Safety and efficacy of melatonin for sleep disorders?

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What do we really know about the safety and efficacy of melatonin for sleep disorders? (2021)
David J. Kennaway


ABSTRACT

Melatonin is a hormonal product of the pineal gland, a fact that is often forgotten. Instead, it is promoted as a dietary supplement that will overcome insomnia, as an antioxidant, and as a prescription-only drug in most countries outside the United States of America and Canada. The aim of this review is to step back and highlight what we know about melatonin following its discovery 60 years ago. What is the role of endogenous melatonin; what does melatonin do to sleep, body temperature, circadian rhythms, the cardiovascular system, reproductive system, endocrine system, and metabolism when administered to healthy subjects? When used as a drug/dietary supplement, what safety studies have been conducted? Can we really say melatonin is safe when it has not been systematically studied and many studies show interactions with a wide range of physiological processes? Finally, the results of studies investigating the efficacy of melatonin as a drug to alleviate insomnia are critically evaluated. In summary, melatonin is an endogenous pineal gland hormone with specific physiological functions in animals and humans, with its primary role in humans to maintain synchrony of sleep with the day/night cycle. When administered as a drug it affects a wide range of physiological systems and has clinically important drug interactions. With respect to efficacy for treating sleep disorders, melatonin can advance the time of sleep onset but the effect is modest and variable. In children with neurodevelopmental disabilities, melatonin appears to have the greatest impact on sleep onset but little effect on sleep efficiency.




Melatonin has been available to consumers in many jurisdictions around the world for many years, but especially in the USA since 1994 when it was declared a dietary supplement. In 1997 David Weaver wrote “An experiment of unprecedented proportions currently is being conducted to assess the effects of melatonin using volunteers from the United States. Unfortunately, this is not a controlled experiment, and it appears that no systematic attempt will be made to determine its outcome. It may only be through retrospective study that we will learn the effects of chronic melatonin treatment” 2. Twenty-three years on it can be argued that little has changed. In 2017 it was estimated that more than three million people in the USA used melatonin, and yet there have been no large-scale long-term safety trials reported. As Lewy et al. noted in 1998, “to date no catastrophes have been related to its use” 3. This would appear to be the case today, but it can take many years to discover adverse health issues resulting from the administration of a drug or the use of a medical procedure even when they are regulated. One example is the evidence emerging recently of changes in body composition during adolescence among girls and the presence of sperm abnormalities in adult males conceived using intra cytoplasmic sperm injection (ICSI)4, a very common technique used for infertile couples since 1992.

The issue of the safety of melatonin administration in children and adults is complicated by the fact that the major manufacturers and suppliers of melatonin are in the vitamin industry and that as a dietary supplement, it is not regulated by the FDA in the USA. There have been some concerns around the quality or purity of melatonin used in the USA produced by manufacturers of dietary supplements5–7. With over the counter (OTC) supply of the hormone in the USA and Canada, rather than by prescription via physicians and pharmacists, it is up to the consumers to report any health issues to authorities or to simply stop taking the hormone.

In the United Kingdom and European Union, a number of formulations have become available in recent years. Circadin (Neurim Pharmaceuticals): “indicated as monotherapy for the short-term treatment of primary insomnia characterized by the poor quality of sleep in patients who are aged 55 or over. Slenyto (Neurim Pharmaceuticals): “indicated for the treatment of insomnia in children and adolescents aged 2-18 with Autism Spectrum Disorder (ASD) and/or Smith-Magenis syndrome, where sleep hygiene measures have been insufficient.” Syncrodin (Pharma Nord); “used for short-term treatment of jet-lag in adults.” Melatonin AGB (AGB Pharma); “used for short-term treatment of jet lag in adults” and for “Insomnia in children and adolescents (6 to 17 years old) with ADHD, where other healthy sleeping routines have not worked well enough.” Melatonin Colonis (Colonis Pharma); “indicated for short-term treatment of jet-lag in adults.” These are quite specific indications. None of the preparations are aimed at Typically Developing (TD) children or adults under 55 y. Yet we know from the literature and sales of melatonin that it is being administered to the wider population off-label by physicians on prescription8–16 in countries where it is regulated (Sweden, Denmark, Norway, Australia), or self-administered in the USA and Canada. Note that since June 2021 in Australia, melatonin is now available as a Schedule 3 drug through pharmacists without a prescription.

There is also the question of what is meant by the term “safe”? Is melatonin safe in the short term or long term? Are there specific sections of the population who should not take melatonin in the short or long term? Is melatonin safe for adults but not for children? Finally, the determination of whether something is safe is going to be affected by what interactions are being looked at and recorded. For example it is possible that long-term melatonin administration may alter the risk of a person developing a metabolic disorder or having a serious drug interaction. Melatonin is predominantly prescribed or self-administered to overcome insomnia, in particular difficulty in falling asleep within an acceptable time, but also in the expectation that it will improve the quality and duration of the sleep period. What could possibly go wrong?





