Melatonin as a medication and supplement explained

Watchedfields:changed
Verifiedrevid:646778032
Drug Name:Melatonin
Tradename:Circadin, Slenyto, others[1]
Dailymedid:Melatonin
Pregnancy Au:B3
Dependency Liability:Physical: Low[2] Psychological: Low
Addiction Liability:Low / none
Routes Of Administration:By mouth, sublingual, transdermal
Class:Melatonin receptor agonist
Receptors:Melatonin receptor
Precursor:N-Acetylserotonin
Source Tissues:Pineal gland
Target Tissues:Widespread, including brain, retina, and circulatory system
Atc Prefix:N05
Atc Suffix:CH01
Legal Au:S4
Legal Au Comment:[3] [4]
Legal Ca:OTC
Legal Uk:POM
Legal Us:OTC
Legal Eu:Rx, OTC
Legal Status:Rx-only
Bioavailability:2.5–50%
Protein Bound:60%
Metabolism:Liver via CYP1A2 mediated 6-hydroxylation
Metabolites:6-Hydroxymelatonin, N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine
Elimination Half-Life:

20–60minutes[5]
: 3.5–4hours

Excretion:Kidney
Cas Number:73-31-4
Pubchem:896
Iuphar Ligand:224
Drugbank:DB01065
Chemspiderid:872
Unii:JL5DK93RCL
Kegg:D08170
Chebi:16796
Chembl:45
Niaid Chemdb:160011
Synonyms:N-Acetyl-5-methoxy tryptamine[6]
Iupac Name:N-[2-(5-Methoxy-1''H''-indol-3-yl)ethyl]acetamide
C:13
H:16
N:2
O:2
Smiles:COC1=CC2=C(NC=C2CCNC(C)=O)C=C1
Stdinchi:1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16)
Stdinchikey:DRLFMBDRBRZALE-UHFFFAOYSA-N
Melting Point:117

Melatonin is a dietary supplement and medication as well as naturally occurring hormone.[7] As a hormone, melatonin is released by the pineal gland and is involved in sleep–wake cycles. As a supplement, it is often used for the attempted short-term treatment of disrupted sleep patterns, such as from jet lag or shift work, and is typically taken orally.[8] There is evidence of its benefit for this use, however, it is not strong.[9] A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.[10]

Side effects from melatonin supplements are minimal at low doses for short durations (in the studies reported about equally for both melatonin and placebo).[11] Side effects of melatonin are rare but may occur in 1 to 10 patients in 1,000. They may include somnolence (sleepiness), headaches, nausea, diarrhea, abnormal dreams, irritability, nervousness, restlessness, insomnia, anxiety, migraine, lethargy, psychomotor hyperactivity, dizziness, hypertension, abdominal pain, heartburn, mouth ulcers, dry mouth, hyperbilirubinaemia, dermatitis, night sweats, pruritus, rash, dry skin, pain in the extremities, symptoms of menopause, chest pain, glycosuria (sugar in the urine), proteinuria (protein in the urine), abnormal liver function tests, increased weight, tiredness, mood swings, aggression and feeling hungover. Its use is not recommended during pregnancy or breastfeeding or for those with liver disease.[12]

Melatonin acts as an agonist of the melatonin MT1 and MT2 receptors, the biological targets of endogenous melatonin.[13] It is thought to activate these receptors in the suprachiasmatic nucleus of the hypothalamus in the brain to regulate the circadian clock and sleep–wake cycles. Immediate-release melatonin has a short elimination half-life of about 20 to 50minutes. Prolonged-release melatonin used as a medication has a half-life of 3.5 to 4hours.

Melatonin was discovered in 1958.[14] It is sold over the counter in Canada and the United States;[15] in the United Kingdom, it is a prescription-only medication.[16] In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54.[17] In the European Union, it is indicated for the treatment of insomnia in children and adolescents.[18] The US Food and Drug Administration (FDA) treats melatonin as a dietary supplement and as such has not approved it for any medical uses. It was approved for medical use in the European Union in 2007. Besides melatonin, certain synthetic melatonin receptor agonists like ramelteon, tasimelteon, and agomelatine are also used in medicine.[19] [20] In 2021, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.[21] [22]

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.[23]

A prolonged-release form of melatonin is approved for use as a medication in Europe for the treatment of insomnia in certain people.

