Melatonin from Plants: Going Beyond Traditional Central Nervous System Targeting – A Comprehensive Review of its Unusual Health Benefits

1. Introduction

Adaptive responses and vegetable growth under stress conditions are regulated by several complex networks of molecules, such as hormones. Melatonin (N-acetyl-5-methoxytryptamine) is included in this group and has a key role in controlling and relieving abiotic stress in tuning with other plant hormones [1,2]. This indoleamine was primarily identified for its several roles in animals but, recently, has been described as an influent and potent regulator of several physiologic pathways in plant and human biology [3,4,5,6].

In plants, it has a vital role in modulating several aspects of plant growth and development. These actions may include the regulation of photoperiodic responses and circadian rhythms. Notwithstanding, it also can contribute to antioxidant and stress resistance in plants. It is produced by many food plants such as olive oil, pistachio, strawberry, cherry, mango, grape, banana, pineapple, orange, papaya, tomato, almonds, hazelnuts, and walnuts, but the amount can vary greatly [7,8,9,10,11,12].

In humans, melatonin is produced mainly by the pineal gland and has a crucial role in the sleep-wake cycle. However, it can be produced by the skin, retina, lymphocytes, gastrointestinal tract, and bone marrow [13,14,15,16,17]. Furthermore, melatonin is essential in homeostasis in the human body, particularly in adulthood. It has a critical role in promoting adaptation through allostasis. As a natural substance, it can be obtained in the diet or utilized as a supplement and therapeutic agent, offering the above-mentioned health benefits [18,19,20,21,22,23].

A melatonin-rich diet is related to several health benefits such as regulation of the circadian rhythm, cardiovascular protection, regulation of the immunological system, epilepsy control, reducing allergic reactions, delaying the aging process, diminishing hormones related to cancer, delaying Alzheimer’s and Parkinson’s disease symptoms, working as an antioxidant and anti-inflammatory molecule [13,14,15,16,17,22,24,25,26,27,28]. This hormone's anti-inflammatory and antioxidant effects contribute much to preventing or treating the cited conditions. Melatonin presents scavenger properties, though it can remove Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS), inhibiting the actions of nuclear factor kappa B (NFκB) and myeloperoxidases pathways. The downregulation in the expression of pro-inflammatory genes reduces the release of interleukin (IL)-1β, IL-6, Tumor Necrosis Factor-α (TNF-α), and many other inflammatory molecules. It can also be associated with the production and activation of the apoptosis-related speck-like protein. Due to the up-regulation in monocyte synthesis, proliferation, and maturation of T and B lymphocytes, melatonin also improves the immune response [23,29,30,31,32]. Figure 1 shows the main effects of melatonin.

Many clinical studies have shown that melatonin can work as an adjuvant therapeutic or an option to prevent and treat several human diseases, such as Alzheimer’s disease [33,34,35], Parkinson’s disease [36], non-alcoholic fatty liver disease [35,37,38], rheumatoid arthritis [39,40,41], multiple sclerosis [42], polycystic ovary syndrome [43,44], dermatitis [45,46], COVID-19 [47], and sepsis [48]. Figure 1 shows the effects of melatonin in humans.

Since melatonin has been extensively studied in sleep-related disorders and other neurodegenerative diseases, this comprehensive review aims to draw on clinical trials to show the effects of this hormone beyond its commonly observed purposes.

2. Summary of Melatonin Biosynthesis in Plants

Melatonin is a hormone described much in mammals, amphibians, and birds. In the synthesis pathways, tryptophan (Trp) results in melatonin [2,49,50,51,52]. Trp is converted into tryptamine through the shikimic acid pathway, mainly by chloroplasts by the enzyme tryptophan decarboxylase (TDC). A similar path is mediated by tryptophan hydroxylase (TPH) to transform tryptophan into 5-hydroxytryptophan. These two enzymes are essential for synthesizing melatonin in vegetables [7,17,53]. Tryptamine and 5-hydroxytryptophan are transformed into serotonin by the enzyme tryptamine 5-hydroxylase and TDC, respectively. On the other hand, serotonin goes through other conversions by different enzymes depending on its location. In the cytoplasm, serotonin is converted into N-acetylserotonin through serotonin N-acetyltransferase (SNAT), which is methylated by N-acetylserotonin methyltransferase (ASMT) to produce 5-methoxy tryptamine. Another possible path for serotonin in the chloroplast is methylation by caffeic acid O-methyltransferase (COMT) to the conversion in N-acetylserotonin, which also undergoes methylation to generate melatonin. Plant melatonin production may involve several complex enzymatic pathways in different transformation routes depending on environmental conditions and organelle [7,54,55,56].

