Ketamine, once best known as a pet anesthetic and party drug, is taking the United States by storm. Dozens of ketamine treatment centers are operating from coast to coast.

Big cities like Baltimore, Boston, and Phoenix have them. So do Charleston, S.C., and Boise, Idaho. Two such clinics are in sparsely populated New Mexico. And one national chain went from a pair of clinics to 10 in fewer than 2 years.

“There’s been a mad rush on the part of desperate patients to seek care,” said ketamine researcher Jeffrey A. Lieberman, MD , chair of the psychiatry department at Columbia University, New York; director of the New York State Psychiatric Institute; and a past president of the American Psychiatric Association.

Never mind that these expensive treatments for conditions like depression are not covered by insurers or approved for this use by the Food and Drug Administration. Other questions also persist. “There is a considerable body of evidence that proves it really does work,” Dr. Lieberman said. “But we don’t know the extent of the range of conditions for which it might be effective, what the optimal frequency and concentration for dosing is, and what the long-term consequences are.”

To make matters more complicated, it’s anesthesiologists – not psychiatrists – who are leading the way toward a ketamine-infused future.

“This was a truly novel breakthrough in the field, but we have to be careful. We have to develop this rationally,” said ketamine researcher Gerard Sanacora, MD, PhD , lead author of an APA consensus statement published in JAMA Psychiatry ( 2017;74[4]:399-405) urging caution on use of ketamine for mood disorders, and professor of psychiatry and director of the Depression Research Program at Yale University, New Haven, Conn.

For now, however, hundreds and perhaps even thousands of patients are serving as ketamine test cases with psychiatrists only assisting remotely, if at all.

A stunningly rapid rise

Sara M. Markey, MD , is one of the rare psychiatrists in the United States who’s fully embraced ketamine treatment for mental illness.

She recalled first hearing about ketamine as an anesthetic in medical school. Best known as an anesthetic in animals, it’s also occasionally given to children and adults, although the drug’s dissociative properties have prevented widespread use.

In 2006, word spread about ketamine’s use as a painkiller. “I also began hearing and reading about its potential use/efficacy in treatment-resistant depression,” said Dr. Markey, who practices in Denver. “It was difficult to find information about ketamine, and many of my colleagues were hostile to the idea of using ketamine in clinical practice.”

She persisted, however, and prescribed intranasal and oral ketamine to depressed patients with “mild success.” She also saw patients whose psychiatrists refused to consider ketamine.

In early 2016, with Steven P. Levine, MD , a New Jersey psychiatrist who pioneered ketamine use for depression, Dr. Markey opened a ketamine infusion clinic in the Mile High City.

At at that time, it was only the second in a national chain called Ketamine Treatment Centers . Now, not even 2 years later, the chain has a new name – Actify Neurotherapies – and a total of 10 clinics from San Francisco and Beverly Hills, Calif., to Palm Beach, Fla.; Raleigh, N.C.; and New York City.

“It is wonderful,” she said, “to have an opportunity to provide a medication to people that does not cause weight gain, has very few medication interactions, and which is well tolerated and generic.”

Big short-term benefits

Treatment outcomes with ketamine – which is thought to act on glutamate and N-methyl-D-aspartate receptors – can be dramatic. “Some patients describe the ketamine treatments as life saving,” said Allison F. Wells, MD, an anesthesiologist who runs a clinic in Houston.

One depressed young man who tried ketamine at a Phoenix clinic in 2013 reportedly told the news site that he “felt good for a week” after his first treatment: “Not the kind of bipolar ‘good’ where I’d be manic. I just felt pleasant, and not crazy or compulsive. I felt normal for the first time in a long time.” Another depressed patient told National Public Radio that ketamine transformed his life: “I remember I was in my bathroom, and I literally fell to my knees crying because I had no anxiety; I had no depression.”

Enrique A. Abreu, DO , an anesthesiologist who offers ketamine therapy in Seattle and Portland, Ore., said he’s seen anxiety relief and a decrease in rumination in these patients. “They’re able to go back to work; a lot haven’t been able to work for a long time. And motivation is a big thing. They’re able to do things they haven’t been able to do.”

In addition, ketamine can reduce suicidal thinking, Dr. Markey said. “I am continually astounded to hear patients who come in with acute or chronic suicidal thinking report that those ideas and/or intrusive thoughts have disappeared. When they are absent, people need to be reminded of when they had them. They seem to have forgotten about them.”

‘Mystical experiences’

Dr. Markey said a retrospective analysis of about 740 patients at her chain’s clinics showed a response rate of about 75%. Other research has shown similarly high response levels.