Circadian rhythm sleep disorders

Melatonin may be useful in the treatment of delayed sleep phase syndrome.

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.[24]

Melatonin appears to have limited use against the sleep problems of people who work shift work.[25] Tentative evidence suggests that it increases the length of time people are able to sleep.

REM sleep behavior disorder

Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson's disease and dementia with Lewy bodies.[26] [27] [28] However, clonazepam may be more effective.[29] In any case, the quality of evidence for both treatments is very low and it is unclear whether either is definitely effective.

Dementia

A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease.[30] A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect.[31] Melatonin may, however, help with sundowning (increased confusion and restlessness at night) in people with dementia.[32]

Available forms

A prolonged-release 2mg oral formulation of melatonin sold under the brand name Circadin is approved for use in the European Union in the short-term treatment of insomnia in people age 55 and older.[33] [34]

Melatonin is also available as an over-the-counter dietary supplement in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3mg to 10mg or more. It is also possible to buy raw melatonin powder by the weight.[35] Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, oral films, or liquids.[36] It is also available for use sublingually, or as transdermal patches.[37] Several inhalation-based melatonin products with a wide range of doses are being sold but the safety remains to be evaluated.

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.

Contraindications

Contraindications of melatonin include hypersensitivity reactions among others. It is not recommended in people with autoimmune diseases due to lack of data in these individuals. Prolonged-release pharmaceutical melatonin (Circadin) contains lactose and should not be used in people with the lactase deficiency or glucose–galactose malabsorption. Use of melatonin is also not recommend in women who are pregnant or breastfeeding or in people with liver disease.

Adverse effects

Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses. Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials, and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo.[38] [39] Prolonged-release melatonin is safe with long-term use of up to 12 months.[40] Although not recommended for long-term use beyond this,[41] low-dose melatonin is generally safer, and a better alternative, than many prescription and over-the-counter sleep aids if a sleeping medication must be used for an extended period of time. Low doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect but instead appear to cause drowsiness for a longer period of time.[42]

There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor.[43] 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.[44]

Melatonin can cause nausea, next-day grogginess, and irritability.[45] In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.[46] [47]

Melatonin can lower follicle-stimulating hormone levels.[48] Melatonin's effects on human reproduction remain unclear.[49]

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy.[50]

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.[51]

Overdose

Melatonin appears to be relatively safe in overdose. It has been administered at daily doses of up to 300mg without causing clinically significant adverse reactions in the literature. The most commonly reported adverse effect of melatonin overdose is somnolence. Upon melatonin overdose, drowsiness may be expected and the compound should be cleared within 12hours. No special treatment is needed for melatonin overdose.

Interactions

Melatonin is metabolized mainly by CYP1A enzymes. As such, inhibitors and inducers of CYP1A enzymes, such as CYP1A2, can modify melatonin metabolism and exposure. As an example, the CYP1A2 and CYP2C19 inhibitor fluvoxamine increases melatonin peak levels by 12-fold and overall exposure by 17-fold and this combination should be avoided. CYP1A2 inducers like cigarette smoking, carbamazepine, and rifampicin may reduce melatonin exposure due to induction of CYP1A2.

In those taking warfarin, some evidence suggests there may exist a potentiating interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.[52]

Pharmacology

Pharmacodynamics

Melatonin acts as an agonist of the melatonin MT1 and MT2 receptors, the biological targets of endogenous melatonin. Endogenous melatonin is normally secreted from the pineal gland of the brain. Melatonin is thought to activate melatonin receptors in the suprachiasmatic nucleus of the hypothalamus to regulate the circadian clock and sleep–wake cycles. When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg[53]) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.[54]

Pharmacokinetics

Absorption

The bioavailability of melatonin is between 2.5 and 50%. Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60minutes of administration, and is then eliminated.[55] Usual doses of exogenous melatonin of 1 to 12mg produce melatonin concentrations 10 to 100times higher than endogenous peak levels.[56]

Distribution

The plasma protein binding of melatonin is approximately 60%. It is mainly bound to albumin, α1-acid glycoprotein, and high-density lipoprotein.

