Is melatonin addictive? What research says

Is melatonin addictive? The way this molecule works is already very telling. Melatonin is the signal for darkness: when the light fades, it tells the body that night has begun. The message is short-lived, with a half-life of under an hour, and by morning the molecule has already left the scene. The following evening, it is again the fading light that triggers the signal, from the beginning, just like every evening.

Studies have followed this line of inquiry for weeks and, in the longest case, for a full year, on people who took melatonin every evening. With three questions in mind: was a higher dose needed over time? What happened on the night they stopped? And, in the meantime, how much was the body still producing on its own?

The answers, with their numbers, are provided below. From there, we arrive at the 1 mg dose of Italian supplements and the timing, which is part of the authorised indication. Finally, what changes when the tablet dissolves under the tongue.

What melatonin is and how it regulates sleep

1. LIGHT DECREASES
2. RETINA
3. SUPRACHIASMATIC NUCLEUS
4. PINEAL GLAND / MELATONIN
5. ↓ DARKNESS SIGNAL

Melatonin is a hormone produced by the pineal gland, a small structure in the centre of the brain, when the light fades. The command comes from the suprachiasmatic nucleus of the hypothalamus, which reads the light intensity through the retina and synchronises the body's twenty-four-hour rhythm to it. Secretion begins in the evening, reaches its peak in the middle of the night, and ceases towards the morning; bright light, at any time, suppresses it [1].

Melatonin acts on the MT1 and MT2 receptors, which are distributed throughout many tissues, and its job is to inform the body that it is night. It is a time signal: it tells the body which phase of the day it is in, and the body consequently organises its temperature, sleep-wake cycle and the other functions that follow the light-dark cycle [1].

Synthesis starts from tryptophan, an amino acid from the diet, which is converted into 5-hydroxytryptophan (5-HTP), then into serotonin and finally, in the evening, into melatonin.

Our 5-HTP, a griffonia seed extract standardised to 20% 5-hydroxytryptophan, provides the direct precursor to serotonin, the molecule from which the pineal gland produces melatonin when the light fades; on the label, it bears the physiological effect 'relaxation (sleep)'. It is upstream in the chain that produces the signal, and in this way, it is complementary to melatonin.

Melatonin and dependence: what studies on tolerance and withdrawal have measured

The word 'dependence' covers three different concerns, which are measured separately in studies: tolerance (needing an ever-increasing dose for the same effect), withdrawal syndrome (symptoms when stopping), and rebound insomnia (worse sleep than at baseline in the nights after the last dose).

The longest study is that of Lemoine and colleagues from 2011: 244 adults between 20 and 80 years of age with primary insomnia took melatonin, 2 mg every evening, for six or twelve months, followed by two weeks of discontinuation. Over the months, the dose maintained the same effect, without tolerance. Upon discontinuation, there were neither withdrawal symptoms nor rebound insomnia, but rather a residual benefit. And the body's own production of melatonin, measured via the nocturnal urinary metabolite, remained unchanged [2].

In a previous study by the same group, 170 people aged 55 and over took melatonin 2 mg for three weeks in a placebo-controlled trial: upon discontinuation, once again, there was no rebound insomnia and no withdrawal effects, with rare and mild adverse events [3].

The 2013 meta-analysis by Ferracioli-Oda pooled 19 randomised placebo-controlled trials, involving 1,683 people with primary sleep disorders, using different doses and formulations. Melatonin reduced the time it took to fall asleep by about 7 minutes and increased total sleep time by about 8 minutes compared to placebo. The authors describe the effect as “modest” and note that it “does not appear to dissipate with continued use” [4]: the same dose continues to work as well as it did at the beginning. The minutes refer to people with a diagnosed sleep disorder and should be read as such.

Lemoine’s studies used 2 mg, double the dose of Italian supplements. If discontinuation was clean with 2 mg for a year, the reasoning holds even more true for 1 mg.

