Melatonin – Overview
While melatonin was formerly only recognized as a hormone that promotes sleep, more recent studies have led to a greater comprehension of the various physiological functions of melatonin in the human body (1). It is considered a chronobiotic substance, that is, melatonin has the ability to influence the pacemaker or circadian clock (2).
It also has a cytoprotective property by reversing inflammatory damage in neurodegenerative and aging diseases. Low levels of melatonin in the blood characterize advancing age (3) and influence the prominent cognitive symptoms found in Alzheimer’s disease and dementia; likewise, its low levels are related to motor symptoms such as in Parkinson’s disease (4).
With the development of this understanding has arisen a broad, rising trend in the usage of melatonin supplementation, which now has uses outside of its traditional role as a sleep aid (1). More exhaustive studies are required to assess its age-related cytoprotection.
Synthesis and Secretion
In 1958, Aaron Lerner discovered melatonin and extracted it from the bovine pineal (5). The synthesis of melatonin in the pineal gland depends on the dark-light cycle. Darkness promotes melatonin production and secretion, but light inhibits it. The suprachiasmatic nucleus (SCN) of the hypothalamus receives and transmits light information from the retina to the pineal gland. It begins to secrete shortly after sunset, peaks in the middle of the night (between two and four in the morning), and then gradually declines in the second part of the evening. 80% of the hormone’s synthesis occurs at night. Serum concentrations are modest, up to 20 pg/ml during the day (6). It is also known that the seasons of the year, gender, and age of the individual affect its production. The liver is the main site for maintaining circulating levels of this molecule (7).
Melatonin has also been found in extra-pineal locations, including the retina, bone marrow cells, platelets, skin, lymphocytes, the cerebellum, and particularly the gastrointestinal system of vertebrate species. Melatonin can also be produced by the enterochromaffin cells; these are a type of enteroendocrine cell and neuroendocrine cell that reside alongside the subepithelial layer of the digestive tract playing a crucial role in gastrointestinal motility and secretion (8).
The pinealocytes primarily produce melatonin from the amino acid tryptophan. Serotonin is converted to melatonin by two enzymes, which are mostly present in the pineal gland. The pineal gland receives noradrenergic and neuropeptidergic inputs that regulate the activity of both enzymes. Additionally, norepinephrine stimulates the enzymes that produce melatonin. Melatonin is swiftly released into the systemic circulation after synthesis, allowing it to reach both central and peripheral target tissues (9).
Mechanism of Action
Melatonin is chemically an indolamine compound, a group of neurotransmitters, that is largely generated by the pineal gland and released into the blood. It is the epicenter of circadian cycles. Exogenously administered indoleamine can be given orally, sublingually, topically, or by transdermal patches. It may be purchased over the counter (without a prescription) to treat depression and sleeplessness.
In order to stabilize bodily rhythms, the hormone melatonin is regarded as an endogenous synchronizer and a chrono-biotic molecule, that is, a substance that amplifies oscillations or modifies the timing of the central biological clock, which is housed in the suprachiasmatic nucleus of the hypothalamus (10).
According to multiple studies, it is revealed that the mitochondrion is the prime site where melatonin is synthesized. Mitochondria are the main source of free radicals, which are helpful for jet lag and other disturbances like sleep insufficiency, along with the treatment of disoriented circadian rhythm clocks.
Melatonin may also be used as an antioxidant treatment. Its antioxidant activity is mainly due to its property of free radical scavenging, which is only due to its molecular structure, which has electron-rich aromatic indole rings. Due to this, it is considered an electron donor and significantly reduces oxidative stress (10).
Melatonin regulates circadian rhythms by synchronizing the hormonal environment within the cycle of light and dark outside. The activation of two classes of membrane-specific receptors—high-affinity ML1 sites and low-affinity ML2 sites—is the route with the greatest characterization. Many central and peripheral tissues, including the heart and arteries, lungs, liver, ovaries, uterus, breast, prostate, kidney, small intestine, adipocytes, and skin, have been identified to contain melatonin receptors (11).
Melatonin protects the brain from oxidative stress and regulates a number of physiological processes, including retinal functioning, free radical detoxification, immune system modulation, blood pressure, and autonomic cardiovascular regulation (12). Melatonin is well known for its role in regulating body mass and energy expenditure in animals by halting the accumulation of body fat with aging (13). Melatonin has physiological effects on sexual development and reproduction in animals by cyclically suppressing the gonadotropin-releasing hormone (GnRH) gene expression (14).
