Memory disturbances in “Ecstasy” users are correlated with an altered brain serotonin neurotransmission

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Abstract Rationale: Methylenedioxymethamphetamine
(MDMA) is known to damage brain pre-synaptic serotonin
(5-HT) neurons. Since loss of 5-HT neurons has been
implicated in memory loss, it is important to establish
whether MDMA use may produce changes in postsynaptic
5-HT receptors and memory function in humans. Objectives:
To investigate whether MDMA use leads to
compensative alterations in post-synaptic 5-HT2A receptors
and whether there is a relation with memory disturbances.
Methods: Brain cortical 5-HT2A receptor densities
were studied with [123I]-5-I-R91150 SPECT in five
abstinent MDMA users and nine healthy controls. Memory
performance was assessed using RAVLT. Results:
[123I]-5-I-R91150 binding ratios were significantly higher
in the occipital cortex of MDMA users than in controls,
indicating up-regulation. Mean cortical 5-HT2A receptor
binding correlated positively with RAVLT-recall
in MDMA users. Conclusion: Our preliminary results
may indicate altered 5-HT neuronal function with correlated
memory impairment in abstinent MDMA users.
Key words MDMA · Ecstasy · SPECT · 5-HT2
receptor · Memory
Use of the popular recreational drug (±)3,4-methylenedioxymethamphetamine
(MDMA, “Ecstasy”) leads to toxic
effects on brain serotonin (5-HT) presynaptic neurons
in humans, as recently reported (McCann et al. 1998;
Semple et al. 1999). While neurotoxic effects of MDMA
on 5-HT neurons lead to 5-HT depletion, little is known
about the effects of this depletion on postsynaptic 5-HT2
receptors. Furthermore, since MDMA-induced 5-HT depletion
may lead to impairment of functions in which
5-HT and 5-HT2 receptors are involved (such as learning
and mnemonic function), it is important to study the effects
of MDMA on 5-HT2 receptors and memory (Buhot
et al. 1997). This is of particular interest, since several
studies have found that recreational MDMA users display
significant memory impairments, whereas their performance
on other cognitive tests is generally normal
(Krystal et al. 1992; Parrott et al. 1998).
Recent development of [123I]-5-I-R91150, a radioligand
with high affinity and selectivity for the 5-HT2A receptor
subtype, has made it possible to assess the density
of postsynaptic 5-HT2A receptors in the living human
brain, using single photon emission computed tomography
(SPECT). Cortical binding of [123I]-5-I-R91150 for
5-HT2A receptors is specific and reversible, as shown by
inhibition of binding by ritanserin and displacement by
ketanserin. Furthermore, the cortico-cerebellar ratios at
pseudo-equilibrium reflect a distribution similar to that
expected from post-mortem studies (Busatto et al. 1997).
The present pilot study was designed to investigate
whether MDMA use leads to quantitative alterations in
[123I]-5-I-R91150 labelled post-synaptic 5-HT2A receptors
and related memory functions.
Five individuals with a history of MDMA use
[“MDMA group”; mean age: 23.6 years (SD 5.3),
men/women: 4/1, time since last dose: 4.6 months (range
2–11), lifetime number of tablets: 218 (50–500), mean
education: 13 years (6)], and nine age-, and educationmatched
control subjects [mean age: 22.8 years (SD 2.9),
men/women: 4/5, mean education: 15 years (5)] participated
in the study. All MDMA subjects had used at least
50 tablets. The controls were healthy subjects with no
L. Reneman · J. Booij
Graduate School of Neurosciences,
Department of Nuclear Medicine, Academic Medical Center,
1105 AZ Amsterdam, The Netherlands
B. Schmand
Department of Neurology, Academic Medical Center,
1105 AZ Amsterdam, The Netherlands
W. van den Brink
Amsterdam Institute for Addiction Research
and Department of Psychiatry, Academic Medical Center,
1105 BC Amsterdam, The Netherlands
B. Gunning
Department of Child-Adolescent Psychiatry,
Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
L. Reneman ())
Department of Nuclear Medicine, F2N, Academic Medical Center,
Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
e-mail:, Fax: +31-20-6976508
Psychopharmacology (2000) 148:322–324 © Springer-Verlag 2000
Liesbeth Reneman · Jan Booij · Ben Schmand
Wim van den Brink · Boudewijn Gunning
Memory disturbances in “Ecstasy” users are correlated
with an altered brain serotonin neurotransmission
Received: 20 August 1999 / Final version: 25 November 1999
self-reported use of psychoactive drugs, including
MDMA. Recruitment was through advertisements (local
newspapers). Participants agreed to abstain from use of
psychoactive drugs for at least 2 months before the
study, and were asked to undergo urine drug screening
(with an enzyme-multiplied immunoassay for amphetamines,
barbiturates, benzodiazepine metabolites, cocaine
and metabolite, opiates, and marijuana) before enrolment.
After testing urine samples, exclusion criteria
were: a positive drug screen; pregnancy; a severe medical
or neuropsychiatric illness that precluded informed
consent; claustrophobia; and neuropsychiatric disease in
which 5-HT has been implicated. Written informed consent
was obtained from all participants. The procedures
used were approved by the local ethics board and have
therefore been performed in accordance with the ethical
standards laid down in the 1964 Declaration of Helsinki.
For SPECT scanning, the Strichmann Medical Equipment
810X tomographic system was used. The transaxial
resolution of this camera is 7.6 mm full-width at halfmaximum
of a line source in air, while the axial resolution
is 13.5 mm. Each acquisition consisted of at least 15
slices (acquired in a 128´128 matrix), 3 min per slice,
and with a slice distance of 5 mm. The energy window
was set at 135–190 keV. Subjects lay in the supine position
with the head aligned in a parallel to the orbitomeatal
line, and were positioned such that the scanning volume
initially included the cerebellum. Acquisition was
commenced 2 h after IV injection of approximately
140 MBq [123I]-5-I-R91150 (radiolabelling as described
by Busatto et al. 1997), a time when specific binding is
maximal and stable for up to 8 h following injection.
Analysis of scans was performed blind to subject status.
For analysis of [123I]-5-I-R91150 binding, a standard
template with regions of interest (ROIs) was constructed
manually from co-registered MR images. For positioning,
we used these MR images as a guide. The template,
including ROIs for the frontal, parietal, and occipital
cortex, was placed on three consecutive SPECT slices.
Additional templates were constructed with ROIs for the
cerebellum and temporal cortex. Mean cortical signal
densities were calculated (mean counts/pixel of frontal,
parietal, temporal, occipital cortex). An investigator unaware
of the participant’s history performed ROI analysis.
The uptake in the cerebellum, presumed free from 5-
HT2A receptors, was used as a reference for background
radioactivity (non-specific binding+free ligand) (Busatto
et al. 1997). Relative indices of “specific” binding are
calculated as: “mean” ROI binding/cerebellar binding=5-
HT2A binding ratio.
Memory was assessed the day prior to SPECT imaging
using the Rey Auditory Verbal Learning Test (RAVLT).
The RAVLT is a verbal memory test. The immediate verbal
memory comprised RAVLT logical memory, the delayed
verbal memory incorporated RAVLT-recall, and
Overall, [123I]-5-I-R91150 binding ratios were higher
in the MDMA group than in controls, and reached statistical
significance in the occipital cortex [mean 2.04
(SD 0.20) versus 1.74 (0.19), P<0.05 Mann-Whitney
U-test Fig. 1], indicating an up-regulation of postsynaptic
5-HT2A receptors.
In the MDMA group, a significant lower number of
recalled words in the RAVLT-recall was observed than in
controls [8.14 (3.4) versus 12.3 (1.8), P<0.001; Fig. 2].
