The Los Angeles County medical examiner's conclusion that the cause of "Friends" star Matthew Perry's death was the "acute effects" of ketamine has sparked interest in the drug. While experts note that ketamine is generally safe under medical supervision, the Perry case highlights potential risks.

Perry was found dead in his hot tub on Oct. 28. The medical examiner concluded the death was an accident. The high levels of ketamine found in his blood could cause "lethal effects" from cardiovascular overstimulation and respiratory depression, the Los Angeles County medical examiner said in a report.

Other contributing factors in the actor’s death included drowning, coronary artery disease and the effects of buprenorphine, a medication used to treat opioid use disorder. Perry was undergoing ketamine infusion therapy every other day for a while but had reduced that intake more recently, and his last known infusion was a week and a half before his death.

The medical examiner noted the ketamine could not have been from that session, as it typically disappears from the system in detectable amounts within three to four hours.

What is ketamine?

A legal medication commonly used medically as an anesthetic, ketamine has been increasingly offered "off-label" at private clinics to treat depression and other mental health disorders. In 2006, the National Institute of Mental Health concluded that an intravenous dose of ketamine had rapid antidepressant effects.

About 300 clinical trials have been held, and they have broadly found that ketamine is extremely fast-acting compared with traditional antidepressants and can relieve depression for a period that can last days or weeks. A prescription version of ketamine called Spravato, given through a nasal spray, was approved in 2019 by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression.

The number of ketamine clinics in the U.S. has risen from a few dozen to several hundred in the last few years. Ketamine is "generally really safe," said Dr. Michael Bottros, chief of clinical operations and medical director for pain services with Keck Medicine of the University of Southern California (USC). Side effects such as dissociation aren’t as worrisome in a medical setting when ketamine is infused, because "health care professionals will be ensuring that patients are not moving around unsupervised."

But Bottros said that based on the autopsy findings, which indicated ketamine was found in his stomach, Perry may have taken ketamine orally, and the risk is that "there was too much taken at once." The physician cautioned that he did not know what the prescription dose for Perry was, but "the level in his blood is higher than it would be" for what is considered an "appropriate" oral dose.

And "the problem here is that he was in a hot tub," Bottros said. In a dissociated state, he said, someone could sink into a tub without realizing it. Bottros said the tragedy should not dissuade people from being treated with ketamine under the supervision of medical professionals. "There has to be a healthy balance between the concerns along with the known benefits," he said.

Physicians also urged people not to write off ketamine for medical treatment in light of the tragedy. When doctors turn to ketamine for patients with depression, "these are patients who might not have anything else left for them" because typical treatments have failed, Bottros said. "Ketamine could be lifesaving for them."

About overdoses

"Ketamine overdose by itself is exceedingly rare," said Dr. Siddarth Puri, associate medical director of prevention for the Substance Abuse Prevention and Control division at L.A. County’s public health department. In general, much of the overdose concern around ketamine surrounds mixing it with other substances that can also affect breathing or heart rate, such as alcohol or opioids, he said.

People are also at higher risk of bad outcomes if they have underlying conditions such as high blood pressure or breathing problems, Puri said. In medical settings, Puri said, "Your doctor is making sure your heart can manage and respond to ketamine appropriately, your breathing is OK, you’re not having any kind of allergic reaction," and other medications will not compound its effects.

He cautioned people who are obtaining ketamine in other ways or using it outside of medical settings to make sure to test for possible contaminants such as fentanyl and avoid using it alone.