Ketamine has exploded in popularity—not as the “dissociative anesthetic” it was once labeled as, nor as a psychedelic club drug—but as a therapeutic treatment.

Rueda Carrillo L, Garcia KA, Yalcin N, Shah M. Ketamine and its emergence in the field of neurology. Cureus. 2022;14(7):e27389.

 

 

Ketamine is used to treat certain neurological conditions, including migraine, seizure, stroke, and traumatic brain injury. Some experts also believe ketamine to be a breakthrough treatment option for patients with treatment-resistant depression, anxiety, post-traumatic stress disorder, and other psychiatric issues.

Yavi M, Lee H, Henter ID, Park LT, Zarate CA. Ketamine treatment for depression: a review. Discov Ment Health. 2022;2(1):9.

 

But the landscape around ketamine is also controversial and complex. While esketamine, or Spravato (which is molecularly different from ketamine)—a nasal spray designed for treatment-resistant depression—is the only federally approved ketamine treatment option (and must be administered under clinical supervision), ketamine itself isn’t FDA-approved for treating any psychiatric disorders. To further complicate things, off-label use of ketamine is not illegal.

Research C for DE and. FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray. FDA. Published online February 16, 2022.

Jacobs A. F. D. A. Issues warning over misuse of ketamine. The New York Times. Published October 11, 2023.

 

 

In response, the United States Food & Drug Administration (FDA) issued a statement on October 10 warning patients and healthcare providers about the “potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders.” 

The FDA says that these compounded drugs are not FDA-approved, which means their safety, effectiveness, and quality hasn’t been assessed prior to being marketed.

Jacobs A. F. D. A. Issues warning over misuse of ketamine. The New York Times. Published October 11, 2023.

 

Additionally, the use of “compounded ketamine products without monitoring by a health care provider for sedation (sleepiness), dissociation (disconnection between a person’s thoughts, feelings, and sense of space, time, and self), and changes in vital signs (such as blood pressure and heart rate) may put patients at risk for serious adverse events,” according to the FDA.

This wasn’t the first time the FDA issued a ketamine warning. Early last year, the agency published a health risk alert regarding the at-home use of compounded ketamine nasal spray. 

 

Given the lack of FDA approval, is ketamine unsafe or ineffective?

 

That ketamine is not FDA-approved for the treatment of any psychiatric disorder doesn’t mean that the drug isn’t effective, says David Feifel, MD, PhD, director of Kadima Neuropsychiatry Institute. He’s been working with ketamine for 15 years. 

“FDA approval is a function of a lot of things, including economics.There’s a long application system, and the process costs hundreds of millions of dollars. Ketamine is off-patent and it’s old, so no one owns rights for it,” Dr. Feifel says. “But any drug company would be thrilled to get ketamine in their roster if they could have rights to it.”

But there are routes to a patent. “You can get a patent on a drug compound, or a method patent, which can take an old drug and give it a new purpose. That you can get approved,” Dr. Feifel clarifies. 

Dr. Feifel says that even without FDA approval, “Nobody in psychiatry who is reasonable would disagree that ketamine is a blockbuster and breakthrough for psychiatric disorders. Data are very clear at this point, even though there's skepticism.”

According to a 2021 review published Frontiers in Neuroscience, “[K]etamine can make a genuine leap forward in the therapy of depression. Its clear effectiveness in reducing symptoms of depression and suicidal ideation, either after a single administration, or especially when administered repeatedly in addition to another antidepressant, is an extremely promising factor in the treatment of depression.”

Carboni E, Carta AR, Carboni E, Novelli A. Repurposing ketamine in depression and related disorders: can this enigmatic drug achieve success? Front Neurosci. 2021;15:657714.

 

Regarding the issue of safety, it really comes down to how ketamine is being prescribed and taken, Dr. Feifel says. 

“Many providers are jumping into this because it’s a business model with no experience. They often don’t have the training, so we see a lot of non mental health specialists giving infusions and treating psychiatric illness,” Dr. Feifel says. For the highest-risk patients, like those with treatment-resistant depression, they may be treated by those who are the least trained, Dr. Feifel adds.

Echoing the FDA’s warning, Dr. Feifel notes that patients who take ketamine at home—after being prescribed the drug via, for example, a telemedicine company with little oversight—might face risks. Ketamine can be disorienting, even at low doses, he notes. There’s also the chance that patients taking ketamine at home and without supervision may experience addictive behaviors, as some low-dose ketamine treatments produce an immediate,but short-lived, effect. Dr. Feifel also notes that patients who don’t see an effect,because a dose is too low, may assume that ketamine doesn’t work—and they might quit altogether. For these reasons, he says, trained professionals should oversee the administration of ketamine. 

Kristin Anderson, LCSW, Founder of Madison Square Psychotherapy, a NYC-based private practice, agrees: “I’m optimistic [about] the potential of ketamine therapy [but] also very concerned [about] the actual implementation of this treatment in the field. In my work, I’ve seen the negative impacts of uncontrolled ketamine use, and I worry about the lack of oversight that’s happening at the moment.”

The marketing is a key issue, she says, echoing Feifel’s thoughts. “There are many facilities and companies out there putting out sleek Instagram ads, downplaying the real side effects of ketamine and offering an addictive drug with little oversight. Rather than a real focus on client care, I worry that dollar signs are driving many of these startups. If more regulation and oversight isn’t put into place, I worry that we could be facing a serious wave of ketamine addiction in the coming year,” Anderson says. 

 

Who should be taking ketamine?

 

Dr. Feifel says that the iconic patient is someone with clinical depression, perhaps with suicidal ideation. This is typically a patient who has tried other first-line treatments to no avail. 

“But it goes beyond that iconic candidate,” Dr. Feifel says. It may be beneficial for patients with obsessive-compulsive disorder, anxiety, and post-traumatic stress disorder, but those patients may not all be equally responsive to the treatment. 

According to Ryan S. Sultan, MD, Assistant Professor of Clinical Psychiatry at Columbia University Irving Medical Center in New York, MDs shouldn’t prescribe ketamine without a confirmed diagnosis of treatment-resistant depression or another qualifying mental health condition. MDs should also assess potential benefits and risks for each patient, Dr. Sultan says, underscoring that patients who do qualify should be monitored during treatment, with careful recording of side effects and adverse reactions.