Ketamine, a versatile compound with various applications such as anesthesia, antidepressant therapy, substance misuse, and the exploration of altered states of consciousness, remains enigmatic in its mechanisms of action, particularly regarding its neurophysiological and therapeutic effects in humans. Like the classic psychedelics, ketamine elicits lasting mood improvements after a single or few administrations. Extensive animal research has demonstrated that both ketamine and classic psychedelics enhance neuroplasticity, reopening developmental windows for learning and alleviating mood disorder symptoms in preclinical models. However, translating these findings to humans has proven challenging. Using the novel positron emission tomography (PET) tracer [11C]-UCBJ alongside functional magnetic resonance imaging (fMRI), we investigated neuroplastic changes induced by a single psychedelic dose of ketamine in healthy participants (n = 11), measured 1 to 8 days post-administration. Our findings revealed a significant negative correlation between increased synaptic density within the default mode network (DMN) and functional brain activity metrics. Specifically, increased synaptic density in the posterior cingulate cortex (PCC)—a key hub of the DMN—was associated with reduced influence of the PCC on whole-brain informational dynamics. Moreover, we observed decreased high-order within-network integration and enhanced communication between low- and high-order functional networks, indicative of a flattening of the cortical hierarchy during the acute drug state. These results suggest that the reorganization of brain functional architecture induced by ketamine during the altered state of consciousness persists in the days following administration and is linked to enhanced neuroplasticity. This mechanism may underpin the rapid and enduring therapeutic effects of ketamine and related compounds, including classic psychedelics.
