David N. Neubauer, MD

Melatonin is ubiquitous. It is present in nearly all life forms, including plants and animals, and even single cell organisms. Evolutionarily, it dates back billions of years serving essential cellular processes with its antioxidant and free radical scavenging functions, and more recently as a 

 in the regulation of circadian rhythms and the sleep-wake cycle.

 As humans, we benefit from our endogenous melatonin in support of our complex cellular activity and in helping to orchestrate wide-ranging physiological processes influenced by our circadian system.

 We are not conscious of most melatonin actions, but certainly experience its effects on sleep and waking.

It is useful to think of our endogenous melatonin in 2 ways: 1) reactions occurring intracellularly that do not necessarily involve specific melatonin receptors and 2) the more familiar circadian role associated with regular changes in circulating melatonin and effects on melatonin receptors. Although present in a variety of tissues, circulating melatonin is predominantly produced in the pineal gland under the control of the master 

 transcription-translation loops in the hypothalamic suprachiasmatic nucleus (SCN), which is entrained by exposure to the light-dark cycle.

Normally, plasma melatonin levels are very low during the daytime and gradually rise in the evening as bedtime approaches, typically about 2 hours before a person’s natural sleep onset time; however, the actual clock time of the melatonin rise can vary considerably among individuals. Melatonin production also can be suppressed by light exposure, so this can be a factor affecting the circulating levels and sleep patterns. Usually melatonin plateaus at a relatively high level throughout the night and then declines by morning. When the pineal gland produces melatonin, it is immediately released into the bloodstream and cerebrospinal fluid. This pattern of markedly elevated melatonin levels during the nighttime has led to its description as the “hormone of darkness.” Note that the production of melatonin is primarily under circadian control: while bright light during the nighttime time will suppress it, darkness during the daytime will not turn it on.

The circulating melatonin levels provide the body’s physiology with a clock and a calendar. Changing melatonin concentrations reinforce circadian activity in nearly all tissues and the changing duration of nighttime melatonin secretion reflects the time of year, especially important for seasonally breeding species.3 As humans, our ability to fall asleep at our typical bedtime and the robustness of our circadian cycle are both reinforced by melatonin interacting with the MT1 and MT2 receptors that are highly concentrated in the SCN. The normally coordinated functioning of homeostatic and circadian processes promotes our nighttime sleep of about 8 hours and our daytime-evening wakefulness of about 16 hours.

From late afternoon into the evening, the SCN-driven circadian system produces arousal that counters the homeostatic sleepiness that has accumulated since the morning awakening, thus allowing sustained functioning into the evening. Typically, we are the most alert in the early evening than any other time of the day or night. With approaching bedtime, the rising melatonin agonist activity at the SCN melatonin receptors decreases the stimulation, leaving the homeostatic sleepiness unopposed, thus facilitating bedtime sleep onset. It is notable that the melatonin action is not sedation, but rather a reduction in the evening circadian arousal.

In everyday life, we think of melatonin as a widely available, fairly benign, and maybe helpful sleep aid product. In the United States, it is categorized as a dietary supplement, although in some countries it requires a prescription. Unlike official over-the-counter (OTC) products, which are highly regulated (composition, manufacturing, indications, labeling, and marketing), dietary supplements have little oversight. Studies analyzing consumer melatonin products have shown varying amounts of the compounds, as well as the presence of other unlabeled and sometimes surprising ingredients.

Does exogenous melatonin taken as a dietary supplement enhance sleep? Is it safe?

There is a reasonable argument that taking evening melatonin might augment the natural process of reducing circadian arousal to help people fall asleep more quickly. In general, meta-analyses and systematic reviews of evening melatonin doses compared with placebo show statistically significant improvements in sleep onset that are of questionable clinical 

 Studies have shown little or no benefit for sleep maintenance or total sleep time. The best evidence is for people having a circadian rhythm phase delay (“night owls”), blind individuals with the non-24-hour sleep-wake rhythm disorder, and some children with neurodevelopmental disorders.

