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Melatonin Supplementation Safety and Efficacy

Melatonin Supplementation Safety and Efficacy

Melatonin has become quite a controversial ingredient, with many health influencers and practitioners cautioning against its use. In this article, we review the literature demonstrating the efficacy of melatonin as well as the safety concerns associated with melatonin supplementation.

What is Melatonin and How Does it Work?

Melatonin is a hormone, just like testosterone, estrogen, or cortisol. The word hormone simply means that it is a chemical released from one tissue that exerts its effects on another tissue. For example, cortisol is produced from the adrenal glands and has effects on other tissues such as the liver and pancreas. Melatonin is produced by a small gland in the brain called the pineal gland and has effects on several different tissues including the brain, heart, pancreas, and muscle. Melatonin secretion is associated with the regulation of our circadian rhythms, sleep-wake cycle, and body temperature [1].

Studies have shown that melatonin deficiency is associated with many negative health-related outcomes including sleep disorders. For example, nocturnal peak melatonin concentrations seem to decline as we age [2], which may explain, in part, poor sleep as we get older. Lower melatonin concentrations have also been associated with age-related cognitive diseases such as Alzheimer’s [3]. Furthermore, children with several neuropsychiatric and developmental disorders have shown melatonin deficiencies and symptoms are improved once circadian rhythms are properly restored [4][5]. Now, what we don’t know is what came first, the chicken or the egg? These data are not causal, and we cannot conclude that lower melatonin levels contribute to the development of these disorders. It could be that these disorders lead to lower melatonin levels. Nonetheless, there is a relationship between natural melatonin production, sleep, and cognitive impairment.

Next, let’s discuss the data that support the use of melatonin supplementation for improving sleep-related outcomes.

The Effects of Melatonin Supplementation on Sleep

Plenty of studies have demonstrated that melatonin supplementation can improve sleep-related outcomes across a wide range of populations [6][7][8]. Since melatonin supplementation has been extensively studied and there are dozens of studies on the subject, we will be focusing mainly on reviewing meta-analysis on the topic. For those of you who don’t know, a meta-analysis is a study of studies. Essentially, a meta-analysis will look at data from multiple clinical trials on a subject to come up with an overall conclusion on the subject.

The first meta-analysis we are reviewing investigated the effects of melatonin supplementation on sleep quality in adults who had poor sleep-related outcomes assessed by the PSQI [7]. PSQI stands for the Pittsburg Sleep Quality Index, which is a validated questionnaire used to assess sleep quality. Let’s quickly discuss how the PSQI works in order to understand the findings of this meta-analysis. The PSQI includes different questions that assess an individuals sleep quality over the past month. The questions are grouped into seven different components [9] including:

  • sleep duration
  • sleep disturbance
  • sleep latency
  • daytime dysfunction due to sleepiness
  • sleep efficiency
  • overall sleep quality
  • sleep medication use

    Each of the components is scored from 1-3, with 3 meaning more dysfunction. The score of each of the components is then added up to provide a total final score. The higher the score, the worse the sleep outcome.

    The results of the meta-analysis demonstrated that overall, melatonin supplementation improved PSQI scores by 1.24 points on average, or roughly 6%. Now, 6% does not seem like a huge improvement, but the reason why it’s so low is because there were a wide range of studies included in this meta-analysis across different populations. For example, some studies looked at melatonin supplementation on sleep in individuals with Alzheimer’s, cancer, or Parkinsons disease. The researchers conducted some follow-up analysis looking to see whether different populations were affected differently by supplementation. The follow up analysis demonstrated that individuals with respiratory diseases, metabolic disorders (e.g., obesity, diabetes, cardiovascular disease), and sleep disorders improved PSQI scores by ~2 points (~10%) after supplementing with melatonin compared to individuals with mental or neurodegenerative diseases, who did not really experience any benefits from supplementation.

    The next meta-analysis we will review investigated the effects of melatonin supplementation on primary sleep disorders [8]. Primary sleep disorders are those that are not associated with or caused by another medical condition. For example, insomnia is defined as habitual sleeplessness or the inability to sleep. Mental disorders can contribute to the development insomnia. Mental disorder-induced insomnia would be an example of a “secondary” insomnia. “Primary” insomnia would be if you have insomnia and it’s not caused by any other medical condition.

