Melatonin as a medication and supplement
Clinical data | |
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Pronunciation | /ˌmɛləˈtoʊnɪn/ ⓘ |
Trade names | Circadin, Slenyto, others[1] |
Other names | N-Acetyl-5-methoxy tryptamine[2] |
AHFS/Drugs.com | Consumer Drug Information |
License data | |
Pregnancy category |
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Dependence liability | Physical: Low[4]
Psychological: Low Physiological data |
Source tissues | Pineal gland |
Target tissues | Widespread, including brain, retina, and circulatory system |
Receptors | Melatonin receptor |
Precursor | N-Acetylserotonin |
Metabolism | Liver via CYP1A2 mediated 6-hydroxylation |
Legal status | |
Legal status | |
5-methoxytryptamine | |
Elimination half-life | IR: 20–60 minutes[7][9][10] PR: 3.5–4 hours[11][8] |
Excretion | Kidney |
Identifiers | |
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JSmol) | |
Melting point | 117 °C (243 °F) |
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Melatonin is a
Side effects from melatonin supplements are minimal at low doses for short durations (in the studies reported about equally for both melatonin and placebo).
Melatonin acts as an
Melatonin was discovered in 1958.
Medical uses
Insomnia
There is no good evidence that melatonin helps treat insomnia and its attempted use for this purpose is recommended against by the American Academy of Sleep Medicine.[28]
A
Circadian rhythm sleep disorders
Melatonin may be useful in the treatment of delayed sleep phase syndrome.[9]
Melatonin is known to reduce jet lag, especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation.[30]
Melatonin appears to have limited use against the sleep problems of people who work shift work.[31] Tentative evidence suggests that it increases the length of time people are able to sleep.[31]
REM sleep behavior disorder
Melatonin is a safer alternative than
Dementia
A 2020
Available forms
A
Melatonin is also available as an
The American Academy of Sleep Medicine (AASM) said that the melatonin content in unregulated (without a USP verified mark) supplements can diverge widely from the claimed amount; a study found that the melatonin content ranged from one half to four times the stated dose.[41]
Contraindications
Adverse effects
Melatonin appears to cause very few
There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor.[46] Specifically, taking exogenous melatonin shortly after a meal is correlated with impaired glucose tolerance. Therefore, Rubio-Sastre and colleagues recommend waiting at least 2 hours after the last meal before taking a melatonin supplement.[47]
Melatonin can cause
]Melatonin can lower follicle-stimulating hormone levels.[51] Melatonin's effects on human reproduction remain unclear.[52]
Some supplemental melatonin users report an increase in
Increased use of melatonin in the 21st century has significantly increased reports of melatonin overdose, calls to poison control centers, and related emergency department visits for children. The number of children who unintentionally ingested melatonin supplements in the US has increased 530% from 2012 to 2021. Over 4,000 reported ingestions required a hospital stay, and 287 children required intensive care. The American Academy of Sleep Medicine says there is little evidence that melatonin supplementation is effective in treating insomnia in healthy children.[41]
Overdose
Melatonin appears to be relatively safe in
Interactions
Melatonin is
In those taking warfarin, some evidence suggests there may exist a potentiating interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.[54]
Pharmacology
Pharmacodynamics
Melatonin acts as an
Pharmacokinetics
Absorption
The
Distribution
The
The membrane transport proteins that move melatonin across a membrane include, but are not limited to, glucose transporters, including GLUT1, and the proton-driven oligopeptide transporters PEPT1 and PEPT2.[57][58]
Metabolism
Melatonin is
Elimination
In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva.[13] Melatonin is excreted in the urine 2 to 5% as the unchanged drug.[6][8]
Melatonin has an
Chemistry
Melatonin, also known as N-acetyl-5-methoxytryptamine, is a
History
The first
It was approved for medical use in the European Union in 2007.[8]
Society and culture
Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada.[13] FDA regulations applying to medications are not applicable to melatonin,[63] though the FDA has found false claims that it cures cancer.[64] As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin.[30] In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.[65] According to Harriet Hall caution is advisable, since quality control is a documented problem. 71% of products did not contain within 10% of the labelled amount of melatonin, with variations ranging from -83% to +478%, lot-to-lot variability was as high as 465%, and the discrepancies were not correlated to any manufacturer or product type. To make matters worse, 8 out of 31 products were contaminated with the neurotransmitter serotonin.[66][67]
Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic, which limits the risk of contamination or the means of transmitting infectious material.[63][68]
Melatonin is the most popular over-the-counter sleep remedy in the United States, resulting in sales in excess of US$400 million during 2017.[69] In 2021, it was the 257th most commonly prescribed medication in the US, with more than 1 million prescriptions.[26][27]
Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.[70] The FDA considered whether these food products could continue to be sold with the label "dietary supplements". On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a food additive.[71] Bebida Beverage Company received a warning letter in 2015 for selling a melatonin-containing beverage.[72]
Research
Psychiatry
Depression
Some research supports an antidepressant effect of melatonin.[73]
Bipolar disorder
Melatonin, along with ramelteon, has been repurposed as a possible adjunctive treatment for manic episodes in bipolar disorder.[74] However, meta-analytic evidence is somehow inconsistent and of limited interest so far, although the small samples of trials do not allow ruling out its beneficial effect.[74] In any case, current evidence does not support the use of add-on melatonin-receptor agonists for mania.[74]
Anxiety
Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with benzodiazepine in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.[75]
Headaches
Tentative evidence shows melatonin may help reduce some types of headaches including cluster and hypnic headaches.[76][77]
Cancer
A 2013 review by the National Cancer Institute found insufficient evidence for melatonin having anti-cancer effects.[78] A 2022 review found that melatonin supplementation had a small improvement in survival of people with cancer at one year.[79][80] One review found that melatonin may alleviate chemotherapy-related side effects.[81]
Protection from radiation
Both animal
Epilepsy
A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.[88]
Dysmenorrhea
A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhea secondary to endometriosis.[89]
Delirium
A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.[90]
Gastroesophageal reflux disease
A 2011 review said melatonin is effective in relieving
Tinnitus
A 2015 review of studies of melatonin in tinnitus found the quality of evidence low, but not entirely without promise.[92]
References
- ^ "Melatonin – Drugs.com". Drugs.com. Retrieved 12 October 2018.
- ^ "Melatonin". Sleepdex. Retrieved 17 August 2011.
- ^ a b https://www.tga.gov.au/resources/auspar/auspar-melatonin-1
- ^ a b c "Pros and cons of melatonin". Mayo Clinic. Retrieved 20 August 2022.
- ^ https://www.tga.gov.au/resources/auspar/auspar-melatonin-link-immela-melakso-voquily
- ^ PMID 28503116.
- ^ PMID 33540815.
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y Circadin: EPAR - Product Information ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS (Report). European Medicines Agency (EMA). 2 February 2021. EMEA/H/C/000695 - IA/0066. As PDF. Archived 31 October 2022 at the Wayback Machine Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ PMID 28648359.
- ^ S2CID 38857779.
- ^ S2CID 1403262.
- ^ ISBN 978-0-323-32602-5.
- ^ PMID 15635761. Retrieved 5 June 2013.
- ^ PMID 28671376.
- ^ ISBN 978-0-85711-338-2.
- PMID 26844312.
Evidence for benzodiazepine hypnotics, melatonin agonists in the general adult population, and most pharmacologic interventions in older adults was generally insufficient
- ^ a b c d e "Melatonin: Side Effects, Uses, Dosage (Kids/Adults)". Drugs.com. Retrieved 9 January 2019.
- ^ a b "Slenyto EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 31 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ a b "Summary Safety Review – MELATONIN (N-acetyl-5-methoxytryptamine) – Review of the Safety of Melatonin in Children and Adolescents". Government of Canada. Health Canada. 10 December 2015. Retrieved 9 January 2019.
- ^ a b c "Melatonin- Oral". Government of Canada. Health Canada. 28 August 2018. Retrieved 9 January 2019.
- ^ S2CID 235744969.
- ^ a b "Melatonin". www.drugbank.ca. Retrieved 29 January 2019.
