Melatonin - It’s not just for SLEEP and YOU NEED TO TAKE IT.

Melatonin Supplementation

Antioxidant Defense, Anti-Inflammatory Actions,

& Therapeutic Potential Across the Lifespan

A Comprehensive Research Synopsis

Prepared by Dr. Lily Woods, PhD

February 2026

1. Introduction

Melatonin (N-acetyl-5-methoxytryptamine) is a phylogenetically ancient indoleamine that has evolved over billions of years from its origins in primitive photosynthetic bacteria to its current multifaceted roles in human physiology. First isolated from bovine pineal glands by Aaron Lerner in 1958, melatonin was initially understood primarily as a circadian rhythm regulator and sleep-promoting hormone. However, more than six decades of accumulated research—led most prominently by Dr. Russel J. Reiter of the University of Texas Health Science Center at San Antonio—has fundamentally expanded our understanding of this remarkable molecule, revealing it to be one of nature’s most versatile antioxidants, a potent anti-inflammatory agent, an immunomodulator, and a molecule with significant oncostatic properties.

Dr. Reiter, a Clarivate Analytics Highly Cited Scientist, Editor-in-Chief of Melatonin Research, and recipient of three honorary doctor of medicine degrees, has published extensively on melatonin for over 60 years. His landmark co-publications in Science and Nature in 1965 (with Roger A. Hoffman) helped establish melatonin research as a distinct field. His laboratory’s subsequent work revealed melatonin as a potent endogenous hydroxyl radical scavenger (1993), identified its novel metabolite cyclic-3-hydroxymelatonin (c3OHM), and ultimately proposed melatonin’s reclassification as a mitochondria-targeted antioxidant—a concept that has profoundly influenced precision medicine and longevity science.

This synopsis integrates findings from foundational papers reviewed by Dr. Lily Woods (Hardeland & Pandi-Perumal, 2005; Mayo et al., 2005) with the extensive body of work by Dr. Reiter and other leading researchers, providing a comprehensive overview of melatonin’s importance across the domains of antioxidant defense, inflammation, mitochondrial biology, neuroprotection, oncology, and aging.

2. Melatonin as a Multifaceted Antioxidant

2.1 Direct Free Radical Scavenging

The direct free radical scavenging capacity of melatonin was first documented by Reiter’s laboratory in 1993, when Tan, Poeggeler, Manchester, and Reiter identified melatonin as a potent endogenous hydroxyl radical scavenger. As reviewed by Hardeland and Pandi-Perumal (2005), melatonin reacts with hydroxyl radicals at extraordinarily high rate constants (1.2–75 × 10¹⁰ M⁻¹s⁻¹), functioning as a broad-spectrum single-electron donor against hydroxyl radicals, carbonate radicals, singlet oxygen, peroxynitrite-derived species, and numerous other reactive oxygen and nitrogen species (ROS/RNS).

In his landmark 2016 review “Melatonin as an Antioxidant: Under Promises but Over Delivers” in the Journal of Pineal Research (now cited over 1,000 times), Reiter and colleagues further demonstrated that melatonin chelates transition metals involved in the Fenton/Haber–Weiss reactions, thereby reducing formation of the hydroxyl radical—one of the most destructive radical species in biology. Reiter emphasized that the combination of direct scavenging and metal chelation makes melatonin’s antioxidant profile fundamentally different from that of conventional antioxidants such as vitamin C or vitamin E, which operate through more limited mechanisms.

2.2 The Scavenger Cascade: Melatonin as a Prodrug

A central theme in both the Hardeland & Pandi-Perumal (2005) review and Reiter’s body of work is the concept of the “scavenger cascade.” When melatonin neutralizes free radicals, it generates biologically active metabolites rather than inert byproducts. The sequential cascade proceeds as follows: melatonin → cyclic 3-hydroxymelatonin (c3OHM) → N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) → N1-acetyl-5-methoxykynuramine (AMK). Each metabolite retains or gains antioxidant and anti-inflammatory capacity, allowing up to four or more free radicals to be sequentially eliminated per parent molecule.

