Ketamine for Depression: Benefits, Treatment, and Risks

Updated 2 years ago on November 23, 2022

The world of psychedelics is changing. I didn't realize how much until I visited Nushama, a psychedelic wellness center in midtown Manhattan. Before visiting, I expected the clinic to be something between one of those new millennial-oriented dental offices that all my friends had started going to, and Kim Kardashian's house: clean lines, neutral colors and white chairs. Well, I was right about the chairs. But the experience created by Nushama is far from neutral.

Pink nude nymphs are painted on the walls, brought together to create a mural of cherry blossom trees. Heavenly music plays all over the place. Upon entering, I was greeted by a ceiling draped with white and pink flowers, and the receptionist handed me water infused with fruit with a warm smile. "We want people to enter a dream world, a wonderland," says Jay Godfrey, former fashion designer and co-founder of Nushama.

As I walked down the hallway to meet Nushama's medical director, Steven Radowitz, M.D., I noticed all the closed doors to my left. Next to each of them was a sign with the name of a pioneer in the psychedelic community. And behind those closed doors were patients being given intravenous doses of ketamine.

Ketamine was first developed in the 1960s as a potential anesthetic. It worked but also had psychoactive effects, which attracted people interested in its recreational use. It became popular among "club kids" in the 1980s and '90s, New York Magazine reported, and continues to be used for recreational purposes, often referred to as "K" or "Special K." In 1999, it was listed in Schedule III of the U.S. Controlled Substances Act, which means it has "moderate to low potential for physical and psychological dependence," according to the American Addiction Centers.

However, scientists and physicians have never given up on its medicinal potential. And recently, ketamine has become of interest as a possible treatment for mental illness, especially in cases of severe or treatment-resistant depression.

Ketamine affects many different neurotransmitter systems, Dr. Radowitz says, including a specific transmitter known as glutamate, which can affect mood and a person's ability to form new neural connections. The drug can inhibit the so-called default mode network in the brain, which "affects the creation of patterns based on past experiences," he says. Ketamine suspends the default mode network, which "allows the brain to create new pathways, new patterns, new ways of thinking that are less dependent on past events," Dr. Radowitz explains. Ideally, it can help nudge the patient toward a new perspective, alleviating symptoms of depression.

The benefits of ketamine sound promising. But technically, the FDA has not yet approved the use of ketamine to treat mental illness--only as an anesthetic, although a ketamine derivative called esketamine, which comes in the form of a nasal spray, is approved by the FDA for the treatment of resistant depression. However, according to the American Psychiatric Nurses Association, ketamine is increasingly being prescribed "off-label" to treat severe depression, as well as other psychiatric disorders and chronic pain.

When we spoke with Robert Meisner, M.D., founder of the Ketamine Medical Service in the Department of Psychiatric Neurotherapy at Harvard McLean Hospital, he said he felt "an ethical responsibility, despite the lack of FDA approval, to develop a program based on data, safety and evidence, given the extraordinary increase in depression and suicidality in the United States." Both intravenous ketamine infusions and intranasal administration of esketamine are available at the McLean Clinic.

The subtleties and nuances of working with off-label medications

To be clear, off-label use of the drug is extremely common and not illegal. However, Dr. Meisner notes, the lack of sufficient regulatory oversight in clinics that administer intravenous ketamine to treat depression is becoming increasingly problematic. It is up to those who prescribe and administer ketamine to ensure that the drug is administered safely. And often patients have to pay a large out-of-pocket cost. (At Nushama, a six-week series of infusions, including an extra session, will cost you $4,500; if you can confirm a dual diagnosis of chronic pain and depression, insurance can cover at least part of the cost, Godfrey says.) Dr. Meisner says an unexpected aspect of his work has been communicating with insurance companies to make them understand the psychiatric use of ketamine. "We've seen a lot of progress over the last 18 months as companies have cooperated with us and others," he says. Now most of the procedures McLean offers are at least partially covered by insurance.

Non-standard delivery methods include lozenges, intramuscular injections and, most common in ketamine clinics, intravenous infusions, says Amanda Itzkoff, M.D., a New York psychiatrist specializing in interventional psychiatry and psychiatry with psychedelics and CEO of Curated Mental Health. Clinics tend to focus on infusions for a number of reasons. First, IVs allow ketamine to be used with nearly 100 percent bioavailability, which means how well the drug or substance is absorbed by the body and reaches its target-in this case the brain," Dr. Itzkoff says.

IVs also help health care providers adjust the dose more easily. "It's an intravenous infusion, so we can stop it at any time," Dr. Radowitz says.

"We can really modify and adapt or customize the experience based on each person's needs."

This helps ensure that patients are not overwhelmed by the effects. With an intramuscular injection or a lozenge, "once taken, that's it," Dr. Radowitz says. "And that's it." The same is true of nasal sprays. "Once esketamine is administered, you can't stop taking it," Dr. Meissner says.

Intravenous administration of ketamine has another advantage. Forms of the drug that can be taken at home (such as lozenges or nasal sprays) can increase the risk of addiction, Dr. Radowitz notes. "Taking small doses daily can be a little more euphoric than higher doses [such as with ketamine infusion]," he says.

Although ketamine does not have as high an abuse potential as, for example, Adderall, according to the DEA classification system, "if misused, these drugs can still lead to abuse or dependence," according to the American Addiction Center. Dr. Meisner says that when he created the service, he was "concerned" "that we were administering a drug that could lead to physiological and psychological dependence." (Physiological dependence or addiction occurs when the body becomes physically dependent on a substance, and psychological dependence refers to "the patient's craving for an altered state that he experiences under the influence of a drug," he explains.)

Dr. Meisner's service has inherited patients who appear to have been psychologically dependent and may be physiologically dependent after receiving non-evidence-based dosing in other facilities. At McLean, physicians do not prescribe ketamine therapy to those who have a history of addiction to the drug or to drugs such as heroin and fentanyl. Ketamine "tickles the opiate receptors" in the brain, Dr. Meissner notes, so concerns about its potential for abuse and addiction are understandable, and caution is essential.

Who can take intravenous ketamine?

Depending on the clinic, it may or may not require a referral from a physician to begin ketamine infusions. The Nushama clinic doesn't require one, but many patients are referred there anyway through a general practitioner or other mental health professional, Godfrey says. At McLean, patients must get a referral from an actively prescribing psychiatrist or psychiatric nurse.

However, regardless of the referral requirement, all clinics must conduct a thorough medical and/or psychiatric evaluation before agreeing to treat a patient, as Ketamine IV therapy is not suitable for everyone. In addition to being inappropriate for people with a history of addiction or substance use disorders, it can be harmful for people with active mania, mental illnesses such as bipolar disorder and schizophrenia, or any type of psychosis or delirium, Dr. Itzkoff notes. People with uncontrolled high blood pressure or thyroid disease are also excluded, as are pregnant women.

According to Dr. Itzkoff, good candidates are patients with treatment-resistant depression who do not respond to standard oral medications. These traditional medications usually include selective serotonin inhibitors (SSRIs), which have either not helped them, have caused negative side effects, or have had only a partial response.

During the evaluation, prospective patients discuss their medical history, psychiatric history, and any problems, traumas, or issues they've had in their mental health history to determine if this treatment is right for them, Dr. Radowitz says.

What to expect during the session?

If you and your psychiatric team decide that ketamine therapy might be helpful to you and the clinic gives you the "green light," you will start a series of infusions. The number depends on your needs and, to some extent, on the clinic. At McLean, the series usually starts with three or four infusions to see how you will respond. If your symptoms improve, you may be given three to four more infusions and then complete the series with two to four more infusions. At Nushama and Curated Mental Health clinics, a series of six infusions is pretty standard. "We start with a dose based on weight and then adjust the dose based on the patient's response," Dr. Itzkoff says. There is an optimal range for intravenous ketamine administration, she says, which is 0.8 to 1.2 milligrams per kilogram of body weight. For a 125-pound person, that means a minimum of 45 mg of ketamine.

The environment is an important aspect of the infusion process. "For example, we dim the lights, set up the room so the patient is comfortable, they lean back, they have a blanket, they can use shade for their eyes or cover their eyes, and the nurses help them with that," Dr. Itzkoff says.

At Dr. Itzkoff's clinic, the infusion lasts 40 minutes, and, she says, patients begin to feel the effects of the drug after about 15 minutes. People experience "a feeling of altered or almost dreaming," Dr. Itzkoff says. "The infusion stops at the 40th minute, and it takes about 15 minutes for the patient to, as we say, 'come to their senses,' that is, return to about their original mental state." After the procedure, patients should consider themselves "slightly altered" for the rest of the day; they should be able to return to some normal activities, but they're not allowed, such as driving or operating heavy machinery, Dr. Itzkoff says.

After completion of the infusion, patients are usually under medical and psychiatric observation. At the McLean Clinic, new patients are monitored for an hour and a half after the infusion and slightly less as the number of infusions increases. During this observation, blood pressure, heart rate, mental status, behavior and basic vital signs are monitored to make sure the patient is stable both psychiatrically and medically, Dr. Meisner says.

Dr. Meissner strongly recommends that anyone receiving ketamine treatment also receive therapy. "We don't consider it mandatory that patients receive some form of general psychotherapy, simply because we know: when a patient is treated with pharmacological agents and also participates in psychotherapy, the results are universally better. But that's a general principle," he says. However, there are different schools of thought as to whether psychotherapy should be given concurrently or immediately after ketamine treatment, which is known as ketamine-assisted psychotherapy.

At the most reasonable dosage for treating depression with ketamine, Dr. Meissner says the psychotherapy is "incredibly difficult" and "lacks value." This distinguishes it from other new psychedelic treatments, including psilocybin or ayahuasca, where both "psychotherapy and biological changes" are needed to provide value, he notes. For this reason, neither Nusham nor McLean provides psychotherapy after the infusions, although at Nusham patients meet with an integration coach who "helps them extract key insight" from their experience after the infusion, Godfrey says. Dr. Itzkoff, in contrast, practices ketamine-assisted therapy, in which "patients usually receive ketamine in a different way than intravenously, or the dose is administered more slowly or a smaller dose is given. This is done mainly so that the patient can participate in psychotherapy," according to Dr. Itzkoff's website.

Side effects worth mentioning

Ketamine is a dissociative agent. "So patients can have hallucinations. They can become completely confused. Their perception of time may be drastically different from reality. They may feel like they are watching themselves from afar," Dr. Meissner adds. Other, more minor side effects include blurry or double vision, nausea or vomiting, and increased respiratory secretion. "These are all side effects that are reasonably likely to occur or at least one of these physiological effects will occur in most people," Dr. Meissner says. "In general," he adds, "if you do adequate screening during counseling, we have found that these treatments are fairly well tolerated.

Regular use of the drug can also cause liver damage, although the liver usually improves after ketamine is discontinued. It has also been associated with interstitial cystitis, a painful chronic disease of the bladder. "It is not uncommon for us to ask patients with symptoms localized to the urinary tract to see a urologist for further evaluation," Dr. Meissner says.

Ketamine also tends to raise your blood pressure, he says. If your blood pressure is poorly controlled--for example, due to poor control in the clinic--you could be at risk for a heart attack or catastrophic complications from an existing aneurysm. In a few rare cases (which Dr. Meissner could not elaborate on, noting that these cases are under investigation), patients have allegedly died from ketamine treatment. But Dr. Meissner stresses that this tends to happen in poorly regulated environments. "When I get a phone call and an attorney from different states says something very bad has happened, they're curious about X, Y and Z, the context in which this catastrophic event occurred is often in the private sector, with very few providers, little oversight of evidence-based dose control, and from over-promising results for diseases with no evidence base," he says. That's why it's so important to choose a reputable clinic that takes patient safety seriously, and be sure to work closely with a mental health professional you trust if you think ketamine might be a good option for you."

Life after intravenous injection of ketamine

"People may think that ketamine is like magic and that maybe it will work immediately and completely cure their depression. Although it gives excellent results, there is no cure for depression at this time," Dr. Itzkoff emphasizes. Even after administration of ketamine, one should continue to monitor symptoms and work with a therapist or mental health professional, "because depression tends to be a relapsing condition," she says.

"Currently, we still consider depression to be a chronic illness that needs to be treated as such," Dr. Meissner says. Although people with severe or treatment-resistant depression may experience periods of symptom-free treatment after ketamine therapy, the length of these intervals can vary, he explains. For some patients, a repeat series of treatments every five months may be sufficient; for others, every five weeks, he adds.

"Ketamine is not meant to be a treatment," Dr. Radowitz says. In fact, he doesn't see depression as something that needs to be treated in the first place. He sees it as a symptom or a precursor to the wrong course of events. And for too long, he says, the medical community has "suppressed the messenger" with traditional treatments for depression, such as antidepressants. While he admits that "there is a place for them," he also argues that they can suppress the symptom rather than address the cause. He compares this to the use of pain medication for a broken leg. Yes, it will help dull or mask the pain (aka "the messenger"), but you still need a targeted tool (like a cast) to help repair the fracture or ligament dislocation.

The hope with intravenous ketamine is to "awaken people to an awareness of where that misalignment is; it's about getting to the source to objectively see where we're out of tune and help people realign," Dr. Radowitz says.

Dr. Meissner adds that he considers ketamine and escetemine "two useful tools in the modern psychiatric kit," but says we are "only scratching the surface." For years, the same SSRIs or SNRIs have been invented or redesigned, Dr. Meissner explains. "We released Prozac, changed the chemical structure a little bit [and] named it differently, and then did the same thing over and over again, despite relatively small differences in the likelihood of patient response."

But for ketamine and other new psychedelics, he hopes for a change. "The mechanisms of ketamine, like those of developing psychedelics, do seem to bring something new to the table," Dr. Meissner says. There is "reason for cautious optimism."

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