Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter September 4, 2013

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors

  • Yuriy Dobry EMAIL logo , Timothy Rice and Leo Sher

Abstract

Background: At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination.

Objective: The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy.

Data sources: An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included “serotonin syndrome”, “ecstasy”, “MDMA”, “pediatric”, and “SSRI”. Additional references were incorporated from the bibliographies of these retrieved articles.

Results: MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction.

Conclusion: The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.


Corresponding author: Yuriy Dobry, MD, Department of Psychiatry, Mount Sinai School of Medicine, Box 1240, New York, NY 10029, USA

References

1. Kelly BC. Mediating MDMA-related harm: preloading and post-loading among ecstasy-using youth. J Psychoactive Drugs 2009;41:19–26.10.1080/02791072.2009.10400671Search in Google Scholar PubMed

2. Mohamed WM, Ben HS, Cassel JC, de Vasconcelos AP, Jones BC. MDMA: interactions with other psychoactive drugs. Pharmacol Biochem Behav 2011;99:759–74.10.1016/j.pbb.2011.06.032Search in Google Scholar PubMed

3. Hall AP, Henry JA. Acute toxic effects of ‘Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 2006;96:678–85.10.1093/bja/ael078Search in Google Scholar PubMed

4. Martins SS, Ghandour LA, Chilcoat HD. Pathways between ecstasy initiation and other drug use. Addict Behav 2007;32:1511–8.10.1016/j.addbeh.2006.11.003Search in Google Scholar PubMed PubMed Central

5. Kaye S, Darke S, Duflou J. Methylenedioxymethamphetamine (MDMA)-related fatalities in Australia: demographics, circumstances, toxicity and major organ pathology. Drug Alcohol Depend 2009;104:254–61.10.1016/j.drugalcdep.2009.05.016Search in Google Scholar PubMed

6. Research Reports: MDMA (Ecstasy) Abuse. What is the scope of MDMA abuse in the U.S.? Available at: http://www.drugabuse.gov/publications/research-reports/mdma-ecstasy-abuse/what-scope-mdma-abuse-in-us. Accessed on February 25, 2012.Search in Google Scholar

7. Ronsley R, Smith DH, Garland EJ. Do hospital and community SSRI usage patterns in children and adolescents match the evidence? J Can Acad Child Adolesc Psychiatry 2010;19:218–26.Search in Google Scholar

8. Rutter M, Taylor EA. Child and adolescent psychiatry, 4th ed. Oxford: Blackwell Publishing Company, 2002.Search in Google Scholar

9. Clavenna A, Rossi E, DeRosa M, Bonati M. Use of psychotropic medications in Italian children and adolescents. Eur J Pediatr 2006;166:339–47.10.1007/s00431-006-0244-7Search in Google Scholar PubMed

10. Magno Zito J, dos Reis S, Gardner JF, Magder L, Soeken K, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med 2003;157:17–25.10.1001/archpedi.157.1.17Search in Google Scholar PubMed

11. Christie KA, Burke JD Jr, Regier DA, Rae DS, Boyd JH, et al. Epidemiologic evidence for early onset of mental disorders and higher risk of drug abuse in young adults. Am J Psychiatry 1988;145:971–5.10.1176/ajp.145.8.971Search in Google Scholar PubMed

12. Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M, et al. Cannabis use and mental health in young people: cohort study. Br Med J 2002;325:1195–8.10.1136/bmj.325.7374.1195Search in Google Scholar PubMed PubMed Central

13. Shedler J, Block J. Adolescent drug use and psychological health: a longitudinal inquiry. Am Psychol 1990;45:612–30.10.1037/0003-066X.45.5.612Search in Google Scholar

14. Grella CE, Hser YiI, Joshi V, Rounds-Bryant J. Drug treatment outcomes for adolescents with comorbid mental and substance use disorders. J Nervous Mental Dis 2001;189:384–92.10.1097/00005053-200106000-00006Search in Google Scholar PubMed

