Memory impairment
Article abstract—To examine the neurotoxic potential of continued MDMA
in abstinent MDMA
(“Ecstasy”) use in humans and its functional consequences over the course of1 year, 15 MDMA users participated in a longitudinal study in which they (“Ecstasy”) users: A
completed a brief neuropsychological test battery composed mainly of retro- longitudinal
spective and prospective memory tasks. Subjects were abstinent for 2 weekson initial and 1-year testing. Continued use of MDMA was associated with investigation
progressive decline in terms of immediate and delayed recall.
NEUROLOGY 2001;56:966–969 Konstantine K. Zakzanis, PhD; and Donald A. Young, PhD Several experimental studies indicate that Ϯ3,4- Hence, given that sleep deprivation is a noted finding in methylenedioxymethamphetamine (MDMA or “Ec- MDMA users and affects cognitive performance, partici- stasy”) damages brain serotonin (5-HT) in animals pants were tested both at baseline and follow-up, when (including nonhuman primates) and possibly they reported at least 7 nights of 7 to 9 hours of continuous humans.1-3 As such, a significant proportion of users sleep. Moreover, all subjects agreed to abstain from all may eventually be at risk for long-term neurotoxico- drugs for at least 2 weeks before testing at baseline and logic effects, particularly in the hippocampus, a follow-up. Their drug-free status was confirmed by urine brain region believed to play an important role in and blood drug screens. Given that the half-life of MDMA learning and the consolidation of new memories. In- in animals is 1 to 2 hours, the 2-week period of abstinence deed, emerging neuropsychological literature sug- was deemed long enough to rule out any withdrawal ef- gests that repeated use of MDMA produces lasting fects, including sleep deprivation.8 These exclusionary cri- teria were met at both baseline and follow-up. Participants Despite this evidence, the longitudinal sequela of were not paid for their time but were reimbursed for travel MDMA use on memory function has received little (i.e., parking) expenses. Informed consent was obtained attention. It is currently unclear whether continued MDMA use produces progressive memory impair- Participants were tested twice over a period of 12 ment over time. Accordingly, this investigation ex- months. No attrition occurred in terms of subject participa- amined the neurotoxic potential of continued MDMA tion over the 12 months. Most participants were male use in humans and its functional consequences over (80%) and had completed approximately 14 years of educa- the period of 1 year. Direct evidence regarding this tion. The modal age of participants was 24.1 years at base- should address questions regarding the relationship between the neurotransmitter serotonin and higher Procedure. Participants completed a brief neuropsy- chological test battery after describing their characteristicMDMA use and other drug experience. Neuropsychological Methods. Participants. Fifteen MDMA users partici-
measures included into the test battery were the Wechsler pated in the study. All participants were recruited by word Adult Intelligence Scale–III (WAIS-III) Vocabulary and of mouth and, hence, were self-referred, having learned Block Design subtests and the Rivermead Behavioral about ongoing research on the consequences of MDMA use.
Memory Test (RBMT). The RBMT was developed to detect Subjects were all fluent English-speaking individuals. Ex- impairment of everyday memory functioning. Reported in- clusion from the study was warranted when subjects re- terrater reliability with this test is excellent with 100% ported a past or current history of major medical illness agreement and test–retest stability for the complete form (e.g., neurologic, renal, endocrine, or hematologic), current is good (r ϭ 0.85). Standardized profile scores were re- major psychiatric illness as determined by the Structured corded for all items on the RBMT. The items included are Clinical Interview of the Diagnostic and Statistical Man- ual III–Revised (DSM-SCI-III-R), a positive drug screen for First and second name. The subject is shown a photo- illicit or prescribed psychoactive drugs, or current alcohol graphic portrait and asked to remember the first and sec- dependence. Subjects were also excluded if they reported a ond name of the person in the photograph immediately current pregnancy, migraine, dyslexia, or eating disorder.
after presentation and after a delay.
Most participants, however, reported erratic or highly er- Belonging. A possession belonging to the subject is bor- ratic sleep habits, typically coinciding with MDMA use.
rowed and secreted (e.g., in a drawer or cupboard). The par-ticipant is requested to ask for the belonging at the end of thetest session and to remember where it has been hidden.
