Susan Gayhart walks into the Nova Health Recovery clinic’s waiting room, greeted by comfortable couches, a warm rug and the soft glow of the TV. She is here for a ketamine infusion to treat her depression.
In the last decade, clinicians have found that low-dose ketamine can aid patients like 52-year-old Gayhart, who have difficult-to-treat depression. Though ketamine was originally used as a sedative and later well-known for being a party drug, recent research heralded its use as a therapeutic for suicidality.
An assistant escorts Gayhart to one of the clinic’s three rooms, puts an IV line in her, and places a pulse oximeter on her fingertip. The Virginia resident is seated in a comfortable brown leather couch, surrounded by textured photos and bright lamps that all have a “healing vibe.” She asks that the clinic’s music be shut off, so she can listen to her own carefully curated instrumental playlist.
“I wouldn’t want other people to be around me … I need to feel safe,” she said in an interview, happy to only have her husband, Geoffrey, by her side. He has moonlighted as a patient advocate for the past six years, missing only one of her appointments.
Seven minutes into the infusion, she feels tipsy and closes her eyes for the remaining 45 to 60 minutes. Gayhart describes ketamine as a “euphoric” and more internal experience than other psychedelics. “Colors and textures pop. It’s like a diffuser, or salt rocks,” she said. Once the infusion is complete, she spends 15 minutes seated, adjusting to reality. She cannot drive for the next four hours so Geoffrey takes her home.
Gayhart is among the 30% of patients who also have treatment-resistant depression , characterized by persistent sadness and failing to respond to two consecutive treatments. Gayhart’s depression did not respond to any treatment, including drug cocktails and electroconvulsive therapy, until ketamine.
Hedonism to Hospitals: a Brief History of Ketamine
In 1962, ketamine was chemically conceived to replace its highly unstable sibling PCP, known by the street name angel dust.. PCP led to alarming post-treatment psychosis in humans, but ketamine proved to be a safe anesthetic without psychotic aftereffects. It was classified as a “dissociative anesthesia,” meaning it both makes you feel separate from the outside world and numbs you.
In 1970, the Federal Drug Administration approved ketamine as an anesthetic. It was efficient to use on wounded soldiers during the Vietnam War, especially those who could not be transported to or monitored at medical facilities like other anesthetics required.
Over the next decade, ketamine waltzed from war-zones to dance floors. Also known as Special K, it became a Friday night staple that could double as either a stimulant or sedative (and at times, a date rape drug), depending on the dose. New York professionals mixed cocaine with ketamine while street dealers sold it cheaply, free from the stigma of cocaine cartels or the addictive nature of MDMA and alcohol. Of course ketamine still came with risks: abusing it leads to a slew of medical conditions, including severe bladder dysfunction.
In 1999, the United States made ketamine a federally controlled substance in an attempt to stop its illicit use. While ketamine’s recreational stardom has slowed, its claim to fame continues in the medical world. In the last 20 years, ketamine has been effective for over a dozen conditions, notably treating PTSD, epileptic seizures, and, returning to its anesthetic roots, sedating violent patients in a prehospital setting.
At the turn of the millennium, research found that ketamine could also be used to treat depression. While most traditional antidepressants manipulate the serotonin pathway that makes us happy, ketamine manipulates glutamate receptors that wire connections in the brain. Creating new connections cannot change fundamental aspects of your life. But they can, in part, allow patients to become more resilient, according to Dr. Christopher Sendi, who is currently Gayhart’s ketamine provider.
“Ketamine does not change who you are. It doesn’t change your preferences. It doesn’t make you like pink when you like blue. It won’t make you like one type of food versus another,” Sendi explained. “It increases your ability to have better cognition, to understand things in slightly different contexts, and to have a little more internal reserve to take the beatings of your day-to-day life.”
The Futile Fight for FDA approval
While scientists learned more about 61-year-old ketamine, pharmaceutical companies raced to bring a ketamine-mimic to the market. In 2019, Johnson & Johnson’s Janssen succeeded. They obtained FDA approval for a nasal spray called Spravato, the first new drug to treat depression in 30 years. Spravato was greeted with public acclaim. However, a number of concerns, including an approximately 15% difference between Spravato and a placebo, did not convince many scientists, patients like Gayhart and even some members who voted against the drug at the FDA’s own approval meeting.
