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Cortical Serotonin Transporter Density and Verbal Memory in Individuals Who Stopped Using 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy")
Preliminary Findings
Liesbeth Reneman, MD;
Jules Lavalaye, MD;
Ben Schmand, PhD;
Frederik A. de Wolff, PhD, DSc;
Wim van den Brink, MD, PhD;
Gerard J. den Heeten, MD, PhD;
Jan Booij, MD, PhD
Arch Gen Psychiatry. 2001;58:901-906.
ABSTRACT
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Background Although the popular drug 3,4-methylenedioxymethamphetamine (MDMA or
"ecstasy") has been shown to damage brain serotonin (5-HT) neurons in animals,
the fate and functional consequences of 5-HT neurons after MDMA injury are
not known in humans. We investigated the long-term effects of MDMA use on
cortical 5-HT neurons in humans and memory function, because brain 5-HT has
been implicated in memory function.
Methods Twenty-two recent MDMA users, 16 ex-MDMA users who had stopped using
MDMA for more than 1 year, and 13 control subjects. The effects of MDMA use
on cortical 5-HT neurons was studied by means of single-photon emission computed
tomography with iodine 123–labeled 2ß-carbomethoxy-3ß-(4-iodophenyl)
tropane ([123I]ß-CIT) by quantification of brain 5-HT transporter
densities. Verbal memory performance was assessed with the Rey Auditory Verbal
Learning Test.
Results Mean cortical [123I]ß-CIT-labeled 5-HT transporter density
was significantly lower in recent MDMA users than in controls (1.17 vs 1.28
[–9%]) but not in ex-MDMA users (1.24 vs 1.28 [-3%]). Recent and
ex-MDMA users recalled significantly fewer words than did controls on the
immediate recall (47.0 and 48.0 vs 60.0, respectively; P = .001) as well as the delayed recall (9.8 and 10.1 vs 13.1, respectively; P = .003). Greater use of MDMA was associated with greater
impairment in immediate verbal memory. However, memory performance was not
associated with [123I]ß-CIT binding to cortical 5-HT transporters
or duration of abstinence from MDMA.
Conclusion The present study suggests that, while the neurotoxic effects of MDMA
on 5-HT neurons in the human cortex may be reversible, the effects of MDMA
on memory function may be long-lasting.
INTRODUCTION
ALTHOUGH GENERALLY regarded as relatively safe, the popular recreational
drug 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") has increasingly
been shown to lead to toxic effects on brain serotonin (5-HT) neurons in animals
and possibly in humans. In animals, damage to 5-HT neurons has been demonstrated
by reductions in various markers unique to 5-HT axons, including the density
of 5-HT transporters (SERTs).1, 2, 3, 4, 5
Since the SERT is located on the presynaptic axons and axon terminals of 5-HT
neurons, it is considered to be a reliable marker of 5-HT neurotoxic changes.
With the development of imaging techniques such as positron emission tomography
and single-photon emission computed tomography (SPECT), it is now possible
to measure SERT densities in the human brain. Recent imaging studies have
shown decreases in central SERTs in MDMA-treated primates and human MDMA users.6, 7, 8
Few functional consequences of MDMA-induced neurotoxic effects have
been identified, however, either in animals or in humans. Since MDMA-induced
5-HT neurotoxic damage may lead to impairment of functions in which 5-HT is
involved (eg, memory function), it is important to study the effects of MDMA
not only on 5-HT neurons but on memory function as well. Memory function is
of particular interest because several studies have found that MDMA users
display significant memory impairments, whereas their performance on other
cognitive tests is generally normal.9, 10, 11
While the short-term neurotoxic effects of MDMA on 5-HT neurons and
memory have been studied extensively, little is known about the long-term
effects in humans. Studies in nonhuman primates have shown that, up to 7 years
after treatment with MDMA, neocortical brain regions remain partially denervated
while others show evidence of complete recovery. Therefore, it is of particular
interest to establish the long-term fate of cortical 5-HT neurons after MDMA
injury in the human brain.
