Does supplemental melatonin suppress endogenous melatonin production?

Comment by InpharmD Researcher

Melatonin supplementation is most efficacious when endogenous melatonin levels are low (e.g. during daytime or in individuals who produce insufficient amounts of melatonin). The majority of studies suggest that melatonin supplementation does not suppress endogenous production even with long-term use (1 year).

Background

The 2015 American Academy of Sleep Medicines (AASM) guidelines for management of different circadian rhythm sleep-wake disorders support the use of strategically-timed melatonin for certain scenarios based on limited evidence (All WEAK recommendations):
Delayed sleep-wake phase disorder (DSWPD) in adults with/without depression and adolescents with/without psychiatric conditions.
24-hour sleep-wake rhythm disorder (N24SW) in blind adults.
Irregular sleep-wake rhythm disorders (ISWRD) in adolescents with neurological disorders. [1]

The 2017 AASM guidelines for primary insomnia do not recommend melatonin due to lack of quality evidence. An internal meta-analysis performed on three clinical trials in patients age > 55 years observing use of melatonin 2 mg nightly for 3 weeks did not find clinical significance (standardized mean difference [SMD] 0.21; 95% confidence interval -0.36 to 0.77) for sleep quality. Heterogeneity of included studies affected the review of other clinical parameters. Based on the limited data, melatonin did not observe significant clinical benefits on sleep latency, total sleep time, wake after sleep onset, quality of sleep, and sleep efficiency. [2]

The 2017 European Sleep Research Society guidelines for sleep disorders does not recommend melatonin for treatment of insomnia based on evidence from meta-analyses that question the clinical benefit. While melatonin may reduce sleep-onset latency and quality, the effect was modest at best (i.e. reducing time to sleep by only a couple of minutes). [3]

Natural Medicines Database supports the use of melatonin (likely effective) for delayed sleep phase syndrome (DSPS) to reduce the time to fall asleep. The conclusion was based on a series of clinical trials supported by meta-analysis which showed melatonin dose from 0.3 to 5 mg daily for 4 weeks improved sleep and quality of life. Long-term benefits, however, are not clear and there may be risk of relapse to pre-treatment sleeping status. Evidence for insomnia is also conflicting as the benefits seen were mostly a modest improvement in time to sleep with minor effect on sleep quality. [4]

Excretion of melatonin peaks between one to three years of age and is similar among genders. Endogenous melatonin secretion may decline with age. [5] People who suffer from an insufficient amount of environmental light may have decreased endogenous melatonin secretion. [6]

Melatonin supplementation is most efficacious when endogenous melatonin levels are low (e.g. during daytime or in individuals who produce insufficient amounts of melatonin). [7] Some conditions such as insomnia or depression can result in low levels of melatonin. [8]

A meta-analysis assessed fifty articles regarding melatonin safety, of those twenty-six found no statistically significant adverse events, while twenty-four articles reported on at least one statistically significant adverse event. The authors concluded melatonin adverse events were generally minor, short-lived, and easily managed, with the most commonly reported adverse events relating to fatigue, mood, or psychomotor and neurocognitive performance. [9]

Several studies, published more than twenty years ago, report exogenous melatonin does not suppress its endogenous production. [10], [11], [12]

References:

[1] Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2015;11(10):1199-236.
[2] Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(2):307-349.
[3] Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26(6):675-700.
[4] Melatonin. Natural Medicines Comprehensive Database. Therapeutic Research Center. Somerville, MA. Updated May 22, 2020. Accessed: June 15, 2020.
[5] Nathan PJ, Wyndham EL, Burrows GD, Norman TR. The effect of gender on the melatonin suppression by light: a dose response relationship. J Neural Transm (Vienna). 2000;107(3):271-279. doi:10.1007/s007020050022
[6] Cagnacci A, Soldani R, Yen SS. Contemporaneous melatonin administration modifies the circadian response to nocturnal bright light stimuli. Am J Physiol. 1997;272(2 Pt 2):R482-R486. doi:10.1152/ajpregu.1997.272.2.R482
[7] Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018;175(16):3190-3199. doi:10.1111/bph.14116
[8] Cardinali DP, Srinivasan V, Brzezinski A, Brown GM. Melatonin and its analogs in insomnia and depression. J Pineal Res. 2012;52(4):365-375. doi:10.1111/j.1600-079X.2011.00962.x
[9] Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Complement Ther Med. 2019;42:65-81
[10] Mallo C, Zaidan R, Faure A, Brun J, Chazot G, Claustrat B. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinol (Copenh). 1988;119:474–480.
[11] Lissoni P, Rovelli F, Pittalis S, et al. Therapy with melatonin does not suppress its endogenous production in healthy volunteers. Recenti Prog Med. 1999;90:84–85.
[12] Matsumoto M, Sack RL, Blood ML, Lewy AJ. The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. J Pineal Res. 1997;22:42–44.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Does supplemental melatonin suppress endogenous melatonin production?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Table 1 for your response.


