Characteristic, Synthesis, and Non-Photic Regulation of Endogenous Melatonin

Abstract

Several researchers have confirmed that the melatonin hormone is significant to the body’s circadian rhythm, hence, the need to explore the connection between the two aspects. The circadian rhythm is a natural endogenous process that controls essential body functions as it affects hormone release, body temperature, sleep patterns, and eating habits. In that view, the circadian rhythm relies on melatonin to synchronize the night and day cycles. Melatonin plays a significant role in controlling the circadian rhythm by facilitating quality sleep at night and alertness during the day. In effect, understanding the acute non-image-forming visual effects of melatonin will help derive ways to ensure the circadian rhythms operate efficiently for healthy body functions.

1. Introduction

Melatonin was discovered in 1958 by an American professor and dermatologist, Aaron B. Lerner, at the Yale University School of Medicine. Lerner and his colleagues were investigating for something that could help in curing skin diseases, which led them to isolate a hormone from bovine pineal gland extracts [1]. The scientists gave the hormone its name due to its property of lightening amphibians' skin pigmentation by inhibiting the melanocyte hormone's skin-darkening aspect. The researchers aimed to use melatonin in curing skin diseases, but in the mid-1970s, they illustrated that the hormone could regulate the circadian rhythm in the pineal glands of living organisms [2, 3]. Specifically, the subsequent years, specifically 1993, also saw extensive research on the hormone, leading to its discovery as an oxidant [3, 4]. Precisely, melatonin discovery began as an investigation of cures to skin diseases, leading to the discovery of its connection with the circadian rhythm. As such, delving into the discovery of melatonin will provide a background to its significance in the circadian rhythm.

1.1 The endogenous hormone melatonin

Endogenous melatonin hormone undergoes various processes in integrating with circadian rhythm to initiate sleep and facilitate several nighttime physiologic functions. Notably, endogenous melatonin is what the body naturally makes instead of exogenous melatonin, which is synthetically produced as a pill, supplement, capsule, or liquid. Melatonin secretion can occur from other body tissues, but the pineal gland, an endocrine gland in the brain, is primarily responsible for secreting the endogenous melatonin [5]. When the optic nerve senses darkness, it sends a signal to the pineal gland, which then responds by releasing melatonin to perform its nighttime functions. Once secreted, endogenous melatonin goes into the bloodstream, and cerebrospinal fluid then begins to send signals to other organs [5]. The circulation then carries the hormone from the brain to the rest of the body, where melatonin receptors detect the rush in circulation and transmit the signal to the body that it is nighttime [6, 7]. In essence, endogenous melatonin production relies on retinal photoreceptors detecting light and darkness and sending signals to the pineal gland [6, 8]. Its circulation to the body then leverages its chemical, making it convenient for distribution [7]. Endogenous melatonin has several chemical properties, and its hydrophilic and lipophilic nature making it easily dissolvable in water and lipids [6]. Besides, the chemical representation of melatonin is N-acetyl-methoxytryptamine, which derives from the processes it undergoes during its synthesis [7]. In short, endogenous melatonin is critical in facilitating essential body functions due to its chemical properties and interaction with other organs. Thus, the endogenous melatonin overview gives an insight into its production and distribution processes, as outlined below.

