Hello I Want to Die Please Fix Me

by Anna Mehler Paperny

  17

  Old Illness, New Tricks—From Psychedelics to Smartphones

  Gerard Sanacora speaks of his work with a fervour out of keeping with his measured academic diction, peppered as it is with qualifiers—“as far as we know”; “for the most part”; “this probably isn’t the same in all brain regions.” “In my mind it is probably the most exciting development, at least for mood disorders, in the past fifty years. I really do see it as a game changer….It just opens up a whole new vista of treatments.”1

  “It” is ketamine. Otherwise known as Special K—a hallucinogenic street drug popular at raves. Up until recently its medical use was mostly as an anaesthetic. Now it appears to be pretty much the fastest-acting antidepressant ever. It’s been shown to work on people who don’t respond to anything else. It’s also a dissociative hallucinogen prone to misuse, its antidepressant effects wear off rapidly and while we know repeated frequent use can badly damage your cognition (and worsen mood disorders) we don’t know how or whether it can be clinically administered safely in multiple doses over a long period of time. Oh, and studies of its efficacy have so far involved teensy test-group sample sizes. Even if you combine them all they’re pretty small. “We’re just starting to scratch the surface,” Sanacora says, sitting at a table in the unassuming office in New Haven, Connecticut, from which he heads Yale University’s Depression Research Program. Part of the electric joy underlying this scratching of the surface is that, for the first time, researchers could be coming up with a treatment that brings with it a better sense of how depression works on a neurochemical level.

  But the more Sanacora and his colleagues find out, the more complicated everything gets. It isn’t as simple as having too much or too little of one chemical or another. It’s more likely a case of too much signal or flexibility in one area and too little in another; feedback loops gone awry.

  He thinks depression is less about chemical surfeits and shortages and more about the brain’s ability to adapt to its environment.

  Every experience you ever have changes your brain’s make-up: neurons fire, new connections are forming as you’re reading these words. Neuroplasticity is the way your brain stores and retrieves new information and the way it changes to fit changing environments or circumstances. If your brain has trouble adapting, has trouble forming new connections or trimming extraneous ones, that’s a problem.

  If depression is in part a plasticity issue, and if ketamine can remedy that even temporarily, Sanacora hopes it’ll be possible to capitalize on that window of optimized flexibility to teach the brain new coping mechanisms, through cognitive behavioural therapy or similar.

  It’s still early, early, early days.

  There’s a growing pool of evidence indicating that first shot of ketamine is effective. But the numbers of people involved in these studies get a lot smaller when it comes to longer-running studies examining the effects of multiple doses. In order for a drug to be approved for a specific use (as an antidepressant in this case) you usually need to follow thousands of people to ascertain not only whether it’s effective at a given dose over a given time period, but whether it’s safe and what the side effects are, and whether the safety and efficacy differ in different populations. You need lots of people and lots of time for that.

  Thanks to human misuse and animal experiments we already know ketamine can wreck your brain if you take too much of it too often or for too long, and that there’s a very fine line between the ideal therapeutic dose and a severely damaging one.

  “What I see clinically that really worries me,” Gerard Sanacora says, taking a moment to curb his enthusiasm, “is people who take it all the time. There’s good evidence that people who abuse ketamine or use it on a regular basis do have cognitive impairments. There’s evidence of structural abnormalities.”

  The Food and Drug administration approved ketamine for the treatment of depression in March 2019.2 (As of this writing, it hasn’t been approved by Health Canada but is being offered in some private clinics.) But probably tens of thousands of patients had already been prescribed ketamine off label before that. For example, at Yale, Sanacora had used it clinically, outside of research, for patients that were very well screened. And he felt that the risk-benefit ratio justified the use.

  Just don’t try it at home. “I would never recommend that. Period. Zippo.”

  Queasiness around giving people a month’s worth of ketamine to take home and spray up their noses goes beyond the drug’s potential to be misused and diverted, sold on the street. It can also be dangerous even if taken as directed. Even Sanacora’s patients who get it clinically have to be closely supervised every time.

  “It’s relatively safe, but if you start treating thousands or tens of thousands of people, people are going to die.”

  Ketamine is exciting enough to be enticing some pharmaceutical companies to get back into the game despite depression’s business-case turnoffs.

  It’s easy to be skeptical of corporate bromides on the importance of finding new and improved depression treatments, especially given the industry’s failure to do so over the past half-century. But Husseini Manji, head of Janssen pharmaceutical company’s Neuroscience Therapeutic Area, sounds genuinely jazzed about ketamine when I call him up.

  “Depression is so disabling for so many people. And for many people, they don’t get an adequate response to the existing treatment. And even if they do, it often takes four to eight weeks [to take effect] .”3

  Manji is heading up Janssen’s ketamine research. One of his studies took people with treatment-resistant depression, who’d been depressed for at least three continuous years and had gone through at least six antidepressants. Many had been failed by ECT, as well. Half got intravenous ketamine, half got an intravenous saline solution. The results were astonishing: within two hours, 60 percent of the ketamine patients began to respond; within a day, 70 percent did. That’s a huge response for any illness. But even more so for depression, for which, as he pointed out, most treatments take at least six weeks to kick in, if you’re lucky. “This was staggering,” Manji said, his serious tone belying the excitement in his voice. The magic didn’t last long: depression symptoms returned within a week. But it was something. “That got everyone very excited.”

  He and his colleagues focused on intranasal administration, the way you’d spray a decongestant up your nose. It’s simpler and requires fewer personnel than intravenous use—you don’t need people trained to administer an IV drip, for example—but it’s also a more efficient delivery system than a pill, he says. Pills are better for controlled, consistent release of an active ingredient as it meanders through your digestive tract and into your bloodstream. With ketamine, Manji said, you want it into your brain ASAP. “There’s actually a direct nose-to-brain connection, so we thought intranasal administration might do that.”

  They also switched to ketamine’s molecular mirror image, the esketamine isomer, which is in theory more potent—you can get an adequate dose in very few drops. Industry observers say it’s also arguably easier to patent something that’s just a teensy bit different from what’s been in use in various forms for decades: so instead of having a cheap molecule everyone can use, you have an expensive, patented one (patents are important; pharma companies are not in this biz to be nice).

  Manji figures ketamine’s mechanism of action is several steps downstream from what we’ve been doing all these years. It’s more direct, he says, than inhibiting the sucking up of neurotransmitters like serotonin and dopamine into the neuron. So if we’re taking a more biochemically direct route, he reasons, that could explain the relatively rapid effect and why ketamine has worked on people for whom more conventional treatments have failed.

  Yes, ketamine will make you high, especially the first time you get it. “You feel that the room might not seem quite real, or you don’t seem quite real. You might be floating or something like that.” But he argues that their studies so far indicate you can use ketamin
e chronically, under close medical observation, at least in the medium term, without it damaging your cognition. “If anything, we see cognition improve, because depression itself is associated with impaired cognition.”

  It isn’t yet clear how long you’ll have to keep squirting esketamine up your nose or at what frequency before you achieve and maintain remission. Manji hopes that adding traditional antidepressants and psychotherapy after about four weeks of esketamine will let you gradually reduce the frequency of ketamine doses without losing their ameliorative effect. But here, again, we need more longer-term studies with more people to see how that goes.

  One such Janssen study published in early 2018 found people who got esketamine in addition to their regular antidepressants (first twice-weekly, then weekly, then semi-weekly up-the-nose doses) had better depression scores, on average, than the people who got a placebo, and most of them stayed in relative remission eight weeks into the study.4 Here, again, the sample size was relatively small (sixty-seven people total, which meant that just thirty-four got the intervention in the first phase) and I’d wonder how blinded your study is if the placebo is water with a bittering agent made to taste like esketamine, but which won’t make you high. Surely you would notice pretty quickly. Either way, encouraging to the layperson. It’ll be nice to see how they propose patients hang on to that lessening of shit symptoms.

  Janssen also tested esketamine on suicidal inpatients, who either got ketamine plus “treatment as usual” (antidepressant and/or psychotherapy), or placebo plus treatment as usual and found that it had significant effects, on top of whatever else they were taking.

  But, I asked Gerard Sanacora, as we walked down the stairs of his university building and out into New Haven sunshine, even if you can alleviate someone’s pressing desire to die in the immediate term—which, don’t get me wrong, would be awesome—would you be any more willing to release that person from an emergency department or a psych ward knowing the magic potion you’d just given them would wear off within days of their hospitalization? He agrees he’d be hesitant, too.

  Husseini Manji of Janssen Pharma admits there’s been inadequate attention paid to the public health crisis that is suicide and depression. “Because the field is so complex and so uncertain, most companies have decided to focus on things they feel more confident about. Which I think is very unfortunate because the unmet need of psychiatric disorders is so staggering. Once we get more confident then we can make headway. Then [R&D investment] will all come flooding back. The hope is that esketamine is part of that new era.”

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  FOR SPECIAL K as an antidepressant, the high is a bug. For magic mushrooms as antidepressant, it’s a feature.

  The first tiny-scale studies into the use of psilocybin capsules—pills containing the active ingredient in magic mushrooms—are predicated in large part on the positive correlation between the patient’s “mystical” experience and a reduction in depression symptoms. Here I have to be honest: medical mysticism is not my thing. But that’s the magic behind using mushrooms to cure incurable depression, so here we go.

  Darrick May wants to be a psychedelics-assisted therapist but so far he just gets to play one in pilot studies.

  The Maryland-based Johns Hopkins University psychiatrist designed America’s first trial examining the efficacy and safety of psilocybin to treat treatment-resistant depression (a similar, similarly small study had shown promising results in the UK the year before). Twenty-four people with severe depression who’d been failed by multiple treatments would be divided into two groups of twelve. Each would get two doses of psilocybin a week apart but one would go through the process ten weeks later. “This way everyone gets psilocybin.” 5

  You can’t have a double-blind (or single-blind, or any kind of blind) trial when everyone knows whether they’ve gotten high or not: the placebo effect’s too obvious. There’s no good sham treatment to use as a control, Darrick May tells me. So, staggering the groups is not the gold standard, but is better than nothing.

