The first proper brain scan involving the effects of mescaline found the drug ignoring the regions where psychedelic research has spent a decade studying, settling instead on the one structure no one really expected.
Sometime around 3,700 BC, someone in what is now southwest Texas cut two tops off a peyote cactus and dried them. They spent most of the twentieth century in a drawer at the Witte Museum in San Antonio, and when chemists finally analyzed them in the early 2000s, the mescaline was still detectable — roughly 2% alkaloids by weight, 5,700 years on.
Those dried-out cactus tops, where the drug compound is concentrated, remain the oldest plant drug ever to give up a major bioactive compound to chemical analysis. And with thousands of years of use, mescaline remains a bit of a scientific mystery.
Mescaline became a Schedule 1 substance under the Controlled Substances Act in 1970, and the classification effectively ended research on it. LSD and psilocybin eventually clawed their way back into laboratories for scientific research, but mescaline, the older compound by several thousand years, doesn’t have the same level of lab testing.
Now, a new study in Neuroscience Bulletin has become the first to properly look, and the answer is not what most expected.
Researchers at Northeastern University’s Center for Translational Neuroimaging scanned 24 rats, evenly split by sex. After a single dose of mescaline, while the animals were awake (anesthesia flattens the very signals a drug study is trying to read), the drug largely ignored the forebrain. It went almost entirely for the cerebellum, which is a strange location for a psychedelic.
The cerebellum is the lump at the back and bottom of the brain where balance and motor coordination live. It also holds more than half of all the neurons in the brain, and everything it computes leaves through just three narrow output channels.
An interpretation, proposed by neuroscientist Anna Devor in 2002, is that the cerebellum is the “Great Gate.” As the brain receives sensory information, it acts as a filter that suppresses the sensory information that the brain already predicted and passes along only what it did not expect. A working brain spends most of its time discarding what it saw coming.
Under mescaline, the gate appeared to come off its hinges.
Activity inside the cerebellum dropped sharply, while its connections outward multiplied to the hippocampus, the thalamus, the sensory cortex, and the midbrain. Quieter on the inside, wired to far more on the outside. The researchers read this as a filter that has stopped filtering and started broadcasting, pushing raw sensory information into regions that normally receive it neatly packaged.
“Wouldn’t it be devastating if you didn’t ‘gate’ all of that sensory information out?” senior author Craig Ferris explained in a university press statement.
The clearest evidence for that reading came from a smell test. Rats were given almond odor, a reliably rewarding stimulus, and in the control group, it lit up 48 of the 169 brain regions the team tracked. Under mescaline, the response was essentially abolished, flattened close to nothing across the board.
Broken down by modality, smell, touch, and hearing were all measurably blunted, while the visual system showed no significant change at all — a peculiar result for a compound whose entire cultural reputation rests on what it does to sight.
The authors put the discrepancy down to species differences, reasonably enough given that rats navigate by nose and whisker, but it remains one of the odder findings in the paper. What makes this significant is the comparison.
Mescaline, LSD, and psilocybin all act on the same target, the 5-HT2A serotonin receptor, and all three produce broadly similar experiences in people, which has encouraged researchers to treat findings from one as transferable to the others. However, brains don’t seem to cooperate.
Earlier work from this same lab found LSD acting on the prefrontal cortex, thalamus, and hippocampus, and psilocybin engaging cortico-striato-thalamic circuits. Mescaline’s acute signature sat in neither place.
“The power of mescaline to me is that it is doing something different than other psychedelics,” said lead author Noah Cavallaro. “Essentially, the cerebellum is being shut down internally, but it’s talking more to other parts of the brain.”
The distinctiveness is narrower than it first appears, though. The lab’s own psilocybin work also produced pronounced cerebellar hyperconnectivity, so the sprawling network changes are not unique to mescaline; what looks specific to it is the acute suppression, the cerebellum falling quiet while the rest of the brain carried on largely unaffected.
“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.
That being said, there are some cautions offered in the paper. First, these were rats, and rat and human brains differ most in the cerebellar-cortical wiring. Second, only one dose was tested. Third, the team did not monitor heart rate or breathing during scanning, so ordinary cardiovascular effects cannot be cleanly separated from neural ones.
Lastly, the researchers also flagged recent work showing that the scanner signal itself can run opposite to a brain region’s actual oxygen use, which complicates reading any of these images as direct neural activity. The one previous attempt to image mescaline in humans, a small study decades ago, found a different pattern entirely.
With all that being said, the paper presents a key social issue. Mescaline’s status as a drug has left it largely untested, and only now are we learning about what it can do to the brain, outside of the anecdotes of its users.
After fifty years of regulatory silence, scientists are just starting to answer a question people have arguably been asking since the Neolithic.
MJ Banias is a co-founder of The Debrief, covering science and technology news. You can email him at mj@thedebrief.org or follow him on LinkedIn.