Melatonin: Benefits, Side Effects, and Research

Melatonin is mostly known for its crucial role in sleep-wake cycle regulation, but it is a versatile molecule that exhibits potent antioxidant, anti-inflammatory, anti-cancer, and immunomodulatory functions. It also has potential anti-aging properties.

What is melatonin?

Melatonin (5-methoxy-N-acetyltryptamine) is an indolamine, which was discovered in 1958 as a result of a search for an amphibian skin color-lightening agent [1]. Aaron Lerner and his colleagues isolated melatonin from the bovine pineal gland and showed that the molecule prevents frog skin darkening by inhibiting melanocyte-stimulating hormone.

It was eventually demonstrated that melatonin is the main hormone that regulates circadian rhythms in humans. Its synthesis is inhibited by light and enhanced by darkness peaking in the middle of the night. The secretion of melatonin from the pineal gland is regulated by a central pacemaker located in the hypothalamus. Once this pacemaker receives a signal of dim light, melatonin is released from the pineal gland and into the circulatory system [2].

The starting molecule for melatonin is the amino acid tryptophan, which, via a series of enzymatic reactions, is first converted into serotonin and, finally, into melatonin. Although initially discovered in the pineal gland, where the enzymes required for melatonin conversion from serotonin are mostly found, melatonin is present in many tissues and is synthesized in the mitochondria of, likely, all cells [3].

Melatonin is thought to have originated as an antioxidant in bacteria, which was eventually phagocytosed by primitive eukaryotes and evolved into mitochondria [4]. Therefore, it is not surprisingly that various animal and plant foods contain melatonin, which functions primarily as a free radical scavenger.

Sources of melatonin

Melatonin-rich foods can be regarded as promising nutriceuticals (“nutrition” + “pharmaceuticals”) that act as antioxidants in people. Plant foods are generally richer in melatonin than animal foods. Nuts, seeds, and Chinese medicinal herbs contain particularly high concentrations of melatonin, although the amount varies not only among species but even within the same species, depending on environmental factors [5].

In addition, melatonin supplements of various concentration and formulations are easily available on the market. As with other supplements, however, due to the lack of strict manufacturing regulations, the amount claimed on the label often deviates significantly from the actual amount present [6].

Therapeutic uses of melatonin

Sleep disorders

Most clinical applications of melatonin have been explored in circadian misalignments and sleep disorders, in which the molecule is used as a “chronobiotic agent”. Although there are conflicting data on how effective melatonin supplementation is for jet lag, most studies report reduced severity and alleviated fatigue following melatonin intake [7].

Studies have also shown that melatonin improves sleep quality in people not only with primary sleep disorders, such as insomnia and delayed or advanced sleep phase disorder, but also people suffering from respiratory diseases, metabolic disorders, and blindness [8, 9]. However, each of these disorders requires individual adjustments of dosage and different durations and times of administration.

Whether melatonin is effective at managing sleep disturbances caused by lifestyle choices is not clear. Night shift work was shown to inhibit melatonin production [10]. However, the results of melatonin supplementation studies in shift workers are inconclusive [7].

Neurodegeneration

The beneficial effect of melatonin observed in various chronic diseases, including neurodegenerative disorders, is likely not just due to its function as a sleep regulator but also its antioxidant effect.

The two are intimately intertwined: sleep is a state characterized by increased antioxidant activity [11], which is particularly important for nervous tissue, where elevated oxidative stress is common.

People with chronic neurodegenerative diseases often have a high degree of oxidative stress and numerous sleep disturbances, such as difficulty falling asleep, awakenings during the night, and sleepiness during the day.

The causative relationship between oxidative stress and poor sleep quality is not clear. Nevertheless, melatonin supplementation was shown to improve sleep by reducing oxidative stress in patients with multiple sclerosis [12].

It was also shown to reduce oxidative damage in a pilot study in patients suffering from hereditary neuropathy, which is characterized by poor sleep quality, although its effect on sleep was not assessed in this study [13].

Melatonin might be effective in fighting sleep disturbances associated with such age-related diseases as Parkinson’s and Alzheimer’s [2, 14]. The mechanism is unknown, but Alzheimer’s disease is characterized by both decreased melatonin levels [15] and increased oxidative stress, which can be alleviated by melatonin supplementation, at least in mice [16].

On the molecular level, in addition to scavenging reactive oxygen species and stimulating antioxidant enzymes such as superoxide dismutase (SOD2) via regulating sirtuin 3 (SIRT3), melatonin supports mitochondrial fusion and biogenesis while decreasing mitochondrial fission, i.e. degradation [3].

Moreover, melatonin augments the transfer of healthy mitochondria from intact neurons to damaged neurons, thereby rehabilitating the latter [17]. It was shown that melatonin exhibits a neuroprotective role in stroke models by improving neuronal survival [18].

In addition, the expression of melatonin receptors in neural stem cells suggests an important role of melatonin in neurodevelopment. Numerous melatonin receptors are expressed in various human tissues, including the vasculature.

Cardiovascular diseases

Interestingly, in the vascular system, melatonin can act either as a vasoconstrictor or vasodilator by activating M1 and M2 melatonin-specific receptors, respectively [19]. At the same time, the antioxidative effect of melatonin is receptor-independent and is believed to at least partly explain its benefits for cardiovascular health.

Overall, melatonin was shown to decrease nocturnal blood pressure not only in people with hypertension but also in healthy people, albeit in several small-sized studies [19].

Numerous animal studies demonstrated the heart-protective effect of melatonin following ischemic reperfusion injury, i.e. when the blood flow is restored following a lack of oxygen supply [20].

In addition, in vitro and in vivo studies show that melatonin is able to prevent the progression of atherosclerosis via several mechanisms by reducing oxidative stress and inflammation. For example, melatonin reduces the levels of oxidized low-density lipoprotein (LDL) [21].

Human trials confirming this effect are, however, absent. In fact, a study conducted in menopausal women to assess the effect of melatonin on lipid levels did not show any difference between the experimental and control groups [22].

Importantly, people with coronary heart disease and congestive heart failure demonstrate reduced serum melatonin levels [19], suggesting that melatonin supplementation might be beneficial in these groups.

Another potentially beneficial effect of melatonin is the inhibition of platelet aggregation, which makes it a promising anticoagulant agent particularly in light of the COVID-19 pandemic [23]. Indeed, melatonin supplementation reduces thrombosis and improves recovery in COVID-19 patients [24, 25].

Immunomodulatory function and cancer

The anti-inflammatory properties of melatonin could also contribute to its success in helping fight infectious diseases. In general, the regulation of immunity by melatonin is complex: the molecule acts via multiple pathways affecting different immune cells, such as lymphocytes and macrophages, in a context-specific manner [26].

The ability of melatonin to stimulate natural killer cells and T lymphocytes makes it a promising anti-cancer agent. Moreover, melatonin was shown to augment apoptosis of cancer cells by inhibiting the mTOR pathway and suppressing the transcription factor NF-κB [27].

Immune system modulation to fight cancer is an actively researched approach. Studies show that melatonin might prime the immune system to actively respond against cancer cells.

Clinical trials suggest that melatonin can augment the effect of chemotherapy and radiotherapy for various types of cancer [28, 29]. A recent study in women with breast cancer showed that topical melatonin application is effective against skin burns following radiation [30].

Skin and intervertebral disc rejuvenation

Similar to other antioxidants such as vitamin C and vitamin E, melatonin is considered a potent skin protectant. Indeed, a melatonin-based cream was shown to reduce the signs of skin aging in a study conducted on fifteen women aged over 45 years [31].

In addition, melatonin is capable of inhibiting extracellular matrix (ECM) degradation by stimulating autophagy and reducing oxidative stress and inflammation [32]. ECM remodeling is a major driver of skin aging and age-associated intervertebral disc degeneration.

Anti-aging gold mine? 

Given that pineal melatonin production is reduced not only in disorders but also in the elderly [33], is melatonin-replacement therapy a viable approach to slowing down aging?

Mounting data suggest that melatonin is involved in regulating several hallmarks of aging, including mitochondrial dysfunction, genomic instability, telomere attrition, disabled macroautophagy, and chronic inflammation. From this point of view, melatonin could be considered a true anti-aging molecule capable of retarding aging [34].

However, conclusions about the effect of melatonin supplementation mostly come from studies in cell cultures and animal models. Meanwhile, clinical trials are sparse, mostly restricted to people with a specific disease, and often fail to show impressive results.

Several model organisms, including rats and mice, are nocturnal, therefore, the question arises: is it even reasonable to make conclusions about melatonin effects in humans based on rodent data?

Research shows that the overall effect of melatonin is the same regardless of the animal’s daily cycle and determines such biological events as insulin sensitivity/resistance, regulation of blood pressure and temperature, and energy expenditure [9]. Circadian rhythm regulation is still only half of the functions of melatonin.

Safety profile

Melatonin supplementation is generally safe and well-tolerated even at high doses (10 mg to 400 mg). At the same time, a systematic review and meta-analysis published in 2021 found that melatonin increases the likelihood of adverse events when the dosage exceeds 10 mg [35]. Among the reported side effects are tiredness, drowsiness, and headaches.

Conclusion

Melatonin demonstrates multiple beneficial effects by regulating a plethora of molecular processes in various cells. However, most of these effects were shown in vitro or in animals. Clinical trials with positive outcomes following melatonin supplementation are mostly limited to specific pathological conditions, often when it’s used as an adjuvant. Nevertheless, if given in the right physiological context, melatonin could be considered a promising anti-aging compound that is generally safe even at high dosages.

Disclaimer

This article is only a very brief summary, is not intended as an exhaustive guide, and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

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