Melatonin supplementation may benefit patients with acute ischemic stroke not eligible for reperfusion therapies: Results of a pilot study


      • It is found that melatonin can exert a neuroprotective effect against various neurodegenerative disorders.
      • Preclinical studies have elucidated melatonin’s neuroprotective effects in ischemic brain damage.
      • We found treatment with melatoninmight improve functional and neurological recovery outcomes in patients with acute ischemic stroke.
      • Our data support the previous hypothesis that early treatment with neuroprotective agents like melatonin may be helpful in treating ischemic stroke.



      We explored the potential efficacy of melatonin in the treatment of patients with acute ischemic stroke.


      This double-blind, placebo-controlled single-center clinical trial was conducted on 65 patients with acute ischemic stroke not eligible for reperfusion therapy. All patients received routine acute stroke management. Melatonin and placebo were administrated orally at a dose of 20 mg once daily for five days. The severity of neurological deficit and stroke-related functional disability was assessed on the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale score (mRS), respectively, on days 5, 30, and 90 after treatment.


      All patients completed the 5-day treatment period, and no serious adverse event was observed. While on day 5, the neurological status and stroke-related functional disability were comparable in both groups, on days 30 and 90, melatonin treatment resulted in a higher reduction in the median NIHSS and mRS score than placebo. Moreover, the overall changes in the NIHSS and mRS scores through a three-month follow-up assessment were significantly greater in the melatonin group than in the placebo group. The analysis of NIHSS scores distribution on day 90 showed a significant difference between the study groups in favor of the melatonin treatment. However, in relation to the functional independence criteria, defined as an mRS < 3, there were no significant differences between the groups at different study time points.


      Although preliminary, our findings support the hypothesis that early treatment with melatonin may be helpful in improving functional and neurological recovery following stroke.

      Trial registration

      The trial was registered at (identifier code: IRCT20120215009014N378). Registration date: 2021-01-28.


      tPA (tissue plasminogen activator), BBB (blood-brain barrier), ROS (reactive oxygen species), CT (computed tomography), MRI (magnetic resonance imaging), NIHSS (National Institute of Health Stroke Scale), mRS (modified Rankin Scale), CABG (coronary artery bypass grafting), ITT (intention-to-treat), GPx (glutathione Peroxidase), GR (glutathione reductase), SOD (superoxide dismutase), Bcl-2 (B cell lymphoma proto-oncogene protein), Bax (Bcl-2-associated X-protein), NF-κB (nuclear factor kappa-B), Nrf2 (nuclear factor erythroid 2–related factor 2), TNF-α (tumor necrosis factor-α), IL-6 (interleukin 6), CAT (catalase)


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        • Campbell B.C.
        • De Silva D.A.
        • Macleod M.R.
        • Coutts S.B.
        • Schwamm L.H.
        • Davis S.M.
        • et al.
        Ischaemic stroke.
        Nat Rev Dis Primers. 2019; 5: 1-22
        • Feigin V.L.
        • Abajobir A.A.
        • Abate K.H.
        • Abd-Allah F.
        • Abdulle A.M.
        • Abera S.F.
        • et al.
        Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.
        Lancet Neurol. 2017; 16: 877-897
        • Paciaroni M.
        • Bogousslavsky J.
        Primary and secondary prevention of ischemic stroke.
        Eur Neurol. 2010; 63: 267-278
        • Powers W.J.
        • Rabinstein A.A.
        • Ackerson T.
        • Adeoye O.M.
        • Bambakidis N.C.
        • Becker K.
        • et al.
        Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
        Stroke. 2019; 50: e344-e418
        • Kaur J.
        • Zhao Z.
        • Klein G.M.
        • Lo E.H.
        • Buchan A.M.
        The neurotoxicity of tissue plasminogen activator?.
        J Cereb Blood Flow Metab. 2004; 24: 945-963
        • Ong C.-T.
        • Wong Y.-S.
        • Wu C.-S.
        • Su Y.-H.
        Outcome of stroke patients receiving different doses of recombinant tissue plasminogen activator.
        Drug Design Develop Ther. 2017; 11: 1559
        • Rao N.M.
        • Levine S.R.
        • Gornbein J.A.
        • Saver J.L.
        Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the National Institute of Neurological Disorders and Stroke tissue-type plasminogen activator trials.
        Stroke. 2014; 45: 2728-2733
        • Fisher M.
        • Brott T.G.
        Emerging therapies for acute ischemic stroke: new therapies on trial.
        Stroke. 2003; 34: 359-361
        • Deb P.
        • Sharma S.
        • Hassan K.
        Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis.
        Pathophysiology. 2010; 17: 197-218
        • George P.M.
        • Steinberg G.K.
        Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments.
        Neuron. 2015; 87: 297-309
        • Allen C.L.
        • Bayraktutan U.
        Oxidative stress and its role in the pathogenesis of ischaemic stroke.
        Int J Stroke. 2009; 4: 461-470
        • Mittal M.
        • Siddiqui M.R.
        • Tran K.
        • Reddy S.P.
        • Malik A.B.
        Reactive oxygen species in inflammation and tissue injury.
        Antioxid Redox Signal. 2014; 20: 1126-1167
        • Liu R.
        • Pan M.-X.
        • Tang J.-C.
        • Zhang Y.
        • Liao H.-B.
        • Zhuang Y.
        • et al.
        Role of neuroinflammation in ischemic stroke.
        Neuroimmunol Neuroinflamm. 2017; 4: 158-166
        • Wu L.
        • Xiong X.
        • Wu X.
        • Ye Y.
        • Jian Z.
        • Zhi Z.
        • et al.
        Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury.
        Front Mol Neurosci. 2020; 13: 28
        • Genovese T.
        • Mazzon E.
        • Paterniti I.
        • Esposito E.
        • Bramanti P.
        • Cuzzocrea S.
        Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats.
        Brain Res. 2011; 1372: 92-102
        • Zhao Z.
        • Cheng M.
        • Maples K.R.
        • Ma J.Y.
        • Buchan A.M.
        NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat.
        Brain Res. 2001; 909: 46-50
      1. Drieu A, Levard D, Vivien D, Rubio M: Anti-inflammatory treatments for stroke: from bench to bedside. Therap Adv Neurol Disord 2018;11:1756286418789854.

