October 2016
San Francisco Magazine
DYING TO LIVE
IN HOPES OF CURING HIS DEBILITATING DEPRESSION, THE AUTHOR TURNS TO THE PSYCHEDELIC DRUG KETAMINE AND WAGES AN EXPERIMENT IN “VOLUNTARY DEATH.”
BY JAMES O’BRIEN
ON A COOL EARLY
morning in late summer my wife and a dead man head south 370 miles to Los Angeles. The dead man has my name, my voice, my increasingly despondent slouch. He is me without my spirit, which has seemingly absconded, carrying with it all hope. We leave our home in Oakland just after dawn, long before the fog has burned away. My wife, Terri, drives. Neither of us feels much like talking. We're traveling to a doctor's office in downtown Santa Monica, but my ultimate destination today is somewhere non-geographical, a place where only I can go.
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My iPod feeds a random mix into the car's sound system, and, as we roll onto I-5 somewhere south of Tracy, a song by the garage-punk band the Satelliters shuffles up. I hear the singer growl out an invitation, or maybe it's a challenge: Take a trip to your soul/Take a trip to your mind, man / Come on and travel down the depths / And feel what you can find there ... on the way inside your head.
"Oh my God," I say, uttering my first words since leaving home. "That's exactly what I'm doing today!" Terri nods; she sees the connection, just doesn't want to indulge my premonition. This isn't an omen, her silence seems to say. Just a song. By the time we hit the Grapevine a few hours later, I've queued up the track five, six, maybe seven times. I'm clearly driving Terri crazy, but I can't help myself. It just seems so appropriate. I'm going on a trip inside my head, man. That afternoon, I enter a bland building that stands in wan contrast to the sharp blue Santa Monica sky. I take the elevator to a beige room on the eighth floor, and there I meet Dr. Steven Mandel, an anesthesiologist and the founding physician of Ketamine Clinics of Los Angeles, who greets me wearing scrubs. After I hand over a check for $1,500 and fill out a questionnaire, I'm led to an examination room where Mandel lays me on a gurney, hooks me up to an IV, and begins infusing approximately 80 milligrams of the drug ketamine into my system. The moment when the needle penetrates my skin, the slight pain of it, is thrilling. I have no idea what will happen to me while I am on this drug, a Schedule III controlled substance (street names: K, Special K, Super Acid, Purple, Jet) that is increasingly considered by researchers and psychiatrists to be a potentially life-changing antidepressant. I have no idea what the outcome of this treatment will be, but, despite the unrelieved depression of the last decade of my life, I'm hopeful. It's an emotion I haven't felt in a long, long time.
I received my first diagnosis of major depression 30 years ago and have dealt with it at varying levels of intensity ever since. One day in therapy about five years ago, my psychologist asked me how I would feel if the chronic depression that I've long struggled with was "it”. What if there was no medication that could ease my state? How would I cope, she asked, if this was the way I was going to be for the rest of my life? She left little room for denial: I had begun to run out of options.
In the 10 years since the winter of 2006, when depression's icy grip returned after a brief remission, I have tried Prozac, Zoloft, Lexapro, BuSpar, Effexor, and Wellbutrin. I have taken Effexor and Wellbutrin in tandem with lithium and also in tandem with Abilify. I've tried some of the above alongside other drugs not specifically developed as antidepressants, but that were thought might be helpful anyway -- drugs for Parkinson's, for instance. I've tried acupuncture, light therapy, prayer. I have been taught mindfulness meditation, dialectical behavior theory, cognitive behavioral coping skills. I have had my genes, blood, and thyroid tested. And still I wake up many mornings with what feels like an enormous sense of loss.
"THE LONGER SOMEBODY'S DEPRESSED, THE MORE SERIOUS THE DEPRESSION, THE MORE FREQUENT THE EPISODES, THE MORE CHANGES OCCUR IN THE BRAIN. IT IS A PERSISTENT MISERY."
Sometimes it is so profound I can't talk. It's not sadness, it just feels like sadness. It is grief without grief. It manifests physically as a weight like a medicine ball in my core. It causes a low-grade vibrating anxiety to pulse through my limbs. It clogs my brain, weakens my reasoning. It encourages me to isolate myself for weeks at a time, embarrassed by my stupidity. It has produced in me an off-putting, brooding intensity, an occasionally gloomy contrariness, and has contributed to lost friendships and a shipwrecked career.
Often I deny that I am sick and accuse myself of all varieties of personal failings. I feel ashamed of my condition. Because of my shame, and partly as a way of shielding my loved ones from concern, I try to cover up the depression. I get up early every day. I groom and I exercise. I go to work and am able to interact with colleagues. I am not addicted to booze or cigarettes or narcotics. I am never manic. I do not have panic attacks. I just have this intractable feeling of sorrow that once, many years ago, was receptive to antidepressant Prozac saved my life when I was in my 20s and again in my 30s -- but no longer is. It is painful to smile. Every picture of me for the last decade looks like a mug shot. And I'm guilty.
"This can't be it," I said to my psychiatrist that day, suddenly pissed off. "I won't last." I could not envision living the rest of my life with the ceaseless self-doubt, with a self-consciousness so acute it felt like stage fright. The technical term for this half-dead, numbing feeling is anhedonia, which means you can't feel pleasure. For me, it's like I died and no one told me. I remember feelings. I can approximate the normal human responses to them. I understand how to mimic human emotions at the appropriate times. But in a sense I'm acting.
There's science to back up my psychiatrist's dismal diagnosis: Recent brain imaging studies suggest that depression can compound over time unless something is done to stem its flow. The condition can actually damage your brain. "In some ways, it's as if the brain evolves," says Dr. Charles Debattista, a professor of psychiatry and behavioral sciences at Stanford Medical Center. "The longer somebody's depressed, the more serious the depression, the more frequent the episodes, the more changes occur in the brain. And it is as if the brain is learning to become depressed, and it becomes more challenging in time to treat that depression. For many patients, it is a persistent misery."
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When Debattista says this to me one afternoon in his office at Stanford, I think, not for the first time, about the exit bag. It's a device consisting of a plastic bag, some elastic, a hose, and a helium tank that, when self-administered, supposedly asphyxiates you to death calmly and painlessly. There have been nights over the past 10 years when I would use my phone to search the Internet for information on how to construct an exit bag, all while my wife was sleeping beside me. Sometimes I'd just look at pictures or diagrams of the bag. I would read forum commentaries by people for whom the bag had failed, some of whom were determined to try again. Occasionally my wife would stir. Sometimes she'd wake up for a moment and tell me she loved me and give me a sleepy kiss, and I would be sure to turn the screen away so she wouldn't see what I was looking at. Or I would hide the phone under the blanket and quickly pick up a book and pretend to read. It was always a heartbreaking moment.
IT WAS LATE
2014 and early 2015, around the time of the exit bag obsession, that the so-called ketamine cure began seeping into my consciousness. I'd begun to run across news stories about the increasing—if still experimental—use of psychedelics for depression. A story on Al Jazeera America asked, "Could Ketamine Become the Next Great Depression Drug?" Other stories mentioned clinical trials that seemed to be sprouting like poppies in early summer. One study out of the United Kingdom reported that ketamine had been shown to help people with severe depression, with 29 percent of subjects seeing their depression scores cut in half.
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Positive reports like these lent credence to older findings that ketamine has antidepressant effects. In small clinical trials, especially starting in the '90s, ketamine appeared to lift deep depression in patients for whom nothing else had worked. In 2000, researchers at Yale found that very small ketamine infusions had significantly decreased depression in seven patients. A study out of the National Institutes of Health in 2006 replicated the Yale results in 18 subjects.
Still, as the lead researcher on that study, Dr. Carlos Zarate Jr., would later tell me, “because of the side effects, many people did not touch it.” We do know a lot about ketamine, at least as an anesthetic. It has been around for 50 years and is used commonly with animals (most famously as a tranquilizer for horses) as well as people. A derivative of the dangerous hallucinogen PCP, it was first tried out in 1964 on prisoners in a Michigan penitentiary, who reported feeling like they were floating in outer space—who acted "skitzy," as Dr. Edward Domino, who was there with those prisoners that day, tells me. Since then, ketamine has been used by researchers to induce the symptoms of schizophrenia in otherwise normal subjects. During the Vietnam War, it was given to American GIs as a "buddy drug," an emergency anesthetic for soldiers to administer to a wounded comrade to ease his pain while awaiting medical help.
