The Dark Side of Ketamine, Depression's Newest Wonder Drug

From media hype to false hope: What happens when ketamine, depression treatment du jour, doesn’t work?

by Patricia Kelly Yeo

The Dark Side of Ketamine, Depression's Newest Wonder Drug

From media hype to false hope: What happens when ketamine, depression treatment du jour, doesn’t work?

by Patricia Kelly Yeo

Fresh off a tropical holiday getaway, Stacey Solomon’s inner world went dark.


The weeklong vacation in Playa del Carmen had been a rare opportunity for the 38-year-old to see her sister, Jen, who lived in New Jersey, halfway across the continent from the Kansas City suburbs where she lived. With their husbands and parents in tow, all four of their young boys–two per sibling–got together to play on the beach of their resort. The whole family of ten, their feet submerged in the foamy waves, posed for sunlit photos as a professional photographer snapped away. Stacey’s husband Matt held her tight as they posed for a couple’s portrait against a resort backdrop.


None of that mattered anymore as the world twisted, distorting like mirrors in a carnival funhouse. “Matt, I’m having bad thoughts again,” she told her husband. It was January 2018, and her all-too-familiar depression had begun to settle back in.


This wasn’t her first bout with major depressive disorder, the official diagnosis listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V), the mental health world’s interminably changing bible of terminology. That episode, defined in the DSM-V as a period of two weeks or more, happened almost 15 years prior when Stacey was 24 and enrolled in a master’s program for social work in New York City. The first one that spring would culminate in Stacey’s first suicide attempt and hospitalization.


Pictured here at age 24, Stacey (right) and Jen (left) were almost twins. This photo was taken the day before she attempted suicide for the first time.

After she’d left the hospital, Stacey flew home to Kansas City, where she and Jen had grown up. There, living with her parents, she recovered, albeit slowly. She took newly prescribed antidepressants and attended daily intensive outpatient therapy. That was the summer she met Matt, then a newly minted lawyer studying for the bar.


This time in 2018, however, was different, she told her father. Steve Simon, 72, was a family medicine physician who lived near her in Leawood, a small city in the Kansas City metropolitan area. He had always been Stacey’s biggest champion, driving her to and from outpatient therapy, sitting in on psychiatrist appointments, and cooking meals for his son-in-law and grandkids when depression left her brain too clouded to put together a grocery list.


It was hard, when his daughter endured her first episode at 24, to believe that Stacey was depressed. Growing up as the younger of the two sisters, Stacey was the optimistic cheerleader to Jen’s pessimistic bitch–in Jen’s own words. At the dinner table, her parents would double over in laughter at the humor she brought out without even realizing it.


“Without making her sound like an airhead, she saw the beauty in things,” Steve says. Visiting Stacey during her first psychiatric hospitalization in 2005, he found his depressed daughter bright and upbeat as she cheered on other patients. “[The hospital staff] told me they hated to see her go, that she could turn [the patients] around,” he says, chuckling.


Stacey and her family on the vacation at the end of 2017–before her longest depressive episode set in.

After her first depressive episode, Stacey would go on to have four more, each accompanied by a suicide attempt. No particular antidepressant regimen, talk therapy, healthy diet, regular exercise–all evidence-based recommendations for managing depression–could keep the illness at bay forever. She had treatment-resistant depression (TRD), a psychiatric research term defined as when two or more different antidepressants don’t result in significant, lasting improvement in symptoms.


“This time is different,” she told Steve. At first, however, things seemed to follow a similar progression: As with the previous episodes, she tried to take her life, spurring hospitalization. Not long after they’d come back from Playa del Carmen, Matt found her in the boys’ bathroom with a bottle of Tylenol, swallowing pill after pill, and managed to stop her in time.


Since he’d met Stacey the summer of her first suicide attempt, Matt supported his wife through several depressive periods. Each time, she’d try to kill herself. Each time, she’d go to the hospital. Each time, she’d get better. “Part of me was relieved because of her pattern [when she was hospitalized],” he says. He thought this episode would yield the same positive outcome.


Released from the hospital with new prescriptions for medication and therapy in the late winter of 2018, Stacey struggled to keep herself alive. Both her parents–particularly Steve– lent help whenever possible, keeping a watchful eye in case her suicidal thoughts became action.


