Researchers have uncovered how low doses of ketamine rapidly reduce symptoms of major depression, providing relief in just hours, with effects lasting several days.
This discovery, published in Molecular Psychiatry, sheds light on ketamine’s unique action in the brain and paves the way for developing safer, more effective treatments for depression.
Ketamine has been used as an anesthetic since the 1960s, but in 2000, scientists discovered its powerful antidepressant effects at much lower doses.
Unlike traditional antidepressants that take weeks or months to work, ketamine provides near-instant relief, particularly for people with severe depression or suicidal thoughts.
“Low-dose ketamine is a lifesaving medication for many people because of its fast and long-lasting effects,” says Gabriela Popescu, senior author of the study and a professor at the University at Buffalo.
How Ketamine works in the brain
Ketamine works by binding to NMDA receptors, a type of neurotransmitter receptor involved in learning, memory, and mood regulation.
These receptors are spread throughout the brain and produce electrical signals essential for brain function. However, when dysregulated, they can contribute to psychiatric symptoms.
Popescu’s research revealed that low-dose ketamine affects only specific NMDA receptors—those that remain active for long periods outside of synapses. This selective binding helps explain why ketamine works so well at small doses without causing the side effects seen at higher, anesthetic doses.
Using advanced techniques, the researchers discovered that ketamine binds to two grooves on the sides of NMDA receptors. At low doses, this slows down the activity of these extra-synaptic receptors, boosting excitatory signals in the brain. This increase in activity lifts depressive symptoms quickly.
Additionally, this heightened excitatory activity triggers the formation of stronger or new synapses in the brain, which helps maintain the antidepressant effects even after ketamine leaves the body.
Why this discovery matters
The study also explains why higher doses of ketamine act as an anesthetic. At these levels, ketamine spills into the central pore of the receptor, fully blocking its activity.
Understanding these mechanisms opens the door to designing new ketamine-like drugs that target the same grooves on NMDA receptors but can be taken orally and may avoid ketamine’s addictive potential.
“This finding offers a clear path for developing safer and more accessible treatments for depression,” Popescu says.
The next step for researchers is to screen existing drugs to find ones that fit into the receptor’s grooves, which could be tested computationally and experimentally.
This groundbreaking research, funded by the National Institutes of Health, could revolutionize how depression is treated and provide hope for millions of people worldwide.
If you care about mental health, please read studies about how dairy foods may influence depression risk, and 6 foods you can eat to improve mental health.
For more mental health information, please see recent studies about top foods to tame your stress, and Omega-3 fats may help reduce depression.
Source: University at Buffalo.
