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Ingredient review

Melatonin

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Description

What is it?

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)

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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

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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