Investigation of Serotonin Neurotransmission in "Ecstasy" Users Employing Combined Dexfenfluramine Challenge and Positron Emission Tomography: a Functional Probe to Assess MDMA Neurotoxicity
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Serotonin release capacity
研究概览
简要总结
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.
详细描述
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 suggested alterations of the 5-HT system in regular users of MDMA. However, most of these findings in humans have been strongly criticised for methodological flaws (e.g. small sample sizes or lack of specificity of the applied radioligands). Consequently, there is as yet no convincing evidence for a selective serotonergic neurotoxicity of MDMA in humans. Moreover, the mechanism of MDMA neurotoxicity in animals is still under debate.
In spite of these reservations, it has been consistently shown that MDMA users display dose-related impairments of verbal and visual-spatial memory, and impairments of executive functions and decision-making cognition. So far, the neuroanatomical basis of these neuropsychological deficits, and their relationship with 5-HT depletion, remain unclear.
On the basis of animal data, it is likely that MDMA at high or cumulative doses damages 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, in addition to the present receptor mapping studies, novel functional assays of serotonergic neurotransmission may be useful to clarify this issue. Specifically, we suggest that 5-HT challenge studies using positron emission tomography (PET) in conjunction with the serotonin releaser dexfenfluramine [(+)FEN] may test the functional integrity of the 5-HT system in the living human brain.
Aims: To overcome impediments of previous imaging studies we propose to use a more direct approach to assess the integrity of serotonergic function in the human brain. 5-HT2A receptor mapping with PET and [18F]-altanserin, in combination with (+)FEN challenge, shall be used to investigate the 5-HT release capacity in current and former users of MDMA in comparison to drug-naïve control subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •Female sex
- •Positive drug urine screening (with exception for cannabis)
- •Relevant somatic, neurological or psychiatric illness
- •Current use of psychotropic medication
研究组 & 干预措施
Placebo
干预措施: dexfenfluramine (Drug)
Dexfenfluramine
Dexfenfluramine HCL
干预措施: dexfenfluramine (Drug)
结局指标
主要结局
Serotonin release capacity
时间窗: 14 days
\[18F\]-altanserin binding to 5-HT2A receptors following dexfenfluramine challenge compared to placebo
次要结局
- Cognition(14 day)
- Prolactin and cortisol(14 days)
- Mood and mental state(14 days)
研究者
Boris B. Quednow
Prof. Dr. Boris Quednow, University Hospital of Psychiatry Zurich.
University of Zurich