The development of iodine 123–labeled 2ß-carbomethoxy-3ß-(4-iodophenyl)
tropane ([123I]ß-CIT), a radioligand that binds with high
affinity to SERTs, has made it possible to assess the density of SERTs in
the living human brain, by means of SPECT.12, 13
The purpose of the present study was to investigate the density of cortical
[123I]ß-CIT–labeled SERTs and memory function in recent
MDMA users who were abstaining from use, and in MDMA users who had not been
using MDMA for more than 1 year. Also, this study examined whether possible
memory deficits in MDMA users correlate with decrements in the density of
[123I]ß-CIT–labeled SERTs, and whether memory deficits
in MDMA users are dose related.
SUBJECTS AND METHODS
PARTICIPANTS
Two groups of ecstasy users were compared with ecstasy-naive controls.
Subjects were recruited by means of flyers distributed at venues associated
with the "rave scene" in Amsterdam, the Netherlands, with the help of UNITY,
an agency that provides harm-reduction information and advice. Experimental
and control groups were thus recruited from the same community sources. Subjects
selected were group-matched for sex and age (between 18 and 45 years), otherwise
healthy, and with no psychiatric history.
Twenty-two recent but abstinent ecstasy users (mean [±SD] time
since last dose before study, 2.4 ± 2.4 months; "MDMA group") and 16
ex–ecstasy users (29.0 ± 20.4 months; "ex-MDMA group") were recruited.
The eligibility criterion for the MDMA group was lifetime previous use of
a minimum of 50 tablets of ecstasy. The ex-MDMA group had to have taken a
minimum of 50 tablets but stopped using ecstasy at least 1 year before the
study. The 13 controls were healthy subjects with no self-reported previous
use of ecstasy.
All participants agreed to abstain from use of psychoactive drugs (including
MDMA) for at least 3 weeks before the study and were asked to undergo urine
drug screening to assess current exposure to psychoactive drugs (with an enzyme-multiplied
immunoassay for amphetamines, barbiturates, benzodiazepine metabolites, cocaine
and metabolite, opiates, and marijuana) before enrollment. After urine samples
were tested, exclusion criteria were as follows: a positive drug screen, pregnancy,
a severe medical or neuropsychiatric illness that precluded informed consent,
and a lifetime psychiatric disorder. Use of prescribed psychotropic medications,
such as 5-HT reuptake inhibitors, had to be stopped for at least 3 weeks before
the study. Subjects were interviewed with the computer-assisted 2.1. version
of the Composite International Diagnostic Interview (Core version 2.1, 1997;
World Health Organization, Geneva, Switzerland) to screen for current DSM-IV Axis I diagnoses.
Subjects were informed that reimbursement for participation was contingent
on no evidence of drug use on the urine sample. The institutional medical
ethics committee approved the study. All participants provided written informed
consent after the study was completely described to them.
IMAGING
Subjects underwent SPECT imaging (810X tomographic equipment; Strichman
Medical Equipment Inc, Medfield, Mass). This 12-detector single-slice scanner
has a full-width at half-maximum resolution of approximately 7.5 mm. Each
acquisition consisted of approximately 15 slices (acquired in a 64 x
64 matrix) at 3 minutes per slice (interslice distance, 5 mm). The energy
window was set at 135 to 190 keV. Subjects lay supine with the head parallel
to the orbitomeatal line. Acquisition was commenced 4 hours after intravenous
injection of approximately 3.8 mCi (140 MBq) of [123I]ß-CIT
(specific activity, >5 mCi/nmol [>185 MBq/nmol]; radiochemical purity, >98%),
a time when specific binding to SERTs is stable.14
Reconstruction and attenuation correction of all images were performed as
earlier described.15
For binding analysis, a standard template with regions of interest was
constructed manually from magnetic resonance images. For positioning we used
these images as a guide. A template, including regions of interest for the
frontal, temporal, parieto-occipital, and occipital cortex, was placed on
3 consecutive SPECT slices, demonstrating best visualization of the striatum
(typically 30 mm above the orbitomeatal line), by an investigator unaware
of the participant's history. An additional template was constructed with
a region of interest for the cerebellum. The binding in the cerebellum, presumed
free from SERTs, was used as a reference for background radioactivity (nonspecific
binding + free ligand). Since no differences in [123I]ß-CIT
uptake ratios between cortical brain regions were observed in all groups under
study, we calculated mean cortical SERT densities (mean counts per pixel of
frontal, temporal, parieto-occipital, and occipital cortex). Cortical binding
ratios were calculated as cortical binding divided by binding in the cerebellum.
