Restless Leg Syndrome and Melatonin

March 22, 2014

Is there a link between the two?

Jacob Schor

ND, FABNO

This small study may in time be seen as one of the first clinical trials that eventually lead to a change in the way we approach restless leg syndrome (RLS) treatment in clinical practice.

Reference

Whittom S, Dumont M, Petit D, Desautels A, Adam B, Lavigne G, Montplaisir J. Effects of melatonin and bright light administration on motor and sensory symptoms of RLS. Sleep Med. 2010;11(4):351-355.

Design

Simple open trial design

Participants

Eight subjects with restless leg syndrome (RLS)

Study Medication and Dosage

The subjects were studied at night under 3 conditions: at baseline, after administration of melatonin, and during bright light exposure.

Outcome Measures

The severity of RLS symptoms was assessed by the suggested immobilization test (SIT), which allows quantification of both sensory and motor manifestations (SIT-PLM) of RLS.

Key Findings

There was a significant increase of SIT-PLM index when subjects took melatonin compared to both baseline and bright light conditions. Bright light exposure had no effect on leg movements but did produce a significant decrease in sensory symptoms. Exogenous melatonin may have a detrimental effect on motor symptoms, and bright light exposure produced small but significant improvement in leg discomfort.

Practice Implications

This small study may in time be seen as one of the first clinical trials that eventually led to a change in the way we approach restless leg syndrome (RLS) treatment in clinical practice.

Though it is rare for patients to present with RLS as their chief complaint, the condition is common, affecting 10–11% of the general population. Being female increases risk and so does the number of children a woman has had: Having 1 child nearly doubles the risk of having RLS, 2 children triples the risk, and 3 or more children increase the odds ratio to 3. 57.¹ It is surprising that more patients don’t complain about RLS.

RLS symptoms also follow a circadian pattern, being worse in the late evening at a time when presumably melatonin levels are either increasing or peaking.

Sir Thomas Willis first described RLS symptoms in 1685.² Karl Axel Ekbom, a Swedish neurologist, is credited with writing the first modern clinical description and is also credited with naming the condition.³ The disease is actually being renamed; what we call restless leg syndrome will soon be known as Ekbom disease. “The main characteristics are the strong urge to move, accompanied or caused by uncomfortable, sometimes even distressing, paresthesia of the legs, described as a “creeping, tugging, pulling” feeling. The symptoms often become worse as the day progresses, leading to sleep disturbances or sleep deprivation, which leads to decreased alertness and daytime functions.”⁴

To comprehend the potential significance of this current paper by Whittom et al, we must review the current understanding of this disease.

Almost from the start, research on RLS has focused on iron deficiency, with Ekbom reporting an association in 1960.⁵ In 2005 Thorpy described RLS as an iron-deficiency symptom. This model explained the higher incidence of RLS in women.⁶

Over the last 7 years, several clinical trials have suggested that IV iron infusions will improve RLS symptoms. In an open label series, Earley started patients on single 1,000 mg doses of infused iron initially and then gave 450 mg if the patients’ ferritin levels dropped below 300 mcg/l. These patients experienced benefit.^7,8,9 An interim report on a placebo-controlled trial by Earley’s group at Johns Hopkins published in 2009 had not yet found measurable benefit at the time of writing.¹⁰ A different RCT published in 2009 by Swedish researchers did report that iron transfusions reduced RLS symptoms both in both short term and long term.¹¹ We can probably say that iron infusions help some patients at least some of the time.

It is interesting—and counterintuitive—to note that blood donation does not worsen RLS symptoms.¹²

The relationship between iron and RLS is more complicated than a simple iron deficiency. In RLS the regulation of iron absorption and transport differs from that of healthy people. Earley reported that after the initial infusion, ferritin levels in his RLS subjects declined an average of 6.6 mcg/l/week, faster than the expected rate of <1 mcg/l per week. The faster the ferritin level dropped, the less likely the subsequent iron treatment was to provide benefit.¹³

Theories to explain RLS now center on iron levels in the brain. Conner et al have published a series of papers reporting on their analysis of brain samples obtained from RLS patients on autopsy. In 2003 their early data suggested that RLS results “from impaired iron acquisition by the neuromelanin cells. … The underlying mechanism may be a defect in regulation of the transferrin receptors. ” In 2004 Connor et al reported in comparing further autopsy results that iron transport to the substantia nigra (SN) in RLS is different due to a defect in iron regulatory protein 1.¹⁴