With Jen in New Jersey and Matt working full-time to support his family, Steve and his wife, Ileene, took it upon themselves to help their daughter recover and live a quasi-normal life. Still, Stacey’s depression persisted, conning her into thinking she couldn’t do anything right. Often, he would drive her to the grocery store. For Stacey, who worked as a holistic nutritionist shopping alongside her clients, to say, “Dad, I don’t know what to buy,” just broke him.


Matt and Stacey with their boys on their July trip to Utah’s Bear Lake in 2018. The summer vacation was one of the last few reprieves from her severe depression.

Aside from a brief reprieve during a trip to Utah’s Bear Lake with Matt and the kids, Stacey’s depression continued to worsen, and she was hospitalized for a second suicide attempt. The family toyed with the idea of electroconvulsive therapy (ECT), but Stacey vetoed the idea for fear of memory loss, one of ECT’s landmark side effects. Desperate and running out of options, her longtime psychiatrist suggested a new, experimental treatment: intravenous ketamine.


Originally an anesthetic synthesized in 1962, ketamine is a drug more commonly associated with warehouse parties and Erowid psychonauts channeling Timothy Leary. Despite its reputation as a recreational controlled substance, the drug is still widely used in medical practice as an anesthetic in humans and animals, the latter giving rise to a few of its street names like “cat tranquilizer” and “kitty flip.” In recent years, however, psychiatrists have begun to see ketamine as a new option in treating major depressive disorder and other mental illnesses.


At higher dosages, it’s capable of inducing a trance-like, dissociative state of altered consciousness, known as a “K-hole.” In some cases, the drug can cause hallucinations and delusions. In smaller doses, however, ketamine induces a mild sedative, analgesic effect, and anesthesiologists still use the drug for its original purpose, albeit with careful monitoring.


When Stacey’s psychiatrist Dr. X* gave them the suggestion, longtime family medicine physician Steve was already well aware of ketamine’s medical potential. In his own practice, he’d even prescribed it orally, at low doses, to patients suffering from chronic pain and migraines. With her father’s input, Stacey agreed to start ketamine treatment in August 2018, seven months after her depressive episode began.


*The family declined to name the specific doctors.


Although the FDA would go on to approve Spravato, a nasally administered form of the drug in 2019, most ketamine patients received the drug intravenously, including Stacey. At these privately run ketamine clinics, doctors provide treatment based on research protocols in the absence of standardized dosing, monitoring and decision-making guidelines.


Since ketamine delivered intravenously is not FDA approved for treating depression, insurers typically don’t cover infusions. Dr. Y’s practice was cash-only. Though that fact sent Steve’s sense for hucksterism tingling, he and Stacey nurtured some amount of optimism. Fluent in medical literature, Steve availed himself of the large body of promising research on ketamine, growing more excited as he pored through summary findings. Among her patients, Dr. Y said she’d seen a 90 percent success rate–success defined loosely as any week-over-week improvement in symptoms according to a depression scale survey a patient takes at the start of each weekly visit.


Buoyed by research-backed hope and the clinic’s self-reported success, Stacey started ketamine treatment in August 2019, visiting for weekly infusions over the course of eight weeks. Within three weeks, her depression had improved by 25 percent, as measured by her self-reported assessments that she took at the start of every ketamine visit. But the relief was short lived. By the end of the treatment that September, she felt she was no better than before she’d started.


Stacey (center, in black and white striped dress) at a birthday dinner in August 2018. Since she was too depressed to complete everyday tasks, Steve (right) would help her with childcare and other errands.

The treatment had failed–or, in medical parlance, Stacey had failed IV ketamine. She was in the minority that saw little to no improvement. The hope she had gleaned over the two months of treatment went to nothing. Still, her family felt they weren’t out of options. They could always look for more options. They would find something that would work.


With Stacey’s consent, Steve arranged for another outside assessment for transcranial magnetic stimulation (TMS), a newer, gentler form of electromagnetic stimulation to the brain. The treatment looked promising, with a 50 to 60% effectiveness rate, and fewer side effects than ECT.


Before that could happen, Stacey Solomon was gone.


