One of the oldest psychedelics meets modern brain imaging

For millennia, people have used the psychedelic mescaline as a spiritual and religious tool. Mescaline is a naturally occurring chemical found in cacti, mainly peyote cacti, that are located in the Southwest United States and Mexico. The drug has been used for 5,700 years, according to archaeological evidence, making it one of the oldest hallucinogens.

Subscribe to our newsletter for the latest sci-tech news updates.

New research from Northeastern University suggests the drug may not just help people understand the divine; mescaline may also contribute to hallucinations and changes in sensory perception similar to those reported in some psychiatric conditions. The study is published in Neuroscience Bulletin.

"The power of mescaline to me is that it is doing something different than other psychedelics," said doctoral student Noah Cavallaro, who conducted the study with Craig Ferris, a professor who specializes in psychology and pharmaceutical sciences at Northeastern.

Cavallaro noted that mescaline and psychedelics like LSD and psilocybin produce similar "hallmark effects" such as visual distortions, altered perception and changes in cognition. But mescaline appears to be doing something different in the brain compared with these other classical psychedelics.

"If two compounds produce similar hallucinogenic symptoms through different neural pathways, comparing them could help us pinpoint what's actually causing those specific experiences," Cavallaro said.

A different signal in the brain

At Northeastern's Center for Translational Neuroimaging (CTNI), Ferris and students are at the forefront of this movement, using MRI machines to examine the brains of live, awake rodents that have been given drugs such as marijuana and psychedelics, including mescaline, psilocybin and LSD.

"We went through our cannabis phase and have a number of publications out on our animals smoking weed," Ferris said. "Now we're in our psychedelic phase."

According to the research, a dose of mescaline elicited what Cavallaro called a "paradoxical" effect on the cerebellum, the part of the brain responsible for motor control that acts as a "gatekeeper" for processing sensory information.

"Essentially, the cerebellum is being shut down internally, but it's talking more to other parts of the brain," said Cavallaro, who also studied the effects of psilocybin on the brain in a similar experiment with the lab.

Ferris said that this "hyperconnectivity" among different parts of the brain was also seen in rodents that had been given LSD and psilocybin. But mescaline's unique dampening effect on the cerebellum, and the cerebellum's role as a gatekeeper of sensory information, suggested that the region could contribute to the drug's hallucinatory effects, Cavallaro said.

"Your whole body—internally and externally—is being inundated by sensory information," Ferris added. "Wouldn't it be devastating if you didn't 'gate' all of that sensory information out? You would be basically hallucinating."

By "gating," Ferris was referring to the cerebellum's process of filtering and triaging sensory information so that the body can respond appropriately.

Testing smell and sound

But while a person can describe their mescaline-induced conversations with God, or the vivid images or colors they may see while on the drug (two commonly reported reactions to mescaline, Ferris said), a rodent, alas, cannot. So researchers used sound and smell (olfactory) stimuli to test whether rodents' sensory perception was altered as a result of a mescaline dose.

The rodents had no reaction to a "rewarding" smell while they were high, according to the research.

The drugged rodents had a mixed response to sounds in a test to measure a key gatekeeping feature of the cerebellum called "prepulse inhibition"—a neurological function in which a weak tone, or prepulse, suppresses the brain's "startle" response when the tone is repeated suddenly or loudly.

"If I was standing behind you and I clapped a loud sound, you would jump—you'd be startled by that sound," Ferris said to explain the concept. "But then if I did it seconds later ... you would completely ignore it."

To test this response, researchers exposed drugged rodents to a series of tones at low, middle and high frequencies. The rodents' cerebella were able to effectively "gatekeep" and filter out the repeated loud sounds at the high and low frequencies, according to the study. But when exposed to sounds at the middle frequency, the rodents "failed miserably," Ferris said.

"When you look at the brain activity data, and you see all that deactivation in the cerebellum, it raises the question, is the cerebellum being shut down completely or is it selectively filtering out signals?" Cavallaro explained. "What we were able to determine with both the prepulse inhibition and with the olfactory tests was it's a selective filter."

Links to psychiatric symptoms

Patients with some psychiatric disorders also can have difficulty gatekeeping sensory stimuli, Ferris said. For example, post-traumatic stress can be triggered by certain sounds, and it can feature "auditory illusions," the phenomenon in which the brain interprets a sound wave differently from its actual physical properties—for example, making someone hear sounds that aren't there or perceive impossible acoustic properties.

People experiencing their first episode of schizophrenia show hyperconnectivity patterns similar to those shown by rodents exposed to mescaline, according to the research.

From rodent scans to the clinic

Cavallaro said the next step in the research is to measure how different doses affect cerebral activity and expand the research beyond the lab.

"This is a drug that hasn't made its way into the clinic," Cavallaro said. "To draw the translational gap between rodents and humans, I think the clinic is the next step."

More information: Noah Cavallaro et al, Mescaline Alters Cerebellar Function, Global Connectivity, and Frequency-Selective Acoustic Gating: A BOLD fMRI Study in Awake Rats, Neuroscience Bulletin (2026). DOI: 10.1007/s12264-026-01632-3

This story is republished courtesy of Northeastern Global News news.northeastern.edu.

Provided by Northeastern University