Is there evidence that long term daily use of melatonin causes harm?

Is there evidence that long term daily use of melatonin causes harm?

Comment by InpharmD Researcher

As with many supplements, large-scale, long-term evidence for melatonin is lacking. Current data are limited to several small studies that suggest no definitive increase in adverse effects occurs with prolonged use of melatonin, and suggest that long-term melatonin exposure would not significantly influence endogenous melatonin levels. However, studies are generally characterized by small sample sizes and a lack of comparative design, and effect of melatonin dosage and timing also require further investigation. Patient-specific monitoring is warranted with chronic melatonin use to ensure both long-term efficacy and safety.

Background

A 2021 international task force expert opinion suggested melatonin is well-tolerated with the most frequent adverse events being headache, dizziness, and nausea; no serious adverse events have been reported. However, as the majority of evidence for melatonin use is short-term, it is unclear how long-term use may impact patient health. [1]

A 2023 narrative review examined chronic administration of melatonin, focusing on its physiological and clinical implications. The review collated data from multiple sources, including PubMed and Google Scholar, incorporating both recent and older studies relevant to its subject matter. Melatonin's effectiveness in inducing sleep was detectable though modest for the general population. While optimal dosage remains unspecified, melatonin's short-term adverse effects were noted as minimal and typically resolving upon cessation of use. Moreover, long-term studies did not show significant differences between melatonin and placebo in terms of adverse outcomes, suggesting safety at low to moderate dosages, particularly around 5-6 mg daily or lower. The review underscores the potential benefits of prolonged melatonin use in specific patient populations, such as individuals with autism spectrum disorder, and hints at ongoing research into its role in cognitive decline and longevity. [2]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there evidence that long term daily use of melatonin causes harm?

Level of evidence

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

Please see Tables 1-4 for your response.

THE EFFECT OF LONG-TERM MELATONIN SUPPLEMENTATION ON PSYCHOSOMATIC DISORDERS IN POSTMENOPAUSAL WOMEN
Design	Randomized, double-blind, placebo-controlled study N= 60
Objective	To evaluate the effect of melatonin supplementation on female hormones release and the alteration in climacteric symptoms
Study Groups	Placebo group (n= 30) Melatonin group (n= 30)
Inclusion Criteria	Women aged 51 – 64 years, 4 – 10 years after the last menstrual period, with average and severe climacteric symptoms and without steroid hormonal replacement therapy
Exclusion Criteria	Metabolic, mental or organic diseases, particularly of the liver and kidney, and other diseases requiring pharmacotherapy
Methods	Patients were randomly divided into two groups: Group I received placebo (2 × 1 tablet) and Group II received melatonin (3 mg in the morning and 5 mg at bedtime) for 12 months. Serum levels of 17β-estradiol, FSH, melatonin, and urinary 6-sulfatoxymelatonin were measured before and after the study. Kupperman Index and BMI were also assessed.
Duration	12 months
Outcome Measures	Primary: Change in Kupperman Index (KI) Secondary: Change in BMI, serum levels of 17β-estradiol, FSH, melatonin, and urinary 6-sulfatoxymelatonin
Baseline Characteristics		Group I (n = 30)	Group II (n = 30)
	Age, years	58.4 ± 4.1	59.6 ± 6.4
	BMI, kg/m²	30.8 ± 3.8	30.9 ± 3.5
	KI, points	28.4 ± 2.9	29.1 ± 2.8
	Bilirubin, µmol/L	10.4 ± 0.2	11.3 ± 0.3
	ALT, IU/L	25.4 ± 4.3	26.7 ± 6.1
	AST, IU/L	24.8 ± 3.8	25.6 ± 5.9
	GFR, ml/min	89.4 ± 12.1	88.9 ± 11.9
Results		Group I (Placebo)	Group II (Melatonin)	p-value
	KI (points) before	28.4 ± 2.9	29.1 ± 2.9	-
	KI (points) after	25.3 ± 2.8	19.7 ± 3.1	<0.001
	BMI (kg/m²) before	30.8 ± 3.4	30.9 ± 3.4	-
	BMI (kg/m²) after	30.8 ± 3.4	28.1 ± 2.3	<0.05
Adverse Events	Melatonin was well tolerated, with only three women (10%) reporting increased fatigue in the morning during the first week of treatment, which did not require discontinuation or dose reduction.
Study Author Conclusions	Melatonin supplementation therapy exerts a positive effect on psychosomatic symptoms in postmenopausal women and can be recommended as a useful adjuvant therapeutic option in the treatment of these disorders.
Critique	The study's strengths include its randomized, double-blind, placebo-controlled design and the comprehensive assessment of psychosomatic symptoms. However, limitations include the small sample size and the lack of detailed assessment of individual sleep complaints, which could impact the overall Kupperman Index results. Additionally, the study did not explore the impact of melatonin on other potential psychosomatic symptoms beyond sleep disorders.

Table 1 References:
[3] Chojnacki C, Kaczka A, Gasiorowska A, Fichna J, Chojnacki J, Brzozowski T. The effect of long-term melatonin supplementation on psychosomatic disorders in postmenopausal women. J Physiol Pharmacol. 2018;69(2):10.26402/jpp.2018.2.15. doi:10.26402/jpp.2018.2.15

Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial
Design	Randomized double-blind placebo-controlled trial N= 67
Objective	To investigate the effects of long-term melatonin supplementation on quality of life and sleep in haemodialysis patients
Study Groups	Melatonin group (n= 33) Placebo group (n= 34)
Inclusion Criteria	Stable haemodialysis patients aged 18 to 85 years with a haemodialysis history of at least 3 months, subjective sleep problems according to the Epworth Sleepiness Scale (ESS), and mean sleep onset latency longer than 15 min
Exclusion Criteria	Current melatonin use, known hypersensitivity to melatonin, severe psychological or neurological disease, unstable angina pectoris, NYHA class IV heart failure, pregnancy, participation in another clinical trial 1 month prior to the start of this study
Methods	Patients received melatonin 3 mg immediate release tablets or placebo for 12 months. Primary endpoint was quality of life parameter 'vitality' measured with MOS SF-36. Secondary outcomes included sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations. Actigraphy recorded wrist movements to assess sleep patterns. Salivary melatonin concentrations were measured at baseline and after 6 months
Duration	12 months
Outcome Measures	Primary: Improvement in vitality score of MOS SF-36 Secondary: Improvement in sleep onset latency, sleep efficiency, actual sleep time, nighttime salivary melatonin concentrations
Baseline Characteristics		Melatonin (n= 33)	Placebo (n= 34)
	Number of males (%)	19 (58%)	22 (65%)
	Age, years	65.5 ± 11.7	64.4 ± 12.0
	Kt V-1 per week	4.1 ± 0.6	4.2 ± 0.7
	Body mass index, kg/m2	26.3 ± 4.4	25.6 ± 5.4
	Dialysis duration per week, h	11.2 ± 1.2	11.3 ± 1.9
	Dialysis vintage, months	30.6 ± 27.3	28.3 ± 22.5
Results		Melatonin (n= 33)	Placebo (n= 34)	p-value
	Vitality score improvement	-1.9%	-	-
	Sleep efficiency improvement at 3 months	7.6%	-	-
	Actual sleep time improvement at 3 months	49 min	-	-
Adverse Events	No side effects of melatonin were reported during the study.
Study Author Conclusions	Although short-term benefits of melatonin on sleep were previously reported, this long-term study found that positive effects disappeared over time (6-12 months). Vitality did not improve with melatonin treatment. Further research is needed to understand the mechanism behind the loss of effect with chronic use.
Critique	The study's high drop-out rate limits the strength of its conclusions. While short-term benefits were observed, the lack of long-term effects raises questions about the sustained efficacy of melatonin. The study may have been underpowered due to the high drop-out rate, and the timing and dosage of melatonin administration may not have been optimal. Further research is needed to explore alternative dosing strategies and potential synergistic treatments.

Table 2 References:
[4] Russcher M, Koch BC, Nagtegaal JE, et al. Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial. Br J Clin Pharmacol. 2013;76(5):668-679. doi:10.1111/bcp.12093

Prolonged-release melatonin for insomnia – an open-label long-term study of efficacy, safety, and withdrawal
Design	Prospective 6–12-month open-label study N= 244
Objective	To investigate the efficacy, safety, and withdrawal phenomena associated with 6–12 months PRM treatment
Study Groups	Completed 6 months (n= 112) Completed 12 months (n= 96)
Inclusion Criteria	Community dwelling adults aged 20–80 years with primary insomnia, who participated in a placebo-controlled, double-blind dose-ranging trial of PRM
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, or use of hypnotic medications in the past 2 weeks
Methods	Participants received PRM 2 mg nightly, followed by a 2-week withdrawal period. Main outcome measures included patient-reported sleep quality ratings, adverse events, vital signs, laboratory tests, and withdrawal symptoms (CHESS-84). Nocturnal urinary 6-sulfatoxymelatonin excretion was assessed upon discontinuation
Duration	6–12 months of treatment with a 2-week withdrawal period
Outcome Measures	Primary: Patient-reported sleep quality ratings Secondary: Adverse events, withdrawal symptoms, endogenous melatonin production
Baseline Characteristics		All patients (N= 244)
	Age, years	55.3 ± 13.0
	Female	69%
	Caucasian	99%
	Concomitant medications at entry	79%
	Concomitant medications during study	94%
Results		6 months (n= 112)	12 months (n= 96)
	Nights per week rated 'good' or 'very good'	54%–56%	54%–56%
	Days per week with 'good' or 'very good' mood	67%–68%	67%–68%
	Adverse events during withdrawal	20%	13%
Adverse Events	No deaths reported. Serious adverse events included duodenal sphincterectomy, myocardial infarction, and others, but were not related to PRM. Common adverse events included pharyngitis, back pain, and asthenia. No suppression of endogenous melatonin production.
Study Author Conclusions	Results support the efficacy and safety of PRM in primary insomnia patients aged 20–80 throughout 6–12 months of continuous therapy. PRM discontinuation even after 12 months was not associated with adverse events, withdrawal symptoms, or suppression of endogenous melatonin production.
Critique	The study's open-label design may introduce bias, and the lack of a control group limits the ability to attribute improvements solely to PRM. However, the study provides valuable long-term safety and efficacy data, showing no tolerance development or significant withdrawal effects.

Table 3 References:
[5] 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

Melatonin Administration Alters Semen Quality in Healthy Men
Design	Double-blind, crossover study N= 8
Objective	To determine the effects of long-term melatonin administration on semen production and pituitary-gonadal hormone secretion in healthy men
Study Groups	Nonresponders (n= 6) Responders (n= 2)
Inclusion Criteria	Healthy men, within ±10% of ideal body weight, normal semen analysis according to WHO guidelines, normal serum gonadotropin-gonadal steroid hormone levels
Exclusion Criteria	History of cryptorchidism, varicocele, infection, testicular trauma, or any medication use
Methods	Participants received 3 mg melatonin or placebo orally at 1700 hours daily for 3 months, followed by a 2-week washout, then crossover to the alternate treatment for another 3 months. Semen and blood samples were collected every 3 months to measure semen quality and hormone levels.
Duration	6 months of treatment with a 2-week washout period
Outcome Measures	Primary: Sperm concentration and motility Secondary: Serum and seminal plasma hormone levels (testosterone, E2, melatonin, LH, FSH)
Baseline Characteristics		All subjects (N= 8)
	Age, years	23.4 ± 1.2
	BMI, kg/m2	23.9 ± 1.2
	Testicular volume, mL	23.1 ± 1.3
Results		Nonresponders (n= 6)	Responders (n= 2)	p-value
	Sperm concentration	-12.2 ± 11.6	-20.0 ± 1.4	0.01
	Sperm motility	-0.8 ± 7.1	-20.5 ± 12.0	0.02
	Seminal plasma E2	-1.0 ± 24.6	64.0 ± 9.9	0.01
	Seminal plasma testosterone	0.0 ± 0.5	-1.2 ± 0.8	0.04
	Seminal plasma T:E2	0.0 ± 2.4	-26.2 ± 3.7	0.03
	Serum E2	-12.8 ± 17.0	38.0 ± 2.8	0.007
	Serum testosterone	0.7 ± 4.8	-0.5 ± 0.7	NS
	Serum T:E2	49.7 ± 51.3	-265.0 ± 94.0	0.0007
Adverse Events	No adverse events reported.
Study Author Conclusions	Long-term melatonin administration is associated with decreased semen quality in some healthy men, likely due to inhibition of aromatase at the testicular level.
Critique	The study's small sample size and the variability in individual responses limit the generalizability of the findings. The crossover design is a strength, but the study lacks a long-term follow-up to assess the persistence of effects after cessation of melatonin administration.

Table 4 References:
[6] Luboshitzky R, Shen-Orr Z, Nave R, Lavi S, Lavie P. Melatonin administration alters semen quality in healthy men. J Androl. 2002;23(4):572-578.