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No one can say for certain how the drug became known to the wider, partying public, but those returning war veterans may have spread the word that a little Special K made for an interesting trip inside your brain. By the 1970s, ketamine had become a beloved little brother to LSD. Perhaps its most famous acolyte was Dr. John C. Lilly, a physician, psychoanalyst, biologist, physicist, and researcher known for his efforts to decode the language of dolphins, work made famous in the Mike Nichols film Day of the Dolphin. Lilly did so much ketamine that he insisted he was communicating with beings from the year 3001. Later, high on the drug, he almost drowned in his swimming pool. Another committed user, D.M. Turner, author of The Essential Psychedelic Guide, did drown, in his bathtub. A third ketamine enthusiast, a psychic and writer named Marcia Moore, disappeared; her remains were reportedly found later in the crook of a tree in a forest.
In the '80s, ketamine became a popular club drug that, when snorted, injected or swallowed in pill form, made users, as one experienced friend of mine describes it, feel like they were "dancing on a sinking ship." People still seek what is called the K-hole; take enough of the stuff and you will have what has been described as a kind of out-of-body, near-death experience that some find exhilarating, some terrifying. Famous psychonaut Timothy Leary described his trips on ketamine as “experiments in voluntary death." Today its abuse is so rampant in China that the country has tried to have it recategorized as a Schedule I drug, meaning that, having no medical use, it is strictly illicit and illegal. Its emergence as a recreational drug confounds the 91-year-old Domino. "To my astonishment," he says, "there are too many people who enjoy acting as though they were nuts." Ketamine, says Domino, is like wildfire. "Control it," he says, "or you're going to have nothing but damage."
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Because of its history of abuse and a shortage of clinical proof, the use of ketamine for depression has faced significant resistance within the psychiatric community.
Many brain and drug researchers say we don't yet know enough about ketamine to begin prescribing it for depression. The only real proof of ketamine's efficacy, they say, is to be found in carefully designed, double-blind, placebo-controlled clinical studies repeated over time. But because it is an older, generic drug, there isn't a lot of profit to be made off ketamine, so studies are usually funded by the federal government—a reticent researcher of illegal drugs, to say the least—and not by big pharmaceutical companies. In large part this is why ketamine studies have been relatively small, with relatively tiny sample sizes. According to a recent analysis by the American Psychiatric Association, fewer than 200 patients have ever been studied in such trials. Dr. Charles Nemeroff, the chair of an APA task force that is compiling an official set of recommendations for physicians considering prescribing ketamine to patients, is more than a little circumspect about the drug's clinical usage. "I received an email from a clinician," he says, "who told me that he had 1,500 patients that he was giving routine and regular ketamine treatments to. My question would be, We have no data on repeated use of ketamine: Is it safe? Is it effective?"
But such resistance may be futile. Slowly, inevitably, patients and their anecdotes of miraculously vanquished depression are starting to get the upper hand on scientific skeptics. Clinicians at Kaiser Northern California have been prescribing ketamine for depression since late 2014, with upward of 70 patients—people who have in some cases failed to respond to as many as 10 different therapies previously—having received the drug. Dennis Hartman, founder of the Ketamine Advocacy Network, an online listing of clinics and clearinghouse of information on the drug, calls the Kaiser ketamine program a watershed moment; finally, a massive, mainstream HMO is acknowledging the effects of the drug and covering its use. Elsewhere, Stanford's Department of Psychiatry and Behavioral Sciences, under Debattista, is enrolling subjects in the most rigorous ketamine study yet. It's a six-site trial led by Massachusetts General Hospital and funded by the National Institute of Mental Health (NIMH). Ultimately, it will involve 100 subjects and seek to answer many of the outstanding questions about using ketamine to treat depression: What is the most effective dose? How long do the effects of one dose last? How do you determine who is the best patient to give ketamine to?
What these studies are not yet attempting to do is discern how exactly ketamine works on depression. It's thought that ketamine differs from common antidepressants—which tend to regulate production of the neurotransmitters serotonin and norepinephrine, and which take weeks to have any effect—by stimulating the release of glutamate, among other neurotransmitters. Past studies out of Yale posited that by triggering glutamate action, ketamine is repairing parts of the brain damaged by chronic depression—or rather by the stress that such depression induces. But all of this remains in the realm of theory.