On October 10, Matt believed his wife had gone to the spa to finally use the spa certificate he’d given her a few months before. But several hours passed as his phone calls went unanswered. He checked in with Steve to see if Stacey was with him and Ileene. She wasn’t. Using Find My iPhone, Matt tracked down her phone’s location: a local gun shop.


He jumped into his car and drove over. When he got there, the scene had already been blocked off by police. Ambulance sirens blared. She hadn’t even left the parking lot before she pulled the trigger.


It was the worst day of his life.


Matt would tell his kids their mother had died of what he called a “single-car accident.” Messages from Stacey’s friends, clients, and neighbors poured into his inbox, people he’d never even met or knew existed, to tell him just how much Stacey meant to them. The next day, the TMS clinic called Steve to confirm Stacey’s appointment. “Are you still planning to come?”


“Well, I wish I could,” he said.


Stacey Solomon's Lifelong Battle with Depression

Stacey's upbeat personality and ability to deeply connect with others often hid the worst of mental illness, except from those closest to her. Listen to her family members below describe Stacey in terms of life, not death.


For the family fighting to keep Stacey alive, ketamine likely seemed like a wonder drug. For Stacey herself, it felt like the last thing she could throw at the condition that had lurked in the background for nearly her entire adult life. “Ketamine treatment was the last best hope in her mind,” Matt says.


After Dr. Y told her people felt better after the first or second treatment, Matt says she went in there thinking, “Maybe I’m one of those people.” When she wasn’t, it only added to the increasing sense of futility, that even this “last best hope” would not save her.


“We all wanted it to work. Of course we did,” Steve says. “We loved our daughter and wanted her to get back into life. She loved life.” He and Ileene, Stacey’s mother, both believe that she died because she felt like there was nothing else that could help her.


By best estimates, 17.1 million Americans, or 7.1 percent of adults, are diagnosed with some form of major depression in a given year. Of those, up to one third experience a treatment-resistant form of the disease, like Stacey. Despite a host of management options like antidepressant drugs and other psychiatric medications; and non-pharmacological interventions like therapy, yoga, and diet and exercise regimes, there is no one-size-fits-all cure for depression, one of the most common forms of mental illness.


To add even one more drug to the arsenal against depression, then, would seem a boon for patients and mental health providers alike. But when a drug associated more with the New York after hours scene and recreational use sees relatively widespread, off-label use for mental health purposes, there’s bound to be unintended second-order consequences.


A Brief History of Ketamine: Dissociative Anesthetic, Club Drug, and Novel Antidepressant

Ketamine’s ability to induce hallucinations and feelings of dissociation was discovered not long after its synthesis in 1962 at Parke-Davis, a pharmaceutical research company that operates as a subsidiary of Pfizer today. Since then, the DEA Schedule III drug (moderate to low potential for dependency) was used during the American occupation of Vietnam, at ’90s warehouse raves, and within the contemporary psychiatrist’s office.

  1. 1962: The birth of ketamine

    In Detroit, Mich., organic chemist Calvin Lee Stevens synthesized a phencyclidine derivative known as CI-581, later renamed ketamine. Ketamine resulted from pharmaceutical research company Parke-Davis’s long search for new anesthetic agents, which began in the mid-1950s and also led to the development of PCP.

  2. 1970s: Use in the Vietnam War

    After the FDA approved clinical use of ketamine in 1970 following several years of patient trials, U.S. army physicians stationed in Vietnam began administering the drug during field surgery. Because of its portability and relatively low risk profile, ketamine would become the most common field anesthetic of the Vietnam War.

  3. 1990s: Special K at the rave

    Illicit use of ketamine grew in tandem with the rise of electronic music and rave culture. Like MDMA, ketamine’s psychoactive effects can enhance the listening experience, albeit that of a lower tempo than mainstream EDM. By the 90s, snorting Special K was inextricable from the burgeoning deep house music scene.

  4. 2000: Researchers discover ketamine's antidepressant effect

    Operating on the basis that glutamate activity plays a major role in depression, Yale medical researchers conducted the first clinical trials of ketamine in patients with depression. In a placebo-controlled, double-blind study, they discovered ketamine significantly reduced depression symptoms, setting off a new subset of research into its underlying mechanisms.

