**2.1 Melatonin and disorders of the sleep-wake cycle**

Circadian disturbances of the sleep-wake rhythm are associated with disconnection of the synchronization of the endogenous circadian rhythm and environmental influences. Melatonin signals the onset of darkness, and activation of its production indirectly depends on the activity of intrinsically photosensitive retinal ganglion cells (ipRGC) or true light-sensitive retinal ganglion cells. However, there is also an endogenous melatonin release profile that allows SCN activation regardless of external light, maintaining sleep-wake rhythms and neuroendocrine rhythms in a 24-hour cycle. However, the absence of external-stabilizing effect of zeitgeber (daily light change) can lead to the formation of a non-24-hour sleep-wake cycle. For example, in completely blind subjects, it is quite common (in 50–75% of cases)

to observe a non-24-hour sleep-wake disorder (non-24-hour sleep-wake disorder), the occurrence of which is associated with the inability to synchronize with changes in light [17]. Circadian rhythm disorders can be divided into conditions that may be caused by endogenous or exogenous factors. The first subgroup includes the syndrome of delayed onset of sleep and wake phases (advanced sleep-wake phase disorder), early onset of the sleep phase (delayed sleep-wake phase disorder), irregular sleep-wake rhythm disorder (irregular sleep-wake rhythm disorder), and non-24-hour sleep-wake cycle (non-24-hour sleep-wake disorder). The group with exogenous causes of occurrence includes jet lag disorder, a disorder caused by a shift work schedule (shift work disorder) or a result of behavioral features of going to bed and violation of the work and rest regime in the format of about 24-hour circadian rhythm. The circadian rhythm is regulated by melatonin, while the production of melatonin itself is regulated by external influences, the most important of which is the effect of light, which activates the retinal ganglion cells containing the light-sensitive pigment melanopsin. External influences with excessive activation of signal systems implemented through SCN excitation are caused by the lifestyle of modern people, the use of electronic devices. Such excessive activation can lead to difficulty in initiating sleep, reducing its duration [18]. A decrease in melatonin secretion serves as one of the main mechanisms for the occurrence of such a disorder as delayed sleep phases [19]. There is a positive modulating effect of melatonin on the circadian rhythm of sleep-wakefulness and sleep efficiency both in pathology and in healthy subjects [20].

In separate studies in patients with delayed onset of sleep and wake phases in combination with attention deficit hyperactivity disorder, therapy was performed at a dose of 10 mg, lasting for 4 or more years. The therapeutic effect of melatonin was shown in reducing the start time of sleep and increasing the time of wakefulness in these patients. The use of melatonin in a dose of 3 mg for the treatment of disorders of the sleep-wake cycle in children did not show any effects on the process of puberty in the long-term period. However, it should be noted that these studies are isolated and do not carry a sufficiently high level of evidence [21]. However, even this long-term use of melatonin was not accompanied by any significant or serious adverse events.

**Table 1** presents data on the efficacy of melatonin and its agonists in various forms of sleep-wake disorder [21].

According to the recommendations for the treatment of these conditions, melatonin and its agonists have a sufficient level of evidence when applied to the diagnosis of delayed onset of sleep and wake phases and irregular sleep-wake


**23**

*Clinical Use of Melatonin in the Treatment of Sleep Disorders*

rhythm syndrome. Concerning the recommendations on the dose of melatonin, no consensus has been formed, since in studies on the basis of which recommendations are formed with the use of a wide variety of doses of melatonin, from 0.3 to 10 mg. For the non-24-hour sleep-wake cycle syndrome alone, in 2014, the US Food and Drug Administration (FDA) approved a melatonin agonist (tasimelteon)

However, individual studies have demonstrated a high therapeutic effect in the treatment of completely blind patients with N24HSWD immediate-release melatonin preparations. Taking a 0.5–10 mg of melatonin helped accelerate the synchronization of the endogenous sleep-wake rhythm with a 24-hour rhythm, according to the profile of the production of melatonin and cortisol. Also, separate studies demonstrate that drugs with modified melatonin release can also be effective in stabilizing circadian rhythms in completely blind patients with N24HSWD [22]. The so-called sleep-wake cycle disturbance states, namely, "jetlag," which occurs when changing time zones during an eastbound flight, can be corrected quite well with exogenous melatonin. In separate studies, various doses of melatonin (from 0.5 to 10 mg) used at bedtime, 3 days before the transmeridian flight and 5 days after it, were used to treat jetlag [23, 24]. The effectiveness of melatonin in most studies was already shown during the first 3 days after the completed flight, but subsequently, patients who did not take melatonin showed the same sleep-wake cycle characteristics as the group of people taking it. The main effect of melatonin in the first 3 days after the transmeridian flight was an increase in the duration and quality of night sleep, based both on subjective sensations and on the data of objective methods for recording sleep patterns (polysomnography and

At the same time, melatonin had a positive effect on latency and duration of sleep. Melatonin agonists have also shown their effectiveness in accelerating adaptation to a new time zone. Melatonin agonists (ramelteon and tasimelteon) are approved by the FDA for the treatment of time zone change syndrome ("jet lag"). As a pharmacological method of treating these types of disorders, the use of agomelatine, long-acting melatonin, and tasimelteon was approved by the European Medicines Agency. Most studies have evaluated the effects of melatonin on jet lag when changing time zones eastward, but there are also few studies showing its effectiveness in treating jet lag with a transmeridian flight (12 time zones) westward [27, 28]. A definitive statement regarding the most effective dose of melatonin in jet lag treatment cannot be made; however, separate studies have shown a greater efficacy of a 5 mg immediate-release melatonin dose relative to the

Melatonin, as a dietary supplement, is used widely enough but is not an approved treatment for these types of disorders. The reason for this, as a rule, is the lack of sufficient evidence in the form of clinical trials conducted at the appropriate

Insomnia is a pathological condition caused by a variety of endogenous and exogenous factors. Insomnia is characterized primarily by the difficulty of initiating and maintaining sleep, which results in low-quality daily activity. People suffering from chronic insomnia are usually more prone to psychiatric disorders, primarily anxiety-depressive disorders, and cardiovascular diseases [29]. With age, the prevalence of insomnia increases; one of the reasons for this is an involutional decrease in the level of secretion of melatonin [30], a decrease in its concentration with SCN [6]. According to epidemiological studies, 6% of adults in industrialized countries

group of patients taking 2 mg delayed-release melatonin [24].

level to evaluate the clinical effects.

**2.2 Melatonin in the treatment of insomnia**

*DOI: http://dx.doi.org/10.5772/intechopen.92656*

as a therapy.

actigraphy) [25, 26].

### **Table 1.**

*The use of melatonin and its agonists in various types of disorders of the sleep-wake cycle.*

*Melatonin - The Hormone of Darkness and Its Therapeutic Potential and Perspectives*

in pathology and in healthy subjects [20].

serious adverse events.

**Type of disorder (syndrome)**

Delayed onset of the phases of sleep and wakefulness

Non-24-hour sleep-wake

Irregular rhythm of sleep-wakefulness

cycle

forms of sleep-wake disorder [21].

to observe a non-24-hour sleep-wake disorder (non-24-hour sleep-wake disorder), the occurrence of which is associated with the inability to synchronize with changes in light [17]. Circadian rhythm disorders can be divided into conditions that may be caused by endogenous or exogenous factors. The first subgroup includes the syndrome of delayed onset of sleep and wake phases (advanced sleep-wake phase disorder), early onset of the sleep phase (delayed sleep-wake phase disorder), irregular sleep-wake rhythm disorder (irregular sleep-wake rhythm disorder), and non-24-hour sleep-wake cycle (non-24-hour sleep-wake disorder). The group with exogenous causes of occurrence includes jet lag disorder, a disorder caused by a shift work schedule (shift work disorder) or a result of behavioral features of going to bed and violation of the work and rest regime in the format of about 24-hour circadian rhythm. The circadian rhythm is regulated by melatonin, while the production of melatonin itself is regulated by external influences, the most important of which is the effect of light, which activates the retinal ganglion cells containing the light-sensitive pigment melanopsin. External influences with excessive activation of signal systems implemented through SCN excitation are caused by the lifestyle of modern people, the use of electronic devices. Such excessive activation can lead to difficulty in initiating sleep, reducing its duration [18]. A decrease in melatonin secretion serves as one of the main mechanisms for the occurrence of such a disorder as delayed sleep phases [19]. There is a positive modulating effect of melatonin on the circadian rhythm of sleep-wakefulness and sleep efficiency both

