We have been inundated with comments and questions regarding the safety of ketamine due to the tragic death of Matthew Perry. In my opinion, the coroner’s decision to list the immediate cause of death as, acute ketamine toxicity, was meant to sensationalize Perry’s history of addiction. Typically, in such a case, the immediate cause of death would be listed as drowning.  This would then be followed by a line that reads, due to or as a consequence of: ____________ which is where the underlying cause would be listed. For example, drowning was listed as the immediate cause of Whitney Houston’s death, not her drug use. The same for Dennis Wilson of the Beach Boys who drowned but had a very high blood alcohol content.

As CNN Chief Medical Correspondent, Dr. Sanjay Gupta explained, the ketamine likely caused dissociation and lack of bodily awareness, which tragically led Mr. Perry to drown while in his hot tub… Dr. Gupta continues to say that ketamine …in and of itself, is not likely to lead to someone to die except for the fact that he was also in a pool… (Link to Dr. Gupta’s interview)

I know reports about ketamine deaths can raise concerns over the safety of this treatment. However, it’s important to understand Mr. Perry’s case in context. In addition to the last therapeutic ketamine infusion he received a week and a half before his death, he was obviously self-administering ketamine as a recreational drug. This is based on ketamine’s very short half-life and the fairly high levels found in his blood. The ketamine he received during his last infusion would have long been out of his system. Even though we do prescribe ketamine for use at home, the dose is far lower than what Mr. Perry would have consumed. In addition, the informed consent our patients sign specifically states another adult needs to be present when it is taken.

Please feel free to reach out if you have any other questions or concerns. When administered properly, ketamine therapy remains an extremely safe and effective treatment option. As always, our highest priority is the wellbeing, health, and safety of our patients.


Richard L. Bowen, MD

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Maya Singer
February 12, 2021

AT SEVEN O’ CLOCK on a recent evening, I dim the bedroom lights, call out a reminder to my boyfriend to rouse me in an hour with a gentle tap, and close the door. “Have a great trip,” I hear him say from the living room as the two ketamine tablets I’ve pressed into the pockets of my cheeks dissolve, leaving a bitter residue. Minutes later, I’m flying over water that reflects a sourceless golden light. Am I the light? The thought triggers a sensation of being stretched like taffy in all directions. It’s not my body being stretched—I don’t have a body anymore—but the immaterial me moving in tune with the ambient music in my headphones. I stretch and spread until at last I’ve dissolved—pixelated—at which point a small voice in my head calls out, “Do you really think this will help you quit smoking?”

The last time I was on ketamine, I was hooked up to an IV following surgery. This time, the drug—in general medical use as an anesthetic since 1970—arrived on my doorstep courtesy of Mindbloom, a new telemedicine company specializing in ketamine-based psychedelic therapy. This was no shady dark-web deal: Prescribed by a psychiatric nurse practitioner following an extensive intake evaluation, and compounded by a licensed pharmacy, the ketamine came bundled with an eye mask, a hardbound journal, and a blood-pressure cuff that I was instructed to use before and after dosing, to test my vitals. The tablets themselves were housed in a mirrored pouchette with the tagline ACHIEVE YOUR BREAKTHROUGH spelled out in sleek, sans serif font. I was tempted to post a shot to Instagram, but I had a Zoom call with my psychedelic-integration coach in half an hour, and I wanted to meditate first.

Welcome to the brave new world of psychedelic wellness. After decades underground, hallucinogens such as ketamine, LSD, psilocybin, and MDMA are getting a fresh look from the medical establishment, thanks to myriad studies suggesting silver bullet–like efficacy in the treatment of anxiety, depression, and addiction, among other ailments. MDMA, renowned for its bliss-inducing effect—hence the street name “ecstasy”—is on course to be approved for the treatment of post-traumatic stress disorder (PTSD) within the next year or two. Synthetic forms of psilocybin, the active compound in magic mushrooms, were given “breakthrough” designation by the FDA in 2018, allowing for fast-tracking of drug trials. Meanwhile, this past November, Oregon became the first state in the nation to legalize psilocybin for medical use, an advance not lost on the investors flocking to start-ups like MindMed and Compass Pathways, both of which are developing psilocybin treatments in anticipation of a cannabis-style psychedelics boom. A mental-health revolution is at hand—and it’s long overdue, according to experts such as Frederick Streeter Barrett, Ph.D., assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine and a faculty member at the university’s recently opened Center for Psychedelic & Consciousness Research.