In the MDMA group, but not in controls, mean cortical
5-HT2A receptor binding highly correlated (Spearman’s
rho) with recall [r=–0.98 (P=0.005), r=–0.29 (P=0.46),
respectively; Fig. 2]. Age, sex, extent of previous
MDMA use, and education had no significant effect on
this correlation (P=0.28, 0.17, 0.25, and 0.16, respectively).
The high 5-HT2A receptor binding in the occipital cortex
in the MDMA group may be caused by 5-HT depletion.
It is known that severe 5-HT depletion causes upregulation
of 5-HT2 receptors (Heal et al. 1985). Moreover,
MDMA-treated monkeys showed most severe
5-HT depletion in the occipital cortex. In these monkeys,
14 months after MDMA administration 5-HT levels
were still reduced in the occipital cortex by 97%
(Scheffel et al. 1998). In a recent SPECT study, MDMA
users showed a significant reduction only in occipital
5-HT neurons (Semple et al. 1999). Thus, the presently
observed up-regulation of 5-HT2A receptors in the occipital
cortex may reflect MDMA-induced brain 5-HT neurotoxicity.
In the present study, MDMA users showed significant
deficits in delayed memory tasks, consistent with reports
of memory problems in previous studies (Bolla et al.
1998; Parrott et al. 1998). Numerous laboratory studies
with rats and monkeys have shown that MDMA produces
serotonergic neurodegeneration. This has been demonstrated
in various brain areas including the hippo-
Fig. 1 The mean and individual [123I]-5-I-R91150 binding ratio in
the occipital cortex: controls versus MDMA users. Mean occipital
binding ratios were calculated as occipital binding/binding in the
cerebellum. *Statistical significant difference in binding ratio between
controls and MDMA users
campus, which is important for memory functioning
(Hatzidimitriou et al. 1999). There is also clinical evidence
for 5-HT brain damage in humans (Squier et al.
1995; McCann et al. 1998; Semple et al. 1999). There is
therefore consistent evidence that memory deficits found
in the present study may at least be attributed to MDMAinduced
5-HT deficits, particularly since high densities of
5-HT2A receptors (an indirect measure of 5-HT depletion)
were associated with lower performance on the delayed
memory tests. This provisional finding is in agreement
with a recent study which showed that the extent of memory
impairment correlated with the reduction of brain 5-
HT, as indexed by CSF 5-HIAA (Bolla et al. 1998). We
observed in this study that only individuals with apparent
higher densities of occipital 5-HT2A receptors (presumably
reflecting a greater extent of 5-HT injury) demonstrated
detectable difficulties with memory function.
All participants in the MDMA group in our study reported
that they had abstained from use of MDMA or
other psychoactive drugs for at least 2 months before the
study. Although most of the MDMA users had experimented
with other recreational drugs (mainly alcohol and
cannabis), none was a known 5-HT neurotoxin in human
beings, and was therefore not likely to account for changes
in [123I]-5-I-R91150 binding to 5-HT2A receptors.
This pilot study was performed using small samples.
Nevertheless, this study at least suggests an intriguing
relationship between 5-HT2A receptor densities and
memory performance in MDMA users. Because of the
small sample size, the observed correlation cannot be
said to be a definitive finding, and future studies investigating
5-HT neurotransmission and memory performance
in MDMA users need to be conducted.
In conclusion, we provide additional evidence suggesting
that human MDMA users are susceptible to
MDMA-induced brain 5-HT neuronal injury and related
functional disturbances, by showing a correlation between
5-HT2 receptor densities and memory disturbances.
Thus, reductions in 5-HT, as indexed by elevated
cortical 5-HT2 receptor densities, may be responsible for
decrements in abstinent MDMA users.
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serotonin innervation patterns in the forebrain of monkeys
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years previously; factors influencing abnormal recovery.
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Fig. 2 Correlation between
mean cortical [123I]-5-I-R91150
binding ratios and memory
function (number of words remembered
on RAVLT recall
trial) in control and MDMA
group. SPECT data are expressed
as cortical binding over
cerebellar binding

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