While ketamine is made up of both R and S form chemicals, Spavarto uses esketamine, which contains only the S form of ketamine. Esketamine functions by blocking the same pathway as ketamine and is used alongside traditional antidepressants. So why do Janssen, and it’s VC-backed peers in Big Pharma, not simply manufacture ketamine, which is cheaper and better known?
Money.
Since ketamine’s patent expired in 2002, companies cannot make a profit from studying or marketing the drug. Instead, they manufacture ketamine-mimics, which are patentable. Without pharmaceutical interest, it seems unlikely that ketamine will ever be endorsed by the FDA as an antidepressant.
Although ketamine is FDA-approved for use as an anesthetic, it is “off-label” for use in depression. The consequences of being off-label are complex. Though there are common off-label medical practices like prescribing steroids for back pain or aspirin for a heart attack, FDA approval of drugs like Spravato provides regulation on their use and advertising.
Pharma companies “can get into trouble” with the FDA for falsely advertising a drug like Spravato, said Samuel Wilkinson, an assistant professor of psychiatry and depression researcher at Yale University. On the other hand, “providers are small fish in the eyes of the FDA” and independent clinics can “say what they want and there’s not really a check on that.”
Privately run medical ketamine clinics — these small fish — have been popping up around the country since 2014. Some have been found to lack thorough screening protocols, never communicate with patient’s psychiatrists, and even offer treatments that are not backed by any published evidence. Ketamine is simply regulated by state medical boards. These medical boards “really only get involved if something bad happens … if there is a lawsuit,” Wilkinson said.
Cristina Cusin, director and founder of the MGH Ketamine clinic, underscored the importance of “specialized clinics that deliver infusions with a certain frequency, [and] where there is the expertise to handle patients.” Beyond accurately establishing ketamine dosage, she said the psychiatric component of working with often-fragile patients’ complex histories and suicidal ideation requires specialized training that you cannot find in any clinic.
Apart from regulating the sanctity of medical treatment, being off-label also causes ketamine to be classified as an “experimental” drug for psychiatric patients. In turn, insurance companies can selectively cover ketamine for anesthesia or pain, but not mental health needs and ketamine clinics rely exclusively on patients paying out-of-pocket.
“If you were feeling cynical, [you] might suspect this may be influenced by the billion dollar traditional antidepressant industry,” John Morgan Freeman, the director of marketing at Ketamine Wellness Centers wrote in an email statement. He explained that despite various questions about the effectiveness and long-term use of traditional antidepressants, they remain the only drugs insurance will cover.
The conundrum becomes apparent: useful medical treatments exist without FDA approval, but FDA approval would improve the odds of insurance covering the treatment.
“It’s a complex system that the average person doesn’t quite understand,” Wilkinson said. Yet, following months of news about the Covid-19 vaccine and FDA approval, laypeople are invested in the intricacies of the FDA approval processes. This is especially true for children, women, and psychiatric patients since they are commonly excluded from clinical trials, so even approved drugs are often considered “off-label.” .
Gerard Sanacora, Co-Director of the Yale Depression Research Program and one of the co-authors of the esketamine clinical trials has observed this change in public perception. “People are very hesitant to think about using anything that is still considered not fully FDA approved in terms of the vaccine,” he said. “But in terms of most medications I don’t think anybody really knows what’s indicated [approved] and what’s not.”
Others, like Gayhart, know that ketamine lacks FDA approval, but still want to try the treatment. “I think that for a lot of people who suffer chronically, and in my case, decades, [ketamine] was my last thing,” Gayhart explained. In the future she hopes to advocate for ketamine approval and usage directly from the FDA or Congress. “I haven’t really found any crusaders that want to do this. It’s kind of overwhelming to approach it from a single person standpoint.” Sanacora explained that building a package for FDA approval requires “hundreds of millions if not billions of dollars of studies.”
Thus the vicious cycle continues: without FDA approval, ketamine treatment remains unregulated and expensive, but getting this approval would break the bank for any individual or institution. A pharmaceutical company could choose to back the research, but there is no incentive — a lucrative patent — at the end of the road for them to do so.
Bench to bedside: How Ketamine Reaches Patients
Nevertheless, patients like Gayhart, who take the initiative to seek ketamine have found help. “Helpers arrive dressed not in firefighter or search and rescue uniforms but lab coats,” Gayhart wrote for a blog on The Ketamine Academy. In 2015, she awoke from a coma after a failed suicide attempt. Her husband found an article in Psychology Today that described nascent ketamine trials and she decided it would be her last shot.