The current data continue to suggest that RLS is a neurological disorder involving abnormal levels of iron in various parts of the brain. Mitochondrial ferritin (FtMt) levels correlate between iron levels and mitochondrial function in the SN. Autopsy samples from RLS patients have more FtMt than control samples. Neuromelanin-containing neurons in the SN were the predominant cell type expressing FtMt. These results suggest that increased numbers of mitochondria in neurons in RLS and increased FtMt might contribute to insufficient cytosolic iron levels in RLS SN neurons; these results are consistent with the hypothesis that energy insufficiency in these neurons may be involved in the pathogenesis of RLS.¹⁵

In 2011 Connor et al reported finding an iron regulatory protein that is decreased in RLS. They suggest that this leads to an alteration in iron management at the blood-brain interface. Thus there are “fundamental differences in brain iron acquisition in individuals with restless legs syndrome.” These researchers now identify a decrease in transferrin receptor expression in the microvasculature of the brains of RLS patients as that leads to demylination of neurons in the brain as possibly the underlying problem.¹⁶

Let us return to the current Whittom paper under analysis and see how it may relate to this understanding of how iron dysregulation underlies RLS.

Serum iron levels have long been thought to fluctuate according to a circadian rhythm, and the general consensus has been that they are higher in the morning, although not all data support this.¹⁷

RLS symptoms also follow a circadian pattern, being worse in the late evening at a time when presumably melatonin levels are either increasing or peaking.¹⁸ Working a rotating night shift, a practice that will likely disrupt melatonin production and circadian cycles, increases RLS symptom intensity. ¹⁹ Micahud et al, who had looked for biochemical markers correlating with RLS symptoms, wrote in a 2004 report that “changes in melatonin secretion were the only ones that preceded the increase in sensory and motor symptoms in RLS patients. This result and those of other studies showing that melatonin exerts an inhibitory effect on central dopamine secretion suggest that melatonin might be implicated in the worsening of RLS symptoms in the evening and during the night.”²⁰

A 2007 paper reported that melatonin changes the expression of transferrin receptors in the pineal glands of rats. These are the “membrane bound glycoproteins which function to mediate cellular uptake of iron from transferrin.” Melatonin reduced transferring receptors.²¹ If melatonin can affect iron movement in the brains of rats, it would be a fair assumption that it may do the same in humans.

Two earlier papers looking at melatonin and RLS should be mentioned. Austrian researchers made the correlation that people with RLS often complain of insomnia and that melatonin may help insomnia, so they tested melatonin levels in individuals who have RLS hoping to find a deficiency. They did not. “Insomnia in RLS does not seem to be correlated with a deficit of melatonin.”²²

An earlier paper published in 2001 will confuse the matter. Assuming that there was a deficiency of melatonin in RLS, German researchers gave 3 mg of melatonin to RLS patients for 6 weeks. They reported improved well-being and a reduction in limb movements in 7 of the 9 patients in their trial.²³ Is there an explanation that will reconcile these contradictory results, or are we simply looking at an example of why the results of small open trials without control groups should be viewed with caution?

Let us assume for the moment that the results of both trials are true and that some unrevealed difference in protocol or patient selection accounts for the contrasting results. Then we might conclude that melatonin sometimes improves RLS symptoms and sometimes worsens them. In either event, moderating melatonin should be considered in patients with RLS.

It would make sense to find out how a particular patient will respond to melatonin supplementation as a first step in treating RLS. Depending on their reaction, it may be useful to encourage or discourage melatonin production. For example appropriate frequency lighting can be used to either increase or decrease melatonin production.

The relationship between ferritin and RLS is now well established, and levels should be monitored and corrected in all patients complaining of RLS.

One last bit of information is worth mentioning. An extract of the herb Salvia miltiorrhiza called Tanhinone II was recently reported to prevent brain iron dyshomeostasis. Though no published data as of yet appear in PubMed that suggest using these extracts to treat RLS, a number of proprietary herbal formulas do contain significant percentages of the herb and are sold specifically to treat RLS.²⁴

Categorized Under

• Abstracts & Commentary

Jacob Schor, ND, FABNO, is a graduate of National University of Naturopathic Medicine, Portland, Oregon, and recently retired from his practice in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is a past member of the board of directors of the Oncology Association of Naturopathic Physicians and American Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician’s Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the past Abstracts & Commentary editor.

References

1. Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. 2004;164(2):196-202.

2. Coccagna G, Vetrugno R, Lombardi C, Provini F. Restless legs syndrome: an historical note. Sleep Med. 2004;5(3):279-283.

3. Teive HA, Munhoz RP, Barbosa ER. Professor Karl-Axel Ekbom and restless legs syndrome. Parkinsonism Relat Disord. 2009;15(4):254-257.

4. Mitchell UH.Nondrug-related aspect of treating Ekbom disease, formerly known as restless legs syndrome. Neuropsychiatr Dis Treat. 2011;7:251-257.

5. Ekbom KA. Restless legs syndrome. Neurology. 1960;10:868-873.

6. Thorpy MJ. New paradigms in the treatment of restless legs syndrome. Neurology. 2005;64(12 Suppl 3):S28-33.

7. Earley CJ, Heckler D, Allen RP. The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med. 2004;5(3):231-235.

8. Earley CJ, Heckler D, Allen RP. Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome. Sleep Med. 2005;6(4):301-305.

9. Ibid.

10. Earley CJ, Horská A, Mohamed MA, Barker PB, Beard JL, Allen RP. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med. 2009;10(2):206-211.

11. Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord. 2009; 24(10):1445-1452.

12. Burchell BJ, Allen RP, Miller JK, Hening WA, Earley CJ. RLS and blood donation. Sleep Med. 2009;10(8):844-849.

13. Earley CJ, Heckler D, Allen RP. Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome. Sleep Med. 2005;6(4):301-305.

14. Connor JR, Wang XS, Patton SM, Menzies SL, Troncoso JC, Earley CJ, Allen RP. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology. 2004;62(9):1563-1567.

15. Snyder AM, Wang X, Patton SM, Arosio P, Levi S, Earley CJ, et al. Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J Neuropathol Exp Neurol. 2009;68(11):1193-1199.

16. Connor JR, Ponnuru P, Lee BY, et al. Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome. Sleep Med. 2011;12(6):614-619.

17. Ridefelt P, Larsson A, Rehman JU, Axelsson J. Influences of sleep and the circadian rhythm on iron-status indices. Clin Biochem. 2010;43(16-17):1323-1328.

18. Duffy JF, Lowe AS, Silva EJ, Winkelman JW. Periodic limb movements in sleep exhibit a circadian rhythm that is maximal in the late evening/early night. Sleep Med. 2011;12(1):83-88.

19. Sharifian A, Firoozeh M, Pouryaghoub G, et al. Restless Legs Syndrome in shift workers: A cross sectional study on male assembly workers. J Circadian Rhythms. 2009;7:12.

20. Michaud M, Dumont M, Selmaoui B, Paquet J, Fantini ML, Montplaisir J. Circadian rhythm of restless legs syndrome: relationship with biological markers. Ann Neurol. 2004;55(3):372-380.

21. Kaur C, Sivakumar V, Ling EA. Expression of tranferrin receptors in the pineal gland of postnatal and adult rats and its alteration in hypoxia and melatonin treatment. Glia. 2007;55(3):263-273.

22. Tribl GG, Waldhauser F, Sycha T, Auff E, Zeitlhofer J. Urinary 6-hydroxy-melatonin-sulfate excretion and circadian rhythm in patients with restless legs syndrome. J Pineal Res. 2003 Nov;35(4):295-296.

23. Kunz D, Bes F. Exogenous melatonin in periodic limb movement disorder: an open clinical trial and a hypothesis. Sleep. 2001;24(2):183-187.

24. Yang L, Zhang B, Yin L, Cai B, Shan H, Zhang L, Lu Y, Bi Z. Tanshinone IIA prevented brain iron dyshomeostasis in cerebral ischemic rats. Cell Physiol Biochem. 2011;27(1):23-30.

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Circadian rhythm of restless legs syndrome: relationship with biological markers

Comparative Study

. 2004 Mar;55(3):372-80.

doi: 10.1002/ana.10843.

Martin Michaud 
¹
, Marie Dumont, Brahim Selmaoui, Jean Paquet, Maria Livia Fantini, Jacques Montplaisir

Affiliations

Affiliation

• ¹ Sleep Disorders Center, Sacré-Coeur Hospital, 5400 boulevard Gouin Ouest, Montréal, Quebec, Canada.

• PMID:

  14991815

• DOI:

  10.1002/ana.10843

Comparative Study

Martin Michaud et al.

Ann Neurol.

2004 Mar.

. 2004 Mar;55(3):372-80.

doi: 10. 1002/ana.10843.

Authors

Martin Michaud 
¹
, Marie Dumont, Brahim Selmaoui, Jean Paquet, Maria Livia Fantini, Jacques Montplaisir

Affiliation

• ¹ Sleep Disorders Center, Sacré-Coeur Hospital, 5400 boulevard Gouin Ouest, Montréal, Quebec, Canada.

• PMID:

  14991815

• DOI:

  10.1002/ana.10843

Abstract

Recently, it was suggested that the intensity of restless legs syndrome (RLS) symptoms may be modulated by a circadian factor. The objective of this study was to evaluate, during a 28-hour modified constant routine, the nycthemeral or circadian variations in subjective leg discomfort and periodic leg movements (PLMs) and to parallel these changes with those of subjective vigilance, core body temperature, and salivary melatonin. Seven patients with primary RLS and seven healthy subjects matched for sex and age entered this study. Although the symptoms were more severe in patients than in controls, a significant circadian variation in leg discomfort and PLM (p < 0.01) was found for both groups. In both groups, the profiles of leg discomfort and PLM were significantly correlated with those of subjective vigilance, core body temperature, and salivary melatonin. However, among these variables, the changes in melatonin secretion were the only ones that preceded the increase in sensory and motor symptoms in RLS patients. This result and those of others studies showing that melatonin exerts an inhibitory effect on central dopamine secretion suggest that melatonin might be implicated in the worsening of RLS symptoms in the evening and during the night.

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Publication types

MeSH terms

Substances

Active substance MELATONIN* (MELATONINUM*) | Compendium – drug reference book

• Pharmacological properties
• Indications MELATONIN*
• Application MELATONIN*
• Contraindications
• Side effects
• Special instructions
• Interactions
• Overdose
• Diagnosis
• Recommended alternatives
• Trade names

Medicines containing the active substance MELATONIN*

Vita-Melatonin ^®

tablets 3 mg blister, № 30

Kiev Vitamin Plant

Prices in pharmacies wakefulness; used mainly for sleep disorders. Endogenous melatonin is produced by the pineal gland. It is believed that exogenous melatonin can have anticonvulsant, antidepressant, antineoplastic, neuroprotective, antioxidant and gonadotropic effects and exhibit other types of biological activity. It has some therapeutic activity in the treatment of tinnitus, migraine, neurodegenerative diseases, epilepsy, and breast cancer.

After oral administration, melatonin undergoes significant first pass metabolism through the liver to form 6-sulphaoxymelatonin; the bioavailability of melatonin is 30-50%. When taken orally at a dose of 3 mg, C _{max in blood serum and saliva is reached by the 20th and 60th minute, respectively. Melatonin penetrates the BBB and is determined in the placenta. With repeated use during the day, a certain amount of melatonin may accumulate in adipose tissue. Medium T ½ – 45 min. In addition to the formation of 6-sulfoxymelatonin, it is metabolized in the liver by glucuronidation. It is excreted in the urine as 6-sulfoxymelatonin and unchanged melatonin (0.01%).}

insomnia (including depression) and other sleep disorders.

Adults with mild insomnia are given orally or sublingually 0.3–3 mg approximately 1–2 hours before bedtime. If necessary, the dose is increased to 6 mg.

For depression-related sleep disorders and other sleep disorders, 5-10 mg orally 1-2 hours before bedtime.

pregnancy and lactation.

usually develop within a few days after the start of use. Possible prolonged sedation, headache, depression, sinus tachycardia, pruritus, rash, nightmares, dyspepsia, abdominal pain.

is prescribed with caution to elderly patients, patients with depression, dementia, epilepsy, liver and kidney diseases, endocrine pathology, immunodeficiency states.

Melatonin can cause drowsiness, so you should be careful when driving vehicles and working with potentially dangerous mechanisms.