Hardeland and Pandi-Perumal estimated that approximately 30% of overall melatonin degradation proceeds through this kynuric pathway (rather than hepatic 6-hydroxylation), with the proportion potentially higher in extrahepatic tissues such as the brain. AMK, the terminal metabolite, proved to be a more potent cyclooxygenase-2 (COX-2) inhibitor than acetylsalicylic acid, with relative COX-2 selectivity. This led the authors to characterize melatonin as a prodrug of AMK—a concept with significant implications for understanding melatonin’s total protective capacity.

2.3 Indirect Antioxidant Actions: Enzyme Modulation

Beyond direct scavenging, melatonin operates through extensive enzyme modulation. Hardeland and Pandi-Perumal (2005) documented that melatonin upregulates glutathione peroxidase (the most consistent finding across tissues), glutathione reductase, superoxide dismutases (Cu/Zn-SOD, Mn-SOD), glucose-6-phosphate dehydrogenase, and γ-glutamylcysteine synthase—thereby supporting the glutathione redox cycle. Simultaneously, melatonin downregulates pro-oxidant enzymes including 5- and 12-lipoxygenases and nitric oxide synthases, limiting peroxynitrite formation and its destructive radical derivatives.

Reiter’s 2016 review systematized these findings into a comprehensive framework, noting that melatonin also potentiates other antioxidants including ascorbate, Trolox (α-tocopherol analog), reduced glutathione, and NADH through redox-based regeneration. In vivo, melatonin prevented decreases in hepatic ascorbate and α-tocopherol levels under chronic oxidative stress—an important synergistic property that distinguishes it from antioxidants that function in isolation.

2.4 Summary: Five Antioxidant Mechanisms

Mechanism Key Findings

Direct Radical Scavenging

Reacts with •OH, CO₃⁻•, ¹O₂, peroxynitrite-derived species at rate constants up to 7.5 × 10¹¹ M⁻¹s⁻¹; chelates transition metals to block Fenton chemistry.

Antioxidant Enzyme Upregulation

Stimulates GPx, GR, SOD (Cu/Zn and Mn isoforms), G6PD, and γ-GCS, reinforcing the glutathione redox cycle across multiple tissues.

Pro-oxidant Enzyme Downregulation

Suppresses 5- and 12-lipoxygenases and NOS isoforms, reducing peroxynitrite formation and downstream radical generation.

Synergy with Other Antioxidants

Potentiates ascorbate, Trolox, GSH, and NADH via redox regeneration; prevents hepatic depletion of vitamins C and E under chronic stress.

Mitochondrial Protection

Enhances Complex I and IV activity, improves ATP synthesis, reduces electron leakage at nanomolar concentrations via a quasi-catalytic model.

Adapted from Hardeland & Pandi-Perumal (2005) and Reiter et al. (2016)

3. Melatonin as a Mitochondria-Targeted Antioxidant

Perhaps the most consequential conceptual advance in melatonin research has been the proposal, championed by Reiter and colleagues, that melatonin should be classified as an endogenous mitochondria-targeted antioxidant. This proposal rests on several converging lines of evidence.

First, intracellular distribution studies have consistently shown that melatonin concentrations in mitochondria greatly exceed those in the blood, with the indole apparently accumulating against a concentration gradient via oligopeptide transporters PEPT1 and PEPT2. Second, when Lowes and colleagues compared melatonin’s efficacy against synthetic mitochondria-targeted antioxidants MitoQ and MitoE in a severe sepsis model, melatonin performed comparably or superiorly—reducing hepatic protein carbonyls and plasma lipid hydroperoxides at least as effectively as these purpose-engineered molecules. Third, Reiter’s group noted that pinealectomy paradoxically causes mitochondrial melatonin levels to rise, suggesting that mitochondria possess their own melatonin synthetic capacity—a finding consistent with the endosymbiotic theory that mitochondria evolved from melatonin-producing bacteria.

