Melatonin: Debunking Testosterone Level Myths and More

Melatonin is widely recognized as an essential hormone that controls and balances sleep rhythm such as sleep-wake timing [1] and seasonal rhythmicity in vertebrates. It has also been studied for its effects on testosterone levels, especially in adult males. In addition, it has a lesser-known (but very important) role as an antioxidant [2]. We have touched briefly on melatonin in a previous article about sleep hormones and their effect on the GABA system here.

Sleep is of fundamental importance for anabolic processes that repair and rejuvenate the body overnight. It has also been described as neuroprotective, whereby the brain cleanses itself of damaging free radicals and reorganizes itself, specifically via the brain’s glymphatic system. Research in rodents has shown that sleep depletion causes cellular damage that can potentially lead to errors in replication and metabolic abnormalities [4]. Impaired sleep, seen in conditions like insomnia, leads to negative changes in cognition, behavior, and/or judgment [3]. For more information on why we sleep, read here.

Insomnia is a condition that affects around 30% of the population and there seems to be consensus across nations for this percentage [5,6]. Insomnia describes difficulty in getting to sleep, staying asleep, and achieving restful sleep. It is associated with co-morbidities such as diabetes, sleep apnea, and medication side effects (to name just a few), and therefore represents a significant public health challenge [7].

As a consequence of poor sleep quality, melatonin supplementation is very popular to promote better and more restorative sleep. However, many people wonder whether melatonin really works or if affects testosterone levels or even lowers them.

In this article, we will investigate melatonin, the rationale for supplementation, as well as possible risks and contraindications for its use.

What is Melatonin and How Does it Work?

Melatonin, or 5-methoxy-N-acetyltryptamine, is secreted from the pineal gland deep within the brain (although this is not the only place… see below) [8]. It was originally discovered and isolated from the pineal glands of cows in 1958 by Aaron Lerner [9].

Melatonin is derived from the essential amino acid tryptophan. Tryptophan is biosynthesized to serotonin, after which enzymes within the pineal gland transform serotonin into melatonin [10], which is then released into circulation to reach central and peripheral tissues.

Melatonin exerts its action on circadian rhythms such as the sleep-wake rhythm, neuroendocrine rhythms, or body temperature cycle due to its effects on MT1 and MT2 receptors [11-13].

It is also a powerful antioxidant and free radical scavenger that is twice as active as vitamin E [14]. Through complex signaling processes via its receptors, melatonin promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase among others [13,15].

In response to darkness, the pineal gland commences melatonin production, whereas light exposure causes this process to slow or cease. Exposure to light before bed suppresses the onset of melatonin and shortens its duration [16]. This is regulated by the suprachiasmatic nucleus in the hypothalamus. If you are a practitioner, learn more in the Chronobiology module in the Essential Certification of Health Optimization Medicine and Practice at homehope.org.

Melatonin is also directly produced in the mitochondria, the energy factories of the cell, and influences glucose metabolism. In fact, the pineal gland only produces around 5% of the total melatonin in the body [17].

Melatonin Supplementation

Melatonin is available in certain jurisdictions as a predominantly low-dose dietary supplement and it is commonly used to help with sleep, but is there a fundamental need for this?

In most studies, melatonin supplementation (both short-term melatonin supplementation and long-term melatonin supplementation) decreases sleep onset latency, increases total sleep time, and improves the quality of that sleep. In simple terms, it speeds up the process of getting to sleep and helps with staying asleep [18].

As we age, melatonin production decreases, which can lead to a reduction in the skin's antioxidant capacity, making it more susceptible to oxidative stress, as well as dysregulating the clock genes that regulate circadian rhythm [19]. Therefore, melatonin supplementation in older adults might have a rational basis.

There are several different types of melatonin supplements available, comprising natural (obtained from the pineal gland of mammals) and synthetic (i.e., man-made) varieties [20].

A recent meta-analysis of available research studies conducted by scientists in Iran found that supplementing with exogenous melatonin had positive effects on sleep quality based on the Pittsburgh Sleep Index Assessment Tool [21]. These beneficial effects were found in adults with respiratory diseases, metabolic disorders, and primary sleep disorders but not mental disorders, neurodegenerative conditions, or other diseases.

Is Melatonin Supplementation Safe?

In general, animal and human studies show that melatonin supplementation is safe over the short term, even in extreme doses. High doses have been used for a variety of conditions, most recently COVID-19 prevention and treatment, whereas low doses are used to treat jet lag and sleep problems [22].

While mild adverse effects like dizziness, headaches, nausea, and sleepiness have occasionally been reported, studies have investigated the relationship between melatonin administration and serum testosterone levels as well (more on this shortly). Moreover, long-term randomized clinical studies have indicated that melatonin only induces mild adverse effects compared to a placebo [23-25]. However, due to a lack of human studies, pregnant and breastfeeding women are advised not to use exogenous melatonin until further investigations have been carried out. Additionally, in pediatric populations, melatonin should be used at both the patient’s and physician’s discretion [26].

