Renee St.Clair has suffered from major depression most of her adult life, starting in her mid-20s. She was consumed by mental - and physical - pain defined by thoughts of hopelessness and loneliness. The San Diego attorney, now 50, regularly eyed a bridge near her office and considered jumping. She engaged in cutting, was hospitalized three times and once attempted an overdose.
In addition to talk therapy, St.Clair has been on more than 50 antidepressants, mood stabilizers, and other medications, often in combination. They'd work for a while, in the best cases a few years, before the darkness returned.
In early 2018, St.Clair's psychiatrist recommended a clinic that offered a medication she'd never heard of: ketamine. Once there, she nervously agreed to an injection, then sat back as colorful hallucinations, including a cartoon monkey playing poker, filled her mind. Most of her subsequent treatments were more sinister, including once when she feared that her brain, which was floating across the room, might never return to her body.
But after nine treatments spread over a month, St.Clair awoke in the morning and leaped out of bed to a new world. "Colors were brighter, my car felt faster, and I had none of the heavy thoughts from the day before," she said. The exuberance lasted only 24 hours, but for the first time in decades, St.Clair felt hopeful. She went back for dozens more ketamine treatments until stopping two years ago. Her depression symptoms have returned but are now managed by medication, and she has not once considered suicide. "I believe the ketamine saved my life," she said, although she's clear that the medicine is not a cure.
Hopeful stories like this have sent people with depression flocking to a rapidly growing number of commercial clinics to seek out treatment with ketamine, a drug that produces a passing psychedelic high. Sales of the medication are soaring, with the Food and Drug Administration citing a jump of nearly a million vials between 2013 and 2017 (the last year figures are available). Much of that increase has occurred in the clinic setting, the agency notes.
Take-home ketamine, anyone?
Not surprisingly, a growing number of companies are rushing to open or buy clinics and create branded chains to capitalize on the excitement. But amidst the fervor are increasing concerns about broad fluctuations in clinical protocols, staffing levels at clinics and the safety of one of the newest wrinkles: take-home ketamine administered by telehealth.
Ketamine is not technically a psychedelic; rather, it is an anesthetic, delivered by infusion or injection. It was approved in 1970 by the FDA for use as anesthesia. Since a drug cleared by the FDA can then be prescribed for any condition - a practice known as "off-label" prescribing - a growing number of doctors and clinics are touting ketamine therapy as a way to treat depression, suicide ideation, anxiety, posttraumatic stress disorder, obsessive-compulsive disorder, and other mental health conditions.
In 2019, Johnson & Johnson won FDA approval to market esketamine, a molecular variation of ketamine, as a nasal spray under the brand name Spravato for treatment-resistant depression or suicidal ideation in conjunction with an oral antidepressant. Its high price (and, some say, lower effectiveness) have limited its sales compared to generic ketamine given by infusion or injection. Some compounding pharmacies make their own nasal spray versions of generic ketamine, but in February, the FDA warned that these unapproved products have caused adverse reactions, including delusions and panic attacks, in some patients.
Until recently, ketamine clinics were primarily small, mom-and-pop affairs. But now a growing number of corporations are trying to corner the market.
Aspiration: Becoming world's largest chain of psychedelic clinics
Irwin Naturals, a maker of nutritional supplements, recently purchased one independent clinic in Vermont and two in Georgia, which followed the acquisition of seven other clinics this year, including five in Florida. In a press release announcing the initial acquisition, the company stated its intention to ultimately "become the world's largest chain of psychedelic mental health clinics."
Another company, Revivalist, recently branched out beyond its Tennessee roots to open clinics in North Carolina, Michigan, Washington, D.C., and other locations. Another, Ketamine Wellness Centers, currently has 13 clinics in nine states, with plans for more by the end of the year. "We're adding an average of 70 to 80 new patients on a monthly basis," said Kevin Nicholson, chief executive officer. The company has also made arrangements with the Veterans Administration in Illinois and Minnesota to provide ketamine treatments to vets with PTSD and major depression.