15. Crews F, He J, Hodge C. Adolescent cortical development: a critical period of vulnerability for addiction. Pharmacol Biochemistry Behav 2007;86:189–99.10.1016/j.pbb.2006.12.001Search in Google Scholar PubMed

16. Wegerer V, Moll GH, Bagli M, Rothenberger A, Ruther E, et al. Persistently increased density of serotonin transporters in the frontal cortex of rats treated with fluoxetine during early juvenile life. Child Adolesc Psychopharmacol 1999;9:13–24.10.1089/cap.1999.9.13Search in Google Scholar PubMed

17. de Jong TR, Snaphaana LJ, Pattija T, Veeninga JG, Waldinger MD, et al. Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats. Eur Neuropsychopharmacol 2006;16:39–48.10.1016/j.euroneuro.2005.06.004Search in Google Scholar PubMed

18. Simpson KL, Weaver KJ, de Villers-Sidani E, Lu JY, Cai Z, et al. Perinatal antidepressant exposure alters cortical network function in rodents. Proc Natl Acad Sci USA 2011;108:18465–70.10.1073/pnas.1109353108Search in Google Scholar PubMed PubMed Central

19. Preskorn SH, Ross R, Stanga CY. Antidepressants: past, present, and future. Berlin: Springer, 2004.Search in Google Scholar

20. Psychiatric Prescriptions for 2009. Psych Central. Available at: http://psychcentral.com/blog/archives/2010/04/26/top-25-psychiatric-drugs-in-2009. Accessed on February 25, 2012.Search in Google Scholar

21. Pratt L, Brody D, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005–2008. NCHS Data Brief, No. 76, October 2011.Search in Google Scholar

22. Corell CU, Kratochvill CJ, March JS. Developments in the pediatric psychopharmacology: focus on stimulants, antidepressants and antipsychotics. J Clin Psychiatry 2011;72:654–670.10.4088/JCP.11r07064Search in Google Scholar PubMed

23. Nizamie SH, Suresh KP. Fluoxetine-induced extrapyramidal symptoms: case reports. Indian J Psychiatry 1998;40:87–89.Search in Google Scholar

24. Rushton JL, Clark SJ, Freed GL. Pediatrician and family physician prescription of selective serotonin reuptake inhibitors. Pediatrics 2000;105:82.10.1542/peds.105.6.e82Search in Google Scholar PubMed

25. Spinks D, Spinks G. Serotonin reuptake inhibition: an update on current research. Curr Strategies Med Chem 2002;9: 799–810.10.2174/0929867024606795Search in Google Scholar PubMed

26. Leonard HL, March J, Rickler KC, Allen AJ. Pharmocology of the selective serotonin reuptake inhibitors in children and adolescents. J Am Acad Child Adolesc Psychiatry 1997;36: 725–36.10.1097/00004583-199706000-00008Search in Google Scholar PubMed

27. Gardier AM, Malagic I, Trillat C, Jacquot AC, Artigas F. Role of 5-HTI, autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies. Fundam Clin Pharmacol 1996;10:16–27.10.1111/j.1472-8206.1996.tb00145.xSearch in Google Scholar PubMed

28. Ziervogel CF. Selective serotonin re-uptake inhibitors for children and adolescents. Euro Child Adolesc Psychiatry 2000;9:I20–I26.10.1007/s007870070016Search in Google Scholar PubMed

29. Baumann P, Bertschy G. Pharmokintic-pharmodynamic relationship of selective serotonin reuptake. Inhibitors Nord J Psychiatry 1993;47:13–9.10.3109/08039489309104120Search in Google Scholar

30. Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S. [11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats. Synapse 2003;47:123–33.10.1002/syn.10155Search in Google Scholar PubMed

31. Catterson ML, Preskorn SH. Pharmacokinetics of selective serotonin reuptake inhibitors: clinical relevance. Pharmacol Toxicol 1996;78:203–8.10.1111/j.1600-0773.1996.tb00206.xSearch in Google Scholar PubMed

