Ketamine For Depression: Benefits, Treatment, and Risks

The world of psychedelics is changing. I hadn’t realized how much until I visited Nushama, a psychedelic wellness center in midtown Manhattan. Before arriving, I expected the clinic to be an aesthetic crossover between one of those new Millennial-focused dentist offices all my friends started going to, and Kim Kardashian’s home: clean lines, neutral colors, and white chairs. Well, I was right about the chairs. But the experience curated by Nushama is far from neutral.

The walls boast pink nude nymphs clumped together to create a mural of cherry blossom trees. Celestial music plays throughout the facility. And upon entry I was greeted by a ceiling draped with white and pink flowers and handed fruit-infused water by a receptionist with a warm smile. “We want people to walk into a dream world, a wonderland,” Jay Godfrey, former fashion designer and cofounder of Nushama, tells PS.

Walking down the corridor to meet with Nushama’s medical director, Steven Radowitz, MD, I took note of all the closed doors to my left. Next to each was a plaque printed with the name of a different pioneer in the psychedelic community. And behind those closed doors were patients being administered intravenous doses of ketamine.

Ketamine was first developed in the 1960s as a potential anesthetic. It worked, but it also had psychoactive effects, which appealed to people interested in its recreational uses. It became popular among “club kids” in the 1980s and ’90s, New York Magazine reports, and continues to be used recreationally, often referred to as “K” or “Special K.” It was labeled a Schedule III substance of the US Controlled Substances Act in 1999, which means it has a “moderate to low potential for physical and psychological dependence,” per the American Addiction Centers.

Scientists and medical professionals never gave up on its medicinal potential, though. And recently, ketamine has gained interest as a possible mental health treatment, specifically in cases of severe or treatment-resistant depression.

Experts Featured in This Article:

Robert Meisner, MD, is the founding medical director of the ketamine service in the division of psychiatric neurotherapeutics at Harvard’s McLean Hospital.

Amanda Itzkoff, MD, is a NY-based psychiatrist specializing in interventional psychiatry and psychedelic-assisted psychiatry and CEO of Curated Mental Health.

Steven Radowitz, MD, is Nushama’s medical director.

Jay Godfrey, MD, is cofounder of Nushama.

“Ketamine has an effect on many different neurotransmitter systems,” says Dr. Radowitz, including a specific transmitter known as glutamate, which can impact mood and one’s ability to form new neural connections. The drug can inhibit what’s called the default mode network in the brain, which “has an effect on creating patterns based on past experiences,” he says. Ketamine will put that default mode network on hold, which “allows the brain to create new pathways, new patterns, new ways of thinking, less dependent on past events,” Dr. Radowitz explains. Ideally, this may help nudge a patient toward a new perspective, alleviating symptoms of depression.

The benefits of ketamine sound promising. But technically, the FDA hasn’t yet authorized ketamine as a mental health treatment — only as an anesthetic, although a derivative of ketamine called esketamine, which comes in the form of a nasal spray, is approved by the FDA for treatment-resistant depression. Still, ketamine is increasingly being administered “off label” for severe depression as well as other psychiatric disorders and chronic pain, according to the American Psychiatric Nurses Association.

When PS spoke to Robert Meisner, MD, the founding medical director of the ketamine service in the division of psychiatric neurotherapeutics at Harvard’s McLean Hospital, he said that he felt “an ethical responsibility, despite the absence of an FDA approval, to develop a data-driven, safety-first, evidence-based program, given the extraordinary rising rates of depression and suicidality in the United States.” At McLean, both IV ketamine infusions and intranasal esketamine administration are available.