“Multiple clinical trials suggest that a single low dose (0.5mg/kg) of IV ketamine results in a 50%-70% response rate in patients with treatment-resistant depression,” reported a 2016 clinical review. “Additional research has shown that depressed patients can experience symptom relief as early as 2 [hours], and lasting up to 2 weeks after a single administration of IV ketamine,” according to the review in Evidence Based Mental Health ( 2016 May;19[2]:35-8 ).

Patients remain conscious during treatment, said anesthesiologist Gregory Simelgor, MD , who runs a ketamine clinic near Minneapolis. As for side effects, “a lot of them feel like they’re flying, and some of them have a mystical experience, wondering about the mysteries of life. And some dissociate.”

Adverse effects can include nausea and headache in patients with a history of migraine, he said. Over the long term, ketamine use can lead to incontinence and urinary urgency, he said.

As for ketamine addiction, Dr. Simelgor calls it unlikely at the lower doses that are used. However, he said, “I can’t say 100% that it won’t cause addiction.”

Who benefits? The jury’s still out

Considering its positive effects, why shouldn’t the mental health community embrace ketamine? Because, two prominent researchers say, best practices are still absent in a whole range of areas.

For example, there’s no agreement about who should undergo ketamine treatments beyond patients with treatment-resistant depression, especially those who have failed or cannot undergo electroconvulsive therapy. Ketamine therapy also is being touted by some as a treatment for a long list of other conditions from obsessive-compulsive disorder and anxiety to fibromyalgia and chronic pain disorders.

There are also limited data about dosing, making it “not possible to clarify the relative benefits and risks of doses other than 0.5 mg/kg delivered intravenously over 40 minutes,” cautioned Dr. Sanacora and Samuel T. Wilkinson, MD , also at Yale, in a 2017 commentary in JAMA ( 2017;318[9]:793-4 ).

In fact, they write, “Most published data supporting the use of ketamine as a treatment for mood disorders are based on trials that have followed up patients for just 1 week after a single administration of the drug.”

Unchartered waters

There’s also no accepted protocol beyond a typical six treatments over 2 or more weeks. This is relevant because the benefits of a series of treatments often fade away after a few weeks.

“Some patients describe the results lasting indefinitely, while most patients who respond to the treatments get to the point where they are going roughly 4-12 weeks with sustained results,” Dr. Wells said.

“When the effects start to wear off, they don’t crash,” said Dr. Abreu. Instead, he said, symptoms slowly reappear.

It’s typical for patients at Dr. Abreu’s clinic and others to return within a couple of months to go through another round of ketamine treatments. In some cases, “they continue to see us indefinitely to get them back up to where they need to be with a booster type of session,” he said.

Ketamine treatment costs vary widely, and insurers don’t cover this off-label treatment. The clinic operators quoted in this article reported a range of per-infusion costs from $350 (Dr. Markey’s clinic in Denver) to $675 (Dr. Abreu’s clinics in the Northwest).

“We have to have a talk with them: Can you afford this? This is going to take a significant amount of money every month to keep you well,” Dr. Abreu said. On the other hand, he said, the need for other medications goes away, eliminating that cost. (“They’re on [selective serotonin reputake inhibitors] usually,” he said, “but those drugs don’t work.”)

Nonpsychiatrists in forefront

At Dr. Markey’s clinic in Denver, all patients are required to see either her or a psychiatrist colleague. Some other ketamine clinics are run by psychiatrists, but that’s far from common.

Clinics often have no mental health professionals on staff and are run by anesthesiologists or other kinds of physicians.

Some clinic owners, Dr. Wells said, require patients to be under the care of a psychiatrist, neurologist, pain doctor, or other appropriate professional. “I do not intend, nor do I act, to displace psychiatrists, or the relationships our patients have with their psychiatrists, or the care they receive from their psychiatrists,” she said.

In the Northwest, Dr. Abreu said his patients take mood questionnaires, and he’s experimenting with a text-based mood monitoring system. In the Minneapolis area, anesthesiologist Dr. Simelgor is looking for a psychiatrist or psychiatrist partner for his ketamine clinic. “My thinking,” he said, “is that we need to work together.”

Still, there do not appear to be any requirements that ketamine clinic practitioners have connections to mental health professionals. Yet, as Dr. Sanacora put it: “Delivering the drug is the easiest part of the treatment. The hard part is managing the depression.”

Dr. Lieberman, Dr. Wells, Dr. Abreu, Dr. Simelgor, and Dr. Markey reported no relevant disclosures. Dr. Sanacora reported consulting fees and research contracts for multiple drug makers over the past 24 months. He holds shares in Biohaven Pharmaceuticals and is a coinventor on a U.S. patent (No. 8778979) on using glutamate agents to treat mental disorders held by Yale University.


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