That March, she travelled from Virginia to New Jersey and interviewed with Steven Levine, a board-certified psychiatrist. He determined Gayhart was a “prime candidate” for ketamine treatment. She drove to New Jersey each week to receive ketamine infusions on Monday, Wednesday, and Friday for the next two weeks. After the first three doses, Gayhart said her “thoughts were still anxious,” but her “body was not” — a change that her family also noticed. “Even after the first week, I felt some relief,” Gayhart said. “It wasn’t ideal. But it was better than nothing, and I hadn’t responded to anything before.” After all, the traditional antidepressants she tried took 6-8 weeks to kick in.
After her first six infusions, she realized she couldn’t travel across states so frequently. Levine referred her to Dr. Charles Moseley, who was located 30 minutes away from her home in Virginia. She took a risk being his first patient, but it paid off — she spent the next five years with him before the pandemic struck and Dr. Moseley closed his office. “I was overwhelmed [and] upset,” she recalled. “How am I going to afford the infusions? Who is going to give me the infusions?”
Then she found Dr. Sendi’s office, which closed for only five days during the pandemic. Sendi said the “average person who walks into [the] clinic is going to make some bad decision,” so his role is to help them handle the aftermath. Though ominous at first, his thinking is all about being realistic.
Onboarding patients involves an intake on the phone to ensure there are no disqualifying medical conditions and then a second interview to pinpoint patients’ specific mental health needs. This initial evaluation costs $350 and each ketamine infusion is $480. He tells patients, “I can’t change your husband, I can’t change your job, I can’t make your boss like you. Neither can medications.”
Cusin echoed this, explaining that ketamine does not always work and comes with caveats when it does. Drawing a parallel to cardiovascular disease, she said that although doctors can “remove the blockage in the artery,” that causes the attack, patients need to change their diet and exercise regimens. Similarly, while ketamine helped relieve Gayhart of acute suicidality, she still uses cognitive behavioral therapy and meditation to readjust her lifestyle.
As a patient, the uncertainty of this long-term care can be unsatisfying. Sagar Jilka, a patient and public involvement coordinator at the Maudsley Biomedical Research Centre, conducted over 20 focus groups with ketamine users to listen to their concerns. He said that ketamine research and treatment should be more concerned with public protection and communication. “Not only do we need more research, but that research needs to be articulated in a way that public communities can understand,” he says.
Depressing Disparities: Ketamine Fails to Reach BIPOC Patients
Interestingly, when it comes to this public protection, BIPOC patients are most likely to be left out. In fact, Jilka acknowledged that his own focus groups are almost exclusively composed of white British women.
When asked if the treatment is reaching minority patients, Cusin immediately answered “No.” She said that because ketamine is largely not covered by insurance, her clinic only accepts patients who have been referred from their psychiatrist. This filters out patients who cannot afford psychiatric care or struggle with mental health appointment adherence, both issues that appropriately affect BIPOC groups. Sendi is more optimistic about Nova’s demographic and says a wide range of patients “just find [the clinic] on their own, because they’re desperate.”
Of course, desperation is hardly a viable solution for clinical trial recruitment. “Despite the fact that clinical trials don’t cost anything, it has been a challenge to enroll minority subjects, particularly Blacks,” Wilkinson shared, pointing out a barrier exists in early stage research even if the price tag is removed.
Data from clinical trials does not accurately represent the racial diversity of America while data outside of clinical trials is not in one consolidated hub, given there are more than 10,000 people who are treated at independent clinics. Thus, while Sanacora says he can’t think of any biological reason that ketamine treatment would differ between ethnicities or races, he agreed that there is no data to confirm.
There is data, however, showing that BIPOC patients bear the heaviest burden of depressive disorders, and they’ve faced increased rates of suicidality during COVID-19 quarantine. Though the pandemic’s effect on mental health is not well understood yet, Sanacora foreboded that “it’s not going to be good.”
This confluence of concerns about BIPOC patients and mental health will shape ketamine’s journey. After all, the drug — which has weathered through war trenches, danced until dawn in packed clubs, and evaded pharmaceutical companies with an inimitable style — must still reach millions of people in need.
Luckily, ketamine has patient-turn-advocates like Gayhart, who already has a platform and a following that trusts her. “A lot of people are missing out [on ketamine], and a lot of people are dying from suicide, because they can’t get help.” Gayhart said. “My role is to educate. I can share my experience, strength and hope with people.”
Image Courtesy of Dr. Cristopher Sendi.