The reason lies in the molecule’s pharmacology. Melatonin acts as a time signal and is eliminated rapidly: Harpsøe’s 2015 systematic review of 22 human pharmacokinetic studies reports a half-life of about 45 minutes [5]. The evening dose is already out of the system within a few hours. The habit of a bedtime routine exists, and it is different from physical dependence: a routine can be changed, and in the studies, those who stopped slept as before or better than before.

Stopping melatonin: what happens to your body’s own production

WHAT THE STUDIES MEASURED

• TOLERANCESAME DOSE, SAME EFFECT
• DISCONTINUATIONNO WITHDRAWAL SYMPTOMS
• OWN PRODUCTIONUNCHANGED

The most practical question remains: does the pineal gland, upon receiving melatonin from an external source, stop producing its own? Studies have answered this by directly measuring the body’s own production via nocturnal urinary 6-sulphatoxymelatonin, the main product of the liver’s metabolism of melatonin [1]. In Lemoine’s 2011 study, after six to twelve months of 2 mg every evening, this value was unchanged compared to before the treatment [2]. With 1 mg, half that dose, the conclusion holds even better.

The physiological explanation is straightforward. The body’s own production is controlled by light, via the suprachiasmatic nucleus: when light fades in the evening, the signal is triggered, regardless of how much circulated the previous evening [1]. The ingested molecule is eliminated in a few hours [5], and the next evening the cycle restarts from darkness.

On a broader endocrine level, the numbers also add up. Terzolo and colleagues in Turin followed six healthy volunteers for two months, with 2 mg per day: the responses of the pituitary gland, adrenal gland and testis to specific stimuli and the levels of prolactin and thyroid hormones were the same before and after. The group was small, but they were healthy individuals [7].

In the studies, discontinuation was abrupt, without gradual reduction, and was followed by a residual positive effect on sleep [2]. How and when to stop remains a personal choice, and if you are undergoing other treatments, it is a question to ask your doctor.

Melatonin every day: side effects reported in studies

Besag's 2019 systematic review collected 37 randomised placebo-controlled studies, with daily doses from 0.15 to 12 mg and observations up to 29 weeks. The most frequently reported adverse events were daytime sleepiness (1.66%), headache (0.74%), other sleep disorders (0.74%) and dizziness (0.74%). No event was judged to be life-threatening, and most resolved on their own within a few days or upon discontinuation. The same authors report that there are few truly long randomised studies: this is the limitation within which the conclusions on very long-term use should be read [6].

Andersen's 2016 review on the safety of melatonin in humans reaches similar conclusions: mild effects such as dizziness, headache, nausea and sleepiness, comparable to placebo even in the long term. The authors add a specific indication: during pregnancy and breastfeeding, due to the absence of studies, melatonin should be avoided [8].

Pregnancy and breastfeeding are therefore ruled out. The same applies to high doses, children and use with medication: in the presence of a pathology or ongoing therapy, the assessment is up to a doctor.

How much melatonin can you take: why the dose in supplements is 1 mg and what the authorised claims are

AUTHORISED CLAIM

1 mg

MAXIMUM AMOUNT IN SUPPLEMENTS

The same number, 1 mg, almost always appears on the labels of melatonin supplements in Italy. The reason lies in two documents.

Regulation (EU) 432/2012 authorises the claim for melatonin "Melatonin contributes to the reduction of time taken to fall asleep", and links it to a specific condition: the claim may only be used for a food which contains 1 mg of melatonin per quantified portion, accompanied by the information that the beneficial effect is obtained by consuming 1 mg of melatonin close to bedtime. The Ministry of Health, with its note of 24 June 2013, established that this 1 mg intake, useful for supporting the authorised claims, is at the same time also the maximum permissible intake in supplements. Above 1 mg per dose, in Italy, melatonin is a medicinal product.

The second claim authorised by the same Regulation concerns travel: "Melatonin contributes to alleviating the effects of jet lag", for foods containing at least 0.5 mg per portion, with the information that the beneficial effect is obtained by consuming a minimum of 0.5 mg close to bedtime on the first day of travel and for a few days after arrival at the destination. Our 1 mg tablet meets this condition. We have written a six-step guide on where to read the condition of use for a claim, and how to distinguish it from the rest of the label: How to read a supplement label.