Mitochondria can also produce melatonin using a skmilar pathway. In summary, Trp can be transformed into N-acetyltryptamine and N-acetylserotonin. This compound can finally be converted to serotonin. Alternatively, Trp can produce serotonin that is further converted to melatonin. The contribution of mitochondria to the production of melatonin seems to be increased under stress conditions, and depending on the environment, the contribution of this organelle and chloroplast may change [17]. Figure 2 summarizes the biosynthesis of melatonin in chloroplasts and mitochondria.

The production and accumulation of melatonin amounts can vary widely among different plant parts and plant species. It was first described in grapes and after in olive oil. Depending on the plant, its highest levels are in the seed, skin, leaves, roots, grain, flower buds (embryonic stage of flowers), and ripe fruits [7,54,57,58,59,60]. Table 1 shows some examples of plants and their respective amounts of this hormone.

As pointed out above, melatonin can improve or prevent several human conditions (Figure 3). In the next Fs, we discuss the role of melatonin in unusual diseases.

3. Melatonin in Cardiovascular Diseases and MAFLD

Cardiovascular diseases (CVD) are considered the main cause of death on the globe. They are related to several conditions, such as obesity, diabetes, hypertension, metabolic syndrome, and liver disease (such as Metabolic-Associated Fat Liver Disease - MAFLD) [69,70,71,72,73,74]. Some studies have shown that melatonin can be used to shortten the effects of risk factors for CVD and MAFLD [24,74,75]. Table 2 shows clinical studies involving melatonin and the diseases mentioned above.

AMI, Acute Myocardial Infarction; CTnI, Cardiac Troponina-I; FMD, flow-mediated dilatation; IL-1β, interleucina-1beta; iNOS, inducible nitric oxide synthase; MAFLD, Metabolic Associated Fat Liver Disease; NIHSS, National Institute of Health Stroke Scale; mRS, modified Rankin Scale score; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NT-Pro BNP: N-Terminal Pro–B-Type Natriuretic Peptide ↓: reduction.In a randomized study, some authors [76] investigated the effects of melatonin on the circadian cycle and social and environmental factors. Their results showed that rotating night-shift work results in moderate sleep quality impairment and insulin resistance. Melatonin improved sleep quality but did not significantly interfere with insulin resistance in these workers.

Based on the knowledge that using melatonin affects blood pressure regulation, Ramos et al. [77] investigated the effects of this hormone in subjects receiving a high-sodium diet for 10 days. Their results showed that melatonin can be beneficial in reducing blood pressure in young, healthy, normotensive adults.

Mehrpooya et al. [78] conducted a double-blind, placebo-controlled study in patients diagnosed with acute ischemic stroke and not eligible for reperfusion therapy to assess the possible benefits of melatonin supplementation over traditional treatment for these patients. 65 patients were divided between placebo and melatonin (20mg/day for 5 days) groups. After melatonin supplementation, patients were evaluated 5, 30, and 90 days later. The results showed a mean reduction in the National Institute of Health Stroke Scale and modified Rankin Scale score. However, there was no significant difference in the functional independence criteria.

Hoseini et al. [79] performed a randomized, double-blind, placebo-controlled clinical to evaluate the role of melatonin supplementation in heart failure patients with reduced ejection fraction. 92 patients were randomized between placebo and melatonin groups. The melatonin group received 10 mg of melatonin orally once daily for 24 weeks. After the intervention, there was a reduction in NT-Pro BNP >>> N-Terminal Pro–B-Type Natriuretic Peptide (NT-Pro BNP) levels, accompanied by an improvement in the quality of life measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ). However, there were no significant changes in echocardiographic parameters.

Hoseini et al. [80] investigated the role of melatonin intake on endothelial function in subjects with heart failure and dcreased ejection fraction through a randomized, double-blind, placebo-controlled clinical trial. 92 patients received either placebo or 10mg/day of melatonin for 24 weeks. After treatment, there was a significant increase in flow-mediated dilatation (FMD); however, there were no changes in blood pressure, total antioxidant capacity, and MDA levels.

Dwaich et al. [81] analyzed the effect of different dosages of melatonin in patients undergoing coronary artery bypass grafting through a double-blind, placebo-controlled study. 45 patients were allocated into three groups according to the treatment employed: placebo group, melatonin 10mg/day treatment group, and melatonin 20mg/day treatment group from the fifth day before surgery. The results indicated that the individuals treated with melatonin showed an increase in the ejection fraction associated with a reduction in heart rate and a reduction in the levels of cardiac enzymes such as CtnI (Cardiac Troponina-I), IL-1β, inducible nitric oxide synthase (iNOS), and caspase-3. These changes were most prominent in the group treated with 20 mg of melatonin daily.

