Death of Matthew Perry: Even before the actor's death, experts were concerned about the “Wild West” of ketamine treatment

LOS ANGELES — Among the five people charged in connection with the death of actor Matthew Perry are two doctors: According to federal officials, one of them agreed to sell ketamine from his former clinic, and the other distributed the drug to Perry and taught his live-in personal assistant how to inject it.

Perry was given several injections on the day of his death, the U.S. Attorney's Office for the Central District of California said. An autopsy revealed that the amount of ketamine in his body had reached the level required for general anesthesia.

The case has put a spotlight on the loose prescribing practices of ketamine, a hallucinogen that has been approved for use as an anesthetic for decades. It has a long history as a party drug and has been studied in recent years as a possible treatment for depression, post-traumatic stress disorder and chronic pain. Because it is already on the market, patients seeking relief can obtain different versions of it, sometimes in clinics that are available only for cash and without supervision.

Ketamine is classified as a Schedule III drug by the U.S. Drug Enforcement Administration, meaning it has a low to moderate potential for physical or psychological dependence. A drug's classification limits how often a patient can fill their prescription and requires the prescriber to be registered with the DEA and follow certain dispensing and storage requirements.

“You can’t hand out prescriptions for ketamine like candy,” said Dr. Gerard Sanacora, director of the Yale Depression Research Program.

Yet people are finding ways to abuse the drug – particularly in prescriptions mixed by individual pharmacies and in generic drugs – and divert it from healthcare.

When the FDA approves a drug, doctors have the freedom to prescribe it for purposes other than those intended in studies. Typically, such “off-label” uses of prescription drugs make up only a small portion of the prescriptions written for that drug.

In the case of ketamine, off-label use of the generic version has exploded, driven by a purely cash-based business model and ketamine's growing reputation as a quick fix for all kinds of ailments.

Sanacora believes that greater regulation of the medical use of ketamine is needed, but that trade-offs must be considered.

“The question is how many restrictions to put in place, because you don't want to make it even harder for people to use it as an anesthetic. But of course we need a registry or something to know when people are using it outside of that situation,” he said.

“We simply don't know how many people are getting this drug. We don't know what dosage is being used. We don't know the side effects.”

Ketamine is a booming business

Estimates from the federal government's National Survey on Drug Use and Health suggest that ketamine use is still relatively rare: In 2023, only about 2% of adults reported having used the drug at some point in their lives.

But a 2023 study by medical records company Epic Research found that ketamine prescription rates in the U.S. increased by more than 500% between 2017 and 2022, with the lion's share of prescriptions being written for pain management.

Epic's data covers traditional medical facilities that use its medical records systems, so small, cash-only clinics are not included, the company said.

Meanwhile, research shows an increasing number of ketamine clinics have opened in the U.S., offering intravenous infusions, injections, or even oral forms of ketamine such as lozenges for a range of ailments. Market research firm Grand View Research estimates that the ketamine clinic market will have reached $3.4 billion in 2023 and predicts that it will continue to grow at about 10% per year through 2030.

During the isolation caused by the Covid-19 pandemic, more and more telemedicine companies began prescribing ketamine therapy online and giving people instructions on how to use it at home. Today, online prescriptions make up nearly half of the market, according to the Grand View report.

In October, the FDA warned about the increasing use of manufactured drugs, including lozenges. The dangers highlighted by the agency include psychological complications, increased blood pressure and respiratory depression.

“Ketamine is not approved by the FDA for the treatment of psychiatric disorders and additional clinical trials are needed to adequately investigate the benefit-risk profile and conditions for safe use of ketamine in the treatment of psychiatric disorders,” the report said.

Dr. Steven P. Cohen, professor of anesthesiology at Northwestern University's Feinberg School of Medicine, says some ketamine clinics clearly put profit ahead of patients.

Cohen said clinics often don't have patients examined by a doctor. He's heard of patients being given 35 to 40 milligrams of ketamine at once, which can be subtherapeutic — in his experience, about 400 milligrams spread over a week is needed to effectively treat depression. He says clinics may not monitor patients' progress and that they usually have to pay cash for each treatment. “It's disgusting. It's the Wild West,” he said.

This is in sharp contrast to the requirements for esketamine, a ketamine derivative that is FDA-approved for treatment-resistant depression and available by prescription.

The FDA has strict requirements for the use of the nasal spray, sold under the name Spravato. Users must be closely monitored for two hours after each dose because of possible side effects such as loss of consciousness or sedation and dissociation, or an unpleasant feeling of disconnection from one's body. The drug can also cause slowed breathing.

A drug “dangerous … in the wrong context”
Cohen says he personally used ketamine successfully to treat a patient whose nerve dysfunction caused constant itching for four years. He has also heard of ketamine being used to treat persistent pain after treatment for Lyme disease.

But ketamine is marketed to treat a range of problems, he says – including obsessive-compulsive disorder, post-traumatic stress disorder and generalized anxiety disorder – sometimes without that use being supported by rigorous scientific studies.

In Perry's case, the actor took ketamine to relieve depression, according to the autopsy report, but there was evidence that he had developed a growing craving for the drug. In the press release about the charges in Perry's death, the U.S. Attorney's Office for the Central District of California said doctors sold the drug to Perry despite being informed at least a week earlier that his ketamine addiction was “getting out of control.” Perry had been open about his struggle with substance abuse disorder.

According to experts, ketamine is not physically addictive, as opioids can be, and people who take it regularly and then stop usually do not experience withdrawal symptoms.

“You're living in what I call 'K-lands,' 'ketamine lands,' and coming back to reality might be uncomfortable, but to my knowledge you're not going to go through any physical withdrawal symptoms. So some people would say that's psychologically addictive,” said Dr. Joseph Palamar, deputy director of the Division of Population Health at New York University.

Palamar says he is particularly concerned about unsupervised use of the drug at home because of situations like Perry's: According to the autopsy report, the actor drowned in the heated end of his swimming pool after taking large doses of the drug.

“It's not the most dangerous drug by far, but it can be dangerous if used in the wrong context,” says Palamar, who is also deputy director of the National Drug Early Warning System (NDEWS), an organization that watches for early signs of drug epidemics.

Palamar says it is very difficult to obtain data on ketamine-related deaths, but that he has heard of at least two other deaths through websites participating in the NDEWS network.

“Even if you are the most responsible person, this is a prescription drug and it can be dangerous,” he said.

If you take the drug unsupervised at home: “What if you think it would be a good idea to cook while you're taking ketamine and then accidentally burn down the house? Or you think it would be a good idea to drive? You're out for a walk and you get hit by a car?”

“All of these things, all of these behavioral issues associated with it, these are things that worry me because there is no regulation,” he said.