Appointment. The alarm is set for 20 minutes, and the From the Division of Life Sciences (Dr. Zakzanis), University of Toronto; participant is required to ask a particular question relat- and Centre for Addiction and Mental Health (Dr. Young), Archway Clinic, ing to the near future when the alarm sounds.
Received September 8, 2000. Accepted in final form December 16, 2000.
Pictures. Line drawings of 10 common objects are Address correspondence and reprint requests to Dr. Konstantine K. Zakza- shown, one at a time, for 5 seconds each. The participant is nis, University of Toronto at Scarborough, Division of Life Sciences (Neuro- required to name each picture and after a filled delay, to science), 1265 Military Trail, Toronto, Ontario, M1C 1A4 Canada; e-mail: select the original 10 from a set of 20.
966 Copyright 2001 by AAN Enterprises, Inc.
Table 1 Characteristics of methylenedioxymethamphetamine use
Table 2 Other drug exposure
at baseline and at 1-year follow-up Values are expressed as mean (range).
* Based on number of capsules ingested per day, assuming 100 † Usual dose (mg) multiplied by the frequency per month.
Values are n (%) of individuals within the group who reported Story (immediate and delayed). The participant is any prior use of a drug in the listed drug class at baseline and at asked to listen to a short passage of prose being read aloud. The participant is then required to recall as much of MDMA ϭ methylenedioxymethamphetamine; LSD ϭ lysergic it as possible immediately and again after a delay.
acid diethylamide; PCP ϭ phencyclinide.
Faces. The participant is shown pictures of five faces, one at a time, for 5 seconds each. After a filled delay,the subject is required to select the original five from a (immediate recall) and duration of MDMA use (r ϭ Ϫ0.60, Route (immediate). The examiner traces a short route within the room. The route is composed of five sections.
The participant is required to reproduce the route rotoxic potential of continued MDMA use in humans and its functional consequences in terms of memory Results. MDMA and other drug use. To provide an es-
over the period of 1 year. The main finding of the timate of the intensity, frequency, and duration of MDMA current longitudinal study is that continued use of use, detailed information about prior MDMA use was ob- MDMA is associated with different aspects of mem- tained from a structured interview that ascertained the ory decline. For example, the ability to recall a short number of milligrams per capsule of MDMA generally passage of prose being read aloud immediately and taken at one time (each capsule was assumed to equal 100 after a delay was found to decline significantly. This mg, based on previously published estimates4), the number decline suggests impairment in retrospective mem- of times that MDMA was taken per month, and the total ory, given that performance on the three RBMT pro- number of months of MDMA use. A dose variable—a com- spective tests—1) remembering to ask the bination of intensity and frequency—was also calculated experimenter to telephone for a taxi; 2) remembering by multiplying the self-reported milligrams ingested in a to deliver a message; and 3) remembering to ask for single MDMA session (which could last hours and involve the return of a personal belonging—did not decline several separate doses of MDMA) by the number of MDMA with continued MDMA use. Moreover, no changes in sessions per month.4 Table 1 summarizes the characteris- test scores were observed in terms of orientation for tics of MDMA use at baseline and at follow-up. Table 2 time and place and knowing the date.
illustrates the other drug exposure in the participant sam- This investigation also indicates that vocabulary and the ability to recall first and second names may Longitudinal analyses. Over the period of 1 year, test be adversely affected by the frequency of MDMA use, scores either declined or remained static, but did not im- and that the ability to immediately recall a route prove (table 3). Paired sample t-tests revealed large decline may be related to the duration of MDMA use. With effects in terms of total RBMT score (Cohen’s d ϭ 0.92; p Ͻ0.001) and in terms of the RBMT story immediate (Cohen’s these correlative findings in mind, it may be neces- sary to examine other cognitive functions in MDMA ϭ 0.57; p Ͻ 0.01) and delayed (Cohen’s d ϭ 0.83; p Ͻ users (e.g., word retrieval, visuospatial ability, in- Interaction effects were computed in terms of change cluding topographic or navigational ability, supervi- scores (follow-up Ϫ baseline) and their correlative relation- sory attentional control, and executive functions).
