The goal of this clinical trial is to learn about the effects of the combination of ketamine and realtime functional magnetic resonance imaging (fMRI) neurofeedback training in individuals with cocaine use disorder. The main questions the investigators aim to answer are: * Can the investigators observe a positive, significant effect on percentage of cocaine use days of both interventions combined as well as stand alone interventions? * Is there a significant transfer effect of the neurofeedback training? * Is there a significant, ketamine-dependent change in glutamate levels in the nucleus accumbens? Participants will be given ketamine and a realtime fMRI neurofeedback training. Both interventions are placebo-controlled. The investigators will compare the four intervention groups to investigate the effects of the stand-alone effects of the intervention and the combination of it.
Cocaine is the most frequently used stimulant worldwide, and its consumption rate in Europe indicates a continuing upward trend. Cocaine use is associated with great harms for affected individuals, their families, and the society. Unfortunately, until today no pharmacotherapy has been approved for the treatment of cocaine use disorder (CUD) due to lack of efficacy of tested compounds. The investigators therefore propose, to use latest advancements in proton magnetic resonance spectroscopy (1H-MRS) and real time functional magnetic resonance imaging neurofeedback training (rt-fMRI NFT) to develop a neurobiologically informed experimental approach for an individualized and integrated pharmaco-psychotherapy that has the potential to open new avenues for the treatment of CUD, and in addition, to be transferable to other neuropsychiatric conditions. To improve the efficacy of psychotherapeutic interventions in individuals with CUD, the investigators recently developed an rt-fMRI NFT paradigm based on reward imagery to specifically modify maladaptive reward sensitivity by self-regulating the brain's reward circuits. Furthermore, using a 1H-MRS technique, the investigators recently demonstrated that a disturbed glutamate homeostasis in the nucleus accumbens (NAcc), an important hub in the brain's reward system, characterizes cue-induced craving in CUD. This indicates that urgently needed novel pharmacotherapies for addiction treatment should target the glutamatergic system. Thus, to restore the glutamate homeostasis and to boost learning effect of the reward imagery training, the investigators propose to combine reward imagery rt- fMRI NFT with the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, which has direct effects both on glutamatergic signaling and neuroplasticity and has shown therapeutic potential to reduce cocaine craving and cocaine us. The investigators anticipate a) restoration of the glutamate homeostasis in the NAcc b) changes in maladaptive reward sensitivity resulting from rt-fMRI NFT and c) synergistic effects of the pharmacological and the psychotherapeutic effect due to the ketamine-induced neuroplasticity that might open a window of opportunity for imagery-based learning. The investigators hypothesize that these neurobiological adaptions induced by the described interventions underlie their therapeutic effects on cocaine craving and use. The effects of ketamine and reward imagery rt-fMRI NFT in individuals with CUD will be tested in a randomized, placebo-controlled, double blind, parallel group study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
120
single dose of ketamine (0.71mg/kg bodyweight i.v. over 40 minutes)
single dose of placebo (0.9% saline solution i.v. over 40 minutes)
Real-time fMRI based neurofeedback over 20 minutes where participants are instructed to perform reward imagery. The feedback is based on an experimental region. The training is repeated three times.
Sham real-time fMRI neurofeedback training over 20 minutes where participants are instructed to perform reward imagery. The feedback is based on a control region. The training is repeated three times.
Psychiatric University Hospital Zurich, University of Zurich
Zurich, Canton of Zurich, Switzerland
RECRUITINGDecrease in proportion of cocaine use days
Between-group comparison of proportion of cocaine use days measured with Time-Line Follow-Back questionnaire for cocaine use on follow-up visit (t3).
Time frame: Between 5 and 7 weeks after baseline (the first intervention visit)
Changes in fMRI signal of neurofeedback training
Signal changes assessed with fMRI between the non-neurofeedback run 1 on Interention Visit I (t1) and run 3 on Intervention Visit II (t2).
Time frame: Between 1 and 2 weeks after baseline (the first neurofeedback training)
Changes in accumbal glutamate levels
Baseline and acute accumbal glutamate levels assessed with 1H-MRS on Intervention Visit I (t1).
