On a Tuesday afternoon in the Bronx, Eric, a 22-year-old college senior, is alone in his shuttered apartment sinking into a worn and sagging section of his black leather couch. There’s an empty bottle of pharmaceutical nasal spray on the coffee table in front of him next to an overflowing ashtray, an enormous green glass bong, three half-finished Blue Moons, and an iPad covered in crushed-up Percocet. The nasal spray used to be full of liquid Ketamine, and its label reads take 14 sprays bi-daily for Major Depressive Disorder. “It actually helped the depression, and not many things did,” Eric says. “But after that one bottle it was over. No more trials, they said. My psychologist, she’s not…” He pauses, expressionless, then starts a new sentence. “The last time I was honest with her or my parents, they sent me to a mental institution”
Eric was, in fact, institutionalized in Connecticut a few months earlier, where he underwent Electro-Shock Therapy. This treatment sounds like what it is — a seizure-inducing, “last resort” therapy to relieve depression. He’s tried over a dozen medications approved by the Food and Drug Administration, but his depression is treatment-resistant, a clinical term meaning “nothing works”. So Eric vigorously self-medicates. “I know it’s not good for me,” he concedes, leaning down towards the powder-covered iPad with a rolled-up dollar bill in his hand, “but I don’t want to feel a thing right now.”
For almost ten years, Ketamine Infusion Therapy has been performed by psychiatrists and anesthesiologists in small, independent clinics across the United States as a last resort to treat Major Depressive Disorder which won’t yield to other treatments. Ketamine, a legal anesthetic often used as a dissociative club drug, finds response among depressed individuals at a rate nearly twice as high as serotonin-based medications, without the latter’s caustic side effects. Yet like the wobbling clubs and secret raves where young people inhale the drug, pining for euphoria, Ketamine infusion clinics exist in the underground of the medical community. Ketamine Infusion Therapy (KIT) is hard to find, and often even harder to pay for. This despite nearly two decades of copious medical research and thousands of grateful patients who swear by Ketamine’s profound healing potential.
For now, over one million Americans affected by severe depression have little or no access to what is summarized by one doctor as “the safest thing going” in depression treatment. Touted exposés in publications of culture and medicine testify to Ketamine’s efficacy.
The director of the National Institute of Mental Health calls it “the most important breakthrough in antidepressant treatment in decades.” Yet Ketamine Infusion Therapy is a mere mirage for most wanderers in the desert of depression. There’s no sign that depression is on the decline, and the amount of generic drugs produced to treat depression is on the rise. As the body of knowledge on Ketamine continues to grow and astound doctors and patients alike, it begs a question. Perhaps there’s more to healing depression than FDA-approved pills and diet-plus-exercise. In turn, perhaps there’s more to the raver’s pursuit of a dissociative, mystical high than a search for simple kicks.
Numbers Don’t Lie
“Part of what motivated me to start this treatment in the first place was being pissed off,” Dr. Steven Levine tells me over the phone. Dr. Levine founded the Ketamine Treatment Centers of Princeton in New Jersey. Like countless other psychiatrists, he’s seen treatment-resistant depression-like Eric’s smother the psyches of his patients. FDA-approved pills provide relief about one-third of the time. Placebos have roughly the same success rate. Weeks or even months can go by before these drugs, known as SSRIs or selective serotonin re-uptake inhibitors, begin to actually work. Sometimes that relief comes too late.
Fed up, Dr. Levine began administering small amounts of intravenous Ketamine to treat depression in 2011, a practice first studied by Yale Medical School in 2000. Levine rhetorically asks,
“Why aren’t we using this thing that can clearly help a lot of people, and falling back on the safety of FDA approved drugs?”
Though it’s a legal anesthetic, Ketamine must earn new approval from the Food and Drug Administration to be considered an official antidepressant. “And now that this is much more established,” Levine says, “it continues to piss me off that it’s not more widely available to people.” 19 clinics are listed on the Ketamine Advocacy Network, a blog founded by a patient named Dennis Hartman. Hartman, who was profiled in an August 2015 Bloomberg Business article titled “The Ketamine Cure”, scheduled the date for his own suicide before giving treatment one last shot with Ketamine Infusion Therapy.
