My brain on ketamine

Liquid, solid, pollen, insect: no, thank you.

But give me a syringe of liquid ketamine compound, and I’ll happily snuffle that twice a week.

I’m not abusing a substance. I don’t even appear to have developed a dependence on the stuff, which a compounding pharmacy refills for me monthly. It’s part of a cocktail of drugs I’ve been prescribed in an attempt to claw my way out of the sucking mud-pit of depression, to function in the world, to keep from killing myself.

This may come as a surprise to those most familiar with ketamine as an animal tranquilizer or a mind-escaping party drug. The latter use has made it a controlled substance in Canada and the United States. But for life-destroying illnesses ill-addressed for centuries, it offers a new shred of understanding and, just maybe, a modicum of hope.

Evidence of ketamine’s efficacy as a therapy for depression has grown. Studies so far have shown about 20 per cent to 30 per cent of people with treatment-resistant depression achieved remission using the drug, and if you look at those getting any kind of benefit, the figure is more like 50 per cent to 65 per cent. For a population in the grips of awfulness and which has been failed by multiple courses of medication, that’s a whole lot better than nothing. So doctors, researchers and entrepreneurs alike are starting to bring ketamine into the mainstream as a treatment for psychiatric illnesses – primarily to tackle treatment-resistant depression, but potentially also bipolar disorder and post-traumatic stress disorder (PTSD).

And there’s a massive need. I guarantee you know someone, whether you know it or not, who is struggling with mental illness and for whom existing treatments aren’t sufficient. Thanks to decades of underfunding research into a mind-bogglingly complex organ, our arsenal of brain treatments is meagre and haphazard.

But for now, ketamine as a treatment for mood disorders is an option primarily for privileged Canadians. You need deep pockets or a generous insurance plan to access it. Its boosters hope enough evidence will convince provinces to fund it as a treatment option – but Canadians’ access to any psychiatric treatment, much less something this seemingly controversial, remains grossly inequitable.

We’ve sucked at addressing depression for far too long. Surely the hope ketamine offers (with cautious caveats, including that it doesn’t work for everyone, and we’re still not sure how it works or how to make its effects last) ought to be apportioned according to need.

Research into ketamine treatment has changed our understanding of depression. Until recently, doctors understood depression primarily as a monoaminergic illness, meaning too few of a trio of neurochemicals bouncing around the spaces between neurons. But ketamine – an anesthetic first synthesized in 1956 – is an NMDA receptor antagonist: It gloms onto your brain’s n-methyl-d-aspartate receptors and blocks them, resulting in way more glutamate floating around. Among other things, glutamate facilitates neuroplasticity – your brain’s ability to change and adapt, to form new connections in response to experience. (Ketamine also targets other receptors and affects other neurochemicals, but glutamate is the main one.)

“Among other things, in the brains of people who are affected by depression, there appears to be something abnormal with brain plasticity – something wrong with how the brain cells are connecting and forming new connections with each other,” says Roger McIntyre, a psychology and pharmacology professor at the University of Toronto who helped create a centre specializing in providing ketamine for mood disorders.

Ketamine’s antidepressant effect could also involve a small but crucial brain structure: the lateral habenula, which is, among other things, responsible for processing and relaying negative information – letting you know when you’ve messed up and need to approach a situation differently. (That guy trying to pick you up at the bar, who just can’t take a hint? His lateral habenula may be broken.) Researchers hypothesize that the lateral habenula in depressed people is turned up to 11. What should be an adaptive mechanism instead immerses you in an endless sense of failure.

One of ketamine’s immediate effects is to turn that volume way down by blocking “bursting activity” facilitated by those NMDA receptors – what psychiatrist Joshua Rosenblat calls “removing the weeds.” Dr. Rosenblat, a researcher at University Health Network and the University of Toronto’s psychiatry department, thinks about the mood-disordered mind as a garden gone to seed: You have to weed the plot before you can plant something better – “basically, planting those seeds and allowing those new neuropathways to grow and flourish,” he says, so as to create room for more positive neuroactivity, such as concentration, energy and functionality.

