, 1-2 hours before dim-light onset for 1-4 weeks in children

Outcomes
time to ‘lights-off’, sleep onset and melatonin onset, sleep offset, and sleep latency sleep duration, general health scores, and function status scores; Sleep onset, onset latency and dim-light melatonin onset increases with earlier circadian time of administration (80)(81)(90)
Class of evidence


B
Dosing & administration
0.3-2 mg (slow- release) per day, 1-2 hours before bedtime after the evening meal for 3-weeks to 6 months in the elderly with melatonin deficiency

Outcomes
sleep quality/efficiency, maintenance, morning alertness, QoL, and Clinical Global Impression (CGI) scores sleep latency, sleep initiation time, and wake-time after sleep onset May improve daytime psychomotor performance. No withdrawal upon discontinuation, or build up of tolerance (18)(32)(44)(52)(92)(93)(95)(100)
Class of evidence


B
Irritable bowel syndrome
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3-5 mg per day at bedtime for 2-8 weeks in adults

Outcomes
abdominal pain, bloating and constipation rectal pain threshold Improves overall IBS, extracolonic IBS, and QoL scores (9)(51)(69)(82)
Class of evidence


B
Jet lag
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
0.5-5mg (fast-release) close to bedtime at the destination of travel for 3 days prior to flight and 3-5 days post-flight in adults

Outcomes
jet lag symptoms including compromised sleep quality, greater time to sleep onset, fatigue and daytime sleepiness, and days to normalize sleep patterns rate of jet lag prevention; most effective when travelling east and over 5 time zones (36)(62)(63)(83)(84)
Class of evidence


A
Dosing & administration
2 mg (slow-release) at night at the destination of travel for 4 days after arrival in adults

Outcomes
time to fall asleep, number of awakenings and time spent awake after sleep onset sleep duration and quality to the same extent as zopiclone
May not be as effective as fast-release formulations (60)(84)
Class of evidence


C
Migraine
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3 mg (fast-release) or 4 mg (slow-release) for < 3 months in adults

Outcomes
 migraine prophylaxis with similar efficacy to amitriptyline (6)(20)(50)
 
Class of evidence


A
Multiple sclerosis
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
25 mg per day, 1 hour before bedtime for 6 months in adults

Outcomes
 serum pro-inflammatory cytokines and markers of oxidative stress (71)
 
 
Class of evidence


C
Nocturnal hypertension
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
2-3 mg (slow- release) per day, 1-2 hours before bedtime for 3-4 weeks in adults

Outcomes
SBP and DBP (7)(25)(73)
Class of evidence


A
Dosing & administration
1.5-2 mg per day, 1-2 hours before bedtime for 2-4 weeks in the elderly

Outcomes
SBP and DBP (26)(27)
Class of evidence


C
Polycystic ovarian syndrome
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
10 mg per day, 1 hour before bedtime for 12 weeks in adults

Outcomes
sleep quality, insulin sensitivity, and PPAR-γ and LDL-R expression anxiety and depression scores, insulin, HOMA-IR, total cholesterol, and LDL-C (77)
 
 
Class of evidence


B
Pre-surgical anxiety and sedation
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3-10 mg, 60-100 minutes prior to standard anesthetic administration in adults

Outcomes
anxiety, sedation; most effective in combination with alprazolam; no cognitive/psychomotor impairment as seen with midazolam anxiety as effectively as gabapentin anxiety before, during, and after surgery, perioperative pain, fentanyl requirements, and with higher doses intraocular pressure in cataract surgery (1)(38)(43)(56)(64)
Class of evidence


B
Dosing & administration
0.1-0.5 mg/kg with/without acetaminophen or paracetamol 45 minutes before anaesthetic administration in children

Outcomes
 pre-operative anxiety as effectively as midazolam, dose of propofol needed for anaesthesia compared with midazolam, post-operative agitation as effectively as dexmedetomidine and midazolam, post-operative excitement and sleep disturbance 2 weeks post-surgery; as effective as midazolam to induce sedation (19)(59)(70)
Class of evidence


B
Radio- chemotherapy-induced side effects
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
20 mg per day at night starting 7 days prior to and adjunct with radiotherapy and chemotherapy

Outcomes
 risk of asthenia, cachexia, fatigue, hypotension leukopenia, nausea/vomiting, myelosuppression, neurotoxicity, thrombocytopenia (47)(48)(49)(76)(96)
Class of evidence


A
Rapid eye movement sleep behavior disorder
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3 mg per day 30 minutes before bedtime for 4 weeks in adults

Outcomes
number of 30‐s REM sleep epochs without muscle atonia CGI score (42)
Class of evidence


C
Sleep disturbance in Alzheimer’s disease
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
2 mg (slow- release) per day, 1-2 hours before bedtime for 24 weeks with standard therapy in the elderly

Outcomes
 sleep efficiency, cognitive performance measured by Instrumental Activities of Daily Living (IADL), and Mini-Mental State Examination (MMSE) scores (94)
Class of evidence


B
Dosing & administration
3-6 mg (fast- release) per day, 30 minutes to 2 hours before bedtime for 10 days in the elderly with mild cognitive impairment or Alzheimer’s type dementia

Outcomes
 rest-activity rhythm, sleep quality, and duration sleep onset latency, and nocturnal activity; May improve ADAS cognition and non-cognition scores (4)(40)
Class of evidence


C
Sleep disturbance in attention deficit hyperactivity disorder
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3 mg (40kg) (fast-release) per day in the evening for 4 weeks in children