    Unlike the previous study that assessed improvements using PSQI scores, this meta-analysis looked at three specific sleep-related outcomes including sleep latency (how long it takes you to fall asleep), sleep quality, and total sleep time. Unfortunately, the researchers did not appropriately define sleep quality and the name itself makes it hard to pinpoint exactly what they’re measuring. A total of 19 studies were included in this meta-analysis with 14 of them investigating the efficacy of melatonin for primary insomnia, 4 studies on delayed sleep phase syndrome, and 1 study on REM sleep behavior disorder. These are all different primary sleep disorders.

    Melatonin supplementation improved sleep latency on average by ~7 minutes. Studies using higher doses and longer duration improved sleep latency more than shorter studies with lower doses. Similarly, melatonin supplementation improved total sleep time by ~8 minutes and, again, longer duration studies with higher doses showed greater benefits. Melatonin also showed pretty much the same benefits for sleep quality, but we won’t go deep into those since sleep quality was not properly defined in this meta-analysis.

    In the conclusion section, the authors go on to discuss that the findings of this meta-analysis show that melatonin supplementation has small but meaningful benefits for improving sleep in individuals with primary sleep disorders. However, the effects of melatonin are not as great as sleep medications such as benzodiazepines. This is to be expected. A supplement will never be as strong as a prescription medication. Nonetheless, that’s exactly the point; melatonin may provide a small benefit with no side effects or development of tolerance, while prescription medications do.

    There are other meta-analyses demonstrating the benefits of melatonin supplementation on sleep across different populations including in children with ASD [10], more on primary sleep disorders [6], and in children and adolescents [11]. Rather than boring you with the specifics of each of these studies though, we will quickly summarize the overall findings of the literature as it currently stands:

    • Melatonin supplementation seems to improve sleep related outcomes in individuals who have primary sleep disorders, but not secondary sleep disorders.
    • Melatonin supplementation seems to have a cumulative effect where taking it for longer durations seems to provide greater benefits than short durations.
    • Supplementing with higher doses seems to be provide more benefits. (We discuss dosing in further detail later in this article.)

    Is Melatonin Safe?

    Although melatonin has been extensively studied as a supplement for decades, some individuals warn against its use for various reasons. Common anti-melatonin claims include:

    • Melatonin is a hormone (so it must be dangerous)
    • Melatonin suppresses the onset of puberty
    • Products including melatonin may be incorrectly reporting the dosage
    • The benefits of melatonin are minimal at best

    In this section, we will discuss each of these arguments, their merits, as well as their shortcomings. Furthermore, we will review the available research literature on the safety of melatonin supplementation.

    Is Melatonin a Hormone?

    Yes, melatonin is a hormone. This fact is one of the primary arguments against melatonin use. But is it a valid argument?

    Many people get scared when they hear the word 'hormone'. Statements like, “You can’t go to the store and buy other hormones like testosterone over the counter, so why can you buy melatonin?” are made by several prominent figures in the evidence-based health field. However, in the simplest of terms, the word 'hormone' simply describes a molecule that is secreted from one tissue and exerts its effects on other tissues.

    Yes, hormones regulate most of our physiological functions, and they have complex interactions as well. However, just because something is a hormone, does not make it inherently dangerous. Furthermore, in many instances, using hormone therapy as a treatment for low hormone production is extremely helpful. For example, individuals with hypothyroidism are prescribed thyroid hormone and individuals with low testosterone are prescribed testosterone treatment.

    Although we should always be careful with what we use and understand the risk/reward of any supplement before using, it isn't logical to vilify an entire classification of molecules just because they are “hormones.”

    Does Melatonin Interfere with other Hormones?

    Another argument against melatonin usage is that it "suppresses the onset of puberty" or, if you are post-pubescent, may “interfere with certain hormone systems.”

    First let’s address the effects of melatonin supplementation on the onset of puberty. Nocturnal melatonin concentrations are highest in young children (1-3 years old) and slowly drop throughout childhood until the children reach puberty [12]. Melatonin suppresses the release of hormones that are important for the development of puberty such as gonadotropin releasing hormone [13]. Therefore, it is speculated that melatonin plays an important role in regulating the onset of puberty. However, this does not mean that melatonin supplementation inherently suppresses puberty. First, several short-term studies demonstrate that melatonin supplementation is safe in children [10][11]. There isn’t a plethora of long-term data investigating the effects of melatonin supplementation on the onset of puberty. A narrative review by Boafo et al., reviewed three studies that reported the relationship between melatonin supplementation and the onset of puberty in children and concluded that there is little to no evidence that melatonin supplementation impacts the onset of puberty [14].