Ketamine generates an antidepressant response for about 70–80% of Dr. Levine’s patients. At the Portland Ketamine Clinic run by Dr. Enrique Abreu, it’s 68–75%. When Abreu collected his data for an August 2015 article in the Pharmaceutical Journal titled “The Secret Life of Ketamine”, his patients, roughly 100 of them, had received 18–26 infusions each with no adverse side effects. During a 2013 interview on the podcast Life Unedited with syndicated talk show host John Aberle, Dr. Levine said he’s never observed “a single, adverse medical event” when administering Ketamine. Three years later, that observation hasn’t changed.
“There’s been a few thousand treatments administered since then and it still holds, we still haven’t seen any adverse medical events, either acutely or over time.”
Contrast this with the side effects of traditional antidepressants, and it’s night and day.
“We know there’s long term harm with FDA-approved treatments like Abilify or Seroquel. We know those medicines cause diabetes, metabolic syndrome, all types of side effects…it’s almost a guarantee.”
These medicines modulate the flow through the brain of serotonin, a neurotransmitter which produces feelings of well-being. In theory this will correct the “chemical imbalance” believed to cause depression in the first place. But Ketamine acts with a more comprehensive approach which is beginning to alter the clinical understanding of depression (which has never been more than vague).
Dr. Carlos Zarate is the chief of the Neurobiology and Treatment of Mood Disorders section at the National Institute of Mental Health. His 2006 randomized trial with Ketamine was the first study after Yale’s, and he’s now Ketamine’s loftiest advocate in the psychiatric community. As he told the Pharmaceutical Journal, depression is a disease between the brain’s circuits and synapses, structures literally eroded by crashing waves of chronic stress and depression. By “rapidly modulating” this neural network, Ketamine repairs the circuitry, restoring connections throughout the brain and allowing signals of well-being to begin flowing again.
As an anasthetic, “Ketamine disconnects the mind from the perception of pain,”. As an antidepressant, it has a similar effect on psychological pain. Patients can dissociate for the first time from their daily reality of pain, frustration and anxiety. Though an infusion only lasts an hour, the respite can help those with treatment-resistant depression forge new perspectives on their lives. The infusion initiates a sort of “out-of-body experience”, allowing patients to experience their pain and trauma in a more neutral way, according to Dr. Levine.
“Out-of-body” experiences and other similar pharmacological phenomena appear in clinical research with psychedelic hallucinogens. In 2010, researchers at New York University found that Psilocybin, the hallucinogenic molecule in magic mushrooms, can induce “ego-free states” which ameliorate “existential distress” for terminally-ill individuals, as reported by The New Yorker. Research into Psilocybin and Lysergic Acid Diethylamide, LSD, ballooned in the late 1950s and 1960s. According to Dr. Rick Strassman, who’s began researching the psychedelic compound Di-methyl Tryptamine or DMT in 1988 at the University of New Mexico,
“psychedelics were the growth area in psychiatry for over twenty years.”
Yet psychedelic drugs escaped from the laboratory and onto the streets, and their chief proponents became young people who liked to “dose” and dance to new, off-kilter music. Public opinion shifted and stigma shattered the clinical repute of psychedelic hallucinogens. International studies suggested such drugs could help psychiatrists demystify brain function and dysfunction, but after 1970 research tapered off and the drugs were nearly forgotten about.
While Ketamine is not technically a psychedelic or a hallucinogen, it does cause hallucinations, and one long-term recreational user pegged a Ketamine trip as “similar to psychedelic experiences.” With its prevalence in the underground electronic music scene, and its potential for abuse, Ketamine could suffer the same fate as previous mind-altering molecules. In May, the United Nations rejected a proposal from China which would have placed a worldwide ban on Ketamine.
Water, Water Everywhere
Though there’s under 20 providers listed on the Ketamine Advocacy Network, Dr. Abreu believes as many as 40 other clinics in the United States offer the treatment without advertising it because the stigma for Ketamine is “hard to get around.” Not all Ketamine clinics are created equal, not by a long shot. A provider can be left off the Advocacy Network’s database for many reasons. Either it charges fees which are “extremely high”, it represents a “poor standard of care”, its protocols are not supported by peer-reviewed research, or it markets services with “outlandish claims, or serious factual errors.” The most careful doctors like Levine and Abreu keep counsel with each other to check their practices against those of their colleagues.
