Scientists May Have Misjudged How Psychedelics Work
Mescaline showed a distinct neural signature but shared cerebellar connectivity changes with other psychedelics.
When studying psychedelics, scientists made a fatal error.
They assumed that if two psychedelics worked the same way, so must they all.
In a new study from Northeastern University, a team led by Prof. Craig Ferris found that the oldest known psychedelic, mescaline, defied this rule entirely.
“Because there were no mescaline data, people extrapolated from psilocybin and lysergic acid diethylamide (LSD). Our results suggest the extrapolation was wrong, which means a good deal of what is said about ‘the psychedelics’ as a class actually rests on two compounds,” Ferris told Technology Networks.
However, despite their differences, the results also highlighted a shared neural circuit, potentially revealing the mechanism behind the psychedelic experience itself.
Using mescaline to understand psychedelic science
Mescaline is one of humanity's oldest ceremonial psychedelics, yet science knows surprisingly little about how it affects the brain. While Indigenous cultures have used mescaline-containing cacti for thousands of years, modern neuroimaging has largely dismissed the compound.
“Mescaline was placed in Schedule 1 in 1970, and the research effectively stopped. Before our study, the only neuroimaging of mescaline in the literature was a SPECT study by Hermle and colleagues in 1992, in 12 volunteers. The first double-blind, placebo-controlled human trial appeared only in 2024, from Klaiber and colleagues in Basel,” said Ferris. “For a compound with archeological evidence of ceremonial use going back several thousand years, that is a remarkably thin record.”
Most modern research has focused on LSD and psilocybin, which both bind to the same 5-HT2A serotonin receptors, leaving researchers to assume that they worked identically across the brain.
Previous studies from the Northeastern group have shown distinct signatures: LSD alters cortical, thalamic, and cerebellar circuits in a dose-dependent manner, while psilocybin triggers widespread surges in brain activity alongside cerebellar hyperconnectivity.
But focusing purely on shared receptors misses differences in local network behavior.
To truly understand the psychedelic experience, Ferris and the team wanted to look beyond LSD and psilocybin; by imaging mescaline, they aimed to compare its neural profile against their previous findings.
How mescaline altered brain connectivity
The team administered a 50 mg/kg dose of mescaline to 24 awake male and female rats during high-field functional magnetic resonance imaging (fMRI) scanning. They tracked blood oxygen level-dependent (BOLD) signals to measure fluctuations in blood oxygenation, allowing them to see local changes in neural activity.
Mescaline produced a signature dramatically different from LSD and psilocybin.
“Mescaline produced no increase in positive BOLD anywhere in the 169 brain areas we measured, and instead a sustained negative BOLD signal confined almost entirely to the cerebellum and hindbrain,” said Ferris.
Despite the reduction in cerebellar activity, the cerebellum's functional connections to the rest of the brain expanded dramatically.
“The deep cerebellar nuclei gained connections to the thalamus, somatosensory cortex, midbrain, and hippocampus,” explained Ferris. “The hippocampal result was the one that stopped us: in vehicle-treated animals there is essentially no functional connection between the hippocampus and the cerebellar nuclei, and after mescaline there were connections to seven of the nine hippocampal subregions.”
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Since the drop in activity was restricted exclusively to the cerebellum rather than affecting the entire brain, the team concluded it reflected true neural suppression rather than a systemic change in blood flow.
“But divergence is only half of the picture, and probably the less important half,” said Ferris.
“Underneath those different global fingerprints, all three compounds share one thing: a dramatic increase in connectivity between the cerebellum, including the deep cerebellar nuclei, and the rest of the brain,” he added. The “prefrontal cortex, olfactory bulb, thalamus, accumbens, and somatosensory cortex were essentially untouched. That degree of regional restriction is unusual, and it argues against a purely systemic explanation: an effect driven entirely by cardiovascular change would have appeared everywhere rather than in one structure.”
Psychedelic impact on sensory processing
From music tasting like colors, sounds rippling into visual shapes, and everyday sensory boundaries dissolving, humans undergoing a psychedelic trip often report their perception of the world melting around them.
To test how this altered connectivity affected perception, the team evaluated sensory processing by measuring the rats' brain responses to a familiar, pleasant scent and by testing how effectively they filtered out repetitive sound pulses.
