Co-Boost: Ketamine and Neurofeedback-Training: Effects on Neuroplasticity in Cocaine Addiction

Sponsor

Dr. med. Marcus Herdener (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06125054

Collaborator

University of Zurich (Other), University of Vienna (Other), University of Campania "Luigi Vanvitelli" (Other)

120

Enrollment

Location

Arms

Anticipated Duration (Months)

4.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cocaine Use Disorder Cocaine Dependence	Drug: Ketamine Drug: Placebo Behavioral: real-time fMRI neurofeedback training Behavioral: sham real-time fMRI neurofeedback training	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomized, placebo-controlled, double blind, parallel group, single center studyRandomized, placebo-controlled, double blind, parallel group, single center study

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Boosting and Guiding Neuroplasticity by Combining Ketamine With Neurofeedback-assisted Learning - Towards an Individualized and Integrated Pharmaco-psychotherapy for Cocaine Addiction

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Mar 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rt-fMRI NFT / Placebo Participants get real time neurofeedback based on an experimental regions' activity and receive a 0.9% saline solution (i.v.) over 40 minutes.	Drug: Placebo single dose of placebo (0.9% saline solution i.v. over 40 minutes) Other Names: 0.9% saline solution Behavioral: real-time fMRI neurofeedback training 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 twice.
Experimental: rt-fMRI NFT / Ketamine Participants get real time neurofeedback based on an experimental regions' activity and receive 0.71mg ketamine (i.v.) per kilogram bodyweight.	Drug: Ketamine single dose of ketamine (0.71mg/kg bodyweight i.v. over 40 minutes) Behavioral: real-time fMRI neurofeedback training 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 twice.
Placebo Comparator: sham NFT / Placebo Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive a 0.9% saline solution (i.v.) over 40 minutes.	Drug: Placebo single dose of placebo (0.9% saline solution i.v. over 40 minutes) Other Names: 0.9% saline solution Behavioral: sham real-time fMRI neurofeedback training 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 twice.
Experimental: sham NFT / Ketamine Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive 0.71mg ketamine (i.v.) per kilogram bodyweight.	Drug: Ketamine single dose of ketamine (0.71mg/kg bodyweight i.v. over 40 minutes) Behavioral: sham real-time fMRI neurofeedback training 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 twice.

Outcome Measures

Primary Outcome Measures

Decrease in proportion of cocaine use days [Between 5 and 7 weeks after baseline (the first intervention visit)]
Between-group comparison of proportion of cocaine use days measured with Time-Line Follow-Back questionnaire for cocaine use on follow-up visit (t3).
Changes in fMRI signal of neurofeedback training [Between 1 and 2 weeks after baseline (the first neurofeedback training)]
Signal changes assessed with fMRI between the practice (t1) and the transfer run (t2).
Changes in accumbal glutamate levels [Before and during infusion (same day)]
Baseline and acute accumbal glutamate levels assessed with 1H-MRS on Intervention Visit I (t1).

Secondary Outcome Measures

Changes in urine cocaine and cocaine metabolites [Baseline (screening visit) up to 19 weeks later (Follow-up Visit)]
Changes in cocaine and cocaine metabolites via urine analysis as objectified measure of cocaine use.
Cocaine craving [From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
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.
Severity of cocaine use disorder [From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
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.
Current motivation to change cocaine use behaviour [From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
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.
Hedonic capacity [From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
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.
Experience of pleasure across different domains [From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
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.
Emotion regulation skills [Baseline (screening visit) and up to 19 weeks later (Follow-up Visit)]
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.
Depressive symptoms [Baseline (screening visit), up to 14 weeks later (Intervention Visit II), and up to 19 weeks later (Follow-up Visit)]
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.
Perceived stress [Baseline (screening visit), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey)]
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.
Self-esteem [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)]
Changes in self-esteem assessed with the Rosenberg Self-esteem Scale, ranging from 0 to 30 where higher scores indicate a higher self-esteem.
Self-efficacy, optimism, and pessimism [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)]
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.
Subjective effects of ketamine infusion [2 hours post 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.
Effects of ketamine infusion on mystic experiences [2 hours post infusion]
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.
Sustained changes in accumbal glutamate levels [Baseline (pre infusion, Intervention Visit I) and up to 2 weeks after infusion and neurofeedback training (Intervention Visit II)]
Assess sustained effects of the infusion and the neurofeedback training on baseline accumbal glutamate levels with 1H-MRS.
Glutamate levels during craving paradigm [Up to 2 weeks post infusion and neurofeedback training]
Assess the effects of the infusion and the neurofeedback training on glutamate levels measured by 1H-MRS during a craving paradigm.
Functional connectivity [Baseline (Intervention Visit I) and up to 2 weeks later (Intervention Visit II)]
Changes in functional connectivity measured with fMRI during resting state
Changes in Brain Derived Neurotrophic Factor [0.5 hours pre infusion and 2 hours post infusion]
Assess changes in Brain Derived Neurotrophic Factor (BDNF) through blood analysis before and after the infusion.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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