Psychedelics work on the brain by increasing the functional connection between the thinking and sensory regions, temporarily blurring the line between perception and thought, an international consortium of neuroscientists has found.

In what researchers say is the largest analysis of psychedelic brain imaging to date, investigators studied more than 500 brain scans from nearly 270 people under the influence of psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), mescaline, or ayahuasca. Despite their chemical differences, all five drugs acted on the brain in a similar way, creating what the researchers call a “neural fingerprint of psychedelic states.”

Rather than causing individual brain networks to fall apart — a narrative that has long shaped clinical thinking about how these drugs work therapeutically — investigators found psychedelics heightened communication between parts of the brain involved in abstract thinking and self-reflection and regions responsible for vision, touch, and other sensory information.

The findings offer the most comprehensive picture yet of how psychedelics alter brain connectivity during a psychedelic drug experience.

“The distinction between inner experience and outer perception is blurred,” lead investigator Manesh Girn, PhD, a neuroscientist at the University of California, San Francisco, told Medscape Medical News. “The brain is being shaken out of its usual way of dividing cognitive and perceptual processing.”

The study was published online April 6 in Nature Medicine.

An International Effort 

Interest in psychedelics’ therapeutic potential has grown rapidly in recent years. More than 400 clinical trials on psychedelic therapy are currently registered with the ClinicalTrials.gov database, including a number of studies on LSD, psilocybin, and methylenedioxymethamphetamine that have received FDA breakthrough designation. 

And yet, the neuroscience of how these drugs affect brain function has remained unclear. Prior studies have produced contradictory findings, with disagreement over which brain regions are affected by psychedelics and how the drugs impact brain function. 

To resolve these inconsistencies, Girn and colleagues created the BOLD Psychedelic Consortium, an international collaboration that aggregated raw imaging data from five countries and three continents. 

“If psychedelic research is to mature responsibly, it needs large-scale, coordinated evidence,” senior investigator Emmanuel Stamatakis, PhD, a cognitive neuroscientist at the University of Cambridge in the UK, said in a statement.

The newly published meta-analysis encompasses 11 datasets including 267 unique participants and more than 500 resting-state functional MRI (fMRI) scans. Psilocybin was represented in six datasets (106 participants) and LSD in four (119 participants). 

Mescaline, DMT, and ayahuasca each contributed a single dataset with 31, 16, and nine participants, respectively. Most studies used within-subject, double-blind, randomized, placebo-controlled crossover designs, though the ayahuasca dataset lacked a placebo condition. 

All data were reprocessed through a standardized pipeline. The investigators used resting-state fMRI, which measures changes in blood oxygenation as a proxy for neural activity, and applied Bayesian hierarchical modeling, a framework that quantifies both the size and the certainty of each effect. 

“Instead of asking simply whether an effect exists, we asked how certain we are about it,” senior author Danilo Bzdok, MD, PhD, a computer scientist at McGill University in Montreal, Quebec, said in a statement.

Cross-Talking in the Brain 

The most robust finding across drugs and datasets was increased functional connectivity between transmodal association networks — including the default mode and frontoparietal networks — and unimodal sensory networks involved in vision and movement. 

The effects were most consistent for psilocybin and LSD, with more variable patterns for the other compounds. 

The serotonin 2A receptor, the primary target of classic psychedelics, is expressed most densely in the brain’s thinking regions. Girn speculates that the drugs may disrupt those areas first, with effects rippling outward to sensory regions.

Deeper in the brain, two structures involved in coordinating perception and action — the caudate and putamen — showed the most consistent increases in communication with sensory cortex. But the thalamus, which many researchers have theorized acts as a sensory gatekeeper that psychedelics force open, did not show reliable changes in the analysis.

The drugs also identified heightened connections between the dorsal striatum, a deep brain structure involved in coordinating perception and action, and cortical sensory regions. 

“For years, individual studies suggested dramatic changes in brain networks under psychedelics but results often differed. When we looked at everything together, a consistent pattern emerged,” Girn said.

The study also challenged the idea that psychedelics shut down the default mode network, the brain’s self-referential processing center, and a frequent target of clinical discussion around psychedelic therapy for depression. 

Girn said clinicians should move past characterizations of psychedelic brain effects as networks being “turned off” or “shut down.”

For researchers developing psychedelic therapeutics, Girn said cellular and molecular studies remain the primary mode of investigation, with imaging data as a secondary screening tool for biomarkers. However, he noted that while candidate predictive biomarkers exist, the field requires substantially larger datasets before any biomarker approaches clinical readiness.

Still, Bzdok said the shared brain signature across compounds could inform future therapeutic design. 

“This is a breakthrough in how we think about psychedelic drugs,” he said. “For the first time, we show there’s a common denominator among drugs that we currently consider completely separate.”

Questions Remain 

While the study’s methodology is well executed, it doesn’t address the possibility that some observed connectivity changes reflect direct vascular effects of the drugs rather than altered neural activity, said Peter Bandettini, PhD, chief of the Section on Functional Imaging Methods and director of the functional MRI facility at the National Institute of Mental Health, Bethesda, Maryland.

That distinction matters because the therapeutic rationale for psychedelic-assisted therapy rests on a specific mechanistic story — that the drugs change how brain networks communicate, Bandettini told Medscape Medical News. But psychedelics also act on serotonin receptors on cerebral blood vessels, causing vasoconstriction, and fMRI measures blood flow changes rather than neural activity directly. 

A 2025 Nature Neuroscience study found that psychedelics disrupt the relationship between blood flow and neuronal activity in mice — most prominently in the same brain regions implicated in human studies. If part of what fMRI detects reflects vascular effects rather than neurons communicating differently, the mechanistic picture may be less complete than it appears.

However, Bandettini, who was not involved in the study, said this gap may not be a significant limitation of the study. 

“If psychedelic drugs are affecting the brain’s vasculature, they’re probably affecting the rest of the brain too,” he said, adding that he believes the drugs produce a genuine neural effect, but that fMRI alone cannot confirm this with certainty.

One question the study doesn’t answer is what happens to the hyperconnectivity between brain regions after the acute effects of psychedelics have passed. Bandettini said that’s a study he’d like to see next, with fMRI playing a key role in assessing the long-term impact of psychedelics on brain function. 

He also suggested future research could incorporate fMRI alongside complementary modalities such as simultaneous electroencephalography or high-resolution laminar fMRI. High-resolution laminar fMRI can distinguish activity in specific cortical layers, making it a promising approach that could resolve both the vascular question and the open question of whether psychedelics act from the top of the brain’s hierarchy on down, or the reverse, he said. 

Girn acknowledged the latter’s limitation. 

“This is a first-pass benchmark,” Girn said. “Research is needed to characterize the distinct substates that people go through [while the drugs are taking effect]. You can make that connection with the right data.”

The study was supported by the Brain Canada Foundation, the National Institutes of Health, the Canadian Institute of Health Research, and others. Study authors’ disclosures are reported in the original article. Bandettini reported no relevant financial relationships.