Clinical Trial: Neurobiological Adaptations and Pharmacological Interventions in Cocaine Addiction

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

Official Title: Neurobiological Adaptations and Pharmacological Interventions in Cocaine Addiction: The Role of Glutamate

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 Summary:

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
Sponsor: Psychiatric University Hospital, Zurich

Current Primary Outcome:

  • 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] [ Time Frame: 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) ]
    - Changes in basal glutamatergic neurotransmission in the nucleus accumbens in cocaine addiction will be assessed via 1H-MRS.
  • 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] [ Time Frame: 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. ]
    • The impact of n-AC on glutamatergic neurotransmission in cocaine addiction will be assessed via 1H-MRS.
  • Impact of n-acetylcystein on craving assessed by visual analog scales [ Time Frame: 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. ]
    • Craving will be assessed via subjective ratings on visual analog scales
    • The impact of n-AC will be assessed by comparing craving in cocaine dependent individuals under n-AC and placebo.

      • Original Primary Outcome: Same as current

      Current Secondary Outcome: Alterations in frontostriatal networks indicated by connectivity coefficients assessed by functional magnetic resonance imaging [ Time Frame: Alterations in frontostriatal will be assessed by comparing n-AC and placebo condition with an average time interval of 2 weeks. ]

      • Alterations in frontostriatal networks will be assessed via magnetic resonance imaging.


      Original Secondary Outcome: Same as current

      Information By: Psychiatric University Hospital, Zurich

      Dates:
      Date Received: May 20, 2015
      Date Started: March 2015
      Date Completion:
      Last Updated: April 28, 2017
      Last Verified: April 2017