What is the Effect of Melatonin Supplementation on Testosterone Levels?

There have been some reports in the popular press that melatonin supplementation lowers testosterone levels and testosterone secretion but there is no evidence of this. A cross-sectional study from 2022 showed that low-dose melatonin (approximately 1 mg per day for more than 30 days) had no association with testosterone levels in males over the age of 18 in the United States [27]. These findings are consistent with an older double-blind, placebo-controlled study that found no impact of oral melatonin (at a larger dose of 6 mg per day for one month) on the secretion of male reproductive hormones, including testosterone, in healthy adult men [28].

A key area of concern with melatonin supplementation is the fact that the declared concentration of melatonin in a given product might not be congruent with the dose on the label [29,30]. A very recent study in the Journal of the American Medical Association showed that only 12 out of 30 reviewed preparations contained quantities that were within 10% of those advertised, with some containing up to 347% of the declared amount [31]. This is why it is essential to buy melatonin (and all your supplements) from manufacturers that adhere to strict standards such as GMP and third-party testing, and who are willing to share all this information with you if you request it. 

Summary

In this article we have provided some background on melatonin, what it is, how it works, and how supplementation can be used to improve sleep quality, especially as we age. We have also discussed the (very few) contraindications and risks associated with melatonin supplementation plus the lack of any convincing data that testosterone levels will drop using it.  

If you are having challenges with sleep induction and maintenance, melatonin may be something to consider to help, especially with travel and as we age. However, if you are interested in a more comprehensive sleep solution, check out Tro Zzz, our buccal troche formulated for sleep that has melatonin as one of its main ingredients + 7 more to help you fall asleep, stay asleep, and wake up feeling refreshed.

References

[1]          M. Emet, H. Ozcan, L. Ozel, M. Yayla, Z. Halici, A. Hacimuftuoglu, A Review of Melatonin, Its Receptors and Drugs, Eurasian J Med. 48 (2016) 135–141. https://doi.org/10.5152/eurasianjmed.2015.0267.

[2]          R. Hardeland, Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance, Endocrine. 27 (2005) 119–130. https://doi.org/10.1385/endo:27:2:119.

[3]          A.R. Eugene, J. Masiak, The Neuroprotective Aspects of Sleep, MEDtube Sci. 3 (2015) 35–40.

[4]          C.A. Everson, C.J. Henchen, A. Szabo, N. Hogg, Cell injury and repair resulting from sleep loss and sleep recovery in laboratory rats, Sleep. 37 (2014) 1929–1940. https://doi.org/10.5665/sleep.4244.

[5]          T. Roth, Insomnia: definition, prevalence, etiology, and consequences, J Clin Sleep Med. 3 (2007) S7-10.

[6]          S. Ancoli-Israel, T. Roth, Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. I, Sleep. 22 Suppl 2 (1999) S347-353.

[7]          S. Bhaskar, D. Hemavathy, S. Prasad, Prevalence of chronic insomnia in adult patients and its correlation with medical comorbidities, J Family Med Prim Care. 5 (2016) 780–784. https://doi.org/10.4103/2249-4863.201153.

[8]          P. Pévet, Melatonin, Dialogues Clin Neurosci. 4 (2002) 57–72. https://doi.org/10.31887/DCNS.2002.4.1/ppevet.

[9]          S. Tordjman, S. Chokron, R. Delorme, A. Charrier, E. Bellissant, N. Jaafari, C. Fougerou, Melatonin: Pharmacology, Functions and Therapeutic Benefits, Curr Neuropharmacol. 15 (2017) 434–443. https://doi.org/10.2174/1570159X14666161228122115.

[10]        V. Simonneaux, C. Ribelayga, Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters, Pharmacol Rev. 55 (2003) 325–395. https://doi.org/10.1124/pr.55.2.2.

[11]        M. Karasek, K. Winczyk, Melatonin in humans, J Physiol Pharmacol. 57 Suppl 5 (2006) 19–39.

[12]        C. Ekmekcioglu, Melatonin receptors in humans: biological role and clinical relevance, Biomed Pharmacother. 60 (2006) 97–108. https://doi.org/10.1016/j.biopha.2006.01.002.

[13]        R. Jockers, P. Delagrange, M.L. Dubocovich, R.P. Markus, N. Renault, G. Tosini, E. Cecon, D.P. Zlotos, Update on melatonin receptors: IUPHAR Review 20, Br J Pharmacol. 173 (2016) 2702–2725. https://doi.org/10.1111/bph.13536.

[14]        C. Pieri, M. Marra, F. Moroni, R. Recchioni, F. Marcheselli, Melatonin: a peroxyl radical scavenger more effective than vitamin E, Life Sci. 55 (1994) PL271-276. https://doi.org/10.1016/0024-3205(94)00666-0.