Dominguez-Rodriguez et al. [82] investigated the role of intravenous melatonin administration in reducing cardiac damage in patients who presented within 6 hours Acute Myocardial Infarction (AMI) symptoms through a phase 2, single-center, prospective, randomized, double-blind, placebo-controlled study, 272 patients were randomized to receive placebo or intravenous melatonin 11.61 mg 30 min before percutaneous revascularization and remaining doses for the subsequent 120 min. Surviving patients were evaluated 90 days after the intervention, and it was possible to observe a reduction in cardiac damage and improvement in clinical criteria in patients in the melatonin-treated group.

Regarding MAFLD, Bahrarni et al. [75] conducted a randomized, double-blind, placebo-controlled clinical trial to investigate the action of melatonin supplementation in patients diagnosed with this liver disease. 45 patients were randomized to receive placebo or 6mg of melatonin orally once daily for 12 weeks. After treatment, there was a significant improvement in anthropometric parameters such as weight and waist circumference, in addition to a reduction in blood pressure, a reduction in serum levels of leptin and alanine aminotransferase, and a decrease in the degree of liver fat in the group treated with melatonin.

According to some authors, melatonin has some effects that produce a unique therapeutic adjuvant for treating cardiovascular conditions, such as regulation of circadian rhythms (adaption for internal and external environmental changes), works as an anti-inflammatory, antioxidant (free radical scavenger), protecting cells from oxidative damage. These effects permit the integrity of endothelial cells, preventing atherosclerosis, which is considered a major contributor to CVD. Moreover, melatonin properties potentially reduce CVD risk factors, ameliorating metabolic disorders [74,83,84].

4. Effects of Melatonin on Rheumatoid Arthritis

Besides the many effects of melatonin in the human body, some authors have also Besides the many effects of melatonin in the human body, some authors have also demonstrated that it can benefit bone and cartilage-related disorders such as osteoarthritis, rheumatoid arthritis, and bone fracture healing [85,86,87]. The effects of melatonin in reducing oxidative stress (reducing ROS and malonaldehyde) and inflammation (reducing he release of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α), is important in the improvement of rheumatoid arthritis since it is characterized by an autoimmune, chronic systemic connective tissue disease, resulting in joint inflammation and systemic complications like pain, restriction of movements, and significant reduction in the quality of life [85,88,89,90,91].

This hormone can regulate the relationship between inflammation and myogenesis in rheumatoid arthritis synovial fibroblasts and myoblasts. Furthermore, it can regulate pro-inflammation and atrophy in differentiated myocytes and myoblasts by interfering in the NFκB signaling route. The oral administration of melatonin in a mouse collagen-induced arthritis model showed significant improvement in hind limb grip strength, arthritic swelling, and pathological muscle atrophy [85,91,92]. Although melatonin has potential effects in rheumatoid arthritis, only two clinical trials were performed to evaluate its effects on this inflammatory condition. Table 3 shows clinical trials investigating this hormone's effects on rheumatoid arthritis.

5. Effects of Melatonin on Polycystic Ovary Syndrome (PCOS)

Polycystic ovaries syndrome (PCOS) is one of the most common endocrine conditions in reproductive-age women. It is marked by ano or oligo-ovulation, polycystic ovarian morphology, and signs of hyperandrogenism. The main symptoms include infertility, menstrual irregularities, and hirsutism. PCOS can also be linked to insulin resistance/diabetes, obesity, and metabolic syndrome. For these reasons, it is also associated with CVD. Anxiety and reduction in the quality of life are also reported [93,94,95].

Many researchers have investigated the effects of melatonin in PCOS and showed that the benefits include improving metabolic risk parameters. Melatonin receptors are found in ovarian granulosa cells, and minor modifications in these receptor genes are linked to a higher risk of PCOS in sporadic cases or familial origin [96,97]. Some interesting studies have shown the effects of melatonin supplementation in women with PCOS. The results are shown below and are summarized in Table 4.

Mousavi et al. [98] performed an investigation to evaluate the role of melatonin and magnesium supplementation in the amounts of inflammatory markers and oxidative stress in women with POS. 84 women were randomized into 4 different groups according to the treatment used: placebo, melatonin (2 tablets of 3mg each), magnesium oxide (tablet of 250mg), or melatonin+magnesium oxide (2 tablets of 3mg of melatonin each+tablet of 250 mg magnesium oxide) for 8 weeks. After treatment, there was a reduction in weight, body mass index, waist circumference, and TNF-α in the group treated with melatonin+magnesium oxide and melatonin alone, a reduction in hirsutism, and an increase in total antioxidant capacity (TAC) in the group treated with melatonin+oxide of magnesium only [94].