The Ins and Outs of Going Off-Label

To be clear, off-label usage of a drug is extremely common and is not illegal. However, Dr. Meisner notes, a lack of sufficient regulatory oversight in clinics that administer IV ketamine for depression appears to be increasingly problematic. It’s on those prescribing and administering ketamine to ensure that users have a safe experience. And often, it’s on patients to pay high out-of-pocket costs. (At Nushama, the six-week infusion series, including an optional bonus session, will run you $4,500; if you can prove a dual diagnosis of chronic pain and depression, insurance may cover at least some of the cost, says Godfrey). Dr. Meisner says that an unexpected aspect of his job has been speaking with insurance companies to get them to understand the psychiatric usage of ketamine. “Over the past 18 months, we have seen remarkable progress as companies have collaborated with us and others,” he tells PS. Now, most treatments that McLean offers are at least partially covered by insurance.

Off-label delivery methods include lozenges, intramuscular injections, and, most common at ketamine clinics, intravenous infusions, says Amanda Itzkoff, MD, a NY-based psychiatrist specializing in interventional psychiatry and psychedelic-assisted psychiatry and CEO of Curated Mental Health. Clinics tend to focus on infusions for a number of reasons. For one, IV drips allow for the use of ketamine that is nearly 100 percent bioavailable, which refers to how well the drug or substance is absorbed by the body and can reach its destination — in this case, the brain, Dr. Itzkoff says.

IVs also help medical professionals regulate the dose more easily. “It’s an IV infusion, so we can stop it at any time,” says Dr. Radowitz.

This helps ensure that patients are not overwhelmed by the effects. With an intramuscular injection or a lozenge, “once you take it, you take it; it’s in,” Dr. Radowitz says. “And that’s it.” The same applies to nasal sprays. “Once esketamine has been administered, the administration cannot be stopped,” says Dr. Meisner.

There’s another benefit to IV ketamine. Forms of the drug that can be taken at home (i.e. the lozenge or nasal spray) may increase the risk of addiction, Dr. Radowitz notes. “Taking small amounts on a daily basis could be a little bit more euphoric than the higher doses [like the kind given in ketamine infusions],” he says.

While ketamine doesn’t have as high a potential for abuse as something like Adderall, according to the DEA’s classification system, “when misused, these drugs can still lead to abuse or addiction,” the American Addiction Center reports. Dr. Meisner says he was “concerned” when he started the service “that we were introducing a medication that could lead to physiologic and psychologic addiction.” (Physiologic dependence or addiction occurs when the body becomes physically dependent on a substance, while psychologic addiction refers to “cravings a patient has for the altered state that one experiences when under the influence of some drug,” he explains.)

In his work, Dr. Meisner’s service has inherited patients who appear to be psychologically dependent and may be physiologically dependent after receiving non-evidenced based dosing at other facilities. At McLean, practitioners don’t give ketamine therapy to anyone with a history of addiction to the drug or to drugs like heroin and fentanyl. Ketamine “tickles opiate receptors” in the brain, Dr. Meisner notes, so the concern over its potential for abuse and addiction is understandable, and caution is crucial.

Who Is Eligible For IV Ketamine?

Depending on the clinic, a medical referral may or may not be required in order to start ketamine infusions. At Nushama, it’s not required, but many patients are still being referred there via therapist or another mental health professional, says Godfrey. At McLean, patients must be referred from their actively prescribing psychiatrist or psychiatric nurse practitioner.

Regardless of referral requirement, however, all clinics should perform a thorough medical and/or psych intake before agreeing to treat a patient as ketamine IV therapy is not for everyone. In addition to being inappropriate for people with a history of addiction or substance-use disorders, it can be harmful to people who deal with active mania; psychiatric disease like bipolar disorder and schizophrenia; or any type of psychosis or delusion, notes Dr. Itzkoff. People with uncontrolled high blood pressure or thyroid disease are also excluded as well as those who are pregnant.

Good candidates are patients who are exhibiting treatment-resistant depression and haven’t responded to standard oral medications, Dr. Itzkoff says. These traditional medications typically include selective serotonin inhibitors (SSRIs) that have either not worked for them, have caused negative side effects, or have only enacted a partial response.

During the evaluation, prospective patients will discuss their medical history, psychiatric history, and any challenges, traumas, or issues they’ve had in their mental health history to determine whether or not this treatment is for them, says Dr. Radowitz.