[15]        R.J. Reiter, J.C. Mayo, D.-X. Tan, R.M. Sainz, M. Alatorre-Jimenez, L. Qin, Melatonin as an antioxidant: under promises but over delivers, J Pineal Res. 61 (2016) 253–278. https://doi.org/10.1111/jpi.12360.

[16]        J.J. Gooley, K. Chamberlain, K.A. Smith, S.B.S. Khalsa, S.M.W. Rajaratnam, E. Van Reen, J.M. Zeitzer, C.A. Czeisler, S.W. Lockley, Exposure to room light before bedtime suppresses melatonin onset and shortens melatonin duration in humans, J Clin Endocrinol Metab. 96 (2011) E463-472. https://doi.org/10.1210/jc.2010-2098.

[17]        R.J. Reiter, R. Sharma, S. Rosales-Corral, W. Manucha, L.G. de A. Chuffa, D.A.P. de C. Zuccari, Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells, Int J Mol Sci. 22 (2021) 12494. https://doi.org/10.3390/ijms222212494.

[18]        E. Ferracioli-Oda, A. Qawasmi, M.H. Bloch, Meta-analysis: melatonin for the treatment of primary sleep disorders, PLoS One. 8 (2013) e63773. https://doi.org/10.1371/journal.pone.0063773.

[19]        L. Anghel, L. Baroiu, C.R. Popazu, D. Pătraș, S. Fotea, A. Nechifor, A. Ciubara, L. Nechita, C.L. Mușat, I.A. Stefanopol, A.L. Tatu, A.B. Ciubara, Benefits and adverse events of melatonin use in the elderly (Review), Exp Ther Med. 23 (2022) 219. https://doi.org/10.3892/etm.2022.11142.

[20]        R.L. Riha, The use and misuse of exogenous melatonin in the treatment of sleep disorders, Curr Opin Pulm Med. 24 (2018) 543–548. https://doi.org/10.1097/MCP.0000000000000522.

[21]        G. Fatemeh, M. Sajjad, R. Niloufar, S. Neda, S. Leila, M. Khadijeh, Effect of melatonin supplementation on sleep quality: a systematic review and meta-analysis of randomized controlled trials, J Neurol. 269 (2022) 205–216. https://doi.org/10.1007/s00415-020-10381-w.

[22]        Z. Menczel Schrire, C.L. Phillips, J.L. Chapman, S.L. Duffy, G. Wong, A.L. D’Rozario, M. Comas, I. Raisin, B. Saini, C.J. Gordon, A.C. McKinnon, S.L. Naismith, N.S. Marshall, R.R. Grunstein, C.M. Hoyos, Safety of higher doses of melatonin in adults: A systematic review and meta-analysis, J Pineal Res. 72 (2022) e12782. https://doi.org/10.1111/jpi.12782.

[23]        L.P.H. Andersen, I. Gögenur, J. Rosenberg, R.J. Reiter, The Safety of Melatonin in Humans, Clin Drug Investig. 36 (2016) 169–175. https://doi.org/10.1007/s40261-015-0368-5.

[24]        F.M.C. Besag, M.J. Vasey, Adverse events in long-term studies of exogenous melatonin, Expert Opin Drug Saf. 21 (2022) 1469–1481. https://doi.org/10.1080/14740338.2022.2160444.

[25]        N. Buscemi, B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, S. Vohra, T.P. Klassen, G. Baker, Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis, BMJ. 332 (2006) 385–393. https://doi.org/10.1136/bmj.38731.532766.F6.

[26]        R. Abramova, P. Campbell, J. Baron, K. Patel, S. Parmar, Review of Melatonin Supplementation for Sleep Disorders in Pediatric Special Populations, J Pharm Pract. 33 (2020) 533–539. https://doi.org/10.1177/0897190019845982.

[27]        J. Zizzo, R. Reddy, N. Kulkarni, R. Blachman-Braun, R. Ramasamy, Impact of Low-Dose Melatonin Supplementation on Testosterone Levels in U.S. Adult Males, Urology. 169 (2022) 92–95. https://doi.org/10.1016/j.urology.2022.07.048.

[28]        R. Luboshitzky, M. Levi, Z. Shen-Orr, Z. Blumenfeld, P. Herer, P. Lavie, Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men, Human Reproduction. 15 (2000) 60–65. https://doi.org/10.1093/humrep/15.1.60.

[29]        M.M. Grigg-Damberger, D. Ianakieva, Poor Quality Control of Over-the-Counter Melatonin: What They Say Is Often Not What You Get, J Clin Sleep Med. 13 (2017) 163–165. https://doi.org/10.5664/jcsm.6434.

[30]        L.A.E. Erland, P.K. Saxena, Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content, J Clin Sleep Med. 13 (2017) 275–281. https://doi.org/10.5664/jcsm.6462.

[31]        P.A. Cohen, B. Avula, Y.-H. Wang, K. Katragunta, I. Khan, Quantity of Melatonin and CBD in Melatonin Gummies Sold in the US, JAMA. 329 (2023) 1401–1402. https://doi.org/10.1001/jama.2023.2296.