• PATRICIA FRANCISCONE Mendes Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, S.P., Brazil
  • Karin Argenti Simon Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (ICAQF-UNIFESP), Diadema, S.P., Brazil
  • Isis Machado Hueza Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (ICAQF-UNIFESP), Diadema, S.P., Brazil



Special K, K-hole, Immunotoxicity, Ketamine, Alcohol


Objective: Studies have shown that ketamine (K) and ethanol (E) have immunomodulatory activity; however, few studies were performed with concomitant treatments. Thus, we evaluated the toxic and immunotoxic effects of this association.

Methods: Wistar rats were distributed into four groups (n=8/group), each receiving one of the following treatments, for 28 d: K group (15 mg/kg of ketamine, intraperitoneally); E group [1.0 ml of ethanol 10% (approximately 0,08g/rat), gavage]; KE group, receiving both treatments; and Control (Co) group, receiving only vehicles. On day 29, animals were euthanized for biochemical, hematological, histopathological and immunological evaluation.

Results: Although the experimental conditions did not elicit changes on immune parameters, some biochemical alterations were detected in the different groups. Even in the absence of nutritional and histopathological changes, or renal and hepatic markers that could indicate tissue damage, a reduction on alkaline phosphatase levels in rats from K and KE groups was observed. Moreover, changes in lipid markers [cholesterol, triglycerides and high-density lipoproteins (HDL)] were found in the different groups studied, suggesting that K and E could promote a synergic/antagonistic effect.

Conclusion: In conclusion, despite biochemical alterations promoted by K and E, associated or not, the doses here employed did not promote immunotoxic effects on rats treated for 28 d. (response to the suggestion in the end of the paper). 


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Tavares BF, Beria JU, Lima M. Prevalência do uso de drogas e desempenho escolar entre adolescentes. Rev Saude Publica 2001;35:150-8.

Macht DI. The history of opium and some of its preparation and alkaloids. JAMA 1915;64:477-61.

Booth M. Opium-a history, New York: St Martin’s Griffin; 1998.

Orth APS, More CLO. Funcionamento de famílias com membros dependentes de substâncias psicoativas. Psicologia Argumento 2008;26:293-303.

Focchi GRA. Dependência de drogas: uma abordagem para leigos. Psyquiatry Online Brazil 2004;9:1-15.

Silva FCC, Dantas RT, Cito MCO, Silva MIG, Vasconcelos SMM, Fonteles MMF, et al. Ketamina, da anestesia ao uso abusivo: artigo de revisão. Rev Neurosci 2010;18:227-37.

Suvarna Y, Shivamurthy MC. Therapeutic use of dependence causing agents: the past and the present. J Crit Rev 2016;3:44-7.

WHO. Ketamine: update review report. Geneva, Switzerland: World Health Organization; 2015.

Yen CF, Hsu SY, Cheng CP. Polysubstance use and its correlates in adolescent ecstasy users in Taiwan. Addict Behav 2007;32:2286-91.

Kenna GA, Lewis DC. Risk factors for alcohol and other drug use by healthcare professionals. Subst Abuse Treat Prev Policy 2008;3:1-8.

Food and Drug Administration-FDA. Ketamine abuse. FDA Drug Bull 1979;9:24.

Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs 2000;32:419-33.

UNODC. World drug report. Vienna: United Nations Publications: United Nations office on Drugs and Crime; 38. p. 2016

Advisory Council on the Misuse of Drugs-ACMD. A consultation on proposals to reschedule ketamine under the Misuse of Drugs Regulations; 2014. p. 1-15.

DEA. Schedules of Controlled Substances: Placement of Ketamine into Schedule III. United States: U. S. Department of Justice-Drug Enforcement Administration; 1999.

Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol 1983;79:565-75.

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351-4.

Zarate CAJr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-Methyl-D-Aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856-64.

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanaesthetic effects of the noncompetitive NMDA antagonist ketamine in humans. Arch Gen Psychiatry 1994;51:199-214.

Abanades S, Peiro AM, Farre M. Club drugs: old medicines as new party drugs. Med Clin 2004;123:305-11.

Wolff K, Winstock AR. Ketamine from medicine to misuse. CNS Drugs 2006;20:199-18.

Sun J, Li F, Cheng J, Xu J. Effect of ketamine on NF-kappa B activity and TNF-alpha production in endotoxin-treated rats. Ann Clin Lab Sci 2004;34:181-6.

Beilin B, Rusabrov Y, Shapira Y, Roytblat L, Greemberg L, Yardeni IZ, et al. Low-dose ketamine affects immune responses in humans during the early post-operative period. Br J Anaesth 2007;99:522-7.

Roussabrov E, Davies JM, Bessler H, Davies JM, Shapira Y. Effect of ketamine on inflammatory and immune responses after short-duration surgery in obese patients. Open Anesthesiol J 2008;2:40-5.

Zahler S, Heindl B, Becker BF. Ketamine does not inhibit inflammatory responses of cultured human endothelial cells but reduces chemotactic activation of neutrophils. Acta Anaesthesiol Scand 1999;43:1011-6.

Weigand M, Schmidt H, Zhao Q, Plaschke K, Martin E, Bardenheuer HJ. Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro. Anesth Analg 2000;90:206-12.

PDF. Alcohol and Drug Problem Overview. New York: Partnership for a; 2010. p. 5.

UNODC. World Drug Report 2012. New York: United Nations Publications: United Nations office on Drugs and Crime; 2012. p. 112.

Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci 2003;28:263-74.

Schuckit MA. Alcohol-use disorders. Lancet 2009;373:492-501.

Molina PE, Happel KI, Zhang P, Kolls JK, Nelson S. Focus on: alcohol and immune system. Alcohol Res Health 2010;33:97-108.

Garcia LS, Comim CM, Valvassori SS, Reus GZ, Stertz L, Kapczinski F, et al. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:450-5.

Rezin GT, Gonçalvez CL, Daufenbach JF, Fraga DB, Santos PM, Ferreira GK, et al. Acute administration of ketamine reverses the inhibition of mitochondrial respiratory chain induced by chronic mild stress. Brain Res Bull 2009;79:418-21.

Réus GZ, Nacif MP, Abelaira HM, Tomaz DB, dos Santos MA, Carlessi AS, et al. Ketamine ameliorates depressive-like behaviors and immune alterations in adult rats following maternal deprivation. Neurosci Lett 2015;584:83-7.

Wai MSM, Chan WM, Zhang AQ, Wu Y, Yew DT. Long-term ketamine and ketamine plus alcohol treatments produced damages in liver and kidney. Hum Exp Toxicol 2012;31:877-86.

Engleman EA, Rodd ZA, Bell RL, Murphy JM. The role of 5-HT3 receptors in drug abuse and as a target for pharmacotherapy. CNS Neurol Disord Drug Targets 2008;7:454-67.

Coffin P, Galea S, Ahern J, Leon AC, Vlahov D, Tardiff K. Opiates, cocaine and alcohol combinations in accidental drug overdose deaths in New York City. Addiction 2003;98:739-47.

Coffin P, Sherman S, Curtis M. Underestimated and overlooked: a global overview of drug overdose and overdose prevention. London: International Harm Reduction Association; 2010.

Peters A, Davies T, Richardson A. Multi-site samples of injecting drug users in Edinburgh: prevalence and correlates of risky injecting practices. Addiction 1998;92:253-67.

EMCDDA. The state of drugs problem in Europe. Luxembourg: Publications Office of the European Union: European Monitoring Centre for Drugs and Drug Addiction; 2012.

ACMD. Ketamine: a review of use and harm. London, England: Advisory Council on the Misuse of Drugs; 2013. p. 48.

WHO. Expert Committee on Drug Dependence. Geneva, Switzerland: World Health Organization; 2006.

