Melatonin: A cutaneous neuroendocrine regulator

Mansak Shishak; Kritika Pandey; Pushpit Singh

doi:10.25259/CSDM_99_2026

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2026

:6;

105

doi:

10.25259/CSDM_99_2026

Melatonin: A cutaneous neuroendocrine regulator

Mansak Shishak^1,, Kritika Pandey², Pushpit Singh³

1Department of Dermatology, Fortis Hospital, Vasant Kunj, New Delhi, India.

2Department of Dermatology, Sculpt Clinic, Gurgaon, Haryana, India.

3Department of Research, Fortis Hospital, Vasant Kunj, Delhi, India.

*Corresponding author: Mansak Shishak, Department of Dermatology, Fortis Hospital, Vasant Kunj, New Delhi, India. mansakshishak@gmail.com

Received: 2026-04-30, Accepted: 2026-06-15, Published: 2026-08-31

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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Shishak M, Pandey K, Singh P. Melatonin: A cutaneous neuroendocrine regulator. CosmoDerma. 2026;6:105. doi: 10.25259/CSDM_99_2026

INTRODUCTION

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone derivative of the essential amino acid, tryptophan. It is an amphiphilic free radical scavenger that functions not only as a hormone but also carries additional autocoid, paracoid, and antioxidant properties.^[1] It plays a central role in regulating circadian rhythms, sleep-wake cycles, and overall maintenance of physiological homeostasis. First discovered in the bovine pineal gland by Lerner, it was observed as a factor with inhibitory effects on melanocyte-stimulating hormone (MSH) of frog skin, with associated potency in relation to serotonin.^[2] Believed to be classically released from pineal glands with the primary role of overseeing the circadian rhythm, melatonin has since been recognized as a ubiquitous molecule with multiple synthesis sites and functions extending far beyond sleep cycle regulation. Emerging evidence has revealed its roles beyond chronobiology, particularly in skin physiology and dermatologic health. The skin is not only a target organ for melatonin but also possesses the enzymatic machinery necessary for its local synthesis and metabolism, highlighting the existence of a cutaneous melatoninergic system. Melatonin exhibits potent antioxidant, anti-inflammatory, immunomodulatory, and photoprotective properties that contribute to maintaining skin homeostasis. These diverse biological activities have generated growing interest in its therapeutic potential for conditions ranging from inflammatory dermatoses to impaired wound healing. Nevertheless, despite the expanding body of evidence, a critical assessment of the current literature is needed to clarify the strength of existing evidence, identify knowledge gaps, and determine the translational relevance of melatonin in clinical dermatology. Therefore, the objective of this focused review is to comprehensively evaluate melatonin’s mechanisms of action in the skin and its emerging applications in dermatologic practice.

MATERIAL AND METHODS

This review was conducted using PubMed, Scopus, Embase, and Google Scholar databases. Search words using combinations of the keywords “melatonin”, “skin melatonin”, “cutaneous neuroendocrine system”, “melatonin and dermatology”, “circadian rhythm”, “pineal melatonin”, “melatonin and wound healing”, “melatonin and inflammatory dermatoses”, “melatonin and microbiome”, and “melatonin and photoaging” were included. Original research articles, clinical studies, experimental studies, case reports, systematic reviews, and randomized controlled trials relevant to cutaneous biology and dermatologic applications of melatonin were included. Articles lacking relevance to dermatology or providing insufficient clinical data were excluded. The objective of this review is to summarize current evidence regarding melatonin as a cutaneous neuroendocrine regulator and to highlight its emerging role in dermatologic health and disease.

Origin and evolution

Over three billion years ago, with the earliest origins of photosynthesis in ancient bacteria (cyanobacteria), the rise of atmospheric oxygenation led to photosynthetic metabolism and the need for free radical scavengers. A distinct endosymbiotic system led to the production of melatonin’s potent antioxidant activity via mitochondria and chloroplasts.^[3] To date, it is presumed that they retain and produce melatonin for its multi-function role, thus establishing its role across all living entities. Further development of binding sites and receptors allowed the signaling transduction processes to activate; most functions are mediated by G-protein coupled receptors in the membranes of animal cells.^[4,5]

