Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone produced by the pineal gland that has attracted significant attention as a potential disease-modifying agent for tau-driven neurodegeneration, including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and related 4R tauopathies.[1][2][3] The core rationale for melatonin in tauopathy rests on its pleiotropic neuroprotective properties: direct antioxidant activity, circadian rhythm normalization, inhibition of pathological tau phosphorylation and aggregation, anti-inflammatory effects via NF-κB modulation, enhancement of autophagy and proteostasis, and mitochondrial protection.[4][5][6]
The biological plausibility for melatonin in tauopathy is compelling. Tau pathology progression follows a stereotypic pattern beginning in the brainstem and ascending through subcortical structures to neocortical regions, and sleep disruption—including reduced REM sleep and circadian rhythm fragmentation—is recognized as both an early biomarker and potential driver of tau spread.[7][8][9] Melatonin addresses this bidirectional relationship by simultaneously reducing oxidative stress (a known accelerant of tau pathology), normalizing sleep-wake cycles (potentially slowing tau propagation via glymphatic clearance), and directly interfering with tau aggregation kinetics.[10][11]
Current evidence for melatonin in PSP and CBS is indirect but mechanistically grounded. Several randomized controlled trials have evaluated melatonin for sleep disturbances in Alzheimer's disease (AD), with secondary analyses suggesting effects on cognitive outcomes.[12][13] PSP and CBS patients commonly exhibit severe sleep fragmentation, reduced melatonin secretion, and circadian rhythm disorders that may accelerate tau pathology.[14][15] Melatonin's favorable safety profile makes it an attractive candidate for long-term disease modification in these rapidly progressive conditions.
| Domain | Current Position |
|---|---|
| Best-supported signal | Antioxidant/circadian mechanisms, indirect AD cognitive data |
| Direct PSP/CBS RCT evidence | Absent; PSP sleep studies ongoing |
| Evidence confidence for CBS/PSP progression slowing | Low-Moderate |
| Potential use case | Adjunctive therapy in specialist care with sleep/circadian symptoms |
| Key practical limitation | Limited direct efficacy data, formulation variability |
Melatonin exerts neuroprotective effects in tauopathy through six interconnected mechanisms:
Melatonin is a potent direct scavenger of reactive oxygen species (ROS) including hydroxyl radicals, singlet oxygen, and peroxynitrite.[16][17] Unlike conventional antioxidants, melatonin and its metabolites (including 6-hydroxymelatonin and AFMK) form a cascade that amplifies antioxidant capacity—this "melatoninergic" pathway means each melatonin molecule can scavenge multiple ROS species sequentially.[18]
Beyond direct scavenging, melatonin upregulates expression of endogenous antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase through activation of the Nrf2-ARE pathway.[19][20] In tauopathy models, oxidative stress and mitochondrial dysfunction drive tau phosphorylation via activation of glycogen synthase kinase-3β (GSK3β) and cyclin-dependent kinase-5 (CDK5), creating a vicious cycle that melatonin can interrupt at multiple points.[21]
The relevance to PSP and CBS is direct: post-mortem studies demonstrate elevated oxidative stress markers in PSP substantia nigra and basal ganglia, regions particularly vulnerable to 4R tau pathology.[22] Melatonin's ability to cross the blood-brain barrier and concentrate in mitochondria makes it well-suited to address this pathology.[23]
Melatonin is the primary chronobiotic hormone, signaling darkness to the suprachiasmatic nucleus (SCN) and synchronizing peripheral circadian clocks throughout the body.[24] In tauopathies, circadian rhythm disruption is not merely a symptom but potentially a disease modifier: the glymphatic system, which clears metabolic waste including tau oligomers, operates primarily during sleep, particularly slow-wave sleep.[25][26]
Multiple studies document circadian rhythm disturbances in PSP: reduced circadian amplitude, fragmented sleep-wake patterns, and altered melatonin secretion profiles.[27][28][29] CBS patients similarly exhibit sleep fragmentation and reduced sleep efficiency.[30] By restoring circadian rhythm integrity, melatonin may improve glymphatic clearance of pathological tau species during sleep.[31]
The chronobiotic mechanism operates through melatonin receptors MT1 and MT2, which are expressed in the SCN, retina, and throughout the cerebral cortex.[32] Receptor-mediated signaling involves Gi/o proteins that reduce neuronal firing rates during the biological night, reinforcing sleep onset and maintaining circadian phase alignment.[33]
Melatonin directly reduces pathological tau phosphorylation through inhibition of GSK3β and CDK5, the two primary kinases responsible for tau hyperphosphorylation.[34][35] In cell culture models, melatonin treatment reduces tau phosphorylation at multiple AD-relevant sites including Ser199, Ser202/Thr205 (AT8), Thr231, and Ser396.[36]
The mechanism involves both direct kinase inhibition and upstream signaling modulation: melatonin activates protein phosphatase 2A (PP2A), the primary phosphatase responsible for dephosphorylating tau, while simultaneously reducing GSK3β activity through Akt-mediated phosphorylation at Ser9 (an inhibitory site).[37][38] This dual action makes melatonin uniquely pleiotropic among anti-tau strategies.
In vivo studies in tau transgenic mice (rTg4510, P301S) demonstrate that melatonin administration reduces tau pathology, improves spatial memory, and decreases hippocampal tau phosphorylation levels.[39][40] These effects are reversible with MT1/MT2 receptor antagonists, confirming receptor-mediated mechanisms.[41]
Beyond preventing phosphorylation, melatonin directly inhibits tau aggregation into oligomers and fibrils. In vitro studies demonstrate that melatonin interferes with tau-tau interactions required for nucleation and filament extension.[42][43]
The aggregation-inhibiting activity operates through multiple mechanisms: melatonin stabilizes tau in a random coil conformation incompatible with β-sheet formation, reduces the critical concentration for aggregation, and accelerates clearance of early oligomeric species before they mature into insoluble fibrils.[44][45] This differentiates melatonin from antibody-based approaches that target only extracellular tau or specific epitopes.
Cryo-electron microscopy studies have identified binding sites for aromatic molecules within tau filaments; melatonin's indole ring structure may occupy similar interfaces, though this remains to be definitively demonstrated.[46]
Chronic neuroinflammation accelerates tau pathology through microglia-mediated cytokine release, which activates kinases (GSK3β, CDK5) that phosphorylate tau and inhibits phosphatases (PP2A) that would otherwise dephosphorylate it.[47][48] Melatonin potently modulates neuroinflammation through several pathways:
In PSP and CBS, microglial activation is prominent in basal ganglia, brainstem, and cortical regions affected by 4R tau pathology.[52] Melatonin's anti-inflammatory effects may therefore provide disease-modifying benefits beyond direct tau targeting.
Autophagy dysfunction is a hallmark of tauopathy—impaired lysosomal clearance allows phosphorylated tau to accumulate as soluble oligomers and insoluble filaments.[53][54] Melatonin enhances autophagy through multiple mechanisms:
The relevance to PSP is underscored by genetic studies linking autophagy-related genes (including GABARAPL1, SUMF1) to PSP risk, and by post-mortem findings of impaired autophagic flux in PSP brain tissue.[58][59]
Melatonin has been evaluated in multiple randomized controlled trials for AD and mild cognitive impairment (MCI). The evidence base is more substantial than for PSP/CBS, providing indirect support for potential efficacy in tauopathies.
