Peripheral endocannabinoid concentrations are not associated
with verbal memory impairment during MDMA intoxication
R. de la Torre
J. G. Ramaekers
K. P. C. Kuypers
Received: 29 May 2017 /Accepted: 7 November 2017 / Published online: 16 November 2017
The Author(s) 2017. This article is an open access publication
Background Preclinical data have suggested involvement of the
endocannabinoid (eCB) system in MDMA-induced memory im-
pairment. Clinical research has shown that blockade of the 5-HT
receptor nulls memory impairment during MDMA intoxication.
Interestingly, studies have demonstrated that the eCB and the 5-
HT system interact. It was hypothesized that MDMA would
cause an increase in eCB concentrations together with a decrease
in memory performance, and that combining MDMA with a 5-
receptor blocker ketanserin would lead to a counteraction of
the MDMA effects on eCB concentrations and memory.
Methods Twenty healthy recreational polydrug users entered a
double-blind placebo-controlled within-subject study.
Participants received a pre-treatment (ketanserin 40 mg, placebo)
followed 30 min later by a treatment (MDMA 75 mg, placebo).
Verbal memory was tested by means of a 30-word learning test.
Endocannabinoid concentrations (anandamide (2-AG); N-
arachidonylethanolamine (AEA)) were assessed in blood at
baseline, before (90 min post-treatment) and after cognitive tests
(150 min post-treatment).
Results Findings showed that MDMA impaired memory
90 min post-treatment in the word learning task. This effect
was a replication of previous studies using the same dose of
MDMA (75 mg) and the same learning paradigm. Contrary to
our hypothesis, MDMA did not affect eCB concentrations,
nor did ketanserin block MDMA-induced memory impair-
ment. Ketanserin caused an increase in AEA concentrations,
180 min after administration.
Conclusion Current findings suggest that peripherally mea-
sured endocannabinoids are not associated with the verbal
memory deficit during MDMA intoxication. Trial registration
Previous placebo-controlled experimental studies have con-
sistently shown that a single dose (75 mg) of (R,S)-3,4
methylenedioxymethamphetamine (MDMA) impairs memo-
ry for verbal information (e.g., de Sousa Fernandes Perna et al.
2014; Kuypers and Ramaekers 2005). The neurobiological
mechanism underlying this impairment has been studied and
it was suggested that the MDMA-induced elevation in plasma
cortisol concentrations was not related to the observed deficit
(Kuypers et al. 2013). van Wel and colleagues demonstrated
that blockade of the serotonin-2A (5-HT
) receptor, by
means of a single dose of ketanserin, prevented the memory
impairment after a single dose of MDMA (van Wel et al.
2011). The detailed neurobiological mechanism behind the
MDMA-induced memory deficit has yet to be elucidated.
* K. P. C. Kuypers
Department of Neuropsychology and Psychopharmacology, Faculty
of Psychology and Neuroscience, Maastricht University,
Maastricht, The Netherlands
Integrative Pharmacology & Neurosciences Systems Research
Group, Institut Hospital del Mar d’Investigacions Mèdiques,
Universitat Autonoma de Barcelona, Barcelona, Spain
Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol,
Spanish Biomedical Research Centre in Physiopathology of Obesity
and Nutrition (CIBEROBN), Santiago de Compostela, Spain
Universitat Pompeu Fabra, CEXS-UPF, Barcelona, Spain
Psychopharmacology (2018) 235:709–717