Perry was injected multiple times the day of his death, the US Attorney's Office for the Central District of California said, and an autopsy showed the amount of ketamine in his system had reached the level used for general anesthesia.
The case has turned a spotlight on loose prescribing practices around ketamine, a hallucinogen which has been approved for decades as anesthesia. It has a long history as a party drug and in recent years, it has been studied as a possible treatment for depression, post-traumatic stress disorder and chronic pain. Because it's already on the market, patients looking for relief are able to access versions of it, sometimes through cash-only clinics with no oversight.
Ketamine is classified as a schedule III drug by the US Drug Enforcement Administration, meaning it has low to moderate potential for physical or psychological dependence. Scheduling a drug puts limits on how often a patient can refill their prescription and requires prescribers to be registered with the DEA and adhere to certain requirements for dispensing and storage.
"You cannot hand out prescriptions for ketamine like candy," said Dr. Gerard Sanacora, director of the Yale Depression Research Program.
Still, people find ways to misuse the drug - especially compounded drugs, which are custom-mixed by individual pharmacies, and generic forms - and to divert it from medical settings.
When the FDA approves a drug, it allows doctors freedom to prescribe it for uses beyond what it was studied to do. Typically, such "off-label" uses of prescription drugs represent a minority of prescriptions written for that medication.
In ketamine's case, off-label use of the generic version has exploded, driven by an all-cash business model and ketamine's growing reputation as a quick fix for all manner of miseries.
Sanacora says that he thinks more regulation of medical ketamine is needed but that there are tradeoffs to consider.
"There's this difficult thing about how much restriction do you put on it, because you don't want to make it more difficult for people to use it as an anesthetic, but clearly, we need a registry or something to know when people are using it outside of that situation," he said.
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"We just don't know how many people are getting this drug. We don't know what doses it's being used at. We don't know what the adverse events are."
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 said that they had taken the drug at some point in their life.
But a 2023 study by the medical records company Epic Research found that ketamine prescription rates in the US increased more than 500% between 2017 and 2022, with the lion's share of prescriptions written to treat pain.
Epic's data covers traditional medical settings that use its medical records systems, so small, cash-only clinics wouldn't be included, the company said.
Meanwhile, an increasing number of in-person ketamine clinics have opened in the US, research shows, marketing intravenous infusions, injections or even oral forms of ketamine like lozenges for a number of ailments. Market research firm Grand View Research estimates that the market for ketamine clinics had reached $3.4 billion in 2023 and projects that it will continue to grow about 10% a year through 2030.
During the isolation of the Covid-19 pandemic, a growing number of telehealth companies began prescribing ketamine therapy online and guiding people how to use it at home. Today, online prescribing accounts for almost half the market, according to the Grand View report.
In October, the FDA warned about growing use of compounded forms of the drug, including lozenges. Dangers highlighted by the agency include psychiatric events, increased blood pressure and respiratory depression.
"Ketamine is not FDA approved for the treatment of any psychiatric disorder, and additional clinical studies are needed to adequately investigate ketamine's benefit-risk profile and safe-use conditions in the treatment of psychiatric disorders," it said.
Dr. Steven P. Cohen, a professor of anesthesiology at Northwestern University's Feinberg School of Medicine, says some ketamine clinics are clearly putting profits before patients.
Cohen said the clinics often don't have a doctor evaluate patients. He's heard of patients being given 35 to 40 milligrams of ketamine at a time, which may be subtherapeutic - in his experience, it takes about 400 milligrams given over a week effectively treat depression. He says clinics might not monitor patients' progress, and they're usually expected to pay cash for each treatment. "It's disgusting. It's the Wild West," he said.
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It stands in sharp contrast to requirements around esketamine, a derivative of ketamine that's approved by the FDA for treatment-resistant depression and available by prescription.
The FDA has strict requirements for use of the nasal spray, sold under the name Spravato. Users must be directly monitored for two hours after each dose because of the potential for side effects including loss of consciousness or sedation and dissociation, or a feeling of being disconnected from your body, which can be unpleasant. The drug can also cause slowed breathing.
A drug 'dangerous ... in the wrong context'
Cohen says he himself has used ketamine to successfully treat a patient whose misfiring nerves drove them to itch constantly for four years. He said he's also heard of ketamine being used to treat lingering pain after Lyme disease treatment.
But ketamine is being marketed to treat a range of problems, he says - including obsessive-compulsive disorder, post-traumatic stress disorder and generalized anxiety disorder - sometimes ahead of rigorous scientific study to back up that use.
In Perry's case, the actor was using ketamine to ease depression, according to the autopsy report, but there were suggestions that he had developed a growing need for the drug. In the news release on the charges brought in Perry's death, the US 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 "spiraling out of control." Perry had been open about his struggles with substance use disorder.
Experts say ketamine isn't physically addicting the way an opioid drug can be. People who use it regularly and then stop don't typically have withdrawal symptoms.
"You live in what I call 'K lands,' 'ketamine lands,' and coming back to reality might be unpleasant, but you're not going to go through a physical withdrawal, to my knowledge. So some people would say that's psychologically addicting," said Dr. Joseph Palamar, an associate director in the Department of Population Health at New York University.
Palamar says he worries about unsupervised use of the drug at home specifically because of situations like Perry's: The actor drowned in the heated end of his pool after taking large doses of the drug, according to the autopsy report.
"It's not the most dangerous drug by any means, but it can be dangerous if used in the wrong context," said Palamar, who is also deputy director of the National Drug Early Warning System, or NDEWS, a group that watches for early signs of drug epidemics.
Palamar says that it's very hard to get data on deaths related to ketamine but that he's heard of at least two others through sites that participate in the NDEWS network.
"Even if you're the most responsible person, that's a scheduled drug that could be dangerous," he said.
If using the drug at home, unsupervised, "what if you think it's a good idea to cook as you're using the ketamine and then you accidentally burn the house down? Or you think it's a good idea to drive? You take a walk outside and you get hit by a car?"
"So all these things, all these behavioral problems associated, these are things I worry about because it's unregulated," he said.
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