Is Melatonin Safe for Long-Term Use?

Does it prevent our body from making melatonin on its own? Are there withdrawal effects when you stop taking it? These are all great questions we are asked often. To answer them, let’s review what melatonin is, what it is used for, and what the research is saying.

What is melatonin?

Melatonin is a hormone that is produced in response to darkness by the pineal gland. It was once thought that its sole purpose was to regulate our internal circadian rhythm (our internal 24 hour clock) and aid in sleep[1]. However, we are now discovering it has roles far beyond this. We now know melatonin has anti-oxidant, anti-ageing, immunomodulating and anticancer properties as well[2]. Research suggests that melatonin may also play roles in our levels of human growth hormone[3] [4], eye health [5] [6], Gastroesophageal reflux disease (heartburn) treatment [7] [8] [9], anxiety prevention[10] [11], and the treatment (adjunctive) and prevention of cancers such as breast cancer[12] [13].

Here's what the research says:

To date, researchers appear to agree that supplementing melatonin (including doses up to 100mg/day) is well tolerated and is not typically associated with any serious adverse affects[14] [15]. The mild adverse effects that have been reported include drowsiness, headaches and dizziness and nausea[16]. Of these mild adverse effects, research suggests they either resolve spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment[17]. Melatonin has not been found to be addictive in nature nor cause hangover symptoms[18], which is why it has been considered as a possible alternative to many sleep medications. In addition to this, research also suggests that the supplementation of melatonin does not interfere with the bodies internal production of melatonin once treatment has ceased[19] [20]. This makes sense when we consider that the half life (the time it takes for half of a drug to be cleared) of melatonin is only 1-2 hours depending on the formulation. This means that in 1-2 hours 50% of the melatonin will be removed from the body. Therefore, in 5 hours the amount of melatonin in the body is negligible and the body knows start producing a “new batch” of melatonin in the pineal gland as soon as you are exposed to light in the morning. Given that melatonin has a short half life, melatonin only targets sleep onset and not maintenance. Because of the short half life, we see so many prolonged release formulations of melatonin to slow down the absorption into the bloodstream to ensure the levels of melatonin are maintained in blood stream for a longer period to extend its sleep benefits. Prolonged release formulas allow you to maintain higher active levels of melatonin throughout the night if your goal with supplementing melatonin is to prevent nighttime waking.

But what about our more vulnerable populations such as children or elderly people?

In children, research suggests adverse effects of melatonin supplementation were few and mild[21]. Of these adverse effects, fatigue and somnolence were mentioned and were found to resolve with dose reduction. In addition, studies on pediatric populations looking at the long term effects of melatonin supplementation (two, three and four years on average) in doses of 2mg-10mg/day, found no notable long term effects on vitals signs or measures of child growth[22] [23]. In a two year long study assessing sleep, growth and puberty in children taking melatonin, a two week placebo period was implemented after treatment to assess withdrawal effects to which there were no apparent signs of withdrawals (mallow).

A 2022 review article discussing the safety of melatonin use in the elderly found that adverse effects were similar to those found in adult populations such as dizziness, nausea and headaches[24].However, there may be an increased risk of hypothermia if melatonin levels reach above normal physiologic levels as well as fractures in those who are at risk of falling due to the possibility of daytime sedation [25]. In regards to discontinuation, research suggests there is no evidence of withdrawal effects in populations 55 years and older[26].

It is important to note that the above research does not include individuals on medications or health concerns/diagnoses outside the parameters of each individual study. Therefore, it is important to discuss melatonin supplementation with your healthcare provider before taking.

In summary, it is SAFE to say melatonin is SAFE for those who are taking melatonin long term as recommended by their health care provider for one of the many clinical benefits we see with melatonin supplementation. 

[1] Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013 May 17;8(5):e63773. doi: 10.1371/journal.pone.0063773. PMID: 23691095; PMCID: PMC3656905.

[2] Bhattacharya S, Patel KK, Dehari D, Agrawal AK, Singh S. Melatonin and its ubiquitous anticancer effects. Mol Cell Biochem. 2019 Dec;462(1-2):133-155. doi: 10.1007/s11010-019-03617-5. Epub 2019 Aug 26. PMID: 31451998.

[3] Forsling ML, Wheeler MJ, Williams AJ. The effect of melatonin administration on pituitary hormone secretion in man. Clin Endocrinol (Oxf). 1999 Nov;51(5):637-42. doi: 10.1046/j.1365-2265.1999.00820.x. PMID: 10594526.

[4] Valcavi R, Zini M, Maestroni GJ, Conti A, Portioli I. Melatonin stimulates growth hormone secretion through pathways other than the growth hormone-releasing hormone. Clin Endocrinol (Oxf). 1993 Aug;39(2):193-9. doi: 10.1111/j.1365-2265.1993.tb01773.x. PMID: 8370132.

[5] Lundmark PO, Pandi-Perumal SR, Srinivasan V, Cardinali DP. Role of melatonin in the eye and ocular dysfunctions. Vis Neurosci. 2006 Nov-Dec;23(6):853-62. doi: 10.1017/S0952523806230189. PMID: 17266777.

[6] Yi C, Pan X, Yan H, Guo M, Pierpaoli W. Effects of melatonin in age-related macular degeneration. Ann N Y Acad Sci. 2005 Dec;1057:384-92. doi: 10.1196/annals.1356.029. PMID: 16399908.

[7] Pereira Rde S. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole. J Pineal Res. 2006 Oct;41(3):195-200. doi: 10.1111/j.1600-079X.2006.00359.x. PMID: 16948779.

[8] Kandil TS, Mousa AA, El-Gendy AA, Abbas AM. The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease. BMC Gastroenterol. 2010 Jan 18;10:7. doi: 10.1186/1471-230X-10-7. PMID: 20082715; PMCID: PMC2821302.

[9] Pereira Rde S. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole. J Pineal Res. 2006 Oct;41(3):195-200. doi: 10.1111/j.1600-079X.2006.00359.x. PMID: 16948779.

[10] Khare A, Thada B, Jain N, Singh D, Singh M, Sethi SK. Comparison of Effects of Oral Melatonin with Oral Alprazolam used as a Premedicant in Adult Patients Undergoing Various Surgical Procedures under General Anesthesia: A Prospective Randomized Placebo-Controlled Study. Anesth Essays Res. 2018 Jul-Sep;12(3):657-662. doi: 10.4103/aer.AER_90_18. PMID: 30283171; PMCID: PMC6157235.

[11] Ghaeli P, Solduzian M, Vejdani S, Talasaz AH. Comparison of the Effects of Melatonin and Oxazepam on Anxiety Levels and Sleep Quality in Patients With ST-Segment-Elevation Myocardial Infarction Following Primary Percutaneous Coronary Intervention: A Randomized Clinical Trial. Ann Pharmacother. 2018 Oct;52(10):949-955. doi: 10.1177/1060028018776608. Epub 2018 May 11. PMID: 29749262.

[12] Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017 Jun 13;8(24):39896-39921. doi: 10.18632/oncotarget.16379. PMID: 28415828; PMCID: PMC5503661.

[13] Yang A, Peng F, Zhu L, Li X, Ou S, Huang Z, Wu S, Peng C, Liu P, Kong Y. Melatonin inhibits triple-negative breast cancer progression through the Lnc049808-FUNDC1 pathway. Cell Death Dis. 2021 Jul 16;12(8):712. doi: 10.1038/s41419-021-04006-x. PMID: 34272359; PMCID: PMC8285388.

[14] Menczel Schrire Z, Phillips CL, Chapman JL, Duffy SL, Wong G, D'Rozario AL, Comas M, Raisin I, Saini B, Gordon CJ, McKinnon AC, Naismith SL, Marshall NS, Grunstein RR, Hoyos CM. Safety of higher doses of melatonin in adults: A systematic review and meta-analysis. J Pineal Res. 2022 Mar;72(2):e12782. doi: 10.1111/jpi.12782. Epub 2021 Dec 30. PMID: 34923676.

[15] Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. doi: 10.1007/s40261-015-0368-5. PMID: 26692007.

[16] Savage RA, Zafar N, Yohannan S, et al. Melatonin. [Updated 2021 Aug 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534823/

[17] Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review. CNS Drugs. 2019 Dec;33(12):1167-1186. doi: 10.1007/s40263-019-00680-w. PMID: 31722088.