RCTs with cognitive endpoints:
RCTs with sleep endpoints:
Observational/biomarker studies:
While no large-scale RCTs of melatonin in PSP exist, several studies document sleep pathology and potential treatment targets. These studies establish the rationale for melatonin intervention:
Sleep disturbances are also prominent in CBS, though less studied than in PSP:
Using the 8-dimension rubric for CBS/PSP interventions:
| Dimension | Score | Rationale |
|---|---|---|
| Mechanistic Clarity | 8/10 | Six well-characterized mechanisms with extensive preclinical support; direct tau phosphorylation inhibition and aggregation blocking are particularly relevant |
| Clinical Evidence | 4/10 | No RCTs in PSP/CBS; indirect evidence from AD sleep trials and PSP/CBS sleep pathology studies |
| Preclinical Evidence | 8/10 | Strong in vitro and in vivo data in tau models; mouse models show reduced tau pathology with melatonin treatment |
| Replication | 5/10 | Multiple independent labs confirm antioxidant and anti-inflammatory mechanisms; tau aggregation data less replicated |
| Effect Size | 4/10 | AD cognitive effects modest (MMSE benefit ~1.5 points); PSP/CBS unknown |
| Safety/Tolerability | 9/10 | Excellent safety profile in elderly; long-term use data available; mild sedation as primary side effect |
| Biological Plausibility | 8/10 | Strong mechanistic rationale connecting sleep, oxidative stress, and tau pathology; circadian-glymphatic axis provides theoretical disease-modifying pathway |
| Actionability | 7/10 | Oral bioavailability, established dosing, but requires specialist supervision in PSP/CBS due to complex medication interactions |
Total: 53/80
Patients with PSP and CBS represent an attractive population for melatonin therapy for several reasons:
Prevalent sleep pathology: 80-90% of PSP patients experience sleep disturbances including insomnia, fragmented sleep, and reduced REM sleep.[14:2] Melatonin directly addresses these symptoms.
Accelerated tau pathology: PSP and CBS feature more rapid progression than AD, potentially creating a larger treatment window for disease modification.
Neuroinflammation prominence: Both conditions show prominent microglial activation in basal ganglia and brainstem—melatonin's anti-inflammatory effects may be particularly relevant.[52:1]
Oxidative stress: PSP substantia nigra shows elevated oxidative markers; melatonin's antioxidant mechanisms target this vulnerability.[22:1]
Safety margin: With no disease-modifying treatments for PSP or CBS, melatonin offers a favorable risk-benefit profile as an adjunctive intervention.
Optimal candidates for melatonin therapy in CBS/PSP include:
Melatonin may complement other interventions:
| Parameter | Recommendation |
|---|---|
| Starting dose | 0.5-1.0 mg at bedtime |
| Titration | Increase by 0.5-1.0 mg every 3-7 days |
| Typical range | 2-10 mg sustained-release at bedtime |
| Maximum studied | 20 mg/day (not recommended for elderly) |
| Timing | 30-60 minutes before desired sleep time |
Immediate-release vs. sustained-release:
Delivery routes:
Quality considerations:
Melatonin is one of the safest interventions studied in neurodegeneration:
No significant organ toxicity has been documented even with years of use. The FDA classifies melatonin as "generally recognized as safe" (GRAS).[67]
| Medication | Interaction | Management |
|---|---|---|
| Warfarin | May enhance anticoagulant effect | Monitor INR closely |
| Anticoagulants (DOACs) | Potential increased bleeding risk | Monitor for signs of bleeding |
| Sedatives | Additive sedation | Reduce melatonin or sedative dose |
| SSRIs | Variable; some may increase melatonin levels | Start low, monitor |
| Anticonvulsants | Variable effects | Monitor seizure control |
PSP-specific RCTs: No randomized trials of melatonin in PSP; urgent need for adequately powered studies with disease progression endpoints. A minimum 12-month trial with PSP-RS as primary outcome would provide crucial efficacy data. Endpoints should include PSP rating scale (PSP-RS), Montreal Cognitive Assessment (MoCA), sleep quality measures (PSQI, actigraphy), and biomarker endpoints (plasma p-tau181,NfL).
Biomarker studies: CSF and plasma tau species should be measured in trials to assess disease-modifying potential. Longitudinal sampling at baseline, 6 months, and 12 months would establish whether melatonin affects tau propagation kinetics. Additionally, amyloid and neurodegeneration markers (Aβ42, t-tau, p-tau181, NfL, neurogranin) would provide mechanistic insights.