Physiology confirms the order of magnitude. In Zhdanova's 2001 double-blind study, 30 people over 50 years of age received placebo and three doses of melatonin (0.1, 0.3 and 3 mg) in random order half an hour before bedtime, for one week each. The physiological dose of 0.3 mg restored nocturnal plasma melatonin to normal levels and restored sleep efficiency; the 3 mg dose also improved sleep, but it induced hypothermia and left plasma melatonin elevated even during daytime hours [9].

One milligram is within the physiological order of magnitude, and we consider it a precise choice: the amount that is enough to give the signal, without carrying it over into the next day. Higher doses are medicinal products and are a matter for a doctor.

Melatonin 1 mg: when to take it and why the time is part of the claim

"Close to bedtime" is the condition of use written in the Regulation, and it is the line printed on our label: "Take 1 tablet daily, close to bedtime, letting it dissolve under the tongue." It is the only product in our catalogue where the time is part of what has been authorised. Melatonin tells the body it is night, and the time to tell it is when night is about to begin.

In practice, this means about half an hour before turning off the light: someone who goes to bed at 23 would dissolve the tablet around 22:30. This is the interval used in studies—in Zhdanova's work the dose was taken thirty minutes before bedtime [9]—and it makes the signal from the tablet coincide with the one the body is already preparing on its own. Taken mid-afternoon, the same signal arrives at the wrong time.

When travelling, the reference point changes: the time that matters is the one at the destination. The Cochrane review by Herxheimer and Petrie compiled ten randomised studies in passengers, airline crews and military personnel. Melatonin taken close to bedtime at the destination, between 22 and midnight local time, reduced jet lag on flights crossing five or more time zones; doses between 0.5 and 5 mg showed similar efficacy (in Italian supplements, the maximum nevertheless remains 1 mg), and the benefit increases with the number of time zones crossed, being greater eastward.

The authors insist on the timing: taken at the wrong time of day, the same dose causes drowsiness and delays adaptation to the local time [10]. It is therefore taken shortly before bedtime on the first day of travel and on the days after arrival, according to the destination's clock.

For the general picture on timing, meals and forms, we refer you to the guide Supplements morning or evening, on a full or empty stomach.

Sublingual melatonin: why we chose the tablet that dissolves under the tongue

The 2015 review by Harpsøe reports a bioavailability of about 15% for melatonin taken orally and swallowed, with a range of 9 to 33% between studies, and a plasma peak at around 50 minutes for immediate-release forms. Most of the molecule is metabolised by the liver during its first pass, before reaching the general circulation [5]. The 2015 systematic review by Zetner on alternative routes of administration notes that oral transmucosal administration gives higher plasma concentrations than the classic oral route, because it avoids first-pass metabolism [11].

This is why we chose the sublingual tablet. The Melatonina Sublinguale 1 mg is left to dissolve under the tongue without water: it provides 1 mg of melatonin per tablet, in packs of 120 orodispersible tablets, which at a dose of one per day last for 120 days. It is sugar-free, sweetened with stevia, and has a wild berry flavour.

The technical part of the formula also follows our "clean" choice: the silica comes from an extract of young bamboo stems standardised to 70%, and neither silicon dioxide nor magnesium stearate appear on the label. We have written about what distinguishes a sublingual tablet from other forms in Capsules or tablets: how the form of a supplement is chosen, and about the role of each technical ingredient in Excipients in supplements: what they are for and which ones matter.

One milligram in the evening, and you don't even need a glass of water on your bedside table.

Melatonin and light: the evening routine in which the signal works

Light is the regulator of melatonin. It is the suprachiasmatic nucleus that reads it through the retina and determines when the pineal gland should start producing it; intense evening light, including screens, delays or suppresses that production [1]. Someone who takes melatonin and then stays for an hour under a bright light sends the body two opposite messages at the same time: the tablet says it is night, the illuminated ceiling says it is still day.

