Psychedelics can make people experience themselves and the world in striking ways—forms morph and sounds distort, and they can even lose their sense of self, a fleeting condition known as ego death. But what happens inside the brain to cause such sensations isn’t fully understood.

A new comprehensive analysis published today in the journal Nature Medicine significantly advances this understanding. The research pooled results from nearly a dozen brain imaging studies from the U.S., Europe, and South America and revealed that psychedelics generate a high degree of chatter between regions of the brain involved in sensory perception and those for thinking. 

Usually, the brain’s perception of the external world is very distinct from our memory and abstract thinking. This is suggesting the psychedelics might close that gap between how we think and how we perceive—between the internal and external.

Understanding psychedelics’ functions has become increasingly important as interest in their ability to treat mental health conditions like anxiety and depression explodes. Psychedelics are an emerging therapeutic, so knowing more about how they work can help us theoretically optimize their healing potential.

(These drugs could be a game-changer for end-of-life care.)

Providing a consistent analysis

Typically, researchers investigate a drug’s mechanism before testing it in humans, but since initial research on psychedelics was conducted more than fifty years ago, before the advent of effective brain scanning technology like the functional magnetic resonance imaging (fMRI) used in this analysis, scientists are working to catch up now.

Visualizing the brain is also important to confirm that the psychedelic itself—rather than expectations about the drug—creates the health improvements. Because the hallucinogenic effects are obvious, researchers cannot prevent people from knowing whether they received the drug or a placebo in so-called “blinded” studies, possibly influencing the results.

(Can psychedelics live up to their hype?) 

Prior imaging studies have been small, often analyzing fewer than a dozen individuals each. This has led to inconsistent findings and difficulties drawing reliable conclusions. For example, some research has highly emphasized disruptions to the brain’s default mode network—the area responsible for defining our sense of self—during a psychedelic experience while others focused on altered activity across many parts of the brain. 

For this research, scientists at seven institutions in five countries shared imaging data from more than 500 scans of 267 subjects (some took a psychedelic more than once). The researchers applied a standardized framework to analyze the disparate data.
This paper is a tour de force that applies consistent analyses to several independent psychedelics datasets, and it seems they come as close as possible to the truth in how psychedelics change fMRI signals at the population leveL.

Inducing fundamental changes in the brain

Brain images analyzed in the new study came from people experiencing the effects of “classic” psychedelics, a category that includes psilocybin, lysergic acid diethylamide (LSD), mescaline, dimethyltryptamine (DMT), and the DMT-containing brew, ayahuasca. (All are schedule 1 drugs that remain illegal at the federal level in the United States, outside of clinical trials.) 

While not everyone’s brains reacted the same—especially across different psychedelics—the similarities were striking. 

The analysis confirmed that the compounds don’t impact a single part of the brain but fundamentally change how the brain is processing information and relating to the world, and that can shake people up in ways that could be conducive to therapeutic change, in terms of breaking people out of ruts and usual ways of perceiving.

This expanded integration of information across regions of the brain “may be how [psychedelic therapy] can break down rigid cognitive patterns and increase flexibility of thought, which has been proposed as one explanation of how they can produce healing in patients with depression and addictive disorders. Importantly, unusual activity also appeared in brain regions involved in more basic tasks such as movement. This may explain why some physical symptoms of Parkinson’s disease, in addition to mood issues, improved after people took a dose of psilocybin in a clinical setting, according to preliminary research published last year.

More to learn about psychedelics

Still, scientists say much more research is needed. For one, “I would have liked to see some inclusion of how age and sex may impact the effects of psychedelics.

And the study included brain images from only a few minutes under the influence, while a psychedelic trip typically lasts for hours. Researchers envision a time when brain mapping reveals the full range of experiences people report. There’s a huge variety one can have over time—whether that’s having insane visual experiences or ‘ego death,’ or remembering memories or processing emotions, looking to future research to characterize how those might look differently in the brain and how that could relate to outcomes in therapy.

Also not examined: how or whether some of the changes continued in the days and months after the trip ended.

So while the analysis offers the strongest evidence yet for how the brain operates on the drugs, “In terms of human research, we’re quite early stages. We have barely even scratched the surface.