Detecting neuroplastic effects induced by ketamine in healthy human subjects: A multimodal approach.
Claudio Agnorelli, Joseph Peill, Gabriela Sawicka, Danielle Kurtin, Ekaterina Shatalina, Kirran Ahmad, Matthew B Wall, Catarina Rua, Kate Godfrey, Natalie Ertl, Graham Searle, Katie Zhou, Martin Osugo, Brandon Weiss, Kyle T Greenway, Andrea Fagiolini, Robin Carhart-Harris, Paul M Matthews, Eugenii A Rabiner, David Nutt, David Erritzøe
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism March 21, 2026 DOI: 10.1177/0271678x261431447 via PubMed
Summary
AI-generated from the abstractA single intravenous dose of ketamine (1 mg/kg) in eleven healthy men altered brain chemistry and connectivity days later. Glutamate levels rose in the anterior cingulate cortex (ACC). Functional coupling between the ACC and the dorsolateral prefrontal cortex decreased, while coupling between the ACC and the amygdala increased. Participants whose PET scans indicated increased synaptic plasticity showed reduced intrinsic activity in default mode network (DMN) regions. The findings suggest the DMN is a central hub where ketamine may reshape brain hierarchies, offering clues to its therapeutic mechanisms.
Study at a glance
| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 11 |
| Population | Healthy male human subjects |
| Intervention | Ketamine |
| Dose | 1 mg/kg, intravenous |
| Duration | 1-8 days after administration |
| Topics | Default mode network Ketamine Neuroplasticity |
| Keywords | MRI PET |
| Key finding | Ketamine increased ACC glutamate levels and altered ACC functional connectivity with dlPFC and amygdala, with DMN activity changes linked to synaptic plasticity. |
Abstract
We investigated ketamine's neuroplastic effects in healthy human subjects using integrated Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) measures before and 1-8 days after a single psychedelic dose of ketamine (1 mg/kg, intravenous). Eleven male participants underwent two PET/MRI scans with [11C]-UCBJ (synaptic density/plasticity), 1H-MRS (glutamate and GABA) and resting-state fMRI (intrinsic brain activity, functional connectivity), before and after ketamine. While group-level analyses showed no significant increases in PET synaptic markers, ketamine administration resulted in significantly elevated glutamate levels within the anterior cingulate cortex (ACC). Functional connectivity analyses revealed reduced coupling between the ACC and the dorsolateral prefrontal cortex (dlPFC) and increased coupling between the ACC and the amygdala in the days following ketamine administration. Our multimodal analysis revealed that participants showing an increase in [11C]-UCBJ volume distribution (VT), a putative index of synaptic plasticity, showed a correlated reduction in intrinsic activity within regions belonging to the default mode network (DMN). By linking molecular, cellular and network-level changes, our results point to the DMN as a central hub where ketamine may reshape brain hierarchies in the long term, providing new directions for understanding its therapeutic mechanisms and developing targeted treatments.