Its direct action further activates its two receptors, MT1 and MT2, which upregulate the antioxidant defense system, increasing the activity of antioxidant enzymes, e.g., glutathione peroxide and superoxide dismutase. It exerts its effect by acting via receptor-independent mechanisms that involve the direct interaction of melatonin with other molecules.
MT1 and MT2 are transmembrane receptors that span around proteins that belong to the G-protein. The family of this protein is known as GPCR, which means G protein-coupled receptors, and is a superfamily that has a high affinity to bind and activate at low concentrations of Melatonin (10).
The latest findings determined that the neuroprotection of melatonin on brain injury induced by ischemia/reperfusion was mediated by MT1 receptors located in the mitochondria and not in the membrane (15). This is remarkable because a GPCR like the MT1 is known as a cell-surface receptor that transmits extracellular signals into the cell.
The in vitro physiological response of melatonin is achieved in a range of 10-8 to 10-9 M (16, 17). However, many of the studies on neuroprotective and anti-inflammatory effects in animals use higher doses.
Through an alternative pathway to that of melatonin receptors, it has antioxidant and cleansing properties (18) by inhibiting the synthesis of pro-oxidant enzymes and facilitating that of antioxidant enzymes. Melatonin exceeds the capacity of vitamins C and E to protect from oxidative damage (19). Melatonin also exerts cytoprotection in ischemia (independently of free radical scavenging) via mitochondrial membrane stabilization (20).
Pharmacokinetics and Pharmacodynamics
Melatonin is rapidly removed after intravenous injection (distribution half-life of 0.5 to 5.6 minutes). Within 60 minutes of oral treatment, the plasma concentration peak is notable. Biphasic plasma concentration declines with half-lives of 2 and 20 minutes. With a typical dosage of 1-5 mg, melatonin concentrations may be reached within an hour of consumption that is 10- 100 times higher than the nocturnal physiological peak, returning baseline levels in 4-8 hours. Melatonin is rapidly metabolized after intravenous or oral administration, mostly in the liver and secondly in the kidney (21).
Side Effects of Melatonin
- As seen in both animal and human research, melatonin’s acute toxicity is very low. At supraphysiological levels, melatonin might result in modest adverse pharmacological responses such as headaches, sleeplessness, rash, gastritis, and nightmares (1).
Most often reported adverse effects are linked to tiredness, mood, or psychomotor and neurocognitive function. These are typically minor, transient, and manageable. Supplement use may also have adverse effects that develop into habits and cause reliance. Melatonin’s short-term effects prompt us to think about the negative long-term repercussions of consuming melatonin supplements (22).
- A few studies reported unfavorable endocrine (such as reproductive health parameters and glucose metabolism) and cardiovascular (such as blood pressure and heart rate) outcomes that may be modified by dosage, the timing of doses, and possible interactions with antihypertensive medications (23).
- According to preliminary data, long-term melatonin use is linked to worse semen quality in a number of healthy men, most likely due to aromatase suppression at the testicular level (24).
- Exogenous melatonin should not be used during pregnancy, nevertheless, as there aren’t any human studies to back up its therapeutic effects or danger of side effects.
Anxiety, exhaustion, mood changes, nightmares, rashes on the skin, and palpitations. The majority of AEs are self-resolving. With a few exceptions, oral melatonin supplementation in humans has a generally favorable safety profile.
- Dosing in line with natural circadian rhythms is probably an easy way to avoid or mitigate the majority of negative effects.
- Melatonin dosages are to be started off low, and then they should be gradually increased as the body becomes used to them. This will enable the user to slumber without experiencing any negative side effects and will let the body become used to the supplement. The body retains melatonin for roughly 5 hours after ingesting it, but taking too much of it can alter the circadian cycle. This can cause daytime sleepiness by interfering with the circadian cycle.
- When a circadian rhythm with a basal zero level throughout the day needs to be preserved for a physiological function, a prolonged exposure to melatonin may also imitate an “artificial darkness” situation in which the body assumes a night circadian rhythm even when there is day time (26).
- For individuals with certain autoimmune illnesses, such as rheumatoid arthritis, or those who have undergone organ transplantation, doctors should use this medication carefully since inflammation flares are liable to change throughout the day (1).
- Clinicians need to be cautious when treating individuals whose livers aren’t working well since they can’t metabolize melatonin as well. Nevertheless, experts came to the conclusion that melatonin did not result in hepatotoxicity based on a number of clinical experiments (26).
- Melatonin, being a tiny amphiphilic molecule, passes into breast milk and may have unfavorable effects on nursing infants, such as drowsiness and daytime sleepiness (27).
- Clinicians should use caution while treating dialysis patients due to the potential of worsened side effects from the inability to remove melatonin sufficiently (26).