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Last Update: August 8, 2022.

Continuing Education Activity

Synthetic melatonin is a dietary supplement. The FDA does not regulate supplements. Consequently, melatonin is not officially FDA-approved for any indication. However, melatonin receptor agonists such as ramelteon and tasimelteon are FDA-approved for the treatment of insomnia. Non-FDA-approved Indications for melatonin include insomnia. Despite the lack of FDA approval, melatonin is considered the first-line pharmacologic therapy for the treatment of insomnia by the American Academy of Family Physicians (AAFP). It is relatively safe with a low risk of side effects. There are other indications as well surrounding sleep-related concerns, including shift work and jet lag. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant melatonin interactions pertinent for interprofessional team members in treating patients with conditions where it is of clinical value.


  • Explain the mechanism of action of melatonin.
  • Identify the indications where exogenous melatonin might prove beneficial.
  • Review the potential adverse effects of melatonin.
  • Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might use supplemental melatonin.
Access free multiple choice questions on this topic.


Synthetic melatonin is a dietary supplement. The FDA does not regulate supplements. Therefore, melatonin is not officially FDA-approved for any indication. However, various melatonin receptor agonists are on the market, such as ramelteon and tasimelteon, which are FDA-approved for the treatment of insomnia.[1][2]

Non-FDA Approved Indications for Melatonin


Despite the lack of FDA approval, melatonin is considered the first-line pharmacologic therapy for the treatment of insomnia by the American Academy of Family Physicians (AAFP). It is relatively safe with a low risk of side effects. Studies on the efficacy of melatonin supplementation for the treatment of insomnia have varied. Still, one metanalysis by Ferracioli-Oda showed that subjects taking melatonin fell asleep an average of 7 minutes faster, stayed asleep about 8 minutes longer, and reported better sleep quality than subjects receiving a placebo. Doses used, results, and study quality varied considerably between trials.[3]

Melatonin has been studied and recommended primarily for the treatment of the following:[4][5][6][7]

  • Primary insomnia (insomnia not due to some secondary cause)
  • Age-related insomnia
  • Jet lag disorder
  • shift work sleep disorder
  • Post-traumatic brain injury
  • Neurodegenerative disorders

Ongoing Research

Although there are no formal recommendations currently, clinical research is ongoing on the role of melatonin treatment for other conditions, such as:[8][9][10][11]

  • Cancer
  • Metabolic disorders
  • Cardiovascular disorders
  • Gastrointestinal (GI) conditions
  • Neurodegenerative disorders
  • Mental disorders
  • Pain syndromes
  • Reproductive dysfunctions

Mechanism of Action

Synthesis of Endogenous Melatonin

Endogenous melatonin is a hormone produced naturally, synthesized, and secreted primarily in the pineal gland. Melatonin production begins with tryptophan, which is converted via a several-step pathway to serotonin in other parts of the brain. Some serotonin produced makes its way to the pineal gland, converted to melatonin in a cyclic, light-dependent process.[12]

The conversion of serotonin to melatonin is controlled by the hypothalamus's suprachiasmatic nucleus (SCN), the coordinator of the body's circadian rhythms. Information about low light to dark conditions travels from the retina along the retinohypothalamic tract to the SCN. The SCN, in turn, sends signals through the sympathetic nervous system to the superior cervical ganglia, which innervates the pineal gland. 

Sympathetic stimulation of the pineal gland upregulates the production of the enzyme arylalkylamine N-acetyltransferase (AA-NAT). AA-NAT functions to convert serotonin to N-acetyl-serotonin, the rate-limiting step in melatonin formation. This intermediate is then converted to melatonin. Studies have shown that bilateral surgical removal of the superior cervical ganglia or SCN in rats stops AA-NAT activation and eliminates the rhythmic pattern of melatonin secretion, which disrupts the sleep-wake cycle.[13][14][15]

Functions of Endogenous Melatonin

The best-known purpose of melatonin is its role in the promotion of sleep. Melatonin is released from the pineal gland into the third ventricle and from there into circulation. Melatonin is involved in regulating the body's sleep-wake cycles through its interactions with the suprachiasmatic nucleus of the hypothalamus and the retina, promoting sleep and inhibiting wake-promoting signals via interactions with its MT1 and MT2 receptors.[16]