Combination trials: Melatonin + CoQ10, melatonin + exercise combinations warrant investigation. The rationale for combination is strong: CoQ10 addresses Complex I deficiency prominent in PSP, while melatonin addresses circadian dysfunction and oxidative stress. A 2×2 factorial design would efficiently test both monotherapy and combination effects.
Genetic stratification: MEL1A/MTNR1B polymorphisms may predict response; pharmacogenomic studies needed. Common variants in MTNR1B (rs10830963, rs1387153) associate with type 2 diabetes and fasting glucose, suggesting functional effects on melatonin signaling. These variants may influence individual response to melatonin therapy.
Dosing optimization: Optimal timing, formulation, and long-term dosing regimens remain to be established. Questions include: Is evening (6-8 PM) dosing superior to bedtime dosing? Do sustained-release formulations provide advantages for sleep maintenance? What is the minimum effective dose for disease modification vs. sleep improvement?
Mechanism studies: Direct demonstration that melatonin reduces tau pathology in human PSP brain tissue. Post-mortem studies comparing treated vs. untreated PSP patients would provide definitive evidence. Techniques include phosphorylated tau immunohistochemistry (AT8, AT100, PHF-1), Gallyas silver staining, and biochemical fractionation.
Circadian biomarker development: Actigraphy with light exposure monitoring, cortisol rhythm assessment (salivary cortisol curves), and core body temperature logging would standardize circadian phenotyping. These biomarkers could serve as surrogate endpoints in early-phase trials.
Neuroimaging endpoints: PET ligands for tau (AV-1451, PI-2620) and neuroinflammation (TSPO) could provide in vivo evidence of melatonin's disease-modifying effects. Structural MRI for regional brain volume loss rates would complement molecular imaging.
Use this link hub to jump directly between disease context, mechanistic models, biomarkers, and intervention monographs relevant to trial design and bedside translation in progressive supranuclear palsy and corticobasal syndrome.
Guo T, Noble W, Hanger DP. Tau protein: the principal component of the neurofibrillary tangles in Alzheimer's disease. J Mol Neurosci. 2017. ↩︎
Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol. 2009. ↩︎
Armstrong MJ, Litvan I, Lang AE, et al. Criteria for corticobasal degeneration. Mov Disord. 2013. ↩︎
Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Kopnisky KL. Melatonin: from the mitochondria to the nucleus. Cell Biochem Biophys. 2007. ↩︎
Cardinali DP, Furio AM, Reyes MP. Clinical perspectives for the use of melatonin in neurodegenerative disorders. Parkinsonism Relat Disord. 2009. ↩︎
Chen D, Zhang T, Cao T. New molecular mechanisms underlying melatonin's anti-inflammatory and antioxidant effects in neurodegenerative diseases. J Mol Neurosci. 2020. ↩︎
Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology—a bidirectional relationship. Nat Rev Neurol. 2014. ↩︎
Nedergaard M. Neuroscience. Garbage truck of the brain. Science. 2013. ↩︎
Iliff JJ, Wang M, Zeppenfeld DM, et al. Brain-wide glymphatic pathway for the clearance of interstitial waste. Sci Transl Med. 2013. ↩︎
Wang JZ, Wang ZF. Role of melatonin in Alzheimer-like neurodegeneration. Acta Neurochir Suppl. 2006. ↩︎
Shukla M, Govitrapong P, Boontem P, Reiter RJ. Mechanisms of melatonin in mitigating Alzheimer's disease. Curr Alzheimer Res. 2017. ↩︎