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 metabolized in the liver by cytochrome P450 enzyme CYP1A2 to 6-hydroxymelatonin. Metabolites are conjugated with sulfuric acid or glucuronic acid for excretion in the urine. Some of the metabolites formed via the reaction of melatonin with a free radical include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).

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. Melatonin is excreted in the urine 2 to 5% as the unchanged drug.

Melatonin has an elimination half-life of about 20 to 60 minutes.[59] The half-life of prolonged-release melatonin (Circadin) is 3.5 to 4hours.

Chemistry

Melatonin, also known as N-acetyl-5-methoxytryptamine, is a substituted tryptamine and a derivative of serotonin (5-hydroxytryptamine). It is structurally related to N-acetylserotonin (normelatonin; N-acetyl-5-hydroxytryptamine), which is the chemical intermediate between serotonin and melatonin in the body. Synthetic melatonin receptor agonists used in medicine like ramelteon, tasimelteon, agomelatine, and piromelatine (still in clinical trials) are analogues of melatonin.

History

The first patent for its use in circadian rhythm disorders was granted in 1987 to Roger V Short and Stuart Armstrong at Monash University,[60] and the first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995.[61] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.[62] The New England Journal of Medicine editorialized in 2000: "With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear."[63]

It was approved for medical use in the European Union in 2007.

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. FDA regulations applying to medications are not applicable to melatonin,[64] though the FDA has found false claims that it cures cancer.[65] 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. In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.[66] 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.[67] [68]

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.[69]

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.[70] In 2021, it was the 257th most commonly prescribed medication in the US, with more than 1million prescriptions.

Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.[71] 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.[72] Bebida Beverage Company received a warning letter in 2015 for selling a melatonin-containing beverage.[73]

Research

Psychiatry

Depression

Some research supports an antidepressant effect of melatonin.[74]

Bipolar disorder

Melatonin, along with ramelteon, has been repurposed as a possible adjunctive treatment for manic episodes in bipolar disorder.[75] 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. In any case, current evidence does not support the use of add-on melatonin-receptor agonists for mania.

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.[76]

Headaches

Tentative evidence shows melatonin may help reduce some types of headaches including cluster and hypnic headaches.[77] [78]

Cancer

A 2013 review by the National Cancer Institute found insufficient evidence for melatonin having anti-cancer effects.[79] A 2022 review found that melatonin supplementation had a small improvement in survival of people with cancer at one year.[80] [81] One review found that melatonin may alleviate chemotherapy-related side effects.[82]

Protection from radiation

Both animal[83] and human[84] [85] [86] studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species which are generated during exposure.[87] Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without known, major side effects.[88]

Epilepsy

A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.[89]

Dysmenorrhea

A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhea secondary to endometriosis.[90]

Delirium

A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.[91]

Gastroesophageal reflux disease

A 2011 review said melatonin is effective in relieving epigastric pain and heartburn.[92]

Tinnitus

A 2015 review of studies of melatonin in tinnitus found the quality of evidence low, but not entirely without promise.[93]