Biological Mechanism of Melatonin According to Current Research

  • Cancer suppression: Activating tumor suppressor genes such as p53, oncostatic activity, modulation of estrogen and androgens, immunomodulation, increased cytokine production leading to cancer suppression. 
  • Bone deposition: MT2 receptors are found on osteoblasts, suggesting a role for melatonin in regulating their function.
  • Metabolic disorders: Anti-oxidative effects, anti-inflammatory effects, regulation of lipid and glucose metabolism.
  • Cardiovascular diseases: Anti-hypertensive effects
  • GI conditions: Anti-oxidative effects, anti-inflammatory effects
  • Neurodegenerative disorders: Activation of mitochondrial cell survival pathways that may protect against neurodegeneration caused by mitochondrial dysfunction. Regulation of apoptosis. Prevention of vasoconstriction of cerebral arteries.
  • Mental disorders: Anxiolytic; the melatonin receptor agonist agomelatine, is approved to treat depression in Europe. 
  • Pain syndromes: Anti-nociceptive, anti-inflammatory, and analgesic effects
  • Reproductive functions: Involvement in several pathways resulting in a reduced risk of complications, gonadotropic secretion, and higher rates of mature oocytes and quality embryos.[17][18][19]


Melatonin Content of Supplements

 FDA does not regulate supplements as supplements are generally presumed safe. However, this can lead to concerns about the actual concentrations of supplements, including melatonin. One study analyzed 31 melatonin supplements and found that actual melatonin content ranged from -83% to +478% of the labeled content.[20] Variable tablet content can make accurate dosing challenging and may be responsible for some of the wide ranges of efficacy reported in various trials. One way to assure correct dosing is to look for supplements with approval from the United States Pharmacopeia, an independent non-profit organization. Searching for supplements marked “USP verified” can help assure the quality and dosing of supplements.

Routes of Administration [21] [22]

  • Oral tablet
  • Oral liquid
  • Rectal suppository
  • Transdermal patch

Formulations [23]

  • Immediate-release
  • Extended-release
  • Combined immediate and extended-release


As the FDA does not regulate melatonin as a drug, effective dosing is not well-defined. The dose used in studies varied from 0.1 to 10 mg, administered up to two hours before bedtime.

Maximum Dosage

Not defined in trials

Elimination Half-Life

One to two hours, depending on the formulation


Highly variable, 1% to 74%, likely dependent on formulation and dose


Ninety percent of melatonin is metabolized in the liver primarily by the enzyme CYP1A2. Metabolism of melatonin occurs by hydroxylation, converting it to 6-Hydroxymelatonin. Consequently, it is conjugated to sulfuric or glucuronic acid and excreted in the urine. A smaller amount is excreted in feces.[24]

Adverse Effects

Melatonin is relatively non-toxic, although some mild side-effects have been reported with higher doses and extended-release formulations, including:[25]

  • Drowsiness
  • Daytime sleepiness
  • Headaches
  • Nausea

No evidence suggests that people develop tolerance to melatonin. Avoid melatonin with benzodiazepines or zolpidem as it can lead to excessive sedation.[26]


Pregnancy and Breastfeeding

Pregnant or breastfeeding women should avoid the use of melatonin due to insufficient evidence of safety.[19][27]

Renal Dosing

Clinicians should exercise caution for patients undergoing dialysis due to the risk of increased adverse effects due to the inability to adequately clear melatonin.[28]

Hepatic Dosing

Clinicians should exercise caution in patients with impaired liver functioning due to decreased ability to metabolize melatonin. Nevertheless, based upon several clinical trials, researchers concluded that melatonin doesn't cause hepatotoxicity. Likelihood score: E (unlikely cause of clinically apparent liver injury).[29]

Autoimmune Conditions

Clinicians should exercise caution for patients with some autoimmune diseases such as rheumatoid arthritis or post-organ transplant. Melatonin stimulates the function of the immune system via the production of interleukins IL-1, IL-2, IL-6, and IL-12, interferon-gamma, helper T cells, cytotoxic T cells, B-cell precursors, and T-cell precursors. However, the clinical significance of this effect is not yet precise.[30]


  • Monitor for improvement in insomnia.
  • Monitor for adverse drug reactions such as daytime sleepiness and headache related to melatonin therapy.[31]


  • The acute toxicity of melatonin, as observed in both animal and human studies, is remarkably low. Melatonin may cause minor adverse drug reactions, such as headache, insomnia, rash, gastritis, and nightmares at supraphysiological doses. Researchers could not discover an LD50 (lethal dose for 50% of the subjects) in animals. Melatonin is not fatal even at a dose of 800 mg/kg in animal studies.
  • In humans, preliminary observations suggest that long-term melatonin administration is associated with decreased semen quality in several healthy men, probably through aromatase inhibition at the testicular level.[32]

Enhancing Healthcare Team Outcomes

Insomnia is a common complaint seen in both the outpatient and inpatient setting. Melatonin is a safe first-line sleep aid that may help promote a regular sleep cycle. In addition, melatonin is one of the few over-the-counter supplements that healthcare providers can recommend for insomnia. Although not FDA-approved, melatonin is widely used for insomnia and jet lag disorders. Hence, all the pertinent healthcare providers need to know the mechanism, off-label indications, adverse effects of melatonin.

