Molecular structure of ketamine

By Emma Yaskinski


Ketamine has been used as an anesthetic in dentistry since it became commercially available in the 1970s.

The anesthesia medicine has also gained popularity for several other potential uses - including the off-label treatment of depression. In higher doses, ketamine is used illegally as a club drug, known for inducing out-of-body experiences.

Recently, the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists published new guidelines for the use of ketamine to relieve acute pain, but also recommended that more research is needed to identify which patients are most likely to benefit from its use.

However, an August study suggests that the drug may have more in common with opioids such as oxycontin than previously thought, urging healthcare providers to exercise greater caution in using the drug.

Opioids exert their effects by binding to opioid receptors in the brain, which is responsible for their rewarding and pain-relieving effects. While ketamine’s mechanism is not fully understood, it’s thought to act primarily on the glutamate system, which is involved in learning and memory. However, the glutamate pathways are associated with many other neurotransmitter pathways in the brain and can modulate the way those function.


“The findings suggest that ketamine’s acute antidepressant effect requires opioid system activation.”


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Ketamine is currently being used off-label because, while traditional antidepressants can take weeks to exert their effects, ketamine’s antidepressant effects kick in almost immediately. But the new study suggests that if the opioid system is blocked, ketamine’s antidepressant effects are limited – suggesting that ketamine is also somehow activating the opioid system.

The researchers used a drug called Naltrexone, which is commonly used to block the effects of opioids by blocking the opioid receptors. When the receptors are blocked, the opioids cannot bind to them to relieve pain. The researchers gave 12 patients with treatment-resistant depression naltrexone or a placebo, followed by ketamine.

They found that the patients who received naltrexone before ketamine experienced limited relief from depression compared to those who had received only a placebo before the ketamine.

Professor Alan F. Schatzberg
Professor Alan F. Schatzberg

“The findings suggest that ketamine’s acute antidepressant effect requires opioid system activation,” the authors wrote.

"We think ketamine is acting as an opioid," Alan F. Schatzberg, one of the study's authors and a professor of psychiatry and behavioral sciences at Stanford University, told NPR. "That's why you're getting these rapid effects." Schatzberg is financially involved with several pharmaceutical companies.

He cautioned that though the drug’s effects are not as potent as opioids, it may still have the potential to lead to similar negative outcomes such as addiction. Larger studies are needed to determine the extent of these possibilities and to further elucidate ketamine’s mechanism of action.


Author: Contributing writer Emma Yasinski received her Master of Science (MS) in science and medical journalism from Boston University. Her articles have also appeared at, Kaiser Health News, NPR Shots, and Genetic Engineering and Biotechnology News.

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