Outcomes
time to sleep onset, and dim light melatonin onset sleep duration (9)
Class of evidence


B
Sleep disturbance in autism spectrum disorder
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
2-5 mg (slow- release) per day for 10 days and titrated up to 15 mg (if unresponsive) 20-30 minutes before bedtime for up to 3-4 months in children

Outcomes
sleep latency by ~30 minutes sleep duration, sleep efficiency with higher doses, clinician and parent impressions of improvement May improve externalizing behaviors (11)(24)(74)(97)(98)
Class of evidence


B
Sleep disturbance in cystic fibrosis
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3 mg per day, 2 hours before bedtime for 3 weeks in children and young adults

Outcomes
 sleep efficiency exhaled breath condensate nitrite (13)
Class of evidence


C
Sleep disturbance in depression
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
5-10 mg (slow- release) per day at night for 4 weeks adjunct to fluoxetine in adults

Outcomes
 sleep quality (15)
Class of evidence


C
Sleep disturbance in epilepsy
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
6 mg (<30 kg; 30 kg; >age of 9)(fast- or slow-release) as add-on therapy to AEDs within 1 hour of bedtime for 4-8 weeks in children

Outcomes
sleep latency and wakefulness after sleep onset, REM sleep duration, parasomnias score, and total sleep score slow-wave sleep duration and REM latency (28)(39)
Class of evidence


C
Sleep disturbance in neurodevelopmental disorders
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
0.5 mg (fast- release) titrated up to 12 mg over 4 weeks if unresponsive, 45 minutes before bedtime for 12 weeks in children

Outcomes
 sleep duration sleep onset latency, but may wake up earlier (3)(23)(97)
Class of evidence


B
Sleep disturbance in Parkinson’s disease
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
3-5 mg per day, within 1 hour before bedtime for 1 for 2-4 weeks in adults

Outcomes
sleep quality and quantity sleep disturbance, and daytime sleepiness (16)(53)
Class of evidence


C
Dosing & administration
50 mg per day, 30 minutes before bedtime for 2 weeks in adults

Outcomes
 sleep duration (16)
Class of evidence


C
Dosing & administration
25 mg twice per day for 1 year in adults

Outcomes
COX-2 activity, levels of nitrates/nitrites and lipoperoxides (58)
 
Class of evidence


C
Sleep disturbance in schizophrenia
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
2-3 mg (slow- release) for 2-3 weeks

Outcomes
sleep efficiency/quality, depth and duration, morning alertness, mood, and daytime functioning awakenings, and sleep onset latency (78)(85)
Class of evidence


C
Sleep disturbance in traumatic brain injury
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
2 mg (slow- release) per day, 2 hours before bedtime for 4 weeks in adults

Outcomes
 sleep quality, efficiency, and scores for vitality and mental health scores for anxiety, depression and fatigue (22)
Class of evidence


C
Sleep disturbance in tuberous sclerosis
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
5-10 mg per day, 20 minutes before bedtime for 2 weeks in children

Outcomes
sleep duration Normalizes melatonin patterns in responders and higher doses may continue to improve sleep latency, duration and fragmentation (33)(34)(57)
Class of evidence


C
Temporo-mandibular disorders
General outcomes from A-level evidence
No data currently available.
 
Dosing & administration
5 mg per day at bedtime for 4 weeks in adults

Outcomes
pain scores, and use of other analgesics pain threshold (91)
Class of evidence


C

Adverse effects

Melatonin is generally considered safe with short-term oral administration, even with large doses. However, it is not recommended to take melatonin if pregnant or breast-feeding. (2) The most common adverse effects are considered mild and may include dizziness, headaches, nausea, sleepiness, or hypothermia. Most cases are resolved within a few days or upon discontinuation. Rare cases of agitation, fatigue, mood swings, nightmares, skin irritation, and heart palpitations have been reported. (5)

Pharmacokinetics

Absorption

  • The oral bioavailability of melatonin is approximately 15%. 
  • Oral immediate-release formulations result in maximum plasma concentrations after approximately 45 minutes. 
  • Slow-release formulations result in maximum plasma concentrations after approximately 2 hours and 45 minutes. (35)
  • Sublingual preparations are absorbed at a rate comparable to oral formulations but result in higher maximal plasma concentrations by bypassing first pass metabolism. (99)

Distribution

  • Melatonin is widely distributed to tissues with Melatonin receptors (ML1) and (ML2). (87)
  • Melatonin is both lipid- and water-soluble, and can readily cross the blood-brain barrier. (46)
  • Melatonin receptors are widely located in cardiovascular tissues, T and B lymphocytes, and adipocytes, as well as in the adrenal glands, kidneys, lungs, liver, gallbladder, small intestine, ovaries, uterus, breasts, prostate, and skin. (87)

Metabolism

  • Extensive first-pass metabolism likely contributes to melatonin’s low oral bioavailability, particularly due to its high affinity to CYP1A2. (17)
  • Melatonin is primarily metabolized in the liver by CYP1A2, with smaller metabolic activity from CYP2C19 and CYP2C9. 
  • Some metabolism may occur in the intestines or skin by CYP1A1 and CYP1B1. (79)

Excretion

  • Melatonin is excreted in the urine.
  • Most melatonin is excreted in its sulfurated (~90%) or glucuronidated-forms (~10%), though up to 5% may be expelled in its unmetabolized form. (87)
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