MEMORY TESTING
The Dutch Adult Reading Test (DART)16, 17
was administered as an estimate of verbal intelligence. The DART is the Dutch
adaptation of the National Adult Reading Test,18
a short reading test for the estimation of premorbid verbal IQ.
Memory was assessed within 1 day of SPECT imaging by means of the Rey
Auditory Verbal Learning Test (RAVLT).19 The
subject memorizes a series of 15 words in 5 learning trials (RAVLT immediate
recall). After a 20-minute delay, the subject is asked to recall the words
(RAVLT delayed recall), followed by recognition of the 15 items between 15
distractor words (RAVLT recognition). Raw scores are used.
STATISTICAL ANALYSES
Differences in mean cortical [123I]ß-CIT binding ratio
and RAVLT scores (RAVLT immediate recall, RAVLT delayed recall, and RAVLT
recognition) were analyzed by analysis of covariance, with 1 between-group
factor (group) and 3 covariants (age, sex, and DART IQ). When a significant
main group effect was observed, Bonferroni post hoc tests were performed to
analyze differences between groups. Differences between the 3 groups with
regard to demographic variables and other drug exposure were analyzed by analysis
of variance. Differences in characteristics of MDMA use between both MDMA-using
groups were studied with the t test.
Pearson correlation analyses were performed between RAVLT scores and
mean cortical [123I]ß-CIT binding ratio, between RAVLT scores
and duration of abstinence from MDMA, between RAVLT scores and extent of previous
MDMA, and between RAVLT scores and extent of previous cannabis, amphetamine,
and cocaine use. Because age, sex, and vocabulary have been shown to be highly
associated with most memory tests, we also performed partial correlations
to control for age, sex, and DART IQ on tests for which the correlations were
significant. The chance of a type I error ( ) was set at .05 by 2-tailed
tests of significance. In cases where Bonferroni corrections were made, statistical
significance within the text is reported as a corrected P (corrected P = .017 [.05 ÷ 3] [3
paired comparisons]). All data were analyzed with SPSS version 9.0 (SPSS Inc,
Chicago, Ill) and are presented as mean ± SD unless otherwise indicated.
RESULTS
CHARACTERISTICS OF THE SAMPLE
The 3 groups were similar in age and sex distribution. The level of
education was significantly lower in MDMA users. However, MDMA users did not
differ from controls in verbal intelligence (DART IQ) (Table 1).
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Characteristics of Subjects*
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Apart from the anticipated differences between groups caused by inclusion
criteria, no significant differences between MDMA groups were observed. Whereas
the MDMA group had on average not used MDMA for months, the ex-MDMA group
had on average not used MDMA for nearly 2.5 years (Table 1). Recreational drug use of alcohol and tobacco was comparable
between the different groups. The MDMA users indicated having used more cannabis
in the year before this investigation than had controls, although this difference
did not reach statistical significance. The use of amphetamine and cocaine
was significantly higher in the MDMA group than in the control and ex-MDMA
groups (Table 1). None of the
subjects under study reported using drugs other than the ones listed in Table 1, such as phencyclidine hydrochloride
or opiates, in the year before this study.
IMAGING
No differences in [123I]ß-CIT uptake between cortical
brain regions were observed in all groups under study. Analysis of variance
showed a significant main effect of group (F2.5 = 4.63, P = .02), with current MDMA users having lower (-9%) mean cortical
[123I]ß-CIT binding ratios than controls (Figure 1). No significant differences in mean cortical binding ratios
of ex-MDMA users were observed when compared with control subjects (-3%; Figure 1).