Keeping the two messages aligned costs little. In the last hour before bedtime, lower the lights and turn off screens, or at least turn the brightness down to the minimum. It also helps to go to sleep at more or less the same time on Saturday and Sunday: the internal clock adjusts based on repetition, rather than on the hours slept in a single night. Then there is the bedroom: in the dark, nightly production continues undisturbed until the morning.

A 1 mg tablet shortly before bedtime, as part of an evening like this, is a routine that can be kept for months: in studies, the dose maintained the same effect for up to a year [2][4]. And it can be stopped whenever you want, because those who stopped slept as before or better than before [2][3].

Frequently asked questions

Does melatonin cause dependence or tolerance?

In the studies that have measured it, no. In 244 adults who took 2 mg of melatonin every evening for six to twelve months, the dose maintained the same effect and, upon discontinuation, both withdrawal symptoms and rebound insomnia were absent [2]; the meta-analysis of 19 randomised studies reports an effect that "does not appear to dissipate with continued use" [4]. A habit of the evening routine can form, which is different from a physical dependence.

What happens if I take melatonin every evening?

In studies of up to one year of daily intake, the effect remained stable and adverse events were rare and mild, mainly daytime sleepiness and headache, in less than 2% of people [2][6]. There are few very long randomised studies: this is the criterion with which to read the conclusions on use for years.

What happens when you stop taking melatonin?

In studies, discontinuation, even after twelve months of 2 mg every evening, occurred without withdrawal symptoms and without rebound insomnia, with a residual benefit on sleep in the subsequent weeks [2][3].

Does melatonin block the pineal gland's natural production?

In Lemoine's 2011 study, the body's own production, measured as nocturnal urinary 6-sulphatoxymelatonin, was found to be unchanged after six to twelve months of taking 2 mg every evening [2]. Nocturnal production is controlled by light, and ingested melatonin is eliminated within a few hours, with a half-life of approximately 45 minutes [5].

How much melatonin can you take per day?

In supplements in Italy, the maximum intake is 1 mg per daily dose (note from the Ministry of Health of 24 June 2013), and this is the same amount to which Regulation (EU) 432/2012 links the authorised claim on the time taken to fall asleep. Above 1 mg, melatonin is a medicinal product, and the decision rests with the doctor.

When should 1 mg of melatonin be taken?

Shortly before bedtime; in practice, about half an hour before turning off the light: someone who goes to bed at 23 takes it at around 22:30. This is the condition of use for the authorised claim and the directions for use on our label ('Take 1 tablet daily, shortly before bedtime, allowing it to dissolve under the tongue'), and it is also the interval used in studies on the physiological dose [9].

Is melatonin also useful for jet lag?

Regulation (EU) 432/2012 authorises the claim 'Melatonin contributes to alleviating the effects of jet lag' for foods that contain at least 0.5 mg per portion, with the information that the beneficial effect is obtained by taking a minimum of 0.5 mg shortly before bedtime on the first day of travel and for a few days after arriving at the destination. Our 1 mg tablet meets this condition. The reference time is that of the destination: in the Cochrane review on jet lag, melatonin taken close to bedtime at the destination reduced symptoms on flights across more than five time zones, whereas when taken at the wrong time of day, it delays adaptation to local time [10].

Why does sublingual melatonin dissolve under the tongue?

Because when melatonin is swallowed, only a limited amount, around 15% in studies, reaches the circulation due to first-pass metabolism in the liver [5]; the oral transmucosal route avoids this and yields higher plasma concentrations [11]. This is why our tablet is to be dissolved under the tongue, without water.

Can melatonin be taken during pregnancy or while breastfeeding, or be given to children?

Melatonin should be avoided during pregnancy and while breastfeeding: there is a lack of studies verifying its safety, and this is the conclusion reached by Andersen's 2016 review [8]. For children and adolescents, the decision rests with the paediatrician, and the product must be kept out of the reach of children under three years of age. With an ongoing medical condition or treatment already underway, the doctor's opinion takes precedence over the supplement.

