Mescaline Alters Cerebellar Function, Global Connectivity, and Frequency-Selective Acoustic Gating: A BOLD fMRI Study in Awake Rats.
Noah Cavallaro, Priya Rai, David Akins, Sima Soltanpour, Md Taufiq Nasseef, Richard J Ortiz, Rachel Utama, Caitlyn R Cody, Anoushka Mistry, Heather C Brenhouse, Praveen P Kulkarni, Craig F Ferris
Neuroscience bulletin May 21, 2026 DOI: 10.1007/s12264-026-01632-3 via PubMed
Summary
AI-generated from the abstractMescaline, a psychedelic used ceremonially for thousands of years, produces distinct brain effects that differ from LSD and psilocybin. In awake rats, mescaline suppressed BOLD signal in the cerebellum, suggesting it disconnects this region from forebrain areas. However, resting-state scans showed the cerebellum became hyperconnected to the hippocampus, thalamus, somatosensory cortex, and midbrain. Mescaline also eliminated normal brain responses to rewarding smells, indicating disrupted sensory processing. Acoustic startle tests revealed frequency-dependent effects: enhancement at 4 kHz (+27.6%) and 20 kHz (+27.3%), but impairment at 12 kHz (-16.4%). The cerebellum may act as a dysregulated sensory filter, flooding forebrain circuits with unprocessed information, potentially explaining psychedelic-induced perceptual changes.
Study at a glance
| Characteristics | Pharmacological and resting-state fMRI in awake rats Peer reviewed |
|---|---|
| Population | Awake rats |
| Intervention | Mescaline |
| Keywords | Cerebellum Fear Hippocampus Pharmacological MRI Reward |
| Key finding | Mescaline produces cerebellar-selective BOLD suppression and global resting-state hyperconnectivity, abolishes reward-related BOLD responses, and shows frequency-dependent effects on acoustic startle, distinguishing it from LSD and psilocybin. |
Abstract
Mescaline, a 5-HT2A agonist psychedelic used ceremonially for millennia, lacks neuroimaging characterization due to its Schedule 1 status. Using pharmacological and resting-state fMRI in awake rats, we report mescaline's first comprehensive neurobiological profile. Acutely, mescaline produced cerebellar-selective BOLD suppression, suggesting functional disconnection from forebrain structures. Paradoxically, resting-state analysis revealed global hyperconnectivity, with the cerebellum forming enhanced connections to the hippocampus, thalamus, somatosensory cortex, and midbrain. Mescaline abolished normal BOLD responses to rewarding olfactory stimuli, indicating disrupted sensory processing. Pre-pulse inhibition showed frequency-dependent acoustic gating effects: enhancement at 4 kHz (+ 27.6%) and 20 kHz (+ 27.3%), but impairment at 12 kHz (- 16.4%). These findings distinguish mescaline from LSD and psilocybin, implicating the cerebellum as a dysregulated sensory filter that floods forebrain circuits with unprocessed sensorimotor information-a potential mechanism underlying psychedelic-induced perceptual alterations.