ship to the characteristic MDMA use of the participant Clearly, additional research is necessary to deter- sample. Significant relationships were evident in terms of mine the exact neuropsychological mechanism and performance on the WAIS-III Vocabulary subtest and fre- functional consequences of the neurotoxic effects of quency of MDMA use (r ϭ Ϫ0.53, p Ͻ 0.05); RBMT first and second name task and the total number of times Additional research will also have to resolve limita- MDMA was used (r ϭ Ϫ0.63, p Ͻ 0.05); and RBMT route tions that impede the validity of most human MDMA April (1 of 2) 2001 NEUROLOGY 56 967
Table 3 Neuropsychological results at baseline and at 1-year follow-up
WAIS-III ϭ Wechsler Adult Intelligence Scale–III; RBMT ϭ Rivermead Behavioral Memory Test.
research. For instance, given that little quality control use group comparison, Morgan found that perfor- exists for street drugs, most investigations provide only mance of MDMA users was markedly impaired when an estimate at best when calculating the MDMA in- compared with both control groups, even though the take for each subject. As such, for legal and ethical self-reported drug histories of the polydrug group reasons, no control existed over MDMA administration were not significantly different from the MDMA nor was there objective confirmation of the dose or group.5 Any differences found in the drug histories purity of MDMA taken. In keeping with published re- had little effect on the significant association be- ports of ecstasy content,9 however, we deduced that all tween recall performance and MDMA use. Thus, of our participants had indeed used MDMA in various memory deficits associated with MDMA do not seem amounts given the “type of Ecstasy” reportedly used.
to be an artifact of other drug use. This would seem Moreover, Morgan,5 for example, noted that tablets to shed some light on the possibility that a similar sold as Ecstasy can contain MDA (3,4-methylene dioxy- dissociation exists with regard to the current investi- amphetamine), MDEA (3,4-methylenedioxy-ethylamp- gation. Of course, this remains quantitatively unre- hetamine), or mixtures of a range of other compounds solved and requires further examination.
(e.g., caffeine, ephedrine, selegiline, amphetamine, ket- Accordingly, we should emphasize the difficulty of amine, LSD-9). Although some tablets sold as ecstasy drawing conclusions about the effects of MDMA in contain little or no MDMA, most tablets do contain polydrug users. Although we would like to draw neu- rochemical conclusions based on our longitudinal ob- Another issue concerns the drug history of the servations, given the contamination of the group participant sample. That is, self-report of drug- through use of other substances and the relative taking behavior in drug users is notoriously unreli- paucity of information regarding the neurochemical able. As such, it remains unclear whether the effects of MDMA, our desire to relate MDMA use and reported use of MDMA and other drug exposures are gross under or over estimates of actual drug use.
memory dysfunction should not be taken well beyond Given that this was a self-referred sample of users what can be foreseeably derived from our prelimi- with an invested interest in its outcome (note the absence of attrition), it is believed that the self- reported drug-taking behaviors of the participants References
can be loosely described as reliable. It is possible, however, that the memory disturbance may be sec- 1. Aquirre N, Frechilla D, Garcia–Osta A, et al. Differential regu- ondary to polydrug use and not MDMA itself, al- lation by methylenedioxy-methamphetamine of 5-hydroxy- tryptamine 1A receptor density and mRNA expression in rat though indirect evidence suggests otherwise. In a hippocampus, frontal cortex, and brainstem. J Neurochem study using a drug-free control group and polydrug- 968 NEUROLOGY 56 April (1 of 2) 2001
2. Fischer C, Hatzidimitriou G, Wlos J, et al. Reorganization of 6. Parrott AC, Lees A, Garnham NJ, et al. Cognitive performance ascending 5-HT axon projections in animals previously exposed in recreational users of MDMA of “ecstasy”: evidence for mem- to the recreational drug 3,4-methylenedioxymethamphetamine ory deficits. J Psychopharmacol 1998;12:79–83.
(MDMA, “Ecstasy”). J Neurosci 1995;15:5476–5485.
7. Reneman L, Booij J, Schmand B, et al. Memory disturbances in 3. Schmidt CJ. Neurotoxicity of the psychedelic amphetamine “ecstasy” users are correlated with an altered brain serotonin methylenedioxymeth-amphetamine. J Pharmacol Exp Ther neurotransmission. Psychopharmacology 2000;148:322–324.
8. Cho KC, Kumagai Y. Metabolism of amphetamine and other 4. Bolla KI, McCann UD, Ricaurte GA. Memory impairment in arylisopropylamines. In: Cho AK, Segal DS, eds. Amphetamine abstinent MDMA (“Ecstasy”) users. Neurology 1998;51:1532– and its analogs: psychopharmacology, toxicology, and abuse.
New York, NY: Academic Press, 1994:43–77.
5. Morgan MJ. Memory deficits associated with recreational use 9. Wolff K, Hay AWM, Sherlock K, et al. Contents of “ecstasy.” of “ecstasy” (MDMA). Psychopharmacology 1999;141:30–36.
Head size and
Article abstract—In a cross-sectional analysis of 818 healthy older individ-
cognitive ability in
uals (aged 50 to 81 years), head size was found to be related to performanceon tests measuring intelligence, global cognitive functioning, and speed of nondemented older
information processing, but not memory. These relations were not confounded adults are related
by educational level, socioeconomic background, or height. Large head/brainsize may protect elderly people against cognitive deterioration, supporting areserve hypothesis of brain aging.
NEUROLOGY 2001;56:969–971 Danielle J. Tisserand, MSc; Hans Bosma, PhD; Martin P.J. Van Boxtel, MD, PhD; and Jelle Jolles, PhD During childhood and adolescence, total brain mass size and cognitive performance are related in a increases and as a consequence so does head size. In healthy elderly population. We examined global cog- the 20s, the volume of the brain starts to decrease, nitive functioning with MMSE and administered whereas head size remains constant throughout life.1 tests that assess the function of specific cognitive Hence, head size is an indicator of maximal mature domains. All associations were controlled for the po- brain size. Larger brains may contain more neurons tentially confounding influences of height, socioeco- and synaptic connections and may therefore provide nomic background, and educational level. To test a greater reserve against cognitive decline when tis- these hypotheses, we used data from 818 nonde- sue loss or brain damage occurs.2,3 In elderly sub- mented elderly subjects who participated in the jects, small head/brain size has been found to be a vulnerability factor for cognitive dysfunctioning.
Katzman et al.4 found at autopsy that the main dif- Method. Subjects. Participants took part in the MAAS,
ference between 10 nondemented subjects who had a longitudinal study into the determinants of cognitive signs of Alzheimer brain pathology and subjects aging.9 In this study, 1869 subjects, initially nondemented without such signs was that the former had heavier and carefully screened for health problems, will be moni- brains and more large neurons. The authors sug- tored for 12 years. For the current study, the data of par- gested that having a larger brain protected these ticipants 50 years and older (n ϭ 818; 431 men, 387 subjects from developing Alzheimer symptomatology.
Several studies have found evidence for such an as- Measurements. A standard neuropsychological test sociation between head/brain size and cognitive battery was administered to assess cognitive functioning.
ability.5-7 These studies mainly focused on demented A full description of the tests used can be found else- subjects. Only one large study8 focused on a healthy where.9 In short, global cognitive performance was exam- elderly population (n ϭ 825) and reported that ined with the MMSE. The Stroop Color-Word Task was smaller head size was associated with low Mini- used to measure speed of information processing. The Mental State Examination (MMSE) scores.
Word Learning Task was used to assess the ability to learn The goal of the current study was to investigate (WLT Total) and retrieve (WLT Recall) verbal information.
whether we could corroborate the finding that head To estimate IQ, four subtests of the Groningen IntelligenceTest (GIT; comparable to the Wechsler Adult IntelligenceScale) were used: Arithmetic, Vocabulary, Mental rotation,and Analogies.
From the Brain & Behavior Institute, Maastricht University, the Head size (in mm) was determined twice with a tape measure placed around the subjects’ head, 0.5 cm above Received July 7, 2000. Accepted in final form December 23, 2000.
the eyebrows and over the occipital protuberance. The Address correspondence and reprint requests to Dr. D.J. Tisserand, Brain & mean of the two values was used for further analysis.
Behavior Institute, Maastricht University, Dr. Tanslaan 10, 6229 ET Maas- tricht, the Netherlands; e-mail: [email protected] Height was measured to the nearest millimeter. Educa- Copyright 2001 by AAN Enterprises, Inc. 969

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