Jeff Winograd couldn’t get off his couch. He’d hit rock bottom with the depression he’d had since he was 20. It felt paralyzing. “I was suicidal,” he says. “I would sit and try to figure out how I was going to do it without hurting my kids.”
For 25 years, he’d tried virtually every antidepressant on the market and went to talk therapy. “The depression was just a constant,” says Winograd, 54, who lives in Portland, Oregon.
Around that time, a doctor friend told him about ketamine for treatment-resistant depression. It wasn’t an FDA- approved treatment. But Winograd says it saved his life.
But for every success story like Winograd’s, there are headlines about clinics that skirt the law. Misuse and addiction. Even deaths, including that of actor Matthew Perry, from improper use. So for people considering whether ketamine therapy might help them with depression, PTSD, or other mental health conditions, is the promise worth the risk?
Keep in mind that casual use isn’t a treatment for depression, and the FDA has warned that ketamine and compounded ketamine products aren’t approved to treat any psychiatric disorders. (A ketamine-derived drug called esketamine is approved for some people as part of treatment-resistant depression in a certified clinical setting.) But doctors have developed a protocol for medically supervised use that research shows may help some people who don’t get relief from other medications.
What Is Ketamine?
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 medicine doctor and founder of Insight Ketamine in Santa Fe, New Mexico. 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 other names. Partiers inject it, put it in drinks, snort it, or add it to joints or cigarettes.
“Ketamine can produce temporary effects including feelings of unreality, visual and sensory distortions, distorted feelings about one’s body, 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 studies ketamine’s antidepressant effects.
The trip lasts about two hours. There are risks, which is why it should only be given under the supervision of a doctor. The most serious are unconsciousness, high blood pressure, and slowed breathing. The drug could also cause long-term problems, including bladder problems and addiction, if misused. 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 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.
Receiving Ketamine
In 2019, the FDA approved a prescription 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.
Esketamine 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 two hours after the dose.
For treatment-resistant depression, patients usually get the esketamine nasal spray twice a week for one to four weeks. Then they take it once a week for weeks five to nine, and then once every week or two after that.
The esketamine nasal 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 have FDA approval for mental health conditions – include IV infusion or a shot in the arm, or oral compounded formulations. Most research looks at ketamine given by IV.
At his clinic, Stewart sees patients who have been diagnosed by other health care providers with a treatable condition. His patients start with six infusions spread over three weeks. “Treatment protocols are based on the patient’s specific diagnosis and research,” Stewart says.
The dose is tightly defined. “There’s a very narrow range of doses where ketamine is effective for depression but not anesthetic,” Krystal says.
For treating other conditions – such as anxiety, pain, PTSD, or bipolar disorder – there are differences in doses, number of treatments, and length of time between treatments. But the general idea is the same.
Most research stops the initial treatment at 6 weeks. There’s no evidence to suggest that more than 6 weeks in a row brings more benefits. But some people come back for boosters if symptoms return.
At Stewart’s clinic, 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.
What Ketamine Treatment Felt Like
Christa Coulter-Scott, 55, started ketamine treatment in a clinic in Gainesville, Georgia, in 2021, where her care was supervised by an on-site nurse practitioner. Coulter-Scott had had depression and anxiety since childhood and was diagnosed with PTSD and chronic pain as an adult.
“Before ketamine, I felt anxiety, PTSD, and depression ruled my life,” she says. “I couldn’t enjoy anything.”
Like Winograd, she’d tried many antidepressants over the years. Ketamine therapy helped her depression and PTSD, but not her anxiety.
The treatment session felt “like a spiritual journey. I felt warm, safe, and confident,” she says. “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.”
For Winograd, ketamine treatment felt like 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.”
None of the doctors interviewed for this story were involved in Winograd’s or Coulter-Scott’s care.
Therapy Is Part of the Treatment
At Stewart’s clinic, after the mind-altering part of the ketamine experience is over, a health care 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 give IV ketamine tend to recommend patients continue taking their regular antidepressants, too. As for the esketamine 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,” Krystal says.
The antidepressant effects wear off in hours, days, or a couple of weeks in people who only get a single infusion. The series of infusions has longer-lasting effects.
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.”
How Ketamine Affects the Brain
The way you feel during the treatment isn’t the antidepressant effect. That happens later.
“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 antidepressant effects of ketamine happen in the days and weeks after the drug (at the appropriate dose) is in your system, Krystal says.
Major depression affects the brain in many ways. People with long-term or severe depression may lose some important connections in their brains (called synapses) that let nerve cells communicate.
“We think that the number of synapses goes down because severe stress triggers reactions in the brain that eliminate these synaptic connections,” Krystal says.
Those lost connections start to regrow within 24 hours of the first dose of medically supervised ketamine, according to research using PET brain scans. 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 in the brain involved in mood use a chemical 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 those glutamate receptors – the catcher’s mitts – get so worn out or weak that they can’t grasp the glutamate anymore.
