Ghrelin Alleviates MDMA-Induced Disturbance of Serum Glucose and Lipids Levels in the Rat

  • Ravieh Golchoobian Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Fatemeh Nabavizadeh Mail Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Mehrdad Roghani Neurophysiology Research Center, Shahed University, Tehran, Iran.
  • Alireza Foroumadi Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. AND Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
  • Maryam Mohammadian Department of Physiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Hepatotoxicity, 3, 4-methylenedioxymethamphetamine, Ghrelin, Glucose, Triglyceride, LDL


Hepatotoxicity is one of the clinically adverse effects of ecstasy (3, 4-methylenedioxymethamphetamine; MDMA) consumption. The detoxification tissue, liver, plays a central role in maintaining circulating levels of glucose and lipid. Hypoglycemia and hypotriglyceridemia have been reported due to ecstasy abuse. Ghrelin is a 28-amino-acid peptide secreted predominantly from the stomach. It has been demonstrated that ghrelin has hepatoprotective effects and is able to increase blood glucose concentration. In the current study, we explored the effect of hepatotoxic dose of MDMA and therapeutic use of exogenous ghrelin on the serum levels of glucose and lipids in four groups of rats. MDMA caused a severe and transient reduction in circulating levels of glucose and triglyceride and increased serum LDL. However, cholesterol and HDL levels remained unchanged. Meanwhile, altered hepatic architecture was observed with intracellular vacuolation that may indicate intracellular accumulation of lipid droplets. In addition, following ghrelin administration, the blood sugar levels improved and LDL levels returned to the baseline value, and ghrelin treatment did not improve triglycerides levels. These results showed that MDMA causes hypoglycemia, hypotriglyceridemia, and hyper LDL-cholesterolemia. To our knowledge, this is the first report showing ghrelin administration could improve hypoglycemia and normalize LDL levels induced by MDMA and partially restore hepatic architecture.


Bershad AK, Miller MA, Baggott MJ, de Wit H. The effects of MDMA on socio-emotional processing: Does MDMA differ from other stimulants? J Psychopharmacol 2016;30:1248-58.

Ferraz-de-Paula V, Ribeiro A, Souza-Queiroz J, Pinheiro M, Vecina J, Souza D, et al. 3, 4-Methylenedioxymethamphetamine (MDMAEcstasy) decreases neutrophil activity through the glucocorticoid pathway and impairs host resistance to Listeria monocytogenes infection in mice. J Neuroimmune Pharmacol 2014;9:690-702.

Karch SB. A historical review of MDMA. Open Forensic Sci J 2011;4:20-4.

Steinkellner T, Freissmuth M, Sitte HH, Montgomery T. The ugly side of amphetamines: short-and long-term toxicity of 34methylenedioxymethamphetamine (MDMA,‘Ecstasy’), methamphetamine and D-amphetamine. Biol Chem 2011;392:103-15.

Carvalho M, Pontes H, Remião F, L Bastos M, Carvalho F. Mechanisms underlying the hepatotoxic effects of ecstasy. Curr Pharm Biotechnol 2010;11:476-95.

Ellis A, Wendon J, Portmann B, Williams R. Acute liver damage and ecstasy ingestion. Gut 1996;38:454-8.

Henry J, Jeffreys K, Dawling S. Toxicity and deaths from 3, 4-methylenedioxymethamphetamine (" ecstasy").Lancet 1992;340:384-7.

Garbino J, Henry J, Mentha G, Romand J-A. Ecstasyingestion and fulminant hepatic failure: livertransplantation to be considered as a last therapeuticoption. Vet Hum Toxicol 2001;43 :99-102.

Caballero F, Lopez-Navidad A, Cotorruelo J, TxoperenaG. Ecstasy-induced brain death and acute hepatocellularfailure: multiorgan donor and liver transplantation.Transplantation 2002;74:532-7.

Beitia G, Cobreros A, Sainz L, Cenarruzabeitia E.Ecstasy‐induced toxicity in rat liver. Liver 2000;20:8-15.

Andreu V, Mas A, Bruguera M, Salmerón JM, Moreno V,Nogué S, et al. Ecstasy: a common cause of severe acutehepatotoxicity. J Hepatol 1998;29:394-7.

Kwack SJ, Yoon KS, Lim SK, Gwak H-m, Kim JY, Um YM, et al. A one-generation reproductive toxicity study of 3, 4-methylenedioxy-n-methamphetamine (MDMA,Ecstasy), an amphetamine derivative, in C57BL/6 mice. JToxicol Environ Health A 2014;77:1431-42.

Nordlie RC, Foster JD, Lange AJ. Regulation of glucose production by the liver. Annu Rev Nutr 1999;19:379-406.