In a 2024 review in Ageing Research Reviews, Reiter, Sharma, Manucha, and colleagues further elaborated on melatonin’s mitochondrial actions in neurons, demonstrating that melatonin reduces electron leakage from the electron transport chain, elevates ATP production, detoxifies intramitochondrial ROS/RNS, and—via the SIRT3/FOXO pathway—upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Critically, the authors showed that melatonin can reverse Warburg-type metabolism in pathological neurons, restoring pyruvate entry into mitochondria and rescuing acetyl coenzyme A production—which itself supports melatonin synthesis via arylalkylamine N-acetyltransferase (AANAT). This creates a protective feedback loop: adequate melatonin sustains mitochondrial function, and healthy mitochondria produce melatonin.

The clinical relevance is profound. Hardeland and Pandi-Perumal’s quasi-catalytic model (2005) proposed that melatonin donates electrons to the respiratory chain while its cation radical competes with O₂ at iron-sulfur cluster N2, reducing superoxide formation—effects observed at remarkably low (nanomolar) concentrations. This suggests that even modest restoration of melatonin levels in aging individuals could meaningfully preserve mitochondrial function.

4. Anti-Inflammatory Actions: COX-2, iNOS, and Beyond

4.1 Foundational Evidence: Mayo et al. (2005)

The original research by Mayo, Sainz, Tan, Hardeland, Leon, Rodriguez, and Reiter (2005), published in the Journal of Neuroimmunology, was the first study to identify COX-2 and inducible nitric oxide synthase (iNOS) as specific molecular targets of melatonin and its kynuramine metabolites. Using LPS-activated RAW 264.7 macrophages, the investigators demonstrated that melatonin dose-dependently inhibited COX-2 protein expression without altering constitutive COX-1 levels—demonstrating selectivity for the inducible inflammatory isoform. Both AFMK and AMK similarly prevented COX-2 activation.

A critical finding was that N-acetyl-cysteine (NAC), a well-established antioxidant, did not significantly reduce COX-2 expression, while 6-methoxy-melatonin (a structural analog) only partially prevented the COX-2 increase. These controls established that melatonin’s anti-inflammatory effects are not exclusively mediated by free radical scavenging but involve additional, structurally specific signaling mechanisms. Functional confirmation came from reductions in prostaglandin E₂ (PGE₂) and nitric oxide (NO) concentrations in the treated macrophages.

4.2 Broader Anti-Inflammatory Significance

The identification of melatonin as a selective COX-2 suppressor without COX-1 effects carries significant therapeutic implications. Traditional NSAIDs that suppress COX-1 produce gastrointestinal side effects, including ulceration and bleeding. Melatonin and its metabolites (particularly AMK) represent a novel class of anti-inflammatory agents that avoid these risks. Because COX-2 overexpression is implicated in both neurodegenerative diseases (e.g., Alzheimer’s) and cancer, the selective COX-2 suppression by melatonin has relevance across multiple disease domains.

More recent research has extended these findings to show that melatonin modulates NF-κB signaling, reduces pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-18), suppresses NLRP3 inflammasome activation, and influences macrophage polarization toward anti-inflammatory M2 phenotypes. These properties position melatonin as a modulator of “inflammaging”—the chronic low-grade inflammation that is now recognized as a hallmark of biological aging and a driver of age-related cardiometabolic, neurodegenerative, and neoplastic diseases.

5. Neuroprotection and Neurodegenerative Disease

The convergence of melatonin’s antioxidant, anti-inflammatory, and mitochondrial protective properties has made it a compelling candidate for neuroprotective interventions. Brain aging changes the biological clock’s function, decreasing melatonin synthesis and contributing to emerging neurological irregularities. A ten-fold decrease in pineal melatonin production has been observed in octogenarians compared with teenagers, resulting in significant attenuation of the antioxidant, anti-inflammatory, and mitochondrial-optimizing effects of melatonin.

5.1 Alzheimer’s Disease

Melatonin has demonstrated anti-amyloidogenic properties in preclinical models, redirecting amyloid precursor protein (APP) processing toward the non-amyloidogenic pathway—potentially by suppressing glycogen synthase kinase-3β (GSK3β) activity. It also mitigates the neurotoxic effects of amyloid-β oligomers, reduces tau hyperphosphorylation, and protects hippocampal neurons from oxidotoxicity. Clinically, a placebo-controlled multicenter trial demonstrated that 2 mg prolonged-release melatonin administered for six months significantly improved cognitive performance and sleep efficiency in patients with mild to moderate Alzheimer’s disease. Patients with Alzheimer’s disease consistently show reduced melatonin levels in both cerebrospinal fluid and blood, raising the question of whether supplementation might slow disease progression if initiated early.

