Much remains unknown about use of sedative

Though it’s perhaps most associated in Colorado with the death of Elijah McClain, ketamine is a medication that can work for people whose depression isn’t helped by other treatments — but much remains unknown, and it’s up to the patient to figure out if a provider is a good choice.

Ketamine is a heavy sedative that also can relieve pain. In the case of McClain, the 23-year-old was given a too-large — and ultimately fatal — dose of ketamine by paramedics after Aurora police forcibly arrested him three years ago,

But when it comes to the drug’s use in fighting treatment-resistant depression, studies have found that people who respond to ketamine tend to report their symptoms improve within hours — a significant difference from the weeks it can take for conventional antidepressants to take effect.

But it hasn’t been used for depression long enough to know if there are side effects that emerge over time, and researchers are still working out the optimal dose and treatment duration.

No agency in Colorado oversees ketamine infusion clinics, and the U.S. Food and Drug Administration doesn’t have jurisdiction over “off-label” prescribing — giving patients an approved drug for an unapproved use. The state boards that license doctors and nurses oversee people who work in the clinics in the same way that they do any doctor or nurse, and could take action if they received complaints that patients were being harmed.

The situation is the same nationwide, creating a bit of a “Wild West” where patients have to be informed consumers, said Dr. Gerard Sanacora, director of the Yale Depression Research Program. That doesn’t mean patients shouldn’t try ketamine if they haven’t been helped by other options, but providers have a duty to make it clear how much uncertainty remains, he said.

“It’s hard to say, ‘This is the right way,’ ‘This is the wrong way,’” he said. “The bottom line is we really don’t know much about intravenous ketamine.”

Questions about who it may help

Unlike psilocybin, the active ingredient in magic mushrooms, which Coloradans voted to allow to be used in “healing centers,” ketamine has been FDA-approved for decades, but only for use as an anesthetic. In recent years, however, clinics have popped up as evidence grew that the drug relieved depression symptoms in some people who weren’t helped by conventional medications.

One of the advantages of ketamine is speed — a study looking at 47 people found that 64% of those who received the drug reported their symptom severity had been cut roughly in half one day after their infusion. That study, like most others, tested ketamine in people who hadn’t been helped by at least two types of antidepressants.

Some clinics are relatively strict about sticking to those criteria. Dr. Eve Langston, an anesthesiologist at Vitalitas Denver, said most of their referrals come from mental health providers treating people whose depression has proven resistant to conventional treatment. They don’t take patients who are currently misusing substances or experiencing mania, those with a history of psychosis, or those who haven’t tried other treatments, she said.

“It is definitely a medication that should be considered for people who have exhausted the traditional options for treating depression,” she said.

That’s in line with a  2017 consensus statement from the American Psychiatric Association, which recommended that providers offering ketamine treatment screen patients for a history of drug misuse or psychosis, as well as for cardiac problems that could be exacerbated.

Others push the envelope more on who they’ll treat.

Dr. Wade Grindle, who owns Boulder Mind Care and Transcendant Ketamine Care of Colorado in Fort Collins, will see some patients who have mania, so long as they don’t also have psychosis, and don’t necessarily require people with depression to have tried two medications before — though most have tried more than that, he said. Patients need to show documentation of a condition that can be helped by ketamine, like depression or chronic pain.

“Someone can’t just walk in off the street and say, ‘I want to get high,’” he said.

Unlike most providers, they also see patients under 18, since ketamine is safe as an anesthetic for that group and there’s a crisis of youth mental illness and suicide, Grindle said. There isn’t much data on how repeated ketamine use could affect developing brains, though, since anesthetics aren’t typically used multiple times in a month.

Most of the studies of ketamine tried a dose of no more than one-half milligram for every kilogram (2.2 pounds) of a person’s weight, given four to six times over two to three weeks. Langston said most of her patients receive that dose, though occasionally it makes sense to go lower or somewhat higher. They continuously monitor patients’ heart rates and blood oxygen levels, and periodically check their blood pressure during the infusion, she said.

“We’re all anesthetic physicians, so we’re all very conscious of what higher doses of ketamine can do,” she said.

An alternative comes with strings

There’s more evidence for esketamine, which accounts for half of the ketamine that’s given in infusions. The FDA approved it in the form of a nasal spray sold under the brand name Spravato, for adults whose depression hasn’t improved with other medications. Some members of an FDA advisory committee expressed reservations about esketamine, because there was no data about its long-term effects, according to Kaiser Health News.

Getting FDA approval requires large-scale testing for safety and effectiveness — something pharmaceutical companies aren’t likely to invest in for intravenous ketamine, since there isn’t much money to be made from a decades-old generic drug, Sanacora said.

The studies of ketamine so far have been small, and some scientists have raised concerns that the placebo effect could be skewing them, since patients who received ketamine most likely figured it out. The placebo effect occurs when the brain expects relief, and produces chemicals that reduce symptoms.

Esketamine comes with significant strings attached, Sanacora said: only certain pharmacies and physicians are allowed to handle it; patients have to take it with a traditional antidepressant; it must be given in a medical office; and patients have to stay for two hours of observation after receiving it.

“When the FDA granted the approval, that was part of the package. That had some unintended consequences,” he said.

By contrast, there aren’t any binding rules on administering ketamine infusions, meaning it’s far easier and cheaper to treat patients that way, even though there’s more research to back esketamine, Sanacora said. (Insurance is unlikely to cover off-label ketamine infusions, though, which may make esketamine the less expensive option if patients can find someone to give it.)

“Each one of these little hurdles you put up reduces access to some people,” he said.

Effects on emotions may help with pain

Esketamine hasn’t been studied for one of the more popular reasons people turn to intravenous ketamine. Both Langston and Grindle reported demand from people with chronic pain that hasn’t improved with conventional treatment.

Dr. Steven P. Cohen, professor of anesthesiology and critical care medicine at Johns Hopkins Medicine, said ketamine doesn’t reduce the severity of pain or increase people’s tolerance of it. Rather, it seems to affect some people’s emotional experience of pain, which makes it a useful tool for different types of chronic pain, he said.

While ketamine itself is cheap, constant monitoring is expensive, which means it likely won’t be a first-line treatment for chronic pain any time soon, Cohen said. And there’s concern about long-term damage to the liver and bladder that’s been seen in recreational users who take it at high doses for an extended time, he said.

It’s difficult to tell how much of the reduction in pain after ketamine treatment is a placebo effect because a great deal of the benefit from multiple types of pain medication comes from our belief that they work, Cohen said. People tend to have stronger placebo reactions to procedures like infusions rather than pills, and unlike many medications, ketamine has obvious side effects, reinforcing the belief that it’s working, he said.

But even if a drug works largely because the patients believe it works, it can be worthwhile if they are able to get back to their lives, Cohen said.

“People who have a placebo effect, they’re functionally better. They sleep better,” he said.

“Part of the treatment plan”

It’s also not totally clear how ketamine — or conventional medications, for that matter — act to reduce depression.