The patient often takes melatonin as an over-the-counter supplement. However, clinicians(MDs, DOs, NPs, PAs) can recommend melatonin for insomnia and jet lag disorders. Pharmacists should counsel the patient regarding the adverse effect of melatonin and not combine it with other CNS depressants such as benzodiazepines and alcohol. In addition, it is important to counsel the patient that the FDA does not regulate supplements, and there is no FDA approval for melatonin. Nursing staff can monitor response to melatonin therapy.

If insomnia fails to resolve with melatonin therapy, the clinician should seek psychiatrist consultation for underlying disorders. The patient may also require sleep medicine physician consultation if the clinician suspects primary sleep disorders. As depicted above, multiple healthcare providers, including clinicians(MDs, DOs, NPs, PAs), pharmacists, nurses, and specialists, can be involved in patient care related to melatonin therapy if needed. Consequently, a collaborative interprofessional team approach with patient-centered care can achieve optimal benefits related to melatonin therapy. [level 5]

Review Questions


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Neubauer DN. Tasimelteon for the treatment of non-24-hour sleep-wake disorder. Drugs Today (Barc). 2015 Jan;51(1):29-35. [PubMed: 25685859]
Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773. [PMC free article: PMC3656905] [PubMed: 23691095]
Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520. [PubMed: 12076414]
Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EEK, Soh CK, Car J. Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action. BMC Med. 2018 Feb 05;16(1):18. [PMC free article: PMC5798185] [PubMed: 29397794]
Grima NA, Rajaratnam SMW, Mansfield D, Sletten TL, Spitz G, Ponsford JL. Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial. BMC Med. 2018 Jan 19;16(1):8. [PMC free article: PMC5774131] [PubMed: 29347988]
Gringras P, Nir T, Breddy J, Frydman-Marom A, Findling RL. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957.e4. [PubMed: 29096777]
Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017 Jun 13;8(24):39896-39921. [PMC free article: PMC5503661] [PubMed: 28415828]
Sun H, Gusdon AM, Qu S. Effects of melatonin on cardiovascular diseases: progress in the past year. Curr Opin Lipidol. 2016 Aug;27(4):408-13. [PMC free article: PMC4947538] [PubMed: 27075419]
Shukla M, Govitrapong P, Boontem P, Reiter RJ, Satayavivad J. Mechanisms of Melatonin in Alleviating Alzheimer's Disease. Curr Neuropharmacol. 2017;15(7):1010-1031. [PMC free article: PMC5652010] [PubMed: 28294066]
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Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005 Feb;9(1):11-24. [PubMed: 15649735]
Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018 Aug;175(16):3190-3199. [PMC free article: PMC6057895] [PubMed: 29318587]
Mul Fedele ML, Galiana MD, Golombek DA, Muñoz EM, Plano SA. Alterations in Metabolism and Diurnal Rhythms following Bilateral Surgical Removal of the Superior Cervical Ganglia in Rats. Front Endocrinol (Lausanne). 2017;8:370. [PMC free article: PMC5767240] [PubMed: 29375476]
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Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008 Jul;85(3):335-53. [PubMed: 18571301]
Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A. A Review of Melatonin, Its Receptors and Drugs. Eurasian J Med. 2016 Jun;48(2):135-41. [PMC free article: PMC4970552] [PubMed: 27551178]
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Carrillo-Vico A, Lardone PJ, Alvarez-Sánchez N, Rodríguez-Rodríguez A, Guerrero JM. Melatonin: buffering the immune system. Int J Mol Sci. 2013 Apr 22;14(4):8638-83. [PMC free article: PMC3645767] [PubMed: 23609496]
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Luboshitzky R, Shen-Orr Z, Nave R, Lavi S, Lavie P. Melatonin administration alters semen quality in healthy men. J Androl. 2002 Jul-Aug;23(4):572-8. [PubMed: 12065466]
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