Ketamine has been used clinically for over 50 years, but its mechanisms remain largely unclear. Its hypnotic effects are mainly mediated by blocking NMDA and HCN1 receptors, while cholinergic, aminergic, and opioid systems modulate sedation and analgesia. Ketamine's effects on chronic pain and depression outlast drug levels, likely due to a secondary increase in synaptic connectivity triggered by a neuronal response to a hyper-glutamatergic state.
Selfhood depends on brain processes that allow a person to experience being a distinct, capable agent. It includes a hierarchy of components: core self (awareness of existence), embodied self (sentience), executive self (agency), and higher-order cognition. Consciousness and selfhood are related but not identical; understanding selfhood helps explain partial consciousness during anesthesia. Brain-imaging and EEG studies show that anesthetic drugs selectively impair self-related networks, especially the anterior insula and salience network, causing depersonalization at moderate doses while preserving disembodied self-awareness. Unlike natural sleep, where loss of agency and sentience tracks with decreasing self-awareness, anesthesia maintains posterior brain connectivity even at high concentrations, possibly marking a core self involved in reduced energy homeostasis.