*The physiology of melatonin

It must always be remembered that although melatonin is often referred to as a dietary supplement, a drug, or an antioxidant, it is a hormone that is produced in the pineal gland and secreted into the blood. Its production is very tightly controlled such that there is negligible production during the day17. It is not until a few hours prior to the onset of sleep that the biological clock in the suprachiasmatic nucleus (SCN) initiates adrenergic stimulation of melatonin production by the pineal gland. The actual timing of the onset of melatonin production varies between individuals, but the duration of active secretion is approximately 8 h, with the result that secretion ceases around 0300 h - 0400 h18. Blood melatonin levels then gradually decrease so that they are undetectable again by approximately 0800 h - 0900 h. The timing of the melatonin onset is correlated with habitual sleep times and wake times19. The amount of melatonin produced by humans each night is quite low, in the order of 40 lg20–22. Exposure to light during the evening can have 2 consequences, acute suppression of melatonin production in the first part of the night23 and a subsequent delay in the appearance of melatonin production on the following night. Exposure to light in the early morning (after 0300 h) has a little acute impact on the levels of melatonin but may result in an earlier onset of melatonin production on the following night. In the field of chronobiology, this phenomenon is called the phase response to light. This pattern of melatonin production and phase sensitivity to light is likely preserved in all animals, importantly regardless of whether they are behaviourally active during the light period (diurnal; humans, primates, sheep, etc.) or active during the dark period (nocturnal; rats, mice, hamsters, etc.) or active during the early evening and/ or early morning (crepuscular or auroral; cats, guinea pigs, etc.). This means of course that the presence of endogenous melatonin need not coincide with sleep or the administration of melatonin induce sleep in nocturnal animals.

The duration of active melatonin secretion is determined by the daylength, such that in the short days of winter the duration of melatonin secretion is longer than that during the summer.
Many animals use this changing pattern of melatonin production to synchronize their breeding (ovulation, sexual behavior, parturition) to the optimal time of the year for their species. For example, hamsters use the approach of short days to shut down reproductive function, while sheep use the shortening days to initiate sexual activity. Of course, humans are not known to have overtly seasonal variations in fertility and we have engineered ways of extending the light period with the use of candles and gas and electric lighting. Nevertheless, humans retain the ability to extend the duration of melatonin secretion when placed under strict photoperiod conditions24,25.





*Melatonin receptors

Two specific high-affinity membrane receptors (hMT1 and hMT2) are present in brain regions such as the SCN and thalamus where they may be expected to be involved in the initiation of sleep. But it will be appreciated that the receptors are widely distributed throughout the brain and the rest of the body. These sites include the cerebellum, occipital cortex, parietal cortex, temporal cortex, frontal cortex, hippocampus, retina, brown and white adipose, fetal kidney, coronary artery, granulosa cells, myometrium, pancreatic alpha and beta cells, testis, and placenta26. We should therefore expect that administration of melatonin is going to impact multiple physiological systems, not just those associated with sleep. Thus melatonin is a pleiotropic hormone, but it is rarely considered a pleiotropic drug by clinicians or dietary supplement manufacturers.




*The role of endogenous melatonin

It is clear that the circadian rhythm of melatonin production and secretion is not critical for life. In animals, removal of the pineal gland appears to have a relatively minor impact on the overall health of the animal and they can survive and thrive for many years. For example, sheep pinealectomised 6 years previously remained healthy and were able to get pregnant and deliver healthy lambs27. Of course, the best evidence for the apparent redundancy of melatonin is evidenced by the inability of all the major strains of laboratory mice to produce melatonin28,29, the very strains that underpin much of our understanding of mammalian physiology! Similarly, humans appear to survive well following the removal of the pineal gland and the subsequent total elimination of circulating melatonin30. In that particular study, no systematic changes in sleep quality or polysomnography features were found and there were similar sleep onset latencies pre-and post-operatively. Underpinning the nonessential requirement for pineal melatonin production is the long-known occurrence of significant numbers of healthy individuals who produced almost undetectable amounts of melatonin each night. The percentage in the population may be in the order of 5 10%31. Interestingly, however, Rahman and colleagues have reported altered sleep architecture in subjects with very low saliva melatonin levels32. Suppression of melatonin production is a common side effect of beta-blockers like atenolol and it has been suggested that a contributing factor to insomnia experienced by many patients taking these drugs is melatonin suppression. Indeed in a trial of melatonin administration to hypertensive patients treated with atenolol or metoprolol, there was an increase in total sleep time, sleep efficiency, and decreased sleep onset latency to Stage 2 sleep33. The lack of overt major consequences of melatonin deficiency does suggest that melatonin has a regulatory or modulatory role rather than a primary direct role in controlling physiological systems. Thus the melatonin rhythm which is generated by the suprachiasmatic nucleus and the circadian timing system not only feeds back to the SCN but also provides a rhythmic hormonal signal to the rest of the body via its receptors. In many animal species, therefore, melatonin is an important transducer of circadian and seasonal rhythms to the reproductive and other systems. In humans, it has been much more difficult to assign this type of role for melatonin even though there is some evidence that humans have preserved some aspects of photoperiodicity25,34.




