Chronic administration of the common club drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is associated with long-term depletion of serotonin (5-HT) and loss of 5-HT axons in the brains of rodents and non-human primates, and evidence suggests that recreational MDMA consumption may also affect the human serotonergic system. Moreover, it was consistently shown that abstinent MDMA users have memory de.cits. Recently, it was supposed that these de.cits are an expression of a temporal or rather hippocampal dysfunction caused by the serotonergic neurotoxicity of MDMA. The aim of this study is to examine the memory de.cits of MDMA users neuropsychologically in order to evaluate the role of different brain regions. Nineteen male abstinent MDMA users, 19 male abstinent cannabis users and 19 male drug-naive control subjects were examined with a German version of the Rey Auditory Verbal Learning Test (RAVLT). MDMA users showed widespread and marked verbal memory de.cits, compared to drug-naive controls as well as compared to cannabis users, whereas cannabis users did not differ from control subjects in their memory performance. MDMA users revealed impairments in learning, consolidation, recall and recognition. In addition, they also showed a worse recall consistency and strong retroactive interference whereby both measures were previously associated with frontal lobe function. There was a signi.cant correlation between memory performance and the amount of MDMA taken. These results suggest that the memory de.cits of MDMA users are not only the result of a temporal or hippocampal dysfunction, but also of a dysfunction of regions within the frontal cortex.
Alexander M P , Stuss D T (2000) Disorders of frontal lobe functioning . Semin Neurol20: 427–437
2.
Alexander M P , Stuss D T , Fansabedian N (2003) California Verbal Learning Test: performance by patients with focal frontal and nonfrontal lesions . Brain126: 1493–1503
3.
Ali S F , Newport G D , Scallet A C , Binienda Z , Ferguson S A , Bailey J R , Paule M G , Slikker W Jr (1993) Oral administration of 3,4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate . Neurotoxicol Teratol15: 91–96
4.
Alting von Geusau N , Stalenhoef P , Huizinga M , Snel J , Ridderinkhof K R (2004) Impaired executive function in male MDMA (‘ecstasy’) users . Psychopharmacology (Berl)175: 331–341
5.
Anderson M C (2003). Rethinking interference theory: executive control and the mechanisms of forgetting . Journal of Memory and Language49: 415–445
6.
Back-Madruga C , Boone K B , Chang L , Grob C S , Lee A , Nations H , Poland R E (2003) Neuropsychological effects of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) in recreational users . Clin Neuropsychol17: 446–459
7.
Baddeley A (2003) Working memory: looking back and looking forward . Nat Rev Neurosci4: 829–839
8.
Baldo J V , Delis D , Kramer J , Shimamura A P (2002) Memory performance on the California Verbal Learning Test-II: findings from patients with focal frontal lesions . J Int Neuropsychol Soc8: 539–546
9.
Beebe D W , Ris M D , Dietrich K N (2000) The relationship between CVLT-C process scores and measures of executive functioning: lack of support among community-dwelling adolescents . J Clin Exp Neuropsychol22: 779–792
10.
Benedict R H , Zivadinov R , Carone D A , Weinstock-Guttman B , Gaines J , Maggiore C , Sharma J , Tomassi M A , Bakshi R (2005) Regional lobar atrophy predicts memory impairment in multiple sclerosis . AJNR Am J Neuroradiol26: 1824–1831
11.
Bhattachary S , Powell J H (2001) Recreational use of 3,4-methylenedioxymethamphetamine (MDMA) or ‘ecstasy’: evidence for cognitive impairment . Psychol Med31: 647–658
12.
Bigler E D , Rosa L , Schultz F , Hall S , Harris J (1989) Rey-Auditory Verbal Learning and Rey-Osterrieth Complex Figure Design performance in Alzheimer's disease and closed head injury . J Clin Psychol45: 277–280
13.
Bolla K I , McCann U D , Ricaurte G A (1998) Memory impairment in abstinent MDMA (‘Ecstasy’) users . Neurology51: 1532–1537
14.
Buchert R , Thomasius R , Nebeling B , Petersen K , Obrocki J , Jenicke L , Wilke F , Wartberg L , Zapletalova P , Clausen M (2003) Long-term effects of ‘ecstasy’ use on serotonin transporters of the brain investigated by PET . J Nuc Med44: 375–384
15.
