Practice Based Learning: What’s Worth Knowin’ about Melatonin?

Robert Gonsalves

Presented by Rob Gonsalves III, DO (PGY-2)

Clinical Question:

  • Is there such a thing as a toxic dose of Melatonin?


  • Regulates circadian rhythm
  • Synthesized in pineal gland
  • Inhibited by light
  • Retina → SCN → Superior Cervical Ganglion → Pineal Gland
  • Tryptophan is a precursor

Melatonin for sleep:

  • Sleep Onset Latency (SOL): Time from laying down to onset of stage 1 sleep
    • 30 minutes is average
    • Difference of 15 min is “clinically important”
  • Up to 25% of Peds Population has difficulties initiating and maintaining sleep
  • Primary Sleep Disorder:
    • No medical etiology, idiopathic
  • Secondary Sleep Disorders:
    • Associated with medical, neurologic, or substance misuse disorders
  • ADHD: Reports have shown ~60% of children on stimulant medication experience insomnia
    • Vander Hiejden 2007: DB RCT of 105 children
      • Not on stimulant medication
      • 3 mg qhs <40 kg, 6 mg qhs >40 kg
      • Reduction in SOL of 24 minutes
      • Increased total sleep time 33 minutes
    • Tjon Pain Gi 2003: Open Label study of 27 children on methylphenidate: reduction in SOL anywhere from 1-3 hours depending on duration of tx
  • Autism Spectrum Disorders
    • Anderson 2008: Cohort study of 107 children:
      • 60% reported improved sleep
      • 1% reported worse sleep
      • Remaining either no sleep concerns, no effect on sleep, undetermined

Other applications:

Disclaimer: Larger RCTs Needed!

  • As an antioxidant:
    • Free Radical Scavenger
    • Stimulation of antioxidative enzymes
      • GSH Peroxidase, GSH Reductase, G6PD, SOD
    • Enhances Efficiency of Electron Transport Chain (ETC)
  • Promising results in reducing oxidative stress in the NICU:
    • Perinatal asphyxia
    • Adjuvant treatment in sepsis
    • Respiratory Distress Syndrome
    • Neonatal surgery
  • Newborn feeding:
    • Melatonin in BM reflects circadian rhythm
    • “Day Milk” vs “Night Milk”
    • Time-appropriate milk improved sleep parameters in one DB study
  • Pediatric Anesthesia:
    • Premedication: Varying results when compared to midazolam
  • Neuroprotection in epilepsy:
    • Possibly related to antioxidant properties
  • Adolescent Idiopathic Scoliosis (AIS):
    • Melatonin decreased in patient’s with AIS
    • Prospective Analysis: 40 pts with moderate – severe AIS
      • 22 had “normal” melatonin – 16 of which had stable scoliosis
      • 16 with low melatonin treated: 12 developed stable, 4 progressive

Adverse events:

  • Few serious events associated with melatonin use
  • Headache, dizziness, nausea, drowsiness, rash
  • Report of 6 children with neurological deficits found increased seizure frequency
  • Other reports with children on AEDs showed no adverse events
  • British Questionnaire of 1,918 children on melatonin
    • 18% had adverse events: new onset/increased sz frequency, hyperactivity, agitation, nightmares, constipation
    • Uncontrolled Setting – unclear if attributable to melatonin
  • Possible effect on Luteinizing Hormone
  • Few reports of gynecomastia
  • Case report of autoimmune hepatitis

Melatonin overdose?

  • Severe toxicity has not been reported
  • Lexicomp: “A median lethal dose has not been determined, even at extremely high doses”
    • Human volunteers taking 6g of melatonin nightly for 1 month had no adverse reactions
  • Acute overdose is not expected to result in any significant clinical toxicity
  • Cited adverse affects discussed previously


Sánchez-Barceló EJ, et al. Clinical uses of melatonin in pediatrics. Int J Pediatr. 2011; 2011:892624.

Shamseer L, Vohra S. Complementary, holistic, and integrative medicine: melatonin. Pediatr Rev. 2009 Jun;30(6):223-8.

Reiter RJ, et al. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol. 2003;50(4):1129-46.

Seabra ML, et al. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000 Nov;29(4):193-200.

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