β-adrenergic blockers, clonidine, dexamethasone, fluvoxamine, and some other drugs may alter endogenous melatonin secretion.

Melatonin can affect the effectiveness of hormonal drugs (estrogens, androgens, etc.), increase the binding of benzodiazepines to specific receptors, so their simultaneous administration requires medical supervision.

Melatonin may potentiate the antitumor effect of tamoxifen.

The dopaminergic and serotonergic effects of methamphetamine may be enhanced when used concomitantly with melatonin.

Melatonin may potentiate the antibacterial action of isoniazid.

cases of melatonin overdose (24–30 mg) have been described. The most likely are disorientation, prolonged sleep, retrograde amnesia.

how it works in the body, how it works in tablets, is it possible to drink without prescription

Daniil Davydov

medical journalist

Author profile

The short answer is: it depends on the dosage.

But you need to keep in mind that melatonin is in principle contraindicated for some people.

Go see a doctor

Our articles are written with love for evidence-based medicine. We refer to authoritative sources and go to doctors with a good reputation for comments. But remember: the responsibility for your health lies with you and your doctor. We don’t write prescriptions, we give recommendations. Relying on our point of view or not is up to you.

What is melatonin

Melatonin belongs to the class of neurohormones — this is the name of all hormones that are synthesized in the brain. Based on available data, melatonin has many biological functions, from fighting inflammation to lowering blood pressure.

What is melatonin – an international textbook for medical students StatPearls

But the main task of melatonin is to maintain the daily rhythms of the body. Simply put, melatonin is responsible for the regulation of our biological clock: it moves it from the “sleep” to the “wake” position, and vice versa.

Why do we need melatonin — an international directory of medicines Drugs.com

This is necessary to separate different physiological processes in time: to make sure that the mechanisms responsible for digestion and, for example, learning, turn on during the day. And at night, during rest, it is more convenient to do other things – for example, the restoration of cells damaged during the day and the formation of a long-term memory that stores the knowledge gained during daylight hours. As a result, the body really starts to work like a clock: it does everything on time, so that different processes do not interfere with each other.

The biological clock, which ensures the smooth functioning of the body, consists of three elements:

1. The retina of the eye, which captures light.
2. The suprachiasmatic nucleus of the hypothalamus, or SCN, is a part of the brain that is sensitive to the change of day and night.
3. The pineal gland is a part of the brain in which melatonin is synthesized.

The eyes inform the SCN of the time of day and it decides whether it is time for the pineal gland to stimulate melatonin

If no light hits the retina, it relays the information to the suprachiasmatic nucleus so that the pituitary gland tells the pineal gland to begin melatonin synthesis. Melatonin is the message “night has come” encrypted in the chemical.

When this neurohormone enters the bloodstream, the brain and internal organs understand that it is time to do night activities. As a result, we begin to feel sleepy. And the more melatonin in the blood, the more you want to sleep.

The influence of light on circadian rhythms, sleep and mood of people – the journal “Somnology”

healthy people is the strongest.

If even a little light hits the retina, it sends another signal to the suprachiasmatic nucleus, and the hypothalamus tells the pineal gland to stop melatonin synthesis. As a result, the body decides that morning is coming, and gradually begins to wake up, that is, it turns off the night processes and turns on the day ones.

The more light, the less melatonin: during the day, the concentration of this hormone in the blood drops 10 times to 20 pg/ml. That is why it is not recommended to use a smartphone and other devices with luminous screens at night: blue light from gadgets suppresses melatonin synthesis and it becomes more difficult to fall asleep.

6 things for healthy sleep

How melatonin drugs and supplements work

People have created melatonin drugs to manually reset their body clock. The body does not care where melatonin enters the bloodstream – from the pineal gland or from a pill.

How melatonin drugs work – an international guide for doctors Uptodate

And if so, then theoretically such drugs can help with insomnia and other conditions in which melatonin is involved in the regulation. For example, with the jet lag syndrome that occurs due to long-haul flights – jet lag. People suffering from jet lag complain of fatigue, insomnia, headache and loss of appetite.

However, medicines and preparations in which melatonin is the active substance have not been fully studied, and their effect is still relatively modest. The strongest evidence for the effectiveness of melatonin is associated with sleep disturbances in blind people, as well as in those who have trouble falling asleep and disturbed sleep-wake cycles. Some authors add jetlag to the list.