What to Expect During a Session

If you and your mental healthcare team decide ketamine therapy may be useful to you and a clinic green-lights you, you’ll start a series of infusions. How many you’ll get depends on your needs and, to some extent, the clinic. At McLean, a series typically starts with three to four infusions to get a sense of how you’ll respond. If your symptoms improve, you might receive another three to four, then finish with a taper series of two to four more infusions. At Nushama and Curated Mental Health, though, a series of six infusions is pretty standard. “We start with a weight-based dose, and then we adjust the dose to the patient’s response,” says Dr. Itzkoff. For IV ketamine, there’s a sweet-spot range, she says, which falls between 0.8 and 1.2 milligrams per kilogram of body weight. For someone weighing 125 pounds, that translates to a minimum of 45mg of ketamine.

Setting is an important aspect of the infusion process. “So, for instance, we dim the lights, we set up the room in such a way that they’re going to feel comfortable, they recline, they have a blanket, they may use an eye shade or close their eyes, and the nurses are there to help them with that,” says Dr. Itzkoff.

Image Source: Curated Mental Health

The infusion runs for 40 minutes at Dr. Itzkoff’s clinic, and she says patients start to feel the effects of the drug about 15 minutes in. People will experience the “feeling of being altered or being almost in a dreamlike state,” says Dr. Itzkoff. “The infusion stops at minute 40, and it takes about 15 minutes for the patient to, what we call, ‘resolve,’ meaning to actually come back to approximately their baseline mental status.” After a treatment, patients should be considered “slightly altered” for the rest of the day; they should be able to go back to some normal activities, but they’re not allowed to drive or operate heavy machinery, for instance, says Dr. Itzkoff.

Patients will typically be monitored for medical and psychiatric evaluation after the infusion is complete. At McLean, new patients are observed for about an hour and a half post-infusion and for slightly shorter periods as they receive more infusions. During this monitoring, their blood pressure, heart rate, mental status, behavior, and critical vital signs are monitored to ensure that the patient is stable, both psychiatrically and medically, says Dr. Meisner.

Dr. Meisner strongly recommends that anyone receiving ketamine treatment also be in therapy. “We consider it just short of mandatory that patients be in some form of general psychotherapy, simply because we know that when a patient is undergoing treatment with pharmacologic agents, as well as invested in psychotherapy, the outcomes are universally better. But that is a general principle,” he says. However, there are different schools of thought on whether or not psychotherapy should be administered alongside or just after one’s ketamine treatments, a practice known as ketamine-assisted psychotherapy.

At most evidence-based dosing for the treatment of depression with ketamine, Dr. Meisner says that psychotherapy is “incredibly hard to do” and “lacks sufficient value.” That makes it different from other emerging psychedelic treatments, including psilocybin or ayahuasca, where both the “psychotherapy and the biologic changes appear to be necessary” to provide value, he notes. For that reason, neither Nushama nor McLean follow up infusions with psychotherapy, although at Nushama, patients will meet with an integration coach that “helps them glean a key insight” from their experience post-infusion, says Godfrey. Dr. Itzkoff, on the other hand, has practiced ketamine-assisted therapy in which “patients typically receive ketamine via a route other than IV, or the dose is administered at a slower rate, or a lower dose is given. This is primarily to allow the patient to participate in psychotherapy,” per Dr. Itzkoff’s website.

Side Effects Worth Mentioning

Ketamine is a dissociative agent. “So patients can hallucinate. They can become quite confused. Perceptions of time can be dramatically different than the reality. They may feel as if they are watching themselves from afar,” adds Dr. Meisner. Other, more minor side effects include blurry or double vision, nausea or vomiting, and increased airway secretions. “All of those things are side effects that have a fair probability of happening, or at least one of those physiologic effects happening to most people,” says Dr. Meisner. “In general,” he adds, “if you do adequate screening during the consultation process, we have found that these treatments are quite well tolerated.”

