A Phase 2 interventional study of Ketamine and Real-time fMRI Neurofeedback Training in Alcohol Abuse/Dependence, Alcohol Use Disorder (AUD) and Alcoholism, sponsored by Dr. med. Marcus Herdener. Recruiting at 1 site in Switzerland. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-12-05.
Sponsored by Dr. med. Marcus Herdener · Phase 2, Interventional, and Treatment
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:
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.
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.
1,606 studies on the registry are indexed under Alcoholism; 329 are open to participants now.
This study's planned enrollment of 75 is below the median of 87 across 1,371 interventional studies indexed under Alcoholism.
Browse Alcoholism studies →Dr. med. Marcus Herdener is the lead sponsor of 2 studies on the registry; 2 are open to participants now.
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Exclusion Criteria:
Participants get real time neurofeedback based on an experimental regions' activity and receive 0.8 mg ketamine (i.v.) per kilogram bodyweight.
Drug: Ketamine · Behavioral: Real-time fMRI Neurofeedback Training
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.
Drug: Ketamine · Behavioral: Sham Neurofeedback Training/ Ketamine
Participants get real time neurofeedback based on an control regions' activity and receive a 0.9% NaCL infusion (placebo).
Behavioral: Real-time fMRI Neurofeedback Training · Drug: Placebo
A single dose of ketamine 0.8 mg ketamine (i.v.) per kilogram bodyweight
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.
Single dose of placebo (0.9% NaCl infusion)
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.
Change in mean alcohol use per day
Change in mean alcohol use per day. Alcohol use is measured via a combination of the digital app and the Timeline Follow-Back Questionnaire.
Time frame: Starting immediately after the intervention visit 2 and ending 4 weeks later (integration visit).
Change in heavy drinking days
Change in heavy drinking days. Defined as five or more standard units of alcohol in a day for a man and four or more standard units of alcohol in a day for a woman. Alcohol use is measured via a combination of the digital app and the Timeline Follow-Back Questionnaire.
Time frame: Starting immediately after the intervention visit 2 and ending 4 weeks later (integration visit).
Changes in glutamat levels during craving
Changes in glutamatergic signalling in the NAcc measured via Magnetic Resonance Spectroscopy (MRS) during craving vs neutral cue exposure.
Time frame: During the intervention visit 1a and 1 week later during the intervention visit 2.
Changes in Brain Derived Neurotrophic Factor
Treatment-induced changes in neuroplasticity assessed using the brain derived neurotrophic factor (BDNF) through blood analysis.
Time frame: During the intervention visit 2 at baseline 30 minutes before and 2 hours after infusion start.
Individual variations in ketamine pharmacokinetics
Changes in ketamine plasma concentrations and its metabolites measured via blood samples taken.
Time frame: During the intervention visit 2 at baseline, 45 minutes, 1 hour 30 minutes before, and 2 hours 30 minutes after infusion start.
Predictive value of baseline rs-fMRI for treatment response
Predictive value of rs-fMRI for treatment response assessed via the two primary outcomes
Time frame: Between 1 and 2 weeks after baseline (screening visit) during the intervention visit 1a.
Changes in alcohol use in blood alcohol metabolites
Blood samples will be collected to analyse markers of alcohol use. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) and Phosphatidyl Ethanol (PEth) will be analysed from blood samples.
Time frame: At baseline (screening visit) and 4 weeks later (integration visit).
Severity of alcohol use disorder
Changes in severity of alcohol use disorder score assessed by the Obsessive Compulsive Drinking Scale, ranging from 0 to 56, where higher scores indicate more compulsive behaviors and obsessive thoughts to use alcohol.
Time frame: From baseline (screening visit) until 6 months later (follow-up survey II).
Changes in alcohol abstinence ability
Changes in individuals confidence in their ability to abstain from alcohol in high risk situations assessed with the Alcohol Abstinence Self-Efficacy Scale, ranging from 0 to 160, where higher scores indicate higher self-confidence in the ability to avoid drinking.
Time frame: From baseline (screening visit) until 6 months later (follow-up survey II).
Experience of alcohol craving
The Visual Analogue Scale for Alcohol Craving on a scale ranging from 0 to 100, where higher scores indicate higher subjective experience of craving.
Time frame: From baseline (screening visit) until 6 months later (follow-up survey II).
Depressive symptoms
Changes in depressive symptoms measured with Beck Depression Inventory. The scale ranges from 0 to 63 where higher scores indicate more severe depressive symptoms.
Time frame: From baseline (screening visit) until 6 months later (follow-up survey II).
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 6 months later (follow-up survey II).
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 6 months later (follow-up survey II).
Perceived quality of life
Changes in the perceived quality of life assessed with the Quality of Life Scale, ranging from 0 to 400, whereas higher scores indicate higher perceived quality of life.
Time frame: From baseline (screening visit) until 6 months later (follow-up survey II).
Posttraumatic stress symptoms
Changes in posttraumatic stress symptoms measured with Posttraumatic Stress Disorder Checklist for DSM-5. The scale ranges from 0 to 80, where higher scores indicate more severe posttraumatic stress symptoms.
Time frame: From baseline (screening visit) until 6 months later (follow-up survey II).
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: From baseline (screening visit) until 6 months later (follow-up survey II).
Subjective effects of ketamine infusion
Assess the acute subjective effects of the infusion with the Five-Dimension Altered State of Consciousness Questionnaire (5D-ASC), ranging from 0 to 100, where higher scores indicate the occurence of altered states of consciousness.
Time frame: 2 hours after the ketamine infusion (intervention visit 2).
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 after the ketamine infusion (intervention visit 2).
Neurofeedback Experience
The Neurofeedback Post Questionnaire (NF-PostQ) asks participants about their used strategies and experiences during neurofeedback training.
Time frame: After neurofeedback training (intervention visit 1b) and up to two weeks later (intervention visit 2).
Daily alcohol use and craving
A Digital app (SEMA3) will document daily alcohol craving and alcohol use using an Ecological Momentary Assessment method.
Time frame: From baseline (screening visit) up to 5 months later (one month prior to follow-up survey II).
Alcohol use in urine alcohol metabolites
Changes in alcohol metabolites via urine analyses as objective measure of alcohol use.
Time frame: From baseline (screening visit) up to one month later (Integration visit)
Plan to share: Yes — Our data will be published on the website of Open Science Framework.
Supporting information: Study protocol, Icf
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Dr. med. Marcus Herdener