    OK, so does melatonin supplementation negatively impact other hormone systems in adults? It would be impossible to review the effects of melatonin supplementation on every single hormone since we have dozens of different hormones circulating through our body. However, what we can look at is the effects of melatonin supplementation on hormones associated with the hypothalamic-pituitary-gonadal axis (HPG). This simply refers to the hormones connecting these three different organ systems. The hypothalamus and the pituitary gland are known as the “master regulators” of hormone function. In other words, they initiate the release of specific hormones that then cause other organs to release subsequent hormones, causing a kind of “hormone cascade.” Remember earlier how we said that melatonin regulates a hormone known as gonadotropin releasing hormone? Well, that’s a hormone that’s released by the hypothalamus, that stimulates the release of luteinizing hormone and follicle stimulating hormone from the pituitary, which then stimulates the release of androgen from the testicles and estrogens from the ovaries. Let’s look at some research addressing this topic.

    First off, it’s important to note that correlation does not equal causation and that the interactions between hormones are complex and not as simple as if you take “X” then “Y” will happen. For example, if melatonin decreased testosterone concentrations, then we would expect older men to have higher testosterone because melatonin naturally decreases as we age. Obviously, that is not the case. This is a perfect example of how complex physiology is, and that it’s not as simple as saying “one thing will cause one effect” e.g., higher melatonin equals lower testosterone.

    We found one very well designed study that investigated the effects of melatonin supplementation on the pituitary-gonadal axis [15]. In this double-blind placebo-controlled study, healthy males were administered 6mg of melatonin per day for one month and their concentrations of several hormones including luteinizing hormone, follicle stimulating hormone, and testosterone were assessed. What’s cool about this study is that not only did they assess the concentration of these hormones but their pulsatility as well. See, hormone concentrations are not “fixed” 24/7. Instead, they typically “pulse” throughout the day because there are times of the day where we produce more of them and times of the day where we produce less. The results showed that melatonin supplementation had no effect on the concentration or pulsatility of hormones associated with the pituitary-gonadal axis. One downside to this study is that only 6 participants were included, which is not a large sample size. However, the results of this study are supported by a study published in 1986 that showed similar results. Supplementing with 2mg of melatonin per day for a month had no effect on any of these hormones [16]. These findings suggest that melatonin supplementation does not negatively affect the HPG axis.

    There are other studies that look at the effects of melatonin supplementation on testosterone in both men and women. Cross-sectional study looking at the relationship between melatonin supplementation (1-3mg/day) and testosterone concentrations found no association between supplementation and total testosterone [17]. However, as expected, BMI and old age were associated with decrements in testosterone. Furthermore, there is evidence that melatonin supplementation may actually improve testosterone concentrations in women with PCOS [18], perhaps due to its benefits on overall sleep since we know that sleep is critically important for optimal endocrine function. Overall, there is no strong clinical evidence that melatonin supplementation may negatively influence testosterone.

    Does Taking Melatonin Decrease Natural Production?

    Another important question to address is whether supplementation influences our natural melatonin production. It was very difficult to find data addressing this, but we did find two studies that looked at the relationship between melatonin supplementation and endogenous melatonin production.

    The study referenced previously investigating the effects of melatonin supplementation on endocrine function also looked at endogenous melatonin production and showed that supplementation does not affect endogenous melatonin concentrations [16]. These results are supported by a subsequent study in 1997 that shows that melatonin supplementation does not affect the endogenous melatonin levels [19]. You might have noticed that these two studies are pretty old, but the truth is we couldn’t find any newer data on this topic. Thankfully, our physiology doesn’t change over time. If melatonin supplementation didn’t influence endogenous melatonin production in the 80’s and 90's, it likely still doesn’t in 2022.

