Ketamine is psychiatrists' secret weapon against depression. Here’s how it works.

Ketamine, a drug once popular in the club scene, is now psychiatrists' secret weapon against depression. Perhaps you've heard of it, either from celebrities' personal stories — such as former NBA player Lamar Odom or Sharon Osbourne— or through the many research studies currently underway to assess its effectiveness.

What you may not know is how the drug works to relieve depression, and why it seems to help patients for whom all other treatments have failed. In that, you wouldn't be alone. Dr. Steven Levine, a board-certified psychiatrist who developed the protocol for the clinical use of ketamine in 2011, says scientists are still nailing it down. The Food & Drug Administration, which approved a nasal spray version of ketamine known as esketamine in 2019, is too. As the science world continues to explore how a drug that was once used as an anesthetic on the battlefield has revolutionized the mental health world, here's what you need to know.

Ketamine offers "a more optimistic model of depression"

Levine says the basic way to explain it is that the drug more or less wakes up the brain and allows it to form new connections. "We think that it affects the glutamate system. Glutamate is a neurotransmitter, [which] are chemical messengers that carry information signals in the brain," he says. "It enables the brain to heal and change and learn and become more resilient."

He believes it's a "more optimistic model of depression" than the one behind drugs like Prozac, which is part of a class of medications known as selective serotonin reuptake inhibitors (SSRIs). The theory behind SSRIs is that depression is caused by a deficit of serotonin, a feel-good chemical, in one part of the brain. Ketamine rests on the idea that depression affects many areas of the brain, inhibiting its "neuroplasticity" — or, "the brain's ability to reorganize itself by forming new neural connections throughout life."

Rebecca Price, associate professor of psychiatry and psychology at the University of Pittsburgh, who researches ketamine, says its ability to affect neuroplasticity may be why patients who benefit from the drug typically feel relief immediately. "Ketamine has quite distinct mechanisms from SSRIs in terms of the brain receptors it acts on," says Price. "The dominant hypothesis for why ketamine works so quickly, even in treatment-resistant patients, is that it rapidly — within about one day — restores neuroplasticity in key brain circuitry involved in regulating mood, cognition and affect."

The mechanism behind ketamine bears some similarities to the main chemical in cough medicine

Levine, who has pioneered much of the work with ketamine and depression, says his interest began a decade ago when he was tapped to give a second opinion for a patient with severe depression. The woman, who had struggled to find relief from other treatments, revealed she'd been using something unusual to treat her depression: cold medicine.

"It was a serendipitous, funny thing. She pretty guiltily admitted to me that the one thing on earth that ever seemed to help, despite the fact that she'd had really good care and a great psychiatrist, was when she had a cough and would take over-the-counter cold medicine," Levine explains. "So she found herself — when she was at her worst — taking a little half cap of it to help her feel better."

Levine became determined to find out the mechanism behind this was and quickly narrowed in on dextromethorphan, the active ingredient in cold medicine. "I was curious ... what is it about dextromethorphan's mechanism that works and then [found] that other medicines shared that mechanism," says Levine. "It brought me back to some of the papers that were starting to be generated around that time, looking at the repurposing of this really old anesthetic called ketamine for this new purpose."

Soon after trying out the hallucinogen on a patient, he saw almost immediate results — and for over a decade, treating more than 6,000 patients has seen them again and again. "I really feel very grateful that I've had the opportunity to sit with so many people who have shared with me how dramatically changed and improved their life is after [ketamine] treatment," says Levine. "It's just, it's difficult to put into words."

The treatment can "dramatically change" lives but works for only 50 percent of patients

Levine stresses that while the drug can work wonders, it is by no means a silver bullet. Many people experience a major lift from the drug, but just as many — for reasons that are unclear — do not. "Only about 50 percent will respond to ketamine treatments, maybe 60 to 70 percent will have that sort of lower bar of clinically meaningful results," says Levine. "So lots of people aren't going to get this great benefit from ketamine. But I have seen people who really were at the end of their rope, who tried everything under the sun ... people who really believe that there was nothing on earth that could help them. I've seen some really amazing dramatic responses. I've been lucky to get lots of hugs."

The drug is helping to push the psychiatry world forward

Price, who is pioneering new research that pairs ketamine treatment with neurocognitive training, confirms that ketamine represents a major breakthrough in the world of mental health treatment. "It was highly significant for us to learn that depression can indeed be reversed this rapidly and profoundly, even in patients who haven’t responded well to existing treatment options," says Price. "I think the field is more open to the idea that we can and should expect better from our treatments for depression and related conditions. Rapid and profound transformations are possible, and we should leave no stone unturned until we can find safe, effective, efficient and durable approaches to help every single person who’s struggling."

Still, Price says the psychiatry world still has a long way to go in embracing new ideas. "The promise and potential of that initial discovery has yet to be fully realized clinically, because of a range of barriers to widespread adoption by providers and patients," she says. "One of the key ones is the lack of well-established, safe, feasible and effective ways to make these rapid effects more enduring in the long term. Rapid relief might be very important in certain clinical situations — for example, perhaps to address a suicidal crisis — but what people ultimately want, need, and deserve is a way to stay well for the rest of their lives."

Ketamine "brings you to the parking lot"

Those still confused about the way that ketamine works may benefit from thinking about it in terms of analogies. While some have likened it to a "flash mob" in the brain, Levine likes to explain it a different way.

"One analogy I use when comparing traditional antidepressants to ketamine is that it's like deciding to go to the supermarket. With traditional antidepressants, you're starting from home and there are a lot of steps. You have to find your keys, get to your car, open the door, turn on the ignition, drive down the street, make lots of turns, get into the parking lot, get out of your car and then walk in and find the frozen food section," he says. "There are lots of opportunities for things to go wrong and get in your way. With ketamine, it's not that it drops you directly into the frozen food section, but it brings you at least to the parking lot. So it's a much shorter route, and it's perhaps the reason more people are able to benefit and in a shorter period of time."

This story was originally published on July 9, 2021, at 3:16 p.m. ET and has been updated.

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