A TLDR; Melatonin’s role and position in SG’s healthcare
Melatonin Research
Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin. It is synthesized by the pineal gland, from its precursor, serotonin.
The main function of the pineal gland is to receive information about the state of the light-dark cycle from the environment and convey this information to produce and secrete the hormone Melatonin.
Physiologically, Melatonin secretion increases soon after the onset of darkness, peaks at 2–4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep.
Melatonin research is a vast field, where results showed that the most frequently cited papers in the field was in the therapeutic application of melatonin in neuropsychiatric diseases and cancer (Meng et al., 2021).
The pharmacokinetic (PK) properties of Melatonin have been studied extensively but due to heterogeneous study designs, there is a lot of inconsistency in regards to Melatonin’s metabolism. Overall, it can be estimated that the following where the time to reach maximum concentration (Tmax) was approximately 50 min following oral immediate-release formulations of melatonin, with the half-life of Melatonin (T1/2) being approximately 45 min (Harpsøe et al., 2015). 90% of Melatonin undergoes CYP1A2 hepatic metabolism. Consequently, it is conjugated to sulfuric or glucuronic acid and excreted in the urine. A smaller amount is excreted in faeces (Ma et al., 2005).
An averaged estimation of bioavailability for oral melatonin has been found to be approximately 15 % (Harpsøe et al., 2015). In addition, it has been elucidated that Melatonin has no selectivity between Melatonin receptor subtypes (M1, M2 and M3) (Meng et al., 2021).
It is established that Melatonin can potentially decrease sleep onset latency (SOL), increases total sleep time and improves overall sleep quality. In addition, it has also been found that the absolute benefits of Melatonin compared to placebo is smaller than other pharmacological treatments for insomnia (Ferracioli-Oda et al., 2013).
Why Melatonin?
There is conflicting evidence on the clinical efficacy of exogenous Melatonin for the treatment of sleep disorders. This may be due to differences in the PK properties of melatonin formulations used in clinical trials — having transdermal, oral, topical, buccal, intravenous and nasogastric formulations (Moroni et al., 2021). It was found that fast-release formulations of melatonin reduce SOL effectively, whereas controlled-release formulations may be better at reducing Wakefulness After Sleep Onset (WASO).
Based on studies, it has been noted that a fast release profile will affect the circadian clock early in the night advancing the circadian phase. In contrast, a controlled release profile will probably affect the clock later in the night yielding a delay in the phase (Moroni et al., 2021). These findings have guided evidence-based decision-making with international experts recommending prolonged-release melatonin at 2–10 mg, 1–2 h before bedtime, for insomnia symptoms. In contrast, immediate release formulations can be considered in cases of circadian sleep disturbances (Palagini et al., 2021).
Circadin® History
As of writing this in October 2022, there is only Prescription-Only Medicine (POM) that contains Melatonin in Singapore — Circadin.
Aside from Melatonin, Circadin prolonged release tablets contain the following excipients: Ammonio methacrylate copolymer, calcium hydrogen phosphate, lactose, colloidal anhydrous silica, purified talc and magnesium stearate. You know, the usual stuff.
Being curious, I gave Circadin’s Singapore Product Information Leaflet (PIL) a cursory look. It claims to work on the melatonin receptor, where it elucidates its main effect based on the current hypothesis that activity on MT1, MT2 and MT3 receptors contribute to sleep-promoting properties.
As written in its PIL, Circadin® 2 mg is mentioned as a “… prolonged release formulation of highest grade of Melatonin”, indicated for primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over. The melatonin in Circadin® is a synthetic molecule, 100% equal to the human melatonin molecule (N-acetyl-5-methoxytryptamine).
According to Circadin’s PIL, the differences in the effects of fast vs slow release formulations is best exemplified by their effects on the blood pressure rhythm. It is stated that Circadin ® (slow-release) improves blood pressure control in nocturnal hypertension, whereas fast-release formulations are not efficacious. This claim however, has not been proven to be significant in past research, with a recent review showing that a controlled-release formulation of melatonin reduced measured BP by 3.57 mm Hg (95% confidence interval: –7.88 to .73; I2 = 0%). In addition to its statistical insignificance, it is also not clinically significant (Lee et al., 2022).
Another claim in Circadin’s PIL states that the effect of Circadin® on sleep latency is no less than that of fast-release melatonin because the brain is very sensitive to low doses of melatonin in the beginning of the night. However, recent studies have shown that to be otherwise due to its different release profile.
A 2016 study was found that the release profile of Circadin ® behaved differently from normal formulations when divided or crushed, with a significantly different release profile as compared to other melatonin formulations. In addition, when Circadin® is divided into halves, Circadin preserves most of its prolonged-release characteristic whereas a quarter-cut and crushed tablet has a more immediate melatonin release profile (Chua et al., 2016).
In addition, a 2018 study established that Circadin ® specifically, when used in its indicated population, is well-tolerated and have no safety concerns when used concomitantly with antihypertensive, antidiabetic, lipid-lowering or anti-inflammatory drugs (Quera-Salva & Claustrat, 2018).
How to use Circadin 2mg tablets?
It is established to be used as a tablet. It should be swallowed whole to maintain prolonged release properties. Crushing or chewing should not be used to facilitate swallowing.
The recommended dose is 2 mg once daily, 1–2 hours before bedtime and after food. This dosage may be continued for up to thirteen weeks
Personal Analysis
After looking through the research on Melatonin, I am definitely fascinated by the state of the field. It is extensive, with more interest in the last decade from American and Chinese institutions. Melatonin is seen as an excellent drug candidate in cancer research, with melatonin receptors being a crucial drug target in sleep mechanisms. I am hopeful that the use of Melatonin can be expanded to other domains more readily once more knowledge has been established.
Zooming in on Circadin, more research has been done specifically on Circadin® to show the medication’s effectiveness in aiding sleep as compared to other Melatonin formulations. Despite the small sample sizes of their studies, it still demonstrates a more rigorous, evidence-based approach as compared to other formulations. This translates to a more favourable regulatory ruling for Circadin as compared to other supplements/medicines that peddle the same stuff.
Interestingly enough, Melatonin is not an FDA-approved substance for any indication. Other melatonin receptor agonists such as agomelatine are indicated for sleep disturbances (though I will not be delving into their mechanisms in this article). Despite all of that, Melatonin is known to be well-tolerated and has a low risk of side effects, hence why it is still recommended by physicians. In fact, a universally agreed upon consensus regarding Melatonin’s maximum dosing remains elusive.
Viewing it from a regulatory standpoint, Circadin ® has been approved by various health regulatory authorities such as EMA, MHRA and even HSA. Standing up to such scrutiny, Circadin® can at least be guaranteed for certain drug standards of quality, safety and efficacy. Without this regulatory approval, supplements can also be used but there may be a larger level of risk involved, aptly phrased as Caveat Emptor — Let the buyer beware.
An example can be seen in 2020, where a melatonin-containing supplement in Myanmar called “LANXI 7 Day Whitening Ginseng Whitening Beauty Melatonin Cream” was laced with mercury.
Currently, the benefits of Circadin ® as compared to other formulations may be more dependent on its release profile than pharmacokinetic properties. Anecdotally, this medication has worked well for some patients. This can be rationalised by looking at its purported use. Indicated only for use in older males with “poor quality of sleep”, its mechanistic activity and formulation does suggest that it can help increase WASO.
However, the same formulation can have different pharmacokinetic and pharmacodynamic effects in males and females. First-pass metabolism is regulated by a family of enzymes called cytochrome P450s. The main CYP450 enzyme involved in the hepatic metabolism of melatonin,CYP1A2, has higher activity in men which can indicate shorter half-life (Moroni et al., 2021). In addition, it is also speculated that males and females have slightly different circadian rhythms, thereby having different effectiveness when using Melatonin-containing products.
Looking beyond Circadin® to other oral formulations such as solid tablets and sublingual tablets, there can be variability in absorption and metabolism of Melatonin. With oral administration, the amount of Melatonin entering systemic circulation varies due to bioavailability and hepatic metabolism. These differences affect the compound’s overall PK and efficacy.