So ketamine comes at depression in a fundamentally different way than other drugs used to treat the illness. Crucially, it also does it faster. While selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors can take weeks to kick in, ketamine – when it works – can do so within hours. Put another way, SSRIs start near the top of the Rube Goldberg machine of your brain’s neurochemistry: They need a lot of downstream steps to take place before they kick in. Ketamine skips to the final kerplunk.

“There’s a rapidity there, a speed that hitherto has not been seen in psychiatry,” Dr. McIntyre says.

Armed with a growing body of evidence, and in the relative absence of public provision, ketamine providers of various stripes are getting in the game. Janssen Pharmaceuticals (owned by Johnson & Johnson), for instance, patented ketamine’s molecular mirror image, esketamine, and sells it as the instranasal spray Spravato. The U.S. FDA approved its use for treatment-resistant depression in 2019, albeit only through a restricted distribution system, and health care providers must monitor patients for at least two hours after they receive a dose. Health Canada issued Spravato a notice of compliance last year.

Meanwhile, private clinics offering ketamine for depression have popped up across Canada, from Saskatoon to Halifax to Toronto. Dr. McIntyre is the founder of one of those clinics, the Canadian Rapid Treatment Centre for Excellence (CRTCE), which started three years ago and is now operating in Ottawa, Montreal and two Toronto locations. (Dr. Rosenblat is the CRTCE’s medical director.) There, trained health professionals offer several treatment options: weekly intravenous infusions, pills to swallow or a liquid to spray up the nose. They’ve given more than 3,000 treatments so far, Dr. McIntyre says.

Another such company is Field Trip Health, which has opened clinics in Toronto, New York, Los Angeles, Chicago, Atlanta and Houston in the past year and provides ketamine-assisted psychotherapy for just about any disorder (though in Canada, it’s just for those with treatment-resistant conditions). Field Trip tries to make the experience as far from doctor’s-office fluorescence as possible. Its Toronto clinic features a moss wall, special lighting, zero-gravity chairs and eyeshades. “It is a very spa-like experience,” says Ronan Levy, Field Trip’s executive chairman. “It’s a place you want to be, as opposed to a place you have to be.”

But at Field Trip, the focus isn’t just on ketamine’s antidepressant effect, but also the opportunity that comes with ketamine’s high. Clients at its Toronto clinic get four to six ketamine sessions, during which they take a pill under the tongue and then immediately undergo a kind of amped-up psychotherapy that aims to take advantage of the brain’s psychedelic state and ketamine-boosted neuroplasticity. Patients can also come back for one-off maintenance sessions.

“During the psychedelic experience, people are very often able to revisit past experiences, past traumas, past events in their lives that may actually be a driving factor or a causal factor” of the disorder, Mr. Levy says. “What would take months or years in conventional therapy can often be achieved in a single session or two sessions.”

Except, according to Dr. Rosenblat, the evidence doesn’t back that up. There have been no randomized controlled trials (RCTs) showing the efficacy of ketamine-assisted psychotherapy, he says. (Mr. Levy sent me a 2019 paper looking at 235 patients from three ketamine-assisted psychotherapy practices in the U.S. that found “clinically significant improvements” in depression and anxiety scores. But that’s not the same as an RCT.)

Not all psychedelics are the same, points out Dr. Rosenblat, the CRTCE’s medical director. Ketamine is different from magic mushrooms, whose active ingredient, psilocybin, has been used in mind-altered psychotherapy. While ketamine has shown efficacy in treating depression on its own, it doesn’t get you the same kind of epiphanies that lend themselves to teasing out through psychotherapy, Dr. Rosenblat says.

“People enjoy the ketamine treatment,” he says, “but extremely rarely would they say to me, ‘That’s the most important experience of my life.’ ”

What worries him is that ketamine-assisted psychotherapy focuses on ketamine’s dissociative effect because that’s when the psychotherapy is taking place. But dissociation doesn’t predict the drug’s antidepressant effect, so if you calculate your dose based on that, he says, you may get the wrong dose for antidepressant treatment.

Dr. Rosenblat and Dr. McIntyre are, however, studying – thanks to funding from the Canadian Institutes for Health Research – what happens when you combine intravenous ketamine with internet-based cognitive behavioural therapy. They’re operating on the hypothesis that ketamine will alleviate your depression enough to let you benefit from psychotherapy you’d otherwise feel too crappy to do, rather than trying to use your dissociation as therapy.

I started on ketamine in a more pedestrian, DIY way: A doctor prescribed it to me after I spent weeks as an in-patient getting unilateral electro-convulsive therapy (ECT). This was the months-long window before life looked seriously grim, and I signed up for ECT on both sides of my head.

He’d had colleagues who’d prescribed ketamine intranasally before, and he thought it was appropriate given the stubbornly treatment-resistant nature of my illness. So I gave it a shot.

A pharmacy mixed me up a liquid ketamine compound and sent me on my way – this crazy lady with a month’s worth of psychoactive substance, the exact scenario that gives drug regulators palpitations and which some experts I talked to warned against. (There is “no take-home whatsoever” for patients at his clinic, Dr. McIntyre says. “We just don’t think that’s the appropriate, safe way to administer it.”)

For the record, it was fine. I did not abuse it or sell it on the street. If I developed a dependence (as I’m still constantly afraid of doing), it’s hidden itself remarkably well.

And after years of downing dozens of drugs that did nothing (my doctor might dispute that), it is revelatory to take a drug and be transported. The dissociative high, the fumbly stumbling – I could live without that. But that suffusion of wellbeing, that deep-seated conviction that everything is going to be okay? That, I could marinate in forever.

Except I can’t. Because that’s the drawback: No sooner am I buoyed by that supple loosening, that widening of avenues, than it dissolves. Even before the trippiness dissipates, the antidepressant effect of ketamine is gone. For me, anyway. I’ve had suicidal ideation within hours of snorting the stuff.

And that, Dr. Rosenblat says, might be a sign it’s not really working. When people feel better on the day of treatment, “that, in my mind, isn’t a true antidepressant effect. That’s just the afterglow of the high of the ketamine.” He adds: “If that’s the only benefit someone is getting … I would not be continuing ketamine for them.”

What he would consider a ketamine-related antidepressant effect is one that lasts days or weeks. And that’s when you start discussing what maintenance dosage might look like.

Because even when ketamine works, it is no cure: It doesn’t make your depression go away forever. Dr. Rosenblat notes that while some question ketamine’s effectiveness as an antidepressant because its effect wears off after a while, so too does that of just about every antidepressant drug. That’s why you have to keep taking them, sometimes for years. “Most treatments with psychiatry are not actually cures,” he says. Maintaining benefit depends on maintaining treatment.

These diseases suck.

I took intranasal ketamine on and off for more than a year. When things got seriously psychically ugly, when I sent a despairing e-mail on a Friday evening and tried to mask tears during a last-minute Telehealth session, my doctor recommended taking it intravenously. Simply put, your body makes better use of ketamine when it’s shot into your vein than when you suck it up your nostril. Think 100 per cent, instead of maybe 30.

I got lucky – and I hate this, because it shouldn’t be a matter of luck: I nabbed a spot at St. Michael’s Hospital’s nascent ketamine-for-depression clinic. St. Mike’s started the clinic this past March, in the middle of a global pandemic that turned hospitals inside-out. But psychiatrist Venkat Bhat and anesthesiologist Karim Ladha pushed for it to open after months of delays thanks to COVID-19. “The pandemic has stopped a lot of things, but it really shouldn’t stop urgent mental health care. And that was one of the guiding principles,” Dr. Ladha says.

(In the interest of full disclosure, Dr. Bhat and Dr. Ladha were in charge of my care while I was a patient at the ketamine clinic. But these interviews took place well after my course ended.)