32. Boyer EW, Shannon M. Serotonin syndrome. N Engl J Med 2005; 352:1112–20.10.1056/NEJMra041867Search in Google Scholar PubMed

33. Gillman PK. A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry 2006;59:1046–51.10.1016/j.biopsych.2005.11.016Search in Google Scholar PubMed

34. US Drug Enforcement Administration. DEA Congressional Testimony. Available at: http://www.justice.gov/dea/pubs/cngrtest/ct032101.htm. Accessed on February 24, 2012.Search in Google Scholar

35. Pentey AR. An exploration of the history and controversies surrounding MDMA and MDA. J Psychoative Drugs 2001; 33:213–21.10.1080/02791072.2001.10400568Search in Google Scholar PubMed

36. Rudnick G, Wall SC. The molecular mechanism of “ecstasy” [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci USA 1992;89:1817–21.10.1073/pnas.89.5.1817Search in Google Scholar PubMed PubMed Central

37. Schifano F. A bitter pill. Overview of ecstasy (MDMA, MDA) related fatalities. Psychopharmacology 2004;173:242–8.10.1007/s00213-003-1730-5Search in Google Scholar PubMed

38. Parrott AC, Rodgers J, Buchanan T, Ling J, Heffernan T, et al. Dancing hot on Ecstasy: physical activity and thermal comfort ratings are associated with the memory and other psychobiological problems reported by recreational MDMA users. Hum Psychopharmacol 2006;21:285–98.10.1002/hup.773Search in Google Scholar PubMed

39. Soar K, Fox HC, Turner JJD, Parrott AC. The relationship between problematic ecstasy use, dosage, and the serotonin syndrome. J Psychopharmacol 2003:17A35.Search in Google Scholar

40. Parrott AC. Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav 2002;71:837–44.10.1016/S0091-3057(01)00711-0Search in Google Scholar

41. Demirkiran M, Jankovic J, Dean JM. Ecstasy intoxication: an overlap between the serotonin syndrome and neuroleptic malignancy syndrome. Clin Neuropharnocol 1996;19:101–92.10.1097/00002826-199619020-00004Search in Google Scholar

42. Parrott AC, Milani RM, Parmar R, Turner JD. Recreational drug use and psychobiological problems, collaborative UK/Italy study: Rome and Padua findings. Psychopharmacology (Berl) 2001;159:77–82.10.1007/s002130100897Search in Google Scholar

43. Morgan MJ. Memory deficits associated with recreational use of ecstasy (MDMA) memory deficits associated with recreational use of ecstasy (MDMA). Psychopharmacology (Berl) 1999;141:30–6.10.1007/s002130050803Search in Google Scholar

44. Morgan MJ. Recreational use of “ecstasy” (MDMA) is associated with elevated impulsivity. Neuropsychopharmacology 1998;19:252–64.10.1016/S0893-133X(98)00012-8Search in Google Scholar

45. McGuire P, Fahy T. Chronic paranoid psychosis after misuse of MDMA (ecstasy). Br Med J 199;302:697.10.1136/bmj.302.6778.697Search in Google Scholar

46. Eadie MJ. Convulsive ergotism: epidemics of the serotonin syndrome. Lancet Neurol 2003;ii:429–34.10.1016/S1474-4422(03)00439-3Search in Google Scholar

47. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacology 1999;13:100–9.10.1177/026988119901300111Search in Google Scholar PubMed

48. Gillman PK. Serotonin syndrome: history and risk. Fundam Clin Pharmacol 1998;12:482–91.10.1111/j.1472-8206.1998.tb00976.xSearch in Google Scholar PubMed

49. Steele D, Keltner NL, McGuiness TM. Are neuroleptic malignant syndrome and serotonin syndrome the same syndrome? Perspect Psychiatr Care 2011;47:58–62.10.1111/j.1744-6163.2010.00292.xSearch in Google Scholar PubMed

50. Fennell J, Hussain M. Serotonin syndrome: case report and current concepts. Jr Med J 2005;98:143–4.Search in Google Scholar

51. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705–13.10.1176/ajp.148.6.705Search in Google Scholar PubMed