“The current model for treating problems like anxiety and depression just isn’t very good,” Barrett says. “Patients take pills every day, for years, and these medications not only have nasty side effects, they often don’t even work. But with psychedelics-­assisted therapy, there’s the potential to truly alter someone’s life with just one or two sessions, because you’re getting at suffering at the source.”MOST POPULAR

I’m not suffering, exactly, but for lack of more technical language, I’ve kind of been freaking out. Straining to maintain a productive work schedule under lockdown, I fell back into the habit of smoking as I write—and soon thereafter, the habit of trying to quit. The addiction struck me as fundamentally psychological: If I was so hooked on nicotine, why did I reach for my American Spirits only when I was stuck at my desk, staring down a deadline? But reach for them I did, and the harder I worked not to—with the aid of gum, apps, hypnosis, you-name-it—the more fixated I became on the fear that I simply could not write without cigarettes. I was starting to feel truly hopeless when I stumbled across a news item about studies showing that with the aid of psilocybin, longtime smokers were quitting cold turkey and sticking with it at rates that put all other remedies to shame; two-thirds of participants in one recent study were confirmed cigarette-free after one year!

Intrigued, I did a little more digging and discovered that ketamine—a dissociative hallucinogen that is already legal for supervised medical use, including in the treatment of depression—seemed to draw out the mind in a way similar to psilocybin by putting the brain in a “neuroplastic” state, explains Julie Holland, M.D., a New York–based psychiatrist and the author of the 2020 book Good Chemistry. “They have different chemical properties, but both ketamine and psilocybin have an ego-dissolving effect, where you’re breaking the mental loop that’s symptomatic of conditions like depression and anxiety and addiction, and allowing the brain to form new connections.”

Maybe a little ego-dissolution was the answer, I mused as I stamped out another butt in the ashtray next to my laptop and googled “ketamine therapy—New York.”

“THE TRUTH IS, WE DON’T REALLY know how this stuff works,” Michael Pollan, author of the best-selling psychedelics primer How to Change Your Mind, tells me. “A leading theory is that psychedelics quiet the brain’s ‘default-mode network,’ and that opens up new pathways for thought.” As Pollan goes on to explain, the default-mode network is where “the ego has its address”—it’s the part of our brains where we construct the narrative of who we are and, thus, the place we get stuck in destructive thought patterns about ourselves. “That could be ‘I’m a worthless person who doesn’t deserve love,’ or it could mean telling yourself that you can’t get through the day without smoking,” Pollan continues. “Either way, the idea is that, by muffling those thoughts, psychedelics help you out of the rut.”MOST POPULAR

Pollan’s précis on the science of psychedelics is reassuringly down-to-earth. For years, I’d been put off by the drugs’ woo-woo connotations, and to judge by the refined, minimalist aesthetics of new ketamine-therapy chains such as Field Trip Health, which has serene locations in New York City, Toronto, Atlanta, Chicago, and Los Angeles, I’m not the only person with zero interest in a tie-dye mental makeover. It’s all a far cry from Timothy Leary and The Electric Kool-Aid Acid Test. But Leary—who famously conducted psychedelics experiments at Harvard in the early 1960s, before he ran afoul of the law and, in turn, helped prompt the criminalization of psilocybin and LSD—does continue to exert an influence: His “set and setting” theory is a cornerstone of all contemporary psychedelics-aided therapy. “Set basically refers to mindset, going into your journey, and setting is your environment,” explains Ronan Levy, who cofounded Field Trip in 2019 after establishing—then selling—Canada’s largest network of cannabis clinics. “They matter as much as the drug you’re taking,” he continues. “You need to be in a place—mentally and physically—where you feel inspired and at ease.”

Because I’d chosen to work with Mindbloom, thanks to their COVID-friendly process, the setting for my four, hour-long treatments, was my bedroom. To be perfectly clear, I wasn’t microdosing. Nor was I popping a pill just to see what colors spilled out of my head. Prior to receiving my Mindbloom package, I spent over an hour on Zoom with a board-certified psychiatric nurse practitioner who quizzed me on everything from my family medical history to my typical responses to stress. (According to Mindbloom founder and CEO, Dylan Beynon, about 35 percent of potential patients are screened out at this point, for reasons such as past experience of psychosis or, at the other end of the spectrum, not meeting the threshold for a diagnosis of anxiety and/or depression.) “Set” was established in conversation with Laura Teodori, my psychedelic-integration-support coach, who—after obtaining confirmation from my boyfriend that he’d check on me every 20 minutes—helped me formulate an “intention” for the trip immediately after our call. My goal, we ascertained, was to recall moments in my life when I could create without smoking. With that in mind, I tucked the tablets inside my mouth, pressed play on the Mindbloom-curated soundtrack that would be piping through my headphones, lowered my eye mask, and waited for my default-mode network to go off-line.

HALLUCINOGENS COME IN MANY FORMS, from the low-dose ketamine I was taking to wallop-packing plant medicines, like ayahuasca and ibogaine and peyote, that have been used in sacred rituals for hundreds, perhaps thousands of years (and that are illegal in the United States). But a feature common to all is the sense of coming into contact with the cosmic. “It’s like there’s no boundary between you and others, or you and the universe,” notes Johns Hopkins’ Barrett, saying that virtually all subjects in psilocybin studies have reported such a feeling of oneness. “Some people call this an experience of God, or nirvana.” I went into my first ketamine journey matter-of-factly, with a problem to solve, and even so, that first trip commenced with a vision of the world rewinding, a kind of reverse big bang that exposed the heretofore invisible filaments connecting everyone and everything. The vision moved me—tears puddled behind my eye mask—and then it yielded to more personal impressions, such as a recurring image of myself, age six or seven, playing with my dollhouse.