    Other Melatonin Concerns

    The last two complaints associated with melatonin, dosing being incorrect on labels and the effects on sleep being minimal, will be addressed together. Both of these complaints are valid. Sometimes the dose presented on a dietary supplement bottle is not accurate. There is evidence that some melatonin supplements can vary from -83% to +400% of what’s actually reported on the bottle [20]. However, this is not an inherent issue with melatonin supplements. Instead, it is an issue of manufacturing practices. This is an issue that affects all dietary supplements and is not unique to melatonin supplements. It's also why you want to purchase dietary supplements only from reputable companies.

    The argument that melatonin's effects on sleep are minimal at best, is not a strong argument against its use. The same logic applies for most sports supplements. Creatine or a pre-workout are not going to have as large of an effect as taking anabolic steroids, and thus, this argument is completely moot.

    Overall, the most common arguments made against melatonin supplementation are not strongly supported by clinical data. Does this mean taking melatonin comes with zero risks? No. Individual responses to melatonin, or any dietary supplement, may vary. However, the data on melatonin shows that it is generally safe and effective, with minimal side effects.

    How Much Melatonin Should I Take?

    The short answer: you should take the smallest melatonin dose possible that provides benefits. We dosed our Sleep product with 2mg of melatonin per serving. There are various reasons why we chose to use 2mg over a higher dose such as 5mg, which is more common in other sleep supplements.

    The first reason we chose 2mg is because we want our customers to start with the lowest effective dose. If you can benefit from taking a lower dose of any supplement, there isn’t a logical reason to supplement with a higher dose. Most studies investigating the effects of melatonin dose between 1-6mg/day. Few studies use higher doses, but the majority fall within this range.

    The first meta-analysis that we reviewed in this article included data from 24 clinical trials that investigate the effects of melatonin supplementation on sleep using the PSQI [7]. Eight of the 24 trials dosed participants with 2mg of melatonin and 4 of them found improvements in PSQI scores. Important to note, only one of these studies was conducted in individuals with primary insomnia and found an improvement in PSQI scores [21]. The second meta-analysis we reviewed investigated the effects of melatonin supplementation on sleep in individuals with primary sleep disorders [8]. A total of 19 clinical studies were included in the analysis, 10 of which used a dose equal to 2mg or less. Six of the 10 studies demonstrated a benefit of supplementation on at least one sleep related parameter (total sleep time, sleep latency, or sleep quality). Therefore, there is evidence that a relatively low dose of 2mg or less may be efficacious for some people.

    The second reason we decided to use a 2mg dose is due to the possibility of developing adverse effects associated with supplementation, although the development of adverse effects is pretty uncommon. A 2016 review investigated the safety of melatonin supplementation and found that only very mild adverse effects such as dizziness, headaches, or nausea, have been reported with melatonin supplementation [22]. Studies with relatively high doses upwards of 6mg/day were assessed in this review and even then, side effects were minimal at best. For example, a clinical trial published in 2000 dosed male participants with 10mg of melatonin per day for 28 days and found no differences in adverse effects between individuals who were supplemented compared to placebo [23]. Another study showed only mild adverse effects over a 6 month period with no relevant differences between the treatment group and placebo group for any safety outcome [26]. If you’d like to read more on this topic, check out these two reviews [22][24]. Overall, the data regarding safety concerns are pretty robust.

    So, why did we choose 2mg and not a higher dose? We chose a 2mg dose for the following reasons:

    • Reason 1: 2mg is well studied and has been shown to improve sleep-related outcomes. We wanted to provide the lowest effective dose and allow customers to increase their dosing if necessary.
    • Reason 2: If there are to be any possible side effects/health concerns, they should be mitigated with smaller doses compared to higher doses.
    • Reason 3: Other ingredients in Sleep, such as Affron, have been associated with an increase in evening melatonin concentrations [25].

    To be clear, a strong argument can be made for higher or even for lower doses of melatonin. Ultimately, we feel confident that 2mg of melatonin is safe and should be beneficial for improving sleep.

    Conclusion and Main Takeaways

    • Melatonin is a hormone produced by the pineal gland which regulates our circadian rhythms, sleep-wake cycle, and body temperature.
    • Melatonin supplementation seems to provide mild benefits for improving sleep in individuals with primary sleep disorders, particularly primary insomnia.
    • While some people have raised concerns with melatonin supplementation, most of these concerns are not well supported by the clinical evidence. Overall, melatonin supplementation has been shown to be relatively safe with minimal side effects.

     

    References

    1. Tordjman, S., et al., Melatonin: Pharmacology, Functions and Therapeutic Benefits. Curr Neuropharmacol, 2017. 15(3): p. 434-443.

    2. Scholtens, R.M., et al., Physiological melatonin levels in healthy older people: A systematic review. J Psychosom Res, 2016. 86: p. 20-7.

    3. Skene, D.J. and D.F. Swaab, Melatonin rhythmicity: effect of age and Alzheimer's disease. Exp Gerontol, 2003. 38(1-2): p. 199-206.

    4. Jan, J.E., et al., Neurophysiology of circadian rhythm sleep disorders of children with neurodevelopmental disabilities. Eur J Paediatr Neurol, 2012. 16(5): p. 403-12.

    5. Mareš, J., et al., Oxidative stress induced by epileptic seizure and its attenuation by melatonin. Physiol Res, 2013. 62(Suppl 1): p. S67-74.

    6. Auld, F., et al., Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med Rev, 2017. 34: p. 10-22.

    7. Fatemeh, G., et al., Effect of melatonin supplementation on sleep quality: a systematic review and meta-analysis of randomized controlled trials. J Neurol, 2022. 269(1): p. 205-216.

    8. Ferracioli-Oda, E., A. Qawasmi, and M.H. Bloch, Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders. Focus (Am Psychiatr Publ), 2018. 16(1): p. 113-118.

    9. Zhong, Q.Y., et al., Psychometric Properties of the Pittsburgh Sleep Quality Index (PSQI) in a Cohort of Peruvian Pregnant Women. J Clin Sleep Med, 2015. 11(8): p. 869-77.

    10. Cuomo, B.M., et al., Effectiveness of Sleep-Based Interventions for Children with Autism Spectrum Disorder: A Meta-Synthesis. Pharmacotherapy, 2017. 37(5): p. 555-578.

    11. Wei, S., et al., Efficacy and safety of melatonin for sleep onset insomnia in children and adolescents: a meta-analysis of randomized controlled trials. Sleep Med, 2020. 68: p. 1-8.

    12. Waldhauser, F., et al., Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab, 1988. 66(3): p. 648-52.

    13. Roy, D. and D.D. Belsham, Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GnRH neurons. Signal transduction mechanisms. J Biol Chem, 2002. 277(1): p. 251-8.

    14. Boafo, A., et al., Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician's perspective. Nat Sci Sleep, 2019. 11: p. 1-10.

    15. Luboshitzky, R., et al., Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men. Hum Reprod, 2000. 15(1): p. 60-5.

    16. Wright, J., et al., The effects of exogenous melatonin on endocrine function in man. Clin Endocrinol (Oxf), 1986. 24(4): p. 375-82.

    17. Zizzo, J., et al., Impact of Low-Dose Melatonin Supplementation on Testosterone Levels in U.S. Adult Males. Urology, 2022.

    18. Alizadeh, M., et al., Metabolic and hormonal effects of melatonin and/or magnesium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Nutr Metab (Lond), 2021. 18(1): p. 57.

    19. Matsumoto, M., et al., The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. J Pineal Res, 1997. 22(1): p. 42-4.

    20. Erland, L.A. and P.K. Saxena, Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content. J Clin Sleep Med, 2017. 13(2): p. 275-281.

    21. Wade, A.G., et al., Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short- and long-term response. Curr Med Res Opin, 2011. 27(1): p. 87-98.

    22. Andersen, L.P., et al., The Safety of Melatonin in Humans. Clin Drug Investig, 2016. 36(3): p. 169-75.

    23. Seabra, M.L., et al., Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res, 2000. 29(4): p. 193-200.

    24. Auger, R.R., et al., 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): p. 1199-236.

    25. Lopresti, A.L., S.J. Smith, and P.D. Drummond, An investigation into an evening intake of a saffron extract (affron®) on sleep quality, cortisol, and melatonin concentrations in adults with poor sleep: a randomised, double-blind, placebo-controlled, multi-dose study. Sleep Med, 2021. 86: p. 7-18.

    26. Wade, A.G., Ford, I., Crawford, G. et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med 8, 51 (2010).

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