Serotonergicg Challengeg of Cognitiveg Functions in Ecstasyy Users Preller K1, Dörig N1, Hasler F2, Vollenweider FX2, Quednow BB1 1 Universityy Hospitalp off Psychiatry,yy, Experimentalp and Clinical Pharmacopsychology,py gy, Zürich,, Switzerland 2 University Hospital of Psychiatry,Psychiatry Neuropsychopharmacology & Brain Imaging,Imaging Zürich,Zürich Switzerland

BkBackgroundg d group x tttreatment: t p≤ 0050,05 group x tttreatment: t p≤ 0050,05 Alterations to the serotonin (5‐HT)) systemy induced byy the consumptionp of ±3,4methylene‐dioxy‐methamphetamine (MDMA(MDMA, “ecstasy”)ecstasy ) have been docu‐ mentedtdiin animalsil[1] ((see FiFig. 1) andd hhumans [2]. MMoreover, memory dfiitdeficits hhave been demonstrated by current and recently abstinent MDMA users [3]. * Pharmacological challenge studies offer an effective way to disclose the relation * between the 5‐HT systemy and cognitiveg impairmentsp shown byy MDMA users,, mainly because this method provides potential to detect subclinical changes in centraltl5‐HT ftifunction. FthFurthermore, littllittle iis kknown aboutbtththe reversibilityibilit off memory deficits once consumers quit using MDMA. We therefore measured memory performance under the influence of the 5‐HT releaser dexfenflurmine in comparisonp to placebop in current and former MDMA users and control subjectsj .

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FiFig. 2:2 MMemory performancef ffor current andd formerf MDMA users andd ddrug‐naïïve controlsl ini baselinebli andd dexfenfluraminedffl i conditiondi i ((means and SEM),SEM) `**´ indicates significant difference in memory score compared to the control group.group

FigFig. 1: Sagittal plane,plane dark‐field photomicrograph of 5‐HT immunoreactive axons in the frontal cortex of a control monkey (A)), a monkey treated with 5mg/kg MDMA (2 times a day for four 4 days) 2 weeks previously (B), and a monkey treated with MDMA 7 years previously (C) (from:( Hatzidimitriou, et al., 1999).) MthdMethods Dexfenfluramineff and placebop were administered double‐blind, randomized, and counter‐balanced on two test days with an interval of 14 days. Memory functioning was measuredd iin 15 abstinentbti tcurrentt MDMA users, 12 fformer MDMA users, andd 13 drug‐naïve controls. All participants were male and matched for age, education, and verbal IQ. Subjects completed various verbal and visuo‐spatial mnemonic tasks ((Reyy Auditoryy Verbal Learningg Test [][RAVLT] and tasks ffrom the Cambridgeg Neuro‐ psychological Test Automated Battery [CANTAB]). Subtests were grouped into three memory didomains andd a memory idindex ildiincluding allll variablesibl ((see TbTab. 1). MMean values were z‐transformed for each individual on the mean of the control group. Memory scores were subjected to a 3 × 2 (group × treatment) repeated‐measures ANOVA, with treatment as within‐subjectj and groupgpas between‐subjectj ffactor.

Working Memory Declarative Memory zVLMT First Trial Memory Score zVLMT 7 Delayed Recall Tab. 2: Baseline neuropsychological test scores for current and former MDMA users and drug‐naïve controls (means and standard deviations; zVLMTVLMT CitConsistency zVLMTVLMT ∑∑1‐5 Tukey‐HSD Posthoc‐test: *p<.05, **p<.01). zPALPAL FiFirst t TrialTi l MemoryM ScoreS zPALPAL EErrors (t(total, t l corrected)td) zPAL First Triall Correct zPAL mean Trialsl to Success zSSP Spanlength zPAL Trials (total, corrected) Discussion zSSP Total Error zSWM Total Error GGroup diffdifferences iin response tto ththe pharmacologicalhlilchallengehll withith zRVPA’ Signalg Detection dexfenfluramine were found for declarative memoryy and the total memoryy index. In contrast to drug‐naïve controlscontrols, MDMA users seem to benefit from the Recognition Memory Index zVLMT p(A) List A All Variables administrationd off dffldexfenfluramine. As mnemonic abilitiesbl off current andd fformer zVLMT p(A) List B MDMA users were sensitive to the serotonergic challengechallenge, these results support zPRM Number Correct previousi findings,fi di whichhi h indicateidit longl ‐termt changesh off theth 5‐HT systemt off MDMA zSRM Number Correct users. The presentp data further suggestgg that these alterations of the 5‐HT systemy TbTab. 1: CfitiConfiguration off memory domains,di identifiedid tifi d byb factorft analysis.li are primarily impairing declarative memory function. Furtherh analysesl revealedldthath current MDMA users showedhdmarkedkdverbalblandd Results visuo‐spatial memory deficitsdeficits, whereas former MDMA users only exhibited deficits iin visuoi ‐spatialti l memory. ThThese resultslt iditindicate ththat t memory dfiitdeficits iin MDMA The dexfenfluramine challenge exerted significant group x treatment interactions in users show greaterg reversibilityy for verbal than for visuo‐spatialp memoryy after two out off ffour memory didomains on a significanceiifi lllevel off p ≤ 0.05 afterf controllinglli consumers quit using MDMA. for dexfenfluramine blood level: declarative memory (F = 3.87; p = 0.03) and the memory idindex (F = 3.45; p = 0.05). CtCurrent MDMA users, fformer MDMA users andd controls did not respondp significantlygydifferent to the pharmacologicalpgchallengeg in Conclusionli working memory (F = 1.58; p = 0.22) and recognition (F = 1.32; p = 0.28) (see Fig. 2). Verbal and visuo‐spatial memory deficits present in MDMA users seem to be Furthermore,h current MDMA users showedhdsignificantiifi dfiideficits iin verbalblandd visuoi ‐ related to alterations of the 5‐HT system. Verbal deficits diminish more strongly spatial memory, whereas former MDMA users only performed worse in specific than visou‐spatialp deficits after MDMA consumptionp is stoppedpp . subtestsbt t relatedltdtto visuoi ‐spatialti l memory whenh comparedd tto controlstl((see TbTab. 2) .

DiDisclosure l The authors declare no conflict of interests. References [1] HidiiiHatzidimitriou, G., MCMcCann, U.D., RiRicautre, G.A. (1999). AlAltered d serotonini iiinnervation patterns iin theh fbiforebrain off monkeysk treatedd withih(/(+/‐) 3,4‐methylenedioxymethamphetaminehl di h h i (MDMA) seven years previouslyil: ffactors iflinfluencing i abnormalblrecovery. Journall off Neuroscience, 19(12)), 5096‐5107. [2] McCann, U.D., Mertl, M., Eligulashvili, V., Ricautre, G.A. (1999). Cognitive performance in (+//‐) 3,4‐methylenedioxymethamphetamine (‘Ecstasy’)‐induced serotonin neurotoxity: clinical studies. Neuropsychobiology, 42(1), 11‐16. [3] Quednow, B.B., Jessen, F., Kuhn, K.U., Maier, W., Daum, I., Wagner, M. (2006). Memory deficits in abstinent MDMA (ecstasy) users: neuropsychological evidence of frontal dysfunction. Journal of Psychopharmacology, 20(3), 373‐384.

KtiKatrin PllPreller ♦ UiUniversity it HitlHospital off Psychiatry,Phit UniversityUi it off ZihZurich♦ LtLenggstr. 31 ♦ 8032 ZüZürich, i h SwitzerlandSitl d ♦ E‐MilMail: [email protected] @bli h h