Bzg A (Federal Centre for Health Education) (2004) Die Drogenaffinität Jugendlicher in der Bundesrepublik Deutschland. Teilband: Illegale Drogen. BzgA, Köln
16.
Christophersen A S (2000) Amphetamine designer drugs – an overview and epidemiology . Toxicol Lett112–113: 127–131
17.
Croft R J , Klugman A , Baldeweg T , Gruzelier J H (2001a) Electrophysiological evidence of serotonergic impairment in long-term MDMA (‘ecstasy’) users . Am J Psychiatry158: 1687–1692
18.
Croft R J , Mackay A J , Mills A T , Gruzelier J G (2001b) The relative contributions of ecstasy and cannabis to cognitive impairment . Psychopharmacology (Berl)153: 373–379
19.
Curran H V (2000) Is MDMA (‘Ecstasy’) neurotoxic in humans? An overview of evidence and of methodological problems in research . Neuropsychobiology42: 34–41
20.
Curran H V , Brignell C , Fletcher S , Middleton P , Henry J (2002) Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users . Psychopharmacology (Berl)164: 61–70
21.
Daumann J Jr , Fischermann T , Heekeren K , Thron A , Gouzoulis-Mayfrank E (2004a) Neural mechanisms of working memory in ecstasy (MDMA) users who continue or discontinue ecstasy and amphetamine use: evidence from an 18-month longitudinal functional magnetic resonance imaging study . Biol Psychiatry56: 349–355
22.
Daumann J , Pelz S , Becker S , Tuchtenhagen F , Gouzoulis-Mayfrank F (2001) Psychological profile of abstinent recreational Ecstasy (MDMA) users and significance of concomitant cannabis use . Hum Psychopharmacol Clin Exp16: 627–633
23.
Daumann J , Fischermann T , Heekeren K , Henke K , Thron A , Gouzoulis-Mayfrank E (2004b) Memory-related hippocampal dysfunction in poly-drug ecstasy (3,4-methylenedioxymethamphetamine) users . Psychopharmacology (Berl) Sep 15, (Epub ahead of print)
24.
de la Torre R , Farre M , Roset P N , Hernandez Lopez C , Mas M , Ortuno J , Menoyo E , Pizarro N , Segura J , Cami J (2000) Pharmacology of MDMA in humans . Ann N Y Acad Sci914: 225–237
25.
Delis D C , Kramer J , Kaplan E , Ober B A (1987) California Verbal Learning Test, Adult Version Manual. Psychological Corporation, San Antonio, TX
26.
Delis D C , Kramer J , Kaplan E , Ober B A (1994) California Verbal Learning-Test, Children's Version Manual. Psychological Corporation, San Antonio, TX
27.
Erdfelder E , Faul F , Buchner A (1996) GPOWER: A general power analysis program . Behavior Research Methods, Instruments & Computers28: 1–11
28.
Fischer C , Hatzidimitriou G , Wlos J , Katz J , Ricaurte G (1995) Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/ δ)3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) . J Neurosci15: 5476–5485
29.
Fisk J E , Montgomery C , Murphy P , Wareing M (2004) Evidence for executive deficits among users of MDMA (Ecstasy) . Br J Psychol95: 457–466
30.
Forrester G , Geffen G (1991) Performance measures of 7-to 15-year-old children on the Auditory Verbal Learning Test . The Clinical Neuropsychologist5: 345–359
31.
Fox H C , Parrott A C , Turner J J (2001a) Ecstasy use: cognitive deficits related to dosage rather than self-reported problematic use of the drug . J Psychopharmacol15: 273–281
32.
Fox H C , Toplis A S , Turner J J D , Parrott A C (2001b) Auditory verbal learning in drug-free Ecstasy polydrug users . Hum Psychopharmacol Clin Exp16: 613–618
33.
Fox H C , McLean A , Turner J J , Parrott A C , Rogers R , Sahakian B J (2002) Neuropsychological evidence of a relatively selective profile of temporal dysfunction in drug-free MDMA (‘ecstasy’) polydrug users . Psychopharmacology (Berl)162: 203–214
34.