Synthesis of melatonin

Melatonin production follows both a central (pineal) and a peripheral pathway. Pineal synthesis: Melatonin synthesis begins with the essential amino acid tryptophan, which converts to 5-hydroxytryptophan and serotonin.^[3] It is regulated by the body’s master clock, present in the hypothalamic suprachiasmatic nucleus (SCN). Light signals detected by retinal photoreceptors (blue-light-sensitive ipRGCs) into biological signals and transmit via the retinohypothalamic tract through sympathetic pathways in the brainstem to the superior cervical ganglia.^[6,7] Extra pineal synthesis: Besides the pineal pathway, melatonin can also be synthesized and secreted in other tissues and organs such as the skin, liver, kidneys, gonads, thyroid, bone marrow, thymus, and the gastrointestinal tract.^[8] Cutaneous synthesis of melatonin has gained considerable attention in recent years. The skin is capable of producing melatonin locally through keratinocytes, melanocytes, fibroblasts, and hair follicle cells.^[9,10] It is derived from its precursor, N-acetyl serotonin (NAS), which is further metabolized to indolic and kynuric metabolites. This process involves the sequential action of tryptophan hydroxylase, aromatic amino acid decarboxylase, arylalkylamine N-acetyltransferase (AANAT), and acetylserotonin O-methyltransferase (ASMT). Locally synthesized melatonin contributes to epidermal barrier integrity, vitamin D synthesis, protection against ultraviolet radiation, regulation of pigmentation, and maintenance of redox homeostasis through G-protein-coupled melatonin receptors, (AhR), and the peroxisome proliferator–activated receptor γ (PPARγ).^[10,11]

These observations support the concept of the skin as an active neuroendocrine organ rather than a target tissue alone. The functions of melatonin on target cells are influenced by secretion patterns and levels of activity. Electromagnetic fields, age, male sex, Cushing syndrome, hypogonadotrophic hypogonadism, and alcoholism appear to be associated with lower melatonin secretion, while female sex, hypergonadotrophic hypogonadism, playing sports, and fasting are linked to higher levels of melatonin secretion.^[12]

Melatonin axes

Melatonin-mitochondria axis

The melatonin-mitochondria axis refers to the bidirectional relationship between melatonin and mitochondrial function. Mitochondria house the synthesis of melatonin, which in turn protects them from oxidative stress and UV-induced damage the mitochondrial membrane.^[13] This axis maintains cellular homeostasis by directly scavenging ROS, preventing lipid peroxidation of mitochondrial membranes, and protecting mitochondrial DNA.^[14] Stefan et al demonstrated the overlapping and differential effects of melatonin and its metabolites using RNAseq analyses on human epidermal keratinocytes.^[15] Metabolites of melatonin -indolic (6-hydroxymelatonin) and kynuric N1-Acetyl-N2-formyl-5-methoxykynurenamine (AFMK) metabolites prevented keratinocyte apoptosis by stimulation of expression of nuclear factor interleukin 3 (NFIL3), highlighting its role in skin barrier repair.^[13]

Melatonin-microbiome axis

There is growing evidence of an interplay between melatonin and the gut microbiota, with melatonin impacting microbial population, diversity, gut motility, and mucosal integrity.^[16] The host circadian rhythm is influenced by the gut microbiome and vice versa.^[16,17] From a dermatologic viewpoint, the gut-skin axis represents an important pathway through which microbiome and its metabolite-derived immune and inflammatory signals may influence cutaneous homeostasis. Dysbiosis and gastrointestinal conditions such as inflammatory bowel disease (IBD) have been associated with several inflammatory dermatoses.^[17] Therefore, the melatonin-microbiome axis may have implications extending beyond gastrointestinal pathologies and could represent a future therapeutic target in cutaneous conditions.^[17-19]

Melatonin in dermatology

Reports suggest the growing role of melatonin in dermatologic conditions: photoprotection due to melatonin’s antioxidant effects and role in preventing damage due to DNA repair mechanisms, antitumor activity, maintaining the integrity of the epidermal barrier, anti-inflammatory and immunomodulating activity in inflammatory dermatoses, and thermoregulation.^[20,21] We highlight some studies that promise utility in clinical settings.

