Clinical Trial: Investigation of Serotonin Neurotransmission in MDMA Users Using Combinated Dexfenfluramine Challenge and PET Imaging

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Investigation of Serotonin Neurotransmission in "Ecstasy" Users Employing Combined Dexfenfluramine Challenge and Positron Emission Tomography: a Functional Probe to Assess MDMA Neurotoxicity

Brief 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 inv

Detailed Summary:

Introduction: Illicit use of the psychostimulant 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is considered a major public health issue. In Switzerland, the proportion of teenage MDMA users has increased continuously in recent years. According to a representative survey from 2002, approximately 3.3% of the 15-16 year old students in Switzerland have taken MDMA at least once. Compared with the corresponding data from 1994 (1.8%) and 1998 (1.9%), the increase of MDMA use among is evident. In another survey from the Swiss Institute for the Prevention of Alcoholism and Drug Addiction (SFA/ISPA) 2.2% of the anonymously interviewed subjects between 15 to 39 years reported experiences with MDMA. Also worldwide, MDMA has become one of the most widely used illegal psychoactive drugs, with millions of regular users.

Acute administration of MDMA produces a rapid and marked release of serotonin (5-HT) via inhibition and reversal of the 5-HT transporter. Since the late 1980s, studies in non-human primates have provided convincing evidence that high doses of MDMA cause a substantial and sustained long-term neurotoxic loss of exclusively 5-HT nerve terminals with an associated depletion of up to 95% of 5-HT in several brain regions. In contrast, other neurotransmitter systems such as dopamine or norepinephrine remain undamaged. Subsequently, two studies with MDMA users have also shown selective decrements in cerebrospinal fluid (CSF) concentrations of 5-hydroxy indoleacetic acid, a marker for 5-HT depletion. In contrast, CSF concentrations of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol, the major metabolites of dopamine and norepinephrine, were unchanged. Some imaging studies with serotonergic radioligands showed reduced 5-HT transporter (SERT) densities in cortical and subcortical brain regions of MDMA users. Moreover, electrophysiological studies have also su
Sponsor: University of Zurich

Current Primary Outcome: Serotonin release capacity [ Time Frame: 14 days ]

[18F]-altanserin binding to 5-HT2A receptors following dexfenfluramine challenge compared to placebo


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Cognition [ Time Frame: 14 day ]
    Changes in cognition (e.g., memory) after dexfenfluramine challenge compared to placebo
  • Prolactin and cortisol [ Time Frame: 14 days ]
    Changes of prolactin and cortisol after dexfenfluramine challenge and placebo
  • Mood and mental state [ Time Frame: 14 days ]
    Changes in mood and mental states after dexfenfluramine compared to placebo


Original Secondary Outcome:

  • Cognition [ Time Frame: 14 day ]
    Chnages of cognition (e.g., memory) after dexfenfluramine challenge compared to placebo
  • Prolactin and cortisol [ Time Frame: 14 days ]
    Changes of prolactin and cortisole aftter dexfenfluramine challenge and placebo
  • Mood and mental state [ Time Frame: 14 days ]
    Changes in mood and mental ststes after dexfenfluramine compared to placebo


Information By: University of Zurich

Dates:
Date Received: February 7, 2011
Date Started: April 2006
Date Completion:
Last Updated: December 14, 2011
Last Verified: December 2011