  5. 2010s: Experimental ketamine clinics spring up nationwide

    As doctors and scientists expanded the body of research examining ketamine’s antidepressant effects, forward-thinking psychiatrists and anesthesiologists began to treat patients with the drug, typically through intravenous infusion. Basing dosages and protocols on research studies, the practice continues to this day in a largely unregulated and piecemeal fashion despite 2017 recommendation by the American Psychological Association.

  6. 2019: FDA approves intranasal ketamine spray

    In March 2019, the FDA approved Johnson and Johnson’s intranasal product Spravato, also known as esketamine, the drug’s left-handed mirror molecule. However, the FDA broke precedent, allowing Spravato to be approved after only a single clinical trial testing for efficacy. Spravato continues to provoke criticism, even among physicians who administer IV ketamine.

Since the seminal study demonstrating ketamine’s antidepressant effects in 2000, a drove of benchside and clinical researchers swooped in to study the drug. Ketamine is a known antagonist of the NMDA receptor that many articles cite as resulting in the buildup of glutamate, an excitatory neurotransmitter. This excess glutamate leads to improved mood, emotional regulation, and cognition–all aspects of mental state that are hampered when a person has depression. Unlike most of today’s antidepressants, which operate on the serotonin hypothesis of depression (read: less serotonin, more depression), ketamine operates on the theory that glutamate is a key player in how depression affects the brain, both directly and through downstream effects.


“Ketamine, when you look at the mechanism, is actually working as more of an activator of neuroplasticity more than anything to do with a neurotransmitter,” says Thomas Henderson, M.D., Ph.D., a Colorado psychiatrist who has incorporated ketamine into his practice since 2013. He primarily uses it for treatment-resistant depressed patients, although he has since given the drug to patients diagnosed with post-traumatic stress disorder.


Though scientists are still uncertain about exact mechanisms, ketamine is thought to treat depression both short and long term. In the brain’s frontal cortex, ketamine inhibits the effects of glutamate, an excitatory neurotransmitter, on certain neurons, resulting in stimulation. Short term, this initial tweak of the glutamate system is responsible for ketamine’s rapid antidepressant effects, i.e. what Henderson calls the temporary “happy juice” effect.

How ketamine works in the brain to treat depression

Unlike most of today’s antidepressants, which increase serotonin levels in the brain, ketamine acts primarily on glutamate, an excitatory neurotransmitter whose effects on depression are still not well understood. This GIF depicts one of the generally accepted rapid mechanisms by which ketamine acts upon the brain. It acts as an antagonist of the NMDA receptor protein (the green tooth-like structure below), preventing ions from entering the neuron (grey). As a ketamine molecule moves from the synapse to the NMDA receptor’s ion channel, it blocks the passage of cations (pink) and prevents glutamate (yellow) from attaching to a secondary binding site. Ketamine’s initial effect results in a subsequent short-term buildup of glutamate, which is thought to be responsible for the fast-acting antidepressant effects of the drug.

How effective are other depression treatments?

Electroconvulsive
therapy (ECT)

58-70%

Though depicted as terrifying “shock therapy” in media, today’s ECT is much gentler, and has re-emerged as a second-line therapy for severe depression.

SSRI's (most major antidepressants)

40-60%

(17% with treatment-resistant depression)

SSRI's are the most commonly used antidepressants today. Unlike ketamine, SSRI’s operate on the basis that depression is caused in large part by insufficient serotonin in the brain. Several studies have found the probability of their overall effectiveness is little more than a coin toss–only an estimated 40 to 60 percent of patients see at least 50 percent improvement in depression symptoms.

Psychotherapy
(ex. CBT, DBT)

50-75%

Old-fashioned talk therapy, which includes short-term cognitive behavioral therapy and other modalities, has been shown to be similarly effective to SSRI’s and other antidepressants in the 50 to 60 percent range, with some reviews saying up to 75 percent of mental health patients across the board see at least some benefit.

Transcranial magnetic stimulation (TMS)

50-60%

Memed online as the “depression helmet,” transcranial magnetic stimulation is a noninvasive therapy that stimulates the brain using magnetic pulses. Though exact mechanisms are unclear, it’s thought to activate brain regions involved in mood regulation. TMS improves depression in 50 to 60 percent of cases, with a third of patients achieving full remission.