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Figure 1. Mean and individual iodine 123–2ß-carbomethoxy-3ß-(4-iodophenyl)
tropane binding ratio in the cortex in control subjects (n = 13) vs 3,4-methylenedioxymethamphetamine
(MDMA or "ecstasy") users (n = 22) and ex-MDMA users (n = 16). Cortical binding
ratios were calculated as cortical binding divided by binding in the cerebellum.
Asterisk indicates statistically significant difference in cortical binding
ratio between recent MDMA users and control subjects (mean ± SD, 1.17
± 0.08 vs 1.28 ± 0.12, respectively) (analysis of variance:
F2.5 = 4.63, P = .02; Bonferroni corrected P = .03). Dagger indicates no statistically significant difference
in cortical binding ratio between ex-MDMA users and control subjects (mean
± SD, 1.24 ± 0.11 vs 1.28 ± 0.12) (analysis of variance:
F2.5 = 4.63, P = .02; Bonferroni corrected P>.99).
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MEMORY PERFORMANCE
As with mean cortical [123I]ß-CIT binding ratios, analysis
of covariance showed a significant main effect of group on RAVLT immediate
recall scores (F2.5 = 8.31, P = .001).
Both current and ex-MDMA users recalled significantly fewer words on the immediate
RAVLT compared with controls (47.0 ± 8.6 and 48.0 ± 12.5 vs
60.0 ± 6.8, respectively; Figure 2). Similar findings were observed for the RAVLT delayed recall (F2.5 = 6.53, P = .003; 9.8 ± 2.9 and
10.1 ± 2.9 vs 13.1 ± 2.1, respectively; Figure 2), but not for RAVLT recognition.
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Figure 2. Mean and individual Rey Auditory
Verbal Learning Test (RAVLT) immediate (A) and delayed (B) recall scores in
control subjects (n = 13) vs 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy")
users (n = 22) and ex-MDMA users (n = 16). Asterisk indicates significantly
fewer words recalled by recent and ex-MDMA users compared with control subjects
on RAVLT immediate recall (analysis of variance: F2.5 = 8.31, P = .001; Bonferroni corrected P = .001 and
.005, respectively). Dagger indicates significantly fewer words recalled by
recent and ex-MDMA users compared with control subjects on RAVLT delayed recall
(analysis of variance: F2.5 = 6.53, P = .003; Bonferroni
corrected P = .004 and .02, respectively).
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Correlation analysis demonstrated no specific relationships between
RAVLT scores and cortical binding ratio, duration of abstinence from MDMA,
or extent of previous cannabis, amphetamine, or cocaine use. However, partial
correlation analysis with RAVLT immediate recall scores was significant for
extent of previous MDMA use (r46 = -0.29, P = .049).
COMMENT
The present study indicates that, in individuals who stopped using MDMA
more than 1 year ago, cortical SERT densities did not differ from those of
control subjects, whereas recent MDMA users showed global decreases in SERTs.
Our findings also indicate that individuals who stopped using MDMA had a deficit
in verbal memory, similar to that of current MDMA users, and that higher lifetime
doses of MDMA are associated with greater decrements in immediate verbal memory
function.