*What does melatonin do when administered to healthy subjects?
-Sleep
-Temperature
-Circadian rhythms
-Cardiovascular system
-Reproductive system
-Prolactin
-Ovary
-Pregnancy outcomes
-Other reproductive issues
-Summary of reproductive effects
-Glucose metabolism
-Other endocrine effects
-Jet lag and shift work
-Drug interactions





*Melatonin safety

In the preceding section, the impact of melatonin administration on sleep (daytime), core body temperature, the cardiovascular system, hypothalamic-pituitary-gonadal axis, glucose control, and other endocrine systems were discussed. With few exceptions, the information reviewed was from studies on the impact of administration of low doses of melatonin to carefully screened healthy adults.

*Efficacy




Conclusion

Melatonin is an endogenous pineal gland hormone that has specific physiological functions in animals and humans. Its primary role in humans would appear to maintain synchrony of sleep with the day/night cycle. When melatonin is administered in high doses (remembering that humans produce only approximately 40 lg over approximately an 8 h period), it affects a range of physiological systems. In healthy adults, immediate-release formulations of melatonin decrease core body temperature and promotes sleep even during the day. It can synchronize sleep rhythms in people with non 24 h sleep patterns. It has also been shown to have effects on the hypothalamic-pituitary-gonadal axis in healthy individuals. It can have cardiovascular actions in healthy people. It can decrease glucose tolerance. It can have important drug interactions. Yet trial authors repeatedly state that melatonin is safe and without side effects in their specific patient groups. Outside of the randomized trials, millions of people with a wide range of co-morbidities are taking melatonin as a dietary supplement for perceived sleep disturbances in what David Weaver2 described as “an experiment of unprecedented proportions.” We do not know what the individual consequences are because no one is monitoring them. Parents and physicians are also giving melatonin to typically developing children as well as children with neurological disorders. Perhaps this is fine for the short term, to establish good sleep habits and hygiene, but there is little justification to administer melatonin for prolonged periods without a proper evaluation of the underlying cause of the sleep disturbance.

With respect to efficacy, this review as with others has confirmed that melatonin advances the time of sleep onset, but even in insomniacs, the effect is quite modest, representing a change from 30 min to get to sleep to 18 min. In the case of children with disabilities, while melatonin appears to have the biggest impact on SOL, even after treatment, the SOL is still around 45 min. Total sleep time is increased modestly (approximately 40 min) in children with developmental disorders but their sleep efficiency remains poor.

In the United States, Canada, and some other jurisdictions OTC melatonin is going to be readily available to the general community for a long time to come and is unlikely to ever be regulated like in the UK, Europe, or Australia. Even in these jurisdictions, off-label prescribing is sure to continue. It is incumbent on the profession and one would hope, the supplement companies to provide potential customers with appropriate information about the efficacy of melatonin for insomnia and the potential for important side effects in people with co-morbidities or taking certain prescription medication. In the case of companies supplying melatonin as a dietary supplement, this is unlikely to occur since they are not permitted to make specific health claims. It appears that we must continue to wait and see if a catastrophe does emerge.
 
Defy Medical TRT clinic doctor
I take 40 mg a night. And continue increasing. I don’t use it for sleep as it does nothing for that. It’s all about anti aging. I can see huge differences.
 
melatonin ony works for me in a small dose to fall asleep ( under 1 mg ) if I take more than 1 mg I can't fall back asleep after I wake up. I don't know why that is..
 
melatonin ony works for me in a small dose to fall asleep ( under 1 mg ) if I take more than 1 mg I can't fall back asleep after I wake up. I don't know why that is..
That's a pretty common response about melatonin. when used for sleep you need a very low dose. I actually take 150 mg before bed. I don't use it for sleep but I use it for health benefits.
 
It's amazing how some can tolerate huge doses, while personally i can not take even 5mg much less 10mg without ruining the next day.
 
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