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Ketamine is emerging as a way to treat depression, but it appears to act like an opioid — and it may carry similar risks, Stanford researchers found.
Clinics are cropping up around the country where people receive ketamine infusions. A handful of pharmaceutical companies are using ketamine as inspiration for new prescription drugs to treat depression. Yet the new research questions whether scientists know enough about chronic ketamine use to introduce it broadly.
The drug blocks NMDA receptors, which scientists think may treat depressive symptoms. Researchers wanted to test whether it was possible to elicit this reaction without activating the brain's opioid receptors.
To block an opioid response, they gave participants naltrexone then infused them with ketamine. To compare that response with the normal response, they also gave participants a placebo before giving them the treatment.
Naltrexone so successfully blocked the anti-depressant effects of ketamine that researchers cancelled the study after the first interval because they felt it wasn't ethical to continue it, said Dr. Nolan Williams, one of the study's authors and a clinical assistant professor of psychiatry and behavioral sciences at Stanford University.
When patients took naltrexone, the opioid blocker, their symptoms did not improve, suggesting ketamine must first activate opioid receptors in order to treat depression, according to the study, published Wednesday in the American Journal of Psychiatry.
That's not to say ketamine cannot be used occasionally, but it does raise questions about using it repeatedly over time, said Dr. Alan F. Schatzberg, co-author of the study and Stanford's Kenneth T. Norris, Jr., professor of psychiatry and behavioral sciences. He likens it to opioid painkillers being an appropriate pain treatment when used once in the emergency room but posing problems, such as the risk of dependence, when used chronically.
"More studies need to be done to fully understand ketamine before it's widely rolled out for long-term chronic use," Schatzberg said.
Researchers planned on studying 30 adults but stopped enrolling patients once they decided combining ketamine and naltrexone was not only ineffective but also "noxious" for many participants. They tested a total of 12 people with both naltrexone and the placebo.
Of those 12, seven who received naltrexone experienced nausea after the ketamine infusion, compared to three in the placebo group. Two participants in each group also experienced vomiting.
Participants who received the placebo and ketamine treatment reported reduced depression symptoms. But those same participants did not see a decrease in depression symptoms after receiving ketamine and opioid-blocker naltrexone.
"We essentially blocked the mechanism for producing the anti-depressant effect, which were opioids," said Williams.
The findings may have implications for clinics offering ketamine infusions and drug manufacturers trying to commercialize ketamine-like drugs.
Ketamine is meant to be used as an anesthetic. Since ketamine is currently not indicated to treat depression, insurance typically doesn't cover the cost of infusions, so people tend to pay out of their own pocket. One session can run more than $500.
Meanwhile, drug giant Johnson & Johnson plans to seek approval from the Food and Drug Administration for its nasal spray esketamine this year after reporting positive results from a Phase 3 trial. Allergan plans to file its drug Rapastinel, which targets the NMDA receptors like ketamine, within the next two years. VistaGen Therapeutics is working on a similar drug.
In a statement, J&J said while the study reviewed ketamine and not esketamine, the findings "are difficult to interpret because of the study's design."