Photoprotection and melatonin

Melasma

Melasma is a challenging pigmentary condition notable for its chronic state of partial or poor response to treatment, associated with hormonal fluctuations and genetic risk factors, observed most often in wheatish-to-brown pigmented skin. A study conducted on 36 patients with melasma who received 3 mg of melatonin orally, together with topical application of melatonin for three months, showed a significant improvement in the condition in comparison to a placebo. Its efficacy was attributed to the antioxidant properties and pigment-suppressing role of melatonin in melasma.^[22,23]

Wound healing

Melatonin in combination with glyoxal enables better cross-linkages in the scaffolding effects of biopolymers such as chitosan-collagen combination. In wound healing, this promotes cell regeneration rates, enhances mechanical durability, retains local thermal conditions, and prevents excessive water binding of affected tissues.^[24] Thus, a well-controlled modification of the physicochemical microenvironment in traumatized tissues can potentially stimulate and repair damage. In the management of malignancies involving radiation beam exposure, acute injury occurs to the epithelial barrier, causing varying grades of radiation dermatitis. A compounded formulation of topical melatonin was reported to prevent the anticipated adverse effects on skin in a case of early-stage breast adenocarcinoma.^[25] A randomized controlled trial of melatonin cream in radiation dermatitis of primary breast cancer demonstrated a protective effect.^[26] However, there remains a lack of large and robust trials on the role of melatonin in wound healing.

Melatonin in inflammatory dermatoses

Based on current dermatologic literature, systemic melatonin therapy has been investigated in atopic dermatitis. It is a highly prevalent chronic inflammatory dermatosis, characterized by pruritus, erythematous plaques or lichenified lesions, that bears a huge impact on quality of life. Melatonin may enable clinical improvement as a therapeutic adjunct via its immunomodulatory and anti-inflammatory effects, besides its direct role in sleep regulation.^[27] In chronic spontaneous urticaria (CSU), melatonin supplementation as a possible new therapeutic option has been considered in view of disrupted sleep patterns and high morbidity secondary to frustration in long-term management.^[28,29]

Photo reactivity and skin senescence

In a study of 20 healthy volunteers on the effects of UV-A and UV-B mediated skin changes, application of 0.6 mg/ cm² melatonin 15 minutes prior to irradiation prevented erythema, in comparison to vehicle alone.^[30] There was no benefit, however, when melatonin was administered post-irradiation.^[31] Cutaneous erythema on photo exposure is an immediate reaction caused by changes in small vasculature and the release of vasodilator intermediaries such as nitric oxide (NO). The role of melatonin in reactivity is best expected as a prophylactic measure in the prevention of post-UV radiation-induced erythema.^[30,31] It has been hypothesized that topically delivered or systemically given melatonin can buffer extrinsic stressors causing skin damage by downregulating enzymatic gene expression, causing italdehyde dehydrogenase 3 type A1, interstitial collagenase (MMP-1), stromelysin 1 (MMP-3), or stromelysin 2 (MMP-10).^[32] Systemically administered melatonin may mitigate senescence-related changes of the skin, such as rhytids, fine lines, solar , and textural irregularities, and improve skin elasticity.^[11]

Cutaneous appendages

Fischer et al conducted a double-blinded, controlled trial evaluating topical melatonin on 40 females with diffuse alopecia and androgenic hair loss. Melatonin was found to induce anagen regrowth over the frontal regions in diffuse alopecia.^[33] While more studies have attempted to assess its utility in androgenic alopecia, there is a lack of data on well-designed trials.^[34] The presence of melatonin in fingernails and toenails suggests that it could serve as a noninvasive biomarker of long-term endogenous melatonin production. Its utility in therapeutic implications remains uncertain.^[35]

Melatonin in chemotherapy-associated reactions

High-dose melatonin has been purported to be of clinical benefit in metastatic melanoma by attenuating the adverse effects of chemoimmunotherapy. An improvement in disease-free survival was observed in patients treated with melatonin following lymph node resection.^[36]

Its role as an adjuvant treatment aims to disrupt the downstream regulation of tyrosine-mediated melanogenesis and reduce levels of cyclic adenosine monophosphate (cAMP) and microphthalmia-associated transcription factor (MITF).^[37] Caution in interpreting its utility in melanoma management is needed. However, its relatively favorable profile in terms of cost and tolerability warrants further clinical efficacy studies and long-term safety data.

The potential role of melatonin in dermatology is summarized in Table 1.