1.1.1 Melatonin synthesis

Melatonin synthesis occurs through acetylation, methylation, hydroxylation, and decarboxylation. Serotonin, a neurotransmitter from the amino acid tryptophan, is the primary precursor to melatonin [9, 10]. Particularly, L-tryptophan derives from protein catabolism or shikimate pathway from chorismate, then tryptophan hydroxylase hydroxylates it on indole rng to release 5-hydroxytryptophan (5-HTP) [10, 11]. Next, 5-hydroxytryptophan and pyridoxal phosphate decarboxylate the intermediate 5-HTP to form serotonin. Serotonin is initially acetylated and later methylated within the pineal gland to form melatonin [10]. In detail, serotonin N-acetyltransferase and acetyl-CoA convert serotonin into N-acetylserotonin [12, 13]. S-adenosyl methionine and hydroxyindole O-methyltransferase form the methylation process to convert N-acetylserotonin into melatonin [13, 14]. The process relies on light exposure to optical nerves since the serum concentrations vary with dark and daylight [13]. In essence, serotonin N-acetyltransferase (NAT) is in low concentration during the daytime and rises during the dark, dark-phase [13, 15]. Notably, although the methyltransferase process does not follow the light exposure pattern, it can only take place after the completion of the first-phase. That means melatonin synthesis is dependent on the light-dark cycle for the successful process completion of a biochemical pathway [10, 13, 15]. In the absence of light (nighttime), noradrenaline binds to α and β adrenergic receptors causing an increase in intracellular Ca²⁺. Intracellular Ca²⁺ increases and potentiate protein kinase C (PKC) and calcium-calmodulin protein kinase (CaM kinase), which in turn increases cAMP and phosphorylation of rate-limiting enzymes in melatonin synthesis (AANAT and HIOMT) (Figure 1) [16]. In simple terms, melatonin synthesis is the hydroxylation and decarboxylation of serotoninbased on the changes in the light-dark cycle. That way, assessing melatonin synthesis acts as a basis for understanding melatonin production phases to help treat sleeping disorders.

Figure 1.

Melatonin structure and biosynthesis pathway. Schematic representation of melatonin chemical structure, synthesis, and secretion. The hormone melatonin is syntheised from tryptophan with the rate-limiting enzymes, AA-NAT and HIOMT. NEinfluence α and β adrenoreceptors on pinealocytes to enhance the activity of intercellular enzymes needed for meltoning synthesis (Adopted from Watson [16]).

1.1.2 Melatonin catabolism

Melatonin catabolism is the process of metabolism that releases energy to facilitate different body functions. Originally, the body’s behavioral and physiological processes aligned to ensure constant energy intake, storage, and usage. Energy is vital because it facilitates human survival, reproduction, growth, and species regeneration. In that light, energy uptake mainly takes place during the day and storage during the night following the effects of the circadian rhythm [16, 17]. Melatonin thus acts as the linkage between energy distribution in the body and the cyclic revolution of the circadian rhythm [16, 17]. The hormone regulates metabolic processes through the concepts of endocrinology and chronobiology, leading to energy balance as the outcome. After its production, melatonin goes to the brain through blood uptake or pineal recess and then undergoes some concurrent pathways to reach its catabolic sites [17, 18]. One of the pathways leads to the mitochondria in different organs where melatonin exists in high concentrations [17, 19]. The hormone thus significantly plays a significant part as a mitochondrial antioxidant due to the high concentrations in the mitochondria, its free radical scavenging characteristic, and its indirect influence on the definition of antioxidant enzymes [17, 18, 20]. Mainly, the precursor to melatonin catabolism is the transmission to various pathways after its synthesis. In effect, exploring the precursor process acts as a basis for understanding melatonin’s catabolic phase.

Primarily, melatonin catabolism occurs in the liver and the kidney, where it undergoes chemical processes for energy production. Melatonin mainly undergoes enzymatic and nonenzymatic redox reactions to produce melatonin metabolite. Nonenzymic are propelled by singlet oxygen, free radicals, and additional reactive intermediates, such as peroxynitrite and HOCL [21]. Non-enzymic melatonin metabolism increases with an upsurge to light exposure leading to the release of N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and melatonin [20, 21, 22]. Conversely, the enzymatic process involves hydroxylation and conjugation into glucuronide and sulfate [21]. The process occurs in the liver where microsomal cytochrome P₄₅₀ monooxygenase (CYP1A2, CYP1A1, or CYP1B1) hydroxylate melatonin to 6-hydroxy-MEL [20, 23]. The end product, 6-hydroxymelatonin, proceeds to conjugate with sulfuric acid via sulfotransferase to form 6-sulfatoxymelatonin (aMT6s) as the primary melatonin metabolite in the kidney [24]. The end product can then be excreted in the urine or catalyzed by UDP-glucuronosyltransferase to form 6-hydroxymelatonin glucuronide [16, 23]. Notably, that makes urine the main component in determining melatonin concentrations and estimating dim light melatonin onset (DLMO) since it accounts for more than 90% of the metabolized melatonin from aMT6s [16]. The bottom line is that the enzymatic and nonenzymatic catalysis products are similar, with minimal evidence of some taxon-site-specific disparities. Therefore, melatonin catabolism acts as the basis for treating sleep disorders by undergoing chemical reactions in the liver and kidney to release melatonin in body fluids, which helps measure concentrations.