Chan WM, Xu J, Fan M, Jiang Y, Tsui TY, Wai MS, et al. Downregulation in the human and mice cerebella after ketamine versus ketamine plus ethanol treatment. Malar Res Treat 2011;75:258-64.

De Kock M, Loix S, Lavand'homme P. Ketamine and peripheral inflammation. CNS Neurol Ther 2013;19:403-10.

Lang TJ. Estrogen as an immunomodulator. Clin Immunol 2004;113:224-30.

Walker SE. Estrogen and autoimmune disease. Clin Rev Allergy Immunol 2011;40:60-5.

FDA. General Toxicology Studies. Rockville, Maryland: Food and Drug Administration; 2009;4:42-67.

Heron I, Berg K. The actions of interferon are potentiated at elevated temperature. Nature 1978;274:508-10.

Roberts NJJr. Impact of temperature elevation on immunologic defenses. Rev Infect Dis 1991;13:462-72.

Idova G, Cheido M, Devoino L. Modulation of the immune response by changing neuromediator systems activity under stress. Int J Immunopharmacol 1997;19:535-40.

Stevens KR, Gallo MA. Practical considerations in the conduct of chronic toxicity studies. Principles and methods of toxicology, New York: Raven Press; 1989. p. 929.

Bosma A, Brouwer A, Seifert WF, Knook DL. Synergism between ethanol and carbon tetrachloride in the generation of liver fibrosis. J Pathol 1988;156:15-21.

Kuzmin A, Liljequist S, Meis J, Chefer V, Shippenberg T, Bakalkin G. Repeated moderate-dose ethanol bouts impair cognitive function in Wistar rats. Addict Biol 2012;17:132-40.

Baptista RFF, Taipeiro EF, Queiroz RHC, Chies AB, Cordellini S. Estresse isolado ou associado ao etanol libera prostanóides em aorta de ratos via α2-adrenoceptores. Arq Bras Cardiol 2012; 102:211-8.

Nelson S, Bagby G, Summer WR. Alcohol suppresses lipopolysaccharide-induced tumor necrosis factor activity in serum and lung. Life Sci 1989;44:673-76.

Greenberg S, Zhao X, Hua L, Wang JF, Nelson S, Ouyang J. Ethanol inhibits lung clearance of Pseudomonas aeruginosa by a neutrophil and nitric oxide-dependent mechanism in vivo. Alcohol Clin Exp Res 1999;23:735-44.

Jerrells TR, Marietta CA, Eckardt MJ, Majchrowicz E, Weight FF. Effects of ethanol administration on parameters of immunocompetence in rats. J Leukocyte Biol 1986;39:499-510.

Abadie-Guedes R, Guedes RCA, Bezerra RS. The impairing effect of acute ethanol on spreading depression is antagonized by astaxanthin in rats of 2 young-adult ages. Alcohol Clin Exp Res 2012;36:1563-7.

ANVISA. Agencia Nacional de Vigilancia Sanitaria; 2016. Available from: [Last accessed on 01 Jul 2017].

Kale MA, Bindu SM, Khadkikar P. Role of antioxidants and nutrition in oxidative stress: a review. Int J Appl Pharm 2015;7:1-4.

Chandra RK. Protein-energy malnutrition and immunological responses. J Nutr 1992;122:597-600.

Prentice AM. The thymus: a barometer of malnutrition. Br J Nutr 1999;81:345-7.

Bourke CD, Berkley JA, Prendergast AJ. Immune dysfunction as a cause and consequence of malnutrition-review. Trends Immunol 2016;37:386-98.

Fataccioli V, Andraud E, Gentil M, French SW, Rouach H. Effects of chronic ethanol administration on rat liver proteasome activities: relationship with oxidative stress. Hepatology 1999;29:14-20.

Rofael HZ. Effect of ketamine pretreatment on cocaine-mediated hepatotoxicity in rats. Toxicol Lett 2004;152:213-22.

Warren RJ, Kirkpatrick RL, Gibson DF, Scanlon PF. Xylazine hydrochloride-induced anorexia in white-tailed deer. JWD 1984;20:66-8.

Van Der Eems K, Brown RD. Effect of caffeine sodium benzoate, ketamine hydrochloride, and yohimbine hydrochloride on xylazine hydrochloride-induced anorexia in white-tailed deer. JWD 1986;22:403-6.

Docherty JR, McGrath JC. A comparison of pre and post junctional potencies of several alpha-adrenoceptor agonists in the cardiovascular system and anococcygeus muscle of the rat. Evidence for two types of post junctional alpha-adrenoceptor. Naunyn Schmiedebergs Arch Pharmacol 1980;312:107-16.

Harrison NL, Simmonds MA. Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol 1985;84:381-91.

Suter PM. Is alcohol consumption a risk factor for weight gain and obesity? Crit Rev Clin Lab Sci 2005;42:197-227.

Lieber CS. Perspectives: do alcohol calories count? Am J Clin Nutr 1991a;54:976-82.

Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A. Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg 1999;89:665-9.

Starkenburg S, Munroe ME, Waltenbaugh C. Early alteration in leukocyte populations and Th1/Th2 function in ethanol-consuming mice. Alcohol Clin Exp Res 2001;25:1221-30.

Szabo G, Mandrekar P, Dolganiuc A, Catalano D, Kodys K. Reduced all reactive T-cell activation after alcohol intake is due to impaired monocyte accessory cell function and correlates with elevated IL-10, IL-13, and decreased IFN gamma levels. Alcohol Clin Exp Res 2001;25:1766-72.

Taniguchi T, Shibatta K, Yamamoto K. Ketamine inhibits endotoxin-induced shock in rat. Anesthesiology 2001;95:928-32.

Pearse G. Normal structure, function and histology of the thymus. Toxicol Pathol 2006;34:504-14.

Singh G, Dhadwal N, Harikumar SL. Experimental models for hepatotoxicity. Asian J Pharm Clin Res 2015;8:70-4.

Verma N. Introduction to hyperlipidemia and its treatment: a review. Int J Curr Pharm Res 2017;9:6-14.

Lieber CS. Mechanism of ethanol induced hepatic injury. Pharmacol Ther 1990;46:1-41.

Lieber CS. Metabolism of ethanol and associated hepatotoxicity. Drug Alcohol Rev 1991b;10:175-202.

Boubekri N, Boukaabache R, Amrani A, Belfarhi L, Zama D, Boumaza O, et al. Hepatoprotective effect of Genista quadriflora munby extract against ethanol induced toxicity. Asian J Pharm Clin Res 2014;7:226-9.

Mössner LD, Schmitz A, Theurillat R, Thormann W, Mevissen M. Inhibition of cytochrome P450 enzymes involved in ketamine metabolism by use of liver microsomes and specific cytochrome P450 enzymes from horses, dogs, and humans. Am J Vet Res 2011;72:1505-13.

Noppers IM, Niesters M, Aarts LP, Bauer MC, Drewes AM, Dahan A, et al. Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain 2011;152:2173-8.

Madsen NB, Tuba J. On the source of the alkaline phosphatase in rat serum. J Biol Chem 1952;195:741-50.

Hoffmann WE, Everds N, Pignatello M, Solter PF. Automated and Semiautomated analysis of rat alkaline phosphatase isoenzymes. Toxicol Pathol 1994;22:633-8.

Bennett JS, Gosset KA, McCarthy MP, Simpson ED. Effects of ketamine hydrochloride on serum biochemical and hematologic variables in rhesus monkeys (Macaca mulatta). Vet Clin Pathol 1992;21:15-8.

González Gil A, Illera JC, Silván G, Illera M. Effects of the anaesthetic/tranquillizer treatments on selected plasma biochemical parameters in NZW rabbits. Lab Anim 2003;37:155-61.