How does ketamine stack up to the other depression treatments?

60-85%

Compared to other treatments for dep- ression, ketamine is still quite effective. Depending on which studies you choose to evaluate, somehwhere between 60 to 85% of patients with treatment-resistant depression see some reduction in their symptoms measured using standardized depression scales.

Though it’s difficult to say at what point psychiatrists and anesthesiologists began to administer ketamine off-label to patients for depression and other mental health issues, the practice had become prevalent enough by 2017 that the American Psychiatric Association (APA) issued a consensus statement on the practice. At the same time, the recommendations outlined in the statement are optional, not mandatory standards of care. The APA recommended those providing ketamine treatment have advanced cardiac life support certification, for instance, as well as an in-depth review of a patient’s medical history. Most importantly, it advocated for a fully informed consent process that makes both risks and benefits clear to the patient.


By the time the APA had released its statement, Henderson had been seeing patients for nearly half a decade. He says he exceeds the APA guidelines in his practice, making sure patients understand the limits and potential side effects of ketamine. “I have this whole shtick with them about dancing turtles,” Henderson says, telling them, “If you see any pink elephants or dancing turtles, please tell me if you do. They are indeed my favorite hallucination.”


“Everybody laughs and we have a good time with it,” he says, chuckling. “I do acknowledge it. I talk about hallucinations as a possibility. We don't see them very often, but it’s possible.” Today, he says he’s seen over 700 patients. 85% have seen “at least some noticeable” benefit, leaving 15% seeing “little to no” benefit – not far off from what Dr. Y told Stacey and her family in 2018.


Of course, by the time the APA issued its guidelines, the cat was already out of the bag. Dozens of ketamine clinics had already sprung up, according to a 2018 STAT News investigation by Megan Thielking, whose investigation found that many clinics maintain websites and online advertising that overhype ketamine’s benefits while downplaying its risks and limitations. “They’re fishing. They’re throwing bait in the water and trying to lure people in,” Columbia psychiatrist Jeffrey Lieberman told Thielking.


By then, media outlets had caught wind of this promising, buzzworthy “club drug cure,” as a 2015 Bloomberg article called the treatment. Reports from The Guardian, CNN, TIME, Newsweek, and others soon followed. Soon, Vice had put its own unique, counterculture-adjacent spin on it, and in 2018, BuzzFeed released a video–“How A Drug Helps Me Cope with My Kids’ Suicides,” featuring Dr. Steven Mandel, a Los Angeles anesthesiologist.


As a drug, ketamine fits squarely into the Millennial zeitgeist, a generation that has collectively reinvented some “Just Say No”-style villains of yesterday into today’s cutting-edge medical treatments. From CBD, a non-psychoactive cannabis derivative, to treat rare forms of pediatric epilepsy; to monitored MDMA experiences for adults on the autism spectrum, controlled substances once thought to have high abuse potential are now increasingly part of mainstream medicine. The same year Stacey took her life, influential journalist Michael Pollan released “How to Change Your Mind,” a book detailing his experiences with microdosing psilocybin mushrooms and LSD and the science behind them.


But as with any popular movement, if the “green rush” of CBD grifters following widespread legalization of cannabis at the state level is any indication, media hype and amplification contributes to a collective sense of false hope. Though Stacey’s widower Matt and her father Steve don’t blame ketamine for their loss, they do believe Dr. Y, the outside psychiatrist, oversold the benefits of the treatment.


