Ketamine and Neurofeedback as Combined Therapeutic Interventions to Target Glutamatergic Neurotransmission in Alcohol Use Disorder

NCT ID: NCT06969937

Last Updated: 2025-12-05

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-01
• Study Completion Date: 2026-12-31

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 on the treatment of individuals with alcohol use disorder (AUD). The main questions the investigators aim to answer are:

• Can the investigators observe a positive, significant therapeutic effect by comparing changes in alcohol use via i) mean alcohol use per day, ii) heavy drinking days one month after the last treatment intervention?
• Are changes in glutamatergic neurotransmission in the nucleus accumbens related to cue-induced cravings in individuals with AUD?
• Is there a significant, ketamine-dependent change in glutamate levels in the nucleus accumbens?

Participants will be given ketamine or placebo and real-time fMRI neurofeedback (rt-fMRI NFT) or sham rt-fMRI NFT.

The investigators will compare three intervention groups to investigate the effects of the stand-alone effects as well as potential synergies between the combination of pharmacological and non-pharmacological intervention.

Detailed Description

For decades, addiction research has focused predominantly on the dopaminergic system. However, preclinical research suggests that alterations of glutamatergic neurotransmission within the nucleus accumbens (NAcc) are crucial for cue-induced drug-seeking behavior, at least in animal models of addiction (Kalivas, 2009). In line with this, three randomized controlled trials have been conducted exploring ketamine as a treatment for alcohol use disorder (AUD) or harmful drinking, each combining ketamine with either memory retrieval destabilization procedures or psychological therapy (Dakwar et al., 2020a; Das et al., 2019a; Grabski et al., 2022a). While ketamine consistently reduced alcohol use in these studies, the variability in treatment responses highlights the need for further investigation into the role of the glutamate system in AUD as well as optimal treatment approaches that maximize safety and efficacy for patients.

Given the significant need to advance both mechanistic and clinical understanding of AUD, this study aims to: (1) explore the role of glutamatergic neurotransmission in AUD; (2) determine whether ketamine can modulate potentially pathophysiological altered glutamate neurotransmission, and how such modulation may be influenced by ketamine metabolism ; and (3) optimize ketamine as a treatment for AUD by leveraging synergies between the additional biological mechanism of action of ketamine (i.e., induced neuroplasticity) and a targeted non-pharmacological neuromodulatory intervention, such as neurofeedback training (NFT), to maximize clinical outcomes.

To evaluate both the mechanistic and therapeutic effects of a single ketamine infusion and rt-fMRI NFT as well as their combined application on AUD, we will assess glutamatergic signalling in the NAcc, changes in neuroplasticity via BDNF, inter-individual differences in the metabolism of ketamine, and clinical symptoms in individuals with AUD.

Therefore, in this randomized, placebo-controlled, double blind, parallel group, single centre study we investigate the extend to which a single administration of ketamine and neurofeedback training, as well as the combination of the two interventions can restore neurobiological changes related to alcoholism and what effect this new treatment method has on the symptoms of AUD.

Conditions

Alcohol Abuse/Dependence; Alcohol Use Disorder (AUD); Alcoholism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

rt-fMRI NFT / Ketamine

Participants get real time neurofeedback based on an experimental regions' activity and receive 0.8 mg ketamine (i.v.) per kilogram bodyweight.

Group Type: EXPERIMENTAL

Ketamine

Intervention Type: DRUG

A single dose of ketamine 0.8 mg ketamine (i.v.) per kilogram bodyweight

Real-time fMRI Neurofeedback Training

Intervention Type: BEHAVIORAL

Participants will undergo a closed-loop rt-fMRI paradigm over 25 minutes. Participants will be instructed to use strategies to downregulate cue-induced cravings. The Intensity of cues will adjust based on the participants neural activity in response to cues. This dynamic feedback mechanism allows for personalized training aimed at improving the participant's ability to manage cravings.

sham rt-fMRI NFT / Ketamine

Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive 0.8 mg ketamine (i.v.) per kilogram bodyweight.

