Jeff Winograd didn’t know an adult life without depression. Since he was 20 years old, he had tried virtually every antidepressant on the market. But he says, “The depression was just a constant.”

By the time he was 45 years old, by then a father of two small children and a struggling-at-the-time film and video producer in Portland, OR, Winograd had hit rock bottom. The depression was so severe that he felt paralyzed by it.

“I sat on the couch all day, unable to move, I couldn’t move my feet,” he says. “And I was suicidal. I would sit and try to figure out how I was going to do it without hurting my kids.”

It was around that time that a doctor friend told him about ketamine for treatment-resistant depression.

Ketamine got its start in Belgium in the 1960s as an anesthesia medicine for animals. The FDA approved it as an anesthetic for people in 1970. It was used in treating injured soldiers on the battlefields in the Vietnam War. 

Emergency responders may give it to an agitated patient who, for example, they have rescued from a suicide attempt. That’s how Ken Stewart, MD, says doctors began to realize that the drug had powerful effects against depression and suicidal thoughts.

“Someone is trying to jump off a bridge and they give him ketamine in the ambulance to calm him down, and 9 months later, he says, ‘I haven’t felt suicidal for 9 months.’

“When enough stories like that started to pile up, doctors said, ‘Maybe there’s something here,’ ” says Stewart, an emergency physician and founder of Insight Ketamine in Santa Fe, NM. Like the drug itself, Stewart got his start in combat medicine during the Vietnam War. Some doctors also use ketamine to treat suicidal thoughts.

Ketamine causes what doctors call a “dissociative experience” and what most anyone else would call a “trip.” That’s how it became a club drug, called K, Special K, Super K, and Vitamin K, among others. Partiers inject it, put it in drinks, snort it, or add it to joints or cigarettes.

“Ketamine can produce feelings of unreality; visual and sensory distortions; a distorted feeling about one’s body; temporary unusual thoughts and beliefs; and a euphoria or a buzz,” says John Krystal, MD, chief of psychiatry at Yale-New Haven Hospital and Yale School of Medicine in Connecticut, where he is a leader in studying ketamine’s antidepressant effects.

The trip lasts about 2 hours. But there are serious risks linked to ketamine’s use, which is why it should only be given under the supervision of a doctor. The most serious are unconsciousness, high blood pressure, and dangerously slowed breathing. The drug could also cause long-term problems, such as ulcers and pain in the bladder; kidney problems; stomach pain; depression; and poor memory. Ketamine could be fatal for people who abuse alcohol or if you take it while you’re drunk.

But the drug’s potential as a treatment for depression and antidote to suicidal thoughts has drawn researchers’ attention. They’ve studied and administered it in controlled, clinical settings to help with treatment-resistant depression and other conditions.

To be clear: Casual use is not a treatment for depression. But doctors have developed a protocol for medically supervised use that may help people who don’t get relief from other medications.

The FDA has warned that ketamine and compounded ketamine products aren’t approved to treat any psychiatric disorder. This means that they haven’t been proven to be safe or effective. In 2019, the FDA approved a nasal spray called esketamine (Spravato) that’s derived from ketamine for treatment-resistant depression, but only in certain people who also take oral antidepressants and only under strict controls in certified health care settings. It may be an option for people who either haven’t been helped by antidepressant pills or who have major depressive disorder and are suicidal. They continue to take their antidepressant pill and receive esketamine at a certified doctor’s office or in a clinic, where a health care provider watches over them for at least 2 hours after the dose.

For treatment-resistant depression, patients usually get the nasal spray twice a week for 1 to 4 weeks; then once a week for weeks 5 to 9; and then once every week or two after that.

The spray has a “black box” warning about the risk of sedation and trouble with attention, judgment, and thinking, as well as risk for abuse or misuse of the drug and suicidal thoughts and behaviors.

Other forms of ketamine – none of which are approved by the FDA for mental health conditions – include IV infusion or a shot in the arm. Most research looks at ketamine given by IV. You can only get it by IV or shot in a doctor’s office.

