Sleeping Tips: Is Supplementation Safe?

One of the most frequently asked questions I get around sleep is, “If I use a supplement containing melatonin, will I become addicted?” or “Will I build tolerance and be unable to sleep without it?”

Let me clear the air on this topic since I recently wrote about many of the benefits melatonin provides in keeping your immune system in peak shape, especially during the cold and flu season.

I can confidently say that melatonin is one of the safest supplements you can take. Of course, when considering the use of melatonin (or any other supplement to treat COVID-19), the safety of each individual product it comes in is of utmost importance. Some products are certainly of higher quality than others.

As reviewed previously, short-term use of melatonin is incredibly safe, even when given in high doses, and the reported adverse effects are limited to occasional dizziness, headache, nausea, and sleepiness. Generally speaking, melatonin's safety profile in humans is very high (Andersen et al., 2016). In clinical trials, doses of 3 mg, 6 mg and 10 mg of melatonin oral intake by patients in ICU showed satisfactory safety when compared to placebo (Bourne et al., 2008; Mistraletti et al., 2010; 2015).

I typically never go beyond 3 mg in practice with my patients, but some studies have even gone as high as 1 gram per day for a month with no adverse effects reported (Nordlund & Lerner, 1977). Although there are no clinical trials to assess the use of melatonin in COVID-19 patients, in individuals with other inflammation-causing diseases, the use of melatonin has shown promising results with respect to boosting the immune system. 

The safety of melatonin has been verified in many human studies. It is important to note that taking Melatonin 1.5 hours or earlier before bed improves its effectiveness and prevents one from experiencing any minor side effects. 

Melatonin Effects in Cytokine Levels in Humans

In a randomized controlled 8-week trial (RCT), oral supplementation of 6 mg per day of melatonin caused a significant decrease in serum levels of the inflammation-producing cytokines IL-6, TNF-α, and the inflammatory cardiac marker hs-Creactive protein (hs-CRP) in patients with diabetes mellitus and teeth & gum disease (periodontitis) (Bazyar et al., 2019). When these powerful cytokines associated with causing tons of tissue damage subside, the immune system is able to work more favorably against overarching pathogens causing disease. 

In another study with patients suffering with severe multiple sclerosis, 25 mg per day of melatonin for 6 months also led to a significant reduction in serum concentrations of the cytokines TNF-α, IL-6, IL-1β, and lipoperoxides (Sánchez-López et al., 2018). In acute phases of inflammation, such as during surgery, (Kücükakin et al., 2008), melatonin intake of 10 mg per day, 6 mg per day, and 5 mg per day for less than 5 days reduced the level of circulating pro-inflammatory cytokines. Lastly, in a meta-analysis of 22 RCTs, it was found that melatonin is associated with a significant reduction of TNF-α and IL-6 level (Zarezadeh et al., 2019). 

All of this clinical evidence (in addition to the past 3 previous posts) suggests that the use of melatonin as a supplement may effectively reduce the inflammation and in turn, lessen the harm caused by many chronic disease and pathogens (i.e., COVID19).  By boosting the immune system, melatonin can improve clinical outcomes.

Any risk of melatonin in COVID-19 is theoretical at this point. The potential beneficial effects of melatonin as adjuvant use in COVID-19 in anti-inflammation, anti-oxidation, and immune response regulation has been repeatedly demonstrated in respiratory disorder models induced by infections and associated complications. Melatonin’s safety profile is near excellent.

And despite the direct evidence of melatonin application in COVID-19 is unclear, both its use in experimental animal models and in humans has continuously documented its efficacy and safety and its use by COVID-19 patients predictably would be highly beneficial.

References

Andersen, L. P. H., Gögenur, I., Rosenberg, J., & Reiter, R. J. (2016). The safety of melatonin in humans. Clinical drug investigation, 36(3), 169-175.

Bazyar, H., Gholinezhad, H., Moradi, L., Salehi, P., Abadi, F., Ravanbakhsh, M., & Javid, A. Z. (2019). The effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status, serum melatonin and inflammatory markers in type 2 diabetes mellitus patients with chronic periodontitis: a double-blind, placebo-controlled trial. Inflammopharmacology, 27(1), 67-76.

Bourne, R. S., Mills, G. H., & Minelli, C. (2008). Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Critical Care, 12(2), R52.

Chen, J., Xia, H., Zhang, L., Zhang, H., Wang, D., & Tao, X. (2019). Protective effects of melatonin on sepsis-induced liver injury and dysregulation of gluconeogenesis in rats through activating SIRT1/STAT3 pathway. Biomedicine & Pharmacotherapy, 117, 109150.

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., ... & Cheng, Z. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet, 395(10223), 497-506.

Kücükakin, B., Lykkesfeldt, J., Nielsen, H. J., Reiter, R. J., Rosenberg, J., & Gögenur, I. (2008). Utility of melatonin to treat surgical stress after major vascular surgery–a safety study. Journal of pineal research, 44(4), 426-431.

Lewandowska, K., Małkiewicz, M. A., Siemiński, M., Cubała, W. J., Winklewski, P. J., & Mędrzycka-Dąbrowska, W. A. (2020). The role of melatonin and melatonin receptor agonist in the prevention of sleep disturbances and delirium in intensive care unit–a clinical review. Sleep Medicine, 69, 127-134.

Lewis, S. R., Pritchard, M. W., Schofield‐Robinson, O. J., Alderson, P., & Smith, A. F. (2018). Melatonin for the promotion of sleep in adults in the intensive care unit. Cochrane Database of Systematic Reviews, (5).

Mistraletti, G., Sabbatini, G., Taverna, M., Figini, M. A., Umbrello, M., Magni, P., ... & Fraschini, F. (2010). Pharmacokinetics of orally administered melatonin in critically ill patients. Journal of pineal research, 48(2), 142-147.

Mistraletti, G., Umbrello, M., Sabbatini, G., Miori, S., Taverna, M., Cerri, B., ... & Salini, S. (2015). Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol, 81(12), 1298-1310.

Nduhirabandi, F., Lamont, K., Albertyn, Z., Opie, L. H., & Lecour, S. (2016). Role of toll‐like receptor 4 in melatonin‐induced cardioprotection. Journal of pineal research, 60(1), 39-47.

Nordlund, J. J., & Lerner, A. B. (1977). The effects of oral melatonin on skin color and on the release of pituitary hormones. The Journal of Clinical Endocrinology & Metabolism, 45(4), 768-774.

Reiter, R. J., Ma, Q., & Sharma, R. (2020). Treatment of Ebola and other infectious diseases: melatonin “goes viral”. Melatonin Research, 3(1), 43-57.

Sánchez-López, A. L., Ortiz, G. G., Pacheco-Moises, F. P., Mireles-Ramírez, M. A., Bitzer-Quintero, O. K., Delgado-Lara, D. L., ... & Velázquez-Brizuela, I. E. (2018). Efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing remitting multiple sclerosis. Archives of Medical Research, 49(6), 391-398.

Shafiei, E., Bahtoei, M., Raj, P., Ostovar, A., Iranpour, D., Akbarzadeh, S., ... & Movahed, A. (2018). Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: A randomized, open-labeled, placebo-controlled trial. medicine, 97(30).

Sun, C. K., Lee, F. Y., Kao, Y. H., Chiang, H. J., Sung, P. H., Tsai, T. H., ... & Chen, Y. L. (2015). Systemic combined melatonin–mitochondria treatment improves acute respiratory distress syndrome in the rat. Journal of Pineal Research, 58(2), 137-150.

Tordjman, S., Chokron, S., Delorme, R., Charrier, A., Bellissant, E., Jaafari, N., & Fougerou, C. (2017). Melatonin: pharmacology, functions and therapeutic benefits. Current neuropharmacology, 15(3), 434-443.

Volt, H., García, J. A., Doerrier, C., Díaz‐Casado, M. E., Guerra‐Librero, A., López, L. C., ... & Acuña‐Castroviejo, D. (2016). Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. Journal of pineal research, 60(2), 193-205.

Wu, X., Ji, H., Wang, Y., Gu, C., Gu, W., Hu, L., & Zhu, L. (2019). Melatonin alleviates radiation-induced lung injury via regulation of miR-30e/NLRP3 Axis. Oxidative Medicine and Cellular Longevity, 2019.

Zarezadeh, M., Khorshidi, M., Emami, M., Janmohammadi, P., Kord-Varkaneh, H., Mousavi, S. M., ... & Alizadeh, S. (2019). Melatonin supplementation and pro-inflammatory mediators: a systematic review and meta-analysis of clinical trials. European journal of nutrition, 1-11.

Zhao, Z., Lu, C., Li, T., Wang, W., Ye, W., Zeng, R., ... & Liu, C. (2018). The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial. Journal of pineal research, 65(4), e12521.

AUTHOR

Dr. Payal Bhandari M.D. is one of U.S.'s top leading integrative functional medical physicians and the founder of SF Advanced Health. She combines the best in Eastern and Western Medicine to understand the root causes of diseases and provide patients with personalized treatment plans that quickly deliver effective results. Dr. Bhandari specializes in cell function to understand how the whole body works. Dr. Bhandari received her Bachelor of Arts degree in biology in 1997 and Doctor of Medicine degree in 2001 from West Virginia University. She the completed her Family Medicine residency in 2004 from the University of Massachusetts and joined a family medicine practice in 2005 which was eventually nationally recognized as San Francisco’s 1st patient-centered medical home. To learn more, go to www.sfadvancedhealth.com.