[18] Cardinali DP, Srinivasan V, Brzezinski A, Brown GM. Melatonin and its analogs in insomnia and depression. J Pineal Res. 2012 May;52(4):365-75. doi: 10.1111/j.1600-079X.2011.00962.x. Epub 2011 Sep 23. PMID: 21951153.

[19] 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 Jan;22(1):42-4. doi: 10.1111/j.1600-079x.1997.tb00301.x. PMID: 9062869.

[20] Hack LM, Lockley SW, Arendt J, Skene DJ. The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms. 2003 Oct;18(5):420-9. doi: 10.1177/0748730403256796. PMID: 14582858.

[21] Maras A, Schroder CM, Malow BA, Findling RL, Breddy J, Nir T, Shahmoon S, Zisapel N, Gringras P. Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2018 Dec;28(10):699-710. doi: 10.1089/cap.2018.0020. Epub 2018 Oct 11. PMID: 30132686; PMCID: PMC6306655.

[22] Malow BA, Findling RL, Schroder CM, Maras A, Breddy J, Nir T, Zisapel N, Gringras P. Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2021 Feb;60(2):252-261.e3. doi: 10.1016/j.jaac.2019.12.007. Epub 2020 Jan 23. PMID: 31982581; PMCID: PMC8084705.

[23] Kennaway, D.J. (2015), Melatonin use in paediatrics. J Paediatr Child Health, 51: 584-589. https://doi.org/10.1111/jpc.12840

[24] Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001 Oct;86(10):4727-30. doi: 10.1210/jcem.86.10.7901. PMID: 11600532.

[25] Should Melatonin Be Used as a Sleeping Aid for Elderly People? Can J Hosp Pharm. 2019 Jul-Aug;72(4):327-329. Epub 2018 Aug 31. PMID: 31452545; PMCID: PMC6699865.

[26] Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007 Dec;16(4):372-80. doi: 10.1111/j.1365-2869.2007.00613.x. PMID: 18036082.

October is Breast Cancer Awareness Month

October is Breast Cancer Awareness Month! 

How can naturopathic medicine support you? No matter where you are on your breast cancer journey, from prevention to survivorship and everything in between, naturopathic medicine can be a useful integrative tool to support your health through:

• Evidence-based dietary recommendations for cancer prevention, during cancer treatments, and to reduce risk of recurrence

• Assessment of risk factors for breast cancer and recommendations to eliminate or reduce the impact of these factors on your health

• Stress reduction supports, including lifestyle recommendations, acupuncture and Traditional Chinese Medicine (TCM), and botanical/nutritional supports

• Laboratory testing and monitoring of important lab values

• Education and advocacy - naturopathic doctors (NDs) take the time to provide education and resources to patients, and can help to bridge a relationship between your conventional care team and your naturopathic team

• Support during conventional care - evidence-based naturopathic recommendations to help safely manage side effects and maintain optimal health during conventional treatments - your ND is knowledgeable on interactions between conventional agents and natural supports

If you are interested in learning about our approach to integrative cancer care and what supports we offer, call us at 306-664-2150 to set up a call for us to answer your questions!

Movement is Medicine - It's never too late to start if you have (or had) Breast Cancer!

The Importance of Physical Activity in Breast Cancer Patients

The World Health Organization (WHO) recommends 150 minutes (about 2.5 hours) of moderate to vigorous-intensity physical activity per week for adults, which has been shown to reduce the risk of developing cardiovascular disease, diabetes and depression, can improve bone health, and reduce all-cause mortality [1, 2]. Additionally, regular physical activity has also been demonstrated to support breast cancer patients before diagnosis, during treatment and in survivorship.

IMPACT OF PHYSICAL ACTIVITY BEFORE DIAGNOSIS

Research has shown that women who were physical activity before being diagnosed with breast cancer had decreased mortality from breast cancer and all-causes compared to women who were not physically active before diagnosis [4, 6]. One of these studies also found that women who were sedentary (not physically active) before diagnosis but started exercising after diagnosis had a 45% lower risk of death from breast cancer compared to women who were not physically-active before or after diagnosis [6]. This impact was achieved just by engaging in brisk walking 2-3 hours per week!

EXERCISE DURING CANCER TREATMENT IS SAFE AND EFFECTIVE

One study looked at how exercise impacts the health of patients with stage II+ breast cancer. They found that engaging in exercise was safe for these patients, and was associated with improvements in quality of life, fitness level, fatigue, strength, mental health, and weight [3]. Another study conducted on breast cancer patients undergoing chemotherapy found that more intense exercise regimens (50-60 minutes 3 times per week) were slightly better than moderate-intensity exercise regimens (25-30 minutes 3 times per week) in improving pain, hot flashes, and strength, however both regimens were effective in managing side effects from chemotherapy [5].

PHYSICAL ACTIVITY AFTER TREATMENT IS STILL BENEFICIAL

Research on breast cancer survivors has also shown benefit. One study found that breast cancer survivors who practiced 150 minutes of moderate-intensity exercise per week had a 27% decrease in all-cause mortality (ie. dying from any cause) and a 25% decrease in breast cancer mortality, compared to women who had lower levels of physical activity [2].

MOVEMENT IS MEDICINE

So, what does this mean? It’s never too late to increase your levels of physical activity! No matter where you are on your health journey, physical activity appears to benefit health by reducing risk of dying from cancer and other causes and improving side effects during treatments. As always, talk to your doctor to make sure you are engaging in physical activity that is safe for you!

WHAT CAN I DO TO INCREASE MY PHYSICAL ACTIVITY LEVELS?

There are a number of ways to increase physical activity and movement in your daily schedule! An easy way to remember the difference between moderate-intensity and vigorous intensity exercising is talking and singing - at a moderate level of intensity, you can talk but would find it difficult to sing; at vigorous-intensity, it would be difficult to talk. Here’s a few ideas:

• Take the stairs instead of the elevator

• Walk or bicycle to work, or walk the kids to school

• Go for walks before or after work, or during the day

• Take up a sport or hobby that involves movement, like dancing, tennis, swimming

• Raking the leaves, shovelling snow, gardening

• Yoga, tai chi and Qigong

• Household chores like vacuuming, mopping

• Our favourite at Saskatoon Naturopathic Medicine: 15 minute at-home dance session - just turn on your favourite song and dance!

References:

[1] https://www.who.int/dietphysicalactivity/physical-activity-recommendations-18-64years.pdf

[2] Beasley, J. M., Kwan, M. L., Chen, W. Y., Weltzien, E. K., Kroenke, C. H., Lu, W., Nechuta, S. J., Cadmus-Bertram, L., Patterson, R. E., Sternfeld, B., Shu, X.-O., Pierce, J. P., & Caan, B. J. (2012). Meeting the physical activity guidelines and survival after breast cancer: Findings from the after breast cancer pooling project. Breast Cancer Research and Treatment, 131(2), 637–643. https://doi.org/10.1007/s10549-011-1770-1

[3] Singh, B., Spence, R. R., Steele, M. L., Sandler, C. X., Peake, J. M., & Hayes, S. C. (2018). A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer. Archives of Physical Medicine and Rehabilitation, 99(12), 2621–2636. https://doi.org/10.1016/j.apmr.2018.03.026

[4] Lahart, I. M., Metsios, G. S., Nevill, A. M., & Carmichael, A. R. (2015). Physical activity, risk of death and recurrence in breast cancer survivors: A systematic review and meta-analysis of epidemiological studies. Acta Oncologica (Stockholm, Sweden), 54(5), 635–654. https://doi.org/10.3109/0284186X.2014.998275

[5] Courneya, K. S., McKenzie, D. C., Mackey, J. R., Gelmon, K., Friedenreich, C. M., Yasui, Y., Reid, R. D., Cook, D., Jespersen, D., Proulx, C., Dolan, L. B., Forbes, C. C., Wooding, E., Trinh, L., & Segal, R. J. (2013). Effects of exercise dose and type during breast cancer chemotherapy: Multicenter randomized trial. Journal of the National Cancer Institute, 105(23), 1821–1832. https://doi.org/10.1093/jnci/djt297

[6] ​​Irwin, M. L., Smith, A. W., McTiernan, A., Ballard-Barbash, R., Cronin, K., Gilliland, F. D., Baumgartner, R. N., Baumgartner, K. B., & Bernstein, L. (2008). Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: The health, eating, activity, and lifestyle study. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 26(24), 3958–3964. https://doi.org/10.1200/JCO.2007.15.9822