First fMRI study of mescaline reveals altered sensory filtering and brain networks

A new study has demonstrated that mescaline produced a distinctive pattern of brain changes in awake rats, reducing activity in the cerebellum while increasing communication between it and several other brain regions. The psychedelic also altered responses to a rewarding smell and changed the brain’s ability to filter sounds, with effects varying according to sound frequency. This research was reported in Neuroscience Bulletin.

Mescaline is a psychedelic compound found in cacti. Indigenous communities in the Americas have used mescaline-containing cacti ceremonially for thousands of years. Modern human studies suggest that mescaline can cause altered visual perception, changes in the sense of time and feelings of separation from one’s usual sense of self.

The drug activates serotonin receptors (specifically the 5-HT2A receptor), which are involved in perception, mood and thinking. LSD and psilocybin act on the same receptor, but research increasingly suggests that different psychedelics may produce different patterns of brain activity. Before the current study, little was known about mescaline’s direct effects on the brain.

The researchers were particularly interested in the cerebellum. It is best known for helping coordinate movement and balance, but it also contributes to attention, memory, emotional regulation and the processing of sensory information.

Led by corresponding author Craig F. Ferris of Northeastern University, the researchers studied 24 rats during the brain imaging portion of the study. Half received 50 milligrams of mescaline per kilogram of body weight, while the others received a control solution.

The rats were trained to tolerate the scanning procedure while awake. Researchers used functional magnetic resonance imaging (fMRI)—which measures brain activity by tracking changes in blood oxygen levels—to measure immediate changes in brain function, communication between brain regions at rest, and responses to the smell of almonds. Almond was used as a standardized rewarding odor, allowing the researchers to test how mescaline affected the brain’s response to a consistent positive sensory cue.

A separate experiment involved 16 rats to test sound filtering. The animals heard a quiet warning tone at 4, 12 or 20 kilohertz 100 milliseconds before a loud burst of white noise. This test measured prepulse inhibition, in which the warning tone normally reduces the animal’s startle response. The reduction in startle indicates how effectively the brain filters sensory information.

Mescaline reduced the volume of brain areas showing typical increases in activity in 26 of 169 examined regions, with the largest effects concentrated in the cerebellum. It also expanded the volume of areas showing suppressed activity in 33 regions. At the same time, the drug increased the number of functional connections across the brain. The cerebellum showed particularly strong connections with the hippocampus (which supports memory and context); the thalamus (which relays and organizes sensory information); the somatosensory cortex (which processes touch and bodily sensations); and the midbrain (which regulates alertness, motivation and reward).

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The rats’ normal response to almond odor was also largely weakened. Brain activity linked to smell, touch and hearing was reduced, while visual regions were less affected. Sound filtering showed a more complicated pattern: prepulse inhibition improved at 4 and 20 kilohertz but worsened at 12 kilohertz.

Ferris, first author Noah Cavallaro, and their colleagues concluded that mescaline did not simply improve or impair sensory filtering overall. Instead, it appeared to change how particular sensory signals were prioritized. They wrote that “this study establishes mescaline as having a distinctive neurobiological profile characterized by cerebellar-selective hypoactivation [reduced activity] coupled with global hyperconnectivity [excessive communication across brain networks].”

Limitations are to be noted. For example, the researchers did not record heart rate, breathing or blood gases during scanning, meaning that some changes measured during the fMRI could have reflected cardiovascular effects rather than altered neural activity. Furthermore, they tested only a single dose of mescaline, and physiological differences mean these results in rats may not fully translate to humans.

The study, “Mescaline Alters Cerebellar Function, Global Connectivity, and Frequency-Selective Acoustic Gating: A BOLD fMRI Study in Awake Rats,” was authored by 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 and Craig F. Ferris.