Perhaps the most remarkable aspect of the ketamine cure is its reported ability, in some patients, to lift symptoms of depression within hours. This rapid action is particularly promising for depressed patients threatening to harm themselves. As it stands now, there is no real emergency treatment for people who turn up at hospitals suicidal. They're typically sedated, monitored, and then treated symptomatically, perhaps with antipsychotic or antianxiety meds. Ketamine for suicidal thoughts, on the other hand, can be practically like ibuprofen for headaches. Several studies have shown that suicidal ideation decreases significantly on ketamine, often within four hours. In a 2010 NIMH study of 33 suicidal patients given ketamine, depression lifted within 40 minutes on average.
"There's no doubt in my mind," says Dr. Mason Turner, head of outpatient mental health services for Kaiser Northern California, that in administering ketamine, "we are saving lives and we have actually prevented suicide attempts." Turner admits that our overall understanding of ketamine as a treatment for depression is suboptimal. "In terms of the body of evidence, I would say it is probably thinner than some other treatments that we use," he tells me. "But there's enough that we feel very comfortable saying that it's a very medically appropriate and very important treatment to offer our patients." He says that Kaiser has had a 70 percent "immediate response" rate with the drug and a 60 percent "long-term response" rate—results that blow almost every other treatment method for long-term depression out of the water.
"MORE THAN ONCE I REACH AN EMOTIONAL EXTREME THAT I IMAGINE FEELS LIKE DYING. 'IS THIS DEATH' I WONDER. 'OR IS THIS THE ROAD TO DEATH THAT EVERYONE TAKES AT THE VERY END?'"
DEPRESSION DOES NOT
necessarily encourage paying attention to details. For a person suffering from the disorder, every situation, no matter how seemingly safe or mundane, carries peril. And so you always look for the shallow end of a problem, dip a toe into it, and quickly retreat. When I talk to Mandel a week before my first infusion, this is what I hear: You will come in Friday afternoon, get your infusion, trip out for about an hour, then go have a nice weekend. It is an offer that I find irresistible, far superior to my few remaining alternatives. It is estimated that up to 30 percent of the approximately 14 million American adults suffering from depression have not responded to traditional antidepressants like Prozac, Lexapro, or Zoloft. Once a depressed person has failed to respond to at least two therapies, he or she is often called "treatment refractory," or "treatment resistant." Options then become extremely limited, expensive, and, for lots of patients, including me, simply frightening. One option is transcranial magnetic stimulation, or TMS, in which technicians, under the supervision of psychiatrists, send magnetized electrical pulses into your brain for 20 to 45 minutes a day, five days a week, for four to six weeks. It costs thousands of dollars and has about a 30 to 50 percent success rate. Another often effective option is electroconvulsive therapy—shock treatment—which artificially induces seizures. ECT affects the memory; with the use of anesthesia, it hurts less than it used to, but the stigma of having undergone shock treatment is palpable, and, to me at least, seemed as likely to induce future shame and depression as to mitigate them.
Because of the cost of such treatments (to secure TMS treatments from a clinic in Berkeley, I would have had to spend a minimum of $5,000 out of pocket) and because of their potential downsides, I decided to take my chances with ketamine. And, frankly, the chances seemed good. The success stories about the drug are indeed legion. I wanted to talk to patients who had undergone ketamine therapy, so my psychiatrist put out a request to colleagues on an online message board. One of the psychiatrists I heard from was Dr. Theodore Henderson, who has a busy ketamine clinic in Denver and who agreed to put me in touch with some of his patients.
Jennifer Newman, 40, lives in Colorado Springs and works for the local NPR station. She told me that she has struggled with paralyzing depression since her teens. She couldn't go out, couldn't answer the phone, was unable to talk to friends. She had a small child and was struck by a fear that she'd be institutionalized. Her brain, she said, felt shriveled up. Over the years, medications would help, but their effects would never last. All of that changed after Newman visited Henderson's ketamine clinic, beginning in February of2015. For her, the drug worked right away. She told me over the phone that ketamine "breathed life into old passages. It helps me utilize tools, things that make me happy. I don't have that block anymore."