Narisawa S, Wennberg C, Millán JL. Abnormal vitamin B6 metabolism in alkaline phosphatase knock-out mice causes multiple abnormalities, but not the impaired bone mineralization. J Pathol 2011;193:125-33.

Farrokhifar SH, Jafari RA, Majd NE, Tabatabaee SRF, Mayahi M. Effects of dietary vitamin E on mucosal maltase and alkaline phosphatase enzyme activities and on the amount of mucosal malonyl dialdehyde in broiler chickens. Vet Res Forum 2013;4:221-5.

Wang Z, Yao T, Song Z. Chronic alcohol consumption disrupted cholesterol homeostasis in rats: downregulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver. Alcohol Clin Exp Res 2010;34:471-8.

Feinman L, Lieber CS. Ethanol and lipid metabolism. Am J Clin Nutr 1999;70:791-2.

Rimm EB, Williams P, Fosher K, Crigui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. Br Med J 1999;319:1523-8.

DeCarli LM, Lieber CS. Fatty liver in the rat after prolonged intake of ethanol with a nutritionally adequate new liquid diet. J Nutr 1967;91:331-6.

Lefevre AF, DeCarli LM, Lieber CS. Effect of ethanol on cholesterol and bile acid metabolism. J Lipid Res 1972; 13:48-55.

Van Der Merwe JN, Du Bruyn DB, Van Der Walt WH, Sly MR. Effects of certain anaesthetics on plasma metabolite concentrations in the baboon (Papio ursinus). J S Afr Vet Assoc 1987;58:125-9.

Rovirosa-Hernandez MJ, Garcia-Orduna F, Caba M, Canales-Espinosa D, Hermina-Lagunes J, Torres-Pelayo VR. Blood parameters are little affected by time of sampling after the application of ketamine in black howler monkeys (Alouatta pigra). J Med Primatol 2011;40:294-9.

Yoshida T, Suzuki K, Shimizu T, Cho F, Honjo S. The effects of ketamine anesthesia on hematological and serum biochemical values in female cynomolgus monkeys (Macaca fascicularis). Jikken Dobutsu 1986;35:455-61.

González Gil A, Silvan G, Illera M, Illera JC. The effects of anesthesia on the clinical chemistry of New Zealand White rabbits. Contemp Top Lab Anim Sci 2004;43:25-9.

Kim CY, Lee HS, Han SC, Heo JD, Kwon MS, Ha CS, et al. Hematological and serum biochemical values in Cynomolgus monkeys anesthetized with ketamine hydrochloride. J Med Primatol 2005;34:96-100.

Venkatesan R, Nagarajan P, Rajaretnam RS, Majumdar SS. Hematologic and serum biochemical values in aged female bonnet machaques (Macaca radiata) anesthetized with ketamine hydrochloride. J Am Assoc Lab Anim Sci 2006;45:45-8.

Baker SC, Stahlschmidt J, Oxley J, Hinley J, Eardley I, Marsh F, et al. Nerve hyperplasia: a unique feature of ketamine cystitis. Acta Neuropathol Commun 2013;1:64.

Gvozdenovic LV, Popovic MR, Jakovljevic VS, Lukic V. Effect of fentanyl, ketamine and thalamonal on some biochemical parameters in ethanol-treated and untreated dogs. Hum Exp Toxicol 1993;12:279-83.

Rezende M, Mama K. Anesthesia for patients with renal disease. Clini Brief; 2015. p. 41-4.

Das SK, Varadhan S, Dhanya L, Mukherjee S, Vasudevan DM. Effects of chronic ethanol exposure on renal function tests and oxidative stress in kidney. Indian J Clin Biochem 2008;23:341-4.



How to Cite

Mendes, P. F. ., K. A. Simon, and I. M. Hueza. “TOXIC AND IMMUNOTOXIC EVALUATION OF KETAMINE AND/OR ETHANOL IN RATS DURING 28 DAYS”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 9, no. 9, Sept. 2017, pp. 205-14, doi:10.22159/ijpps.2017v9i9.20582.



Original Article(s)