Ketamine safety concerns abound as private clinics proliferate

Ketamine represents many patients’ last hope.

The psychoactive drug can be found at more than 570 private clinics across the U.S. as of 2021. It’s mostly marketed as a depression treatment, especially for patients who haven’t responded to other regimens.

“We don’t expect people to go into remission; we hope them to remain alive and not to kill themselves,” said Dr. Cristina Cusin, director of Massachusetts General Hospital’s ketamine clinic in Boston. “I would say 95% of our patients really dislike the experience—they’re terrified of the experience. But when it’s the only thing that keeps you alive, why not?”

Ketamine, first approved by the Food and Drug Administration in 1970 as an anesthetic in operating rooms or emergency departments, is administered at much lower doses in some academic medical center settings, and in investor-owned or independently owned stand-alone clinics.

The proliferation of these clinics, up from 80 in 2016, is concerning to many in the drug safety and mental health fields.

Ketamine is used off-label for depression, meaning there’s no regulatory oversight of doctors’ prescribing patterns, safety protocols or adverse events in patients. The drug is sometimes marketed for a host of other chronic diseases and behavioral diagnoses that have little scientific backing.

But there’s no consensus on who should administer IV ketamine. Mental health practitioners and anesthesiologists are the top providers. Even at sub-anesthetic levels, ketamine can produce intense effects, such as disembodiment, hallucinations and reduced verbal fluency.

Many private clinic providers say ketamine doesn’t need oversight because few to none of their patients have experienced bad outcomes. They say access should be as open as possible. Many patients in studies say the treatment provided euphoria, enlightenment or a new world view that increased insights and growth.

Providers enter the business

Mass General’s Cusin opened the academic medical center’s ketamine clinic in 2015 after years of treatment model development and meetings with insurers to secure coverage. Her program is different from others because of the rigorous data they collect and safety protocols they follow, she said.

Insurers ultimately covered Mass General’s IV ketamine treatments after multiple research presentations on the drug’s effects on severe depression and chronic suicidal ideation, conditions that have the most efficacy data.

Like the majority of providers, Cusin’s clinic offers a choice between light and dark rooms, music, blankets and other comforts for patients.

Since the clinic opened, demand has been high. Cusin isn’t able to say how many patients they serve in a month, because as soon as the clinic starts to turn a profit margin, she reinvests in hiring more providers and expanding space. And as more patients and referring clinicians see positive results, they spread the word. “It’s exponential (growth),” Cusin said.

At the private clinic Ketamine Health and Wellness Center in Texas, owner Dr. Jerron Hill knows treatment can cause a host of adverse events, like hypertension, panic attacks or dissociative episodes.

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Hill starts his mornings as a practicing anesthesiologist at multiple hospitals in the region and then heads to his clinic in the afternoons. He noted that psychiatrists or other mental health professionals must provide referrals, but he also recommends patients start a wellness program to add a holistic component, which includes stress management strategies, clinical nutrition, mindfulness practices and exercise.

“When my patients come here, I do a lot about trying to get to the core problem of what really causes them to have so much pressure and strain in their life that caused their anxiety, that causes them to have depression, and sometimes they know, but sometimes it’s just insidious and they don’t have a reason for it,” Hill said. “But we must control those other factors because that’s what’s going to give patients long-term sustainability.”

Who should administer ketamine?

Cusin and others say ketamine treatment needs a practitioner with mental health training involved. Anesthesiologists have experience administering the drug at much higher dosages in hospital surgeries.

“You can’t just simply say, ‘OK, this doesn’t work, see you,’ because this is a delicate situation,” Cusin said. “There are situations that are more on the psychiatric front (with ketamine) that are difficult, even for me. And I’ve been doing this for years.”

But Hill sees it differently, because of his work with the drug as an anesthesiologist.

“Ketamine should be in the hands of people who are experienced like anesthesiologists or ER physicians, who have the most experience with a very powerful medication because it does have a lot of side effects,” Hill said.

States could mandate that practitioners get training in best practices when ketamine doesn’t help a patient, or look at whether providers need to make therapy available. While there is some research showing that ketamine alone—without therapy—is effective, just like other prescription mental health drugs, it is recommended.

Dr. Juan Pablo Galindo, a psychiatrist who initially worked in a traditional healthcare system, eventually founded his own IV ketamine clinic because he wanted to provide a more meaningful treatment to patients coupled with therapy.

“If one does have a psychedelic experience, where certain aspects of their lives are shown to them in a way they’ve never seen before, and they’re able to integrate that in therapy to create meaningful change, then that would be great,” said Galindo, the owner of Charleston Innerbloom Healing in South Carolina, which opened in October 2021.

But is it safe?

Hill’s clinic, like many other private facilities, doesn’t advertise ketamine just for depression. He also provides the treatment to patients with fibromyalgia, chronic pain, postpartum depression and post-traumatic stress disorder.

For many clinicians at traditional healthcare systems, this is troubling.