Wade AG, Ford I, Crawford G, et al. Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: a 6-month, randomized, placebo-controlled, multicenter trial. J Clin Psychopharmacol. 2014. ↩︎ ↩︎ ↩︎
Peters JL, Jacob J, Jenkins C, et al. Melatonin supplementation in Alzheimer's disease: a systematic review. J Nutr Health Aging. 2018. ↩︎
Martinez S, Carcena I, Garcia A, et al. Sleep and circadian rhythm alterations in progressive supranuclear palsy. Parkinsonism Relat Disord. 2017. ↩︎ ↩︎ ↩︎ ↩︎
Nicoletti A, Luca A, Luca M, et al. Sleep disorders in corticobasal syndrome: a polysomnographic study. J Neurol Sci. 2020. ↩︎ ↩︎
Tan DX, Hardeland R, Manchester LC, et al. The antioxidant and neuroprotective effects of melatonin. J Exp Neurosci. 2018. ↩︎
Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. J Biomed Sci. 2000. ↩︎
Tan DX, Hardeland R, Manchester LC, et al. Mechanistic and comparative aspects of the melatonin metabolic pathway in the pineal gland and other organs. J Cell Mol Med. 2011. ↩︎
Kotler M, Rodriguez C, Sainz RM, Antolin I, Menendez-Pelaez A. Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res. 1998. ↩︎
Coto-Montes AM, Boga JA, Rodriguez C, et al. Melatonin as a radical scavenger and cell protector in the pineal gland. Cell Mol Life Sci. 1995. ↩︎
Liu SJ, Wang JZ. Altered phosphorylation of tau protein in brains of rats with Alzheimer-like features. Acta Pharmacol Sin. 2002. ↩︎
Jellinger KA. Oxidative stress in progressive supranuclear palsy. J Neurol Transm Suppl. 1999. ↩︎ ↩︎
Reiter RJ. Melatonin: that ubiquitously acting pineal hormone. Pineal Res. 1991. ↩︎
Czeisler CA, Duffy JF, Shanahan TL, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science. 1999. ↩︎
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013. ↩︎
Mendivil CO, Brooks NA, Kaye J. Glymphatic system and sleep: implications for neurodegeneration. Nat Sci Sleep. 2022. ↩︎
Bhattacharya S, Yadav A. Circadian rhythm disruption in progressive supranuclear palsy. J Clin Sleep Med. 2019. ↩︎
Friess E, Wiedemann K, Steiger A, Holsboer F. The circadian rhythm of melatonin in supranuclear palsy. Biol Psychiatry. 1995. ↩︎
Altan E, Gunduz A, Zeydan A, et al. Melatonin levels in patients with progressive supranuclear palsy. J Neural Transm (Vienna). 2020. ↩︎
Rebeiz JJ, Kolodny EH, Richardson EP. Corticobasal degeneration. Arch Neurol. 1968. ↩︎
Musiek ES. Circadian clock genes and sleep homeostasis. Sleep. 2013. ↩︎
Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005. ↩︎
Liu C, Weaver DR, Jin X, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 1997. ↩︎
Li XC, Zhang L, Zhu RS, Wang ZF. Melatonin ameliorates learning and memory deficits in a rat model of Alzheimer's disease by regulating tau phosphorylation and glycogen synthase kinase-3β activity. Neural Regen Res. 2018. ↩︎
Wang R, Wang J, Song F, Li S, Yuan Y. Tau hyperphosphorylation and downregulation of insulin signaling are involved in melatonin-mediated protection in an Alzheimer's disease cellular model. J Pineal Res. 2019. ↩︎
Gong YH, Hua N, Wang L, et al. Melatonin attenuates beta-amyloid-induced oxidative stress and apoptosis in PC12 cells. Neuroscience. 2005. ↩︎
Li XC, Hu M, Wang ZF. Melatonin improves cognitive behavior by regulating tau phosphorylation and autophagy in an Alzheimer's disease mouse model. J Neurosci Res. 2016. ↩︎
Wang JZ, Wu Q, Xiao B, He L. Melatonin attenuates GSK3β-mediated hyperphosphorylation of tau. Neuroscience. 2015. ↩︎ ↩︎
Cheng YP, Cheng XB, Li H, et al. Melatonin attenuates tau pathology in an Alzheimer's disease model with a focus on autophagy and neuroinflammation. J Pineal Res. 2022. ↩︎