        • Margaill I.
        • Plotkine M.
        • Lerouet D.
        Antioxidant strategies in the treatment of stroke.
        Free Radical Biol Med. 2005; 39: 429-443
        • Simion A.
        • Jurcau A.
        The role of antioxidant treatment in acute ischemic stroke: Past, present and future.
        Neurol Res Surg. 2019; 2: 1-7
        • Shirley R.
        • Ord E.N.
        • Work L.M.
        Oxidative stress and the use of antioxidants in stroke.
        Antioxidants. 2014; 3: 472-501
        • Tordjman S.
        • Chokron S.
        • Delorme R.
        • Charrier A.
        • Bellissant E.
        • Jaafari N.
        • et al.
        Melatonin: pharmacology, functions and therapeutic benefits.
        Curr Neuropharmacol. 2017; 15: 434-443
        • Pandi-Perumal S.R.
        • BaHammam A.S.
        • Brown G.M.
        • Spence D.W.
        • Bharti V.K.
        • Kaur C.
        • et al.
        Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.
        Neurotox Res. 2013; 23: 267-300
        • Watson N.
        • Diamandis T.
        • Gonzales-Portillo C.
        • Reyes S.
        • Borlongan C.V.
        Melatonin as an antioxidant for stroke neuroprotection.
        Cell Transplant. 2016; 25: 883-891
        • Andrabi S.S.
        • Parvez S.
        • Tabassum H.
        Melatonin and ischemic stroke: mechanistic roles and action.
        Adv Pharmacol Sci. 2015; 2015
        • Ramos E.
        • Farré-Alins V.
        • Egea J.
        • López-Muñoz F.
        • Reiter R.J.
        • Romero A.
        Melatonin's efficacy in stroke patients; a matter of dose? A systematic review.
        Toxicol Appl Pharmacol. 2020; 392: 114933
        • Dwaich K.H.
        • Al-Amran F.G.
        • Al-Sheibani B.I.
        • Al-Aubaidy H.A.
        Melatonin effects on myocardial ischemia–reperfusion injury: Impact on the outcome in patients undergoing coronary artery bypass grafting surgery.
        Int J Cardiol. 2016; 221: 977-986
        • Brott T.
        • Adams Jr, H.P.
        • Olinger C.P.
        • Marler J.R.
        • Barsan W.G.
        • Biller J.
        • et al.
        Measurements of acute cerebral infarction: a clinical examination scale.
        Stroke. 1989; 20: 864-870
      2. Bamford J, Sandercock P, Warlow C, Slattery J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1989;20(6):828-828.

        • Sabetghadam M.
        • Mazdeh M.
        • Abolfathi P.
        • Mohammadi Y.
        • Mehrpooya M.
        Evidence for a beneficial effect of oral N-acetylcysteine on functional outcomes and inflammatory biomarkers in patients with acute ischemic stroke.
        Neuropsychiatr Dis Treat. 2020; 16: 1265
        • Rubattu S.
        • Giliberti R.
        • Volpe M.
        Etiology and pathophysiology of stroke as a complex trait.
        Am J Hypertens. 2000; 13: 1139-1148
        • Wallace D.M.
        • Ramos A.R.
        • Rundek T.
        Sleep disorders and stroke.
        Int J Stroke. 2012; 7: 231-242
        • Meng H.
        • Liu T.
        • Borjigin J.
        • Wang M.M.
        Ischemic stroke destabilizes circadian rhythms.
        J Circadian Rhythms. 2008; 6: 1-13
        • Adamczak-Ratajczak A.
        • Kupsz J.
        • Owecki M.
        • Zielonka D.
        • Sowinska A.
        • Checinska-Maciejewska Z.
        • et al.
        Circadian rhythms of melatonin and cortisol in manifest Huntington’s disease and in acute cortical ischemic stroke.
        J Physiol Pharmacol. 2017; 68: 539-546
        • Fiorina P.
        • Lattuada G.
        • Silvestrini C.
        • Ponari O.
        • Dall'Aglio P.
        Disruption of nocturnal melatonin rhythm and immunological involvement in ischaemic stroke patients.
        Scand J Immunol. 1999; 50: 228
        • Ritzenthaler T.
        • Nighoghossian N.
        • Berthiller J.
        • Schott A.M.
        • Cho T.H.
        • Derex L.
        • et al.
        Nocturnal urine melatonin and 6-sulphatoxymelatonin excretion at the acute stage of ischaemic stroke.
        J Pineal Res. 2009; 46: 349-352
        • Mayo J.
        • Sainz R.
        • Antolin I.
        • Herrera F.
        • Martin V.
        • Rodriguez C.
        Melatonin regulation of antioxidant enzyme gene expression.
        Cell Mol Life Sci. 2002; 59: 1706-1713
        • Kotler M.
        • Rodríguez C.
        • Sáinz R.M.
        • Antolin I.
        • Menéndez-Peláez A.
        Melatonin increases gene expression for antioxidant enzymes in rat brain cortex.
        J Pineal Res. 1998; 24: 83-89
        • Galano A.
        • Tan D.X.
        • Reiter R.J.
        Melatonin as a natural ally against oxidative stress: a physicochemical examination.
        J Pineal Res. 2011; 51: 1-16
        • Lowes D.
        • Webster N.
        • Murphy M.
        • Galley H.
        Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis.
        Br J Anaesth. 2013; 110: 472-480
        • Wang X.
        The antiapoptotic activity of melatonin in neurodegenerative diseases.
        CNS Neurosci Ther. 2009; 15: 345-357
        • Mauriz J.L.
        • Collado P.S.
        • Veneroso C.
        • Reiter R.J.
        • González-Gallego J.
        A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives.
        J Pineal Res. 2013; 54: 1-14
        • Gepdiremen A.
        • Düzenli S.
        • Hacimüftüoglu A.
        • Bulucu D.
        • Süleyman H.
        The effects of melatonin in glutamate-induced neurotoxicity of rat cerebellar granular cell culture.
        Japanese J Pharmacol. 2000; 84: 467-469
        • Hasan Z.T.
        • Al M.Q.Y.M.A.
        • Mehuaiden A.K.
        The effect of melatonin on thrombosis, sepsis and mortality rate in COVID-19 patients.
        Int J Infect Dis. 2022; 114: 79-84
        • Wirtz P.H.
        • Bärtschi C.
        • Spillmann M.
        • Ehlert U.
        • Von Känel R.
        Effect of oral melatonin on the procoagulant response to acute psychosocial stress in healthy men: a randomized placebo-controlled study.
        J Pineal Res. 2008; 44: 358-365
        • Zhou H.
        • Li D.
        • Zhu P.
        • Hu S.
        • Hu N.
        • Ma S.
        • et al.
        Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPAR γ/FUNDC 1/mitophagy pathways.
        J Pineal Res. 2017; 63: e12438
        • Vacas M.I.
        • MdlM D.Z.
        • Martinuzzo M.
        • Falcon C.
        • Carreras L.O.
        • Cardinali D.P.
        Inhibition of human platelet aggregation and thromboxane B2 production by melatonin. Correlation with plasma melatonin levels.
        J Pineal Res. 1991; 11: 135-139
        • Ramos E.
        • Patiño P.
        • Reiter R.J.
        • Gil-Martín E.
        • Marco-Contelles J.
        • Parada E.
        • et al.
        Ischemic brain injury: new insights on the protective role of melatonin.
        Free Radical Biol Med. 2017; 104: 32-53
        • Macleod M.R.
        • O'Collins T.
        • Horky L.L.
        • Howells D.W.
        • Donnan G.A.
        Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke.
        J Pineal Res. 2005; 38: 35-41
        • Fulia F.
        • Gitto E.