Group Type: EXPERIMENTAL

Ketamine

Intervention Type: DRUG

A single dose of ketamine 0.8 mg ketamine (i.v.) per kilogram bodyweight

Sham Neurofeedback Training/ Ketamine

Intervention Type: BEHAVIORAL

Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive 0.8 mg ketamine (i.v.) per kilogram bodyweight. The use of sham-NFT allows for a rigorous assessment of the specific effects of combined rt-fMRI NFT and ketamine by controlling for non-specific factors such as expectancy effects or the therapeutic context.

rt-fMRI NFT / Placebo

Participants get real time neurofeedback based on an control regions' activity and receive a 0.9% NaCL infusion (placebo).

Group Type: EXPERIMENTAL

Real-time fMRI Neurofeedback Training

Intervention Type: BEHAVIORAL

Participants will undergo a closed-loop rt-fMRI paradigm over 25 minutes. Participants will be instructed to use strategies to downregulate cue-induced cravings. The Intensity of cues will adjust based on the participants neural activity in response to cues. This dynamic feedback mechanism allows for personalized training aimed at improving the participant's ability to manage cravings.

Placebo

Intervention Type: DRUG

Single dose of placebo (0.9% NaCl infusion)

Interventions

Ketamine

A single dose of ketamine 0.8 mg ketamine (i.v.) per kilogram bodyweight

Intervention Type: DRUG

Real-time fMRI Neurofeedback Training

Participants will undergo a closed-loop rt-fMRI paradigm over 25 minutes. Participants will be instructed to use strategies to downregulate cue-induced cravings. The Intensity of cues will adjust based on the participants neural activity in response to cues. This dynamic feedback mechanism allows for personalized training aimed at improving the participant's ability to manage cravings.

Intervention Type: BEHAVIORAL

Placebo

Single dose of placebo (0.9% NaCl infusion)

Intervention Type: DRUG

Sham Neurofeedback Training/ Ketamine

Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive 0.8 mg ketamine (i.v.) per kilogram bodyweight. The use of sham-NFT allows for a rigorous assessment of the specific effects of combined rt-fMRI NFT and ketamine by controlling for non-specific factors such as expectancy effects or the therapeutic context.

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

• Informed Consent as documented by signature
• In- and outpatients aged 18 to 65 years of all sexes.
• DSM-IV diagnosis of alcohol use disorder (mild - severe).
• Motivation to reduce or stop alcohol use
• Normal level of language comprehension (German or Swiss-German)
• Good physical health with no unstable medical conditions
• Participants of childbearing potential must use an effective and established method of contraception for the entire study duration
• Comply with the study protocol as explained by investigator

Exclusion Criteria

• History of DSM-IV severe drug dependence other than alcohol (except for caffeine or nicotine) and any opiod use disorder within two months prior to enrolment.
• Hallucinogen and ketamine use 3 months prior to study participation (including regular microdosing).
• Alcohol withdrawal symptoms at any of the treatment visits (V2 and V3) (CIWA-Ar Scale >9).
• 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
• High risk of adverse emotional and behavioral reactions
• 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)
• During the study, new use or dose changes of already existing concomitant medication without prior informing the investigators.
• Taking medications that are known to modualte uridine diphosphate glucuronosyltransferase-enzyme
• Medication directly affecting glutamate signaling (e. g. anticonvulsant medication)
• Inhibitors of UGT1A9 and 1A10 should be discontinued at least five half-lives prior to the administration of ketamine.
• Monoamine oxidase and aldehyde or alcohol dehydrogenase inhibitors should be discontinued at least 5 half-lives prior to the dose of ketamine.
• 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 < 17 or > 35
• Allergy, hypersensitivity, or other adverse reaction to previous use of ketamine
• Contradictions to magnetic resonance imaging
• Concurrent participation in other clinical study

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Zurich

OTHER

Sponsor Role: collaborator

Dr. med. Marcus Herdener

OTHER

Sponsor Role: lead

Responsible Party

Dr. med. Marcus Herdener

Principal Investigator, Head of Center for Addictive Disorders

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Psychiatric University Zurich, University of Zurich

Zurich, , Switzerland

Site Status: RECRUITING

Countries

Switzerland

Central Contacts

Etna Engeli, Dr.

Role: CONTACT

etna.engeli@bli.uzh.ch

+41583842771 ext. +41583842771

Marcus Herdener, PD Dr. med.

Role: CONTACT

marcus.herdener@bli.uzh.ch

+41583845810

Other Identifiers

2024-02294

Identifier Type: -

Identifier Source: org_study_id