Notes and References

  1. News: Melatonin – Drugs.com. Drugs.com. 12 October 2018.
  2. Web site: Pros and cons of melatonin . 20 August 2022 . Mayo Clinic . en.
  3. https://www.tga.gov.au/resources/auspar/auspar-melatonin-1
  4. https://www.tga.gov.au/resources/auspar/auspar-melatonin-link-immela-melakso-voquily
  5. Hardeland R, Poeggeler B, Srinivasan V, Trakht I, Pandi-Perumal SR, Cardinali DP . Melatonergic drugs in clinical practice . Arzneimittelforschung . 58 . 1 . 1–10 . 2008 . 18368944 . 10.1055/s-0031-1296459 . 38857779 .
  6. Web site: Melatonin. Sleepdex. 17 August 2011.
  7. Book: Faraone SV . ADHD: Non-Pharmacologic Interventions, An Issue of Child and Adolescent Psychiatric Clinics of North America, E-Book . 2014 . Elsevier Health Sciences . 978-0-323-32602-5 . 888 .
  8. Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T . Melatonin for treatment of sleep disorders . Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services . 5 June 2013 . November 2004 . Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, Under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Rockville, MD: Agency for Healthcare Research and Quality . 108 . 1–7 . 10.1037/e439412005-001 . 15635761 . 4781368 .
  9. Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, Koffel E, Khawaja IS, Ouellette J, Butler M, Kane RL, Wilt TJ . Management of Insomnia Disorder[Internet] . AHRQ Comparative Effectiveness Reviews . 15 . 16 . EHC027–EF . 2015 . 26844312 . Evidence for benzodiazepine hypnotics, melatonin agonists in the general adult population, and most pharmacologic interventions in older adults was generally insufficient .
  10. Matheson E, Hainer BL . Insomnia: Pharmacologic Therapy . American Family Physician . 96 . 1 . 29–35 . July 2017 . 28671376 .
  11. Web site: Melatonin: Side Effects, Uses, Dosage (Kids/Adults). 9 January 2019. Drugs.com.
  12. Web site: Melatonin- Oral . Government of Canada . Health Canada . 9 January 2019 . 28 August 2018 . 1 April 2019 . https://web.archive.org/web/20190401003412/http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=melatonin.oral&lang=eng . dead .
  13. Book: Pevet P, Challet E, Felder-Schmittbuhl MP . Melatonin and the circadian system: Keys for health with a focus on sleep . The Human Hypothalamus: Anterior Region . Handbook of Clinical Neurology . 179 . 331–343 . 2021 . 34225973 . 10.1016/B978-0-12-819975-6.00021-2 . 9780128199756 . 235744969 .
  14. Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL . Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders . Sleep Medicine Reviews . 34 . 10–22 . August 2017 . 28648359 . 10.1016/j.smrv.2016.06.005 . 20.500.11820/0e890bda-4b1d-4786-a907-a03b1580fd07 . free .
  15. Web site: Summary Safety Review – MELATONIN (N-acetyl-5-methoxytryptamine) – Review of the Safety of Melatonin in Children and Adolescents . Government of Canada . Health Canada . 9 January 2019 . 10 December 2015.
  16. Book: British national formulary : BNF 76. 2018. Pharmaceutical Press. 978-0-85711-338-2. 482–483. 76.
  17. Web site: Australian Public Assessment Report for Melatonin . Australian Government Department of Health and Ageing Therapeutic Goods Administration . 9 January 2019 . 2, 4 . January 2011. Monotherapy for the short term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over. .
  18. Web site: Slenyto EPAR . European Medicines Agency (EMA) . 17 September 2018 . 31 May 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  19. Williams WP, McLin DE, Dressman MA, Neubauer DN . Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders . Pharmacotherapy . 36 . 9 . 1028–41 . September 2016 . 27500861 . 5108473 . 10.1002/phar.1822 .
  20. Gabriella Gobbi . Atkin T, Comai S, Gobbi G . Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery . Pharmacol Rev . 70 . 2 . 197–245 . April 2018 . 29487083 . 10.1124/pr.117.014381 . 3578916 . free .
  21. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  22. Web site: Melatonin - Drug Usage Statistics . ClinCalc . 14 January 2024.
  23. Book: Pseudoscience in Therapy: A Skeptical Field Guide . Hupp S, Santa Maria CL . Chapter 10: Insomnia . Carney CE, Lau PH, Kutana S. 147–148 . 2023 . Cambridge University Press . 9781009000611 . 10.1017/9781009000611.011 .
  24. Herxheimer A, Petrie KJ . Melatonin for the prevention and treatment of jet lag . The Cochrane Database of Systematic Reviews . 2 . CD001520 . 2002 . 2010 . 12076414 . 10.1002/14651858.CD001520 . 8958662 .
  25. Liira J, Verbeek JH, Costa G, Driscoll TR, Sallinen M, Isotalo LK, Ruotsalainen JH . Pharmacological interventions for sleepiness and sleep disturbances caused by shift work . The Cochrane Database of Systematic Reviews . 2014 . 8 . CD009776 . August 2014 . 25113164 . 10.1002/14651858.CD009776.pub2 . 10025070 .
  26. McCarter SJ, Boswell CL, St Louis EK, Dueffert LG, Slocumb N, Boeve BF, Silber MH, Olson EJ, Tippmann-Peikert M . Treatment outcomes in REM sleep behavior disorder . Sleep Medicine . 14 . 3 . 237–42 . March 2013 . 23352028 . 3617579 . 10.1016/j.sleep.2012.09.018 . Review .
  27. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VM, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O'Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K . Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium . Neurology . 89 . 1 . 88–100 . July 2017 . 28592453 . 5496518 . 10.1212/WNL.0000000000004058 . Review .
  28. Boot BP . Comprehensive treatment of dementia with Lewy bodies . Alzheimer's Research & Therapy . 7 . 1 . 45 . 2015 . 26029267 . 4448151 . 10.1186/s13195-015-0128-z . Review . free .
  29. Gilat M, Marshall NS, Testelmans D, Buyse B, Lewis SJ . A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials . J Neurol . 269 . 1 . 125–148 . January 2022 . 33410930 . 8739295 . 10.1007/s00415-020-10353-0 . free .
  30. McCleery J, Sharpley AL . Pharmacotherapies for sleep disturbances in dementia . The Cochrane Database of Systematic Reviews . 2020 . CD009178 . November 2020 . 11 . 33189083 . 10.1002/14651858.CD009178.pub4 . 8094738 .
  31. Spinedi E, Cardinali DP . Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer's Disease and Melatonin . Neuroendocrinology . 108 . 4 . 354–364 . 2019 . 30368508 . 10.1159/000494889 . 53101746 . free . 11336/86560 . free .
  32. Book: Gao C, Scullin MK, Bliwise DL . Mild Cognitive Impairment and Dementia . 2019 . Handbook of Sleep Disorders in Medical Conditions . 253–276 . Savard J, Ouellet MC. Academic Press . 10.1016/b978-0-12-813014-8.00011-1 . 978-0-12-813014-8. 88265944 .
  33. Wade A, Downie S . Prolonged-release melatonin for the treatment of insomnia in patients over 55 years . Expert Opin Investig Drugs . 17 . 10 . 1567–72 . October 2008 . 18808316 . 10.1517/13543784.17.10.1567 . 71158456 .
  34. Circadin: EPAR - Product Information ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS. 2 February 2021. EMEA/H/C/000695 - IA/0066. European Medicines Agency (EMA). As PDF. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  35. Web site: Soca R. 28 February 2021. Melatonin Product Availability. Keldik Sleep Circadian and Performance. 11 April 2022. 27 May 2022. https://web.archive.org/web/20220527143716/https://keldik.com/blogs/sleep-circadian-binnacle/melatonin-product-availability. dead.
  36. Kolli AR, Kuczaj AK, Calvino-Martin F, Hoeng J . Simulated pharmacokinetics of inhaled caffeine and melatonin from existing products indicate the lack of dosimetric considerations . Food and Chemical Toxicology . 187 . 114601 . May 2024 . 38493979 . 10.1016/j.fct.2024.114601 . free .
  37. Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EE, Soh CK, Car J . Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action . BMC Medicine . 16 . 1 . 18 . February 2018 . 29397794 . 5798185 . 10.1186/s12916-017-1000-8 . free .
  38. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S . The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis . Journal of General Internal Medicine . 20 . 12 . 1151–8 . December 2005 . 16423108 . 1490287 . 10.1111/j.1525-1497.2005.0243.x .
