Subacute effects of ketamine on neural correlates of reward processing

Abstract 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.