Not everyone is as cautious.
On the Advocacy Network forums under the heading “Buyer Beware”, a patient named Ken warned about a clinic in the Midwest which requires $3250 upfront for six treatments.
“You are taken into an unheated back room that looks more like a storage room…You sit in a recliner and he sticks the IV in your arm, starts the drip, then leaves the room for the next 45 minutes. You don’t even have a heart monitor attached, so nothing is being monitored during the infusion.”
Such a porous standard of care is unacceptable and unabashedly dangerous. Yet without the FDA’s approval, the details of Ketamine treatment remain unregulated. Sound, safe methods are agreed upon by doctors like Levine, Zarate, and Abreu, but there’s no mandate for other clinics to follow those methods. Profit-seeking practitioners can play on the desperation of depressed individuals and “treat” these patients with the bare-minimum of care. Even well-meaning doctors can soil the treatment by relying on less peer-reviewed methods.
The contrast between Ketamine’s scarcity in the medical community and its abundance on the street is unsettling.
One infusion, approximately 50 milligrams based on a patient’s weight, can cost anywhere from $300 to $1,000. On the streets of New York, however, an entire gram costs as little as $40 to $100 depending on who you know. A college junior from Manhattan named Jess bought a gram for $40 from a furniture store in Chinatown.
“My friend who took me there said the right word and one of the employees — they were all named Lee and they were all smoking cigarettes — went to the back of the store and came out with a bag, and it was fuckin’ good.”
Carlos, a college graduate living in one of New York City’s outer boroughs, pays his weed dealer $100 for a gram of liquid Ketalar, one of three names for medical-grade anesthetic Ketamine. This liquid form is more expensive because it’s more pure than the illicitly-produced and often adulterated crystalline Ketamine which comes to America primarily from China.
Clinical and recreational use of Ketamine is a completely different experience, and conflating the two can empower Ketamine’s damaging stigma. “Like any drug of abuse,” Dr. Levine says, “the mindset and setting in which its taken alter the effect.” Imagine the difference between taking one Xanax per day as prescribed for anxiety, and taking four of them in one afternoon, or the difference between taking one Percocet for back pain, and crushing up two or three and peeling back powered lines.
The intent or “mindset” of the person consuming a substance steers the direction of their experience, as does their setting. Where a recreational Ketamine user might take bump after intranasal bump from a dime bag on a crowded, steamy dance floor, a patient injected with a fraction of that amount rests comfortably in a bed or chair next to the doctor. There’s no nasal damage or discomfort, the dosage is stringently monitored, and the only stimuli available are Netflix, relaxing music, or nothing at all depending on the clinic.
Yet grasping the recreational user’s relationship with Ketamine can help demystify the drug’s medical properties. “People have different reactions to drugs,” says Levine, whose always believed self-medication habits can shed light on a patient’s needs.
“Their particular reaction to non-prescription substances, whether it’s alcohol, marijuana, ketamine, whatever it is — there’s often information in that. It often tells us something about the symptoms that person is trying to treat.”
Someone who uses or abuses Ketamine can be chasing a certain state of mind. “You find that when you take enough, many times you come to this place where you feel like you understand things better,” says Tyler, the twenty-something Manhattanite who likened Ketamine to a psychedelic experience, and who used to sell the drug in small amounts. He continues,
“It kind of separates your mind from your body…You sort of reflect on yourself in a certain way, and have these realizations. But often when you come out of it, it’s harder to really remember those realizations, those things you felt like you understood.”
Similar to those with treatment-resistant depression who “self-select” the unorthodox Ketamine infusion therapy because they’ve exhausted all other options, recreational users can be “self-medicating” when they administer a licit or illicit substance to treat their trauma, anxiety, or to just “feel good”. Carlos has been prescribed multiple antidepressants before. He says nothing can rend and rectify his psyche like Ketamine. “When you’re depressed — well, when I’m depressed, I’m usually hyper-focused on myself, on my problems and my life. Ketamine sort of removes me from myself, and I end up realizing my problems aren’t as bad as I thought. It changes my perspective.”