“Ketamine did not cause her death; it accelerated it,” Matt says. “When it didn’t work, she felt like she was at the end. She had no hope left.”


~~~~~~

Daniella Banno, a 34-year old in Indiana, felt similarly. Severely depressed last November, she began a series of ketamine infusions at a clinic in Greenwood, Ind., run by a nurse-assisted anesthesiologist. She’d been aware of the drug’s potential from its wider media coverage, and although her psychiatrist was open to the idea, he didn’t expect much.


Banno’s infusion protocols called for six infusions over a two week period, and she later had two “maintenance” infusions. During each infusion, the psychoactive effects of the drug weren’t terrible, per se, and she felt like her mind was “opening up”–only to be interrupted by the beeping of a heart rate monitor or a phone call from the receptionist’s desk. She was left alone with only the sounds of machines for company.


According to Banno, the ketamine treatments barely made a dent in her depression symptoms. Though there was some improvement, it wasn’t enough to justify the cost: hundreds of dollars per individual treatment session, plus the time she had to take off work.


“I was definitely suicidal afterwards,” Banno says. “I’d tried so many things and that wasn’t even working. I felt hopeless. I was hoping ketamine would offer some sort of solution.” The last thing she wanted to do was try another orange pill bottle full of antidepressants, but that’s exactly what ended up happening, and ultimately working.


Henderson says that the infusion protocol Banno’s ketamine clinic practiced isn’t even based on an understanding of neuroscience behind the drug. In a phone conversation with Paulo Shiroma, M.D., one of the psychiatrists on the vanguard of ketamine treatment, Henderson said to Shiroma, “Hey, I want to understand how you came up with this protocol. Why pick three infusions a week times two weeks?"


“You know what his answer was? It wasn't, ‘Oh well you know the molecular biology blah blah blah and this receptor in the receptor affinity of this and this and the time it takes for such and such to happen’–No.”


According to Henderson, Shiroma said, “Well, I don't know. It sounded good. This is what we do with ECT. So I thought, ‘Why not do it for ketamine?’"


“That was the logic, or lack of logic.” (Shiroma could not be reached via email for response or comment.) Although Henderson acknowledges there is an initial remission in depression symptoms in at least 25 percent of his patients after the first infusion, what he calls the “happy juice effect,” he believes the idea that patients will magically feel better after initial treatment is “horribly, horribly exaggerated–completely blown out of proportion.”


He also disagrees with the seemingly arbitrary protocol followed by most ketamine clinics. “Patients need maintenance treatment because neuroplasticity doesn't happen in two weeks,” Henderson says, as a means of explaining why ketamine clinics recommend maintenance treatment, as Banno’s did. In his practice, he says the number of infusions varies on a case-by-case basis, with some patients experiencing lasting depression relief after as few as four infusions.


“In Stacey’s case, which is tragic, someone should have been talking to her,” he says. Stacey’s death occurred less than four weeks after her final infusion–well within the window of when Henderson says the longer-term neuroplasticity effects of ketamine occur.


He also thinks it’s malpractice for a provider to leave the room while someone is receiving anesthesia, even when a healthcare professional is monitoring vital signs remotely, as in Banno’s case, due to ketamine’s potential to take the mind to strange, dark places.


"I Felt Like My Brain Was a Pinball Machine":
Inside the Anatomy of a K-Hole

What’s it like to trip on ketamine? At higher doses, ketamine’s psychedelic effects come out full force in what's colloqually known as a “K-hole,” an extremely disorienting out-of-body experience. These descriptions from mental health professionals, recreational users, and past patients might give you an idea–scroll right for more.

“It’s just a very strange drug — the strangest drug.”

- Joseph Palamar, MPH, PhD specializing in recreational substances

“I can’t explain to you how normal this doctor’s office was. You fill out the form, old magazines, they call me in and I trip my fucking face off.

-Neal Brennan, 46, comedian, comedian and ketamine patient (did not find helpful)

"[Being in a K-hole] can lead to experiences of a sense of oneness with the universe, a series of interconnectedness…sometimes even a spiritual sort of experience."

-Stephen Bright, PhD, psychologist

“It felt like I was in a pod, ‘It’s a Small World After All’-like pod, crossing my arms now, like a little boat, just going along, through rooms.”

-Neal Brennan

Around minute 20 I started thinking I was dying. I could feel that I was shutting down. I heard beeping and thought that was me flatlining.”

-Alice Levitt, 36, freelance writer and ketamine patient (did find helpful)

“I was falling through my mattress into another dimension… I lost track of reality and time.”