Melatonin is only effective for sleep problems – International Drug Guide RxList

Melatonin may be effective for jet lag MSD

Sleep disorders. Results from 19 clinical trials involving more than 1,500 children and adults showed that people who took melatonin for 2-5 weeks fell asleep 7 minutes earlier and slept about 8 minutes longer than those who received placebo. True, it was not possible to prove that in the end they slept better. The dosages of melatonin taken by the participants varied, ranging from 0.5 to 5 mg on average.

Jetlag. Four studies involving 232 people showed that people who took 3-6 mg of melatonin tablets for 5 days before and after a flight rated the severity of jet lag symptoms on a 100-point scale of 27 points. Those who took the placebo rated the severity of their symptoms on the same scale at 45 points.

Melatonin may well be effective for endometriosis, high blood pressure, anxiety before surgery, jaw pain, low platelets, as an adjunct to chemotherapy for certain tumors, or as a sunburn remedy. But to say for sure, more research is needed to clearly show its effectiveness.

/ Klinicheeskoe -issledovanie /

Why participate in clinical studies in cancer and how to find them

most likely, melatonin does not help to refuse drugs, does not facilitate senile dementia, does not help to adjust the sleep regime for interchangeable work, and does not improve performance in the gym, does not cure infertility and depression.

At the same time, most researchers note that melatonin is a rather promising substance. To finally admit it to the world of big medicine, several large clinical trials will be required. Without this, it is difficult to figure out which diseases benefit from melatonin the most and in what dosages it works best.

Until such studies appear, the attitude towards melatonin in the world is ambiguous. In the USA, for example, there are no medicines with melatonin, but only nutritional supplements that can be bought in any dosage without a doctor’s prescription. Both OTC medicines and melatonin supplements are available in our country.

Preparation with melatonin. Price: 150 R. Source: “Asna” Additive with him. Price: 990 R. Source: “Vitaminonline.ru”

But in the UK, the European Union, Japan, Australia and Canada, melatonin is available only in the form of a prescription drug.

Why melatonin is sold only in drug form in the European Union – Bulletin of the European Medical Agency

The sale of melatonin supplements in these countries is in principle prohibited, and this ban has serious justifications.

What happens if you take melatonin without consulting your doctor

It depends on the concentration of melatonin in the supplement or medication. Studies show that the effect depends on the dosage.

At a daily dose of 0.3-0.5 mg melatonin levels in the blood do not exceed the natural nocturnal peak. As a result, the effect of it is the same as that of “natural” melatonin, that is, a person falls asleep faster and more soundly. Melatonin in such dosages does not harm health.

At a daily dose of 1-10 mg of , the level of melatonin in the blood increases by 3-60 times. Although melatonin itself is not poisonous, at such concentrations it has an overly powerful biological effect on the body. A person who has taken a supplement or medication may experience severe daytime sleepiness, reduced performance, and a drop in body temperature that will feel like an unpleasant chill.

Melatonin 0.3-0.5 mg is considered safe and can be taken by most people without discomfort.

Side effects of melatonin – Drugs.com International Drug Directory

However, it can still cause side effects in some people:

1. Daytime sleepiness.
2. Depressed mood, feeling of irritability.
3. Headache or dizziness.
4. Abdominal pain.

Pregnant women, children under 18, and people with medical conditions should always consult a doctor before buying melatonin products. In pregnant women and children, melatonin sometimes behaves unpredictably. And in people with diseases, the consequences can be very severe.

Melatonin supplements and medicines do not work well with certain medicines. For example, caffeine and the antidepressant fluvoxamine can increase plasma melatonin concentrations, increasing the risk of side effects from taking this drug.

Melatonin: 7 things you need to know – Drugs.com International Drug Formulary

Melatonin can lower nifedipine levels. This is quite dangerous, because nifedipine is a drug for high blood pressure. If such a medicine does not work or is not effective enough, it is life-threatening.

Melatonin supplements and medications cause severe side effects in some patients. For example, they can cause bleeding in people with bleeding disorders, increase blood sugar levels in people with diabetes, provoke convulsions in people with seizure disorders, and increase depression symptoms in people with depression.