Stabilized, Not Shut Down: What Ketamine Really Does to the Brain

Ketamine blurs the line between anesthesia and awareness – patients may be unresponsive, yet their brains still look awake. Now, researchers from the University of Pennsylvania have found that as ketamine dose increases, brain activity doesn’t shut down, it stabilizes.

Published in The Journal of Neuroscience, their study found that ketamine makes brain activity more stable in a dose-dependent way – even as participants reported vivid hallucinations and lost touch with their surroundings.

What ketamine reveals about consciousness

Ketamine is attracting attention not just for its use in anesthesia, but also for its effects on the brain in altered states and its potential in assisting mental health treatment. Unlike standard anesthetics, which shut down brain activity, ketamine does something different. It creates a vivid, internally focused experience while cutting off a person’s responsiveness to the outside world. That makes it hard to monitor with conventional EEG tools.

“Brain activity under ketamine is actually quite similar to the awake brain,” lead researcher Dr. Alexander Proekt, the Robert Dunning Dripps Associate Professor in Anesthesia II at the University of Pennsylvania, told Technology Networks. “If you give somebody an anesthetic dose of ketamine and you try to do surgery on them, that will be fine. But if you put an EEG monitor that is meant to detect a state of anesthesia, it will say the patient is awake.”

This mismatch raises questions about what’s really happening in the brain under ketamine, and whether existing methods are picking up the right signals. Prior research has shown that during normal wakefulness, the brain seems to operate in a finely tuned state, somewhere between too much order and too much chaos. Some researchers refer to this as a “critical” point. Other studies, like those using magnetic stimulation, have shown that this complexity stays intact during REM sleep and ketamine states, but disappears in dreamless sleep or under other anesthetics.

 

 

This new study set out to test how brain dynamics change under increasing doses of ketamine, focusing not on brainwave power, but on how stable or unstable brain activity becomes. The researchers hoped this new measure might be more accurate in tracking how ketamine affects consciousness.

“There’s some excitement about drugs like psilocybin, but they’re not used clinically, whereas ketamine is,” said Proekt. “We were interested in devising a brain measure that can be used to quantify the effects of ketamine in the brain.”

Measuring brain stability under ketamine

The study involved 6 healthy adult men, each fitted with a high-density 128-channel EEG cap. Researchers monitored their brain activity as they received increasing doses of ketamine, starting with a low dose of 0.2 µg/mL, followed by 0.4 µg/mL and ending at a full anesthetic dose of 1.0 µg/mL.

Instead of focusing only on the strength of brainwaves (the standard method), the team used a different approach: they measured how stable or unstable brain activity was over time. This required a mathematical model that tracked how patterns evolved, based on a measure known as eigenvalues. Unlike traditional EEG methods, this model tracked how brain activity evolved over time, offering a more dynamic view of neural behavior.

 

 

As the ketamine dose increased, brain activity became more stable. This shift was most obvious at higher frequencies, even while participants were reporting hallucinations, motion sensations and dream-like experiences.

“I actually did not expect this result to be honest. I expected to see the opposite result,” said Proekt.

The biggest jump in stability happened between the lowest and middle doses – the range commonly used in psychiatric ketamine therapy.

“I naively thought that because under ketamine, people still have experiences, they're just not connected to the real world. I thought that the brain would stay critical. But it didn't,” he added.

The team also built a machine learning model to classify brain states. When fed stability data, it accurately predicted the ketamine dose far better than models using conventional EEG features, achieving 91.7% accuracy, compared to 41.7% using standard spectral features. This could be useful in clinics, where it's still unclear how much ketamine a given patient should receive.

Brain stability could help guide ketamine therapy

Although the study didn’t involve people with depression, it still offers clues about how ketamine might work as a treatment. Instead of focusing on the drug’s chemical effects, it suggests that the altered brain state itself – the dissociation, the hallucinations and the change in brain stability – could be part of what helps some people feel better.

“Ketamine seems to work, at least for some instances of depression and potentially other mental illnesses as well,” said Proekt.

That raises a bigger question: is it the molecule that matters, or the state of mind it creates?

Other drugs with very different mechanisms, such as nitrous oxide or psychedelics, can also ease depression symptoms. What they have in common is a shift in consciousness.

“For psychedelic-assisted psychotherapy, there's very strong clinical agreement that, yes, you need this kind of strange psychedelic state to get resumption of the disease,” said Proekt. “But people are creating drugs that are allegedly devoid of these psychedelic experiences.”

These newer drugs aim to keep the treatment effect while avoiding that altered state, however, it’s not clear yet if that will work.

A brain-based marker like dynamic stability could help solve some of these debates. It could also guide dosing in clinics, especially as doctors try to move beyond the one-size-fits-all approach.

“I’ve only always just had one question,” Proekt said. “Why is it that we’re conscious?”

“I think drugs that disrupt consciousness, like anesthetics, are curious, because they break the system. Drugs that alter how we see the world, I think, are instrumental in understanding how consciousness works,” Proekt concluded.

 

Reference: Dávila DG, McKinstry-Wu A, Kelz MB, Proekt A. The administration of ketamine is associated with dose-dependent stabilization of cortical dynamics in humans. J Neurosci. 2025;45(20):e1545242025. doi: 10.1523/JNEUROSCI.1545-24.2025

 

About the interviewee:

Dr. Alexander Proekt is the Robert Dunning Dripps Associate Professor in Anesthesia II at the University of Pennsylvania. His research focuses on neuronal mechanisms of loss and recovery of consciousness using a combination of neurophysiological and computational methods.