Table 1: Applications of melatonin in dermatology

Study authors	Aim	Study design	Sample size	Methods	Results	Level of evidence
Hamadi et al.^[23]	To assess the clinical efficacy of oral and topical melatonin in patients with melasma.	Prospective placebo-controlled clinical study	36 patients	Thirty-six patients with melasma received oral melatonin (3 mg) along with topical melatonin application for three months. Clinical outcomes were compared with placebo-treated patients.	Patients receiving melatonin showed marked clinical improvement compared to placebo.	Level II–III
Kaczmarek et al.^[24]	To examine the role of melatonin-containing biomaterial scaffolds in wound healing.	In vitro study	Not applicable	Collagen–chitosan scaffolds cross-linked with glyoxal and incorporated with melatonin were evaluated for regenerative capacity and physicochemical stability.	Enhanced tissue regeneration, improved scaffold durability, and accelerated repair processes were observed.	Level V
Garcia et al.^[25]	To explore the usefulness of melatonin in inflammatory skin disorders and radiation dermatitis.	Case report	1 patient	A compounded melatonin cream was used for the prevention and treatment of radiation dermatitis	Melatonin showed supportive benefits in preventing radiation dermatitis	Level V
Zetner et al.^[26]	To evaluate the efficacy of topical melatonin cream in preventing acute radiation dermatitis in breast cancer patients	Double-blind randomized placebo-controlled trial	172 patients	Participants received melatonin cream or placebo during radiotherapy; the severity of radiation dermatitis was assessed	Melatonin cream significantly reduced the severity of radiation dermatitis and delayed the onset of skin toxicity compared with placebo	Level II
Maurer et al.^[28]	To assess the potential role of melatonin supplementation in chronic spontaneous urticaria (CSU).	Expert task force review	Not applicable	The clinical burden of CSU, particularly sleep disturbance and long-term disease-related stress, was evaluated.	Melatonin is proposed as a potential supplementary drug due to its effects on sleep and possible immunoregulation	Level V
Bangha et al.^[30]	To investigate whether topical melatonin suppresses UV-induced erythema and determine optimal application timing	controlled clinical study	20 healthy volunteers	Topical melatonin was applied at different time points before UV exposure; erythema was measured	Melatonin significantly reduced UV-induced erythema when applied before UV exposure, indicating photoprotective effects	Level III
Dreher et al.^[31]	To assess the protective effects of topical melatonin combined with vitamins E and C against UV-induced skin damage	controlled intervention study	20 healthy volunteers	Topical antioxidant formulations applied before UV exposure; erythema response measured	A combination of melatonin with vitamins E and C significantly reduced UV-induced erythema compared with controls	Level III
Fischer et al.^[33]	To evaluate the effect of melatonin on hair growth in women with alopecia	Pilot randomized controlled trial	40 women	Topical melatonin treatment administered to women with androgenetic or diffuse alopecia; hair growth parameters assessed	Melatonin significantly increased the proportion of anagen hair and improved hair growth compared with baseline	Level II
Gomez et al.^[35]	To determine whether nail melatonin content can serve as a non-invasive biomarker of melatonin production	Cross-sectional observational study	84	Nail samples were analyzed for melatonin content and correlated with systemic melatonin levels	Nail melatonin concentration correlated with endogenous melatonin production, suggesting utility as a non-invasive biomarker	Level IV
Lissoni et al.^[36]	To evaluate the adjuvant role of melatonin in malignant melanoma following lymph node resection.	Randomized clinical study	30 patients with node-relapsed melanoma	Patients were randomized to receive either melatonin (20 mg/day orally) or no adjuvant treatment following surgery for lymph node relapse.	Improved disease-free survival was reported in patients receiving melatonin. The study suggested a supportive role of melatonin in melanoma management.	Level II

CSU: Chronic spontaneous urticaria, UV: Ultraviolet

CONCLUSION

Melatonin plays a vital role in physiological bioregulation and maintenance of cellular homeostasis. Increasing evidence supports its function as a cutaneous neuroendocrine regulator involved in antioxidant defense, immune modulation, photoprotection, wound healing, and cutaneous senescence. However, much of the current evidence remains experimental or derived from small clinical studies. Consequently, further well-designed randomized controlled trials, standardized therapeutic protocols, and long-term safety assessments are required before widespread clinical implementation can be recommended. Future investigations exploring the melatoninmitochondria and melatonin-microbiome axes may further expand the therapeutic landscape of melatonin in dermatology.

Ethical approval:

Institutional Review Board approval is not required.

Declaration of patient consent:

Patient's consent not required as there are no patients in this study.

Conflicts of interest:

There are no conflicts of interest

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Financial support and sponsorship: Nil.

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