  When I talked to him he was in the early recruiting stages for the study. He wouldn’t tell me much about participant criteria—how many courses of depression treatment they had to have gone through with no results in order to qualify, for example—because he was afraid people would lie about their medical histories to get in. That’s how popular the promise of free magic mushrooms and hours of quality time with trained professionals talking to you about your feelings can be: he got calls and emails from people in dire depressing straits across the country; he had to choose twenty-four. “It’s kind of a disheartening exercise.”

  Darrick May doesn’t yet know what magic mushrooms’ mechanism of action is. He seemed enthused about the possibilities but also realistic from a clinical perspective. He says studies have shown reduction in subjects’ depression symptoms “was positively correlated to how much of a mystical experience they had—that score on the mystical experience scale.”

  I ask, doesn’t the degree of subjectivity almost guarantee a confirmation bias? People who like the idea of a mystical hippy-trippy experience will love taking psilocybin, will report a mystical experience, and get better after taking it. He admits they’re also going to be the ones to volunteer for the trial. “People that seek out this treatment are very interested in trying it and probably have some positive associations and really believe that it can help them….So that is a bias. But it would be unethical, or it would be impossible, to give it to someone who doesn’t believe in it at all or thinks it’s going to hurt them.” There are plenty of people out there who already self-medicate with shrooms or acid or ayahuasca or whatever hallucinogen they prefer. And, he adds, there’s a lot of discussion in the psychedelic research community as to what clinicians’ role is in encouraging or quashing that: “Is it ethical to recommend a treatment that can be so psychologically impactful, both positive and negative?”

  He does recommend a controlled environment. If you’re going to do psychedelics, use drugs whose make-up has been molecularly confirmed in a health facility, and do them with a doctor, he recommends—not in a yurt in a forest.

  There’s a lot of getting-to-know-you time before your clinical shrooms trip, May says: the clinicians guide you through the process (yes, they are called “guides”), talk with you about your life, your hopes and dreams and what the experience will be like. On the day of, avoid a huge breakfast—messes with absorption—take a urine test and a baseline questionnaire and swallow the psilocybin capsule with a glass of water in a cozy room with a couch, meditation cushions, incandescent lights and the kind of ambience I’d expect in a yogi’s home office.

  “For the first half hour we usually have them look at some picture books, like nature or mandalas—we just want them to relax during that period.” Then you lie down, put eyeshades and headphones on and spend six hours listening to a music playlist and having an “inner experience.”

  Some have bad trips, but with all the preparation and in that controlled environment, it’s rare. Guides tell them to “meet and greet anything that comes up, and be curious about it. If something is scary, then ask, ‘Why is this scaring me?’ and if there’s a monster there, look in the monster’s eyes and say, ‘What are you doing here? What can I learn from you?’”

  Who should get this drug? “It’s too early to say if anybody should be getting this drug. I mean, it has not been proven that it does work. There’s only been pilot studies,” May says. Even he, for all his belief in the power of mystical experiences to attenuate depression over the long term, doesn’t see pharmacies dispensing shrooms any time soon. He doesn’t think patients should be given pill bottles of synthetic psilocybin capsules. The practice should be restricted to the way it’s being provided in his study: in six-hour sessions in a comfy room under the auspices of a trained guide to take care of you. “There’s too much potential for bad outcomes” otherwise.

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  PEOPLE LOVE THE I
DEA of personalized treatment. Everyone wants to be a special snowflake.

  That’s what biomarkers could make possible: if researchers can find those telltale, testable tags in your biology that indicate without a shadow of a doubt whether you have a given disorder, and what treatment you’re most likely to respond to, it would eliminate much of the fumbling guesswork that now characterizes depression treatment.

  But even if efforts to determine who’s most likely to respond to which treatments pan out, that’s of little use if we don’t have effective alternatives for the people found unlikely to respond to existing treatment options. Congratulations, Patient 8473! Blood analysis has determined you’re less likely to respond to antidepressants. Stand by while we develop other treatments and ways to test whether they’ll work on you. Your estimated wait time is…about ten years. Please stay on the line: your health is important to us.

  Don’t tell Madhukar Trivedi, on the cutting edge of this field at the University of Texas Southwestern’s Center for Depression Research and Clinical Care, that biomarkers aren’t worth chasing. The director gives reasons for hope even among our interventions’ limitations.

  “The crux of my work these days is to develop and validate biomarkers. So the short answer is yes, we definitely need to identify specific biomarkers for specific individual patients.” 6 Instead of having a clinician walk you through a series of questions about your thoughts, feelings, mood and ability to accomplish day-to-day tasks to determine whether you have a mood disorder, you could have a blood test or a brain test or a cheek swab or a stool test that would hopefully, Trivedi says, then match the right treatment to the right patient.

  He acknowledges we’re a ways away from being able to do that with any degree of confidence. Is he optimistic? “Depends on the day of the week you ask me, and also my capacity to predict the future.”