52. McCue RE, Joseph M. Venlafaxine- and trazodone-induced serotonin syndrome. Am J Psychiatry 2001;158;2088.10.1176/appi.ajp.158.12.2088Search in Google Scholar PubMed

53. Silins EA, Copeland J, Dillon PG. Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk. Aust N Z J Psychiatry 2007;41:649–55.10.1080/00048670701449237Search in Google Scholar PubMed

54. Richard H, Shwatz MD. Adolescent abuse of dextromthrophan. Clin Pediatric 2005;44:565–8.10.1177/000992280504400702Search in Google Scholar PubMed

55. Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of Linezolid and serotonin agonists. Pharmacotherapy 2006;26:1784–93.10.1592/phco.26.12.1784Search in Google Scholar PubMed

56. FDA updates warnings on methylene blue, linezolid, and serotonergics. Issued October 21, 2011. Available at: http://www.fda.gov/Safety/MedWatch/default.htm. Accessed on January 1, 2012.Search in Google Scholar

57. Altman EM, Manos GH. Serotonin syndrome associated with citalopram and meperidine. Psychosomatics 2007;48:361–3.10.1176/appi.psy.48.4.361-aSearch in Google Scholar PubMed

58. Ener RA, Meglathery SB, Van Decker WA, Gallagher RM. Serotonin syndrome and other serotonergic disorders. Pain Med 2003;4:63–74.10.1046/j.1526-4637.2003.03005.xSearch in Google Scholar PubMed

59. Ailawadhi S, Sung KW, Carlson LA, Baer MR. Serotonin syndrome caused by interaction between citalopram and fentanyl. J Clin Pharm Ther 2007;32:199–202.10.1111/j.1365-2710.2007.00813.xSearch in Google Scholar PubMed

60. Shioda K, Nisijima K, Yoshino T, Kato S. Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:633–40.10.1016/j.pnpbp.2004.01.013Search in Google Scholar PubMed

61. Tao R, Ma Z, Auerbach SB. Differential effect of local infusion of serotonin reuptake inhibitors in the raphe versus forebrain and the role of depolarization-induced release in increased extracellular serotonin. J Pharmacol Exp Therap 2000;294:571–9.Search in Google Scholar

62. Beyer CE, Cremers TI. Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin? Eur J Pharmacol 2008;580:350–4.10.1016/j.ejphar.2007.11.028Search in Google Scholar PubMed

63. Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI. The pharmacology and clinical pharmacology of 3,4 methylenedioxymethamphetamine (MDMA, “Ecstasy”). Pharmacol Rev 2003;55:463–508.10.1124/pr.55.3.3Search in Google Scholar

64. Starr MA, Page ME, Waterhouse BD. The effects of repeated MDMA (3,4 methylenedioxymethamphetamine) administration on neurotransmitter efflux and sensory-evoked discharge in the ventral posterior medial thalamus. J Pharmacol Exp Ther 2011;327:20–31.10.1124/jpet.108.139337Search in Google Scholar

65. Oesterheld JR, Armstrong SC, Cozza KL. Ecstasy: pharmacodynamic and pharmacokinetic Interactions. Psychosomatics 2004;45:84–7.10.1176/appi.psy.45.1.84Search in Google Scholar

66. Farre M, Abanades S, Roset PN, Peiró AM, Torrens M, et al. Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther 2007;323:954–62.10.1124/jpet.107.129056Search in Google Scholar

67. Brosen K, Nielsen PN, Brusgaard K, Gram LF, Skjodt K. CYP2D6 genotype determination in the Danish population. Eur J Clin Pharmacol 1994;47:221–5.10.1007/BF02570501Search in Google Scholar

68. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10:27–34.10.1089/cap.2000.10.27Search in Google Scholar

69. Coore JR. A fatal trip with ecstasy: a case of 3,4-methylenedioxymethamphetamine/3,4- methylenedioxyamphetamine toxicity. J R Soc Med 1996;89:51P–2P.10.1177/014107689608900115Search in Google Scholar

