Neurobiological Adaptations and Pharmacological Interventions in Cocaine Addiction
Condition: Cocaine Addiction
MeSH terms: Cocaine-Related Disorders; Behavior, Addictive
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): N-Acetylcystein; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): n-AC will be given according to a double-blind, placebo-controlled cross-over design. Subjects receive 3 doses of n-AC over 2 consecutive days (total dose=4800mg; individual doses=2x1200mg, 1x2400mg). Subjects will take 2 first doses (à 1200mg) of n-AC 5 days after the screening assessment (one in the morning, one in the evening), and the last dose (2400mg) 1h prior to scanning, with 12 hours dosing intervals in between. Preparation and blinding of n-AC capsules will be performed by the Kantonsapotheke Zürich according to the guidelines of Good Manufacturing Practice.; 14 days before or after, placebo will be administered analogously as described with n-AC. Placebo will be given according to a double-blind, placebo-controlled cross-over design. Subjects receive 3 doses of placebo over 2 consecutive days (total dose=4800mg; individual doses=2x1200mg, 1x2400mg). Subjects will take 2 first doses (à 1200mg) of placebo 1 day before scanning (one in the morning, one in the evening), and the last dose (2400mg) 1h prior to scanning, with 12 hours dosing intervals in between. Preparation and blinding of placebo capsules will be performed by the Kantonsapotheke Zürich according to the guidelines of Good Manufacturing Practice.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science