Canbay A, Bechmann L, Gerken G. Lipid metabolism in the liver. Z Gastroenterol 2007;45:35-41.

Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, et al. Ghrelin inhibits leptin-and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest2004;114:57-66.

Delporte C. Structure and physiological actions of ghrelin. Scientifica (Cairo). 2013;2013.

Kojima M, Hosoda H, Matsuo H, Kangawa K. Ghrelin : discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 2001;12:118-22.

Kobeissy FH, Jeung JA, Warren MW, Geier JE, Gold MS. PRECLINICAL STUDY: Changes in leptin, ghrelin, growth hormone and neuropeptide‐Y after an acute model of MDMA and methamphetamine exposure in rats.Addict Biol 2008;13:15-25.

İşeri SÖ, Şener G, Saglam B, Ercan F, Gedik N, Yeğen BÇ. Ghrelin alleviates biliary obstruction-induced chronic hepatic injury in rats. Regul Pept 2008;146:73-9.

Moreno M, Chaves JF, Sancho‐Bru P, Ramalho F, Ramalho LN, Mansego ML, et al. Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans. Hepatology2010;51:974-85.

Li Y, Hai J, Li L, Chen X, Peng H, Cao M, et al.Administration of ghrelin improves inflammation,oxidative stress, and apoptosis during and after nonalcoholicfatty liver disease development. Endocrine2013;43:376-86.

Çetin E, Kanbur M, Çetin N, Eraslan G, Atasever A.Hepatoprotective effect of ghrelin on carbontetrachloride-induced acute liver injury in rats. Regul Pept2011;171:1-5.

Cerretani D, Bello S, Cantatore S, Fiaschi A,Montefrancesco G, Neri M, et al. Acute administration of3, 4 ethylenedioxymethamphetamine (MDMA) induces oxidative stress, lipoperoxidation and TNFα-mediated apoptosis in rat liver. Pharmacol Res 2011;64:517-27.

Aguirre N, Barrionuevo M, Ramírez MJ, Del Río J,Lasheras B. α‐Lipoic acid prevents 3, 4‐methylenedioxymethamphetamine (MDMA)‐induced neurotoxicity.Neuroreport 1999;10:3675-80.

Jahromi MG, Nabavizadeh F, Vahedian J, Nahrevanian H, Dehpour A-R, Zare-Mehrjardi A. Protective effect of ghrelin on acetaminophen-induced liver injury in rat.Peptides 2010;31:2114-7.

Giboney PT. Mildly elevated liver transaminase levels in the asymptomatic patient. Am Fam Physician2005;71:1105-10.

Moon KH, Upreti VV, Yu LR, Lee IJ, Ye X, Eddington ND, et al. Mechanism of 3, 4‐ methylenedioxymethamphetamine (MDMA, ecstasy)‐mediated mitochondrial dysfunction in rat liver.Proteomics 2008;8:3906-18.

Soto-Montenegro M, Vaquero JJ, Arango C, Ricaurte G,Garcia-Barreno P, Desco M. Effects of MDMA on blood glucose levels and brain glucose metabolism. Eur J NuclMed Mol Imaging 2007;34:916-25.

Boemeke L, Bassani L, Marroni CA, Gottschall CBA.Lipid profile in cirrhotic patients and its relation to clinical outcome. Arq Bras Cir Dig 2015;28:132-5.

Carrera P, Iyer VN. Profound hypoglycemia with ecstasy intoxication. Case Rep Emerg Med 2015;2015.

Montgomery H, Myerson S. 3, 4-methylenedioxymethamphetamine (MDMA, or “ecstasy”) and associated hypoglycemia. Am J Emerg Med1997;15:218.

Lai T-I, Hwang J-J, Fang C-C, Chen W-J. Methylene 3, 4dioxymethamphetamine–induced acute myocardialinfarction. Ann Emerg Med 2003;42:759-62.

Dietschy JM, Turley SD, Spady DK. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 1993;34:1637-59.

Feingold KR, Grunfeld C. Introduction to lipids and lipoproteins. 2015.

Zwirska-Korczala K, Konturek S, Sodowski M, WylezolM, Kuka D, Sowa P, et al. Basal and postprandial plasma in women with moderate and morbid obesity and metabolic syndrome. J Physiol Pharmacol 2007;58:13-35.

Ma S, Ge Y, Gai X, Xue M, Li N, Kang J, et al. Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus. Neurosci Lett.2016;611:28-32.

How to Cite
Golchoobian R, Nabavizadeh F, Roghani M, Foroumadi A, Mohammadian M. Ghrelin Alleviates MDMA-Induced Disturbance of Serum Glucose and Lipids Levels in the Rat. Acta Med Iran. 55(12):736-743.