Serotonergic psychedelics induce distinct patterns of metabolic activity and covariance within biologically informed...

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.