In a double-blind, randomized, placebo-controlled clinical trial, Shabani et al. [99] investigated the effects of melatonin intake on mental health parameters and metabolic and genetic profiles in women with POS. 58 women were randomized between the placebo and melatonin groups (2 capsules of 5mg of melatonin each day), with intervention during 12 weeks. After treatment, melatonin-treated women had better PSQI (Pittsburgh Sleep Quality Index), Beck Depression Inventory index (BDI), and Beck Anxiety Inventory index (BAI) scores compared to the placebo group. In addition, melatonin treatment promoted a reduction in serum insulin and LDL-c levels, a reduction in Homeostasis model assessment of insulin resistance (HOMA-IR), and an increase in PPAR-γ (Peroxisome proliferator-activated receptor gamma) and LDL-receptor gene expression.

Pacchiarotti et al. [100] evaluated the role of co-supplementation with melatonin and myo-inositol in optimizing in vitro fertilization in women with POS through a clinical trial, randomized, double-blind, and controlled by placebo. 526 patients were randomized into three groups according to treatment: control (folic acid: 400 mcg) group A (myo-inositol: 4000 mg, folic acid: 400 mcg and melatonin: 3 mg) and group B (myo-inositol: 4000 mg and folic acid: 400 mcg). Treatment occurred from the first day of the cycle to 14 days after embryo transfer. After the intervention, the quality of the oocyte and the embryo was improved with melatonin+myo-inositol co-supplementation.

Table 4. Effects of melatonin in polycystic ovary syndrome patients (PCOS).

References	Study	Population	Intervention	Duration	Outcomes
[101]	Randomized, double-blind, placebo-controlled clinical trial	84 women with polycystic ovary syndrome were randomized into 4 groups: placebo group (26,200 ± 5.72y, 20♀), melatonin+magnesium group (28.22 ± 6.38y, 22♀), melatonin group (25.57 ± 4.99y, 21♀) and magnesium group (25.57 ± 4.88y, 21♀)	2 tablets a day of 3 mg melatonin each + 250-mg magnesium oxide tablet	8 weeks	↓Weight, BMI, WC in the melatonin and melatonin+magnesium groups. ↓TNF-α in the melatonin and melatonin+magnesium groups. ↓Hirsutism in the melatonin+magnesium group. ↑TAC in the melatonin+magnesium group
[102]	Randomized, double-blinded, placebo-controlled clinical trial (Iran)	58 patients with polycystic ovary syndrome were randomized into 2 groups: placebo (26.0±3.3y, 29♀) or melatonin (26.5±3.5y, 29 ♀)	2 capsules of 5mg of melatonin each a day	12 weeks	↓PSQI, BDI index, BAI index, serum insulin, HOMA-IR, LDL-c in the melatonin group. ↑PPAR-γ and LDL Receptor gene expression in the melatonin group
[103]	Randomized, controlled, double-blind trial (Italy)	526 women with PCOS were randomized into 3 groups: control group (32 ± 3.6y, 195♀), group A (31.2 ± 2.1y, 165♀), and group B (31.5 ± 2.8y, 166♀)	3 mg of melatonin + 4000 mg myo-inositol + 400 mcg folic acid daily	From the first day of the cycle to 14 days after embryo transfer	↑Oocyte and embryo quality with melatonin+myo-inositol supplementation

BAI, Beck Anxiety Inventory; Beck Depression Inventory index (BDI); BMI: Body mass index; HOMA: Homeostasis model assessment of insulin resistance; LDL-c: Low-density lipoprotein; PPARγ: Peroxisome proliferator-activated receptor gamma; PSQI: Pittsburgh Sleep Quality Index; TAC, total antioxidant capacity; TNF-α: Tumor Necrosis Factor-α; WC: waist circumference.

Table 4. Effects of melatonin in polycystic ovary syndrome patients (PCOS).

References	Study	Population	Intervention	Duration	Outcomes
[101]	Randomized, double-blind, placebo-controlled clinical trial	84 women with polycystic ovary syndrome were randomized into 4 groups: placebo group (26,200 ± 5.72y, 20♀), melatonin+magnesium group (28.22 ± 6.38y, 22♀), melatonin group (25.57 ± 4.99y, 21♀) and magnesium group (25.57 ± 4.88y, 21♀)	2 tablets a day of 3 mg melatonin each + 250-mg magnesium oxide tablet	8 weeks	↓Weight, BMI, WC in the melatonin and melatonin+magnesium groups. ↓TNF-α in the melatonin and melatonin+magnesium groups. ↓Hirsutism in the melatonin+magnesium group. ↑TAC in the melatonin+magnesium group
[102]	Randomized, double-blinded, placebo-controlled clinical trial (Iran)	58 patients with polycystic ovary syndrome were randomized into 2 groups: placebo (26.0±3.3y, 29♀) or melatonin (26.5±3.5y, 29 ♀)	2 capsules of 5mg of melatonin each a day	12 weeks	↓PSQI, BDI index, BAI index, serum insulin, HOMA-IR, LDL-c in the melatonin group. ↑PPAR-γ and LDL Receptor gene expression in the melatonin group
[103]	Randomized, controlled, double-blind trial (Italy)	526 women with PCOS were randomized into 3 groups: control group (32 ± 3.6y, 195♀), group A (31.2 ± 2.1y, 165♀), and group B (31.5 ± 2.8y, 166♀)	3 mg of melatonin + 4000 mg myo-inositol + 400 mcg folic acid daily	From the first day of the cycle to 14 days after embryo transfer	↑Oocyte and embryo quality with melatonin+myo-inositol supplementation