While almond odor activated 48 distinct brain regions in the control animals, mescaline completely blocked the brain's expected reaction to a pleasurable scent.
“Mescaline abolished the normal brain response to a rewarding odor, almond, which rats are innately drawn to; a hardwired, evolutionarily salient stimulus stopped registering,” said Ferris.
Sound filtering tests showed a similar disruption: instead of completely shutting down filtering, mescaline improved acoustic gating at low (4 kHz) and high (20 kHz) frequencies but impaired it at an intermediate frequency of 12 kHz.
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Ferris believes these changes reflect a central mechanism: “psychedelic activation of 5-HT2A receptors on Purkinje cells and inferior olivary neurons disrupts that gate, and that the resulting flood of unfiltered sensorimotor information into forebrain circuits is the substrate of hallucination and synesthesia. The senses mixing, the intensification, the dissolving boundary between self and environment—those are what a failed filter feels like from the inside,” said Ferris.
The cerebellum may be the common engine of the psychedelic experience
Despite producing vastly different brain-wide activity patterns, mescaline, LSD, and psilocybin all converged on a single neural circuit.
“The clearest lesson is that the receptor is not the mechanism. Mescaline, LSD, and psilocybin are all 5-HT2A agonists, and the field has generally treated that shared target as license to extrapolate from one compound to the others,” said Ferris.
“We went into this study expecting something resembling our psilocybin data. We did not get it.” — Prof. Craig Ferris
“In fully awake rats given LSD, we reported increased functional connectivity across many networks, and the most unexpected finding was a dramatic hyperconnectivity between the cerebellum, including the deep cerebellar nuclei, and numerous other brain regions. Psilocybin produced a similar effect, particularly at higher doses. Mescaline does the same. Three compounds with quite different global activation profiles converge on one structure,” Ferris added.
“Widespread cerebellar connectivity of that kind is not something we ordinarily see, and I do not think it is incidental,” he explained.
The convergence suggests that psychedelic effects stem from altered sensory filtering in the cerebellum.
“I have argued that this is the foundation of the psychedelic experience itself. More than half the neurons in the brain sit in the cerebellum, and everything they compute is funneled through three pairs of deep nuclei. That is the architecture of a structure built to discard information,” said Ferris.
This model may also explain the mechanism underlying psychiatric conditions such as schizophrenia, which exhibit similar sensory gating deficits and cerebellar hyperconnectivity.
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However, it is important to note that rodent models cannot report subjective experiences. The study also only tested a single dose of 50 mg/kg, and fMRI BOLD signals reflect complex vascular dynamics.
“The deeper issue is that nobody working with BOLD, clinical or preclinical, can currently say precisely what drives the global signal changes we report, and I do not expect that to be resolved soon,” said Ferris.
Future research must translate the findings into human clinical trials.
“If cerebellar hyperconnectivity is the common substrate, it should appear with every classical psychedelic, it should track the intensity of the effect, and interventions that restore cerebellar gating should blunt it. Those are testable, and they are the experiments I would like to see done,” said Ferris.
Reference: 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. doi: 10.1007/s12264-026-01632-3
About the interviewee:
Dr. Craig F. Ferris is a professor of psychology and pharmaceutical sciences at Northeastern University, where he directs the Center for Translational Neuroimaging. His laboratory developed and validated the methods that make functional magnetic resonance imaging (MRI) possible in fully awake, unanesthetized animals—an approach that removes the confound of anesthesia from studies of brain function, and one that is essential to any question about altered states of consciousness.
Across a research career spanning nearly four decades and more than 230 publications—over 60 of them in awake-animal imaging—his group has applied the method to neuropeptides and social behavior, repetitive mild head injury, cannabinoids and, most recently, the classical psychedelics.
He received his BS in biology from the University of Massachusetts and his MS and PhD in physiology from New York Medical College, followed by postdoctoral training in neuroendocrinology and peptide chemistry with Susan Leeman and Robert Carraway at Harvard Medical School. Before moving to Northeastern, he was a professor of psychiatry and physiology and the director of the Center for Comparative Neuroimaging at the University of Massachusetts Medical School. Alongside his academic work, he has co-founded four companies and holds nine issued patents, together with copyrights on several animal MRI atlases.
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