“What do you think was important about the dollhouse?” Teodori asked me in our post-trip call. I was still pretty woozy as we Zoomed—the effect wore off by the next day—but suddenly, it was like a light bulb went on in my head. “I think…I think I was remembering what it felt like to create without smoking,” I told her. “When there wasn’t any pressure, and I could just play.”

This download is part of integration, another cornerstone of modern psychedelic medicine. “The goal is to take advantage of the neuroplastic state, which lasts for about a week after dosing,” explains Beynon. “You want the changes in your brain to stick, so the question becomes, How do you turn these new thoughts into new behaviors?” For me, this entailed finding ways to get back in touch with that dollhouse sense of play.

Easier said than done. My ketamine experiences were clarifying and often even profound, but they didn’t change certain nerve-racking facts of life, such as that I write for a living and thus have deadlines to meet if I wish to pay my bills. Or that it’s hard—like, really hard—to stay motivated in the midst of a global pandemic, when each day brings fresh spurs to panic and depression. “There’s a huge mental-health crisis happening parallel to, and in response to, this pandemic,” notes Benjamin Brody, M.D., assistant professor of clinical psychiatry at Weill Cornell Medicine in New York, and chief of the Division of Inpatient Psychiatry at the university hospital, where ketamine infusions are typically administered. “People who are grieving, people who have lost jobs, people who are feeling disconnected, whose lives have been upended .…” With demand for care rising “across the board,” as Brody notes, it’s no surprise that psychiatrists such as Amanda Itzkoff, M.D., are seeing a huge uptick in inquiries about ketamine therapy. But it may or may not be the right tool for every job, Itzkoff points out.

“The thing is, if you got laid off and you don’t know how you’re going to pay rent, ketamine won’t change that,” says Itzkoff, an early adopter who has been providing ketamine infusions at her Manhattan practice since 2014. “It doesn’t remove the external pressures. But when you’ve got someone with severe depression, who has kind of given up, then there’s real promise in this treatment.” Itzkoff cites the example of a former patient, a high-powered attorney and mother of two, who was on disability and “almost catatonic” when they began working together. “She had to be retrieved from this state,” recalls Itzkoff. “By breaking the negative thought loop—even temporarily—you show someone it’s possible to feel another way. And that,” she adds, “can be channeled toward getting people back on their feet.”

Chad Kuske didn’t just get back on his feet following his first psilocybin treatment a year and a half ago; he experienced what he calls an immediate and profound “sense of meaning and a desire to live.” A former Navy SEAL, Kuske, 40, had tried psychoanalysis and various pharmaceuticals before being medically retired from the service in 2017. Reentering civilian life, he found himself using drugs and alcohol as a way of coping with the anxiety, depression, and alienation that he now comprehends as the symptoms of PTSD. “Nothing else had worked. And I knew that sooner or later, if I kept doing things the same way, my life would be over—either literally or metaphorically, like I’d wind up in jail,” Kuske explains. “The mushrooms helped me see my situation clearly: I was in hell, but it was a hell of my own creation, and I could make the choice whether to stay there and suffer or leave and start the work of changing.”

One of the key insights Kuske has taken away from his trips—and from his integration process, which is ongoing—is that he’s not alone in struggling to meet the challenges of daily life. Likewise, Itzkoff suggests that the feeling of interconnectedness induced by psychedelic therapy—and near-psychedelics, such as ketamine and MDMA—may help alleviate the isolation brought on by COVID. It may also play a role in helping the people hardest hit by the pandemic recuperate: Nautilus Sanctuary, a nonprofit psychedelics-­research and training center in New York, is already planning a study exploring the use of MDMA to treat frontline workers with severe PTSD—one of the many inquiries to expand on the drug’s groundbreaking FDA trials sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), which entered phase three in 2017. Other studies sponsored by the organization have focused on veterans in Israel and the United States, and the Department of Veterans Affairs has exhibited a willingness to approve such studies, so long as they are safe, beneficial, and scientifically sound. 

This kind of conservative approach is merited, notes Weill Cornell’s Brody. “I’m very concerned about this atmosphere, that the floodgates are opening. I work with ketamine, a drug that’s been in use for decades, and even there, we don’t know all that much about its long-term effects,” says Brody, who provides ketamine-infusion therapy only to patients in whom he’s observed severe, treatment-­resistant depression—and who was positively aghast when I relayed rumors that self-dosing with inhalers of esketamine, a synthetic form of the drug given FDA approval for supervised use in 2019, was all the rage in L.A. “Ketamine is a serious drug!” he reiterates. “This isn’t a spa service. It’s not like getting Botox. And what worries me about all these clinics popping up is that people are going to start thinking about it that way.”

Brody is hardly alone in fearing the commercialization of psychedelics—a trend that, if canny investors like Peter Thiel, a backer of Compass Pathways, are correct, is on pace to increase rapidly. “It’s a unique space because so much of the technology has been developed by Indigenous healers,” notes Pip Deely, cofounder of the venture-capital firm Delphi, which is eyeing investments in psychedelics start-ups and supporting a new psilocybin-legalization campaign in Hawaii. “We see a lot of dread that if this all goes the way of cannabis, the people who have been doing this work the longest will be cut out of the conversation, and those Indigenous roots will be erased.” Unprompted, I hear a version of this concern from one Berkshires-area healer who, for legal reasons, prefers to remain unnamed; she tells me that, although she supports expanding access to psychedelics, she worries about the experience becoming pro forma and “clinical.”

Though they come at their misgivings from opposite angles, both traditional healers and Brody are wary of psychedelics’ getting marketed as a quick fix—and in all honesty, I’m the target demographic for that pitch. When I sat down at my computer to fill out Mindbloom’s candidate questionnaire, what I wanted was to detangle a few mental wires. By the time I’d completed my final ketamine treatment, I’d come to realize that those wires were crossed very deep down: My writing-while-smoking problem was really a problem with the little voice in my head telling me that I’m not good enough, I haven’t achieved enough, I’m falling behind. As I wrote in my integration journal after my second session, “Every little deal is a big deal.” I added a frowny face to underline the point.

I can’t blame Mindbloom for my failure of mindset. All my conversations with Teodori were oriented around getting me to probe the heart of my fears, and she was diligent in supporting me as I attempted to integrate the lessons of my journeys into daily life, checking in with me every few days via text and reminding me that she was always available to talk. Alas, I didn’t take her up on that offer as often as I should have—I had a ton of writing to do!—and in the end, I felt changed but not transformed. Which could be a me thing, or it could be a drug thing. Barrett of Johns Hopkins pointed me to studies from the university’s Center for Psychedelic & Consciousness Research indicating that, where smoking cessation is concerned, the more “mystical” the trip, the more effective the treatment. “There’s a big difference between a low dose of ketamine and taking what we call a ‘breakthrough’ dose of psilocybin,” he notes. “That’s where you’re really going to break down your sense of self.”

Is that what I want? Is that what we all want, in some subconscious way? “There’s a spiritual hunger these medicines satisfy,” Pollan points out, and I can attest that once you’ve visited the astral plane, you want to go back. Most hallucinogens are not physically addictive, but the psychedelic experience is itself addicting. I spoke to numerous people for this story who described their encounters with psychedelics as “life changing” in ways large and small; one woman even credited peyote with restoring movement to her paralyzed arm. But Ann Watson’s account is the most relatable. A former VP and fashion director at Henri Bendel in New York City, and now a cochair of The Vaquera Group, a global marketing firm, Watson, 52, is also a self-described “explorer” who, like me, kept a pretty tight lid on her deepest, darkest feelings—until she began working with psychedelics 12 years ago. “My childhood was chaotic; there was a lot of abandonment, but I didn’t associate with the word trauma, because I thought it was reserved for people who have experienced things like rape or war. But I was seeking something,” explains Watson, who tried a variety of treatments to relieve an “ever-present vibration of anxiety,” including counseling and prescribed antidepressants, before experimenting with a long list of psychedelics. Eventually she arrived at a treatment plan with a doctor in Los Angeles she sees four times a year for guided psilocybin trips; she also microdoses psilocybin on a more regular basis, mixing magic mushrooms with Lion’s Mane. “It’s an ongoing process,” she tells me. “The thing is, once you start looking inward, you realize there’s always more to see.”

Perhaps that is the main takeaway from my own journey: that I’m just at the start of it. I have work to do on myself. But in the meantime, I also have work to do, period—as in, I’m on deadline for this piece. And I regret to inform you that as I write these words, I am indeed smoking.

Kaia Roman
February 9, 2021

I’ve shared a lot about my quest to quell anxiety over the years, including in my book, The Joy Plan. Thankfully, daily practices such as mindfulness, meditation, exercise, and a healthy diet have helped me tremendously.

But, like the majority of people in these crazy times, I found that my regular practices fell painfully short during this past year. Throwing a divorce into the mix with a pandemic propelled my negative mental feedback loop into overdrive. I found myself unable to sleep, focus, or even think clearly; I was desperate to find the “off” switch.

Not Special K.

I told my friend Zappy Zapolin, known in celebrity circles as the “Psychedelic Concierge to the Stars,” (with clients like Lamar Odom and Michelle Rodriguez) about my struggles, and he had one word for me. It definitely wasn’t a word I was expecting: ketamine.

Although I had some vague concept of ketamine as a club drug, I had no idea about its extensively studied application for anxiety, depression, PTSD, and addiction. After diving into the literature, I understood that medical ketamine treatments are legal and not to be confused with the crystallized form of ketamine that is snorted through the nose. 

I was most impressed by the 2012 findings at the Yale School of Medicine that many people with chronic depression experience immediate relief after even small amounts of medical ketamine.

This is likely in part because ketamine inhibits the NMDA receptors in the brain, which contributes to its effectiveness as a painkiller and gives the drug its dissociative properties. At a low dose, ketamine appears to induce neurogenesis—new growth of neurons and synapses in the brain—creating an ideal landscape for the creation of new neural pathways. These new neural pathways make it easier to create new ways of thinking and behaving. This is why the medical aspect of ketamine treatments is so essential: A health professional needs to be there to help you navigate this new mental landscape.

In depression and other mental health conditions, brain firing patterns are disordered, and evidence suggests that ketamine-assisted therapy can help restore them. Scientists have pointed to a region in the brain that records all the stress you’ve had in your entire life, called the lateral habenula. When this mechanism gets to a certain tipping point, it goes into a “burst” mode and shuts down the area responsible for dopamine production (no dopamine feels like crap). According to a more recent study in Nature, ketamine blocks this bursting activity, acting like a light switch that turns dopamine production back on instantly.

This is why ketamine-assisted therapies can provide relief from stress and anxiety almost immediately—though there is some question about how long these effects last.

My ketamine experience.

After doing my research and hearing a number of success stories from friends, I decided to give a series of ketamine treatments a try to see for myself.

As much as I wanted relief from anxiety, it still wasn’t easy for me to justify using synthetic medicine. I usually opt for the natural, plant-based option whenever possible. However, I must admit, with each treatment, I experienced new levels of clarity, energy, and inner calm. The results increased in the days and weeks that followed.

While ketamine is not classified as a hallucinogenic, it is a psychedelic (a substance capable of producing profound experiences of reality). A high dose of ketamine puts you to sleep, but at a low dose, you enter a dreamlike state that induces an expanded perspective.

The ideal treatment protocol for depression, based on several studies at Yale, is a series of six sessions over two weeks. Since I don’t have clinical depression but do struggle with anxiety, I decided to have four treatments over two weeks in a clinic. I was later able to beta test an at-home (but clinically sanctioned) program that uses oral ketamine, which was much easier to do during these times of social distance.

My ketamine experience felt like a journey through my own mind, where I encountered beautiful visuals and accessed difficult areas of my life from a new angle. It was as if I was floating outside my body, leaving my habitual state of mind behind, and opening myself to new possibilities.

In my opinion, one of the biggest benefits of ketamine, compared to traditional pharmaceutical antidepressants and anti-anxiety medications, is that it only stays in the body for hours—rather than altering brain chemistry every day. After the treatment, I was so present that I could have gone back to normal activities 15 minutes later.

However, the insights and new perspective that I had while on ketamine stayed with me. In the weeks that followed, I was also able to slip into deeper meditation more easily—which I attribute to ketamine’s potential ability to help calm rumination and a wandering mind.

The promise of psychedelics (when administered in a safe, controlled setting).

I tried ketamine during a time when psychedelic-assisted therapies are gaining more traction, funding, and credibility in American medical spaces.

The FDA has granted “breakthrough therapy” status to various psilocybin and MDMA research programs, fast-tracking their potential rollout. mindbodygreen featured psychedelic assisted-therapy as one of their major wellness trends to watch this year, and the Cleveland Clinic has called ketamine a “Top-10 medical breakthrough” for its antidepressant effect.

This attention comes at a poignant time: Last month, the CDC reported that a whopping 41% of U.S. adults suffered from anxiety in December 2020; this was compared to only 11% in January to July of 2019. In the Household Pulse Survey, 37% of U.S. adults said they felt hopeless more than half of the time in October 2020; that number soared to over 50% for adults under 30. Unfortunately, experts say that these mental health reverberations are likely to persist long after the pandemic is behind us.

At times like this, we need all the help we can get. And while not a miracle cure, ketamine—when administered in a safe, medical setting—was one such helpful treatment for me.

If you’re interested in learning more about ketamine-assisted therapy, listen to our conversation with Gita Vaid, M.D. on the mindbodygreen podcast.