BAI, Beck Anxiety Inventory; Beck Depression Inventory index (BDI); BMI: Body mass index; HOMA: Homeostasis model assessment of insulin resistance; LDL-c: Low-density lipoprotein; PPARγ: Peroxisome proliferator-activated receptor gamma; PSQI: Pittsburgh Sleep Quality Index; TAC, total antioxidant capacity; TNF-α: Tumor Necrosis Factor-α; WC: waist circumference.

6. Effects of Melatonin on Dermatitis

Atopic dermatitis can be described as a chronic inflammatory skin condition with a multifactorial origin. The regular symptoms are itching and lesions. The treatment for this condition can include immunosuppressive agents, steroids, and biological therapies [46,101]. Melatonin has been considered to treat atopic dermatitis as well as dermatitis provoked by irradiation, as shown by the below studies (Table 5).

Zetner et al. [102] investigated the role of topical application of melatonin in improving the quality of life in patients with primary breast cancer undergoing radiotherapy through a randomized, double-blind, placebo-controlled clinical trial. 48 patients were randomized between placebo and melatonin groups. The melatonin group was treated with 1g of cream containing 25mg/g of melatonin twice a day on the skin area irradiated during radiotherapy. After treatment, there was no significant improvement in patients' quality of life treated with melatonin-containing cream compared to placebo cream. However, there was a reduction in breast symptom scores in patients in the melatonin group.

In a randomized, double-blind, placebo-controlled study with children and diagnosed with atopic dermatitis, Taghavi et al. [103] analyzed the effects of melatonin supplementation on the sleep quality of these patients. 70 patients were randomized between the placebo and melatonin groups who received 2 pills containing 3mg of melatonin each day for 6 weeks. After treatment, the melatonin group tended to improve sleep onset latency and total sleep time. Still, there was no statistically significant difference in pruritus, weight, and C Reactive Protein (CRP) scores.

In a randomized, double-blind, placebo-controlled clinical trial, Chang et al. [104] investigated the impact of melatonin supplementation in children with atopic dermatitis. Forty-eight patients were assigned randomly to either the placebo group or the melatonin group, where the latter received oral melatonin at a dose of 3mg per day for a duration of 4 weeks. Following the intervention, the melatonin group exhibited improved SCORAD scores and a reduction in sleep onset latency.

Table 5. Effects of melatonin in dermatitis.

References	Study	Population	Intervention	Duration	Outcomes
[105]	Randomized, double-blind, controlled, clinical trial (Denmark)	48 patients diagnosed with breast cancer undergoing radiotherapy were randomized between the groups: placebo (64± 10y, 22♀) and melatonin group (62± 9y, 26♀)	Application of 1g of cream containing 25 mg/g of melatonin twice a day on the irradiated area of the skin during radiotherapy	from the first day of radiation to the last fraction of radiation	There was no significant difference in quality of life between groups after treatment. ↓BS score in the melatonin group
[106]	Randomized, double-blinded, placebo-controlled trial (Iran)	70 children diagnosed with atopic dermatitis were randomized between the groups: placebo (8.4±2.2y, 17♀ and 18♂) and melatonin (8.9±2.1y, 19♀ and 16♂)	Supplementation with 2 tablets of 3mg of melatonin a day	6 weeks	↓ sleep latency, ↑total sleep time in the melatonin group. There was no significant difference in pruritus, CRP, weight and BMI scores
[107]	Randomized clinical trial used a double-blind, placebo-controlled	48 pacientes com dermatite atópica foram randomizados em dois grupos: placebo (7.3±3.5y, 10♀ e 14♂) e melatonina (13± 54y, 13♀ e 11♂)	3mg/dia de melatonina oralmente	4 weeks	↓ SCORAD index; ↓ sleep latency in the melatonin-treated group
[108]	Phase II, prospective, randomized, double-blind, placebo-controlled study	47 patients undergoing conservative surgery for breast cancer were randomized between the groups: placebo (55y, 21♀) and melatonin (54y, 26♀)	Cream containing 50g melatonin, applied on the irradiated breast twice a day	5 weeks	↓ presence of dermatitis in the group treated with melatonin

CRP: C-reactive protein; BS: breast symptom; SCORAD: Scoring Atopic Dermatitis; ↓: reduction; ↑: increase.