- ^ "Australian Public Assessment Report for Melatonin" (PDF). Australian Government Department of Health and Ageing Therapeutic Goods Administration. January 2011. pp. 2, 4. Retrieved 9 January 2019.
Monotherapy for the short term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.
- PMID 27500861.
- S2CID 3578916.
- ^ a b "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
- ^ a b "Melatonin - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
- ISBN 9781009000611.
- ^ S2CID 71158456.
- ^ PMID 12076414.
- ^ PMID 25113164.
- PMID 23352028.
- PMID 28592453.
- PMID 26029267.
- ^ PMID 33410930.
- PMID 33189083.
- S2CID 53101746.
- S2CID 88265944.
- ^ Soca R (28 February 2021). "Melatonin Product Availability". Keldik Sleep Circadian and Performance.
- PMID 29397794.
- ^ a b Brooks M (23 September 2022). "Experts Issue Health Warning About Giving Melatonin to Kids". Medscape.
- PMID 16423108.
- PMID 16473858.
- ^ "Melatonin: What You Need To Know". NCCIH. National Institutes of Health. Retrieved 2 July 2021.
- ^ Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. 2014.
- PMID 31901302.
- PMID 25197811.
- ^ Bauer B. "Melatonin side effects: What are the risks?". Mayo Clinic. Retrieved 17 August 2011.
- PMID 11602091.
- PMID 18626968.
- PMID 16921343. Archived from the originalon 2 November 2014. Retrieved 24 December 2013.
- S2CID 3442003.
- ISBN 978-0-87983-734-1.
- ^ "Melatonin – Special Subjects". Merck Manuals Professional Edition.
- PMID 16295212.
- ISBN 978-3-8055-9120-1.
- ^ PMID 27314810.
- ^ S2CID 10920415.
- ^ "Method for minimizing disturbances in circadian rhythms of bodily performance and function - Patent US-4665086-A - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 16 April 2022.
- ^ US patent 5449683, Wurtman RJ, "Methods of inducing sleep using melatonin", issued 12 September 1995, assigned to Massachusetts Institute of Technology
- S2CID 19011222.
There is very little evidence in the short term for toxicity or undesirable effects in humans. The extensive promotion of the miraculous powers of melatonin in the recent past did a disservice to acceptance of its genuine benefits.
- PMID 11027748.
- ^ S2CID 18050554.
- ^ "187 Fake Cancer 'Cures' Consumers Should Avoid". U.S. Food and Drug Administration. Archived from the original on 2 May 2017. Retrieved 20 May 2020.
- S2CID 31090576.
- ^ Hall H (15 December 2020). "Melatonin Melatonin supplements are increasingly popular, but the evidence is weak and mixed". Science-Based Medicine. Science Based Medicine. Retrieved 24 December 2020.
- PMID 27855744.
- ^ "Melatonin". Drugs.com. Retrieved 17 August 2011.
- ^ Loria K. "Does Melatonin Really Help You Sleep?". Consumer Reports. Retrieved 16 March 2019.
- ^ Louis CS (14 May 2011). "Dessert, Laid-Back and Legal". The New York Times.
- ^ Rodriguez RR (13 January 2010). "Warning Letter". Inspections, Compliance, Enforcement, and Criminal Investigations. U.S. Food and Drug Administration. Archived from the original on 12 January 2017.
- ^ "Bebida Beverage Company". U.S. Food and Drug Administration. 4 March 2015. Archived from the original on 1 June 2020. Retrieved 8 December 2017.
- PMID 29512136.
- ^ S2CID 237485915.
- PMID 33319916.
- S2CID 28114683.
- S2CID 1196313. Retrieved 12 January 2018.
- PMID 26389506.
- S2CID 263492993.
- PMID 29397794.
- S2CID 38488628.
- PMID 10082913.
- PMID 9008723.
- PMID 27000311.
- PMID 9541644.
- S2CID 40005308.
- PMID 17641465.
- PMID 27513702.
- PMID 27000311.
- PMID 26967259.
- PMID 20082715.
- S2CID 16466238.