Fried P A , Watkinson B , Gray R (2005) Neurocognitive consequences of marihuana – a comparison with pre-drug performance . Neurotoxicol Teratol27: 231–239
35.
Funahashi S (2001) Neuronal mechanisms of executive control by the prefrontal cortex . Neurosci Res39: 147–165
36.
Geffen G M , Butterworth P , Forrester G M , Geffen L B (1994) Auditory verbal learning test components as measures of the severity of closedhead injury . Brain Inj8: 405–411
37.
Gouzoulis-Mayfrank E , Becker S , Pelz S , Tuchtenhagen F , Daumann J (2002) Neuroendocrine abnormalities in recreational ecstasy (MDMA) users: is it ecstasy or cannabis?Biol Psychiatry51: 766–769
38.
Gouzoulis-Mayfrank E , Thimm B , Rezk M , Hensen G , Daumann J (2003) Memory impairment suggests hippocampal dysfunction in abstinent ecstasy users . Prog Neuropsychopharmacol Biol Psychiatry27: 819–827
39.
Gouzoulis-Mayfrank E , Daumann J , Tuchtenhagen F , Pelz S , Becker S , Kunert H J , Fimm B , Sass H (2000) Impaired cognitive performance in drug free users of recreational ecstasy (MDMA) . J Neurol Neurosurg Psychiatry68: 719–725
40.
Green D M , Swets J A (1966) Signal Detection Theory and Psychophysics. J. Wiley, London
41.
Hatzidimitriou G , McCann D U , Ricaurte G A (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with (+/ δ)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery . J Neurosci19: 5096–5107
42.
Helmstaedter C , Elger C E (1996) Cognitive consequences of two-thirds anterior temporal lobectomy on verbal memory in 144 patients: a three-month follow-up study . Epilepsia37: 171–180
43.
Helmstaedter C , Lendt M , Lux S (2001) Verbaler Lernund Merkfähigkeitstest, Manual. Beltz, Göttingen
44.
Helmstaedter C , Grunwald T , Lehnertz K , Gleissner U , Elger C E (1997) Differential involvement of left temporolateral and temporomesial structures in verbal declarative learning and memory: evidence from temporal lobe epilepsy . Brain Cogn35: 110–131
45.
Huestis M A , Cone E J (1998) Urinary excretion half-life of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol in humans . Ther Drug Monit20: 570–576
46.
Insel T R , Battaglia G , Johannessen J N , Marra S , De Souza E B (1989) 3,4-Methylenedioxymethamphetamine (‘ecstasy’) selectively destroys brain serotonin terminals in rhesus monkeys . J Pharmacol Exp Ther249: 713–720
47.
Jacobsen L K , Mencl W E , Pugh K R , Skudlarski P , Krystal J H (2004) Preliminary evidence of hippocampal dysfunction in adolescent MDMA (‘ecstasy’) users: possible relationship to neurotoxic effects . Psychopharmacology (Berl)173: 383–390
48.
Landry M J (2002) MDMA: a review of epidemiologic data . J Psychoactive Drugs34: 163–169
49.
Leathem J M , Body C M (1997) Neuropsychological sequelae of head injury in a New Zealand adolescent sample . Brain Inj11: 565–575
50.
Lehrl S (1999) Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B), 4th edn.Hogrefe, Göttingen
51.
Lyketsos C G , Garrett E , Liang K Y , Anthony J C (1999) Cannabis use and cognitive decline in persons under 65 years of age . Am J Epidemiol149: 794–800
52.
Lyons M J , Bar J L , Panizzon M S , Toomey R , Eisen S , Xian H , Tsuang M T (2004) Neuropsychological consequences of regular marijuana use: a twin study . Psychol Med34: 1239–1250
53.
McCann U D , Mertl M , Eligulashvili V , Ricaurte G A (1999) Cognitive performance in (+/ δ) 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) users: a controlled study . Psychopharmacology (Berl)143: 417–425
54.
McCann U D , Ridenour A , Shaham Y , Ricaurte G A (1994) Serotonin neurotoxicity after (+/ δ) 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’): a controlled study in humans . Neuropsychopharmacology10: 129–138
55.