Further reading

• Supplements morning or evening, on a full or empty stomach: a practical guide
• Capsules or tablets: how to choose the form of a supplement
• Bioavailability of supplements: what it really depends on

Regulatory references and sources

Studies

1. Claustrat B., Leston J., Melatonin: Physiological effects in humans, Neurochirurgie 2015;61(2-3):77-84. PMID 25908646 — doi:10.1016/j.neuchi.2015.03.002.
2. Lemoine P., Garfinkel D., Laudon M., Nir T., Zisapel N., Prolonged-release melatonin for insomnia – an open-label long-term study of efficacy, safety, and withdrawal, Ther Clin Risk Manag 2011;7:301-11. PMID 21845053 — doi:10.2147/TCRM.S23036 (244 adults, 2 mg every evening, 6–12 months).
3. 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;16(4):372-80. PMID 18036082 — doi:10.1111/j.1365-2869.2007.00613.x (RCT, 170 patients, 3 weeks).
4. Ferracioli-Oda E., Qawasmi A., Bloch M.H., Meta-analysis: melatonin for the treatment of primary sleep disorders, PLoS One 2013;8(5):e63773. PMID 23691095 — doi:10.1371/journal.pone.0063773 (19 RCTs, 1,683 subjects).
5. Harpsøe N.G., Andersen L.P., Gögenur I., Rosenberg J., Clinical pharmacokinetics of melatonin: a systematic review, Eur J Clin Pharmacol 2015;71(8):901-9. PMID 26008214 — doi:10.1007/s00228-015-1873-4 (22 studies in humans).
6. Besag F.M.C., Vasey M.J., Lao K.S.J., Wong I.C.K., Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review, CNS Drugs 2019;33(12):1167-86. PMID 31722088 — doi:10.1007/s40263-019-00680-w.
7. Terzolo M., Piovesan A., Puligheddu B., Torta M., Osella G., Paccotti P., Angeli A., Effects of long-term, low-dose, time-specified melatonin administration on endocrine and cardiovascular variables in adult men, J Pineal Res 1990;9(2):113-24. PMID 2177501 — doi:10.1111/j.1600-079x.1990.tb00699.x (6 healthy volunteers, 2 mg for 2 months).
8. Andersen L.P.H., Gögenur I., Rosenberg J., Reiter R.J., The Safety of Melatonin in Humans, Clin Drug Investig 2016;36(3):169-75. PMID 26692007 — doi:10.1007/s40261-015-0368-5.
9. Zhdanova I.V., Wurtman R.J., Regan M.M., Taylor J.A., Shi J.P., Leclair O.U., Melatonin treatment for age-related insomnia, J Clin Endocrinol Metab 2001;86(10):4727-30. PMID 11600532 — doi:10.1210/jcem.86.10.7901 (double-blind RCT, 30 subjects, 0.1-0.3-3 mg).
10. Herxheimer A., Petrie K.J., Melatonin for the prevention and treatment of jet lag, Cochrane Database Syst Rev 2002;(2):CD001520. PMID 12076414 — doi:10.1002/14651858.CD001520 (10 randomised studies in travellers, aircrew and military personnel).
11. Zetner D., Andersen L.P.H., Rosenberg J., Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review, Drug Res (Stuttg) 2016;66(4):169-73 (published online in 2015). PMID 26514093 — doi:10.1055/s-0035-1565083 (10 studies).

Regulatory references

1. Regulation (EU) No 432/2012 — list of permitted health claims; entries for ‘melatonin’ (reduction of time taken to fall asleep; effects of jet lag) with conditions of use.
2. Regulation (EC) No 1924/2006 — nutrition and health claims made on foods.
3. Ministry of Health, note of 24 June 2013, No 0027074-P — intake of melatonin in food supplements (1 mg per daily dose).
4. Legislative Decree of 21 May 2004, No 169 — implementation of Directive 2002/46/EC on food supplements.