  39. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G . Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis . BMJ . 332 . 7538 . 385–93 . February 2006 . 16473858 . 1370968 . 10.1136/bmj.38731.532766.F6 .
  40. Lyseng-Williamson KA . Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years . Drugs & Aging . 29 . 11 . 911–23 . November 2012 . 23044640 . 10.1007/s40266-012-0018-z . 1403262 .
  41. Web site: Melatonin: What You Need To Know . NCCIH . National Institutes of Health . 2 July 2021.
  42. 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.
  43. Garaulet M, Qian J, Florez JC, Arendt J, Saxena R, Scheer FA . Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy . Trends in Endocrinology and Metabolism . 31 . 3 . 192–204 . March 2020 . 31901302 . 7349733 . 10.1016/j.tem.2019.11.011 .
  44. Rubio-Sastre P, Scheer FA, Gómez-Abellán P, Madrid JA, Garaulet M . Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening . Sleep . 37 . 10 . 1715–9 . October 2014 . 25197811 . 4173928 . 10.5665/sleep.4088 .
  45. Web site: Melatonin side effects: What are the risks?. Mayo Clinic. Bauer B . 17 August 2011.
  46. Morera AL, Henry M, de La Varga M . [Safety in melatonin use] . es . Actas Españolas de Psiquiatría . 29 . 5 . 334–7 . 2001 . 11602091 . Safety in melatonin use .
  47. Terry PD, Villinger F, Bubenik GA, Sitaraman SV . Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research . Inflammatory Bowel Diseases . 15 . 1 . 134–40 . January 2009 . 18626968 . 10.1002/ibd.20527 . free .
  48. Juszczak M, Michalska M . [The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion] ]. pl . Postepy Higieny I Medycyny Doswiadczalnej . 60 . 431–8 . 2006 . 16921343 . The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion . 24 December 2013 . https://web.archive.org/web/20141102054834/http://www.phmd.pl/fulltxthtml.php?ICID=453297 . 2 November 2014 . dead .
  49. Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A . Melatonin and human reproduction: shedding light on the darkness hormone . Gynecological Endocrinology . 25 . 12 . 779–85 . December 2009 . 19905996 . 10.3109/09513590903159649 . 3442003 .
  50. Book: Melatonin and the Biological Clock . Lewis A . McGraw-Hill . 978-0-87983-734-1 . 1999 . 23 . registration .
  51. Web site: Brooks M . Experts Issue Health Warning About Giving Melatonin to Kids . Medscape . 23 September 2022 .
  52. Web site: Melatonin – Special Subjects. Merck Manuals Professional Edition.
  53. Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC . Phase-dependent treatment of delayed sleep phase syndrome with melatonin . Sleep . 28 . 10 . 1271–8 . October 2005 . 16295212 . 10.1093/sleep/28.10.1271 . free .
  54. Book: Terman MR, Wirz-Justice A . Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy . limited . S Karger Pub . Basel . 2009 . 71 . 978-3-8055-9120-1 .
  55. Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C . Melatonin: Pharmacology, Functions and Therapeutic Benefits . Current Neuropharmacology . 15 . 3 . 434–443 . April 2017 . 28503116 . 5405617 . 10.2174/1570159X14666161228122115 .
  56. Lalanne S, Fougerou-Leurent C, Anderson GM, Schroder CM, Nir T, Chokron S, Delorme R, Claustrat B, Bellissant E, Kermarrec S, Franco P, Denis L, Tordjman S . Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder . Int J Mol Sci . 22 . 3 . February 2021 . 1490 . 33540815 . 7867370 . 10.3390/ijms22031490 . free .
  57. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP . Update on melatonin receptors: IUPHAR Review 20 . British Journal of Pharmacology . 173 . 18 . 2702–25 . September 2016 . 27314810 . 4995287 . 10.1111/bph.13536.
  58. Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R . Melatonin transport into mitochondria . Cellular and Molecular Life Sciences . 74 . 21 . 3927–3940 . November 2017 . 28828619 . 10.1007/s00018-017-2616-8 . 10920415 . 11107582 .
