Clinical trial NCT06125054: Ketamine and Neurofeedback-Training: Effects on Neuroplasticity in Cocaine Addiction
Official title: Boosting and Guiding Neuroplasticity by Combining Ketamine with Neurofeedback-assisted Learning - Towards an Individualized and Integrated Pharmaco-psychotherapy for Cocaine Addiction
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cocaine Use Disorder
Cocaine Dependence
Keywords: Cocaine
Cocaine Use
Ketamine
Reward Sensitivity
Glutamate
Placebo-controlled
Therapeutic effects
Mechanistic effects
Neurofeedback Training
realtime fMRI
Lead sponsor: Psychiatric University Hospital, Zurich
Sponsor class: OTHER
Collaborators: name: University of Zurich
name: University of Vienna
name: University of Campania Luigi Vanvitelli
First posted: 2023-11-09
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, placebo-controlled, double blind, parallel group, single center study
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Informed Consent as documented by signature
* Male and female cocaine users 18 to 55 years of age
* diagnostic and statisical manual (DSM)-5 diagnosis of CUD
* Willingness to comply with the study protocol as explained by investigator
* Normal level of language comprehension (German or Swiss-German)

Exclusion Criteria:

* Current or lifetime psychotic disorders
* History of severe substance-induced psychosis
* Current or lifetime bipolar I or II disorders
* Current suicidality
* Previous suicide attempts during the last 2 years
* Current severe alcohol use disorder
* Current severe cannabis use disorder
* Current moderate or severe stimulant use disorder (other than cocaine)
* Current moderate or severe benzodiazepine use disorder
* Current opioid use disorder
* First-degree relatives with psychotic disorders
* Beck Depression Inventory Score greater than 25
* Unmedicated or unstable hypertension
* Severe illness (e. g. myocardial ischemia or arrythmias, severe pulmonary secretions, glaucoma, congestive heart failure or angina, significant renal or hepatic impairment)
* Acute infection (e. g. pulmonary or upper respiratory tract infection)
* Insufficient treated or uncorrected hyperthyroidism
* Severe central nervous system related traumas or disorders (e. g. stroke, cerebral trauma with loss of consciousness over more than 24h, epilepsy)
* Increased intracranial pressure
* Medication directly affecting glutamate signaling (e. g. anticonvulsant medication)
* Any unstable psychoactive medication (no changes in compounds within last 4 weeks before start of study)
* Pregnancy or lactation
* Women of childbearing potential with no use of medically accepted contraceptive (e. g.

condoms, contraceptive diaphragm, birth control pill, hormone injection, intrauterine device)

* BMI\>35
* Allergy, hypersensitivity, or other adverse reaction to previous use of ketamine
* Contradictions to magnetic resonance imaging
* Concurrent participation in other clinical study

Primary outcomes:
measure: Decrease in proportion of cocaine use days
timeFrame: Between 5 and 7 weeks after baseline (the first intervention visit)
measure: Changes in fMRI signal of neurofeedback training
timeFrame: Between 1 and 2 weeks after baseline (the first neurofeedback training)
measure: Changes in accumbal glutamate levels
timeFrame: Before and during infusion (same day)
Secondary outcomes:
measure: Changes in urine cocaine and cocaine metabolites
timeFrame: Baseline (screening visit) up to 19 weeks later (Follow-up Visit)
measure: Cocaine craving
timeFrame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
measure: Severity of cocaine use disorder
timeFrame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
measure: Current motivation to change cocaine use behaviour
timeFrame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
measure: Hedonic capacity
timeFrame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
measure: Experience of pleasure across different domains
timeFrame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)
measure: Emotion regulation skills
timeFrame: Baseline (screening visit) and up to 19 weeks later (Follow-up Visit)
measure: Depressive symptoms
timeFrame: Baseline (screening visit), up to 14 weeks later (Intervention Visit II), and up to 19 weeks later (Follow-up Visit)
measure: Perceived stress
timeFrame: Baseline (screening visit), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey)
measure: Self-esteem
timeFrame: 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)
measure: Self-efficacy, optimism, and pessimism
timeFrame: 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)
measure: Subjective effects of ketamine infusion
timeFrame: 2 hours post infusion
measure: Effects of ketamine infusion on mystic experiences
timeFrame: 2 hours post infusion
measure: Sustained changes in accumbal glutamate levels
timeFrame: Baseline (pre infusion, Intervention Visit I) and up to 2 weeks after infusion and neurofeedback training (Intervention Visit II)
measure: Glutamate levels during craving paradigm
timeFrame: Up to 2 weeks post infusion and neurofeedback training
measure: Changes in Brain Derived Neurotrophic Factor
timeFrame: 0.5 hours pre infusion and 2 hours post infusion
Other outcomes:
Locations:
city: Zürich
country: Switzerland
facility: Psychiatric University Hospital Zurich, University of Zurich
Study officials:
References: