Much remains unknown about the use of sedatives

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

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

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

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

No agency in Colorado oversees ketamine infusion clinics, and the US Food and Drug Administration has no jurisdiction over “off-label” prescribing — giving patients an approved drug for an unapproved use. State boards that license doctors and nurses monitor the people who work in the clinics in the same way as any doctor or nurse, and could take action if they receive complaints that patients are being harmed.

The situation is the same across the country, creating something of a “Wild West” where patients need to be informed consumers, said Dr. Gerard Sanacora, director of Yale’s 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 responsibility to clarify 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 that we really don’t know much about intravenous ketamine.”

Questions about who it can help

Unlike psilocybin, the active ingredient in magic mushrooms that Colorado residents voted to allow for use in “treatment centers,” ketamine has been FDA-approved for decades, but only for use as an anesthetic. However, clinics have sprung up in recent years as evidence has emerged that the drug relieves symptoms of depression in some people who have not been helped by conventional drugs.

One of the advantages of ketamine is speed—a study looking at 47 people found that 64 percent of those who received the drug reported that the severity of their symptoms was reduced by roughly half one day after their infusion. This study, like most others, tested ketamine in people who had not been helped by at least two types of antidepressants.

Some clinics are relatively strict about meeting these 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 accept patients who are currently abusing substances or experiencing mania, those with a history of psychosis or those who haven’t tried other treatments, she said.

“This is definitely a drug to consider for people who have exhausted traditional treatment options for depression,” she said.

This is in line with a 2017 consensus statement from the American Psychiatric Association, which recommends that providers offering ketamine treatment screen patients for a history of drug abuse or psychosis, as well as heart problems that may worsen.

Others push the envelope more on who they will 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 as long as they don’t also have psychosis, and people with depression don’t necessarily have to have tried two drugs before — though that most tried more than that, he said. Patients must show documentation of a condition that can be relieved by ketamine, such as 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 because ketamine is a safe anesthetic for that group and there is a crisis of youth mental illness and suicide, Grindle said. However, there isn’t much data on how repeated use of ketamine might affect developing brains, since anesthetics are not usually used multiple times within a month.

Most of the ketamine studies have tried a dose of no more than half a milligram for each 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 this dose, although sometimes it makes sense to go lower or slightly higher. They continuously monitor the patients’ heart rate and blood oxygen levels and periodically check their blood pressure during the infusion, she said.

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

An alternative comes with strings

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

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

Ketamine studies have been few and far between, and some scientists have expressed concern that the placebo effect could skew them, since patients who received ketamine were most likely to understand it. The placebo effect occurs when the brain expects relief and produces chemicals that reduce symptoms.

Sanakora said esketamine comes with significant conditions: only certain pharmacies and doctors are allowed to handle it; patients must take it with a traditional antidepressant; must be given in a medical office; and patients should remain for two hours for observation after receiving it.

“When the FDA gave the approval, it was part of the package. It had some unintended consequences,” he said.

In contrast, there are no binding rules for administering ketamine infusions, meaning it is much easier and cheaper to treat patients this way, even though there is more research to support esketamine, Sanakora said. (However, insurance is unlikely to cover off-label infusions of ketamine, which could make esketamine the cheaper option if patients can find someone to administer it.)

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

Effects on emotions can help with pain

Escetamine has not been studied for one of the most popular reasons people turn to intravenous ketamine. Both Langston and Grindle report demand from people with chronic pain that has not improved with conventional treatment.

Dr. Steven P. Cohen, a professor of anesthesiology and critical care medicine at Johns Hopkins Medicine, said ketamine does not reduce the intensity of pain, nor does it increase people’s tolerance to it. Rather, it appears to affect some people’s emotional experience of pain, making it a useful tool for various types of chronic pain, he said.

Although ketamine itself is inexpensive, ongoing monitoring is expensive, meaning it likely won’t be a first-line treatment for chronic pain anytime soon, Cohen said. And there are concerns about long-term liver and bladder damage seen in recreational users who take it in high doses over a long period of time, he said.

It’s hard to say how much of the pain reduction after ketamine treatment is a placebo effect, because much of the benefit of multiple types of pain medications comes from our belief that they work, Cohen said. People tend to have stronger placebo responses to procedures like infusions than to pills, and unlike many drugs, ketamine has obvious side effects, reinforcing the belief that it works, he said.

But even if a drug works largely because patients believe it works, it may be worth it if they can get back to their lives, Cohen said.

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

“Part of the treatment plan”

It’s also not entirely clear how ketamine — or conventional drugs, for that matter — works to reduce depression.

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