-Tom (pseudonym), 29, recreational K user (did find useful)

After receiving an infusion: “The next thing I knew, I was standing over the Grand Canyon.”

-Samantha Belloso, 23, student and ketamine patient (did find helpful)

“[During the infusion] my mind was opening up, then the blood pressure cuff would go off and I would be taken out of it. Different interruptions every time.”

-Daniella Banno, 34, executive assistant and ketamine patient (did not find helpful)

“The entire time I was crying and begging for him to stop. I felt like my brain was a pinball machine.”

-Emily Kvancz, 42, hairdresser and ketamine patient (did not find helpful)

For Emily Kvancz, 42, a hairdresser and stylist in Santa Barbara, Calif., ketamine ranks high up as one of the worst experiences of her life.


Diagnosed with major depression in her teens, she’d cycled through several different antidepressants, developing tolerance to each one. In the spring of 2019, it happened again. Emily’s mental state teetered precariously, with suicidal thoughts looming at the back of her head. Her longtime psychiatrist, Terrence Early, suggested she try ketamine. Afraid the combination of her long-running anxiety issues and psychoactive drugs wouldn’t mix well, she hesitantly agreed.


Early administered the first injection as Kvancz settled in, donning an eye mask. With Early present, Kvancz settled in with an eye mask on as the drug started to kick in after he administered the injection. “I started seeing colors, racing through tunnels,” she says. “I just felt my mind was completely out of control.” Before ketamine, Kvanz had never recreationally partaken in psychoactive drugs. Her brain took a loop-de-loop on a 90-minute rollercoaster ride as she cried and begged to God to make it stop.


Even with her psychiatrist present, Kvancz’s experience was what Early would later call an “adverse reaction” so severe they didn’t continue with subsequent infusions. “If I didn’t have him sitting there, I would have been climbing the walls,” she says.


After the infusion, she took an Uber home and slept on and off for 30 hours, getting up only to use the restroom and eat light snacks. Then, her depression lifted, like the grey blob in the Zoloft commercials of the early aughts smiling after the cloud disappears.


This “happy juice effect,” as Henderson calls it, lasted for eight days, before Kvancz’s mood crashed again, the depression returning full force. Although it technically improved her symptoms, she says she regrets getting the infusion done.


“Was it worth it? No. That hour and a half, I felt like I was in hell,” she says. “I’ve gone through childbirth. I’ve run a marathon. I’m a pretty strong person–it was just that awful. The most frightening hell I've ever been through.”


She also says she didn’t feel like Early adequately prepared her for the experience of being on ketamine. If Kvancz had known what it could have felt like, she would have turned the treatment down and tried another antidepressant instead, which is what she ultimately did with some degree of success.


Whether stemming from good intentions or profiteering off a patient's desperation for “cures,” overstating ketamine’s benefits is a known risk within the sphere of the nation’s ketamine providers. Thielking’s 2018 STAT News piece shines a light on this at a larger scale, summarizing findings from an in-depth investigation into the marketing and clinical practices at dozens of clinics across the country. “Clinics sometimes overhype the efficacy of ketamine,” she writes. Many offer it to treat conditions for which it has not been studied or in combination with other drugs not well-supported by existing research.


Even among ketamine providers, some have gripes and are well aware of the uneven quality of care, ranging from lack of proper informed consent and management of expectations to a lack of hands-on patient care–behavior Henderson considers malpractice in some cases.


Most startling of all, Kvancz states she now has permanent, mind-altering effects as a result of the ketamine infusion. Her brain works differently than before, she says, chalking it up to the ketamine “opening up” parts of the brain that hadn’t been active before. Every once in a while, she says, she’s suddenly overwhelmed with a sense of dread, like a dark cloud. She compares it to the Dementors in the Harry Potter series trying to suck a victim’s soul.


Though both Banno and Kvancz had subpar experiences with the drug, they both believe ketamine is right–for certain people and in the proper context. “It needs to be in the right setting with mental health professionals debriefing you and talking to you about your experience afterwards,” Banno says. “That was missing from mine.”


The mind’s “opening up,” referenced by both Banno and Kvancz, and acknowledged widely by psychiatrists like Henderson as part of the treatment, is seemingly downplayed or highlighted depending on the provider. Will Siu, M.D., a psychiatrist based in Los Angeles, embraces the conscious-altering component of the ketamine experience when he gives it to his patients.