Another woman I spoke to, June Winsor, also lives in Colorado Springs. She is in her mid-40s and said she was diagnosed with major depression, panic disorder, and agoraphobia. Constantly weepy and occasionally entertaining suicidal thoughts, she tried medications, hypnotherapy, and eye movement therapy. She went to see a shaman. Eventually, she lost her job because of her depression and went on disability. She was preparing to undergo ECT when her psychiatrist told her about ketamine. Winsor went to Henderson's clinic. She had her first infusion in October of 2013. "I went," Winsor told me “from wanting to die to actually wanting to live."
Hartman, the Ketamine Advocacy Network founder, lives in Seattle. He's been ·a CEO, the president of a startup, and a partner in a global consulting firm, but after decades of depression, he could no longer work. He'd already set the date for his suicide. "There's only so much suffering one person can reasonably endure in one lifetime," he told me, “and I decided I'd had enough.” Online late one sleepless night in 2012, he found information on a ketamine trial at NIH. Forty-eight hours later, he was flying east to a government hospital in Bethesda, Maryland, where he received his first infusion of ketamine. His symptoms lifted almost immediately. "My depression is now something I can manage," he said. "I can feel good, which are words that never came out of my mouth for 46 years of my life."
Testimonials like these, of course, aren't science. There are undoubtedly patients for whom ketamine has little or no effect. Even overnight success stories like the above could simply be placebo effects. "In the depression world, this happens all the time," says Debattista. "Something looked really promising when we gave the drug openly, but when we did controlled studies, it didn't look that different than the placebo.
He says that researchers have looked at many potential antidepressants in the past, ones like ketamine that are thought to attack a different chemical messaging system in the brain than traditional antidepressants. "The only thing they have in common so far," says Debattista, "is that they have all failed, every single one of them. When it came time to do the carefully controlled studies to demonstrate their efficacy, even though they looked promising early on, they fell flat."
As my appointment date at the Ketamine Clinics of Los Angeles nears, I am outwardly skeptical. But inside I'm desperately hopeful. Even as I grow apprehensive about tripping on ketamine, I spend my evenings secretly imagining a me like I used to be, a me with confidence, warmth, humor, and energy. A me with an almost absurd level of curiosity about the details of the world around me. I think about how much easier my wife's life will be if I can smile, make eye contact; about how much less my mother will have to worry about me; about all the great writing an undepressed Jim O'Brien could do. I'm envisioning nothing less than a full resurrection.
And so, early in the morning of that day in late summer, after all these years of unabated depression, my wife, my blighted brain, and I head south for my infusions. (The clinic recommends that I purchase, at a cost of $3,300, a series of five infusions, but I opt for two for $1,500.) Terri drops me off on Santa Monica Boulevard, no doubt thankful to be free of that Satelliters song. I enter the office, hand over my check, and prepare to enter the unknown.
Mere minutes after Mandel begins the IV and exits the room, I sense a sudden change in my perception. The eyeball-shaped surgical light in the ceiling stretches out its long arm and peeks under the cloth covering my eyes. It seems very curious about me: Hello there. It is jarring to be stared at like this. I try to cling to reality, constantly checking in with my mind, reminding myself that whatever I'm feeling or seeing isn't real. I recall now a kind of soaring over strange and colorful terrain, and cycling through strong emotions: fear, awe, anxiety, excitement. Each cycle ends with a deep, gasping breath and me wondering if the trip is over or about to get further out-there.
I am listening to my iPod, to a playlist meant to be mellow and uplifting, but I quickly realize that pretty much every mellow song I have is also incredibly depressing. A song with the line "I miss you when the rain is falling" reminds me of this search I am on for a predepression me, a person I seem to remember and whom I miss terribly. A song with the line "I'm going to see the one I love" seems to describe exactly what I hope I am doing inside my brain: finding the old me I loved, as opposed to the current me, whom I hate.
More than once I reach an emotional extreme that I imagine feels like dying. "Is this death?" I wonder. "Or is this the road to death that everyone takes at the very end?" The first time it happens is the only time I'm truly frightened; for a moment I worry I'm not coming back from wherever it is I am. But soon enough, to my great relief, I regain my shaky connection to reality. On death's next incursion, I become more analytic: I wonder if perhaps ketamine has caused some chemical to be released or synapses to be connected that are usually reserved for the process of dying.
I am under (or, as I begin to understand it, "inside") for about 45 minutes, until I hear Mandel call my name. I keep thinking about the stories of how quickly ketamine works, how it zaps depression on the first infusion. As Kaiser's Turner attests, "The effects of ketamine are really, really fast. We usually see results within a day, 24 hours." But it's early in the ketamine experiment as it were, and knowledge is evolving. Until recently, he says, "the traditional thinking was that if you don't respond to the first infusion, you aren't going to respond to successive infusions. [Now] perhaps it's the second infusion, or even the third."
Coming down in the exam room, it's devastatingly clear to me that nothing much has changed. The dead man is still inside me. I can feel the weight of the medicine ball in my core. I don't want Terri, out in the waiting room, to know this, and I text her: "Out in a minute, a whole new me!" But it is a lie. I leave the office feeling almost exactly as I did when I walked in.
As the hot, dry Southern California weekend progresses and I wait to undergo my second infusion on Monday, I grow increasingly depressed. During the day, I go through the motions, act the way I assume a newly uplifted person is supposed to act. At night, I change up my iPod playlist, listening to more upbeat music. We are staying at my father-in-law's house in the Santa Monica Mountains. It is too hot to sleep, and the nights drag on; after midnight, I take a dip in the pool, try to relax, try to float, but instead I just keep sinking.
Finally I'm back in downtown Santa Monica on Monday morning, and Mandel asks me how I handled the first infusion. I tell him that I didn't freak out and I felt normal within an hour. He increases my dose. While I'm inside, the notion hits me again that the treatment isn't working, and that thought makes me feel more negative, and the trip grows darker, literally darker. I'm levitating over a deeply green hillside, like Ireland after a season of rain. I try to enjoy the vision, but then dark, craggy rocks begin to emerge out of the green. Suddenly I can see crowds of tiny beings populating the green areas between the rocks, but then a dark cloud-like sand being kicked up in a churning tide -- encircles them and swallows them up and eventually engulfs the whole landscape. I begin to wonder if I am just a negative spirit and doomed to be one for the rest of my life.
After I come out of my trip, I sit up, pull my phone out, and take a rare selfie. It comes out blurry and seems to capture a look of helpless confusion. The next day, my wife, my niece, and I head up to Santa Barbara, then Avila Beach. I am pretty taciturn, but there is a picture of the three of us in which I am almost smiling. It's something.
On Thursday, as we drive back north, onto 880 and into the outskirts of Oakland, at first I feel more profoundly the disappointment of returning home the same old me. I envy Jennifer and June and Dennis and others I've spoken to, for whom ketamine so quickly worked. I believe their stories, even if for me ketamine has become just another in a long list of ineffective treatments. When I check in with them from time to time, I hear an almost palpable disbelief that they are where they are now. A year after her last ketamine infusion, June says she has reduced her depression meds. Jennifer tells me about the radiance of a Colorado summer. It reminds me of that old lost joy I felt in noticing the world around me.
Recently, I got an even more profound reminder. Flipping through an old notebook, I ran across a list I didn't remember writing titled "Things to write poems about." The list was about 10 years old, compiled during my last remission. Many of the entries are obscure to me now, but I see it as documentary proof of the person I remember, the one I'm still looking for. I'm stunned by its breadth, by the quotidian things that inspired me: a man staring; a colony of potato bugs found under a planter; an estranged sibling; the Battle of the Stronghold; an infant's arm; the photoperiod for chickens; moonrise over a liquor store; a thin wall between two apartments; the mystery of St. Joseph's end; a crab trap out of water; hands crossed; a hot wind; a winter tree.
Reading the list again, I feel a glimmer of optimism that that fascinating world, and that person it fascinated, still exists. I feel something like desire. I recall the hopeful moment of the IV needle's prick. I remember the visions I had in the nights before we drove to Santa Monica, visions of a more peaceful life for myself and everyone I love. These memories motivate me to keep trying. I begin to check my calendar. I know it's time to clear the six weeks necessary for TMS, the magnet treatment, to try again to get back to the world. Maybe, just maybe, hope itself is the cure.