The observed decreases in cortical SERT densities in recent MDMA users
most likely reflects MDMA-induced brain 5-HT neurotoxic effects, since reductions
in SERT densities have been documented in animals with known MDMA-induced
5-HT injury.3, 6, 20, 21, 22, 23, 24, 25, 26, 27
For instance, reductions in 5-HT axons in MDMA-treated monkeys vary from approximately
–95% in the temporal cortex to –83% in the pyriform cortex.21 This is a much stronger effect than on human 5-HT
axons as observed in the present study (on the order of 9%). Interestingly,
Semple and coworkers8 also reported a 10% reduction
in SERT densities in the occipital cortex of recent MDMA users by means of
[123I]ß-CIT SPECT. Even though cortical ß-CIT uptake
is low, displacement studies in rats and monkeys have shown that cortical
uptake of ß-CIT is associated with SERTs.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28
Furthermore, [123I]ß-CIT has been shown to adequately detect
changes in cortical as well as subcortical SERT densities secondary to 5-HT
neurotoxic effects.13, 29 However,
it is an assumption that a decrease in SERT density directly reflects axonal
loss. Several factors, such as allosteric changes in the actual binding unit
of the protein, also could result in decreased binding. Nevertheless, it has
been shown that central 5-HT levels also are reduced after MDMA treatment.30 Furthermore, correlative anatomic studies indicate
that loss of presynaptic SERTs in MDMA-treated animals is related to damage
of 5-HT axons and axon terminals.3, 22, 23
The absence of decreases in SERT densities in ex-MDMA users suggests
reversibility of MDMA-induced changes in brain SERTs in MDMA users. In line
with this, autoradiographic studies have shown a partial recovery of [125I]ß-CIT binding 16 weeks after lesion induction in the frontal
cortex of rats, and complete recovery by 32 weeks.29
In nonhuman primates, cortical 5-HT terminal markers remain decreased up to
7 years after MDMA treatment, although significant recovery occurs compared
with 2 weeks after the lesion induction.21
Our findings of memory impairment in recent MDMA users are consistent
with those of previous reports.9, 10, 11, 31, 32, 33, 34
In agreement with these studies, we observed that greater use of MDMA is associated
with greater impairment in immediate verbal memory. Interestingly, Shum and
coworkers35 reported on RAVLT scores of patients
with age and educational level similar to those of our subjects who had suffered
from severe traumatic brain injury 2 years previously. Criteria for severe
traumatic brain injury were a Glasgow Coma Scale score less than 9 or a duration
of posttraumatic amnesia of more than 7 days. Scores on the immediate RAVLT
were 59.4 in controls vs 47.4 in the patients with traumatic brain injury,
and approximately 13.8 vs 10.8, respectively, on the delayed recall. These
scores are comparable with the scores observed in this study in recent and
ex-MDMA users (Figure 2), which
may indicate the severity and clinical significance of the memory disturbances
induced by MDMA use.
Studies in rats and monkeys have shown that MDMA produces serotonergic
neurodegeneration in various brain areas important for memory function, including
the hippocampus.21 Unfortunately, because of
the relatively low resolution of the SPECT imaging technique, it was not possible
to study all brain regions implicated in learning and memory.
Several studies suggest that SERTs may play an important role in cognitive
processes such as memory function.36 It has
been shown that selective 5-HT reuptake inhibitors in nondemented elderly
depressed patients improved both mood and cognitive function.37
However, we did not observe a correlation between memory function and cortical
SERT densities. It could be argued that memory testing is more sensitive to
MDMA's neurotoxic effects than are SERT densities. Furthermore, the observed
memory deficits in ex-MDMA users may not be attributable to MDMA-induced 5-HT
deficits at all. However, we did observe a negative correlation between extent
of previous MDMA use and immediate verbal memory recall, suggesting that immediate
verbal memory deficits may be at least partially attributable to MDMA use.
Another explanation may be that SERT densities in brain areas implicated in
learning and memory of former MDMA users are still decreased but could, unfortunately,
not be visualized with SPECT (eg, hippocampus or hypothalamus). Finally, although
loss of SERTs is indicative of neuronal degeneration, their restoration does
not necessarily imply normal axonal or neuronal regeneration and therefore
normal behavioral recovery. For instance, after 5-HT axonal degeneration induced
by 5,6-dihydroxytryptamine, abnormal reinnervation patterns of 5-HT axons
coincide with the return of tritiated 5-HT uptake.38
Since it was previously observed by our group that mean (postsynaptic) cortical
5-HT2A receptor binding positively correlated with RAVLT recall
in MDMA users,39 it could be hypothesized that
functional consequences of MDMA-induced brain 5-HT neurotoxic lesions may
be related to postsynaptic rather than presynaptic 5-HT neurons.
The implications of our findings are relevant to people who use MDMA.