Carlos A. Zarate, Jr.
November 2020

From the beginning of the neuropsychiatric drug era, the development of antidepressants has been mostly based on serendipity. One of the first examples, iproniazid, was an antitubercular drug observed to induce euphoric effects in individuals with tuberculosis. Investigators who pursued this intriguing finding argued that similar compounds might have antidepressant properties, ultimately paving the way to developing monoamine oxidase inhibitors (MAOIs) for treating depression. This discovery ushered in the era of monoaminergic-based antidepressants, and the next 50- 60 years consisted mainly of developing ‘‘me too’’ drugs that were largely monoaminergically-based. These medi- cations typically yielded only minor refinements – for instance, improved side-effect profiles – to existing antide- pressants without offering significant advantages in terms of efficacy or remission and recovery rates.1 While it is certainly true that these ‘‘conventional antidepressants’’ did help many, it is equally true that not all were helped. Further- more, these agents are associated with notable limitations, including low remission rates, slow onset of therapeutic effects, and lower efficacy in comorbid psychiatric condi- tions and syndromes. In addition, many of the patients who did respond – or partially responded – to these treatments continued to relapse despite ongoing treatment, developed treatment resistance, attempted suicide, or had impaired functioning. Given the urgent need for better treatments, several targets for new, non-monoaminergic-based anti- depressants have been pursued over the decades; few, if any, novel ones reached the clinic.
In this context, one of many targets of interest is the glutamatergic system.2 Trullas & Skolnick were among the first to examine the possible link between depression and glutamatergic system dysfunction3 and, building on their preclinical work, Berman et al. discovered that ketamine exerted rapid, robust, and relatively sustained antidepres- sant effects in depressed patients.4 Despite the pioneering nature of the results, the paper did not have an immediate dramatic impact on the field. Researchers might have viewed the reported rapid and robust antidepressant effects as a ‘‘fluke’’ or perhaps did not want to test a drug that possessed abuse potential and psychotomimetic effects.

Nevertheless, since then, numerous placebo-controlled studies have shown that subanesthetic-dose ketamine has rapid, robust, and relatively sustained antidepressant effects in individuals with treatment-resistant major depressive disorder and bipolar depression. Building on this growing evidence, investigators wondered whether other N-methyl-D-aspartate receptor (NMDAR) antago- nists might exert antidepressant effects similar to those of ketamine. Unfortunately, NMDAR antagonists or modu- lators of the NMDAR complex (e.g., GLYX-13, CERC-301) have failed in the clinic. Generally speaking, no other tested NMDAR antagonists have shown the same rapid, robust, and sustained antidepressant effects as ketamine; in other words, they are simply not ketamine.2

Despite these setbacks, ketamine itself has led to much more focused research seeking to identify promising characteristics of next-generation treatments. In particu- lar, because ketamine’s antidepressant effects are so rapid, and because the onset and offset of its therapeutic effects are fairly predictable, investigators began using ketamine as a tool – both clinically and preclinically – to decipher its mechanistic effects and identify biomarkers of treatment response. For instance, one series of studies implicated glutamate and gamma aminobutyric acid (GABA) signaling dysfunction in depression; similarly, convergent evidence from behavioral, cellular, and mole- cular ketamine studies supported the theory that enhan- ced a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity – with a concomitant increase in synaptic plasticity – is critical to ketamine’s mechanism of action and may be the key to developing similarly rapid- acting antidepressants.2 On the clinical front, investigating ketamine’s mechanistic properties has led to the explora- tion of a variety of human biomarkers, as well as treat- ment options such as scopolamine and electroconvulsive therapy.
Ketamine clinics – which typically administer racemic ketamine intravenously – have proliferated globally. As a whole, the field has urged caution regarding the need for more research, and several meetings have been conducted to share clinical experience and standardize ketamine use. Perhaps the most salient recent develop- ment is the March 2019 FDA approval of esketamine (Spravato; the S-isomer of ketamine). Spravato can only be dispensed and administered to patients in medically- supervised healthcare settings that provide monitor- ing (Risk Evaluation and Mitigation Strategies). This is particularly important given that ketamine has abuse liability and possesses clinical side effects – including blood pressure changes, dissociation, psychotomimetic effects, cognitive effects, risk of cystitis, and hepatotoxicity (though the latter two are less common). These issues remain a concern despite Risk Evaluation and Mitigation Strategies, especially with long-term use of ketamine or Spravato. Thus, while many safety concerns can certainly be addressed, ketamine’s side effect, safety, and addiction profile suggests that larger and longer-term studies are needed to better characterize the limitations associated with ketamine and ketamine-related treatments. Research is ongoing to examine these concerns as well as separate them from ketamine’s efficacy profile.
Despite these concerns, the research surrounding ketamine has ushered in a new era of considerable hope regarding our ability to develop better treatments for patients with depression. It bears repeating that ketamine is the first antidepressant with a completely new mecha- nism of action. In contrast to conventional repurposed antidepressants, ketamine’s effects are robust, occur rapidly, and effectively treat not only depressive symp- toms but also suicidal ideation, anxiety, anhedonia, and comorbid conditions.5 Studying the precise mechanisms implicated in its unique therapeutic profile has opened the door to the possibility of developing novel and improved versions of ketamine – medicines that retain its unique, broad therapeutic profile without its troublesome side effects and risk of addiction. In many ways, the field’s current focus on ketamine signals the end to the long and often frustrating chapter on conventional antidepressants and the beginning of a new era. This new chapter is likely to be one of many and, although it will not be the end of the story until a cure is found, it promises to be a heartening chapter nonetheless.

