Ingredient review —Melatonin
What is it?
Description
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
Dosing & administration
Atopic dermatitis
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
Class of evidence
c
Central serous chorioretinopathy
General outcomes from A-level evidence
No data currently available.
Dosing & administration
3 mg three times per day for 1 month in adults
Outcomes
best-corrected visual acuity
central macular thickness (21)
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
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
Class of evidence
c
Dosing & administration
6 mg (<30 kg; < age of 9) to 9 mg (>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
Class of evidence
c
Fibromyalgia
General outcomes from A-level evidence
No data currently available.
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
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
Class of evidence
b
Irritable bowel syndrome
General outcomes from A-level evidence
No data currently available.
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
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
Class of evidence
c
Migraine
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
Class of evidence
a
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
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.
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
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) or 6 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 (89)
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
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; < age of 9) to 9 mg (>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
Class of evidence
c
Sleep disturbance in neurodevelopmental disorders
General outcomes from A-level evidence
No data currently available.
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
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
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.
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)
References
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