530. Detecting neuroplastic effects induced by ketamine and classic psychedelics in healthy human subjects

Abstract Background Clinical studies have shown that ketamine and classic psychedelics can produce robust and rapid antidepressant effects after a single or a few administrations. However, the neurobiological mechanisms driving these long-lasting changes remain unclear. A leading framework proposes that both drug classes induce sustained increases in neuroplasticity, potentially reshaping synaptic and neural network function over days to months. Yet most direct evidence comes from animal work, and translational human studies quantifying neuroplasticity-related changes induced by ketamine and classic psychedelics remain limited. Aims & Objectives To quantify and compare sustained neuroplasticity-related effects of ketamine and the classic psychedelic N, N-dimethyltryptamine (DMT) in healthy humans using integrated PET/MRI, bridging synaptic-density markers and large-scale brain dynamics. Specifically, we aimed to (i) test whether a single administration of ketamine or DMT produces measurable post-acute changes in synaptic density, (ii) assess whether ketamine induces sustained changes in glutamate levels, and (iii) determine whether the neuroplastic changes induced by ketamine and DMT covary with persistent alterations in intrinsic brain activity and functional connectivity.

Method: In a series of studies, we used integrated PET/MRI to probe neuroplasticity-related effects of a single administration of ketamine (n =11; 1 mg/kg) and DMT ( n= 7; 27.5 mg) in healthy human participants. Participants underwent PET/MRI sessions at baseline and 1–8 days post-administration. Synaptic density was indexed using the PET tracer [11C]-UCBJ. Glutamate concentration within the anterior cingulate cortex was measured via 1H-MRS (ketamine study only). Whole-brain Intrinsic brain activity and functional connectivity were derived from resting-state fMRI.

Results: Both ketamine and DMT showed trend-level increases in [11C]-UCBJ signal, but these effects did not reach statistical significance at the group level. Following ketamine, we observed significantly increased ACC glutamate levels (M: 21.77 ± 25.35 %; β = 2.92; p = 0.030), alongside persistent reconfiguration of functional brain architecture in the days after dosing, including reduced within-network integrity in higher-order networks, such as the Default Mode Network (DMN), and increased integration between lower- and higher-order networks. Multimodal analyses showed that increases in synaptic-density signal were negatively correlated with intrinsic brain activity in regions of the DMN, and were associated with reduced influence of posterior cingulate cortex (PCC) dynamics on global network organisation (e.g., ketamine: r=-0.69, p=0.02). Discussion & Conclusions Changes in [11C]-UCBJ signal following ketamine and DMT were heterogeneous across healthy individuals, with group-level PET effects remaining trend-level, suggesting substantial inter-individual variability in putative synaptic-density responses. Nonetheless, multimodal analyses revealed a relationship between drug-induced changes in synaptic-density signal and intrinsic brain activity in DMN regions, linking molecular indices of neuroplasticity to sustained alterations in large-scale network dynamics beyond the acute drug state. Ketamine additionally produced sustained elevations in ACC glutamate levels, consistent with longer-lasting modulation of excitatory/inhibitory balance. Overall, these findings support a translational model in which ketamine and DMT may engage plasticity-related processes that couple to persistent reorganisation of high-order networks, while highlighting response heterogeneity as a key feature of neuroplastic effects in humans and an important target for future studies.