Funding for this work was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002857), by a NARSAD Independent Investigator Award, and by a Brain and Behavior Mood Disorders Research Award.
CAZ would like to thank the 7SE research unit and staff for their support and Ioline Henter of the NIMH for invaluable editorial assistance.

CAZ is listed as a co-inventor on a patent for ketamine use in major depression and suicidal ideation; as a co- inventor on a patent for using (2R,6R)-hydroxynorketa- mine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated (R,S)-ketamine meta- bolites for treating depression and neuropathic pain; and as a co-inventor on a patent application for using (2R,6R)- hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government.

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Posttraumatic stress disorder (PTSD) is a devastating mental illness that can follow exposure to life-threatening stress. Although several psychological treatments for PTSD have proven efficacy (1), their dissemination has yet to be widespread, owing in part to their complexity and requirement for expert practitioner training. Furthermore, trauma-focused exposure-based psychotherapies can be quite challenging for patients with PTSD, initially triggering heightened arousal and avoidance that can result in treatment dropout prior to achieving therapeutic benefits. Pharmacotherapeutic options for PTSD have been even more limited in their demonstrated utility, with only two drugs, paroxetine and sertraline, both selective serotonin reuptake inhibitors (SSRIs), approved by the Food and Drug Administration (FDA) for the treatment of PTSD two decades ago (and venlafaxine extended-release showing efficacy but not submitted for FDA approval). These agents also commonly cause side effects before therapeutic effects, contributing to early discontinuation. Whereas many other drugs have been studied for PTSD over the ensuing years (2), none have garnered incontrovertible evidence of efficacy, although several—including prazosin and atypical antipsychotics such as quetiapine and risperidone—have had their successes (3, 4) and failures (5, 6). This disappointing state of affairs has led to calls for a prioritization of efforts to find new treatment approaches and in particular novel targets and agents for drug development for PTSD (7).

There was a time when many of us opted to use the term “pharmacological agents” rather than the colloquial and negatively tinged “drugs” when referring to medication treatments for mental disorders. In the past few years, such semantic distinctions may have become blurred, as many of the novel pharmacological agents being studied for PTSD (and depression) are, indeed, drugs. MDMA (“ecstasy”), psilocybin (“magic mushrooms”), and ketamine (“Special K”) represent the cutting edge of psychiatry’s (re)enchantment with psychedelic drugs for our patients who suffer from the chronic effects of traumatic stress (8, 9). The renaissance of these vintage psychoactive agents is highlighting our field’s struggles to identify and develop potent, novel pharmaceuticals. We have much to learn about the complex and interactive neural systems that drive psychopathology and treatment response in complex disorders such as PTSD.

In this issue of the Journal, Adriana Feder, M.D., and colleagues (10) present results of their important trial of repeated intravenous ketamine administration for patients with PTSD. This article, a follow-up to their study of single-dose ketamine for PTSD (11), makes a compelling argument that repeated dosing of ketamine may eventually have a role to play in the battle against PTSD. This small study demonstrated clear superiority of six intravenous infusions of ketamine compared with midazolam (a psychoactive control) over 2 weeks, with two-thirds of patients considered responders to ketamine compared with one-fifth of those receiving midazolam. In a rarity for mental health studies, the trial was stopped early (with 30 patients enrolled, rather than the preplanned 40 patients) when an interim analysis revealed that ketamine had an insurmountable lead over midazolam. While response (defined as 30% reduction in symptoms) does not represent remission and durability was still limited with a median time to relapse of 27.5 days, these are nonetheless both rapid and robust effects, suggesting that intravenous (and perhaps other delivery methods for) ketamine has tremendous potential as a treatment for PTSD. This conclusion leads to many questions such as “how” and “why.”

Ketamine is an N-methyl-D-aspartate receptor antagonist, although it is still uncertain whether its actions at that receptor mediate its antidepressant, and now anti-PTSD, effects. Considering the strong polygenic association of major depressive disorder and PTSD (12), one might expect there to be considerable overlap in therapeutics. Given that it has also been shown, in preliminary studies, to relieve symptoms of social anxiety disorder (13) and obsessive-compulsive disorder (14), it might be tempting to muse about the pan-diagnostic therapeutic or proresiliency effects of ketamine, which may well be true descriptively but contributes naught to understanding mechanism of action. Similarly, whereas it might seem attractive to test hypotheses about glutamatergic dysfunction underlying the pathophysiology of ketamine-responsive disorders, decades of work trying to link SSRI-responsivity to mental disorder biology have yet to prove informative. That said, it will be critically important to gain insight into ketamine’s mechanisms of action—and we use the plural deliberately—with an open mind to the possibility that different properties of the drug may mediate efficacy for different disorders.

