Melatonin Dependency Dilemma: Exploring Evidence, Safety and Misconceptions
The scientific literature agrees - There is no evidence that melatonin supplementation suppresses endogenous melatonin production.
One of the arguments against regular melatonin use is the claim that it may lead to melatonin dependency and stop our body’s own endogenous melatonin production. After reviewing the literature, I could not find any strong evidence showing individuals can become dependent on melatonin. I suspect much of these concerns come from categorizing melatonin as a hormone or from early animal and in-vitro studies. And although it is a hormone, it’s mechanism in the body is unlike other hormones.
Melatonin signaling and physiology is different and the research supports that.
Most doctors assume that melatonin functions like other hormones - via a negative feedback loop. Meaning when melatonin levels increase, it sends a message to the pineal gland in the brain to turn off production. Some hormone systems like testosterone, cortisol, estrogen or thyroid hormone do behave this way in the body. The body has a well-controlled physiological management system for these hormones. When these hormones become too high or too low the body (mostly the brain) will adjust to correct these levels. Although many hormone systems in the body work this way – melatonin does not.
Shirani A, St Louis EK. Illuminating rationale and uses for light therapy. J Clin Sleep Med. 2009;5(2):155-163.
Melatonin physiology and function in the brain and body
To understand this better, we need to understand how melatonin works. Our body has its own clock or circadian rhythm which is controlled by various structures and receptors in the brain. Melatonin is made and released in the brain by the Pineal gland. It is influenced by light and the absence of light. When light hits the retina in your eye, this message gets sent to the suprachiasmatic nucleus (SCN) in the brain which releases the neurotransmitter GABA. Another part of the brain, the paraventricular nucleus (PVN) senses this GABA and it inhibits production of melatonin by the pineal gland.
When there is darkness in the evening hours, the SCN releases glutamate (instead of GABA) which then is sensed by the PVN. This triggers a cascade of reactions which causes the release of norepinephrine which then causes the pineal gland to release melatonin.
The feedback to the pineal gland and other structures in the brain is not melatonin, but light and neurotransmitters. Melatonin does not signal to the brain if it is making too much melatonin or not. Instead, it is a response to light (mostly blue light). This process has many other checks-and-balances including the body’s own endogenous circadian clock. So even if you were kept in a dark room for 24 hours, your body would not make melatonin all 24-hours but it would disrupt your sense of day and night. The SCN is fascinating, and it will control the body’s own melatonin production. The exception is when there is light during the evening hours which inhibits our own production of melatonin. [1]
3 Major questions around melatonin supplementation
The physiology behind melatonin helps us understand how the body works and what to expect when we try to manipulate or work with the body’s physiology. It is even better when we can validate these mechanisms in human trials. Two of the more well-designed human studies asked the questions:
Does melatonin supplementation turn off our body’s own melatonin production?
Does endogenous melatonin production resume after long-term melatonin use?
Does short term and long-term melatonin use cause withdrawals and worsen sleep?
The findings from these peer-reviewed articles support our expectations of melatonin physiology. Melatonin does not turn off the body’s own production of melatonin, the body does resume its own production (it is likely it never turned off) and after discontinuation there is no significant withdrawal symptoms or worsening of sleep.
Melatonin dependency after short term use:
Matsumoto and colleagues designed a placebo controlled trial to assess if short term use of melatonin in night-shift workers (n=21) would impair their own endogenous melatonin production. The group was given 0.5 mg of melatonin for 7 days and they measured their melatonin levels (plasma) before and after the 7 days. The researchers found that melatonin levels were no different before or after treatment. The normalization of their melatonin levels was the same as the placebo group. If melatonin supplementation did turn off the body’s own production of melatonin, then we would expect to see low melatonin levels after the participants stopped taking melatonin. Since most hormone systems in the body, if they function on a negative-feedback loop, do not recovery within 24 hours. Interestingly, this study also ran the same design with a blind individual (n=1) but instead they gave the participant 50 mg of melatonin. Even at this high dose, melatonin normalized after the trial.
One may argue that 7 days of melatonin was too short or 0.5 mg was too low of a dose to turn off endogenous production. Maybe the Matsumoto trial was too small with only 21 participants. That’s a fair critique. Let’s look at a more longer and larger study.
Melatonin dependency after long-term use:
In another study, Lemoine and colleagues conducted an open-label double-blind placebo controlled trial of 208 individuals with primary insomnia. These individuals were not taking any sleep medications. This study ran for 6 and 12 months. Participants in this study consumed 2.0 mg of a sustained-release melatonin. Instead of measuring plasma melatonin levels, they instead testing urinary levels of a melatonin metabolite called 6-sulfatoxymelatonin (6SMT). Many studies have validated the use of 6SMT as an accurate and reliable marker to assess endogenous melatonin production. This study was able to provide clarity on multiple questions around chronic melatonin use:
Does melatonin improve subjective metrics of sleep? (“How was your night?” regarding sleep quality on the previous day, “How was your mood during the day?”)
