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Matthew Perry's death from the "acute effects of ketamine" may be a harbinger of a larger ketamine addiction problem in the U.S., experts said.

"I believe that this case with Matthew Perry is kind of like a sentinel event," Gerald Busch, MD, MPH, of the American Psychiatric Association's Council on Addiction Psychiatry, told MedPage Today. "Something in a very famous person that is a warning sign that it needs to be looked into further."

While interest in using the anesthetic drug to treat depression and other mental health conditions has grown, the addictive potential of ketamine is still not well understood. But the ease of obtaining it means more people than ever may be using -- and potentially abusing -- it.

Ketamine is approved for the induction and maintenance of general anesthesia during surgery and as a sedative in other settings -- but it's also used off-label for depression and anxiety. (A related drug, esketamine [Spravato] is approved to treat treatment-resistant depression and some cases of major depressive disorder.)

It is a Schedule III controlled drug: less restricted than heroin and oxycodone, but more restricted than alprazolam (Xanax) or zolpidem (Ambien).

In a MedPage Today analysis of data from Symphony Health, new prescriptions for esketamine and ketamine hydrochloride in any form have increased steadily, from 4,740 in August 2022 to 6,705 in August 2023, and then to 11,720 this August. In addition, the total quantity of doses prescribed for non-esketamine forms of ketamine has increased, though the number of new prescriptions appears to have dropped.

The rise in use, experts said, may be partially due to an easing of restrictions on telehealth during the COVID-19 pandemic, during which online services like Mindbloom and Nue Life began facilitating home use of ketamine without an in-person visit, usually in the form of troches (lozenges) shipped from compounding pharmacies.

Ketamine's Addictive Potential

Reddit communities like r/KetamineTherapy and r/Ketamineaddiction are full of information about online ketamine services -- but also stories of overuse and abuse. Accounts of using too much recreational ketamine are common, as are accounts of addictions to troches obtained legally. Users seek help with side effects like "K-cramps," the intense abdominal pain that can come with regular use, and problems with the urinary tract and bladder.

Some users have even described paths similar to Perry's in the lead-up to his death: having first been treated with ketamine infusions, the former "Friends" actor eventually sought out higher doses through channels that could provide dangerous quantities of the drug he may have built a tolerance to.

In an for a 2023 clinical trial on ketamine for depression, one psychiatrist offered a particularly dire warning. Years ago, patients who received oxycodone for pain "reported initial highly positive responses similar to those reported by patients who received ketamine in the current trial, but prescription use was associated with a subsequent epidemic of addiction to both oxycodone and heroin," wrote Robert Freedman, MD, of the University of Colorado Denver.

"There are no barriers to stop a patient who has received ketamine in a referral clinic for severe depression from going to another provider who uses less stringent criteria to provide treatment," he continued. "We need to remember that only a minority of physicians were responsible for the oxycodone epidemic."

Busch, too, drew a comparison between ketamine and other commercialized substances like oxycodone. "Before, it was a very highly circumscribed club drug. Very limited. But then it was commercialized. Anytime you commercialize an addictive drug, you're taking a big risk."

Boris Heifets, MD, PhD, an anesthesiologist from Stanford University in California, told MedPage Today that depending on how addiction is defined, ketamine is both similar to and different from other drugs typically seen as dangerously habit-forming.

"It's almost certainly less habit-forming than a drug like OxyContin. It's probably less habit-forming than a drug like alcohol," he said. "But it is a drug that can certainly be misused and abused."

Mostly, he and Busch said, addiction becomes problematic on a population level when a drug is available to many.

"It just comes back to this math: you take something that's not terribly addictive and give it to a million people and create a problem that you didn't have before," said Heifets. "[For] opioids ... it's like, you don't need a million people, you need a thousand people because it's a lot more addictive."

Heifets put it another way: "Do people use it compulsively despite adverse consequences? Yes," he said of ketamine. "That, to me, is probably the most useful functional definition of addition."

Tolerance to ketamine can build over time. In withdrawal, users can experience muscle aches or myalgias, and what's known as "zaps," a feeling of electricity down the back, explained Brian Hurley, MD, MBA, an addiction physician and president of the American Society of Addiction Medicine (ASAM).

Ketamine overdose can happen, but it's more likely that someone dies as a result of its anesthetic effects, Hurley said. It "puts people at risk for everything from accidents, injuries behind the wheel of the car that can be obviously deadly, [to] another context where falling asleep could be deadly."

Keeping Track of Ketamine Misuse

Problematic ketamine use can also be difficult to track. Though almost every state has a prescription drug monitoring database, there is not yet a national one, and providers don't always check them before prescribing. Hurley said ASAM doesn't have a position yet on telemedicine prescribing of ketamine.

Heifets said it's still unclear whose responsibility it would be to rein in off-label prescribing, though he said the FDA put out a warning about potential risks of compounded ketamine products for the treatment of psychiatric disorders. "It was basically, 'this is the only thing the FDA can do.' So they took as much action as they could," he said.

"As long as the books are kept, the only way to regulate [excessive prescribing] is through state practice boards," Heifets added. "That's not really a DEA [Drug Enforcement Administration] thing, so it's not really clear who has authority here."

Busch, working at the psychiatric emergency department at the Queen's Medical Center in Honolulu last year, said he became so concerned about ketamine, he contacted his local (HIDTA) office.

"I noticed people coming in with ketamine-induced psychosis in a very bizarre state," he said. "Very few cases, but ... they would have, like, a backpack full of these ketamine troches, and then [I] heard isolated incidents of people abusing ketamine or ketamine diversion."

Busch also started seeing larger prescriptions of ketamine troches. "I was concerned, because it seemed like with its legitimization as a treatment, people were kind of disregarding the fact that the ketamine had other consequences," he said.

His local contact wasn't familiar with ketamine issues, so he asked if they could check with other HIDTA areas, and didn't hear back.

Their resources, he said, may be focused elsewhere. "The attention of regulatory agencies is on fentanyl and trying to get a handle on that," he pointed out. "So, in the meantime, you have this other situation bubbling up, and I think there should be at least a call for monitoring, more for diversion."

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