At his clinic, Stewart only sees patients who have referrals from a doctor who diagnosed them with treatment-resistant depression. Stewart doesn’t make these diagnoses. He starts patients with a research-based six infusions spaced over 3 weeks.

“That’s how people get started,” Krystal says. “Two infusions a week, and then they go down to one infusion a week, and then most people go down to eventually one infusion every 2 to 4 weeks.”

Most research stops the initial treatment at 6 weeks. There’s no research to suggest that more than 6 weeks in a row brings more benefits, though people do go back for boosters if symptoms return.

The IV infusion lasts about 40 minutes. The dissociative experience starts quickly and takes about 15 to 20 minutes to wear off after the drip ends. A doctor is always on site during the whole process. The doctor isn’t necessarily in the room with the person being treated but is available if they need anything or become anxious or confused.

While the patient is on the drip, Stewart says, they look asleep. Most don’t move or talk. Though some, he says, may talk or make a comment about the music playing on their headphones or some part of their experience, or perhaps ask where they are. Unless they need something, Stewart says, no one interferes.

Christa Coulter-Scott, a pediatric nurse from Athens, GA, got treatment in a similar setting in Gainesville, GA. She says she didn’t want to wake up. “It was like a spiritual journey. I felt warm, safe, and confident. As the treatment went on, all the weight of stress was taken off of me in layers. I felt like I had the power of the universe at my fingertips.”

It’s a bold statement from a woman in her 50s who had felt powerless to depression and anxiety since childhood. As an adult, she’s also been diagnosed with PTSD and chronic pain. Coulter-Scott has tried 10 different antidepressants over the years. But the dark cloud of depression never budged.

Yet, after ketamine therapy, she says, “My head feels lighter, and I don’t have that gloomy, dark, heavy feeling in my mind. And everything around me looks brighter – the sun, the lights in my office.”

When she returned to work the day after an infusion, she asked a co-worker whether the lighting had been changed. It hadn’t. “I don’t know if it’s a side effect of ketamine or a side effect of being less depressed.”

Winograd describes it similarly. He talks about feeling like he was floating in a color. “It was the first time I understood the expression ‘happy place.’ It was this space where everything that had to do with my real life disappeared, and I didn’t have any of that weight that I carry with me everywhere I go.”

The antidepressant effects of ketamine wear off in hours, days, or a couple weeks in people who only get a single infusion. The series of infusions has longer-lasting effects.

At Stewart’s clinic, after the mind-altering part of the ketamine experience is over, a health provider sits and talks with the patient in a process called integration. Other clinics may recommend that patients continue their talk therapy elsewhere.

“It’s my sense that this is important,” Stewart says. “When people come out of this really profound experience, they have a lot to say, and these are people who have a lot of baggage and a lot of experiential pain. A lot of times, ketamine leads to an unpacking of that baggage.”

Krystal, who provides IV and intranasal ketamine for treatment-resistant mood disorders at the VA Connecticut Health System and Yale-New Haven Hospital, encourages patients to continue with their psychotherapy after ketamine treatment.

Doctors who administer IV ketamine tend to recommend patients continue with their regular antidepressant regimen, too. As for the nasal spray, it’s only approved for use along with an oral antidepressant and only in certified health care settings.

“Ketamine is an intervention, but the notion of ‘treatment’ is much broader than that,” he says.

Weeks, months, or years after their first series of six to eight doses, patients may return for a booster. There is no standard recommendation for when or if people need a booster. They discuss it with their doctor if symptoms of depression start to reappear.

“For about 30% of people who complete the whole series, that’s it. They never come back,” Stewart says. “For those who come back for boosters, it seems the boosters get further and further apart until they eventually don’t need them again.”

For both Winograd and Coulter-Scott, the benefits of ketamine have continued after the trip. Researchers are studying why that may be.

Here’s what they know so far: A few depressed people won’t have the drug trip that ketamine typically causes, yet they still report relief from depression, starting a few days after a dose.

“When ketamine is in your system, you’ll likely have the dissociative effects, but that’s not the treatment,” Krystal says. “That’s just something you go through to get the treatment. The ketamine treatment is the reaction of your brain to ketamine, how your brain responds to exposure to ketamine.”