 However, much of the research with melatonin has been with few subjects, mixed clinical populations, and for short durations, all limiting the quality of the evidence.

Clinical trial assessments of melatonin safety share the same study limitations, so high-quality data are not available. The more common adverse event reports include daytime drowsiness and nightmares, though the rates are low. Generally, melatonin is well tolerated in these placebo comparison studies with typical consumer product doses.

A darker side of both endogenous and exogenous melatonin has been emerging in recent years with investigations of circadian rhythms and 

, specifically examining glucose tolerance, insulin release and sensitivity, weight gain, and the timing of food intake.

 The circadian regulation of metabolism is just right for people who are active, get plenty of light exposure, and have their meals during the daytime, and who are in the dark sleeping during the nighttime. In our society, many people eat at irregular times, including late in the evening and during the night, when our circadian system expects us to be fasting. An evening meal will result in higher glucose and insulin levels compared with the identical meal eaten early in the day. Over time these elevated evening glucose and insulin levels increase the risk for obesity and type 2 diabetes mellitus. The timing of food intake in relation to our evening melatonin rise appears to be an important factor.

 studied the sleep-wake patterns of healthy young adults over a 30-day period that included 1 week of monitoring the timing and content of all food they ate, and also an overnight laboratory assessment of their melatonin patterns and body composition. They found a significant relationship between the timing of food consumption relative to melatonin onset and the percentage of body fat and body mass index, controlling for the actual clock time, caloric amount, activity or exercise level, and sleep duration. Eating food later in the day had a detrimental effect.

These findings are consistent with studies demonstrating the weight loss and metabolic benefits of time restricted eating routines where people consume their meals on a relatively early schedule and fast through the evening and nighttime. Avoiding evening eating close to and following our melatonin rise appears to have advantageous metabolic effects.

If we should avoid eating and digesting food close to our evening endogenous melatonin rise, what are the implications for using exogenous melatonin as a sleep aid? There is evidence that taking melatonin also leads to impairment in glucose tolerance. Rubio-Sastre and colleagues

 studied 21 healthy women, giving them either melatonin 5 mg or a placebo in the morning and evening on different days. An oral glucose tolerance test monitoring glucose and insulin levels for 3 hours began 15 minutes after each dose. Finding that the melatonin use was associated with elevated glucose levels at both time points, they concluded that the optimum timing for melatonin doses should be at least 2 hours after the last meal.

Perhaps the best plan for melatonin to help with sleep is to give our own circadian rhythm and melatonin release a chance to do the job.

 Maintaining regular sleep-wake hours, plenty of daytime activity and light exposure, and early meal timing should aid in stabilizing the circadian cycle. Avoiding bright light in the evening for a few hours prior to bedtime should limit the suppression of melatonin, especially if using reddish low color-temperature lighting, now readily available with LED products. Using electronic screens (eg, phones, tablets, laptops) held close to the face should be limited as bedtime approaches—even when using those devices with blue spectrum-blocking apps or filters. These good sleep habits that facilitate earlier and higher melatonin release may be the solution to achieve an earlier sleep onset.

If one is inclined to take a dose of melatonin to enhance sleep, it probably will help the most when taken prior to bedtime, but ideally well after the last meal.

 Even very low doses result in blood levels hundreds to thousands of time higher than the normal endogenous circulating amount. Low doses should be as effective as high doses, since the primary action of melatonin is not sedation. The ultimate benefit in helping people fall asleep more quickly may take several days or weeks as melatonin advances and stabilizes the circadian system.

The bright side of this “hormone of darkness” is the extraordinary roles it serves in stabilizing our cellular and circadian functioning. If we manage to live our lives closer to our natural circadian physiology, we can avoid melatonin’s potential metabolic darkness.

is associate professor in the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. He spoke at PsychCongress 2020 in a presentation titled Melatonin: What, Why, and Why Not? The author reports he is a consultant with Eisai Inc and Abbott Laboratories.

Melatonin synthesis and function: Evolutionary history in animals and plants

2. Claustrat B, Leston J. Melatonin: Physiological effects in humans. 

3. Arendt J. Melatonin: Countering chaotic time cues. 

4. Erland LA, Saxena PK. Melatonin natural health products and supplements: Presence of serotonin and significant variability of melatonin content. 

5. Buscemi N, Vandermeer B, Hooton N, et al. 

The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis

6. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: Meta-analysis. 

7. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: A meta-analysis. 

8. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. 

9. Garaulet M, Qian J, Florez JC, et al. 

Melatonin effects on glucose metabolism: Time to unlock the controversy

10. Stenvers DJ, Scheer, FAJL, Schrauwen P, et al. Circadian clocks and insulin resistance. 

11. McHill AW, Phillips AJ, Czeisler CA, et al. 

Later circadian timing of food intake is associated with increased body fat

12. Rubio-Sastre P, Scheer FA, Gomez-Abellan P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. 

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Our own melatonin plays an important role in regulating our sleep-wake cycle. Recent evidence raises questions about whether we should be taking extra doses to try to improve our sleep. 

Melatonin: The Dark Side of the Hormone

[[{"type":"media","view_mode":"media_crop","fid":"23345","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_1773185567471","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1823","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"margin: 5px; float: right;","title":" ","typeof":"foaf:Image"}}]]There has been quite a lot of activity in the field of sleep medicine with the development of new pharmacokinetic and pharmacodynamic approaches to treating sleep disorders. Over the past few years, the FDA has approved several new products with indications for insomnia, excessive sleepiness, 

, and restless legs syndrome (RLS). In addition, there are many novel compounds being evaluated as possible sleep-related therapies.

The most recent new medication is tasimelteon, which was approved by the FDA early in 2014 with an indication for treating the non–24-hour sleep-wake rhythm disorder, a type of circadian rhythm disorder. Tasimelteon was developed specifically for totally blind individuals who are unable to achieve normal 24-hour entrainment with the photoperiod and consequently have a free-running circadian cycle.

People with this disorder are challenged by trying to live 24-hour lives with body clocks on longer cycles. They may be synchronized with the day-night cycle and are able to sleep well at night and feel alert during the daytime. Gradually their cycles drift later, to the point where they are 180 degrees out of synchronization and have difficulty with nighttime insomnia and daytime sleepiness. They then cycle back, and the pattern repeats over and over with a periodicity of weeks or months.

Tasimelteon, an agonist of the melatonin receptors, taken at the same time each evening helps stabilize the circadian system at 24 hours to promote more consistent nighttime sleep and daytime alertness. It will be available as a 20-mg capsule.

There have been pharmacokinetic and pharmacodynamic developments among the FDA-approved medications for RLS. The pharmacological approach has been with the dopamine agonists pramipexole and ropinirole. Now there is a 24-hour transdermal patch of rotigotine; it is available in 6 strengths: 1, 2, 3, 4, 6, and 8 mg. For patients with RLS, the recommended dosage is up to 3 mg daily. Gabapentin has been a treatment option for RLS for many years; the FDA approved an extended-release formulation-gabapentin enacarbil-available in 300and 600-mg tablets.

 have been the benzodiazepine receptor agonists-both the older benzodiazepines and the newer-generation non-benzodiazepines. For many years, only immediate-release formulations were available. That changed with extended-release zolpidem. Zolpidem is now available in 3 new formulations. There is an oral spray with single-metered actuations of 5 mg and a sublingual tablet available in 5and 10-mg doses. Both of these formulations are intended for bedtime use as alternatives to the 5 and 10-mg immediate-release tablets. The other new zolpidem formulation is the low-dose (1.75 and 3.5 mg) sublingual tablet intended for middle-of-the-night awakenings when patients have difficulty with returning to sleep and have at least 4 hours remaining before their intended wake up time.