Nicholson said part of the aim of his company's expansion is to make ketamine therapy more widely available. But he also admitted that another goal is to create a large footprint across the country in anticipation of the time when other, more potent, psychedelics might become F.D.A. approved, something experts say could happen within a few years. "The whole plan is to have the infrastructure in place so when F.D.A. approves MDMA, and then psilocybin, we can insert that [into our protocols] without making too many changes," Nicholson said.
Yet in many ways, the business of ketamine is outpacing the research behind the drug.
Business Before Science?
Because it was approved as an anesthetic, ketamine's optimal dosage and frequency of administration had not been established for mental health conditions including treatment resistant depression, according to an "expert opinion" review in the American Journal of Psychiatry, published online in March.
This leaves each clinic to guess what might be best, leading to vastly different protocols. Dosages of the drug, for instance, range from a limit of roughly 1 milligram per kilogram of a person's weight to as high as 8 mg/kg.
Also undetermined: the ideal treatment schedule. One independent clinic, the Baltimore Ketamine Clinic in Sparks, Maryland, recommends two infusions a week for three weeks, with maintenance doses over time as needed. But Ketamine Wellness Centers uses four treatments in the first eight days, then follow-up treatment 10 and 14 days later, followed by monthly infusions for the rest of the year.
Carlene MacMillan, vice president of clinical innovation of Osmind, a company that has worked with more than 300 clinics nationwide providing electronic health records, said she knows of one clinic that infuses patients five days in a row. "That's alarming to me," MacMillan said.
Any protocol should be discontinued if the drug isn't having an effect after about four weeks, according to the 25 authors of the American Journal of Psychiatry review.
Safety parameters are similarly not established, creating possible hazards for patients. "Any licensed [medical] professional can obtain and administer ketamine," Ketamine Wellness's Nicholson said. "It concerns me that someone might see this as a way to make a quick buck."
For example, although experts advise that a trained staff person sit with the client throughout their treatment, Nicholson said some clinics cut corners by using video cameras or periodic check-ins.
And some clinics promote themselves more as wellness spas than medical centers, aren't run by mental health professionals and don't collaborate with those experts, MacMillan said.
The experience of taking ketamine can be intense for a patient, she pointed out, with potentially serious reactions not just during treatment but after. "A lot of clinics are not equipped to handle a crisis that occurs in the middle of the night," she said. "Just telling someone to call 911 is not helpful."
Another concern: Some clinics, including Mindbloom, have begun offering ketamine therapy at home, with the medicine taken as a tablet that dissolves under the tongue. Mindbloom's medical director, Leonardo Vando, said the company takes safety seriously, providing pre-session assessments and post-session counseling and requiring each person to have a friend or relative physically present when the drug is taken.
Vando said the telehealth model significantly expands ketamine's reach. "For many people suffering from anxiety and depression, simple acts like getting out of bed, searching for help, and going to a doctor's office can be huge obstacles to treatment. By providing treatment through telehealth, we can minimize those barriers and make treatment much more accessible," he said.
Cost-saving is a key advantage to the telehealth approach. At Mindbloom, sessions run below $200 per treatment, compared with $400 to more than $1,000 at many clinics.
But Rosalind Watts, Ph.D, a former psychedelics researcher at Imperial College London who now heads the London-based psychotherapy program Acer Integration, worries about take-home ketamine because it leaves out the relationship between practitioners and patients.
"Experienced psychedelic therapists recognize that the actual substance is a small part of the picture, and that the level of interpersonal trust and safety that a participant feels towards their guide has a crucial impact on outcomes," she said. "Human connection is what heals. The drug is just a catalyst."
Ritu Baral, a senior biotech analyst for the investment bank Cowan, follows companies in the field and is concerned about ketamine-at-home businesses. "They tell you to lie down," she said. "But it's a different experience than taking Benadryl."
Christopher Pittenger, a professor of psychiatry at Yale School of Medicine who has researched ketamine, points out that current science doesn't support home use. "We have very little careful research on how oral ketamine should be used or how effective it is for psychiatric symptoms," he said.
The Ketamine Experience
Each ketamine treatment typically lasts under an hour. Users generally report feeling a dream-like detachment known as a "dissociative state," where thoughts come and go erratically, hearing and vision may be altered, and they feel floaty or numb.