1.1.3 Melatonin measurement

Melatonin measurement in humans is critical since it is the basis of treating sleeping disorders by observing different parameters relating to the sleep cycle. Melatonin measurements primarily occur by gauging its concentrations in bioliquids, such as saliva, urine, plasma, and serum [25]. The highest concentrations mainly occur closer to the pineal gland and reduce as it goes further in the body and mixes with other fluids [25]. Besides remaining in the blood and cerebral fluids, the hormone’s hydrophilic and lipophilic nature allows it to diffuse easily into other body fluids, including urine, saliva, amniotic fluid, and sperm [5, 6, 25]. From that perspective, melatonin measurement relies on capturing melatonin increase parameters, one of the common ones being the dim-light melatonin onset (DLMO) [26, 27]. Specifically, DLMO facilitates the melatonin measurements in saliva, blood, or urine samples under dim light. Since there is no stipulated approximation protocol for DLMO, sampling largely relies on observation duration, frequency, and customized estimation threshold [28, 29]. Some of the common DLMO estimation models include enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) [27, 30]. High-performance liquid chromatography (HPLC) stands as a less recognized threshold, while fast-scan cycle voltammetry (FSCV) is an upcoming viable model [26, 31]. From that view, melatonin measurements rely on different thresholds that measure the DLMO parameter. That way, acknowledging the different thresholds for melatonin measurement provides a broader view of different approaches to treating sleep disorders.

Since RIA and ELISA stand as the most popular melatonin measurement models, it is fundamental to understand their operational processes. RIA primarily measures melatonin levels in blood, urine, and saliva through a quantitative analysis of high specificity and sensitivity [28, 30]. The method derives from radioactivity measurement of the radioisotope and uses labeled melatonin, unlabeled melatonin, and anti-melatonin antibodies. Labeled and unlabeled melatonin contest for antibody-binding points, creating a scenario where the increment of any leads to the decrease of the other. Afterward, the bound antibody-melatonin gets into the solid-phase and separates from unbound melatonin [28, 29]. The radioactivity measure of the bound melatonin thus derives results, where high radioactivity represents low levels and vice versa [27, 28, 29]. Conversely, the ELISA model is an immunoenzymatic approach that measures melatonin thresholds in urine, saliva, and blood [26, 28]. The method can operate under different modifications. All rely on impairing the antigen in melatonin’s solid-phase and then progressively replacing it with antigen-specific antibodies, forming an antigen-antibody complex. Next, the resultant medium is rinsed and mixed with the correct amount of enzyme-labeled antibody substrate to attain a color reaction [26, 28]. Eventually, the final results derive from the spectrophotometric measurement, which reveals melatonin levels [28, 32]. In that light, the two melatonin measurement models vary in that one relies on radioactivity and the other on color representation. As such, RIA and ELISA melatonin measurement models help cure sleep disorders by gauging the concentration levels of melatonin in the human body.

1.1.4 Distribution of melatonin receptors

Melatonin functions rely on the hormone’s receptors, hence, the need to determine their distribution in the human body. Notably, the receptors present different biological effects, such as enhancing the expression of antioxidant enzymes like glutathione peroxidase, catalase, and superoxide dismutase through signal transduction [3, 25]. The primary melatonin receptors are melatonin receptor 1 (Mel 1A or M1) and melatonin receptor 2 (Mel 1B or M2) since they are the most widely distributed in the body [25, 33]. M1 mainly has a picomolar binding affinity, and M2 is a nanomolar binding activity with the two receptors falling in G-protein coupled receptors (GPCES) [25]. Other receptors include nuclear orphan receptors in retinoid Z receptors (RZR) or retinoid orphan receptors (RORα) family, as well as quinone reductase II enzyme (MT3 receptor) [34, 35, 36]. Melatonin receptors derive from different tissues, with the highest density expressed from the suprachiasmatic nucleus, retina, and anterior pituitary [25, 34]. From there, they are vastly distributed in the body to enable their biological functions and expression, as illustrated in the table and chart below [37, 38]. Precisely, melatonin receptors consist of M1, M2, MT3, and orphan receptors, which have varying distribution in the body. Thus, assessing the distribution of melatonin receptors will help determine the treatments for sleep disorders (Figure 2 and Table 1).

Figure 2.

Major types of melatonin receptors. cAMP and inositol triphosphate (IP3) are the majorintracellular messengers’ targets of MT1 and MT2. MT3 targets cytosolic quinone reductase-2 and PORa/RZR1 are the major nuclear receptors formelatonin (Adopted from Tarocco et al. [38]).

Mel receptors	Distributions
MT1	SCN, cerebellum, hippocampus, retina, ovary, testis, aorta, coronary blood vessels, liver, kidney, adrenal gland, immune system, skin, and gallbladder.
MT2	SCN, cerebellum, hippocampus, retina, lung, heart, duodenum, granulosa, and adipocytes.
MT3	Liver, kidney, brain, heart, lung, intestine, muscle, brown adipose tissue, and eye.
MT4	Brain, pineal and neurons, and spinal cord.

Table 1.

Distribution of melatonin receptors.

Table list the subtypes of melatonin receptors. MT1 and MT2 are widely distributed in mammalian tissues (Adapted from [16, 25, 38]).

1.2 Circadian rhythm

The circadian rhythm is one of the body’s biological rhythms and comprises a series of body operations under the influence of the biological clock or internal clock. Biological rhythms range from short ones that take 24 hours to long ones that go up to a year [39]. The dominant biological rhythms include the circadian, diurnal, infradian, circalunar, and circannual, with the circadian being a 24-hour cycle. Circadian rhythms are critical because they regulate several body cycles, including sleep, alertness, hormone production, and body temperature, and their interruption may present mild to severe disorders [39, 40]. They derive from natural body factors, with the main ones being cryptochrome and period genes, which code for protein build-up in the cell’s nucleus with the light-dark cycle [39, 41, 42, 43]. Nevertheless, various molecular chemicals can sustain or disrupt the circadian rhythm based on light exposure, environmental cues, prescription drugs, exercise, and eating habits [44, 45, 46]. The factors mainly affect circadian rhythms and cause disorders by breaking the connection with the internal clock. The suprachiasmatic nucleus (SCN) in the brain’s hypothalamus is the internal clock responsible for controlling the circadian rhythm [44, 47, 48]. SCN’s main role is to regulate the pituitary gland and the autonomic nervous system by transmitting signals to manage body activity [44]. Precisely, the process takes place with the intervention of MT1 and MT2 receptors as they help induce the beneficial outcomes of melatonin in correcting sleep disorders. In effect, delving into the circadian rhythm background will guide into understanding its connection with endogenous melatonin.

1.2.1 Circadian rhythm of endogenous melatonin

The everyday sleep-wake cycle relies on the actions of the internal clock and the homeostatic sleep process driven by circadian rhythm and endogenous melatonin. The circadian rhythm is the leading facilitator of endogenous melatonin production following the daily oscillation of internal clock genes throughout the day [49, 50]. Melatonin exhibits a clear circadian rhythm property, as evident from the hormone’s synthesis and secretion mechanism. Despite the presence of non-photic stimuli, such as food, temperature, rest-activity schedule in entertaining circadian rhythm, and the light-dark cycle, is considered as the strongest zeitgeber. From that perspective, light exposure to the retina is immediately transmitted to the suprachiasmatic nuclei, which inhibits melatonin production during the day, by transmitting inhibitory signals to the pineal gland [49]. Melatonin synthesis and secretion have a rhythmic pattern, as the amplitude of secretion (acrophase) is the highest between 02:00 and 04:00h, and the concentration of serum melatonin at night reaches 8-120 pg/ml [50, 51]. The activity of rate-limiting enzymes, AANAT, and HIOMT, found at the highest concentration during the dark hours [52, 53, 54, 55]. The bottom line, light is the central controller of the circadian clock by triggering the activity of the suprachiasmatic clock, which sends signals to the pineal gland for melatonin production. That way, the circadian rhythm is a component of endogenous melatonin, and the two are involved in various body functions based on the reactions of the internal clock.

1.2.2 Melatonin as a marker of circadian phase

Melatonin is the primary marker of the circadian rhythm as it advances the circadian rhythms with changes in the light-dark cycle. It is a chronobiotic molecule or known as the hormone of darkness as it signals the length of night and time of day/year in all tissues. Its potential to cause phase-advance or phasedelay has been proven when administered at a different time of the day [16, 56]. The evening increment in melatonin influences changes in objective markers of drowsiness, including slow eye movement, slow eyeblink rate, and sleep epochs [57]. Melatonin thus acts as a phase marker based on its profile composition, which includes melatonin onset, acrophase or peak time, melatonin mid-range, and mid-range cross [57]. Notably, DLMO is the core element that gives melatonin its property as a marker of the circadian rhythm as it controls the processes of melatonin onset and offset [58]. Additionally, it influences melatonin concentrations across different types of daylight and nighttime, initiating sleep or other biological processes [58]. In a nutshell, melatonin as the main marker coordinates with other circadian phase markers to initiate the sleep cycle and other body functions. Thus, melatonin as a circadian phase marker helps treat sleep disorders by integrating different components of the circadian rhythm.

1.3 Non-Photic factors affecting Endogenous melatonin

Non-photic factors that range from lifestyle preferences, including dietary intake, nicotine, caffeine, and alcohol, or even physiological changes, including menstrual cycle, drugs, and changes in posture, can potentially regulate melatonin rhythms and levels. Hence, it is essential to focus on other factors during the experimental protocol and design to ensure robust and consistent outcomes, including minimizing the possibility of certain confounding factors. Such factors are illustrated below:

1.3.1 Dietary intake

A number of human studies have associated changes in energy restriction and dietary intake with melatonin concentration or synthesis. Some studies reported a 20% melatonin reduction after an energy intake of more than 300 Kcal every day from 2–7 days, with insignificant change in the AMT6s in the human urine [59, 60]. The levels maintained to normal after supplementation of glucose in the short term show that pinealocytes need glucose delivery to function appropriately [60]. Essentially, melatonin has been significantly found in substantive amounts in vegetables, including barley, walnuts, tomatoes, rice, and olives [61]. For example, taking vegetables in the morning has been linked to the higher excretion of urinary aMT6s [62, 63]. There were similar statistics in Japanese women, where a similar increased mean for the urinary aMT6s in a high intake of vegetables than the ones with the lowest consumption, essentially by 16% [59, 64].

The increasing level of melatonin is more likely to result from the stimulatory effects of the consumed products instead of the absorbed dietary food enriched with melatonin [65, 66]. Melatonin is usually found in milk products, especially those produced during the night [62, 67]. Therefore, it is imperative to conclude that nighttime lactation has been associated with various physiological importance attached to it as part of the infant’s diet [61]. Nevertheless, St. Hilaire et al. [68] adds that the possibility of maternal melatonin passing via the milk to the infant leads to enhanced nocturnal sleep [59]. Moreover, sleep parameters improvement and greater urinary metabolites of serotonin were observed in the intake of TRP-enriched commercial milk by the infants. The Figure below demonstrates different changes in levels of maternal salivary melatonin at night time in normal pregnancy.

According to Ahammed et al. [63], the relationship between melatonin levels and the availability of nutrients in urine and plasma was observed in animal research [66, 67]. Further, in rodents, the registered decrease in plasma melatonin was linked with zinc, folate, and magnesium deficiency in mice [61]. B6 vitamin and folate usually serve as the required coenzyme information of serotonin from TRP, while magnesium and zinc, on the other hand, increase AANAT affinity in bond formation with serotonin as well as melatonin formation [61]. Many human studies showed a lack of correlation between the minerals, including zinc, magnesium, and folate, or vitamins, with variations in melatonin in urine or plasma [65].

1.3.2 Posture

Ahammed et al. [63] affirm that different changes have linked postures changes in humans with cardiac autonomic drive. Further studies show variations in heart rate between the sitting and supine, standing and supine, standing, supine and head-down tilt, and head-up postures [60, 65]. The variations in the autonomic balance were observed with the changes in posture from supine vertical sitting or standing posture [60]. Changing posture usually affects the blood volume since there is redistribution of blood during changes in posture, particularly from supine to standing [69]. Studies have suggested a significant variation in the antigravity muscle activities once there are changes in posture, and the muscles are critical in the vascular and vasomotor activity [60, 62].

Nonetheless, these explanations and observations raise a question about the possibility of any variation in the melatonin levels, including saliva, plasma, and urine, via various postures [65]. Salivary and plasma melatonin decreased while moving from the supine to the standing posture and was raised during the reversal of the positions [69, 70]. Additionally, different studies added that raised levels of plasma melatonin during a sitting posture but did not observe any difference in the position change from sitting to the standing posture [64]. On the contrary, recent studies reported raised levels of salivary melatonin during standing posture than in sitting position after collecting samples at midnight but did not observe any difference about 35 minutes ago [70].

1.3.3 Physical activity

St. Hilaire et al. [68] argue that it is controversial how physical exercises can influence endogenous melatonin, although most studies suggest that increased exercise has the potential to influence and regulate endogenous melatonin in two distinct ways: influencing the melatonin rhythm and regulating melatonin levels in physiological fluids [68, 70].

Studies by Kirsz et al. have provided substantive evidence that exercising during night hours has great potential to increase delays in the onset of melatonin [71]. This study was also reported with higher and moderate-intensity/regularly in dim light or dark conditions, including old and younger participants [70]. Further studies report that there is usually rare exercise-induced advance. Nevertheless, further studies observed a phase advance during morning hours than during evening and nighttime exercises [64, 69].

Additionally, exercises have been found to alter/change melatonin levels accurately because of their phase-shifting effects. Following an exercise bout, circulating melatonin was reported to have increased transiently [60]. Nonetheless, this short increase was attributed to vigorous regular training or the progression of regular exercises, including treadmill research [64].

Research has shown increased sympathetic nervous system and secretion of catecholamine, induced by exercises, which can potentially control secretion. Further, exercises have been found to stimulate MRN (midbrain raphe nuclei) that transmits serotoninergic signals to the IGL [72]. The latter can potentially link SCN through NPY release [70]. Also, MRN depends on arousal since the serotonin levels in SCN follow the routine trend of locomotor activity in both nocturnal and diurnal rodents. Because serotonin can indirectly and directly affect SCN, it informs that the ability to enhance mood can be due to its potential in resetting SCN.

1.3.4 Menstrual cycle

According to Minella et al., variations in melatonin levels have been identified across the phases of menstruation. Therefore, increased plasma melatonin was seen in women in LP (luteal-phase) than FP (follicular-phase) [73]. There was also an increase in the melatonin levels in the participants taking a three-phase contraceptive pill. Most of these findings were supported by increased urinary aMT6s during LP [72]. Nonetheless, a one-day area under the plasma melatonin curve was greatly reduced in LP without changes in timing measures as illustrated below [70]. This, therefore, shows a possibility of interaction between melatonin and progesterone, including melatonin serving as a modulator of menstrual phases [66].

Moreover, evidence from studies suggests that the interaction of melatonin and sex hormones results from localizing melatonin receptors with progesterone and estrogen in the periphery and brain, including the increased melatonin receptors in the reproductive tissues [70, 73]. The study also reported a marked increase in melatonin secretion in women using oral contraceptives, particularly synthetic progesterone, as well as melatonin treatment could be essential in enhancing human chronic gonadotropin-stimulated progesterone secretion in human granulosa cells [73]. In contrast, in a low estrogen environment and premenopausal women, oophorectomy contributes to substantially increased melatonin secretion [74].

Further, Gentry et al. [75] add that treating estrogen was found to significantly reduce melatonin synthesis in rat pinealocytes, with reduced melatonin receptors (MTI) being further seen in ovaries in rats [72, 75]. Patients with PMDD (premenstrual dysphoric disorder) have been found to have reduced serotonin levels with changes in timing and the amount of secreted nocturnal melatonin [74]. This finding, however, raises the question of how reduced serotonin, which is the precursor of melatonin synthesis, can change the production of melatonin in the pineal gland Pevet et al. [66].

