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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. Discussion.
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.
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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: d.tisserand@np.unimaas.nl
Height was measured to the nearest millimeter. Educa-
Copyright 2001 by AAN Enterprises, Inc. 969
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