Time frame: Before and during infusion (same day)
Changes in urine cocaine and cocaine metabolites
Changes in cocaine and cocaine metabolites via urine analysis as objectified measure of cocaine use.
Time frame: Baseline (screening visit) up to 19 weeks later (Follow-up Visit)
Cocaine craving
Changes in cocaine craving score assessed by the Obsessive Compulsive Cocaine Use Scale, ranging from 0 to 56, where higher scores indicate more problematic behavior and thoughts.
Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
Severity of cocaine use disorder
Changes in severity of cocaine use disorder assessed by the Obsessive Compulsive Cocaine Use Scale, ranging from 0 to 56, where higher scores indicate more problematic behavior and thoughts.
Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
Current motivation to change cocaine use behaviour
Changes in current motivation to change cocaine use behaviour assessed by an visual analogue scale ranging from 0 to 30 where higher scores indicate a higher motivation to change.
Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
Hedonic capacity
Changes in hedonic capacity measured by the Trait Hedonic Capacity Scale, ranging from 16 to 80, where a higher score indicates a higher hedonic capacity.
Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
Experience of pleasure across different domains
Changes in the experience of pleasure across different domains assessed by the Domains of Pleasure Scale, ranging from 0 to 210 where a higher score indicates a higher experience of pleasure.
Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
Emotion regulation skills
Changes in emotion regulation skills measured with the Negative Mood Regulation expectancies Scale, ranging from 30 to 150 where higher scores indicate higher emotion regulation skills.
Time frame: Baseline (screening visit) and up to 19 weeks later (Follow-up Visit)
Depressive symptoms
Changes in depressive symptoms measured with the Beck Depression Inventory. The scale ranges from 0 to 63 where higher scores indicate more severe depressive symptoms.
Time frame: Baseline (screening visit), up to 14 weeks later (Intervention Visit II), and up to 19 weeks later (Follow-up Visit)
Perceived stress
Changes in perceived stress assessed with a subscale of the Stress \& Coping Inventory, ranging from 21 to 147 where higher scores indicate higher perceived stress.
Time frame: Baseline (screening visit), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey)
Self-esteem
Changes in self-esteem assessed with the Rosenberg Self-esteem Scale, ranging from 0 to 30 where higher scores indicate a higher self-esteem.
Time frame: Baseline (screening visit), up to 14 weeks later (Intervention Visit II), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey)
Self-efficacy, optimism, and pessimism
Changes in Self-efficacy, optimism, and pessimism assessed with the Questionnaire for Self-efficacy, Optimism, and Pessimism (KSWOP-9), ranging from 9 to 36 where higher scores indicate higher self-efficacy, optimism, and pessimism, respectively.
Time frame: Baseline (screening visit), up to 14 weeks later (Intervention Visit II), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey)
Subjective effects of ketamine infusion
Assess the acute subjective effects of the infusion with the Five-Dimension Altered State of Consciousness Questionnaire (5D-ASC), where the global score and each of the 11 subscales range from 0 to 100 and higher scores indicate the occurence of altered states of consciousness.
Time frame: 2 hours post infusion
Effects of ketamine infusion on mystic experiences
Assess the acute subjective effects of the infusion with the Hood's Mysticism Scale, ranging from 20 to 100 where higher scores indicate the occurence of mystic experiences.
Time frame: 2 hours post infusion
Sustained changes in accumbal glutamate levels
Assess sustained effects of the infusion and the neurofeedback training on baseline accumbal glutamate levels with 1H-MRS.
Time frame: Baseline (pre infusion, Intervention Visit I) and up to 2 weeks after infusion and neurofeedback training (Intervention Visit II)
Glutamate levels during craving paradigm
Assess the effects of the infusion and the neurofeedback training on glutamate levels measured by 1H-MRS during a craving paradigm.
Time frame: Up to 2 weeks post infusion and neurofeedback training
Changes in Brain Derived Neurotrophic Factor
Assess changes in Brain Derived Neurotrophic Factor (BDNF) through blood analysis before and after the infusion.
Time frame: 0.5 hours pre infusion and 2 hours post infusion
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