1.3.5 Alcohol

Studies conducted by Hardeland [76] shows that beer and wine with identical amounts of melatonin can potentially influence melatonin level in body fluids. Nonetheless, the influence of chronic or acute consumption of alcohol on levels of melatonin is inconsistent [74, 76]. Social drinking, such as 10–100g of ethanol daily, was found to decrease levels of melatonin in the blood [74]. In another study that involved heavy consumption of beer, 24–48g of ethanol in females and males resulted in a significant rise in serum melatonin following the high content of melatonin in beer [66, 70]. Contrary, repeated or single routine doses of between 15 and 120g ethanol was established to reduce aMT6s over a one-day period with more doses of alcohol [21, 77]. Similar results involved a categorical analysis showed no effect of a single drink, with two drinks leading to a 9% decline, 15% with 3, and 17% reduction with four or more drinks [70]. The above studies considered such factors as medication use, age, and hours of darkness.

1.3.6 Caffeine

Despite a standard cup of coffee was projected to have 40 μg of melatonin, the role of caffeine in the circulation of melatonin concentration remains unclear [69]. Other clinical studies show that a dose of 200 mg of caffeine capsules results in a decrease in the secretion of nocturnal secretion, with another study showing an increase of around 32% in plasma melatonin [77, 78]. A decrease of 7% in the nocturnal melatonin was identified in the healthy young participants after the administration of 400 mg caffeine was repeated at an interval of one week. In similar research, when the participants took coffee, an observation was made that a decline of over 49% night-time aMT6s excretion in a coffee with caffeine than in the coffee without caffeine [69]. Essentially, caffeine was found to serve as an adenosine antagonist inhibiting intracellular cAMP activity, hence, the production of AANAT.

1.3.7 Drugs

Sharafi et al. (2019) argue that drugs, including prescribed, recreational, and conventional ones, have been found to contain different effects on melatonin secretion and synthesis. Atenolol has been linked to significant light-induced phase delays in the onset of melatonin in humans [78]. Psychotropic and antidepressant drugs have been associated with changes in pineal functions and melatonin levels, as shown in Figure 1 [62, 69]. Various types of selective serotonin inhibitors, SSRI, including fluvoxamine, result in a notable rise in plasma melatonin concentrations. While others, including citalopram, showed no effect. Minella et al. (2021) add that tricyclic antidepressants enhance the onset of melatonin and intensify the nocturnal plasma melatonin in people since it acts as noradrenaline re-uptake inhibitors [73].

1.3.8 Nicotine

Cigarettes usually contain polycyclic aromatic hydrocarbons that usually contain CYP1A2 activity, which is required for the metabolism of melatonin in the liver [62, 73]. Therefore, the level of melatonin in habitual smokers is usually low. Administration of chronic nicotine contributes to increased CYP1A2 levels as well enzymatic activity. Such observations were seen in greater amounts in smokers [72, 74]. After experiments were done on smokers prior to and after smoking abstinence have shown changes in endogenous levels of melatonin; however, after administration of oral melatonin (usually 25 mg) during the night, levels of melatonin during the period without smoking were substantially higher than during smoking period [72, 78].

2. Conclusion

Melatonin hormone is a critical component in treating sleep and other body disorders arising from the disruption of the circadian rhythm. Melatonin comes as an endogenous or exogenous hormone, where endogenous derives naturally from the body and exogenous is manufactured in the laboratory. With respect to endogenous melatonin, it derives from the pineal glands in the brain and undergoes various processes before attaining its ultimate outcomes. Particularly, melatonin undergoes biosynthesis and catabolism, and the metabolites are distributed throughout the body to different types of receptors. Melatonin concentration measurement thus becomes possible by testing the end products from different sites using gauging models, such as RIA and ELISA. The essence of understanding melatonin demographics is mainly to connect its connection with the circadian rhythm in facilitating body cycles. Precisely, the melatonin hormone undergoes its processes in resonance with the circadian rhythm for it to complete its physiological pathways. Therefore, exploring the connection between melatonin production and circadian rhythms helps understand the body's physiological processes in contracting or treating sleep disorders. Conclusively, every non-photic factor has been found to have a significant effect on endogenous melatonin. Several studies have exhausted the effects including increase or decrease of melatonin levels upon experiments on the different non-photic factors.