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

Overview

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.

Interventions

• Drug Ketamine
  single dose of ketamine (0.71mg/kg bodyweight i.v. over 40 minutes)
• Drug Placebo
  single dose of placebo (0.9% saline solution 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 three times.
• 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 three times.

Primary outcome measures

• Decrease in proportion of cocaine use days [Time frame: Between 5 and 7 weeks after baseline (the first intervention visit)]
• Changes in fMRI signal of neurofeedback training [Time frame: Between 1 and 2 weeks after baseline (the first neurofeedback training)]
• Changes in accumbal glutamate levels [Time frame: Before and during infusion (same day)]

Secondary outcome measures (12)

• Changes in urine cocaine and cocaine metabolites [Time frame: Baseline (screening visit) up to 19 weeks later (Follow-up Visit)]
• Cocaine craving [Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
• Severity of cocaine use disorder [Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
• Current motivation to change cocaine use behaviour [Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
• Hedonic capacity [Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
• Experience of pleasure across different domains [Time frame: From baseline (screening visit) until 38 weeks later (Follow-up Survey)]
• Emotion regulation skills [Time frame: Baseline (screening visit) and up to 19 weeks later (Follow-up Visit)]
• 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 [Time frame: Baseline (screening visit), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey)]
• 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 [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 [Time frame: 2 hours post infusion]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Switzerland · 1 center

• Psychiatric University Hospital Zurich, University of Zurich — Zurich

Publications

• Trippel AS, Gubser LP, Engeli EJE, Conradi J, Haugg A, Zoelch N, Herdener M. Co-Boost: boosting and guiding neuroplasticity by combining ketamine with neurofeedback-assisted learning-towards an individualised and integrated pharmaco-psychotherapy for cocaine addiction: study protocol for a randomised, placebo-controlled, double-blind, parallel-group, single-centre trial. Trials. 2025 Sep 25;26(1): PMID 40999531

Identifiers

NCT: NCT06125054 · Co-Boost_PUK_2022-01859

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