Another open question for ketamine and other psychedelic agents of its class is whether concomitant psychotherapy yields a greater and more durable treatment response. Research in ketamine-assisted psychotherapy and its optimal application for PTSD is needed, including pairing with evidence-based trauma-focused therapies as the authors and others suggest (15). It is worth noting that this study applies the more medical model of ketamine use with an aim to function as an independent therapeutic. Nonetheless, it cannot be ruled out that ketamine—which has comparable effects on induction of a subset of psychedelic experiences as psilocybin and LSD—might be most durable in its effects if it is followed by psychotherapy (15). Ketamine’s postulated mechanistic properties that enhance neural plasticity may set the stage for greater receptivity to psychotherapeutic engagement and efficacy. Indeed, it is notable that Feder and colleagues found the greatest PTSD symptom reduction at 2 weeks in the subcategory of avoidance, which commonly is more resistant to rapid change in PTSD.

But with effects as large and impressive as seen in this study, one could be forgiven for wanting to jump ahead from the “how does it work” to the “when can we start using it” stage of mental health practitioner inquiry. The number needed to treat in this study was a remarkable 2, the treatment was well tolerated, and ketamine is already being widely used—either off-label intravenously or intramuscularly, or as the FDA-approved intranasal esketamine for treatment-resistant depression or depression with acute suicidality with intent—so extending its use to PTSD could be seen as both obvious and imperative.

However, as Feder and colleagues wisely counsel, there is still much work to be done before ketamine is ready for prime time in the treatment of PTSD. A total of 15 patients were exposed to repeated intravenous ketamine in this study; small, expertly executed trials such as this one are great for providing an impetus to study the treatment in larger samples, where response and tolerability will inevitably be less uniform. It is also important to remember that whereas ketamine and esketamine are filling a void in the management of treatment-resistant depression, patients in this PTSD study were not enrolled because they had treatment-resistant PTSD (which, at present, has no widely accepted definition). That said, half of the patients in this trial had histories of exposure to sexual assault or molestation—trauma types that might be expected to be more treatment-resistant than some others—and approximately half were symptomatic enough to enter the trial despite receiving another pharmacotherapy and/or psychotherapy, yet response was robust. This observation bodes well for ketamine (or esketamine) eventually assuming an important role in the management of treatment-resistant PTSD. But the work needs to be done to establish that therapeutic positioning.

Lastly, how worried should we be about the use of ketamine, a drug that can be abused, in a disorder such as PTSD that is strongly associated with increased drug and alcohol dependence (16)? This study purposefully excluded those with use disorders in the past 3 months. To answer this question, we must take into account that ketamine is also being used to treat substance use disorders, buttressed by animal and human studies suggesting that ketamine may pharmacologically “rewrite maladaptive memories” (17), a rather Orwellian albeit apt phrasing. To achieve this effect, the assumption is that ketamine, when paired with maladaptive memories (substitute “traumatic memories” for the PTSD use case), disrupts their reconsolidation, thereby weakening or ablating those memories. In this study with intravenous ketamine, there was no deliberate pairing of recall of the traumatic memories with the administration of the drug, and yet symptoms improved. Was it the case, then, that patients were thinking about their traumas when the drug was present, and that this adventitious pairing was sufficient for ketamine to have its rapid effects? If true, is it possible that more deliberate recall of the trauma at the time of ketamine administration would result in even stronger (and, possibly, longer-lasting) effects? This is a testable premise that, if upheld, would make ketamine for PTSD that much more special.

Department of Psychiatry, School of Medicine and Herbert Wertheim School of Public Health, University of California San Diego, La Jolla, Calif. (Stein); VA San Diego Healthcare System, San Diego (Stein); and New York University Grossman School of Medicine and Langone Health, New York (Simon).
Send correspondence to Dr. Stein (mstein@health.ucsd.edu).
Dr. Stein has received research grant support from the Department of Defense, the Department of Veterans Affairs, and NIH; he has received consulting fees from Acadia Pharmaceuticals, Actelion, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech; he has stock options in Epivario and Oxeia Biopharmaceuticals; and he receives royalties and editorial stipends from Wiley (Anxiety and Depression), Elsevier (Biological Psychiatry), and Wolters Kluwer (UpToDate). Dr. Simon has received research grant support from the American Foundation for Suicide Prevention, the Department of Defense, the Highland Street Foundation, NIH, and PCORI; she has received salary support from Cohen Veterans Network, consulting fees from Aptinyx, Axovant Sciences, BehavR LLC, Genomind, the Massachusetts General Hospital Psychiatry Academy, Praxis Therapeutics, SpringWorks, Vanda Pharmaceuticals, and Wiley; she has received royalties from American Psychiatric Association Publishing and Wolters Kluwer; and she has spousal equity in G1 Therapeutics and Zentalis.


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CHARLESTON, SC (FOX24 NEWS NOW) — Ketamine is a medication used as anesthesia since the 1970s. It produces a trance-like state that usually helps with pain, sedation, and memory loss. Ketamine has recently been discovered as an alternative treatment to assist with physical and psychological diseases. Dr. Richard Bowen of the Charleston Ketamine Center has been heavily involved in ketamine research and practice. Dr. Bowen and his team have conducted over 2,500 infusions over the past four years. He joins us in the studio today with more insight on the medication.

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