A Prospective Cohort Study on Sustained Effects of Low-Dose Ecstasy Use on the Brain in New Ecstasy Users

It is debated whether ecstasy use has neurotoxic effects on the human brain and what the effects are of a low dose of ecstasy use. We prospectively studied sustained effects (>2 weeks abstinence) of a low dose of ecstasy on the brain in ecstasy-naive volunteers using a combination of advanced MR techniques and self-report questionnaires on psychopathology as part of the NeXT (Netherlands XTC Toxicity) study. Outcomes of proton magnetic resonance spectroscopy (1H-MRS), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI), and questionnaires on depression, impulsivity, and sensation seeking were compared in 30 subjects (12M, 21.8±3.1 years) in two sessions before and after first ecstasy use (1.8±1.3 tablets). Interval between baseline and follow-up was on average 8.1±6.5 months and time between last ecstasy use and follow-up was 7.7±4.4 weeks. Using 1H-MRS, no significant changes were observed in metabolite concentrations of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and creatine (Cr), nor in ratios of NAA, Cho, and mI relative to Cr. However, ecstasy use was followed by a sustained 0.9% increase in fractional anisotropy (FA) in frontoparietal white matter, a 3.4% decrease in apparent diffusion (ADC) in the thalamus and a sustained decrease in relative regional cerebral blood volume (rrCBV) in the thalamus (−6.2%), dorsolateral frontal cortex (−4.0%), and superior parietal cortex (−3.0%) (all significant at p<0.05, paired t-tests). After correction for multiple comparisons, only the rrCBV decrease in the dorsolateral frontal cortex remained significant. We also observed increased impulsivity (+3.7% on the Barratt Impulsiveness Scale) and decreased depression (−28.0% on the Beck Depression Inventory) in novel ecstasy users, although effect sizes were limited and clinical relevance questionable. As no indications were found for structural neuronal damage with the currently used techniques, our data do not support the concern that incidental ecstasy use leads to extensive axonal damage. However, sustained decreases in rrCBV and ADC values may indicate that even low ecstasy doses can induce prolonged vasoconstriction in some brain areas, although it is not known whether this effect is permanent. Additional studies are needed to replicate these findings.

[1]  M. Yoshida,et al.  Cerebral infarction associated with 3,4-methylenedioxymethamphetamine ('Ecstasy') abuse. , 1995, European neurology.

[2]  F. Vollenweider,et al.  Acute Psychological Effects of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) are Attenuated by the Serotonin Uptake Inhibitor Citalopram , 1999, Neuropsychopharmacology.

[3]  W. van den Brink,et al.  Ecstasy use and self-reported depression, impulsivity, and sensation seeking: a prospective cohort study , 2006, Journal of psychopharmacology.

[4]  E. Check.  Psychedelic drugs: The ups and downs of ecstasy , 2004, Nature.

[5]  U. McCann,et al.  (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Clinical Studies , 2000, Neuropsychobiology.

[6]  D J Jenden,et al.  In vivo 1H MRS choline: correlation with in vitro chemistry/histology. , 1996, Life sciences.

[7]  E. Gouzoulis-Mayfrank,et al.  Psychological profile of abstinent recreational Ecstasy (MDMA) users and significance of concomitant cannabis use , 2001, Human psychopharmacology.

[8]  J. Downing.  The psychological and physiological effects of MDMA on normal volunteers. , 1986, Journal of psychoactive drugs.

[9]  A. A. Parsons.  5-HT receptors in human and animal cerebrovasculature. , 1991, Trends in pharmacological sciences.

[10]  Liesbeth Reneman,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[11]  L H Schwamm,et al.  Ischemic stroke: effects of etiology and patient age on the time course of the core apparent diffusion coefficient. , 2001, Radiology.

[12]  F. Vollenweider,et al.  Caveat Emptor: Editors Beware , 2001, Neuropsychopharmacology.

[13]  J W Belliveau,et al.  Functional cerebral imaging by susceptibility‐contrast NMR , 1990, Magnetic resonance in medicine.

[14]  J. Roh,et al.  Diffusion-Weighted MRI and 99mTc-HMPAO SPECT in Delayed Relapsing Type of Carbon Monoxide Poisoning: Evidence of Delayed Cytotoxic Edema , 2004, European Neurology.

[15]  A. Bond,et al.  Angry cognitive bias, trait aggression and impulsivity in substance users , 2004, Psychopharmacology.

[16]  G. Lee,et al.  ‘Ecstasy’-induced subarachnoid haemorrhage: an under-reported neurological complication? , 2003, Journal of Clinical Neuroscience.

[17]  C. Grob.  The Politics of Ecstasy , 2002, Journal of psychoactive drugs.