5.2 Parkinson’s Disease

Melatonin’s neuroprotective effects in Parkinson’s disease relate to its capacity to protect dopaminergic neurons from oxidative damage and mitochondrial dysfunction. A clinical trial with 2 mg prolonged-release melatonin showed beneficial effects on sleep disruption, non-motor symptoms, and quality of life in Parkinson’s patients. A notable case report by Kunz and Bes documented that in a 72-year-old male with REM sleep behavior disorder (a prodromal Parkinson’s marker), sustained melatonin treatment was associated with improved dopamine transporter density and disappearance of clinical signs over four years—a finding that, while preliminary, warrants further investigation.

5.3 The Glymphatic Connection

Recent research has identified an additional neuroprotective mechanism: melatonin appears to enhance the brain’s glymphatic system, which removes toxic proteins (including amyloid-β and tau) during sleep. Because glymphatic clearance is most active during sleep—and because melatonin both promotes sleep and is present in high concentrations in cerebrospinal fluid during the nighttime—this creates a synergistic mechanism linking circadian health to neurodegeneration prevention.

6. Oncostatic Properties and Cancer Research

The oncostatic properties of melatonin have been documented across a wide spectrum of tumor types including breast, prostate, colorectal, lung, gastric, ovarian, and glioblastoma. Mechanisms include apoptosis induction, cell proliferation inhibition, angiogenesis suppression, metastasis prevention, immune modulation via MT1 and MT2 receptors, and epigenetic alteration. As Reiter and colleagues have noted, reduced melatonin production with age could facilitate a constitutive rise in radical-driven mutagenesis, rendering cells more vulnerable to DNA oxidation—a known mechanism for mutation development in carcinogenesis.

6.1 Clinical Trial Evidence

The most extensive clinical trial program was conducted by Italian oncologist Dr. Paolo Lissoni, whose series of randomized trials in the late 1990s and early 2000s demonstrated significant benefits of 20 mg nightly melatonin alongside standard chemotherapy. In his pivotal 1999 study of 250 metastatic solid tumor patients (lung, breast, gastrointestinal, and head/neck cancers), both the one-year survival rate and tumor regression rate were significantly higher in the melatonin group compared to chemotherapy alone. A subsequent five-year follow-up in metastatic non-small cell lung cancer (NSCLC) patients showed that while no patients treated with chemotherapy alone survived past two years, 6% of those receiving concurrent melatonin achieved five-year survival.

A meta-analysis encompassing 21 clinical studies of patients with disseminated solid malignancies found that melatonin reduced the pooled relative risk of one-year mortality to 0.63 (95% CI: 0.53–0.74, p < 0.001), with improved rates of complete response, partial response, and stable disease. Melatonin also significantly reduced chemotherapy-induced adverse events including thrombocytopenia, myelosuppression, neurotoxicity, cardiotoxicity, stomatitis, and asthenia.

A large-scale randomized, double-blind, placebo-controlled trial (AMPLCaRe, n = 709) found no overall benefit of 20 mg melatonin for two-year disease-free survival following NSCLC resection. However, subgroup analysis revealed a 25% hazard reduction in five-year DFS for patients with advanced cancer (stage III/IV), suggesting melatonin’s benefits may be context-dependent. As of 2024, 46 clinical trials involving melatonin in cancer treatment have been registered on ClinicalTrials.gov, with 24 completed and ongoing recruitment in others.

6.2 Chronobiological Timing in Cancer Treatment

A critically important finding from a randomized, double-blind trial in advanced NSCLC patients receiving cisplatin/etoposide confirmed that the timing of melatonin administration matters: only evening-dosed melatonin (20 mg at 8 PM) significantly enhanced overall survival (HR = 0.39, p = 0.031), while morning-dosed melatonin did not produce a survival benefit. This finding aligns with Hardeland and Pandi-Perumal’s (2005) emphasis on consistent evening timing and modern chronomedicine principles—underscoring that when melatonin is administered may be as important as the dose.

