Melatonin for Clinical Improvement in Patients with Ischemic Stroke: A Randomized Clinical Trial


Inflammation, Ischemic stroke, Melatonin


How to Cite

Faraji, F., Talaie Zanjani, A., Rezaie Ashtiani, A., Motamedi, G., & Nourigheimasi, S. (2023). Melatonin for Clinical Improvement in Patients with Ischemic Stroke: A Randomized Clinical Trial. Iranian Red Crescent Medical Journal, 25(2).


Background: Ischemic stroke is the most frequent form of stroke, which imposes considerable cost and causes disabilities for the patients. Melatonin is proven to have anti-oxidant along with anti-inflammatory effects.

Objectives: The present study aimed to examine the effects of melatonin on clinical features of acute stroke in Iranian patients.

Methods: This randomized clinical trial was conducted on 58 patients who were admitted to Valiasr Hospital and Neurology Center in Arak, Iran, from April 2016 to April 2017. Inclusion criteria were: age ≥ 50 years and diagnosis of acute ischemic stroke. All participants were asked to fill out informed consent forms before entering the study. Through simple randomization, an expert nurse divided cases into two groups of 29 people: Group 1 as the intervention group: ASA 80mg/day + Plavix 75 mg/day + melatonin 3 mg (every night one pill for two months), Group 2 as the control group: ASA 80 mg/day + Plavix 75 mg/day + placebo (every night one pill for two months). Canadian Neurological Stroke Scale (CNSS) was recorded for all cases before and after treatment.

Results: Mean age, sex, circulation, cardiovascular accident incidence time, and symptoms were not significantly different between the two groups. Mean of the CNSS was significantly higher after the treatment in both groups. It improved significantly more in the intervention group than in the control group.

Conclusion: Findings of the present study showed that CNSS improved more in the intervention group than in the control group. Therefore, melatonin administration in patients with ischemic stroke will result in better clinical improvements.


Katan M, Luft A. Global burden of stroke. Semin Neurol. 2018;38(2):208-11. doi: 10.1055/s-0038-1649503. [PubMed: 29791947].

Kang X, Zuo Z, Hong W, Tang H, Geng W. Progress of research on exosomes in the protection against ischemic brain injury. Front Neurosci. 2019;13:1149. doi: 10.3389/fnins.2019.01149. [PubMed: 31736691].

Mantz J, Degos V, Laigle C. Recent advances in pharmacologic neuroprotection. Eur J Anaesthesiol. 2010;27(1):6-10.

Cui J, Zhao S, Li Y, Zhang D, Wang B, Xie J, et al. Regulated

cell death: discovery, features and implications for neurodegenerative diseases. Cell Commun Signal. 2021;19(1):1-29. doi: 10.1186/s12964-021-00799-8. [PubMed: 34922574].

Chen X, Cheng C, Zuo X, Huang W. Astragalin alleviates cerebral ischemia-reperfusion injury by improving anti-oxidant and anti-inflammatory activities and inhibiting apoptosis pathway in rats. BMC Complement Med Ther. 2020;20(1):120. doi: 10.1186/s12906-020-02902-x. [PubMed: 32316944].

Watson N, Diamandis T, Gonzales-Portillo C, Reyes S, Borlongan C. Melatonin as an antioxidant for stroke neuroprotection. Cell Transplant. 2016;25(5):883-91. doi: 10.3727/096368915X689749. [PubMed: 26497887].

Garaulet M, Qian J, Florez JC, Arendt J, Saxena R, Scheer FA. Melatonin effects on glucose metabolism: time to unlock the controversy. Trends Endocrinol Metab. 2020;31(3):192-204. doi: 10.1016/j.tem.2019.11.011. [PubMed: 31901302].

Mengel A, Zurloh J, Boßelmann C, Brendel B, Stadler V, Sartor-Pfeiffer J, et al. Delirium REduction after administration of melatonin in acute ischemic stroke (DREAMS): A propensity score-matched analysis. Eur J Neurol. 2021;28(6):1958-66. doi: 10.1111/ene.14792. [PubMed: 33657679].

Chen HY, Hung YC, Chen TY, Huang SY, Wang YH, Lee WT, et al. Melatonin improves presynaptic protein, SNAP‐25, expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats. J Pineal Res. 2009;47(3):260-70. doi: 10.1111/j.1600-079X.2009.00709.x. [PubMed: 19709397].

Lee EJ, Lee MY, Chen HY, Hsu YS, Wu TS, Chen ST, et al. Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J Pineal Res. 2005;38(1):42-52. doi: 10.1111/j.1600-079X.2004.00173.x. [PubMed: 15617536].

Hosseini S, Mofrad AM, Mokarian P, Nourigheimasi S, Azarhomayoun A, Khanzadeh S, et al. Neutrophil to lymphocyte ratio in epilepsy: a systematic review. Mediators Inflamm. 2022;2022:4973996. doi: 10.1155/2022/4973996. [PubMed: 36081651].

Abolhasanpour N, Alihosseini S, Golipourkhalili S, Badalzadeh R, Mahmoudi J, Hosseini L. Effect of melatonin on endoplasmic reticulum-mitochondrial crosstalk in stroke. Arch Med

Res. 2021;52(7):673-82. doi: 10.1016/j.arcmed.2021.04.002. [PubMed: 33926763].

Lee MY, Kuan YH, Chen HY, Chen TY, Chen ST, Huang CC, et al. Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats. J Pineal Res. 2007;42(3):297-309. doi: 10.1111/j.1600-079X.2007.00420.x. [PubMed: 17349029].

Lee EJ, Lee MY, Chang GL, Chen LH, Hu YL, Chen TY, et al. Delayed treatment with magnesium: reduction of brain infarction and improvement of electrophysiological recovery following transient focal cerebral ischemia in rats. J Neurosurg. 2005;102(6):1085-93. doi: 10.3171/jns.2005.102.6.1085. [PubMed: 16028768].

Juan WS, Huang SY, Chang CC, Huang YC, Lin YW, Chen TY, et al. Melatonin improves neuroplasticity by upregulating the growth‐associated protein‐43 (GAP‐43) and NMDAR postsynaptic density‐95 (PSD‐95) proteins in cultured neurons exposed to glutamate excitotoxicity and in rats subjected to transient focal cerebral ischemia even during a long‐term recovery period. J Pineal Res. 2014;56(2):213-23. doi: 10.1111/jpi.12114. [PubMed: 24350898].

Liu L, Cao Q, Gao W, Li BY, Zeng C, Xia Z, et al. Melatonin ameliorates cerebral ischemia‐reperfusion injury in diabetic mice by enhancing autophagy via the SIRT1‐BMAL1 pathway. FASEB J. 2021;35(12):e22040. doi: 10.1096/fj.202002718RR. [PubMed: 34800293].

Mor A, Tankiewicz-Kwedlo A, Krupa A, Pawlak D. Role

of kynurenine pathway in oxidative stress during neurodegenerative disorders. Cells. 2021;10(7):1603. doi: 10.3390/cells10071603. [PubMed: 34206739].

Tang J, Chen R, Wang L, Yu L, Zuo D, Cui G, et al. Melatonin attenuates thrombin-induced inflammation in BV2 cells and then protects HT22 cells from apoptosis. Inflammation. 2020;43(5):1959-70. doi: 10.1007/s10753-020-01270-5. [PubMed: 32705396].

Neumaier F, Weiss M, Veldeman M, Kotliar K, Wiesmann

M, Schulze-Steinen H, et al. Changes in endogenous daytime melatonin levels after aneurysmal subarachnoid hemorrhage–Preliminary findings from an observational cohort study. Clin Neurol Neurosurg. 2021;208:106870. doi: 10.1016/j.clineuro.2021.106870. [PubMed: 34418701].

Chen TY, Lee MY, Chen HY, Kuo YL, Lin SC, Wu TS, et al. Melatonin attenuates the postischemic increase in blood–brain barrier permeability and decreases hemorrhagic transformation of tissue‐plasminogen activator therapy following ischemic stroke in mice. J Pineal Res. 2006;40(3):242-50. doi: 10.1111/j.1600-079X.2005.00307.x. [PubMed: 16499561].

Kondoh T, Uneyama H, Nishino H, Torii K. Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life Sci. 2002;72(4-5):583-90. doi: 10.1016/s0024-3205(02)02256-7. [PubMed: 12467899].

Ersahin M, Toklu HZ, Cetinel S, Yüksel M, Yeğen BC, Sener

G. Melatonin reduces experimental subarachnoid hemorrhage‐induced oxidative brain damage and neurological symptoms. J Pineal Res. 2009;46(3):324-32. doi: 10.1111/j.1600-079X.2009.00664.x. [PubMed: 19215574].

Wang Z, Ma C, Meng CJ, Zhu GQ, Sun XB, Huo L, et al. Melatonin activates the Nrf2‐ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J Pineal Res. 2012;53(2):129-37. doi: 10.1111/j.1600-079X.2012.00978.x. [PubMed: 22304528].

Ayer RE, Sugawara T, Chen W, Tong W, Zhang JH. Melatonin decreases mortality following severe subarachnoid hemorrhage. J Pineal Res. 2008;44(2):197-204. doi: 10.1111/j.1600-079X.2007.00508.x. [PubMed: 18289172].

Ueda Y, Masuda T, Ishida A, Misumi S, Shimizu Y, Jung CG, et al. Enhanced electrical responsiveness in the cerebral cortex with oral melatonin administration after a small hemorrhage near the internal capsule in rats. J Neurosci Res. 2014;92(11):1499-508. doi: 10.1002/jnr.23434. [PubMed: 24964396].

Rojas H, Lekic T, Chen W, Jadhav V, Titova E, Marti RD, et al. The antioxidant effects of melatonin after intracerebral hemorrhage in rats. Acta Neurochir Suppl. 2008;105:19-21. doi: 10.1007/978-3-211-09469-3_4. [PubMed: 19066075].

Hartman R, Rojas HA, Lekic T, Ayer R, Lee S, Jadhav V, et al. Long-term effects of melatonin after intracerebral hemorrhage in rats Acta Neurochir Suppl. 2008;105:99-100. doi: 10.1007/978-3-211-09469-3_20. [PubMed: 19066091].

Chen J, Wang L, Wu C, Hu Q, Gu C, Yan F, et al. Melatonin‐enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. J Pineal Res. 2014;56(1):12-9. doi: 10.1111/jpi.12086. [PubMed: 24033352].

Pei Z, Pang S, Cheung R. Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. J Pineal Res. 2002;32(3):168-72. doi: 10.1034/j.1600-079x.2002.1o847.x. [PubMed: 12074100].

Jung EM, Joo SS, Yoo YM. Nanomolar melatonin influences insulin synthesis and secretion in rat insulinoma INS-1E cells. J Physiol Pharmacol. 2020;71(5). Doi: 10.26402/jpp.2020.5.10. [PubMed: 33571963].

Acuña‐Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H, et al Melatonin, mitochondria, and cellular bioenergetics. J Pineal Res. 2001;30(2):65-74. doi: 10.1034/j.1600-079x.2001.300201.x. [PubMed: 11270481].