Table 5. Effects of melatonin in dermatitis.

References	Study	Population	Intervention	Duration	Outcomes
[105]	Randomized, double-blind, controlled, clinical trial (Denmark)	48 patients diagnosed with breast cancer undergoing radiotherapy were randomized between the groups: placebo (64± 10y, 22♀) and melatonin group (62± 9y, 26♀)	Application of 1g of cream containing 25 mg/g of melatonin twice a day on the irradiated area of the skin during radiotherapy	from the first day of radiation to the last fraction of radiation	There was no significant difference in quality of life between groups after treatment. ↓BS score in the melatonin group
[106]	Randomized, double-blinded, placebo-controlled trial (Iran)	70 children diagnosed with atopic dermatitis were randomized between the groups: placebo (8.4±2.2y, 17♀ and 18♂) and melatonin (8.9±2.1y, 19♀ and 16♂)	Supplementation with 2 tablets of 3mg of melatonin a day	6 weeks	↓ sleep latency, ↑total sleep time in the melatonin group. There was no significant difference in pruritus, CRP, weight and BMI scores
[107]	Randomized clinical trial used a double-blind, placebo-controlled	48 pacientes com dermatite atópica foram randomizados em dois grupos: placebo (7.3±3.5y, 10♀ e 14♂) e melatonina (13± 54y, 13♀ e 11♂)	3mg/dia de melatonina oralmente	4 weeks	↓ SCORAD index; ↓ sleep latency in the melatonin-treated group
[108]	Phase II, prospective, randomized, double-blind, placebo-controlled study	47 patients undergoing conservative surgery for breast cancer were randomized between the groups: placebo (55y, 21♀) and melatonin (54y, 26♀)	Cream containing 50g melatonin, applied on the irradiated breast twice a day	5 weeks	↓ presence of dermatitis in the group treated with melatonin

CRP: C-reactive protein; BS: breast symptom; SCORAD: Scoring Atopic Dermatitis; ↓: reduction; ↑: increase.

Ben-David et al. [105] investigated the effects of creams containing melatonin against radiation-induced dermatitis in patients diagnosed with breast cancer through a phase II, randomized, double-blind, placebo-controlled study. 47 women were randomized to receive placebo cream or melatonin-containing cream twice daily for 5 weeks during radiotherapy treatment. After treatment, it was observed that patients treated with melatonin showed fewer signs of dermatitis compared to those treated with placebo.

7. Effects of Melatonin on Sepsis

Sepsis can be identified as an overpowering host's inflammatory response to infection. This inflammatory cascade induces multi-organ dysfunction syndrome and may cause death. It can be separated into phases, and in the first, macrophage and leukocyte stimulation with subsequent cytokine production is observed, leading to ROS and RNS production and consequent oxidative stress. This last condition leads to endothelial dysfunction and oxidative damage that reaches cells and organs. There is no specific treatment to control sepsis and the inflammation storm, oxidative stress that lead to multi-organ failure and death [106,107,108,109].

In a trial, the researchers investigated the use of melatonin in sepsis patients. After the 5-day treatment, they observed a reduction in hospital stay (reduction of 19.60%) compared to placebo). In the placebo group, there were five deaths, and three were in the melatonin group. They concluded that the use of this hormone improved (without side effects) the course of the disease in surgical patients with severe sepsis [106].

Taher et al., [110] conducted another prospective, double-blind, randomized study, evaluated the benefit of melatonin in patients with early septic shock. Forty patients were randomized to receive a placebo or 50mg of melatonin in a liquid solution for 5 consecutive nights. Study results showed that patients receiving melatonin required significantly lower doses of vasopressors compared to patients receiving placebo. In addition, the melatonin-treated group had fewer deaths, lower SOFA scores, improved severity of organ dysfunction, reduced need for invasive ventilatory therapy and renal replacement therapy, although without statistically significant difference.

Galley et al. [111] evaluated the pharmacokinetics of two different doses of melatonin in sepsis patients due to community-acquired pneumonia through a cohort study. Ten eligible patients were divided into two cohorts according to the dose of melatonin in liquid solution administered: cohort 1 (50mg oral melatonin single dose) and cohort 2 (20mg oral melatonin single dose). After the intervention, a higher maximum concentration of serum melatonin was observed in the group treated with 50mg and a similar maximum concentration of 6-OHMS between the two groups, indicating that the 20mg dose seems to be more adequate for the administration of melatonin in liquid solution.

Aisa-Alvarez et al [112] investigated the role of melatonin and other antioxidant agents as adjuvant therapy in patients with a septic shock through a randomized, controlled, triple-blind clinical trial. Ninety-seven patients were randomized into 5 groups according to the treatment employed: vitamin C group (1mg capsule 4x a day), vitamin E group (400UI capsule 3x a day), N-acetylcysteine group (600mg tablet 2x a day ), melatonin group (50 mg capsule a day) and control group. After 5 days of intervention, it was observed that patients treated with melatonin showed a decrease in the SOFA score, and a reduction in lipid peroxidation and procalcitonin levels.

Table 6 shows clinical trials performed with the use of melatonin in septic patients.

8. Effects of Melatonin on COVID-19

During the last two decades, coronaviruses have spread around the world. The severe acute respiratory syndrome coronavirus (SARS-CoV) was known, but the new one emerged in China in 2019, is named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in a tragic pandemic in 2020-2022 and leading to millions of deaths. Although vaccines and prevention measures are well known against this disease, the virus is still circulating and evolving [113,114,115,116,117].

The virus acts in the spike protein to enter the host cell by the angiotensin-converting enzyme 2 (ACE2) receptor, which is present in most organs. The stimulation of the immune system originates a pro-inflammatory cascade resulting in augmented cytokines production and release, such as IL-1, IL-6, TNF-α, and interferon 1. This scenario can lead to a systemic condition termed cytokine storm that is related to the worst outcomes of the disease [23,118,119,120].

Purinergic signaling that is related to the P2X7 receptor is closely related to the melatonin. The impairment of P2X7 and other receptors contributes to the cytokine storm and the hyper-inflammatory state. This condition initially leads to lung injury and acute respiratory distress syndrome. This hyper-inflammatory state can affect other organs, causing a widespread multi-organ dysfunction [23,121,122].

Melatonin has been considered a potential therapeutic for COVID-19 since, as pointed out before, it can modulate inflammation, oxidative stress, and the immune system. Therefore, it can reduce the cytokine storm and further oxidative conditions. Melatonin can modulate many receptors related to the cytokine storm, preventing hyper-inflammation [32,123,124,125].

As shown in Table 7, some clinical trials investigated the effects of melanin in COVID patients and showed improvement in quality of life, reduced hospitalization time, respiratory symptoms, risk of thrombosis, sepsis, and mortality rate.

9. Effects of Melatonin on Cancer

Like CVD, cancer is considered a leading sake of mortality worldwide, and it is possible to find historical records of this disease since ancient times (the first documented cases are found in civilizations from Egypt and Greece. Despite this high prevalence, many issues should be considered regarding its etiology and treatment [126]. Over the years, immeasurable efforts have been made to uncover the possible causes and appropriate treatment for each type of cancer. Many drugs have been developed that have positive effects on the disease, even leading to remission. However, they are associated with countless side effects. Because of this, compounds of natural origin have been considered in preventing and treating different types of cancer [127,128,129,130,131,132]. For example, Jurju et al [133], informing that Inflammatory bowel disease (IBD) is a chronic inflammatory condition tightly linked to immune system impairment and dysbiosis, resulting in inflammation of the gastrointestinal tract, colorectal cancer, and multiple systemic manifestations, showed that melatonin improves the integrity of the intestinal mucosal barrier, modulates the immune response, and reduces inflammation and oxidative stress. For these reasons, it can help control inflammation in IBD patients, preventing or working as an adjuvant therapy to colorectal cancer.

Besides melatonin's anti-inflammatory and antioxidant effects, it can also exert pro-apoptotic actions on cancer cells, resulting in malignant cell death while preserving healthy cells. Due to these reasons, this hormone arises as a multifaceted molecule with significant therapeutic effects to combat cancer. Its property of modulating immune responses and improving cellular resilience reaches the symptoms and pathophysiological pathways associated with cancer [134,135,136,137].

Some researchers have demonstrated the effects of melatonin on cancer. The study of Li et al [138] pointed out that surgery is a common treatment for lung cancer in the initial phases; however, there is a significant malignancy of other nodules in other areas. Their study combined local radiofrequency ablation associated with melatonin improved clinical outcomes for lung cancer with multiple pulmonary nodules. They observed a reduction of lung injury nodules by diminishing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Melatonin could enhance local radiofrequency ablation-stimulated natural killer (NK) cell activity and re-programmed tumor metabolism.

In another trial, the authors showed that melatonin may be effective in radioprotection against ionizing radiation-induced DNA damage in human lymphocytes [139].

Due to the fact that oral cavity squamous cell carcinoma (OSCC) may be in the sixth most common malignancy, Kartini et al [140] investigated the effects of melatonin in this condition. Surgery is a challenge since the head and neck present critical structures that can be affected by the tumor or treatment. Chemoresistancy is a concern due to the hypoxic microenvironment, which is seen as highly expressed HIF-1α. It is also affected by miR-210 and augmented expression of CD44 and CD133. Due to the powerful antioxidant and oncostatic melanin effects, it is expected that it can improve tumor hypoxia and clinical response. Their results showed that the use of melatonin, compared to placebo, can reduce miR-210, CD44, and miR-210. Moreover, these effects were followed by a decrease in residual tumor percentage.