7. Aging, Longevity, and Precision Medicine

From a precision medicine and longevity standpoint, the convergence of melatonin’s multiple mechanisms positions it as a uniquely relevant intervention for age-related decline. Several themes from the integrated research literature merit emphasis.

7.1 Age-Related Melatonin Decline

Pineal melatonin production declines progressively with age, with octogenarians producing roughly one-tenth the melatonin of teenagers. This decline occurs in parallel with age-related increases in oxidative stress, mitochondrial dysfunction, immune senescence, and chronic inflammation. Both pineal-derived (circulating) and mitochondrial (locally produced) melatonin diminish with age, creating a dual deficit that compounds age-related vulnerability. Reiter’s group has proposed that melatonin supplementation in aging individuals may help compensate for this endogenous decline, preserving mitochondrial function, circadian organization, and redox homeostasis.

7.2 Inflammaging and Immunosenescence

The selective COX-2/iNOS suppression documented by Mayo et al. (2005), combined with melatonin’s broader anti-inflammatory effects on NF-κB, NLRP3, and pro-inflammatory cytokines, positions melatonin as a modulator of inflammaging—the chronic low-grade inflammation now recognized as a central driver of biological aging. The nighttime release of pineal melatonin may play a role in resetting and resynchronizing immune cell mitochondrial function, a process that deteriorates with age. Exogenous melatonin may thus serve a dual role: directly quenching inflammatory pathways while restoring circadian immune regulation.

7.3 Cardiovascular Protection

Melatonin’s capacity to reduce ischemia/reperfusion injury has been extensively documented in both cardiac and cerebral models. Reiter’s 2016 review highlighted compelling evidence in organ transplantation studies, where melatonin prolonged allograft survival to 25 days compared to 8 days in controls and 9 days with ascorbic acid treatment, while also reducing indices of lipid peroxidation and acute-phase protein markers. These findings, combined with melatonin’s effects on oxidative stress, inflammation, and endothelial function, suggest potential cardiovascular protective applications in aging populations.

7.4 Dietary Sources and Supplementation Strategy

Hardeland and Pandi-Perumal (2005) documented that melatonin is present in a wide range of edible plants, with particularly high concentrations in certain seeds (white mustard at approximately 189 ng/g, black mustard at approximately 129 ng/g) and medicinal plants (feverfew and St. John’s wort exceeding 1,000 ng/g). Tart cherries, nuts, and certain herbs also contain measurable amounts. The gastrointestinal tract itself contains several hundred times more melatonin than the pineal gland, released post-prandially in response to tryptophan-rich nutrients. For patients seeking food-first approaches, these dietary sources offer a complementary strategy to supplementation—particularly relevant given melatonin’s amphiphilic nature, which enables efficient intestinal absorption.

8. Safety Profile and Dosing Considerations

Melatonin is remarkably well tolerated across a wide dose range. Hardeland and Pandi-Perumal (2005) noted that daily doses of 30–60 mg were used in ALS trials without harmful side effects. Clinical cancer trials have routinely employed 20 mg nightly for extended periods with an excellent safety profile, reducing rather than increasing chemotherapy adverse effects. The AMPLCaRe trial (n = 709) administering 20 mg for one year reported no significant difference in adverse events between melatonin and placebo groups.

Dosing ranges vary by indication: typical sleep support doses range from 0.5 to 5 mg, while clinical research applications have employed 10 to 50 mg nightly (oral) and up to 50 mg intravenously in critical care settings (sepsis, COVID-19 ICU trials). Consistent evening timing is essential to avoid disrupting circadian rhythmicity. Some caution has been advised in rheumatoid arthritis patients due to potential immunomodulatory interactions, and Hardeland and Pandi-Perumal noted that poorly manufactured preparations may contain oxidation byproducts—making product quality an important consideration.

