Tao Che, an associate professor of anesthesiology at WashU Medicine, and colleagues at the Center for Clinical Pharmacology have uncovered new molecular insights into ketamine’s complex pharmacology. Their findings show that ketamine acts on multiple systems and can directly engage opioid receptors, providing a more complete picture of how the drug works and helping explain ketamine’s dual nature: its powerful therapeutic effects alongside its potential for misuse.
The study was published in June in Nature Structural & Molecular Biology.
Ketamine has long been known for its ability to rapidly relieve treatment-resistant depression and severe pain, often working when other medications fail. Scientists have traditionally believed these effects were mainly due to ketamine blocking N-methyl-D-aspartate (NMDA) receptors, altering how brain signals are passed. However, the new study shows that ketamine and a related compound, phencyclidine (PCP), also can bind to opioid receptors, a receptor family involved in pain relief and addiction. Using cryo-electron microscopy and molecular techniques, Che and his team mapped exactly how these interactions occur at the atomic level. This newfound structural knowledge opens the door for chemists to design next-generation therapeutics that preserve ketamine’s rapid antidepressant effects while minimizing its addictive properties.