[18]  P. F. Renshaw,et al.  Dynamic susceptibility contrast magnetic resonance imaging in neuropsychiatry: present utility and future promise , 1997, European Radiology.

[19]  R. Poland,et al.  Psychobiologic effects of 3,4-methylenedioxymethamphetamine in humans: methodological considerations and preliminary observations , 1995, Behavioural Brain Research.

[20]  G. Gerra,et al.  Serotonergic function after (±)3,4‐methylene-dioxymethamphetarnine (‘Ecstasy’) in humans , 1998, International clinical psychopharmacology.

[21]  S. Brockstedt,et al.  Triggering in Quantitative Diffusion Imaging with Single-Shot EPI , 1999, Acta radiologica.

[22]  Jean-Philippe Ranjeva,et al.  Diffusion tensor imaging in multiple sclerosis: a tool for monitoring changes in normal-appearing white matter , 2004, Multiple sclerosis.

[23]  M. Iyo,et al.  Abnormal cerebral perfusion in chronic methamphetamine abusers: A study using 99mTC-HMPAO and spect , 1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[24]  N. Campeau,et al.  MR imaging and diffusion-weighted imaging changes in metronidazole (Flagyl)-induced cerebellar toxicity. , 2003, AJNR. American journal of neuroradiology.

[25]  F. Vollenweider,et al.  Psychological and Cardiovascular Effects and Short-Term Sequelae of MDMA (“Ecstasy”) in MDMA-Naïve Healthy Volunteers , 1998, Neuropsychopharmacology.

[26]  F. Vollenweider,et al.  Is A Single Dose of MDMA Harmless , 1999, Neuropsychopharmacology.

[27]  P. Sundgren,et al.  Magnetic resonance spectroscopy. , 2005, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[28]  L. Schmued.  Demonstration and localization of neuronal degeneration in the rat forebrain following a single exposure to MDMA , 2003, Brain Research.

[29]  R. Gruetter,et al.  In vivo magnetic resonance spectroscopy of human brain: the biophysical basis of dementia. , 1997, Biophysical chemistry.

[30]  S. Provencher.  Estimation of metabolite concentrations from localized in vivo proton NMR spectra , 1993, Magnetic resonance in medicine.

[31]  K J Rothman,et al.  No Adjustments Are Needed for Multiple Comparisons , 1990, Epidemiology.

[32]  G. D. den Heeten,et al.  Reduced N-acetylaspartate levels in the frontal cortex of 3,4-methylenedioxymethamphetamine (Ecstasy) users: preliminary results. , 2002, AJNR. American journal of neuroradiology.

[33]  K. L. Jansen,et al.  Toxic effect of MDMA on brain serotonin neurons , 1999, The Lancet.

[34]  P F Renshaw,et al.  Dynamic susceptibility contrast MR imaging of regional cerebral blood volume in Alzheimer disease: a promising alternative to nuclear medicine. , 1998, AJNR. American journal of neuroradiology.

[35]  M. Morgan.  Recreational Use of “Ecstasy” (MDMA) Is Associated with Elevated Impulsivity , 1998, Neuropsychopharmacology.

[36]  C. F. Bryan,et al.  Annual Report for 2004 , 2005 .

[37]  P F Renshaw,et al.  Test–retest reliability of DSC MRI CBV mapping in healthy volunteers , 2001, Neuroreport.

[38]  Jim Mintz,et al.  Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy. , 2002, The American journal of psychiatry.

[39]  E. Gouzoulis-Mayfrank,et al.  Self-reported psychopathological symptoms in recreational ecstasy (MDMA) users are mainly associated with regular cannabis use: further evidence from a combined cross-sectional/longitudinal investigation , 2004, Psychopharmacology.

[40]  C. Tempelmann,et al.  Eddy current correction in diffusion‐weighted imaging using pairs of images acquired with opposite diffusion gradient polarity , 2004, Magnetic resonance in medicine.

[41]  Stephen M Smith,et al.  Fast robust automated brain extraction , 2002, Human brain mapping.

[42]  M Hedehus,et al.  Diffusion-tensor MR imaging at 1.5 and 3.0 T: initial observations. , 2001, Radiology.

[43]  M. Colado,et al.  A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response. , 2004, European journal of pharmacology.

[44]  M. Farré,et al.  Contribution of Cytochrome P450 2D6 to 3,4-Methylenedioxymethamphetamine Disposition in Humans , 2005, Clinical pharmacokinetics.

[45]  M. Gorman,et al.  Diffusion-Weighted MRI Correlates of Subacute Methotrexate-Related Neurotoxicity , 2005, Journal of Neuro-Oncology.

[46]  M. Colado,et al.  The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype , 1995, British journal of pharmacology.