9. Key References

Authors / Year

Publication & Key Contribution

Tan, Poeggeler, Manchester & Reiter (1993)

Endocrine Journal. First identification of melatonin as a potent endogenous hydroxyl radical scavenger; discovery of cyclic-3-hydroxymelatonin (c3OHM).

Vijayalaxmi, Thomas, Reiter & Herman (2002)

Journal of Clinical Oncology. Comprehensive review of melatonin’s antioxidant and oncostatic actions from basic research to cancer treatment clinics.

Lissoni et al. (1999)

European Journal of Cancer. Landmark RCT of 250 metastatic solid tumor patients showing melatonin (20 mg/day) increased 1-year survival and tumor regression while reducing chemotherapy toxicity.

Lissoni et al. (2003)

Journal of Pineal Research. 5-year survival data in metastatic NSCLC: 6% five-year survival with melatonin + chemo vs. 0% with chemo alone.

Hardeland & Pandi-Perumal (2005)

Nutrition & Metabolism. Comprehensive review of melatonin as dietary constituent, GI factor, drug, and prodrug; proposed the five-mechanism antioxidant framework and scavenger cascade.

Mayo, Sainz, Tan, Hardeland, Leon, Rodriguez & Reiter (2005)

Journal of Neuroimmunology. First identification of COX-2 and iNOS as specific molecular targets of melatonin and its kynuramine metabolites AFMK and AMK.

Reiter, Mayo, Tan, Sainz, Alatorre-Jimenez & Qin (2016)

Journal of Pineal Research. “Under Promises but Over Delivers” review (1,000+ citations); proposed melatonin as endogenous mitochondria-targeted antioxidant; documented superiority over MitoQ/MitoE.

Tan, Manchester et al. (2016)

International Journal of Molecular Sciences. Documented melatonin’s accumulation in mitochondria, MPTP inhibition, UCP activation, and regulation of mitochondrial biogenesis/dynamics.

Reiter, Sharma, Manucha et al. (2024)

Ageing Research Reviews. Demonstrated melatonin’s reversal of Warburg metabolism in neurons, SIRT3/FOXO pathway activation, and support for mitochondrial transfer via tunneling nanotubes.

Seely et al. / Meta-analyses (2012)

Cancer Chemotherapy & Pharmacology. Meta-analysis of 8 RCTs (n=761): melatonin as adjuvant reduces 1-year mortality with RR 0.63 (95% CI 0.53–0.74) in solid tumors.

10. Conclusion

The body of evidence accumulated over six decades—from Reiter’s foundational discoveries through the detailed mechanistic work of Hardeland, Pandi-Perumal, Mayo, and many others—establishes melatonin as far more than a sleep hormone. It is a pleiotropic molecule operating through at least five distinct antioxidant mechanisms, functioning as a selective anti-inflammatory agent, serving as an endogenous mitochondria-targeted protectant, and demonstrating meaningful oncostatic properties in both preclinical models and clinical trials.

For practitioners in precision medicine and longevity science, several actionable insights emerge from this research. The age-related decline in both pineal and mitochondrial melatonin production creates a progressive deficit that compounds across multiple hallmarks of aging—from oxidative stress and mitochondrial dysfunction to inflammaging and immune senescence. Melatonin supplementation, dosed in the evening to respect circadian physiology, offers a remarkably safe intervention that addresses multiple aging pathways simultaneously. Measuring only parent melatonin levels may underestimate total protective capacity, given the bioactive scavenger cascade through AFMK and AMK. Dietary sources rich in melatonin (tart cherries, nuts, mustard seeds, certain medicinal herbs) provide complementary nutritional strategies. And the emerging evidence for melatonin in cancer adjuvant therapy, neuroprotection, and cardiovascular protection—while requiring further large-scale trials—reinforces the importance of this molecule in comprehensive longevity protocols.

As Reiter himself wrote in 2016, melatonin “under promises but over delivers.” The accumulated evidence bears this out—and the clinical frontier of melatonin research continues to expand.

***Disclaimer: This synopsis is prepared for educational and informational purposes within a clinical research context. It does not constitute medical advice. Supplementation decisions should be made in consultation with a qualified provider, taking into account individual patient circumstances, comorbidities, and concurrent medications.