Ketamine induces a sequence of temporally distinct effects on brain function, yet its impact on reward processing beyond the acute post-administration phase remains unclear. In this single-blind, placebo-controlled, crossover study, 28 healthy participants received 0.5 mg/kg racemic ketamine or placebo via a 40 min intravenous infusion. Functional magnetic resonance imaging was acquired approximately 5 h post-infusion during the Monetary Incentive Delay (MID) task, targeting the subacute phase after resolution of acute dissociative effects.
Plasma concentrations of ketamine and norketamine were obtained for pharmacokinetic modeling and area under the curve estimation. At 5 h post-administration, ketamine did not significantly modulate brain activation during the MID task in either ROI-based or whole-brain analyses, despite measurable subjective drug effects. Pharmacokinetic modeling yielded ketamine and norketamine concentration-time profiles consistent with expected pharmacokinetic patterns, however, neither individual drug exposure nor psychometric measures showed robust associations with MID task-related neural activation.
These findings suggest an absence of detectable task-evoked effects under the present methodological conditions. When considered alongside prior work, they are consistent with the possibility that ketamine’s effects on reward circuitry are time-sensitive and may be more prominent during the acute post-administration phase or in clinical populations with pre-existing reward dysfunction. The authors would like to thank all staff involved in successful study implementation, including medical doctors and technical colleagues, and diploma students of the Advanced Neuroimaging Labs (aNIL, head: R.
Lanzenberger), Department for Psychiatry and Psychotherapy (chair: D. They also express their gratitude to their collaboration partners at the Vienna Science Hub of the University of Vienna. Briem has presented related work from this dataset as an abstract and poster at the 37th European College of Neuropsychopharmacology (ECNP) Congress 2024 (https://doi.org/10.1016/j.nsa.2024.105200).
A preprint of this manuscript has been made available on bioRxiv (https://doi.org/10.1101/2025.09.10.675318). The authors used ChatGPT (OpenAI) to assist with grammar and language optimization during manuscript preparation. All content was reviewed and approved by the authors, who take full responsibility for the final text.
ClinicalTrials.gov: The Effect of Ketamine on Aesthetics and Role for Antidepressant Effects; https://clinicaltrials.gov/study/NCT05320107. This study was partly funded by the Research Cluster ‘Unraveling the aesthetic mind in anhedonia: Insights from pharmacological imaging of the human brain’ between the Medical University of Vienna (PI: Rupert Lanzenberger) and the University of Vienna [Grant number: SO68900012]. This research was funded in whole, or in part, by the Austrian Science Fund (FWF) [Grant-DOI: 10.55776/PAT6608924; 10.55776/KLI1006; PI: R.
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