In the present study we identified that MDMA use is associated not only with
short-term consequences (5-HT neurotoxic effects and memory impairment) but
with long-term consequences as well (memory impairment). These findings will
provide a cogent argument for consumers to make informed decisions about recreational
drug use. In addition, since the consequences of loss of the "serotonergic"
reserve in later life is difficult to predict but could be clinically significant,
the present study indicates the necessity of, and would probably justify,
prospective studies of psychiatric morbidity in MDMA users to foresee future
demands on health care. Furthermore, the present study of MDMA-exposed individuals
with highly selective brain SERT deficits adds to our knowledge about a neurotransmission
system thought to be involved in the cause and treatment of very common psychiatric
illnesses, such as depression.
Several potential limitations of the current study should be mentioned.
First, as with all retrospective studies, there is a possibility that preexisting
differences between MDMA users and control subjects underlie differences in
SERT densities. People with low SERT densities may be predisposed to use MDMA
and to have low SERT densities and/or lower performance on memory tests. Future
studies taking the recently described functional polymorphism in the promoter
for the SERT gene into account could be of interest.40
Second, observed decreases in brain [123I]ß-CIT–labeled
SERT densities and memory performance are unlikely to be caused by immediate
pharmacologic effects of MDMA or other drugs, since MDMA-using participants
reported that they had abstained from use of MDMA or other psychoactive drugs
for at least 3 weeks before the study. Unfortunately, we were not able to
ensure abstinence from MDMA for more than 1 year in the ex-MDMA users. In
future studies, hair-sample analysis may be useful to ascertain long periods
of abstinence from MDMA. Third, follow-up studies in human subjects with known
MDMA-induced neurotoxic effects need to be conducted to allow definite conclusions
on reversibility or permanence of MDMA-induced changes in the human brain.
Finally, although the MDMA users in our study had more experience with other
recreational drugs than did control subjects, none of the drugs is a known
5-HT neurotoxin in human beings, and they were therefore not likely to account
for changes in SERTs or memory performance. In addition, since recent MDMA
users had used significantly more amphetamine and cocaine than controls and
ex-MDMA users, but memory impairments were observed in both recent and ex-MDMA
users, amphetamine and cocaine are not likely to account for changes is SERTs
and/or memory performance. In support of this, we did not observe an association
between RAVLT scores and extent of previous amphetamine or cocaine use. Furthermore,
since no statistical differences in the use of LSD (lysergic acid diethylamide)
and psilocybin were observed between the 3 groups under study, it seems unlikely
that the findings of the present study should be attributed to substances
other than MDMA. We cannot, however, completely rule out the possibility that
the observed memory impairment in the MDMA-using subjects is unrelated to
cannabis use. However, no association between RAVLT scores and extent of previous
cannabis use was observed. In addition, the adverse effects of long-term cannabis
use on cognitive skills have not been clearly demonstrated in the literature
and seem to contradict each other.41 For instance,
Gouzoulis-Mayfrank and coworkers33 did not
observe differences in cognitive performance between cannabis users and ecstasy
users or control subjects.
In summary, our data suggest that MDMA use can lead to neurotoxic changes
in human cortical 5-HT brain neurons and that these changes may be reversible.
However, our data also suggest that the functional consequences of MDMA on
cortical brain 5-HT neurons may not be reversible because individuals who
had stopped using MDMA more than 1 year earlier had impaired memory function,
similar to that of recent MDMA users.
AUTHOR INFORMATION
Accepted for publication March 23, 2001.
This study was supported in part by grant 43894 from the Netherlands
Ministry of Health, Welfare and Sports, The Hague.
From the Graduate School of Neurosciences, Department of Nuclear Medicine
(Drs Reneman, Lavalaye, and Booij); Departments of Neurology (Dr Schmand),
Human Toxicology (Dr de Wolff), and Radiology (Dr den Heeten); and Amsterdam
Institute for Addiction Research and Department of Psychiatry (Dr van den
Brink), Academic Medical Center, Amsterdam, the Netherlands; and Toxicology
Laboratory, Leiden University Medical Center, Leiden, the Netherlands (Dr
de Wolff).
Corresponding author and reprints: Liesbeth Reneman, MD, Department
of Nuclear Medicine, F2-210, Academic Medical Center, Meibergdreef 9, 1105
AZ Amsterdam, the Netherlands (e-mail: l.reneman{at}amc.uva.nl).
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