In the past, Siu, who was featured in Gwynelth Paltrow’s GOOP Netflix series, highlighted the profit motive driving many ketamine providers in Double Blind Magazine, an online publication covering the movement towards using psychedelics as a wellness practice. As also reported in STAT, many clinics cut corners, from failing to perform comprehensive reviews of medical history to literally leaving patients in the dark (of an eye mask).


These days, he’s relaxed his stance somewhat. “I don’t necessarily think doctors are being malicious or purposefully omitting some part of the treatment,” Siu says. He chalks up the inconsistency to a massive learning curve when it comes to prescribing psychedelics, calling them “evocative treatments” different from any other intervention.


Siu is reluctant to say that further regulation of these clinics is justified, saying that availability of ketamine would likely shrink in the face of stricter standards around who can administer the drug. He believes most physicians still view ketamine through a narrow, single molecule-as-treatment lens, rather than as a spiritual and emotional experience.


“If you go to the medical literature, psychiatry as a field still thinks this is a pharmacologic treatment,” he says. “This is a bigger insight that there’s a problem within medicine.” He looks to Ember Health, a New York-based ketamine clinic, as a model where founder and physician Nico Grundmann makes sure each patient has a preexisting relationship with a psychiatrist or therapist and ensures a provider sees each patient one on one.


Though Henderson’s philosophy on ketamine hews much closer to the traditional single-molecule model of how a drug can benefit patients, he acknowledges the potential for negative experiences, which is why he sits with each of his patients as they’re tripping out. Henderson also invokes the need for guidance during infusions, even if, as Siu says, ketamine is much more of an internal experience.


“There's a difference between having a human being there who can reach over and put his hand on your hand and help ground you, versus being alone in a room wondering, ‘Is this what death is like?’” He’s supportive of ketamine-assisted psychotherapy, particularly for trauma, a separate but related use of the drug much closer to what Siu practices with patients.


No matter the mounting research or FDA approval, ketamine still didn’t save Stacey Solomon’s life. On October 12, 2018, her depression won, and she lost. This was a woman who did everything “right” in her fight against the disease. She took her medications as directed. She ate a nutritious diet. She maintained a strong support system of family and friends around her. For her family, the drug represents the fruitless, last-ditch effort to save their wife, sister, and daughter from the disease, a treatment started faute de mieux with so much riding on the hoped-for outcome.


Stacey making s’mores with her youngest son at Bear Lake in Utah on their final trip together. Too young to understand what happened to his mother, he believes she was killed in a car accident.

In an early conversation about Stacey, Jen, speaking on the phone, starts to cry. Her voice on the phone rises and falls, the cadence dropping in and out of the wails as she sobs.


“She hated them,” she says through tears, talking about what Stacey told her about the ketamine infusions. “She could barely move after them, couldn’t...couldn’t do anything.


Ketamine, she says, despite headlines calling it a “miracle” and “wonder” drug, didn’t live up to the hype. Jen misses her sister everyday, and wrote recently about her grieving experience for the online community Modern Loss.


Stacey’s physician father, Steve, doesn’t disavow the drug entirely. Though treatment did little to help his daughter, he believes ketamine treatment has promise for others, as long as the provider fully explains the risks and benefits of the drug to each patient. His sentiment echoes that of Emily Kvancz and Daniella Banno, who despite their negative experiences with the drug believe it is still a worthwhile treatment, even if it didn’t work for them.


With every cutting-edge medical treatment comes fallout, a walking back of overoptimistic claims that the world as we know it will be changed forever. We see this with everything from gene therapy to cannabis derivatives. Then there’s stem cell research, which, like the literature on ketamine, has spawned dozens of clinics putting the promising first draft of science into practice well before wider acceptance. And though the vast majority of ketamine patients walk away with meaningful benefit from the drug, some don’t.


Jen’s voice on the phone starts to crack as she tells me about Stacey’s ketamine experience.


“She did them because she was supposed to do them, because there was supposed to be a payoff at the end,” she says, voice rising. “She wanted to quit, but she didn’t. She hated it.”


“What else was she supposed to believe in?”


Acknowledgements and thanks to: Dana Amihere, Keith Plocek and Peggy Bustamante for code debugging; the Simon and Solomon families; and Thomas Henderson for medical accuracy review.