        • Cuzzocrea S.
        • Reiter R.J.
        • Dugo L.
        • Gitto P.
        • et al.
        Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin.
        J Pineal Res. 2001; 31: 343-349
        • Aly H.
        • Elmahdy H.
        • El-Dib M.
        • Rowisha M.
        • Awny M.
        • El-Gohary T.
        • et al.
        Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study.
        J Perinatol. 2015; 35: 186-191
        • Ahmad Q.M.
        • Chishti A.L.
        • Waseem N.
        Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: A randomized control trial.
        J Pak Med Assoc. 2018; 68: 1233-1237
        • Zhao Z.
        • Lu C.
        • Li T.
        • Wang W.
        • Ye W.
        • Zeng R.
        • et al.
        The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial.
        J Pineal Res. 2018; 65: e12521
        • Sharifnia H.
        • Mojtahedzadeh M.
        • Dianatkhah M.
        • Najafi A.
        • Ahmadi A.
        • Najmeddin F.
        • et al.
        Evaluating the neuroprotective effect of melatonin on patients with hemorrhagic stroke using serum s100b protein as a prognostic marker.
        Jundishapur J Nat Pharm Prod. 2021; 16
        • Dianatkhah M.
        • Najafi A.
        • Sharifzadeh M.
        • Ahmadi A.
        • Sharifnia H.
        • Mojtahedzadeh M.
        • et al.
        Melatonin supplementation may improve the outcome of patients with hemorrhagic stroke in the intensive care unit.
        J Res Pharm Pract. 2017; 6: 173
        • Grima N.A.
        • Rajaratnam S.M.
        • Mansfield D.
        • Sletten T.L.
        • Spitz G.
        • Ponsford J.L.
        Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial.
        BMC Med. 2018; 16: 1-10
        • Dominguez-Rodriguez A.
        • Abreu-Gonzalez P.
        • Jose M.
        • Consuegra-Sanchez L.
        • Piccolo R.
        • Gonzalez-Gonzalez J.
        • et al.
        Usefulness of early treatment with melatonin to reduce infarct size in patients with ST-segment elevation myocardial infarction receiving percutaneous coronary intervention (from the melatonin adjunct in the acute myocardial infarction treated with angioplasty trial).
        Am J Cardiol. 2017; 120: 522-526
        • Haghjooy Javanmard S.
        • Ziaei A.
        • Ziaei S.
        • Ziaei E.
        • Mirmohammad-Sadeghi M.
        The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery.
        Oxid Med Cell Longevity. 2013; 2013
        • Shafiei E.
        • Bahtoei M.
        • Raj P.
        • Ostovar A.
        • Iranpour D.
        • Akbarzadeh S.
        • et al.
        Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: A randomized, open-labeled, placebo-controlled trial.
        Medicine. 2018; 97
        • Srivastava M.P.
        • Bhasin A.
        • Bhatia R.
        • Garg A.
        • Gaikwad S.
        • Prasad K.
        • et al.
        Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-controlled trial.
        Neurology India. 2012; 60: 23
        • Amiri-Nikpour M.R.
        • Nazarbaghi S.
        • Hamdi-Holasou M.
        • Rezaei Y.
        An open-label evaluator-blinded clinical study of minocycline neuroprotection in ischemic stroke: gender-dependent effect.
        Acta Neurol Scand. 2015; 131: 45-50
        • Li Y.
        • Chopp M.
        • Jiang N.
        • Yao F.
        • Zaloga C.
        Temporal profile of in situ DNA fragmentation after transient middle cerebral artery occlusion in the rat.
        J Cereb Blood Flow Metab. 1995; 15: 389-397
        • Steinhubl S.R.
        Why have antioxidants failed in clinical trials?.
        Am J Cardiol. 2008; 101: S14-S19
        • DeGraba T.J.
        • Pettigrew L.C.
        Why do neuroprotective drugs work in animals but not humans?.
        Neurol Clin. 2000; 18: 475-493
        • Andersen L.P.H.
        • Gögenur I.
        • Rosenberg J.
        • Reiter R.J.
        The safety of melatonin in humans.
        Clin Drug Invest. 2016; 36: 169-175
        • Weishaupt J.H.
        • Bartels C.
        • Pölking E.
        • Dietrich J.
        • Rohde G.
        • Poeggeler B.
        • et al.
        Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.
        J Pineal Res. 2006; 41: 313-323
        • Nickkholgh A.
        • Schneider H.
        • Sobirey M.
        • Venetz W.P.
        • Hinz U.
        • Pelzl L.H.
        • et al.
        The use of high-dose melatonin in liver resection is safe: first clinical experience.
        J Pineal Res. 2011; 50: 381-388
      3. Taher A, Shokoohmand F, Abdoli E, Mohammadi Y, Mehrpooya M. A pilot study on the melatonin treatment in patients with early septic shock: results of a single-center randomized controlled trial. Irish J Med Sci (1971-) 2021:1-12.