[47]  M. Morgan,et al.  Ecstasy (MDMA): a review of its possible persistent psychological effects , 2000, Psychopharmacology.

[48]  Linda Chang,et al.  Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users , 2002, Psychiatry Research: Neuroimaging.

[49]  Jörg Daumann,et al.  High Intensity Dependence of Auditory Evoked Dipole Source Activity Indicates Decreased Serotonergic Activity in Abstinent Ecstasy (MDMA) Users , 2000, Neuropsychopharmacology.

[50]  J. Mazziotta,et al.  Automated image registration , 1993 .

[51]  E. Gouzoulis-Mayfrank,et al.  Proton magnetic resonance spectroscopy in ecstasy (MDMA) users , 2004, Neuroscience Letters.

[52]  F. Vollenweider,et al.  3,4-Methylenedioxymethamphetamine (MDMA) Modulates Cortical and Limbic Brain Activity as Measured by [H215O]-PET in Healthy Humans , 2000, Neuropsychopharmacology.

[53]  Caveat Emptor: Researcher Beware , 1999, Neuropsychopharmacology.

[54]  B. Schmand,et al.  Prefrontal N-acetylaspartate is strongly associated with memory performance in (abstinent) ecstasy users: preliminary report , 2001, Biological Psychiatry.

[55]  H. Sumnall,et al.  Self-reported depressive symptomatology in community samples of polysubstance misusers who report Ecstasy use: a meta-analysis , 2005, Journal of psychopharmacology.

[56]  N. Ramsey,et al.  The Netherlands XTC Toxicity (NeXT) study: objectives and methods of a study investigating causality, course, and clinical relevance , 2005, International journal of methods in psychiatric research.

[57]  Scott T. Grafton,et al.  Automated image registration: I. General methods and intrasubject, intramodality validation. , 1998, Journal of computer assisted tomography.

[58]  P. McGuire,et al.  Diversity of Psychopathology Associated with use of 3,4-Methylenedioxymethamphetamine (‘Ecstasy’) , 1994, British Journal of Psychiatry.

[59]  R. de la Torre,et al.  Human pharmacology of 3,4-methylenedioxymethamphetamine ("ecstasy"): psychomotor performance and subjective effects. , 2000, Journal of clinical psychopharmacology.

[60]  F. Vollenweider,et al.  The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3, 4-methylenedioxymethamphetamine (‘Ecstasy’) in healthy volunteers , 2000, Journal of psychopharmacology.

[61]  J. Frahm,et al.  Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS , 1998, Magnetic resonance in medicine.

[62]  S. Kish.  How strong is the evidence that brain serotonin neurons are damaged in human users of ecstasy? , 2002, Pharmacology Biochemistry and Behavior.

[63]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[64]  E. Khantzian.  The Self‐Medication Hypothesis of Substance Use Disorders: A Reconsideration and Recent Applications , 1997, Harvard review of psychiatry.

[65]  T. Murata,et al.  Neuronal damage in the interval form of CO poisoning determined by serial diffusion weighted magnetic resonance imaging plus1H-magnetic resonance spectroscopy , 2001, Journal of Neurology Neurosurgery & Psychiatry.

[66]  Harm J Gijsman,et al.  MDMA Study , 1999, Neuropsychopharmacology.

[67]  R. Schwarting,et al.  Acute and long-term consequences of single MDMA administration in relation to individual anxiety levels in the rat , 2004, Behavioural Brain Research.

[68]  Ralph Buchert,et al.  A voxel-based PET investigation of the long-term effects of "Ecstasy" consumption on brain serotonin transporters. , 2004, The American journal of psychiatry.

[69]  D P Auer,et al.  On the reliability of quantitative clinical magnetic resonance spectroscopy of the human brain , 1995, NMR in biomedicine.

[70]  V. Haughton,et al.  Diffusion tensor MR imaging in diffuse axonal injury. , 2002, AJNR. American journal of neuroradiology.

[71]  P. McGuire,et al.  Toxic effect of MDMA on brain serotonin neurons , 1999, The Lancet.

[72]  A. Parrott,et al.  ‘Is MDMA a Human Neurotoxin?’:Diverse Views from the Discussants , 2000, Neuropsychobiology.

[73]  R. Zimmerman,et al.  Heroin-induced spongiform leukoencephalopathy: value of diffusion MR imaging. , 2000, Journal of computer assisted tomography.

[74]  G. D. den Heeten,et al.  MDMA ("Ecstasy") and its association with cerebrovascular accidents: preliminary findings. , 2000, AJNR. American journal of neuroradiology.

[75]  Z. Szabo,et al.  Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings , 1998, The Lancet.

[76]  Liesbeth Reneman,et al.  Neuroimaging findings with MDMA/ecstasy: technical aspects, conceptual issues and future prospects , 2006, Journal of psychopharmacology.

[77]  R. Buchert,et al.  Long-term effects of ‘ecstasy’ abuse on the human brain studied by FDG PET , 2001, Nuclear medicine communications.

[78]  A. Parrott,et al.  Psychobiological problems in heavy 'ecstasy' (MDMA) polydrug users. , 2000, Drug and alcohol dependence.

[79]  Napapon Sailasuta,et al.  A comparative study of myo-inositol quantification using LCmodel at 1.5 T and 3.0 T with 3 D 1H proton spectroscopic imaging of the human brain. , 2004, Magnetic resonance imaging.

[80]  F. Vollenweider,et al.  3,4-Methylenedioxymethamphetamine (MDMA) Modulates Cortical and Limbic Brain Activity as Measured by (H 2 15 O)-PET in , 2000 .

[81]  H. Gudbjartsson,et al.  The rician distribution of noisy mri data , 1995, Magnetic resonance in medicine.

[82]  G K L Butler,et al.  Impulsivity, risk taking and recreational 'ecstasy' (MDMA) use. , 2004, Drug and alcohol dependence.

[83]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[84]  J. Langston,et al.  Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration , 1988, Brain Research.

[85]  G. D. den Heeten,et al.  Effects of ecstasy (MDMA) on the brain in abstinent users: initial observations with diffusion and perfusion MR imaging. , 2001, Radiology.

[86]  T. Ernst,et al.  Cerebral 1H MRS alterations in recreational 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) users , 1999, Journal of magnetic resonance imaging : JMRI.

[87]  Adolf Pfefferbaum,et al.  Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: a preliminary proton MRS study , 2002, Psychiatry Research: Neuroimaging.

[88]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[89]  J. Patton,et al.  Factor structure of the Barratt impulsiveness scale. , 1995, Journal of clinical psychology.

[90]  M. Zuckerman,et al.  Personality and risk-taking: common biosocial factors. , 2000, Journal of personality.

[91]  J. Helpern,et al.  Neuropsychiatric applications of DTI – a review , 2002, NMR in biomedicine.

[92]  U. McCann,et al.  Pharmacokinetic Profile of Single and Repeated Oral Doses of MDMA in Squirrel Monkeys: Relationship to Lasting Effects on Brain Serotonin Neurons , 2006, Neuropsychopharmacology.

[93]  G. Vaiva,et al.  An “Accidental” Acute Psychosis with Ecstasy Use , 2001, Journal of psychoactive drugs.

[94]  G. Greer,et al.  Subjective reports of the effects of MDMA in a clinical setting. , 1986, Journal of psychoactive drugs.

[95]  G. Bonvento,et al.  SEROTONIN IN THE REGULATION OF BRAIN MICROCIRCULATION , 1996, Progress in Neurobiology.

[96]  F. Schifano.  Potential Human Neurotoxicity of MDMA (‘Ecstasy’): Subjective Self-Reports, Evidence from an Italian Drug Addiction Centre and Clinical Case Studies , 2000, Neuropsychobiology.

[97]  R. Floris,et al.  Diffusion and perfusion MR imaging in cases of Alzheimer's disease: correlations with cortical atrophy and lesion load. , 2001, AJNR. American journal of neuroradiology.

[98]  L. Itti,et al.  Effect of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] on cerebral blood flow: a co-registered SPECT and MRI study , 2000, Psychiatry Research: Neuroimaging.

[99]  J. Stanley,et al.  In vivo Magnetic Resonance Spectroscopy and its Application to Neuropsychiatric Disorders , 2002, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[100]  P. Renshaw,et al.  Applications of Dynamic Susceptibility Contrast Magnetic Resonance Imaging in Neuropsychiatry , 1996, NeuroImage.

[101]  F. Schifano,et al.  Personality dimensions and psychopathological profiles of Ecstasy users , 2001, Human psychopharmacology.

[102]  F. Vollenweider,et al.  Acute psychological and physiological effects of MDMA (“Ecstasy”) after haloperidol pretreatment in healthy humans , 2000, European Neuropsychopharmacology.

[103]  Linda Chang,et al.  Evidence for long-term neurotoxicity associated with methamphetamine abuse , 2000, Neurology.

[104]  M. Zuckerman,et al.  Construct validity for the sensation-seeking scale. , 1968, Journal of consulting and clinical psychology.

[105]  U. McCann,et al.  (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals , 2000, Neuropsychobiology.

[106]  R. Buchert,et al.  Specific neurotoxicity of chronic use of ecstasy. , 2002, Toxicology letters.