70. Gordon CJ, Watkinson WP, O’Callaghan JP, Miller DB. Effects of 3,4- methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat. Pharmacol Biochem Behav 1991;38:339–44.10.1016/0091-3057(91)90288-DSearch in Google Scholar

71. Huether G, Zhou D, Ruther E. Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methyle- nedioxymethamphetamine (MDMA, “ecstasy”’) and its congeners. J Neural Transm 1997;104:771–94.10.1007/BF01285547Search in Google Scholar PubMed

72. Singh AN, Catalan J. Rave drug (ecstasy) and selective serotonin reuptake inhibitor anti-depressants. Indian J Psychiatry 2000;42:195–7.Search in Google Scholar

73. Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208–21.10.1097/00004714-199706000-00012Search in Google Scholar PubMed

74. de la Torre R, Farre M, Ortuno J, Mas M, Brenneisen R, et al. Non-linear pharmacokinetics of MDMA (‘ecstasy’) in humans. Br J Clin Pharmacol 2000;49:104–9.10.1046/j.1365-2125.2000.00121.xSearch in Google Scholar

75. Copelnd J, Dillon P, Gascoigne M. Ecstasy and the concomitant use of pharmaceuticals. Addict Behav 2005;31:367–70.10.1016/j.addbeh.2005.05.025Search in Google Scholar

76. Scholey AB, Parrott AC, Buchanan T, Heffernan TM, Ling J, et al. Increased intensity of Ecstasy and polydrug usage in the more experienced recreational Ecstasy/MDMA users: a WWW study. Addict Behav 2004;29:743–52.10.1016/j.addbeh.2004.02.022Search in Google Scholar

77. Winstock AR, Griffiths P, Stewart D. Drugs and the dance music scene: a survey of current drug use patterns among a sample of dance music enthusiasts in the UK. Drug Alcohol Depend 2001;64:9–17.10.1016/S0376-8716(00)00215-5Search in Google Scholar

78. Wu LT, Schlenger WE, Galvin DM. Concurrent use of methamphetamine, MDMA, LSD, Ketamine, GBH, and flunitrazepam among American youths. Drug Alcoh Depend 2006;84:102–13.10.1016/j.drugalcdep.2006.01.002Search in Google Scholar

79. Davison D, Parrott AC. Ecstasy in recreational users: self-reported psychological and physiological effects. Hum Psychopharmacol Clin Exp 1997;12:91–7.10.1002/(SICI)1099-1077(199705/06)12:3<221::AID-HUP854>3.0.CO;2-CSearch in Google Scholar

80. Ikeda R, Igari Y, Fuchigami Y, Wada M, Kuroda N, et al. Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain. Eur J Pharmacol 2011;660:318–25.10.1016/j.ejphar.2011.03.050Search in Google Scholar

81. Parrott AC. Is Ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, dosage levels, and the changing perceptions of purity. Psychopharmacology 2004;173:234–41.10.1007/s00213-003-1712-7Search in Google Scholar

82. Sloviter RS, Drust EG, Connor JD. Evidence that serotonin mediates some behavioral effects of amphetamine. J Pharmacol Ther 1978;206:348–52.Search in Google Scholar

83. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ. Subchronic fluoxetine treatment induces a transient potentiation of amphetamine-induced hyperlocomotion: possible pharmacokinetic interaction. Behav Pharmacol 2000;11:109–16.10.1097/00008877-200004000-00002Search in Google Scholar

84. Byard RW, Gilbert J, James R, Lokan RJ. Amphetamine derivative fatalities in South Australia-is “Ecstasy” the culprit? Am J Forensic Pathol 1998;19:261–5.10.1097/00000433-199809000-00013Search in Google Scholar

Received: 2012-2-3
Accepted: 2012-4-23
Published Online: 2013-09-04
Published in Print: 2013-09-01

©2013 by Walter de Gruyter Berlin Boston

Downloaded on 28.3.2023 from https://www.degruyter.com/document/doi/10.1515/ijamh-2013-0052/html
Scroll Up Arrow