Clinical trial NCT02626494: Neurobiological Adaptations and Pharmacological Interventions in Cocaine Addiction
Official title: Neurobiological Adaptations and Pharmacological Interventions in Cocaine Addiction: The Role of Glutamate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cocaine Addiction
Lead sponsor: Psychiatric University Hospital, Zurich
Sponsor class: OTHER
Collaborators: name: Zurich Center for Integrative Human Physiology
name: Swiss Federal Institute of Technology
name: Max-Planck-Institut Tübingen
First posted: 2015-12-10
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: This study aims at testing for the impact of glutamatergic changes on drug craving in cocaine addiction, and to evaluate the effects of n-acetylcysteine (n-AC) on both glutamate homeostasis and craving using a randomized, double-blind, placebo controlled cross-over design.

Detailed description: Cocaine addiction is a devastating disorder with potentially harmful psychological, physical and social consequences. Despite its clinical importance, there is currently no approved pharmacological treatment available for cocaine addiction. However, preclinical research has recently identified potentially promising targets for pharmacotherapeutic approaches mainly based on advances in the understanding of neuroplastic alterations associated with repeated cocaine administration in animals.

Preclinical animal models revealed that chronic administration of cocaine leads to decreased basal levels of glutamate within the nucleus accumbens a key region of the neural reward circuitry; in turn, the reinstatement of drug seeking results in enhanced glutamatergic transmission. However, little is known about similar changes in humans, and about their functional role for addictive behavior, mainly due to methodological restrictions. The investigators thus aim to examine the changes associated with chronic cocaine use on glutamate homeostasis in humans using a newly developed proton magnetic resonance spectroscopy (1H-MRS) protocol. This method allows for the quantification of brain metabolites such as glutamate in specific regions of the human brain even within small subcortical volumes of interest such as the nucleus accumbens that have been hitherto difficult to assess.

Interestingly, the administration of n-AC restored the glutamate homeostasis in rats and reduced their drug reinstatement behavior. Therefore, the present study aims at investigating if a pharmacological challenge of n-AC influences glutamate homeostasis in humans and whether these possible modulations are linked to cocaine craving.

Power analyses to identify the sample size of this study, were done with a focus on 1H-MRS, the most critical procedure in this context within our project. Assuming a mean conservative effect size of d=0.80, an α-error probability of 5%, and a conservative power estimation of 80% and considering a drop-out rate of about 30%, investigators plan to measure 30 cocaine dependent patients and 30 healthy controls.

Imaging data of low quality (e.g. due to movement artifacts) will be excluded. If imaging data has to be excluded or if participants do not finish the experiment, the investigators will additionally recruit more participants in order to assess the planned sample size.

Throughout the duration of the entire study, the conductance of pre-defined key processes will constantly be monitored by an independent monitor in specified visit intervals to ensure that the study is conducted in accordance with the approved protocol, good clinical practice, and the applicable regulatory requirement in order to protect the rights and well-being of study participants and integrity of data.

Eligibility criteria: Inclusion Criteria:

* Cocaine use disorder vs. no substance use
* Magnetic resonance imaging compatibility

Exclusion Criteria:

* Regular use of other psychoactive drugs
* Comorbidity of other psychiatric disorders
* Neurological or somatic disease

Primary outcomes:
measure: Glutamatergic alterations in cocaine users assessed by 1H-MRS as glutamate concentrations in the nucleus accumbens expressed as glutamate ratios in relation to water [glutamate/water]
timeFrame: It will be assessed in the placebo condition at either the 1.measurement (approximately 1.5h after ingestion of the last dose), on average 2 days after the initial assessment of the subject or at the 2.measurement (in average 14 days after 1.measurement)
measure: Impact of n-acetylcystein on glutamate homeostasis assessed by 1H-MRS as glutamtate concentrations in the nucleus accumbens expressed as glutamate ratios in relation to water [glutamate/water]
timeFrame: The impact of n-AC will be assessed by comparing n-AC and placebo condition, with an average time interval of 14 days between measurements.
measure: Impact of n-acetylcystein on craving assessed by visual analog scales
timeFrame: The impact of n-AC will be assessed by comparing n-AC and placebo condition with an average time interval of 2 weeks between measurements.
Secondary outcomes:
measure: Alterations in frontostriatal networks indicated by connectivity coefficients assessed by functional magnetic resonance imaging
timeFrame: Alterations in frontostriatal will be assessed by comparing n-AC and placebo condition with an average time interval of 2 weeks.
Other outcomes:
Locations:
city: Zurich
country: Switzerland
facility: Psychiatric University Hospital, Zurich
Study officials:
affiliation: Center for Addicitve Disorders
name: Marcus Herdener, MD
role: PRINCIPAL_INVESTIGATOR
References: