Melissa’s life is changing. Every little thing used to be too big to handle. Taking a shower required too much energy and having to make a decision about food meant she wouldn’t eat. She never got excited about anything and made poor decisions, including moving away from her family in Virginia. She slept a lot because “acting normal” was exhausting.

When she’s depressed, Melissa says, it feels like there’s molasses in her brain, which is frustrating for someone who loves to think and read and write a lot.

After being diagnosed with Major Depressive Disorder (MDD) 20 years ago, the 47-year old transplant specialist nurse has taken a dozen antidepressants. Anything that worked didn’t last, so in September, she decided to try something new: an anesthetic-cum-party drug called ketamine, which has been around for 50 years but was only recently tested as a treatment for depression. “Ketamine is really the first time that I stepped out and tried something radically different,” she said. She had read about the treatment, which has not been approved by the Federal Drug Administration (FDA), in medical journals and found a local clinic on the internet that was willing to treat her.

She’s had five ketamine infusions so far now, and though her life didn’t change overnight, Melissa did immediately experience something she hadn’t felt in a long time: hope. Her depression made her feel like her brain was stuck, calcified in a bad place. She’s not sure if it was the chemical action of ketamine itself or the out-of-body experience that she had when she took it, but the treatment seemed to break the calcification apart and blow up all of her pre-existing concepts about herself. “I have a willingness to look at things in a different way that I didn’t have before,” she said.

Hundreds of people who have been depressed for years say they are no longer depressed after one or more infusions of ketamine.

The National Institute of Mental Health estimated in 2016 that 16.2 million (6.7%) American adults suffered a major depressive episode in the last year. Approximately 29 million Americans take antidepressants. But FDA-approved medications for depression work in only a third of the people who try them and take weeks to have an effect.

Enter ketamine. Unlike other antidepressants, ketamine’s ability to lift depression is immediate, making it especially useful for suicidal patients. Hundreds of people who have been depressed for years say they are no longer depressed after one or more infusions of ketamine, and their stories have been widely reported in the media. Since ketamine is FDA-approved for use as an anesthetic, any doctor can legally prescribe the hallucinogenic drug to treat depression or anything else.

But news of the drug’s potential is not all good. Insurance doesn’t cover ketamine treatment, which is expensive. The FDA has not approved it for depression, and since it is a generic drug, pharmaceutical companies have no reason to fund clinical trials to test it. Health risks of ketamine use include high blood pressure, bladder disease, addiction, and brain damage. And a network of pop-up ketamine clinics may be putting a vulnerable population at risk with the lure of a quick fix hanging on a hefty price tag.

Psychiatrists warn that there is not enough data on the drug to support its use in millions of patients.

Since its use as an antidepressant has not been rigorously tested, doctors don’t know the extent of ketamine’s effectiveness or the long-term safety of the drug. “When we’re not cautious, when we rush hell-bent into new treatments, we sometimes get into trouble,” said Dr. Charles Nemeroff, Chairman of the Department of Psychiatry at University of Miami School of Medicine. “You know, heroin was developed because morphine was addictive, and thalidomide seemed like a good idea at the time, right?”

Nevertheless, some clinicians are excited about ketamine’s promise and many depressed patients are eager to try a new—albeit an expensive—treatment. But some psychiatrists warn that there is not enough data on the drug to support its use in millions of patients.

Medicine for Melancholy

Humankind has always suffered from melancholia. In the past, we thought of it as a spiritual malady, but we now think of it as a physical one.

The calming effect of lobotomies validated the brain as the physical seat of depression in the early 1900s and thirty years later volts of electricity zapped depression with some success. In 1957, doctors started altering the brains of depressed patients by prescribing medications. Prozac, the first selective serotonin reuptake inhibitor (SSRI) took the country by storm in 1987 and variations of the drug followed. SSRIs are still wildly popular. But how well do they work?

SSRIs relieve depression in 25 to 35 percent of patients who take them, but the drugs take four to eight weeks to work—too long for those who are dangerously depressed or suicidal. Many patients can’t take SSRIs because of side effects such as problems with sleep and sexual function; others can’t stop taking them because of withdrawal symptoms such as anxiety and a sensation of “brain zaps.”

Ketamine was not developed as an antidepressant but rather as an anesthetic. Pharmacists first synthesized the drug in 1962 and field surgeons used it to anesthetize wounded soldiers in Vietnam. Thirty years later, researchers studying depression became interested in the drug because of how it works in the brain.

“Special K” got a bad reputation as a street drug, one that’s been hard to shake.

In 2000, scientists at Yale reported that ketamine lifted depression in seven patients. Around the same time, ketamine became a popular recreational drug because of its “dissociative” effects–users report a euphoric sensation of floating and disconnection from reality. Like other psychedelic drugs, “Special K” got a bad reputation as a street drug, one that’s been hard to shake.

Scientists don’t know how ketamine helps patients with depression, but experts agree that it doesn’t work like traditional antidepressants. SSRIs work by elevating levels of neurotransmitters—brain chemicals like serotonin—that affect people’s’ moods. But ketamine may make it easier for depressed brains to change, to get “unstuck” from patterns of negative thoughts and feelings.

“The biggest breakthrough aspect of ketamine is perhaps not ketamine itself, but the door that it opens to other neurobiological mechanisms that seem to be involved in depression,” said Dr. Michael Grunebaum, an Associate Professor of Psychiatry at Columbia University Medical Center and research psychiatrist at the New York State Psychiatric Institute. This could lead to the development of new treatments to help more people, he said.

Pharmaceutical companies are racing to develop ketamine-like drugs and get FDA approval to treat depression. They stand to make billions. In the meantime, some depressed patients desperate to try something new are turning to ketamine clinics.

The Ketamine Clinic Experience

A medical suite in a glassy high-rise office building in downtown San Francisco has three patient rooms. Each is equipped with medical chairs and infusion equipment along with colorful woven rugs. Inspirational sayings like the serenity prayer are posted on the walls. Two months ago, Melissa sat in one of these chairs and envisioned the broken parts of her brain healing back together during her first ketamine experience, as a pump delivered the drug through an IV over a 40-minute period.

Dr. Alison McInnes is the Medical Director of this San Francisco branch of Actify Neurotherapies, which operates ten ketamine clinics across the country. The blue streaks in her blond hair make her eyes pop as she smiles.

Unlike most ketamine clinics, McInnes requires her patients to have outside talk therapy during treatment. But she also gives them a reading list of self-help books, teaches them some “basic tools” like breathwork and mindfulness, and encourages them to take advantage of the numerous positive psychology resources in the Bay Area. This is much more than most ketamine clinics do. Usually, they just administer the drug and send the patient on her way.

“We estimate that around 10,000 people got ketamine treatment for depression in the last couple of years,” said Dr. Gerard Sanacora, a Yale psychiatrist.

Melissa is grateful that her job pays enough for her to get the treatment she wants. Each infusion costs $575 and the Skype sessions with the therapist McInnes recommended cost $180 an hour. She says she doesn’t care what it costs, that she’d pay anything to be rid of The Darkness, as she calls her depression. While Melissa believes the ketamine experiences have helped her make a breakthrough, she says the strength she has gained comes from all of the hard work she’s done with her therapist. “Ketamine didn’t do that for me,” she said. She sometimes wonders if it’s the ketamine or the Zoloft that she’s taking that’s responsible for her improvement, but she doesn’t dwell on it.

A 2017 survey identified 85 physicians who were providing ketamine infusion treatments. Most worked in private practice–not affiliated with a hospital or research institution that would provide oversight–and had only started offering ketamine infusions very recently. “We estimate that around 10,000 people got ketamine treatment for depression in the last couple of years,” said Dr. Gerard Sanacora, a Yale psychiatrist who was one of the authors of the study.

McInnes developed a ketamine treatment program at large HMO four years ago but left to work at the clinic where she could focus exclusively on ketamine treatment. “It’s so gratifying, so magical. I see people making radical transformations and it’s fast, and it works most of the time.”

McInnes says that ketamine treatments only work for patients who “do the work” in therapy by trying to regulate their thinking and moods. But research does show that ketamine alone can have profound, immediate antidepressant effects, although these effects initially only last for about a week Studies show that infusions can become less frequent over time and still be effective, but there are some patients that continue to need the infusions regularly. One of McInnes’ patients got ketamine infusions regularly for a year but six months later became suicidal and had to start the treatment again.

Ketamine can cause severe anxiety or an out-of-body experience that some patients find unpleasant.

McInnes tailors treatment plans to each individual’s needs, but generally follows the 3-2-1 dosing plan: three infusions the first week, two the second, one the third. That’s the schedule recommended by the American Psychiatric Association.

She is offering group therapy so that her patients can encourage one another to continue with the ketamine treatments even after they’ve had an unpleasant session, like a bad trip. Ketamine can cause severe anxiety or an out-of-body experience that some patients find unpleasant. Patients can also encourage one another when they feel like the ketamine is no longer working, which is common, she said. “It’s important for them to hear it from each other to continue, that it’s still working, to not just hear it from me,” said McInnes.

All of the clinics in Actify Neurotherapies keep records on patient safety and outcomes. 74 percent of the company’s 2,000 patients have responded positively to the treatment and 62 percent experience full remission of depression, McInnes says. But it’s impossible to verify these claims, because they have not been reviewed by independent psychiatrists or published.

Nemeroff is advising the Actify group on how to best collect data because although he questions the practices of other ketamine clinics, he thinks that this sort of transparency will go a long way in ensuring that all ketamine clinics follow safe and effective protocols.

“It’s worrisome.”

Skeptical physicians are concerned that clinic doctors may be driven to administer ketamine by profit instead of the interests of their patients.

Some psychiatrists are worried that what happens in these clinics is not properly documented or independently reviewed, especially since there is so little data about ketamine’s effectiveness and safety to guide them. Studies show that ketamine can be addictive and cause brain damage and bladder disease but although thousands are being treated, no one is recording what happens to them. According to guidelines set forth by the American Psychiatric Association, physicians should screen patients to assess all mental health issues and follow the patients after treatment to monitor changes—positive or negative. During ketamine infusions, doctors need to keep an eye on patients’ blood pressure and mental state.

Skeptical physicians are concerned that clinic doctors may be driven to administer ketamine by profit instead of the interests of their patients.

“It’s premature to be providing it as a widespread treatment when the long term safety and effectiveness has not been well studied,” Grunebaum said. He is involved with clinical trials using ketamine, but does not use the treatment in his own practice. There’s still too much to figure out about ketamine, he says, especially since depression is a long-term condition that comes and goes.

A recent meta-analysis of published results included less than 300 patients, much fewer than what the FDA would require evaluating the effectiveness of any drug, according to Nemeroff. “The plural of anecdote is not data,” he said. According to Nemeroff, much more data is needed to determine how well ketamine works, for whom, and under what conditions.

“Some of the clinics are offering—get this—the first treatment for free. That’s like handing out samples of cigarettes,” Nemeroff said.

“There is remarkable financial gain that could be generated by these clinics,” said Nemeroff. For instance, a vial of ketamine costs about $40 and clinics charge between $500 to $1,000 an infusion.” One outpatient surgeon in Freedom, California charges $2,000 per infusion. According to numerous ketamine clinic websites, the fees reflect the overhead costs associated with medical equipment and staff, not the price of the drug itself.

As members of the APA Council of Research Task Force on Novel Biomarkers and Treatments, Sanacora and Nemeroff helped draft guidelines on ketamine in the treatment of mood disorders. The task force acknowledged the increasing interest in using ketamine to treat depression, but urged caution going forward. While they made dosing recommendations for ketamine, they also pointed out that all FDA-approved antidepressants should be kept in consideration as treatment options.

