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Investigation of Serotonin Neurotransmission in MDMA Users Using Combinated Dexfenfluramine Challenge and PET Imaging (DEXFEN_PET)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boris B. Quednow, University of Zurich
ClinicalTrials.gov Identifier:
NCT01296802
First received: February 7, 2011
Last updated: December 14, 2011
Last verified: December 2011
  Purpose

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.


Condition Intervention
Amphetamine-Related Disorders
Amphetamine Abuse
Drug: dexfenfluramine

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Investigation of Serotonin Neurotransmission in "Ecstasy" Users Employing Combined Dexfenfluramine Challenge and Positron Emission Tomography: a Functional Probe to Assess MDMA Neurotoxicity

Resource links provided by NLM:


Further study details as provided by University of Zurich:

Primary Outcome Measures:
  • Serotonin release capacity [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    [18F]-altanserin binding to 5-HT2A receptors following dexfenfluramine challenge compared to placebo


Secondary Outcome Measures:
  • Cognition [ Time Frame: 14 day ] [ Designated as safety issue: No ]
    Changes in cognition (e.g., memory) after dexfenfluramine challenge compared to placebo

  • Prolactin and cortisol [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    Changes of prolactin and cortisol after dexfenfluramine challenge and placebo

  • Mood and mental state [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    Changes in mood and mental states after dexfenfluramine compared to placebo


Enrollment: 50
Study Start Date: April 2006
Study Completion Date: July 2008
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo Drug: dexfenfluramine
oral, 40 mg to 60 mg, single application as a challenge
Other Names:
  • d-fenfluramine
  • Benzeneethanamine
  • (S)-N-Ethyl-1-[3-(trifluoromethyl)phenyl]-propan-2-amine
Experimental: Dexfenfluramine
Dexfenfluramine HCL
Drug: dexfenfluramine
oral, 40 mg to 60 mg, single application as a challenge
Other Names:
  • d-fenfluramine
  • Benzeneethanamine
  • (S)-N-Ethyl-1-[3-(trifluoromethyl)phenyl]-propan-2-amine

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Current and former MDMA users: lifetime use of ≥ 50 tablets of Ecstasy
  • Current MDMA users: Ecstasy use in the last 4 weeks
  • Former MDMA users: at least 1 year of abstinence of Ecstasy and other psychostimulants
  • MDMA-naïve control subjects: no lifetime use of MDMA or other psychostimulants

Exclusion Criteria:

  • Female sex
  • Positive drug urine screening (with exception for cannabis)
  • Relevant somatic, neurological or psychiatric illness
  • Current use of psychotropic medication
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01296802

Locations
Switzerland
University Hospital of Psychiatry Zurich
Zurich, ZH, Switzerland, 8032
Sponsors and Collaborators
University of Zurich
Investigators
Principal Investigator: Franz X Vollenweider, Prof. University Hospital of Psychiatry Zurich
Principal Investigator: Boris B Quednow, Prof University Hospital of Psychiatry Zurich
  More Information

Additional Information:
Publications:
Responsible Party: Boris B. Quednow, Prof. Dr. Boris Quednow, University Hospital of Psychiatry Zurich., University of Zurich
ClinicalTrials.gov Identifier: NCT01296802     History of Changes
Other Study ID Numbers: PUK_Study_72
Study First Received: February 7, 2011
Last Updated: December 14, 2011
Health Authority: Switzerland: Swissmedic

Keywords provided by University of Zurich:
Ecstasy
MDMA
Serotonin
Neurotoxicity
dexfenfluramine
Positron emission tomography
altanserin
5-HT2A receptor

Additional relevant MeSH terms:
Amphetamine-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Dexfenfluramine
Serotonin
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Serotonin Agents
Serotonin Receptor Agonists

ClinicalTrials.gov processed this record on November 27, 2014