Regular use of the drug can also cause liver damage, although it tends to improve once you stop ketamine. It’s also been associated with interstitial cystitis, a painful chronic bladder condition. “It’s not uncommon for us to ask patients who develop symptoms that localize to the urinary tract to see a urologist for further evaluation,” says Dr. Meisner.

Ketamine also tends to increase blood pressure, he says. If your blood pressure isn’t well controlled — due to poor monitoring at a clinic, for instance — you could be at risk for a heart attack or catastrophic complications due to a pre-existing aneurysm. In a few rare instances (which Dr. Meisner could not elaborate on, noting that these cases are under investigation), patients have allegedly died from ketamine treatment. But Dr. Meisner stresses that this tends to happen in poorly regulated environments. “When my phone rings, and it’s an attorney in any number of different states saying something very bad has happened, they’re curious about X, Y, and Z, the context in which that catastrophic event has taken place is often in a private sector, with very few providers, little oversight for monitoring non-evidenced-based dosing, and from over-promising of results for disease states that lack of evidence base,” he says. This is why it’s so important to choose a reputable clinic that takes patient safety seriously and to make sure to work closely with a mental healthcare professional you trust if you think ketamine may be a good option for you.

Life After an IV Ketamine

“People may think that ketamine is like magic and that perhaps it will work right away to completely cure their depression. While it does have excellent results, right now there isn’t a cure for depression,” emphasizes Dr. Itzkoff. Even after ketamine infusions, you should continue monitoring your symptoms and working with a therapist or mental health professional “because depression is generally a recurrent condition,” she says.

“We still consider depression at this moment to be a chronic disease that must be managed as such,” Dr. Meisner says. While people with severe or treatment-resistant depression may have symptom-free periods after ketamine therapy, the length of those intervals will vary, he explains. Some patients only need to come every five months for a booster series; others need to come every five weeks, he adds.

“Ketamine is not not meant to be a cure,” Dr. Radowitz says. In fact, he doesn’t view depression as something that needs to be cured in the first place. He sees it as a symptom or a messenger of a misalignment. And for too long, he says, the healthcare community has been “suppressing the messenger” via traditional depression treatment, like antidepressants. While he admits “there’s a place for them,” he also argues that they can suppress the symptom rather than address what’s causing it. He likens it to using pain medication for a broken leg. Yes, it will help numb or mask the pain (aka the messenger), but you still need a targeted tool (like a cast) to help address the broken or out-of-place ligament.

The hope with IV ketamine is “to awaken people to where this misalignment is; it’s about getting to the source to be able to see, objectively, where are we out of alignment and help people realign,” says Dr. Radowitz.

Dr. Meisner adds that he sees ketamine and esketemine as “two useful tools in the contemporary psychiatric kit” but says that we’re “just scratching the surface.” For years the same SSRIs or SNRIs have been reinvented or redesigned, Dr. Meisner explains. “We’ve released Prozac, changed the chemical structure a bit [and] called it something else, then done the same thing over and over again despite relatively minor differences in the degree to which patients are likely to respond.”

But with ketamine and other emerging psychedelics, he’s hopeful for change. “Ketamine’s mechanisms, as well as those of the pipeline that’s evolving, appear to genuinely introduce something new,” says Dr. Meisner. There’s “reason for cautious optimism.”

If you’re experiencing treatment-resistant depression and think ketamine could be beneficial, have a conversation with your psychiatrist or therapist to discuss your specific medical history, ketamine’s availability in your area, and whether or not it may be a good treatment option for you. If you are thinking of suicide or in emotional distress, please call the National Suicide Prevention Lifeline at 1-800-273-8255 or 988.

Alexis Jones is the senior health and fitness editor at PS. Her passions and areas of expertise include women’s health and fitness, mental health, racial and ethnic disparities in healthcare, and chronic conditions. Prior to joining PS, she was the senior editor at Health magazine. Her other bylines can be found at Women’s Health, Prevention, Marie Claire, and more.