“We don’t have enough evidence to say what is right or what is wrong. But the train has left the station and people are using it, so all we can do is provide some information,” Sanacora said.

Most, but not all, of the ketamine providers surveyed in 2017 reported using the recommended dose of 0.5 mg/kg delivered in an IV over 40 minutes, no more than 2-3 times a week. However, Nemeroff has patients who have had different experiences. At a ketamine clinic in Florida, when his patient did not respond to the recommended dose, she was told doses would escalate far beyond the recommended safe dose. But there is no safety data for this plan, and no proof that it would work, Nemeroff said.

Another patient came from a ketamine clinic in Los Angeles where he had five consecutive infusions in a week and was given a vial of ketamine to take with him, to use intranasally as needed, for $10,000, Nemeroff said. It’s dangerous to provide such a large amount for a patient to use as he wishes, because he might become addicted to ketamine.

“Some of the clinics are offering—get this—the first treatment for free. That’s like handing out samples of cigarettes,” Nemeroff said. “It’s worrisome.”

No regulation. No oversight.

The purpose of ketamine clinics is not to treat depression and other mental health conditions—that would require mental health practitioners utilizing all treatment strategies and medication options.  The purpose of ketamine clinics is to provide one specific drug to people suffering from mental health conditions—a drug not approved by the FDA to treat them—by anyone who can legally write a prescription. And no one is watching.

“This is still very much an experimental treatment, and the problem is we don’t know what we don’t know,” Sancora said.

Ketamine use for depression has not been evaluated by the FDA, and never will be, according to Sanacora. “Ketamine is a generic drug. No one is going to fund the large clinical trials necessary to get FDA approval to treat depression,” he said. But since ketamine was approved by the FDA as an anesthetic, doctors can prescribe it “off-label” for any use, even without proof that it will work of is safe.

A recent report from the US Drug Enforcement Agency indicates that no physicians have been charged with drugs being funneled into the illicit market from ketamine clinics, but it is unclear whether the clinics are on their radar. State medical boards regulate doctors, but they haven’t issued any guidelines on ketamine clinics.

Without undergoing rigorous testing in large clinical trials, it is difficult to determine under which conditions ketamine works best, and for whom. Sanacora has been working with the NIH, FDA and APA regarding ways to collect data about the current use of ketamine by private physicians and ketamine clinics. They all agree that having a ketamine registry—in which doctors or patients could record details about ketamine treatments and their outcomes–would be extremely useful. But no one is willing to fund an organized data collection, even though it is the only way to find out what is unknown.

“This is still very much an experimental treatment, and the problem is we don’t know what we don’t know,” Sancora said.

The Future of Depression

The data collection problem may become moot in a couple of years, he said, as the new drugs that have been developed in the wake of the excitement over ketamine may turn out to work even better with fewer side effects.

New drugs that have been developed in the wake of the excitement over ketamine may turn out to work even better with fewer side effects.

Jansson Pharmaceuticals developed a nasal spray formulation of ketamine called esketamine, which shows promise in treatment-resistant depression in a paper published in JAMA Psychiatry in February 2018. In September 2018, Jansson filed an application to get FDA approval for the drug. Alkermes is testing ALKS 5461, and Allergan’s repastinel is in the running as well. The pharmaceutical data analysis firm Informa has estimated that the current market value for depression medications is $4.6 billion/year in the US and is expected to grow to $7.3 billion by 2024. This figure will be driven, they propose, by the sales of these three new ketamine-like drugs alone.

Like other psychiatrists treating patients with depression, Nemeroff would love to have a new tool or two in his arsenal, but only after the drugs have gone through rigorous testing. “Show me the data,” he said.

But that lies in the future, and right now, Melissa is glad to have her life back. Her face lights up when she talks about work and the unknowns of her future don’t threaten to cripple her now. “I always thought that I was at the mercy of the chemicals in my head,” she said. For the moment, at least, she feels free.

© 2017 Kimber Price / UC Santa Cruz Science Communication Program