Psychedelics Don’t “Shut Down” the Brain—They Connect It

Scientists have identified a single neural signature that explains how five different psychedelics affect the brain.

This global mega-analysis analyzed hundreds of scans to uncover a universal pattern of increased connectivity, showing a consistent spike in communication between high-level thinking centers and basic sensory regions.

Closing the gap in psychedelic research history

For half a century, research into psychedelics was effectively frozen, due to restrictive drug laws that impeded studies. However, more recently, there has been a surge of interest in the topic, with over 300 active clinical trials exploring how these substances might treat depression, anxiety, and addiction. While the medical potential is clear, the science behind how they work is still catching up.

Understanding the neural mechanisms underlying psychedelic effects is needed to move toward precision medicine. Currently, doctors cannot predict how a patient’s brain will respond to a specific dose.

Part of the problem is that previous research has been inconsistent. Different labs have reported topographically opposite results as they worked with small groups and used different methods. Existing evidence is “very fragmented, very nascent with a lot of potential, but not very mature,” said corresponding author Dr. Danilo Bzdok, a neuroscientist at McGill University.

Bzdok’s new study aimed to fix that by combining data from five countries, across three continents, to build a reproducible, data-driven framework. By looking at how these substances function across hundreds of scans, the team hoped to provide a reliable map for the future.

Understanding how psychedelics affect the brain “will inform future drug design for this potentially very important category of drugs for the future of mental health,” explained Bzdok.

Identifying a universal brain signature for psychedelics

The team conducted a mega-analysis of 11 independent datasets, involving 267 participants and over 500 brain scans covering 5 major psychedelics: psilocybin, LSD, DMT, mescaline, and ayahuasca.

Traditionally, scientists thought these drugs worked by silencing the brain.

“The prevailing theory in psychedelic science is this notion of, you take a psychedelic like psilocybin, and it will dissolve or disintegrate your brain networks,” said Dr. Petros Petridis, a psychiatrist at New York University who studies psychedelics.

The study used a uniform preprocessing pipeline and a bespoke Bayesian hierarchical modeling framework to quantify the certainty of each result.

The findings challenged the old “dissolving” theory; instead of shutting down, brain networks responsible for advanced thinking—such as the default mode and limbic networks—became “much more connected among each other than in a sober individual,” said Bzdok.

Specifically, the researchers observed that deep structures, like the thalamus and basal ganglia, showed significantly increased coupling with the brain's sensorimotor circuits.

“The most surprising finding is that, despite the discrepancies in the pharmacology and the pharmaco-physiological properties of these drugs, there is a common denominator of how they affect the human brain,” Bzdok added.

This shared signature suggests that, although the drugs are chemically distinct, they all push the brain toward a similar state of high-level crosstalk.

While LSD and psilocybin looked almost identical, DMT had the largest drug response effect, exhibiting a pattern resembling an amplified version of LSD and psilocybin. Ayahuasca showed a more unique, idiosyncratic pattern.

The limitations of psychedelic neuroimaging

The study provides “a reference for everybody to now go and consolidate or falsify these exciting, but largely speculative, interpretations of how psychedelics lead to these changes in subjective awareness,” said Bzdok.

By moving away from small, isolated studies, the field is gaining a reliable baseline to benchmark future research and inform drug design.

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However, it is important not to overstate the results. The study found that deep brain structures, including the thalamus and caudate, also changed their connectivity, but it is still unknown why.

The data also came from 11 different sites where doses, timing, and how the drugs were given varied significantly.

Petridis warned that “it's hard to make sweeping conclusions or generalizations” when the data is this diverse.

Brain scans also only show blood flow and activity; they don't show the chemistry. As Dr. Shan Siddiqi from Harvard Medical School added: “We have to be cautious about interpreting molecular mechanisms from neuroimaging.”

Despite these caveats, the study highlights how researchers' degrees of freedom—the different ways scientists choose to clean and analyze data—can change the final result. By standardizing the process, the paper sets a bar for the industry.

“As psychedelic research enters a new era of clinical and neuroscientific exploration, our findings provide a critical foundation upon which future investigations can build, ensuring that the field progresses toward greater rigor, reliability, and translational impact,” said the authors.

Reference: Girn M, Doss MK, Roseman L, et al. An international mega-analysis of psychedelic drug effects on brain circuit function. Nat Med. 2026. doi: 10.1038/s41591-026-04287-9

This article is a rework of a press release issued by Nature. Material has been edited for length and content.