  59. Web site: Melatonin . www.drugbank.ca . 29 January 2019.
  60. Web site: Method for minimizing disturbances in circadian rhythms of bodily performance and function - Patent US-4665086-A - PubChem . 16 April 2022 . pubchem.ncbi.nlm.nih.gov.
  61. US . 5449683 . patent . Methods of inducing sleep using melatonin . 12 September 1995 . 16 July 1993 . Wurtman RJ . Massachusetts Institute of Technology .
  62. Arendt J . Melatonin: characteristics, concerns, and prospects . Journal of Biological Rhythms . 20 . 4 . 291–303 . August 2005 . 16077149 . 10.1177/0748730405277492 . 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. . free .
  63. Arendt J . Melatonin, circadian rhythms, and sleep . The New England Journal of Medicine . 343 . 15 . 1114–6 . October 2000 . 11027748 . 10.1056/NEJM200010123431510 .
  64. Altun A, Ugur-Altun B . Melatonin: therapeutic and clinical utilization . International Journal of Clinical Practice . 61 . 5 . 835–45 . May 2007 . 17298593 . 10.1111/j.1742-1241.2006.01191.x . 18050554 . free .
  65. Web site: 187 Fake Cancer 'Cures' Consumers Should Avoid . . https://web.archive.org/web/20170502034227/https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/enforcementactivitiesbyfda/ucm171057.htm . 2 May 2017 . 20 May 2020.
  66. Guardiola-Lemaître B . Toxicology of melatonin . Journal of Biological Rhythms . 12 . 6 . 697–706 . December 1997 . 9406047 . 10.1177/074873049701200627 . 31090576 . free .
  67. Web site: Harriet Hall . Hall H . Melatonin Melatonin supplements are increasingly popular, but the evidence is weak and mixed. . Science-Based Medicine . 15 December 2020 . Science Based Medicine . 24 December 2020.
  68. Erland LA, Saxena PK . Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content . Journal of Clinical Sleep Medicine . 13 . 2 . 275–281 . February 2017 . 27855744 . 5263083 . 10.5664/jcsm.6462 .
  69. Web site: Melatonin. Drugs.com. 17 August 2011.
  70. Web site: Does Melatonin Really Help You Sleep? . Loria K . Consumer Reports. 16 March 2019.
  71. News: Dessert, Laid-Back and Legal . . 14 May 2011 . Louis CS .
  72. Web site: Warning Letter . Rodriguez RR . 13 January 2010 . Inspections, Compliance, Enforcement, and Criminal Investigations . U.S. Food and Drug Administration . dead . https://wayback.archive-it.org/7993/20170112195035/http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm201435.htm . 12 January 2017 . dmy-all .
  73. Web site: Bebida Beverage Company. U.S. Food and Drug Administration. 4 March 2015. 8 December 2017. https://web.archive.org/web/20200601144105/http://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/bebida-beverage-company-03042015. 1 June 2020.
  74. Valdés-Tovar M, Estrada-Reyes R, Solís-Chagoyán H, Argueta J, Dorantes-Barrón AM, Quero-Chávez D, Cruz-Garduño R, Cercós MG, Trueta C, Oikawa-Sala J, Dubocovich ML, Benítez-King G . Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression . British Journal of Pharmacology . 175 . 16 . 3200–3208 . August 2018 . 29512136 . 6057892 . 10.1111/bph.14197 .
  75. Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G . Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials . Journal of Psychiatric Research . September 2021 . 143 . 230–238 . 10.1016/j.jpsychires.2021.09.018. 34509090 . 237485915 .
  76. Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM. 8 December 2020. Melatonin for pre- and postoperative anxiety in adults. The Cochrane Database of Systematic Reviews. 2020. 12 . CD009861. 10.1002/14651858.CD009861.pub3. 33319916. 8092422.
  77. Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA . Potential therapeutic use of melatonin in migraine and other headache disorders . Expert Opinion on Investigational Drugs . 15 . 4 . 367–75 . April 2006 . 16548786 . 10.1517/13543784.15.4.367 . 28114683 .
  78. Evers S, Goadsby PJ . 2005 . Review: Hypnic headache . Practical Neurology . 5 . 3. 144–49 . 12 January 2018. 10.1111/j.1474-7766.2005.00301.x . 1196313 . free .