McCann U D , Szabo Z , Scheffel U , Dannals R F , Ricaurte G A (1998) Positron emission tomographic evidence of toxic effect of MDMA (‘Ecstasy’) on brain serotonin neurons in human beings . Lancet352: 1433–1437
56.
McCardle K , Luebbers S , Carter J D , Croft R J , Stough C (2004) Chronic MDMA (ecstasy) use, cognition and mood . Psychopharmacology (Berl)173: 434–439
57.
Miller G A , Chapman J P (2001) Misunderstanding analysis of covariance . J Abnorm Psychol110: 40–48
58.
Moeller F G , Steinberg J L , Dougherty D M , Narayana P A , Kramer L A , Renshaw P F (2004) Functional MRI study of working memory in MDMA users . Psychopharmacology (Berl)177: 185–194
59.
Morgan M J (1999) Memory deficits associated with recreational use of ‘ecstasy’ (MDMA) . Psychopharmacology (Berl)141: 30–36
60.
Morgan M J , McFie L , Fleetwood H , Robinson J A (2002) Ecstasy (MDMA): are the psychological problems associated with its use reversed by prolonged abstinence?Psychopharmacology (Berl)159: 294–303
61.
O'Hearn E , Battaglia G , De Souza E B , Kuhar M J , Molliver M E (1988) 3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) cause ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence . J Neurosci8: 2788–2803
62.
O'shea E , Granados R , Esteban B , Colado M I , Green A R (1998) The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (‘ecstasy’) . Neuropharmacology37: 919–926
63.
Park S B , Coull J T , McShane R H , Young A H , Sahakian B J , Robbins T W , Cowen P J (1994) Tryptophan depletion in normal volunteers produces selective impairments in learning and memory . Neuropharmacology33: 575–588
64.
Parrott A C (2002) Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity . Pharmacol Biochem Behav71: 837–844
65.
Parrott A C , Lasky J (1998) Ecstasy (MDMA) effects upon mood and cognition: before, during and after a Saturday night dance . Psychopharmacology (Berl)139: 261–268
66.
Parrott A C , Lees A , Garnham N J , Jones M , Wesnes K (1998) Cognitive performance in recreational users of MDMA of ‘ecstasy’: evidence for memory deficits . J Psychopharmacol12: 79–83
67.
Pope H G Jr , Gruber A J , Hudson J I , Huestis M A , Yurgelun-Todd D (2001) Neuropsychological performance in long-term cannabis users . Arch Gen Psychiatry58: 909–915
68.
Pope H G , Gruber A J , Hudson J I , Huestis M A , Yurgelun-Todd D (2002) Cognitive measures in long-term cannabis users . J Clin Pharmacol42: 41S–47S
69.
Postman L , Underwood B J (1973) Critical issues in interference theory . Memory and Cognition1: 19–40
70.
Quednow B B , Kuhn K U , Hoenig K , Maier W , Wagner M (2004) Prepulse inhibition and habituation of acoustic startle response in male MDMA (‘Ecstasy’) users, cannabis users, and healthy controls . Neuropsychopharmacology29: 982–990
71.
Quednow B B , Kuhn K U , Hoppe C , Westheide J , Maier W , Daum I , Wagner M (in press) Elevated impulsivity and impaired decisionmaking cognition in recreational users of MDMA (‘Ecstasy’) . Psychopharmacology
72.
Ranganath C , Knight R T (2003) Prefrontal cortex and episodic memory: integrating findings from neuropsychology and functional brain imaging. In Wilding E , Parker A , Bussey T (eds), Memory Encoding and Retrieval. A Cognitive Neuroscience Perspective. Psychology Press, New York
73.
Ranganath C , Johnson M K , D'Esposito M (2003) Prefrontal activity associated with working memory and episodic long-term memory . Neuropsychologia41: 378–389
74.
Reneman L , Lavalaye J , Schmand B , de Wolff F A , van den Brink W , den Heeten G J , Booij J (2001) Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy’) . Arch Gen Psychiatry58: 901–906
75.
Rey A (1964) L'examen de Clinique en Psychologie. Presses Universitaire de France, Paris
76.
Riedel W J , Klaassen T , Schmitt J A (2002) Tryptophan, mood, and cognitive function . Brain Behav Immun16: 581–589
77.
Riedel W J , Klaassen T , Deutz N E , van Someren A , van Praag H M (1999) Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation . Psychopharmacology (Berl)141: 362–369
Rudnick G , Wall S C (1992) The molecular mechanism of ‘ecstasy’ [3,4-methylenedioxymethamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release . Proc Natl Acad Sci USA89: 1817–1821
80.
Scheffel U , Szabo Z , Mathews W B , Finley P A , Dannals R F , Ravert H T , Szabo K , Yuan J , Ricaurte G A (1998) In vivo detection of short-and long-term MDMA neurotoxicity – a positron emission tomography study in the living baboon brain . Synapse29: 183–192
81.
Semple D M , Ebmeier K P , Glabus M F , O'Carroll R E , Johnstone E C (1999) Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (‘ecstasy’) users . Brit J Psychiatry175: 63–69
82.
Shimamura A P , Jurica P J , Mangels J A , Gershberg F B , Knight R T (1995) Susceptibility to memory interference effects following frontal lobe damage: Findings from tests of paired-associate learning . J Cogn Neurosci7: 144–152
83.
Simon N G , Mattick R P (2002) The impact of regular ecstasy use on memory function . Addiction97: 1523–1529
84.
Sternberg R J , Tulving E (1977) The measurement of subjective organization in free recall . Psychological Bulletin84: 539–556
85.
Stuerenburg H J , Petersen K , Baumer T , Rosenkranz M , Buhmann C , Thomasius R (2002) Plasma concentrations of 5-HT, 5-HIAA, norepinephrine, epinephrine and dopamine in ecstasy users . Neuroendocrinol Lett23: 259–261
86.
Stuss D T , Alexander M P , Palumbo C L , Buckle L , Sayer L , Pogue J (1994) Organizational strategies of patients with unilateral or bilateral frontal lobe injuries in word listening learning tasks . Neuropsychology8: 355–373
87.
Tabachnick B G , Fidell L (2001) Using Multivariate Statistics. Allyn and Bacon, Boston, MA
88.
Thomasius R , Petersen K , Buchert R , Andresen B , Zapletalova P , Wartberg L , Nebeling B , Schmoldt A (2003) Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users . Psychopharmacology (Berl)167: 85–96
89.
Torres I J , Flashman L A , O'Leary D S , Andreasen N C (2001) Effects of retroactive and proactive interference on word list recall in schizophrenia . J Int Neuropsychol Soc7: 481–490
90.
Tuchtenhagen F , Daumann J , Norra C , Gobbele R , Becker S , Pelz S , Sass H , Buchner H , Gouzoulis-Mayfrank E (2000) High intensity dependenceof auditory evoked dipole source activity indicates decreased serotonergic activity in abstinent ecstasy (MDMA) users . Neuropsychopharmacology22: 608–617
91.
Vanderploeg R D , Schinka J A , Retzlaff P (1994) Relationships between measures of auditory verbal learning and executive functioning . J Clin Exp Neuropsychol16: 243–252
92.
Wareing M , Fisk J E , Murphy P N (2000) Working memory deficits in current and previous users of MDMA (‘ecstasy’) . Br J Psychol91: 181–188
93.
Wareing M , Murphy P N , Fisk J E (2004a) Visuospatial memory impairments in users of MDMA (‘ecstasy’) . Psychopharmacology (Berl)173: 391–397
94.
Wareing M , Fisk J E , Murphy P , Montgomery C (2004b) Verbal working memory deficits in current and previous users of MDMA . Hum Psychopharmacol19: 225–234
95.
Waters H S , Waters E (1976) Semantic processing in children's free recall: Evidence for the importance of attentional factors and encoding variability . J Exp Psychol: Hum Learn2: 370–380
96.
Wilson M A , Ricaurte G A , Molliver M E (1989) Distinct morphological classes of serotonergic axons in primates exhibit differential vulnerability to the psychotropic drug 3,4-methylenedioxymethamphetamine . Neuroscience28: 121–137
97.
Zakzanis K K , Young D A (2001) Executive function in abstinent MDMA (‘ecstasy’) users . Med Sci Monit7: 1292–1298