Does melatonin impact subjective metrics of sleep when participants stop melatonin use?
Do participants experience withdrawal or poor sleep after discontinuing melatonin?
Does endogenous melatonin production, measured by 6SMT, change after long term melatonin use?
These questions help us understand the beneficial and negative effects of melatonin use and how it impacts our neurophysiology. As a clinician, I am primarily interested in understanding if melatonin supplementation inhibits production of our body’s own melatonin production and would it likely cause a dependence on melatonin for sleep.
There was no evidence that melatonin supplementation suppresses endogenous melatonin production, and in fact melatonin levels remained normal after 6-months of use in this study. In a subset of the participants (n=15) with insomnia, the investigators tested their urinary melatonin metabolite, 6SMT, two weeks after stopping the 2.0 mg sustained-release melatonin. Their 6MST levels (age-adjusted) were not statistically different to a similar age group without insomnia and they were higher than the group with insomnia.
When we read studies, it is also important to understand if the results are clinically significant. The sleep diary given to participants was designed to help measure subjective metrics of sleep (How was your night? How was your mood during the day?). This is one part of the study that I wish the investigators paid more attention to because this sleep diary was not a validated sleep questionnaire like the PSQI or Epworth that is commonly used with patients or in clinical settings. We must assess the diary with some hesitation; however, the results were very interesting and helped us understand if participants reported any difference in their sleep or mood. Those taking melatonin noticed significant improvement in their sleep and mood after 6 and 12 month.
In the 2-week withdrawal phase after the 6 and 12-month trial, participants were asked about their sleep quality and mood again. Their feedback showed a mild reduction in their sleep quality and mood. However, the reduction was still higher than baseline. Meaning, their sleep quality and mood decreased mildly after stopping the melatonin for 2-weeks, but this was still better than their sleep quality and mood before starting the melatonin.
This suggests that although, and to no surprise, participants slept better while on melatonin, they did not have rebound insomnia when they stopped. Participants also improved their baseline sleep quality after stopping which means that it is possible that melatonin helped them re-calibrate their circadian clock and regulate their body’s own endogenous sleep production. The authors did not come to this conclusion, but it may explain why some people only need melatonin for a short period of time.
Melatonin was also well tolerated. There were no serious adverse events although 1.6% of participants experienced dizziness and 1.2% noticed headaches (3 participants). Other adverse events were related to poor sleep after stopping melatonin. There were some participants who complained of insomnia or sleep-related symptoms during the withdrawal phase like waking during the night or difficulty falling asleep which is not surprising.
Closing remarks
One of the major issues we see around research on nutrients or supplements, is the lack of funding to support these studies. This is often because many of these supplements are not patentable like a pharmaceutical drug and therefore the return on investment is low and incentive to run a study is also low. For instance, it is not possible to patent melatonin as a supplement since it is a naturally produced hormone in the body unless the patent is around the form or delivery of melatonin. Therefore, anyone can formulate and manufacture a melatonin supplement, run large human clinical trials, and publish their research. There is nothing prohibiting another supplement company to make the same melatonin and use other company’s primary research to create claims around their product.
To make informed and evidence-lead decisions for patients we must take whatever research is available, understand the mechanism, biochemistry and physiology of these compounds and apply it for use. Although there are only a few studies on the potential of melatonin dependency (but many on its beneficial effects), Lemoine and Matsumoto’s papers have done an excellent job showing that melatonin does not cause dependency or impair our own endogenous production which suggests a very low risk in recommending melatonin long-term when it fits the patient’s needs.
References
Braam, W., & Spruyt, K. (2022). Reference intervals for 6-sulfatoxymelatonin in urine: A meta-analysis. Sleep Medicine Reviews, 63. https://doi.org/10.1016/J.SMRV.2022.101614
Lemoine, P., Garfinkel, D., Laudon, M., Nir, T., & Zisapel, N. (2011). Prolonged-release melatonin for insomnia – an open-label long-term study of efficacy, safety, and withdrawal. Therapeutics and Clinical Risk Management, 7, 301. https://doi.org/10.2147/TCRM.S23036
Matsumoto, M., Sack, R. L., Blood, M. L., & Lewy, A. J. (1997). The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. Journal of Pineal Research, 22(1), 42–44. https://doi.org/10.1111/J.1600-079X.1997.TB00301.X