But after people with this particular problem receive ketamine, those nerve cell connections get restocked with new glutamate receptors. Think of it as the ketamine helping to make new catcher’s mitts for the glutamate, so that the nerve cells can respond to it again.
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.
Is Ketamine an Opioid?
Ketamine mainly works through glutamate receptors. But research shows that it also needs opioid receptors to have its antidepressant effects. For psychiatrist Alan Schatzberg, 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. That link may help explain the “disastrous outcomes” in some people who have frequently misused ketamine, Schatzberg says.
Of course, any comparison to opioids raises the question of the risk of addiction.
Ketamine Addiction Risk
Both Krystal and Stewart agree that ketamine is addictive, but they say addiction isn’t likely when people receive ketamine under proper supervision by a doctor.
Addiction risk arises when someone has easy access to it without appropriate medical care, Krystal notes. “If you develop the ketamine abuse pattern, there are all kinds of medical consequences.”
Stewart says he’s sure it’s possible to abuse or misuse ketamine, or substances touted as ketamine, outside of a clinic, but “there’s no indication or no data supporting an addiction issue in a therapeutic setting.”
“I think it’s probably less addictive than opioids, but it’s not without its risks,” says Schatzberg, who is the director of Stanford University’s Mood Disorders Center.
Abuse and misuse of the medication are part of the “black box” warning on esketamine.
Ketamine Side Effects: Short-Term and Long-Term
Like all drugs, ketamine can have side effects, even when used under a doctor’s supervision in a clinical setting.
Short-term effects: Most are limited to the time that ketamine is in your system, at the appropriate dose for depression treatment, Krystal says. “You feel sedated. Maybe nauseous. Your blood pressure goes up a little. And you have the dissociative effects – things feel weird or unreal.”
Nausea, dizziness, and lightheadedness can happen occasionally as a patient comes off the ketamine in a supervised session, Stewart says.
Long-term side effects: Krystal says that when used under the recommended protocol for depression, there aren’t known long-term side effects. But if it’s abused, there are.
Ketamine bladder syndrome happens when people chronically use too much ketamine, Krystal and Stewart say. Krystal calls it a telltale sign of abuse. When someone develops ketamine bladder syndrome, they get lesions on their bladder, the lining of their bladder wears away, and they need to urinate frequently.
It’s rare, but 2% to 4% of heavy ketamine users may develop psychosis, Krystal says, noting that the psychosis looks like schizophrenia that won’t respond to antipsychotics. The symptoms can wear off in a few weeks or months, but in chronic, heavy users, it can last for months or years.
Other drugs that cause glutamate release – such as benzodiazepines – can dampen ketamine’s effects. So sometimes, people skip those meds on their ketamine treatment day. But people with bipolar disorder shouldn’t do that because ketamine, in rare cases, can trigger a manic episode. For people who’ve taken benzodiazepines for years, it can be very hard to come off and not completely necessary, so they should ask their doctor.
Ketamine Withdrawal and Tolerance
When someone is treated with ketamine for depression, the effects will eventually wear off. But that’s not the same as withdrawal. If you get ketamine following the clinical protocol for depression, you won’t have withdrawal, Krystal says.
He explains that treatment is designed to make the body more sensitive to ketamine. It does this through infrequent doses. The result: “Every time you give a dose, you get that pinging of the glutamate system in the brain,” Krystal says.
“The opposite happens when you use it frequently: You get tolerant to the effects of ketamine,” he says. “People who misuse ketamine and take it multiple times every day, they become tolerant to ketamine.”
It may not always be clear when the risks outweigh the possible benefits. The FDA has said that additional clinical studies are needed to investigate that. 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 because of the psychosis risk, Krystal says.
Costs and Insurance
Typically, the only ketamine-derived treatment for depression that insurance will cover is the FDA-approved nasal spray esketamine (Spravato).
Because the FDA hasn't 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 follows up with all of his patients throughout their series or if they stop ketamine therapy. “If they are unable to continue therapy, they are directed to other local resources,” he says.
Coulter-Scott continues to get routine booster ketamine infusions and also takes antidepressants and talks to a therapist.
Winograd kept up with ketamine treatment for three years. He got about 30 infusions during that time. But he’s since stopped.
“I am relatively healthy these days, mentally, so the need for ketamine is less, but I still believe I would benefit from it,” says Winograd, who has now gotten back to his life as a self-described jack of many trades. He has a film and video company, works as a freelance web designer, and runs a ballroom with his wife. The ketamine treatment had become too costly and harder to access. He still sees a therapist once a week and takes antidepressants. And he credits ketamine with making those treatments work better.
“Conventional antidepressants continue to do a good job for me, and I only took those because of ketamine. I never would’ve had the space, the mental clarity, to know that that would be a positive thing, because I pushed against it my whole life.”
Likewise, before ketamine treatment, 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.”
