Ketamine Helps Brain Change, But Not Everyone

By rocka 21/08/2026 3 min read 20 views

Ketamine increases neuroplasticity, but the drug’s effects on the brain vary significantly between sexes, according to a new study from the Institute of Science and Technology Austria. The research, which focused on adult mice, found that ketamine can rewire the brain and restore plasticity in females, but not in males. This finding challenges previous assumptions about the drug’s widespread neuroplastic effects and suggests that biological sex plays a critical role in how the brain responds to the anesthetic.

Researchers led by Sandra Siegert and Alessandro Venturino observed that female mice treated with ketamine experienced physical changes in their visual cortex. The brains of these mice began to resemble those of younger animals, with higher levels of neuroplasticity and the ability to form new neural connections. The team used live imaging microscopy to watch this process unfold in real time. They saw microglia—immune cells in the brain—reaching out to neurons and forming new connections. When the mice woke up, the neurons retained more spiny projections, indicating new synaptic contacts.

The effect was not consistent in male mice. While a few males showed similar changes, the response was erratic and often absent. To determine if the microglia were responsible, the researchers killed off these cells and dosed the mice with ketamine. Without microglia, the neurons did not produce more spines, and no new electrical signals were detected. The scientists concluded that ketamine does not directly boost synapses. Instead, it activates microglia, which then stimulate neurons to create new connections, a process that appears to occur almost exclusively in female brains.

The stress hormone connection

The team dug deeper into the molecular mechanisms at work. They found that a gene called Fkbp5, which acts as a stress modulator, was expressed at significantly higher levels in the microglia of female mice treated with ketamine. This gene seemed to be a gatekeeper for the process. When the researchers blocked or deleted Fkbp5, ketamine could no longer activate the microglia, and the new connections did not form.

They also discovered a link between ketamine and the stress hormone cortisol. When the researchers removed the adrenal glands of female mice—thereby stopping the production of cortisol—ketamine no longer triggered the microglia to form connections. This suggests that ketamine and cortisol work together to activate microglia, which then push neurons to rewire themselves.

It is worth noting that the researchers observed that ketamine often makes female mice appear restless or twitchy immediately after waking, a behavior that has been noted by other scientists in the past. The new study provides a potential explanation for this effect, linking it to the sudden activation of microglia and the subsequent surge in neuronal activity.

While these findings are based on rodent models, they raise questions about how ketamine affects humans. Clinical trials have suggested that the drug works differently in women, though critics argue that many studies are not well-controlled enough to rule out other variables. Because it is difficult to observe brain activity in living humans with the same precision as in mice, the exact biological mechanisms in people remain unclear. The discovery that cortisol and a specific gene are involved in this sex-specific plasticity offers a new avenue for research, potentially leading to more targeted treatments for depression and other neuropsychiatric conditions.