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

NCT01296802 | Completed

• 1 other identifier: PUK_Study_72
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Amphetamine-Related Disorders; Amphetamine Abuse

Keywords

Ecstasy; MDMA; Serotonin; Neurotoxicity; dexfenfluramine; Positron emission tomography; altanserin; 5-HT2A receptor

Outcome Measures

Primary Outcomes (1)

• Serotonin release capacity

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

  14 days

Secondary Outcomes (3)

• Cognition

  14 day

• Prolactin and cortisol

  14 days

• Mood and mental state

  14 days

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Drug: dexfenfluramine

Dexfenfluramine

EXPERIMENTAL

Dexfenfluramine HCL

Drug: dexfenfluramine

Interventions

dexfenfluramine DRUG

oral, 40 mg to 60 mg, single application as a challenge

Also known as: d-fenfluramine, Benzeneethanamine, (S)-N-Ethyl-1-[3-(trifluoromethyl)phenyl]-propan-2-amine

Dexfenfluramine; Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• Female sex
• Positive drug urine screening (with exception for cannabis)
• Relevant somatic, neurological or psychiatric illness
• Current use of psychotropic medication

Sponsors & Collaborators

• University of Zurich: lead

Study Sites (1)

University Hospital of Psychiatry Zurich

Zurich, Canton of Zurich, 8032, Switzerland

Location

Related Publications (2)

• Hasler F, Kuznetsova OF, Krasikova RN, Cservenyak T, Quednow BB, Vollenweider FX, Ametamey SM, Westera G. GMP-compliant radiosynthesis of [18F]altanserin and human plasma metabolite studies. Appl Radiat Isot. 2009 Apr;67(4):598-601. doi: 10.1016/j.apradiso.2008.12.007. Epub 2008 Dec 24.

  PMID: 19162492 BACKGROUND

• Quednow BB, Treyer V, Hasler F, Dorig N, Wyss MT, Burger C, Rentsch KM, Westera G, Schubiger PA, Buck A, Vollenweider FX. Assessment of serotonin release capacity in the human brain using dexfenfluramine challenge and [18F]altanserin positron emission tomography. Neuroimage. 2012 Feb 15;59(4):3922-32. doi: 10.1016/j.neuroimage.2011.09.045. Epub 2011 Oct 5.

  PMID: 21996132 RESULT

MeSH Terms

Conditions

Amphetamine-Related Disorders; Neurotoxicity Syndromes

Interventions

Dexfenfluramine

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Nervous System Diseases; Poisoning

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals

Study Officials

• Franz X Vollenweider, Prof.

  University Hospital of Psychiatry Zurich

  PRINCIPAL INVESTIGATOR

• Boris B Quednow, Prof

  University Hospital of Psychiatry Zurich

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Boris Quednow, University Hospital of Psychiatry Zurich.

Study Record Dates

• First Submitted: February 7, 2011
• First Posted: February 15, 2011
• Study Start: April 1, 2006
• Primary Completion: July 1, 2008
• Study Completion: July 1, 2008
• Last Updated: December 15, 2011

Record last verified: 2011-12

Locations

CH (1)