In separate studies in patients with delayed onset of sleep and wake phases in combination with attention deficit hyperactivity disorder, therapy was performed at a dose of 10 mg, lasting for 4 or more years. The therapeutic effect of melatonin was shown in reducing the start time of sleep and increasing the time of wakefulness in these patients. The use of melatonin in a dose of 3 mg for the treatment of disorders of the sleep-wake cycle in children did not show any effects on the process of puberty in the long-term period. However, it should be noted that these studies are isolated and do not carry a sufficiently high level of evidence [21]. However, even this long-term use of melatonin was not accompanied by any significant or

**Table 1** presents data on the efficacy of melatonin and its agonists in various

According to the recommendations for the treatment of these conditions, melatonin and its agonists have a sufficient level of evidence when applied to the diagnosis of delayed onset of sleep and wake phases and irregular sleep-wake

**Efficiency Level of** 

Recommended for adults with or without depression Recommended for children and adolescents without or

Recommended for children and adolescents without or

Recommended for blind adults Low

with concomitant psychiatric pathology

with concomitant psychiatric pathology

neurological pathology

*The use of melatonin and its agonists in various types of disorders of the sleep-wake cycle.*

Not recommended for seniors with dementia. Recommended for children and adolescents with **evidence**

Moderate

Moderate

Low

**22**

**Table 1.**

rhythm syndrome. Concerning the recommendations on the dose of melatonin, no consensus has been formed, since in studies on the basis of which recommendations are formed with the use of a wide variety of doses of melatonin, from 0.3 to 10 mg. For the non-24-hour sleep-wake cycle syndrome alone, in 2014, the US Food and Drug Administration (FDA) approved a melatonin agonist (tasimelteon) as a therapy.

However, individual studies have demonstrated a high therapeutic effect in the treatment of completely blind patients with N24HSWD immediate-release melatonin preparations. Taking a 0.5–10 mg of melatonin helped accelerate the synchronization of the endogenous sleep-wake rhythm with a 24-hour rhythm, according to the profile of the production of melatonin and cortisol. Also, separate studies demonstrate that drugs with modified melatonin release can also be effective in stabilizing circadian rhythms in completely blind patients with N24HSWD [22].

The so-called sleep-wake cycle disturbance states, namely, "jetlag," which occurs when changing time zones during an eastbound flight, can be corrected quite well with exogenous melatonin. In separate studies, various doses of melatonin (from 0.5 to 10 mg) used at bedtime, 3 days before the transmeridian flight and 5 days after it, were used to treat jetlag [23, 24]. The effectiveness of melatonin in most studies was already shown during the first 3 days after the completed flight, but subsequently, patients who did not take melatonin showed the same sleep-wake cycle characteristics as the group of people taking it. The main effect of melatonin in the first 3 days after the transmeridian flight was an increase in the duration and quality of night sleep, based both on subjective sensations and on the data of objective methods for recording sleep patterns (polysomnography and actigraphy) [25, 26].

At the same time, melatonin had a positive effect on latency and duration of sleep. Melatonin agonists have also shown their effectiveness in accelerating adaptation to a new time zone. Melatonin agonists (ramelteon and tasimelteon) are approved by the FDA for the treatment of time zone change syndrome ("jet lag"). As a pharmacological method of treating these types of disorders, the use of agomelatine, long-acting melatonin, and tasimelteon was approved by the European Medicines Agency. Most studies have evaluated the effects of melatonin on jet lag when changing time zones eastward, but there are also few studies showing its effectiveness in treating jet lag with a transmeridian flight (12 time zones) westward [27, 28]. A definitive statement regarding the most effective dose of melatonin in jet lag treatment cannot be made; however, separate studies have shown a greater efficacy of a 5 mg immediate-release melatonin dose relative to the group of patients taking 2 mg delayed-release melatonin [24].

Melatonin, as a dietary supplement, is used widely enough but is not an approved treatment for these types of disorders. The reason for this, as a rule, is the lack of sufficient evidence in the form of clinical trials conducted at the appropriate level to evaluate the clinical effects.
