Serotonergic psychedelics induce distinct patterns of metabolic activity and covariance within biologically informed rat brain networks

Serotonergic psychedelics show therapeutic potential across neuropsychiatric disorders despite transient acute effects. These compounds share serotonin 2 A receptor agonism but differ in broader pharmacology, motivating a systematic comparison of their neurobiological effects. Here, we use [18 F]FDG-PET in rats to assess acute and one-week effects of psilocybin, LSD, and 2C-B on brain metabolic activity and metabolic covariance within biologically informed networks. All three drugs produce distinct acute patterns, with drug-specific alterations in cortico-striato-thalamo-cortical and cortico-amygdalo-hippocampal-hypothalamic networks. Voxel-wise analyses reveal LSD-driven hypometabolic clusters in retrosplenial and hippocampal regions and a 2C-B-specific hypermetabolic cluster in the midbrain. One week after administration, LSD and psilocybin, but not 2C-B, show modest hypometabolism spanning cortical, limbic, and midbrain structures. These findings demonstrate that serotonergic psychedelics induce distinct acute and sustained metabolic signatures, providing a network-level framework for understanding their shared and drug-selective mechanisms and informing therapeutic stratification across neuropsychiatric disorders.