Carlos had some of his first experiences with Ketamine at Camp Bisco, a raucous, remote, drug-fueled frenzy of a music festival which took place in upstate New York from 1999–2013 before community complaints and a mysterious missing permit forced it to relocate to Scranton, PA. Bisco is almost a rite of passage for electronic music heads in the Northeastern United States. After three days of music and camping, most kids leave on cloud nine. Others leave in tears because someone stole their new Nikon digital camera. Still more leave burdened with vivid tales about missing the annual headlining set by Bassnectar because they were nursing a friend who had a drug siezure, or maneuvering to hurl someone’s stash of Ketamine into the campground’s lake for their own good. Drug abuse among certain factions of this crowd is difficult to overestimate.
Ketamine and electronic music are not related by mere coincidence. Instead electronic music is “intimately bound up with the drug culture,” says Simon Reynolds, a critical scholar at Oxford University who traces the historical relationship between drugs and music. These two separate means of mood alteration rival each other’s ability to transport someone to new emotional states. When it comes to electronic music, they often work in tandem, and one can even be a foil for the other. From his 2005 tract “Historia Electronic Preface,” in The Pop, Rock and Soul Reader, Reynolds writes:
Electronic dance music is all about being lost in music, whether it’s being engulfed by the sonic tsunami streaming out of a gigantic rave sound system, or being meditatively absorbed by the microscopic sonic events that pervade more experimental forms of electronica. These states of ego loss and oceanic connection, of being overwhelmed or entranced, are the reason why drug imagery is central to the electronic imagination.
Thus you have the improv rock-electronica band who founded Camp Bisco calling themselves the Disco Biscuits, a 1980s slang term for quaaludes, or the Grammy-award-winning Chemical Brothers writing a song called “Lost in the K Hole.”
Recreational users know that enough Ketamine will thrust you into the mysterious “K-hole” — a state of complete dissociation. Senses are scrambled, muscles are paralyzed, and one’s perception of time is severely distorted. Depending on who you ask, this can be frightening, enlightening or both, but almost anyone will tell you it’s incomparably bizarre. “Almost every time I’m in a hole it’s the same thing,” Carlos told me. “There’s a super intense condensing feeling in my head, and once the densest point is reached, it's like an explosion. Then I’m flying through space past stars and galaxies.” Another user from New Jersey, a self-described “Basshead” (think “Deadhead” but for Bassnectar, and again notice the 1980s drug metaphor), says it’s like a “near-death experience.”
Whatever the connotation of a K-hole among recreational users, a similar experience could be interpreted differently in the context of Ketamine infusion because of the change in intent and setting, those two qualifiers which are so determinant for a subjective drug experience. A patient, who often has never tried a dissociative or hallucinogenic substance and who is seeking an antidepressant effect, will process the effects of Ketamine differently than a recreational user who is likely experienced with drugs and not intractably depressed. When Dr. Levine explains the experiences of his patients, however, one hears vague echoes of the sojourn that Carlos describes. “They’re experiencing some sense of something larger than themselves, a connectedness to the universe, to other people,” Levine says. “So even though they’re feeling disconnected overall, they describe this feeling of connection during the infusion.”
Doctors disagree as to whether or not dissociation is an inherent part of Ketamine’s healing process, or simply a side effect. After all, it’s believed that Ketamine’s antidepressant action comes from its reparation of brain synapses. When the National Institute of Health pooled data from their KIT studies, they found that patients who experienced stronger dissociation experienced a greater antidepressant response. Mount Sinai and the University of Texas Southwestern pooled their research and came to the opposite conclusion. Neither study is conclusive because both look at data that’s already been collected. That’s why Dr. Levine is beginning his own study to see if there is a positive correlation between dissociation and antidepressant response. “I’m going into the study with an open mind. From an intuitive standpoint, I think that likely is the case, especially after all the descriptions from my patients about their experience.”