  79. Book: PDQ Cancer Information Summaries [Internet] ]. Topics in complementary and alternative therapies . May 2013 . 26389506 . National Cancer Institute, National Institutes of Health. ((PDQ Integrative, Alternative, and Complementary Therapies Editorial Board)) .
  80. Lim S, Park S, Koyanagi A, Yang JW, Jacob L, Yon DK, Lee SW, Kim MS, Il Shin J, Smith L . Effects of exogenous melatonin supplementation on health outcomes: An umbrella review of meta-analyses based on randomized controlled trials . Pharmacological Research . 176 . 106052 . February 2022 . 34999224 . 10.1016/j.phrs.2021.106052 . 263492993 . 24 January 2023 . 31 March 2023 . https://web.archive.org/web/20230331122137/https://arro.anglia.ac.uk/id/eprint/707412/1/Lim_et_al_2022.pdf . dead .
  81. Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EE, Soh CK, Car J . Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action . BMC Medicine . 16 . 1 . 18 . February 2018 . 29397794 . 5798185 . 10.1186/s12916-017-1000-8 . free .
  82. Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL . The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials . Cancer Chemotherapy and Pharmacology . 69 . 5 . 1213–1220 . May 2012 . 22271210 . 10.1007/s00280-012-1828-8 . 38488628 .
  83. Meltz ML, Reiter RJ, Herman TS, Kumar KS . Melatonin and protection from whole-body irradiation: survival studies in mice . Mutation Research . 425 . 1 . 21–7 . March 1999 . 10082913 . 10.1016/S0027-5107(98)00246-2 . 1999MRFMM.425...21V .
  84. Reiter RJ, Herman TS, Meltz ML . Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers . Mutation Research . 371 . 3–4 . 221–8 . December 1996 . 9008723 . 10.1016/S0165-1218(96)90110-X .
  85. Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J . Dietary supplements for dysmenorrhoea . The Cochrane Database of Systematic Reviews . 2016 . 3 . CD002124 . March 2016 . 27000311 . 10.1002/14651858.cd002124.pub2 . 7387104 .
  86. Reiter RJ, Herman TS, Meltz ML . Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes . Mutation Research . 397 . 2 . 203–8 . February 1998 . 9541644 . 10.1016/S0027-5107(97)00211-X . 1998MRFMM.397..203V .
  87. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ . One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? . Journal of Pineal Research . 42 . 1 . 28–42 . January 2007 . 17198536 . 10.1111/j.1600-079X.2006.00407.x . 40005308 . free .
  88. Shirazi A, Ghobadi G, Ghazi-Khansari M . A radiobiological review on melatonin: a novel radioprotector . Journal of Radiation Research . 48 . 4 . 263–72 . July 2007 . 17641465 . 10.1269/jrr.06070 . 2007JRadR..48..263S . free .
  89. Brigo F, Igwe SC, Del Felice A . Melatonin as add-on treatment for epilepsy . The Cochrane Database of Systematic Reviews . 8 . CD006967 . August 2016 . 2016 . 27513702 . 10.1002/14651858.CD006967.pub4 . 7386917 .
  90. Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J . Dietary supplements for dysmenorrhoea . The Cochrane Database of Systematic Reviews . 2016 . CD002124 . March 2016 . 3 . 27000311 . 10.1002/14651858.CD002124.pub2 . 7387104 .
  91. Siddiqi N, Harrison JK, Clegg A, Teale EA, Young J, Taylor J, Simpkins SA . Interventions for preventing delirium in hospitalised non-ICU patients . The Cochrane Database of Systematic Reviews . 2016 . CD005563 . March 2016 . 3 . 26967259 . 10.1002/14651858.CD005563.pub3 . 10431752 .
  92. Kandil TS, Mousa AA, El-Gendy AA, Abbas AM . The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease . BMC Gastroenterology . 10 . 7 . January 2010 . 20082715 . 2821302 . 10.1186/1471-230X-10-7 . free .
  93. Miroddi M, Bruno R, Galletti F, Calapai F, Navarra M, Gangemi S, Calapai G . Clinical pharmacology of melatonin in the treatment of tinnitus: a review . European Journal of Clinical Pharmacology . 71 . 3 . 263–70 . March 2015 . 25597877 . 10.1007/s00228-015-1805-3 . 16466238 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Melatonin as a medication and supplement".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.