The ketamine clinic is part of St. Mike’s interventional psychiatry program, which Dr. Ladha says is also looking into such novel treatments as nitrous oxide (yes, laughing gas) and a stellate ganglion block, which uses anesthetic to block nerves in your neck and has shown promise treating PTSD.

The clinic “fits with St. Michael’s focus on serving the underserved,” Dr. Bhat says. Its patients are people who’ve been failed by multiple treatments – mostly drugs, but often also ECT. The clinic is still small in scale, treating just two patients at a time. So far, 20 people have gone through the six IV treatments, delivered over three weeks. I’m one of them.

Importantly, these services are paid for publicly, like any other hospital service. For an illness whose treatments remain disproportionately, inequitably available based on private insurance coverage and ability to pay, that is huge and reprehensibly rare. (By contrast, a ketamine session with Field Trip Health will set you back $750; a session at the CRTCE, about $800 to $850. Some insurers cover some of this.)

Dr. Ladha has no problem with private clinics. He wants more people to have access to a treatment he’s seen work. But “we need to be careful, in a public-health system, having this two-tier thing that’s developing.”

Meantime, he sees ketamine use expanding in the public system. They’ve gotten queries from other hospitals wondering how to set up ketamine clinics of their own. Dr. Bhat says they’d like to scale up, potentially to hundreds of patients a year.

“For me, personally, it’s been a very eye-opening experience – seeing patients on a day-to-day basis with this terrible burden of disease,” Dr. Ladha says. “You have someone come in, they’re not making eye contact, they’re not really speaking to you, and you see them after their second infusion, and they’re like, ‘I cannot believe this – I cleaned my room. …For six years, I wasn’t able to clean my room.’ ”

This is what I was desperately hoping for: some sort of lasting change – maybe even a longer-term version of what I’d felt after instranasal ketamine. A lot of the clinic’s patients come in with similar sky-high hopes, Dr. Ladha says. That’s where he feels a need to harsh the buzz just a bit: “It doesn’t work for everybody. And I think that’s one of the challenging things: There’s so much hype around this medication that people come in with a lot of expectations that this is finally going to be it.”

So after several weeks on a wait list, I went into the St. Mike’s day surgery clinic, double-masked, on six eerily quiet early mornings over three weeks, where the kind nurses remarked on my wimpy veins as they struggled to find an adequately juicy venous entry point for the IV.

I was the blue-gowned weirdo in the unit who’d taken ketamine before. And that complicated things a bit, because my tolerance was … high. During the first few 40-minute sessions, I felt nothing. Without the familiar bitterness of the intranasal solution, I even found myself unsure I was taking ketamine at all. It wasn’t until they doubled my dose, from 0.5 mg per kilogram to one, that things started to kick in.

And then I could have sworn the bed started to move – first ratcheting up and down, then rolling out from the wall toward the door. It was perhaps the most boring hallucination of all time. Dr. Ladha suggested I listen to music, so there I was, bopping my head behind bedside curtains and trying to wrest a shred of lasting wellness from the clear liquid snaking into my vein.

And here’s where I go from a merely unreliable narrator to a seriously conflicted one. After years during which mental wellness has become so foreign, it’s hard to know what to even hope for from treatmentLike being bedridden and hoping you’ll wake up able to fly. But on a couple of occasions, in the days and weeks after my final infusions, I did notice I was able to bounce back from disappointment where otherwise I might have marinated in distress and rumination. I have no idea what weight to ascribe to this. The ketamine definitely did not get rid of suicidal ideation, though I didn’t act on it, which is maybe a good sign (or maybe a sign that I’m just lazy).

Between 30 per cent and 40 per cent of the people who’ve been through the clinic so far have shown significant improvement, Dr. Bhat says. Those are lower efficacy rates than in trials, but that’s to be expected, he adds: They’re including patients who might have been excluded from a trial, potentially because of complicating co-morbidities.

They’re still trying to figure out what the course of treatment should be for patients who show improvement. We know that ketamine’s effect, when it’s effective, doesn’t last. “We’ve not established a definite plan for what the maintenance paradigm is,” Dr. Bhat says. “The idea is to take it down gradually to the minimum frequency people need to be well.”

This is where intranasal ketamine could come in, he says; your body doesn’t use it as efficiently as when it’s delivered via IV, but it might be enough to provide a necessary boost.

That’s what they recommended for me.

I admit I had misgivings about going back to squirting ketamine solution up my nose after my intravenous sessions. Yes, my doctors recommended it, at least for a few months. But what, I asked myself, was my aim here? What if I got back into intranasal use, and it didn’t confer a lasting benefit? Was I willing to risk unknown long-term side effects for the transient oomph that ketamine offered? We know that heavy, frequent ketamine use can hurt your cognition (as well as your urinary tract). But how frequent is frequent? How big a dose causes harm?

I contacted Celia Morgan, the head of psychology and professor of psychopharmacology at the University of Exeter (for this piece, not for personal advice). She has studied some of ketamine’s cognitive effects, and she told me she thinks it’d be safe for chronic use and not harmful to cognition unless taken daily for prolonged periods at doses far higher than anything I’ve received. That was a relief. But there’s still a voice at the back of my head, asking: How prolonged is too prolonged?

One Canadian study shows therapeutic use (four infusions over two weeks) can actually help a sick brain’s function. But we have very little information on where regular use becomes detrimental.

Still, I went back to it. I trust my doctors. And I’m like any other sucker: I like feeling good, even if it’s for a few minutes twice a week, and even if I’m not entirely sure it’s working in the long run.

It might be. It’s possible there’s a subtler lasting effect – that recent bad days would have been far worse were it not for this (maybe imagined) ability to bounce back. It’s possible I just like the fleeting twice-weekly high. My doctor argues it could provide “a different experience of oneself,” a “leavening agent” amid self-recriminatory mush.

It’s been just over a year since my last suicide attempt, a little bit longer than that since the last of my 39 bilateral ECT sessions. From the depths of then-fresh memory loss, I thought I’d never return to work, never rebuild my life.

I have, kind of. I’m working and maintaining the job that keeps me going. I can function, mostly. How much of that is thanks to the half-dozen meds I’m on, including ketamine, I cannot say.

But I want the act of waking up to require something less than herculean strength. For anxiety to be present but not paralyzing. To stop fixating on giving away my dog so I won’t upset him when I off myself. To stop lusting after household poisons.

Ketamine holds promise. It’s pretty much the first novel antidepressant in decades, and the first fast-acting one. It’s changing our understanding of depression and providing evidence that a substance that feels good, that mentally transports, can also do good – no small intimation in a society still waging a war on drugs, but one we’re going to keep encountering as psychedelics enter mainstream therapy.

It’s no get-out-of-psychic-jail-free card. Most people who take it won’t achieve remission. When it does work, you’ll likely need boosters, maybe indefinitely, to make that effect last. There remains a lot we don’t know. And the fact of its potential is perhaps, more than anything else, a sign of how far we still have to go.

But until we come up with something better, or my doctor and I change our minds (or it turns out I’ve seriously screwed my brain or urinary tract), I’ll be here twice weekly, swallowing reservations and filling my nasal passage with an NMDA antagonist.

Ketamine holds promise. It’s pretty much the first novel antidepressant in decades, and the first fast-acting one. It’s changing our understanding of depression and providing evidence that a substance that feels good, that mentally transports, can also do good – no small intimation in a society still waging a war on drugs, but one we’re going to keep encountering as psychedelics enter mainstream therapy.

It’s no get-out-of-psychic-jail-free card. Most people who take it won’t achieve remission. When it does work, you’ll likely need boosters, maybe indefinitely, to make that effect last. There remains a lot we don’t know. And the fact of its potential is perhaps, more than anything else, a sign of how far we still have to go.

But until we come up with something better, or my doctor and I change our minds (or it turns out I’ve seriously screwed my brain or urinary tract), I’ll be here twice weekly, swallowing reservations and filling my nasal passage with an NMDA antagonist.


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