Tracing neural circuits with a specially engineered rabies virus, researchers have found that psilocybin disrupts feedback loops associated with negative thought patterns.
The findings, detailed in a recent study published in Cell, show how psilocybin reshapes connections across the brain, helping explain why a single dose can ease depression symptoms for weeks or even months.
The research, led by Cornell University biomedical engineer Alex Kwan, pinpoints specific changes in brain circuits that could be used in future treatments for depression. The study received additional support from One Mind and the National Institutes of Health.
A Map of the Brain on Psilocybin
For many people, psilocybin provides extended relief from depression. However, the mechanisms behind these brain changes have remained unclear until now. Kwan’s team set out to directly identify which neural circuits are altered by the drug.
The researchers paired psilocybin with a genetically modified rabies virus used for monosynaptic tracing to follow how neurons connected and changed after the dose. With that tracer, the team could visualize shifts in connectivity that earlier mapping tools often missed.
“With psilocybin, it’s like we’re adding all these roads to the brain, but we don’t know where the roads go,” said Kwan. “Here we use the rabies virus to read out the connectivity in the brain, because these viruses are engineered in nature to transmit between neurons.”
Breaking Out of Cortical Loops
A key discovery of the study relates to cortico-cortical feedback loops. While these circuits are important for normal brain function, they can also promote repetitive negative thought patterns commonly seen with depression.
The study found that psilocybin weakens these feedback circuits. This change may help break negative thought patterns, allowing the brain to shift toward more flexible and adaptive ways of processing information.
Strengthening Circuits for Action
They also found that sensory circuits tied to action became more strongly connected following psilocybin use. This shift may help explain why people often describe psilocybin experiences as vivid and intensely physical, and why these experiences can lead to lasting behavioral changes.
At first, Kwan expected to see changes in just a few specific brain circuits. Instead, he was surprised to find that psilocybin’s effects reached across the entire brain, far beyond the limited areas examined in earlier studies.
Activity Determines What Gets Rewired
The results suggest that neurons with higher firing activity are more likely to be affected by psilocybin’s rewiring. This insight allowed the researchers to directly influence the process. By increasing or decreasing activity in a single brain region, they could change how psilocybin impacted neural connections.
“That opens up many possibilities for therapeutics, how you maybe avoid some of the plasticity that’s negative and then enhance specifically those that are positive,” Kwan said.
This finding supports the theory that the brain’s ability to change in response to these drugs may be most effective when combined with structured therapy or behavioral guidance that helps control which circuits are altered for the long term.
Implications for Treating Depression
The results offer a possible explanation for psilocybin’s long-lasting antidepressant effects. Rather than briefly raising serotonin, psilocybin weakens harmful thought loops and strengthens connections that guide adaptive behaviors.
The ability to guide mental rewiring by changing neural activity could be used in new mental health treatment strategies. Combining psychedelics with targeted brain stimulation could help maximize positive changes in the brain, while also minimizing unwanted side effects.
Austin Burgess is a writer and researcher with a background in sales, marketing, and data analytics. He holds a Master of Business Administration and a Bachelor of Science in Business Administration, as well as a certification in Data Analytics. His work combines analytical training with a focus on emerging science, aerospace, and astronomical research.