Expanding the conversation to other forms of administration such as transdermal and buccal routes, there can be increased melatonin bioavailability and can potentially have greater effect on sleep disorders. However, these products are not as popular in Singapore currently.
Holistically speaking, there are different forms of sleep disorders and insomnias such as delayed or advanced sleep phase syndrome (Krystal et al., 2019). This can explain why certain products work better for certain populations. Some types of insomnia are characterized by awaking in the middle of the night after only a few hours of sleep, in this case an adjusted profile release may make a significant difference in the clinical outcomes of sleep (Moroni et al., 2021).
As a disclaimer, this article does not replace any medical advice. However, Melatonin itself is an interesting topic and I am personally intrigued with the state of research regarding this field.
Bibliography
Chua, H. M., Hauet Richer, N., Swedrowska, M., Ingham, S., Tomlin, S., & Forbes, B. (2016). Dissolution of Intact, Divided and Crushed Circadin Tablets: Prolonged vs. Immediate Release of Melatonin. Pharmaceutics, 8(1). https://doi.org/10.3390/pharmaceutics8010002
Ferracioli-Oda, E., Qawasmi, A., & Bloch, M. H. (2013). Meta-analysis: melatonin for the treatment of primary sleep disorders. PloS One, 8(5), e63773. https://doi.org/10.1371/journal.pone.0063773
Harpsøe, N. G., Andersen, L. P. H., Gögenur, I., & Rosenberg, J. (2015). Clinical pharmacokinetics of melatonin: a systematic review. European Journal of Clinical Pharmacology, 71(8), 901–909. https://doi.org/10.1007/s00228-015-1873-4
Krystal, A. D., Prather, A. A., & Ashbrook, L. H. (2019). The assessment and management of insomnia: an update. World Psychiatry : Official Journal of the World Psychiatric Association (WPA), 18(3), 337–352. https://doi.org/10.1002/wps.20674
Lee, E. K.-P., Poon, P., Yu, C.-P., Lee, V. W.-Y., Chung, V. C.-H., & Wong, S. Y.-S. (2022). Controlled-release oral melatonin supplementation for hypertension and nocturnal hypertension: A systematic review and meta-analysis. Journal of Clinical Hypertension (Greenwich, Conn.), 24(5), 529–535. https://doi.org/10.1111/jch.14482
Ma, X., Idle, J. R., Krausz, K. W., & Gonzalez, F. J. (2005). Metabolism of melatonin by human cytochromes p450. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 33(4), 489–494. https://doi.org/10.1124/dmd.104.002410
Meng, Y., Tao, Z., Zhou, S., Da, W., & Tao, L. (2021). Research Hot Spots and Trends on Melatonin From 2000 to 2019. Frontiers in Endocrinology, 12, 753923. https://doi.org/10.3389/fendo.2021.753923
Moroni, I., Garcia-Bennett, A., Chapman, J., Grunstein, R. R., Gordon, C. J., & Comas, M. (2021). Pharmacokinetics of exogenous melatonin in relation to formulation, and effects on sleep: A systematic review. Sleep Medicine Reviews, 57, 101431. https://doi.org/https://doi.org/10.1016/j.smrv.2021.101431
Palagini, L., Manni, R., Aguglia, E., Amore, M., Brugnoli, R., Bioulac, S., Bourgin, P., Micoulaud Franchi, J.-A., Girardi, P., Grassi, L., Lopez, R., Mencacci, C., Plazzi, G., Maruani, J., Minervino, A., Philip, P., Royant Parola, S., Poirot, I., Nobili, L., … Geoffroy, P. A. (2021). International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders. Frontiers in Psychiatry, 12, 688890. https://doi.org/10.3389/fpsyt.2021.688890
Quera-Salva, M.-A., & Claustrat, B. (2018). [Melatonin: Physiological and pharmacological aspects related to sleep: The interest of a prolonged-release formulation (Circadin®) in insomnia]. L’Encephale, 44(6), 548–557. https://doi.org/10.1016/j.encep.2018.06.005