The interesting study performed by Sookprasert et al [141] investigated the use of melatonin in patients with advanced Non-small cell lung cancer (NSCLC). Monthly overnight or morning urine was tested and the marker of DNA damage and repair was measured (8-oxo-7,8-dihydro-2’deoxyguanosine (8-oxodG)). Patients received 10 or 20 mg of melatonin or placebo. Subjects in the melatonin group had better health-related quality of life compared to placebo. A smaller amount of DNA damage biomarkers was found in the melatonin-treated group, suggesting the hormone's protective effects in healthy cells.

In another trial, the authors investigated the effects of melatonin on breast cancer markers (insulin-like growth factor I (IGF-1), estradiol, insulin-like growth factor-binding protein 3 (IGFBP-3), and IGF-1/IGFBP-3 ratio) in postmenopausal breast cancer survivors. The results showed that postmenopausal women with a history of breast cancer who received melatonin did not show modifications in the levels of IGF-1, estradiol, or IGFBP-3 levels [142].

Table 8 brings clinical trials performed with melatonin and cancer.

10. Effects of Melatonin on Dysbiosis

The gut microbiota is indispensable in protecting the gastrointestinal tract, maintaining homeostasis, and, thus, health. Bacteria colonize the gastrointestinal tract after birth, and the microbiota subsequently undergoes many modifications. It is profoundly influenced by diet and environmental factors. When some factor interferes with it, the condition is named dysbiosis [133,143,144,145].

Dysbiosis can lead to several diseases, such as neurodegenerative diseases, diabetes, obesity, cancer, metabolic syndrome, and cardiovascular diseases. Some animal studies have shown that melatonin, due to its anti-inflammatory and antioxidant actions, can affect the gastrointestinal tract and prevent dysbiosis. Moreover, melatonin has the ability to modulate gut microbiota, leading to eubiosis [146,147,148]. Notwithstanding, the anti-obesity and anti-diabetic melatonin effects can also contribute to the improvement of gut microbiota [149,150,151,152]. Although melatonin has a crucial role in gut microbiota maintenance, as shown in animal studies [153,154,155,156,157,158,159,160,161,162,163], we only found one clinical trial in the databases consulted to write this review.

This study is a single-blinded, parallel randomized controlled trial, and the authors investigated the use of melatonin (100 mg daily/12 weeks) in adults (66 ± 3 years). Sleep quality was assessed in the Pittsburg Sleep Quality Index, and Global Sleep Score (GSS). The composition of gut microbiota and short-chain fatty acids in stool were evaluated at weeks 0 and 12. Their results showed that the use of melatonin could exhibit beneficial effects on sleep quality. Furthermore, the authors observed an increase in microbiota diversity as well as a relative abundance of short-chain fatty acids-producing bacteria in the gut [164].

11. Conclusions

Since melatonin can scavenge free radicals and downregulate inflammation (reducing the release of pro-inflammatory cytokines such as pro-inflammatory interleukins, TNF-α, and IFN-1), it can modulate the immune system, reduce apoptosis, adipose tissue mass, insulin resistance, blood pressure, LDL-c, body weight, waist circumference, endothelial dysfunction, and plaque formation. These effects, isolated or combined, can make the use of melatonin a systemic-disease protection. In this study, we showed it can prevent risk factors for several diseases and can work as a therapeutic adjuvant in CVD, MAFLD, rheumatoid arthritis, dermatitis, COVID-19, polycystic ovaries, and sepsis. In summary, we can conclude that melatonin can benefit patients with many diseases besides sleep problems and neurodegeneration.

It is worth noting that using melatonin from plants presents several advantages. Firstly, plant-derived melatonin can be associated with other bioactive compounds, which are also naturally encountered in plants and often possess antioxidant, anti-inflammatory, and other effects. Depending on the plant species, these may be flavonoids, vitamins, and other compound classes. These compounds may also exert synergistic effects, improving bioavailability and imposing fewer adverse effects, making melatonin more cost-effective and available for the final consumer. Additionally, exploring phyto-melatonin helps valorize biodiversity and enhance the therapeutic potential of plants, which is mostly unknown. Finally, extraction methods of melatonin from plants may be more sustainable than synthetic production, which also has high costs depending on the process utilized. This is particularly interesting in the context of an environmentally friendly industry, especially regarding green healthcare. Synthetic medications pass through rigorous regulation processes, while naturally occurring pharmacies are easily regulated, making them more accessible and rapidly available for the consumer.