Dr. Robert Ostroff, a psychiatrist, was instrumental in getting Yale New Haven Psychiatric Hospital’s outpatient and inpatient ketamine program off the ground in 2012. For the most part, patients who come to him are referred by primary-care physicians because other drugs for depression haven’t worked, he said.

“This drug is inappropriately marketed and inappropriately distributed, and I think it’s going to catch up with ketamine (clinics) at some level,” Ostroff said. “There’s an awful lot of hype. People go into clinics run by anesthesiologists, and they may or may not be depressed, they may just be unhappy, and they’re getting drugs they don’t need. I think it’s a problem.”

“If they were, one of the first things that you would see is regulatory boards,” Hill said, adding that he doesn’t think it’s necessary to track patient safety data.

While most academic centers like Mass General publish research on how patients react to ketamine, drop-out rates due to adverse experiences and other safety and efficacy data, the bulk of private ketamine clinics do not; they’re not required to do so. And many drug safety experts say the ketamine research isn’t conclusive enough to even be offered currently.

States could create mandates and take other actions similar to opioid prescription monitoring, since ketamine is a Drug Enforcement Administration Schedule III drug derived from phencyclidine, known as the street drug PCP. But they largely haven’t made any moves to do so.

The American College of Clinical Pharmacology in a January position paper called for states to do something, calling off-label use “serious” and noted that the lack of guidelines for clinic staff on titration, dosage or respiratory/cardiovascular emergencies.

“There are serious concerns regarding the off-label use of IV ketamine, compounded by the inherent safety risk of using an anesthetic agent,” the association wrote.

The association recommended that states mandate treatment and training standards, and that primary-care clinicians become involved to help monitor long-term side effects and create comprehensive treatment plans.

“A major concern about these clinics is that patients are not being adequately evaluated and monitored, both during and following ketamine (treatment), and that their care is not well integrated with the totality of psychiatric and medical care that they may be receiving, or that they may need,” said Dr. Caleb Alexander, a professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health and principal investigator at the Johns Hopkins Center of Excellence in Regulatory Science and Innovation.

Where oversight increased

The lack of ketamine clinic oversight stands in stark contrast to regulation of Janssen Pharmaceuticals’ Spravato. Janssen received a patent by isolating esketamine, a molecule found in ketamine. The FDA approved the branded drug in 2019 for treatment-resistant depression and later for major depressive disorder with acute suicidal ideation. Ketamine is a generic drug and has never been approved for an indication other than as an anesthetic.

Spravato is distributed by providers under one of the strictest Risk Evaluation and Mitigation Strategies systems from the FDA. The agency usually uses REMS for drugs that have higher risk profiles and don’t have much real-world data as it learns more about the treatment’s safety and use in clinical practice.

For every patient who receives Spravato, providers must submit forms to a registry, and must follow a long list of other requirements and standards.

In June 2020, not-for-profit Mental Health Center of Denver opened up Spravato treatment to a small number of patients. Medicare and Medicaid, which cover the majority of their patients, reimburse for the drug, which usually costs thousands of dollars for a month of treatment. Meanwhile, ketamine costs a fraction of that price.

The clinic administers the Spravato nose spray to patients and blocks a two-hour window to monitor them. Patients receive treatment twice a week for four weeks, and then one treatment over four weeks.

But providers spend more time on administrative work and receive lower reimbursement for monitoring patients.

“Just looking at all the guidelines that the FDA has put forth for the Spravato, it’s a little concerning that there are many clinics that are just out there giving IV ketamine infusions, and I don’t know how much of a background or what kind of medical history they’re taking on folks,” said Denise Hosier, a nurse practitioner and director of adult integrated care and nursing services at Mental Health Center of Denver.

The FDA could take some action on ketamine, though not to the extent they can with a new drug. It has the ability to issue drug safety alerts, or apply a black box warning, but to date has not done so.

All the work Hosier and the center have put into their clinic has paid off, she said. Most of the patients go from thinking about suicide every day to not often. Hosier remembers a patient who recounted watching a “Friends” episode.

“She recalled that she found it enjoyable, she laughed out loud and she could not recall the last time that she’d laugh at something,” Hosier said. “I thought about how sad that was, the things that I would take for granted, this woman hadn’t been able to do for years. That’s why I think it is one of the things that I get super excited to talk about.”

Drug safety experts argue that for all the good stories of patients getting better with Spravato, there’s still a crucial system in place that will produce hard data beyond anecdotes to weigh whether its benefits trump the risks.

And if the FDA determined that Spravato needed that kind of rigorous monitoring system, so does ketamine, according to Thomas Moore, a faculty associate at Johns Hopkins’ Center for Drug Safety and Effectiveness.

“It’s one thing to say that physicians need flexibility to use their judgment to prescribe drugs that may be somewhat outside the FDA-approved indications to help patients,” Moore said. “And then entirely another thing to set up businesses to openly advertise and recruit patients to take treatments that clearly do not have the safety precautions that the FDA has required for a virtually identical product.”