Scientists Have Just Mapped Exactly How Psilocybin Rewires Your Brain, And It's Not What They Expected

In what might be the most detailed look yet at how psychedelics actually work, researchers led by Alex Kwan published a paper in Cell this month that traces, neuron by neuron, exactly how psilocybin reshapes the brain's wiring.

And the results are beautifully weird.

The Setup: Catching Brain Changes in the Act

What makes this study remarkable is that instead of just watching brain activity light up on an fMRI scanner (which is cool, but limited), the Kwan lab used a viral tracing technique to literally map which neurons connect to which after a single dose of psilocybin.

They gave mice 1 mg/kg of psilocybin (roughly equivalent to a moderate human dose) and then deployed some clever molecular biology. Using modified rabies viruses that hop backward across exactly one synapse, they could see the entire network of inputs feeding into specific neurons in the frontal cortex.

Alex Kwan described it like Google’s mapping cars roaming all the streets in a neighbourhood. Psilocybin, he explained, “adds all these roads to the brain, but until now, we didn’t know where the roads went.”

Well, what they found was that psilocybin is remarkably selective about which circuits it rewires.

Opposite Effects

Here's where it gets fascinating. The brain has two major types of pyramidal neurons (the main workhorses of the cortex):

PT neurons send their signals down to subcortical regions, which are the deeper, older parts of your brain that handle fundamental functions.

IT neurons keep their connections within the cortex itself, forming the complex loops that underpin higher-level thinking.

What psilocybin did to these two types was almost opposite:

For PT neurons, psilocybin dramatically strengthened inputs from sensory regions, visual areas, and crucially, the retrosplenial cortex (basically your brain's spatial awareness and memory integration centre). Meanwhile, it weakened inputs from the insular cortex (involved in the sense of self) and parts of the prefrontal cortex.

For IT neurons, they saw nearly the reverse pattern. The connections that got stronger in PT neurons got weaker in IT neurons, and vice versa.

As Quan Jiang, the lead author, put it in their data: there was a significant negative correlation between the two cell types' responses. When one went up, the other went down.

Breaking Recurrent Loops

The implications are striking. Psilocybin appears to weaken cortico-cortical feedback loops (the circuits that keep signals bouncing endlessly around the cortex) while strengthening pathways that route sensory information toward subcortical regions that turn perception into action.

Alex Kwan says: “Rumination is one of the main features of depression, where people keep dwelling on the same negative thoughts. By reducing some of these feedback loops, our findings are consistent with the idea that psilocybin may weaken that cycle.”

Think about rumination, or getting stuck in negative thought patterns. Those are essentially overactive recurrent loops in your cortex. The study suggests psilocybin literally weakens those circuits while strengthening more direct, sensory-grounded pathways.

It essentially results in less endless internal chatter, and more direct connection to what's actually happening.

The Activity-Dependent Twist

But here's my favourite part of this study. When the researchers chemogenetically silenced neurons in the retrosplenial cortex during the psilocybin experience, those connections didn't strengthen afterward.

In other words: the rewiring depends on the activity happening during the trip.

This is huge. It suggests that what you experience during a psilocybin session (like the content, the set and setting, what neural patterns are active) actually shapes which circuits get reinforced. The drug creates a window of plasticity, but your brain's activity during that window determines the outcome.

“That opens up many possibilities - how you might avoid negative plasticity and selectively enhance the positive,” said Kwan.

Why This Matters Beyond Mice

Obviously, mouse brains aren't human brains. But the retrosplenial cortex in mice is considered analogous to parts of the human default mode network - that collection of brain regions that's active when you're mind-wandering, ruminating, or caught up in self-referential thought.

Multiple human studies have shown that psilocybin temporarily disrupts the default mode network. This new research suggests it might also durably reshape how that network communicates with the rest of the brain.

The therapeutic implications are staggering. We've seen trial after trial showing that psilocybin can relieve depression for weeks or months after a single session. This study offers the first detailed mechanistic explanation: the drug is literally rewiring the circuits that keep people stuck in negative patterns.

The Bigger Picture

What strikes me most about this research is how precise psilocybin's effects are. This isn't a sledgehammer randomly bashing brain circuits. It's more like a master electrician selectively upgrading specific wiring while downgrading others, across the whole brain.

Kwan himself was surprised by the scale, saying “This is really looking at brain-wide changes. That’s a scale we haven’t worked at before.”

The study also validates something many psychedelic therapists have intuited: that the experience during the session matters. If neural activity shapes the rewiring, then supporting beneficial experiences (connection, safety, insight) is vital for shaping which circuits get reinforced.

There are limitations, of course. This is one dose in mice, focusing on specific neuron types. Human brains are vastly more complex. And we still don't know exactly how changes in mouse medial frontal cortex translate to human experience.

But as a window into the microscopic dance of plasticity that might underlie psilocybin's lasting effects? This is as good as it gets.

What's Next?

The Cornell team is already exploring ways to potentially "sculpt" this plasticity by manipulating neural activity during the psychedelic state. Imagine combining psilocybin with specific cognitive tasks or even non-invasive brain stimulation to target particular circuits. In effect, not just opening the brain to change, but steering that change.

For now, though, this study stands as perhaps the most detailed map we have of how a psychedelic experience becomes a lasting change in the brain's architecture.

One mushroom trip, one rewired brain. Neuron by neuron, synapse by synapse, with remarkable specificity.

Not bad for a mushroom.

The study "Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks" by Quan Jiang, Ling-Xiao Shao, and colleagues was published in Cell on December 5, 2025.