Risk and Reward
While Dr. Levine is trying to unpack the correlation between dissociative experience and depression relief, pharmaceutical companies are less concerned about it. Johnson and Johnson is working toward an intranasal application of Esketamine, like the spray bottle on Eric’s cluttered coffee table. Esketamine is a facsimile of Ketamine, an “analog” in medical parlance. It’s virtually the same molecule and drug, but without the “dissociative side effects” of the original. Naurex in Evanston, IL is developing a novel compound called Rapastinel which has a similar mechanism to Ketamine. According to the Pharmaceutical Journal in “The Secret Life of Ketamine”, the FDA designated Esketamine as a “breakthrough therapy” for treatment-resistant depression based on results from preliminary trials by the pharmaceutical company Janssen from Titusville, NJ. Yet in the same article, Portland’s Dr. Abreu asserts that if drugs like Esketamine are eventually approved by the FDA, they will not be as effective as Ketamine itself. Dr. Levine is more candid regarding a “take-home” nasal spray.. “It’s not particularly effective. There’s a high potential for abuse, and people can take it in an uncontrolled setting, maybe in conjunction with other drugs.”
So why is big pharma racing to develop a less potent version of Ketamine when the real thing appears to be working so well? “The FDA is not scanning the horizon looking for things to approve,” says Dr. Levine. “The FDA is evaluating trials, evidence brought to them by some interested body. And usually, a body has to be interested by a profit motive.” Ketamine is an old, cheap, generic drug that has already been patented as an anesthetic. Despite the mountain of evidence suggesting Ketamine is a revelatory antidepressant, there’s no financial incentive for pharmaceutical companies to expand its use. But if a company like Johnson and Johnson can earn FDA approval for Esketamine, they can send the “new drug” to market and reap the reward. “Do they think it’s actually superior? Of course not,” Levine explains. “But they can patent it and claim that in certain ways it will be superior.”
An over-the-counter drug like Esketamine, or even the Ketamine nasal spray Eric had are no foil for Ketamine Infusion Therapy. Remember, set and setting. Dr. Levine talks to every patient for hours before considering if KIT is even appropriate. Dr. Glen Brooks, who heads the New York Ketamine Infusions clinic from an office above Wall Street, says patients need “the right story” for Ketamine to work, one involving trauma and stress of the utmost severity. Some clinics mandate that patients participate in Cognitive Behavioral Therapy as a corollary to infusion. “Ketamine is not a magic bullet,” says Levine. “It’s worked very well, it’s been very gratifying treating people with this medicine. It’s better than anything else we’ve got, frankly. But it’s a start.” If a depressed individual responds positively to Ketamine, Levine maintains this is only the first step. “It makes things like psychotherapy and supportive therapy even more important- addressing all the things in life that really have a toll taken on them by chronic depression.”
Some insurance companies are edging towards covering KIT, though doctors are not at liberty to say which ones. This would leaven the cost to patients at least slightly. Besides big pharm.’s neglect of the procedure, Ketamine Infusion Therapy is expensive precisely because it’s unorthodox. It requires a unique commitment from its administrants. Again, Dr. Levine displays candor. “At a practitioner level it’s expensive and a pain in the ass.” Anesthesiologists who run clinics are not used to medicating mood disorders. Psychiatrists typically just write prescriptions, and they’re not used to administering invasive treatments. How did Dr. Levine get past his occupational unfamiliarity? “I guess that’s just more how I’m wired,” he says. “I have some tolerance for risk, it’s something that I’m willing to do.”
Risk. It’s the key word in that statement, and in the at-large debate over Ketamine’s medicinal benefits. What are the long-term risks of Ketamine Infusion Therapy? People with treatment-resistant depression are at risk of suicide. Before he left school, Eric was phoning friends and threatening to take his own life. If pharmaceutical companies won’t risk their dime on Ketamine, forward-thinking practitioners like Doctors Levine, Abreu, Brooks and Zarate will continue taking the risk to meet patients halfway. If the definition of insanity is doing the same thing over and over again expecting different results, perhaps taking some risk is the next rational step towards truly healing depression.
Since I began research for this piece, Dr. Levine has opened clinics in Denver, Raleigh, West Palm Beach, and Towson, MD. Within two months, his practice will also open a clinic in Philadelphia, one in Fairfax, VA, and another in Potomac, MD. Dr. Levine is not the only clinician who is expanding his practice, and there are others who have just begun theirs. For more detailed information about Ketamine Infusion Therapy, I recommend reading The Ketamine Papers, published by the Multidisciplinary Association for Psychedelic Studies.