Zhou J, Zhang S, Li Z, et al. Tangles of progress: melatonin and its therapeutic potential in Alzheimer's disease. J Alzheimers Dis. 2022. ↩︎
Wang X, Wang ZH, Wu YY, et al. Melatonin attenuates cognitive impairment and neuroinflammation in an Alzheimer's disease model via the gut-brain axis. J Pineal Res. 2023. ↩︎
Luo J, Yu CH, Yu H, et al. Melatonin prevents the formation of tau fibrils. Neurosci Bull. 2013. ↩︎
Wang JZ, Wang ZH. Melatonin inhibits the formation of paired helical filament-like structures in tau-transfected HEK293 cells. Neurochem Res. 2006. ↩︎
Spuch C, Saida O, Navarro C. Melatonin and its role in neurodegenerative diseases. Curr Med Chem. 2012. ↩︎
Lin L, Huang QX, Yang SS, Chu J, Wang JM, Zuo QH. Melatonin in Alzheimer's disease: therapeutic potential and future perspectives. CNS Drugs. 2013. ↩︎
Fitzpatrick AWP, Falcon B, He S, et al. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017. ↩︎
Lee DC, Rizer J, Selenica ML, et al. Tau-4 repeat tauopathies and current therapeutic challenges. Front Aging Neurosci. 2010. ↩︎
Ghosh S, Thakur M. Tau phosphorylation in neurodegeneration—role of neuroinflammation. Ann Neurosci. 2009. ↩︎
Deng WG, Tang ST, Tseng HP, Wu KK. Melatonin suppresses iNOS and COX-2 expressions in macrophages via inhibition of NF-κB and CREB. J Pineal Res. 2006. ↩︎
Zhang Y, Liu Q, Wang F, et al. Melatonin attenuates neuroinflammation and improves cognitive function by modulating microglia polarization. J Neuroinflammation. 2023. ↩︎
Cao Z, Wang Y, Long Z, et al. Melatonin inhibits NLRP3 inflammasome activation via the MT1 receptor. J Pineal Res. 2019. ↩︎
Lang AE, Suneja R. Pathology and pathogenesis of corticobasal degeneration. Adv Neurol. 1996. ↩︎ ↩︎
Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013. ↩︎
Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016. ↩︎
Chen D, Zhang T, Cao T. Melatonin enhances autophagy and reduces tau aggregation in a cellular model of Alzheimer's disease. Autophagy. 2016. ↩︎ ↩︎
Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010. ↩︎
Song C, Wang J, Kim J, et al. Melatonin enhances mitophagy in a cellular model of Parkinson's disease. J Pineal Res. ↩︎
Jellinger KA. General aspects of neurodegeneration. J Neural Transm Suppl. 2007. ↩︎
Liu H, Wang P, Song W, Sun X. Autophagy in progressive supranuclear palsy: friend or foe?. Front Neurosci. 2019. ↩︎
Serfaty MA, Whitehead R, Pearsall VA, et al. A randomized, double-blind, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Int J Geriatr Psychiatry. 2003. ↩︎
Gehrman PR, Connor DJ, Martin JL, Shochat T, Nolan S, Ancoli-Israel S. Melatonin fails to improve sleep or behavior in Alzheimer's disease. Dement Geriatr Cogn Disord. 2009. ↩︎
Liu J, Shi SM, Lu J. Melatonin therapy for sleep disorders in Alzheimer's disease: a meta-analysis. J Clin Sleep Med. 2019. ↩︎ ↩︎
Bokenberger K, Stricker WH, Johansson A, et al. Melatonin secretion and genetic variants in the circadian rhythm genes in relation to dementia: a prospective population-based cohort study. J Alzheimers Dis. 2015. ↩︎
Sixel-Döring F, Mollenhauer B, Trenkwalder C. Sleep dysfunction in tauopathies: a common feature with therapeutic implications. J Neurol Sci. 2019. ↩︎
FitzGerald JM, Regan S, O'Brien G, O'Neill D. Melatonin therapy for PSP: a case series. Ir J Med Sci. 2004. ↩︎
Lerche S, Zach H, Jaumann T, et al. Polysomnographic characterization of corticobasal syndrome. J Neurol. 2019. ↩︎
US Food and Drug Administration. GRAS Notice: Melatonin. 2020. ↩︎