The two most recent pharmacodynamic additions to the FDA approved insomnia medications were a melatonin receptor agonist (ramelteon-indicated for sleep-onset insomnia) and a selective histamine H1 receptor antagonist (low-dose doxepin-indicated for sleep maintenance insomnia). Other novel compounds have been investigated as possible 

, but most have been abandoned because of safety concerns or insufficient efficacy.

One strategy in promoting sleep in patients with insomnia is the use of an orexin antagonist. The orexin (hypocretin) system, discovered only in the late 1990s, plays a critical role in the regulation of the sleep-wake cycle. Two orexin proteins (orexin A and orexin B) are produced in hypothalamic neurons with widespread brainstem and cortex projections. These proteins interact with 2 orexin receptors (OX1R and OX2R) that have overlapping distributions. Orexin activity stimulates and stabilizes wakefulness. Accordingly, antagonist compounds would have the potential to promote sleep.

Clinical trials are under way with single orexin receptor antagonists (SORAs) and dual orexin receptor antagonists (DORAs). The DORA suvorexant is the one compound in this class that has made its way to an FDA evaluation. The drug initially was not approved at the proposed dosages, but it may be approved with an insomnia indication at lower dosages.

The treatment of excessive sleepiness is a clinical challenge. Modafinil and armodafinil are FDA-approved for treating excessive sleepiness associated with narcolepsy, 

, and shift work disorder. Sodium oxybate, dosed twice at nighttime, is indicated for excessive daytime sleepiness and cataplexy in narcolepsy patients. Several amphetamine formulations also are indicated for treating narcolepsy. A novel pharmacodynamic approach currently being investigated in clinical trials is treating excessive sleepiness with compounds that function as antagonists or inverse agonists of the presynaptic histamine H3 autoreceptor. There is also hope that someday an orexin agonist will become available for the treatment of narcolepsy.

Near the top of a sleep medicine wish list would be a pill to treat the fundamental cause of obstructive sleep apnea-upper airway collapsibility. Some compounds have demonstrated limited benefits but none so far has had reliable efficacy. Fortunately, there are very effective nonpharmacological treatments, including some novel investigational devices that may be approved for treating sleep apnea in the future.

No doubt, further knowledge of the regulation of sleep and wakefulness and advances in the understanding of the pathophysiology of sleep disorders will highlight new pharmacological targets and stimulate new clinical investigation. In the meantime, we should continue to identify sleep disorders among our patients. There are many effective nonpharmacological treatments that complement a rather diverse pharmacopeia at our disposal.

This article was originally posted online on 3/13/2014 and parts of the article have been updated.

Dr Neubauer is Associate Professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins Medicine in Baltimore, MD. He is a consultant for Vanda Pharmaceuticals and Novo Nordisk.

What's new in sleep medicine? The latest developments in both new and novel approaches to treating sleep disorders.

Additions to Our Sleep Armamentarium

What  is sleep normally and what are the primary factors that regulate sleep?  Understanding that the primary factors that regulate the sleep wake cycle are  homeostatic and circadian will help clinicians assess sleep problems in  patients. In this podcast, Dr David Neubauer discusses effective insomnia  management.

Dr Neubauer is Associate Professor at Johns  Hopkins University School of Medicine in Baltimore. He will be speaking at  the upcoming 

US Psychiatric and Mental Health Congress

 in San Diego. His presentation  on Insomnia Management is scheduled for Thursday, November 8 from 4 to 5:30 PM.

Implementing Effective Insomnia Management

Podcasts

What is sleep normally and what are the primary factors that regulate sleep? Understanding that the primary factors that regulate the sleep wake cycle are homeostatic and circadian will help clinicians assess sleep problems in patients.

David N. Neubauer, MD

Articles

Melatonin: The Dark Side of the Hormone

Additions to Our Sleep Armamentarium

Implementing Effective Insomnia Management: Important Issues in Evaluation and Treatment