 

 Prolonged-release melatonin for insomnia –an open-label long-term study of efficacy, safety, and withdrawal

Design

Data from a  prospective 6–12-month open-label study

N= 244

Objective

To investigate the efficacy, safety, and withdrawal phenomena associated with 6–12 months prolonged-release melatonin treatment

Study Groups

Completed 26 weeks (n= 112)

Completed 52 weeks  (n= 96)

Inclusion Criteria

Community-dwelling adults with primary insomnia, who had participated in a placebo-controlled, double-blind, dose-ranging trial of prolonged-release melatonin

Exclusion Criteria

Respiratory-related sleep disorders, circadian rhythm sleep disorders, dyssomnias not otherwise specified, sleep disorder secondary to medical conditions, significant psychiatric or neurological disorders (anxiety, depression, dementia, psychosis), or the use of hypnotic medications in the past 2 weeks

Methods

All participants had a 1 week run-in period with placebo (baseline) followed by a 6-week placebo-controlled dose ranging study with prolonged-release melatonin. Completers who gave their consent for the long-term study were allowed to enter the prospective 6–12 month open-label study. In this phase, all patients received open-label prolonged-release melatonin 2 mg (Circadin®). Participants were instructed to take the study medication regularly after their evening meal, 1–2 hours before bedtime and preferably between 21:00–22:00. Treatment compliance was monitored in all subjects using a monthly tablet count. 

Once the first 100 subjects had completed the 26-week (6  months) open-label period, they were not given the option to continue up to 52  weeks, as safety data for 26 weeks was requested by regulatory authorities. They therefore underwent the  2-week withdrawal period, their study was terminated, and their safety data were summarized (12 months), with a 2-week follow-up period without the study medication (withdrawal).

Duration

52 weeks

Outcome Measures

The main outcome measures were patient-reported sleep quality ratings (diary), adverse events, vital signs, and laboratory tests recorded at each visit, and withdrawal symptoms (CHESS-84 [Check-list Evaluation of Somatic Symptoms]). 

Nocturnal urinary  6-sulfatoxymelatonin (6SMT) excretion, a  measure of endogenous melatonin production, was assessed upon discontinuing long-term melatonin.

Demographics 

The mean age of the population was 55.3 ± 13.0 years and 69% were females. With the exception of one participant of Asian origin, all subjects were Caucasians.

Results

A  clear diurnal rhythm in melatonin production was evident in these patients, with levels of 6SMT over daytime hours (10:00–22:00) 9.80 ± 5.06 µg/12-hour day (range  3–19 µg/12-hour day), which was significantly lower than the night-time levels of  15.3  ±  7.7  µg (median 15  µg; range 4–30  µg; p < 0.01).

Adverse Events

Common Adverse Events: N/A

Percentage that Dropped Out of Study: 15%

Study Author Conclusions

Results support the efficacy and safety of melatonin in primary insomnia patients aged  20–80 throughout 6–12 months of continuous therapy. Discontinuation even after 12 months was not associated with adverse events, withdrawal symptoms, or suppression of endogenous melatonin production.

The long-term administration of prolonged-release melatonin did not cause suppression of endogenous melatonin production as evident by the rhythm in 6SMT in the urine. The presence of such rhythm also confirms that the 6SMT was endogenous rather than a  metabolite of the residual PRM discontinued 2 weeks before. The reported observations are confirmatory and compatible with earlier reports in the literature on the lack of the suppressing effect of exogenous melatonin on its endogenous production.

InpharmD Researcher Critique

While this study is open-labeled with a high dropout rate, it is the largest study to date examining endogenous melatonin production after melatonin supplementation. With this data, it does not appear that endogenous melatonin 



References:

Lemoine P, Garfinkel D, Laudon M, Nir T, Zisapel N. Prolonged-release melatonin for insomnia - an open-label long-term study of efficacy, safety, and withdrawal. Ther Clin Risk Manag. 2011;7:301-311. doi:10.2147/TCRM.S23036