Mary’s depression roared back with a vengeance: three visits in three weeks to the emergency department of a busy inner-city hospital in downtown Toronto. The third time she was actively suicidal, and was whisked away to the psychiatric crisis unit on the bright and airy fifth floor.
I was a medical student at the time, doing a rotation in psychiatry, and was given the task of spending time each day with Mary (I’m using a pseudonym here) to monitor her symptoms, her insight into her illness, and the goals of her care. Nothing the medical team tried seemed to work. She was on the maximum dose of her antidepressant, a selective serotonin reuptake inhibitor (SSRI). An experimental trial of deep-brain stimulation months earlier had little effect. By definition, our 52-year-old patient met the criteria for treatment-resistant depression.
At the time I couldn’t quite understand Mary’s condition — or our futility in treating it. I spent hours each evening searching for something that might help Mary, returning the next day with a new idea: a gratitude journal; spending time in the fifth-floor garden; or revisiting the cognitive behavioral therapy that she had tried before. Mary seemed grateful for my earnestness, but it was unlikely that the strategies I suggested would make a significant long-term difference. Mary never really eased, and she would likely return to the hospital after she was discharged. The psychiatry toolbox was empty.
My mind drifted back to Mary recently when the Food and Drug Administration approved esketamine (Spravato) for treatment-resistant depression to be administered under physician supervision. It’s a derivative of ketamine, a drug commonly used for anesthesia that has also been used recreationally. This is the second time in the past year that a new drug related to a street drug has entered the market, following last June’s FDA approval of Epidiolex, a form of medical marijuana for treating childhood seizures.
This openness to new treatments is a signal to the medical community that best practices can and must change. It’s also a signal that practitioners must be trained to supervise “the trip.”
In clinical trials, esketamine improved depression symptoms within a few hours. It’s believed that the drug acts on what’s called the NMDA/glutamate pathway, a different mechanism than the way SSRIs work, though the exact mechanism of action on the neurotransmitters involved in depression are unknown.
Breakthrough drugs for mental health disorders, and particularly depression, are rare — none since the approval of SSRIs in 1987. Other modalities have instead emerged: deep brain stimulation (which has mixed-reviews); and a helmet that delivers repetitive transcranial magnetic stimulation. As it stands, esketamine is poised to drastically change how psychiatric care is delivered — it will soon be rolled out in VA system.
Yet in its approval of esketamine, the FDA overlooked one essential issue: while psychiatrists provide “talk therapy” and others dispense medications, it’s almost unheard of for a doctor to dispense a psychiatric medication and supervise the reaction for up to two hours. In a mental health care system where waitlists are already weeks long, will the system adapt to allow for this additional period to supervise the immediate effect of the medication?
Ketamine is something of a Jekyll-and-Hyde drug. It has been used effectively as an intravenous anesthetic for more than 50 years, even though it is associated with side effects such increased heart rate and blood pressure, nausea, and what’s called the emergence reaction: After a procedure, some people awaken terrified and combative, occasionally requesting they never be given the drug again.
The Drug Enforcement Administration has listed it as a Schedule III controlled substance since 1999. These are drugs with a moderate to low potential for physical and psychological dependence. Hallucinations were common with the use of the street form of ketamine, often dubbed “Special K.” As it gained popularity at raves and parties in North America in the 1990s and in parts of Asia and Western Europe in the early 2000s, it also came to be known as a “date rape drug.”
The FDA’s approval of esketamine represents medicine’s inherently revisionist tendencies: Best practices and views on traditionally stigmatized modes of treatment ebb and flow. Mindfulness practices like meditation are one example, now joined by psychedelic drugs, which will require doctors to navigate their own cognitive dissonance to keep up with what new research findings demand.
The Multidisciplinary Association for Psychedelic Studies (MAPS) was established in 1986 to support research and education about psychedelics for therapeutic purposes as well as examine how best practices for mental health care may change. Mark Haden, the executive director of MAPS Canada, has written about the systems changes needed to support the mainstream use of psychedelics for medicinal purposes.
“There’s a growing interest in psychedelics among the medical community since they seem to work for some hard-to-treat mental health disorders,” Haden told me. “But for psychedelics like ketamine we need supervised access because the experience [of patients on ketamine] can be challenging, unlike for other drugs used in mainstream psychiatric care, where a patient can simply self-administer at home.”
Before the FDA approval of esketamine, ketamine clinics had popped up all over the U.S. and in some parts of Canada to administer ketamine intravenously off-label for severe depression. Most are run by physicians. These clinics could provide a model of how esketamine can be administered, but they aren’t without their own issues. “There [are] a wide variety of practices. In many cases people are hooked up to an I.V., left in a corner, and then discharged after their experience. There’s no integration or debriefing,” Haden said. “Continuity of care afterwards is also crucial.”
It will likely take several years before a critical mass of psychiatrists obtains the training to administer esketamine and be on board with providing it and the required two-hour supervision. Haden and his colleagues have proposed that “psychedelic supervisors” be involved to help guide these experiences. In addition to psychiatrists, these could be psychologists, social workers, and nontraditional practitioners such as peyote and ayahuasca traditional healers who, with the right training, can administer the drug safely. It goes without saying, though, anyone can claim to be a “healer” and the consequences of visiting underground practitioners can be devastating.
“We have competing systems. The doctor’s office model is one in which the visits are short, and pills are typically dispensed for home use. In traditional medicine models of psychotropic experiences, the healer is actively involved in the care including most crucially the debriefing process,” Haden told me.
Herein lies the tension with esketamine and for two other psychedelics — MDMA (known on the street as ecstasy or Molly) and psilocybin — that are currently in the pipeline for FDA approval for refractory mental health conditions. Such drugs require a fundamental shift in how psychiatric care is delivered and the amount of time each patient may require with a health provider for a given session. Doctors will need to rethink the role of longer, and more in-depth patient encounters in a system that places a premium on the revolving door of mental health care.
If the “psychedelic supervisor” model suggested by experts like Haden is the best way to ensure that esketamine is delivered in the safest way to those who need it, it may depend on collaboration between health care practitioners who are on different sides of the fence when it comes to using psychedelic drugs for treating depression and other mental health issues. And that may be the hardest barrier to overcome.
Amitha Kalaichandran, M.D., is a pediatric resident physician based in Ottawa, Canada.