Here’s What You Should Know About Ketamine As A Treatment For Depression

It’s been nearly a year since actor Matthew Perry, best known for playing Chandler Bing on the show “Friends,” died from a ketamine overdose and drowning in his hot tub. News broke Thursday that five people had been charged in connection to his death, including two doctors, Perry’s assistant and a woman accused of being a drug dealer.

The actor had used ketamine infusion therapy for depression and anxiety, but seemed to become increasingly reliant on the drug toward the end of his life, according to law enforcement officials.

Though ketamine has long been known as Special K, a party drug, it has also been established as an effective treatment for depression, with proper dosing.

Below, experts share what to know about ketamine therapy and when it can become unsafe.

Ketamine is prescribed to people who have “treatment-resistant symptoms of depression,” according to Dr. John Krystal, the chair of the Department of Psychiatry at Yale School of Medicine in Connecticut.

“In other words, they’ve tried more than one antidepressant and they’re still not really getting the clinical response they need,” said Krystal, who is one of the original researchers on ketamine treatment for depression.

Two of the more common kinds of depression medication are selective serotonin reuptake inhibitors, or SSRIs, and serotonin and norepinephrine reuptake inhibitors, or SNRIs. Medications like Lexapro, Zoloft and Prozac fall in the SSRI category, while Cymbalta and Pristiq are in the SNRI category.

These medications “all work through the same general mechanisms of targeting systems in the brain, like norepinephrine and serotonin,” said Krystal. Serotonin and norepinephrine are neurotransmitters that are known for their links to mood, memory and the sleep-wake cycle.

It can take about six to eight weeks for for these medications to build up in a person’s system before the patient starts feeling better.

“Ketamine targets a different chemical system in the brain, called the glutamate system, which provides the information highway for the networks in the brain involved in the regulation of mood and cognition,” Krystal said.

Since ketamine works differently, it can produce faster results than SSRIs and SNRIs in some people.

There are different ways that ketamine can be administered, but it’s only approved by the Food and Drug Administration as a depression treatment in its nasal spray form, with a treatment known as esketamine. Specifically, it’s approved for “treatment resistant depression and major depressive disorder with suicidal ideation and behavior,” said Dr. Paul Kim, the director of the Johns Hopkins Treatment Resistant Esketamine Antidepressant Targeted (TREAT) Depression Clinic in Baltimore.

“Esketamine … is highly regulated. It’s a Schedule III drug, controlled substance, and both the patient and the clinic have to be enrolled in this program called the REMS program. ‘REMS’ stands for ‘risk evaluation and mitigation strategy,’” explained Kim. Certain drugs that have the potential for abuse or serious adverse effects need to be in an REMS program, Kim added. Esketamine is taken under supervision at a clinic.

Ketamine can also be administered intravenously, but IV ketamine is FDA-approved as an anesthesia drug, Kim explained. It’s also used as an off-label medication for treatment-resistant depression.

Since IV ketamine is not FDA-approved as a mental health treatment, it does not have the same level of regulations for this use. That’s not to say that medical clinics don’t properly and safely administer the medication, however; you can get intravenous ketamine treatment at many major medical clinics across the country.

Both IV ketamine and esketamine are effective treatments for depression, Kim said. Unlike medications such as Zoloft and Prozac, ketamine and esketamine are not administered daily. Instead, they’re generally administered a few times a week at first, and then less frequently as a person progresses in their treatment. Moreover, ketamine therapy is often prescribed in addition to a daily antidepressant pill.

Ketamine can also be compounded into a pill that’s taken orally, according to Kim, and some online companies currently offer this treatment. But both Krystal and Kim stressed that it’s important for patients to be monitored in a clinic as they receive any form of ketamine therapy.

“One thing that becomes clear is that oral ketamine is not necessarily more or less safe or effective than IV ketamine or intranasal esketamine when delivered in the clinic. However, if the level of monitoring of blood levels and dose adjustment are not employed, then the variable blood levels could create safety or effectiveness issues,” Krystal said. “Concerns about safety issues would be increased if patients took the oral ketamine at home without adequate clinical supervision.”

The amount of ketamine in Perry’s system was equivalent to what’s given for general anesthesia — not the amount doctors use for depression treatment, which is much less. And he was at home when given the drug, not in a medical setting.

“There are companies that are trying to find ways to make ketamine safer for administration at home, but the Matthew Perry story highlights something extremely important, which is that when patients have more ketamine than they need at home, there’s going to be a risk of misuse,” said Krystal. “And, in fact, a study of home ketamine use found that a high percentage of patients misuse their ketamine.”

When taken under proper supervision in a medical setting, esketamine and IV ketamine are safe, Krystal and Kim said. Ketamine and esketamine are also lifesaving medications that have been shown to reduce the risk of suicide in many people, according to Krystal.

“People have been using ketamine as an anesthetic for a long time, and they know that it’s safe — but again, in a hospital setting,” Kim said. “If it’s being misused, then there’s always a potential that it can become deadly.”

When ketamine is used appropriately, treatment sessions become spaced further and further apart, said Krystal.

But Krystal said that “people who misuse ketamine take ketamine more and more and more over time. When used very infrequently, as we do in treatment, ketamine stimulates regrowth of synaptic connections between nerve cells in those brain circuits involved in emotion.” When it is used recreationally and outside of clinical settings, it can lead to addiction, while also being “toxic to those brain connections and it can even produce symptoms of depression,” Krystal said.

Ketamine and esketamine can be life-changing medications for many people who feel like they’ll never be able to manage their depression.

“I can’t speak to all the clinics that are out there, but I guess my recommendation to readers would be that, really, they should talk to their psychiatrist about ketamine treatment, and hopefully they have some experience referring patients to certain clinics,” said Kim. “A lot of times those clinics should be run by a psychiatrist, or somehow they have a psychiatrist on staff.”

It’s also worth researching the major health systems in your area to see if they offer ketamine therapy. Be wary of places that are “a pop-up type of clinic where it’s operated by a non-mental health professional. Because … anesthesiologists can administer it, and there’s whole sorts of doctors that can give IV ketamine,” Kim said.

Since it’s not FDA-approved, IV ketamine may need to be paid for out of pocket, which can become costly. Kim said FDA-approved esketamine has essentially the same efficacy for mental health treatment.

“At the end of the treatment, there’s really no difference on the effectiveness of IV ketamine over esketamine,” Kim added.

And you should remember that this type of treatment is just one piece of a larger puzzle.

“Esketamine and also IV ketamine, it’s not a cure, right? It’s not like you go and get one treatment, or multiple sets of treatments, and they’re cured from depression,” said Kim. “It just improves the symptoms, and it’s the oral antidepressant — [like] Prozac and Zoloft — those are the ones that hopefully sustain or maintain the beneficial effects.”

It’s also important to continue seeing a psychiatrist who can monitor your symptoms, treatments and overall mental health to ensure you’re on the best path forward.

Need help with substance use disorder or mental health issues? In the U.S., call 800-662-HELP (4357) for the SAMHSA National Helpline.

Call or text 988 or chat 988lifeline.org for mental health support. Additionally, you can find local mental health and crisis resources at dontcallthepolice.com. Outside of the U.S., please visit the International Association for Suicide Prevention.