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

LSD, 2CB and psilocybin change the brain in different ways

A recent 2026 Nature Communications rat study compared psilocybin, LSD and 2C-B using FDG-PET.

All three psychedelics produced distinct patterns of brain glucose metabolism, despite sharing 5-HT2A receptor activity.

2C-B produced a particularly distinct acute metabolic signature, including increased metabolism in midbrain/brainstem regions.

At one week, the drugs continued to show drug-specific metabolic and metabolic-covariance changes.

Psilocybin increased relative metabolism in the insula and strengthened metabolic covariance between the mPFC and insula.

2C-B produced changes involving the VTA/substantia nigra and nucleus accumbens at one week.

Across the whole brain, modest one-week hypometabolism was associated with psilocybin and LSD, but not 2C-B. The findings suggest that serotonergic psychedelics can produce distinct, drug-specific changes in brain networks, rather than a single generic “psychedelic brain” effect.

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.

Gudmundsen, F., Czurylo, J., Rijsketic, D.R. et al. Serotonergic psychedelics induce distinct patterns of metabolic activity and covariance within biologically informed rat brain networks. Nat Commun 17, 9340 (2026). Read Paper

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