Investigation of Serotonin Neurotransmission in MDMA Users Using Combinated Dexfenfluramine Challenge and PET Imaging
Status:
Completed
Trial end date:
2008-07-01
Target enrollment:
Participant gender:
Summary
Illicit use of the psychostimulant "Ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) is
considered a major public health issue. In Switzerland, MDMA and congeners are - after
cannabis and cocaine - number three in the ranking of the most popular illicit drugs.
Worldwide, Ecstasy is estimated to be even the second most popular illicit drug, used by
millions of regular users.
On the basis of animal data, it is likely that MDMA at high or cumulative doses damages
serotonin (5-HT) neurons in the human brain. However, because of a multitude of
methodological problems and a limited number of studies conducted in human subjects, no firm
conclusions can yet be established whether chronic MDMA exposure produces a long lasting 5-HT
deficiency syndrome, with consequent neuropsychiatric risks. To further address the putative
neurotoxicity of MDMA in the human brain, we propose that novel functional assays of
serotonergic neurotransmission may be useful to clarify this issue. We suggest that a 5-HT
challenge study using positron emission tomography (PET) in conjunction with the 5-HT
releaser dexfenfluramine [(+)FEN] may test the functional integrity of the 5-HT system in the
living human brain.
Specifically, in a placebo-controlled study, the 5-HT release capacity of serotonergic
neurons shall be investigated by assessing [18F]-altanserin binding to 5-HT2A receptors
following (+)FEN challenge in former and continuing MDMA users, and age and sex-matched
MDMA-naïve controls. (+)FEN is a potent serotonin releaser without relevant affinity for
5-HT, dopamine (DA) or norepinephrine (NE) receptors, and devoid of acute adverse effects in
man. This makes (+)FEN an ideal pharmacological probe to explore functional integrity of
serotonin neurotransmission.
A second aim of our investigation is to detect possible impairments of cognitive functions
and to study their relationship to serotonin neurotransmission as indexed by PET. In the
course of the neuroimaging study, the investigators therefore also measure cognitive (e.g.
attention, visual and working memory, learning, executive function) and affective functions
(e.g. anxiety, impulsivity), suspected to be altered due to chronic MDMA use. Using
correlational analyses, the investigators aim to determine if circumscribed regions of
altered 5-HT function are associated with specific impairments in cognitive and/or
behavioural parameters.
We hypothesize that (+)FEN-evoked 5-HT release will discernibly alter availability of 5-HT2A
receptors to [18F]-altanserin, with a pattern revealing the spatially heterogeneous
vulnerability of 5-HT innervations to MDMA. The investigators predict that [18F]-altanserin
volume of distribution (DV) will decline following (+)FEN challenge to a lesser extent in
current MDMA users compared to MDMA-naïve control subjects. On the basis of animal data and
recent neuroimaging studies in humans, the investigators hypothesize that functional recovery
in former MDMA users will be manifest by a normalization or overshoot of the 5-HT release
capacity.
Our methodology will allow us to quantitatively assess serotonergic functions in the living
human brain. The novel combination of (+)FEN-induced release of 5-HT from intracellular
storage vesicles and subsequent PET assessment of competitively altered [18F]-altanserin
binding at postsynaptic 5-HT2A receptors will provide a more direct biological marker of in
vivo serotonin function than has been hitherto available. By applying this new
pharmacological challenge/PET neuroimaging approach to groups of current and former users of
MDMA, the investigators shall be able to gain important new insight in the debated functional
consequences of MDMA use, especially concerning the controversy about the reversibility of
5-HT changes following cessation of MDMA use. Successful completion of this project should
have useful implications for public education and harm reduction with respect to MDMA use,
and may also facilitate the development of possible treatment options for chronic MDMA users.