Serotonergic psychedelics induce distinct patterns of metabolic activity and covariance within biologically informed rat brain networks
Frederik Gudmundsen, Julia Czurylo, Daniel Ryskamp Rijsketic, Camilla Trang Vo, Janika Ruuska, Naja S. Jessen, Sophie Woodruff, Christina Baun, Matthias M. Herth, Vladimir Shalgunov, Boris D. Heifets, Patrick M. Fisher, Mikael Palner
Nature Communications August 3, 2026 DOI: 10.1038/s41467-026-75890-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Psilocybin LSD 2C-B |
| Duration | Acute and one-week effects |
| Topics | Serotonin |
| Key findings | Psilocybin, LSD, and 2C-B each induce distinct acute brain metabolic patterns, with LSD-specific hypometabolism 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 across cortical, limbic, and midbrain structures. |
Abstract
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. LSD, Psilocybin and 2C-B are different serotonergic psychedelic drugs with slightly different pharmacology. Here, authors show that while they all share the power to reshape neuronal communication across brain networks, they do so in slightly distinct ways, producing different long-term changes.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |