Ketamine may treat depression by 'flattening the brain's hierarchies,' small study suggests

DENVER—A single dose of ketamine may subtly reshape how different regions of the brain communicate, a new study suggests.

The research, presented June 19 at the Psychedelic Science 2025 conference, is one of the first to investigate ketamine’s impact on neuroplasticity — the ability to adapt to experiences by forming new connections and pathways — in the brains of living people. The findings have not been peer-reviewed yet.

In recent years, clinical trials have demonstrated ketamine's effectiveness in treating depression within a few hours of a single dose. Animal studies suggest that ketamine almost immediately spurs the growth of new dendritic spines — tiny protrusions that form synapses, the connections between brain cells. But it's been hard to pin down how ketamine works in living humans.

To answer that question, the researchers scanned the brains of 11 men using multiple techniques and then administered an intravenous dose of ketamine. One group of the people was re-scanned 24 hours after getting the single dose of the drug, and the other group was scanned again seven days later.

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Normally, the brain processes sensory information via lower-level networks and then feeds that "up the chain" to higher-level networks that orchestrate larger brain processes. Higher level networks also send feedback to lower-order networks, but communication between high and low level networks is less than that within specific networks.

In the new study, scientists used functional magnetic resonance imaging (fMRI), which measures blood flow to different brain regions, to reveal how brain activity changed after treatment. When fMRI activity levels appear synchronized, it can imply the distinct areas are "communicating" with one another. Typically, regions that are part of a network consistently fire together when the brain is performing specific tasks or is in a certain mental state.

After the participants took ketamine, however, activity in specific networks seemed to be desynchronized. The researchers also found an increase in communication between a higher-order network, the default mode network (DMN), and lower-order, sensory networks, such as the somatomotor network, which is linked to the perception of the physical self and bodily sensations. This means that brain regions usually involved in basic sensory processing started communicating more directly and extensively with higher-level regions responsible for complex thought and "orchestrating" brain processes.

"Usually there is more segregation between these higher order and lower order networks," Claudio Agnorelli, a neuroscientist at the Centre for Psychedelic Research at Imperial College London, told Live Science. "But after the ketamine, this hierarchy is kind of collapsed."

The DMN is responsible for "mental time travel," or planning and daydreaming, rather than staying focused on particular tasks in the present. An overactive DMN has been linked to depression and rumination.

The researchers also used positron emission tomography (PET) scans to measure levels of a protein called SV2A, which plays a role in the release of brain signaling molecules. Higher SV2A levels are thought to indicate more connections between brain cells, Agnorelli said.

Although the researchers didn't identify a clear trend in global SVA2 levels after ketamine administration, one brain region tied to the DMN did show clear changes: the posterior cingulate cortex (PCC). The PCC is part of the DMN, and it seems to orchestrate the flow of information in the brain. After ketamine administration, the PCC played a smaller role in orchestrating communication across the brain, even as synaptic connections increased within the PCC.

The finding of increased synaptic density in the DMN suggests ketamine isn't just creating new synapses — it's fundamentally reorganizing how brain networks communicate, Sam Mandel, CEO and co-founder of Ketamine Clinics Los Angeles, told Live Science in an email. "The 'flattening of cortical hierarchy' could explain why patients often report feeling less trapped in rigid thought patterns after treatment."

The authors cautioned that their results are preliminary. The study had just 11 participants, all of whom were men with no underlying conditions, and there was no placebo group for comparison. Moreover, the imaging methods the team used are still being validated as reliable markers of brain changes. The study does, however, help bridge the gap between what is known about ketamine's impact on animals and how it may act in humans, Agnorelli said.

"While we've long understood from animal studies that ketamine promotes neuroplasticity, actually visualizing these synaptic changes in living human brains using a PET tracer is a new development," Mandel said.