The brain can respond in a few ways, depending on the state it was in to begin with. For example, some people with long-term depression lose some important connections in their brains (called synapses) that let nerve cells communicate.

“We think that the number of synapses goes down because depression is so stressful that you actually prune or lose some of the synaptic connections in the brain,” Krystal says.

But research shows that within 24 hours of the first dose of medically supervised ketamine, those lost connections start to regrow. The more synapses the patients grow, the better the antidepressant effects of ketamine are for them.

Ketamine may work in other ways in the brain, too.

Some nerve cells (neurons) in the brain involved in mood use a chemical (neurotransmitter) called glutamate to communicate with each other. The nerve cells need glutamate receptors – think of them like catcher’s mitts for glutamate – in order to join in this communication.

In the brains of some people with depression, those nerve cells don’t get so excited by glutamate anymore. It’s as if the glutamate receptors – the catcher’s mitts – are deactivated or weakened.

But after people with this particular problem receive ketamine, those nerve cell connections get restocked with new glutamate receptors. It’s as if ketamine helps make new catcher’s mitts for the glutamate, so that the nerve cells can respond to it again.

Research suggests that though ketamine’s main action is in glutamate receptors, it needs opioid receptors to have its antidepressant effects, too. For psychiatrist Alan Shatzberg, MD, who did some of the research that uncovered this, that’s concerning.

“It may not matter, but it does concern me, personally, that ketamine works through an opioid mechanism,” he says. The worry, which other researchers have mentioned in studies of ketamine, is that people might require larger and larger doses of ketamine over time in order to feel its effects – as is the case with opioid painkillers. The spreading and tapering of treatments over time should help reduce this risk.

Of course, any comparison to opioids raises the question of the risk of addiction. Abuse and misuse of the medication are part of the “black box” warning on esketamine.

“I think it’s probably less addictive than opioids, but it’s not without its risks,” says Shatzberg, who is the director of Stanford University’s Mood Disorders Center. Indeed, case studies have described people who showed signs of addiction or abused the drug.

It may be too soon to tell whether the risk of addiction or tolerance outweighs the possible benefits. It’s important to note, though, that some recommendations suggest it may not be safe for people who have a history of substance abuse. Many clinical trials have barred people with substance use problems.

It also may not be safe for people who have schizophrenia. “At the antidepressant dose, ketamine transiently worsens their symptoms of psychosis,” Krystal says.

As for the drug’s action on glutamate receptors: Regrowing and reactivating synapses helps the brain’s ability to change, which may help it shift out of depression. That may also explain why antidepressants or psychotherapy that didn’t help before ketamine may help afterward.

Before ketamine, Winograd says he only went to therapy because his family begged him to go. “After I started to feel better,” Winograd says, “my therapist started to make more sense.”

Coulter-Scott says her sleep improved. Trouble sleeping is a common symptom of depression. Raising her granddaughter on her own, she says, she still feels stress, but it doesn’t come along with the darkness and anxiety that she had lived with before.

Typically, the only ketamine-derived treatment for depression that insurance will cover is the FDA-approved nasal spray called esketamine (Spravato).

Because the FDA has not approved IV ketamine for depression, most insurance doesn’t cover it. The cost of an infusion can vary widely and is typically paid out of pocket. A full treatment course can be several thousand dollars.

“Some patients and some practitioners prefer the IV administration to the intranasal administration. But there are not compelling data to conclude that one is superior to the other or to predict who would benefit from one versus the other,” Krystal says.

Some people may not keep up with their treatments, especially if they can’t afford it or if their insurance doesn’t cover it. Stewart says that when people don’t return to his clinic for continued treatment, he doesn’t know whether it’s because they still feel good or because they can’t afford to come back.

Insurance disputes have prevented Winograd from getting a booster, even with the nasal spray, though he and his health care providers feel that he would benefit from it. Still, he says, the big changes that the first series of treatments brought about have lasted.

“That wasn’t a temporary change,” he says. “It was a shift in who I am, how I approach the world, and my feelings towards my own emotions.”