"It's like being in a movie. You're watching your thoughts rather than controlling them," said Ivana Mitic, a certified registered nurse anesthetist who owns the Baltimore Ketamine Clinic. She described one severely depressed client who came to terms with his sister's suicide following ketamine treatments and another who made peace with a sexual assault from decades earlier.
No one is sure exactly how ketamine works. Experts think part of its effect may be that it blocks glutamate, a neurotransmitter that, in excess, can be toxic to brain cells and has been linked to depression and disrupted circadian rhythm and sleep. It may also cause neurons to grow in the brain, leading to changes in thought patterns.
Most research on ketamine so far has involved depression, which is why some experts advocate limiting its use to this diagnosis. Researchers at Stanford University examined anonymized charts of some 500 people with depression, drawn from Osmind's database of electronic records from ketamine clinics across the U.S. More than half showed improvements in two to four weeks and more than a quarter went into remission, they reported in March in the Journal of Affective Disorders. About 8 percent of ketamine recipients saw their depression worsen.
Ketamine's rapid reduction of depression symptoms is striking compared with the slow action of antidepressants. "Ketamine's defining features are its rapid therapeutic onset.and its week-plus-long efficacy after [an] infusion," an international team of researchers concluded in a review in the Journal of Neuroscience published in February 2021.
The rapid action may also be life-saving for people contemplating suicide. Three days after receiving either a 40-minute infusion of ketamine or a placebo infusion of saline, 63 percent of the ketamine group were no longer in danger, compared with 32 percent in the placebo group, according to a study of 150 people with suicide ideation published online in The BMJ in February.
Yale's Pittenger believes the evidence is strong enough that doctors should consider ketamine to treat depression when a rapid response is needed or conventional drugs haven't worked. But the data does not yet support its use for obsessive-compulsive disorder, post-traumatic stress disorder and other conditions, he said, even though many clinics are using it for those purposes.
One significant obstacle to patients being able to access ketamine is that few insurers cover the drug. Kimberly Juroviesky, who has been using ketamine since 2015 for pain, depression, and PTSD from her service in the military, wants to change that.
Juroviesky heads the nonprofit group Ketamine Task Force, which is lobbying Medicare and insurance companies to cover ketamine treatments as they currently do esketamine, so far without success. "It breaks my heart to hear from people who would benefit but can't afford it," she said. St.Clair is also involved with the group, having spent $30,000 out of pocket on her ketamine sessions.
Significant Side Effects
Another drawback: Ketamine may not be as safe as some clinics portray it to be. During the initial clinical trials for Spravato, for example, three people in the treatment group committed suicide a few days or weeks after their treatments, while there were no suicides in the control group, according to the F.D.A. Briefing Document issued before its approval. Writing in the American Journal of Psychiatry, Stanford University psychiatrist Alan Schatzberg says this suggests ketamine might provoke "a protracted withdrawal reaction."
A study published in Drug Safety last year documented 21 cases of liver problems following the repeated use of generic ketamine.
Ketamine can cause other side effects as well. The drug's prescribing label warns of elevated blood pressure, respiratory depression, nausea, and other possible problems. And while some people enjoy the dissociative state, others feel frightened or overwhelmed.
Ketamine can also be abused, a fact made clear by its popularity as an illegal club drug with street names like Special K or Vitamin K that is commonly snorted or smoked. In 2020, Australian researchers documented 68 cases of deaths in that country due to ketamine, the majority from illegal recreational use. In the U.S., a representative sample of 60 emergency departments turned up 44 ketamine-related visits in one year, corresponding to a national estimate of nearly 700 visits, according to the F.D.A. Briefing Document.
Still, people who have researched or benefitted from ketamine insist its problems should not stand in the way of appropriate use. More research needs to be done on which patients are most likely to benefit and what protocol should be used. The financial burden for patients must also be lifted, they said.
"We need to either do big studies to better understand how to use ketamine in a less expensive way, or we need to figure out a way to pay for the uses that have been rigorously shown to work," Yale's Pittenger said.
As for Rene St.Clair, simply having ketamine as an option continues to help St.Clair, even though she hasn't used it since 2019. "Knowing it's there if I need it gives me a measure of hope, because it worked before when so many others did not," she said.
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