Mescaline Alters Cerebellar Function, Global Connectivity, and Frequency-Selective Acoustic Gating: A BOLD fMRI Study in Awake Rats

New research from Northeastern University suggests the drug may not just help understand the divine, mescaline may also contribute to hallucinations and changes in sensory perception that are similar to those reported in some psychiatric conditions.

This new study provides the first comprehensive fMRI characterisation of mescaline's effects on the brain. Unlike LSD and psilocybin, mescaline appeared to produce a distinctive pattern centred on the cerebellum, suggesting that altered cerebellar processing may contribute to psychedelic-induced changes in perception. Note this was an animal study in awake rats, so the findings cannot be directly extrapolated to humans.

Key Findings

1. Selective suppression of cerebellar activity

Mescaline caused a marked reduction in blood-oxygen-level-dependent (BOLD) activity within the cerebellum, with relatively little direct activation in cortical regions.

The authors interpret this as evidence that mescaline temporarily disrupts normal cerebellar processing rather than simply activating the cortex, as has been reported for some other psychedelics

2. Global brain hyperconnectivity - Despite reduced local cerebellar activity, resting-state fMRI demonstrated increased functional connectivity across much of the brain.

3. Disrupted sensory processing - Mescaline abolished the normal BOLD response to a rewarding odour (almond).

4. Frequency-dependent sensory gating

Prepulse inhibition testing demonstrated that mescaline altered sensory filtering differently depending on sound frequency.

Compared with controls:

• 4 kHz: prepulse inhibition increased by 27.6%

• 20 kHz: prepulse inhibition increased by 27.3%

• 12 kHz: prepulse inhibition decreased by 16.4%

Rather than producing a general impairment in sensory gating, mescaline appeared to selectively recalibrate responses to different auditory frequencies.

5. A potentially unique mechanism among psychedelics

The authors propose that mescaline differs from LSD and psilocybin because it primarily disrupts cerebellar sensory filtering.

Their hypothesis is that impaired cerebellar predictive processing allows excessive, poorly filtered sensory information to reach higher brain regions, contributing to the altered perceptions characteristic of the psychedelic state. They describe this as the cerebellum functioning as a "dysregulated sensory filter."

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.

Cavallaro, N., Rai, P., Akins, D. et al. Mescaline Alters Cerebellar Function, Global Connectivity, and Frequency-Selective Acoustic Gating: A BOLD fMRI Study in Awake Rats. Neurosci. Bull. (2026). Read Paper

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