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A growing number of researchers around the world who are pursuing ketamine’s therapeutic potential.
A growing number of researchers around the world who are pursuing ketamine’s therapeutic potential.

Ketamine offers new hope for patients with severe depression Add to ...

Inspired by promising research into ketamine’s therapeutic effects, people are swapping strategies online on how to use the drug to ease their despair. Could ‘Special K’ be a panacea for depression? Wency Leung reports

John woke up one morning feeling almost like his old self.

He got out of bed, took a shower and, for the first time in a long time, felt as though this day would not be his last. His suicidal thoughts had faded overnight.

The previous morning, the 50-year-old Ottawa father of three was given his first intravenous infusion of the drug ketamine as part of a trial for people with treatment-resistant depression.

John (not his real name) had tried various medications for his depression over the years – without improvement. But within hours of receiving his first ketamine infusion, he began feeling better.

“I started feeling the benefits almost right away,” he said. By the next morning, “not completely, but I felt like I could behave like the normal man that I used to be.”

Ketamine, introduced in the 1960s as an anesthetic, is most often used by veterinarians but is sometimes given to patients in emergency departments or in surgery to relieve their pain or sedate them. It can be administered in a number of ways – intravenously, by injection, orally and intranasally.

Nicknamed “special K,” it is also used illicitly as a recreational drug to produce dissociation – an out-of-body experience – and hallucinations. Notoriously, it’s also used as a date-rape drug.

But Pierre Blier, a psychiatrist and director of the mood disorder research unit at the Royal Ottawa Mental Health Centre, is among a growing number of researchers around the world who are pursuing ketamine’s therapeutic potential.

Until 2015, Blier and his team were the only researchers in Canada testing intravenous ketamine on patients with treatment-resistant depression. Since then, a group at the Grey Nuns Community Hospital in Edmonton has been conducting a similar trial, while researchers in six cities across the country are now participating in an international study using a form of ketamine delivered via nasal spray. Some clinicians are also administering ketamine to depressed patients “off-label” – for purposes other than its approved use.

If they’re successful, ketamine could save lives and offer rapid relief to many individuals for whom current treatments don’t work. It’s estimated as many as a third of patients with major depression do not get well, even after trying multiple antidepressants. And amid concerns that the development of novel antidepressants has stalled, ketamine research opens a possible avenue of treatment.

Blier’s trial, conducted over the past year and a half, has found ketamine produces promising results.

There’s reason to remain cautious, however. As Blier explains, there are big unknowns: how the drug actually acts on the brain, how best to administer it and how long its effects last.

Nevertheless, encouraged by early studies, some individuals are taking matters into their own hands, leapfrogging past research and regulatory controls. On sites such as Reddit and the U.S.-based Howtousepsychedelics.org, they’re sharing advice about how to use ketamine to treat themselves.

Robust response

In Blier’s new study involving 34 patients, which he submitted for publication last month, he found that about half of those given ketamine responded to the drug, even though they had tried an average of six other treatments or strategies for their depression without success. What’s more striking, he added, 90 per cent of them experienced a robust decrease in suicidal thoughts.

“This is really exciting because we seem to have a direct effect on suicidal ideation,” said Blier, who is a professor of psychiatry at the University of Ottawa and the Canada Research Chair in Psychopharmacology.

These results suggest the drug acts on suicidal thinking independently from other depressive symptoms, Blier said, but the exact mechanism is unknown. He intends to study this in the next few years.

He began testing ketamine on treatment-resistant patients at the Royal in 2011 and estimates he’s treated more than 50 patients with the drug. Through his work, supported by the Ontario Brain Institute, he hopes to see ketamine infusions made more widely available in the health-care system.

Currently, he explained, the gold standard for patients with treatment-resistant depression is electroconvulsive therapy (ECT). Although ECT can be very effective, it’s not always accessible, especially to patients outside major urban centres. Patients are typically given between eight and 12 treatments over the course of several weeks.

Compared with ECT, ketamine infusions are much cheaper and easier to deliver. Blier could not provide specific cost comparisons, but explained that patients are given low doses of ketamine through an IV, under the supervision of a nurse and doctor, without the need for an anesthetist or operating room, both of which are required for ECT. The drug itself, he added, is “dirt cheap,” costing less than the IV tubes used to administer it.

It starts to work almost immediately in the 50 to 60 per cent of treatment-resistant patients who respond to it, Blier said, while ECT has an efficacy rate of 70 per cent. But it doesn’t cause the same potential side effects, such as memory loss and other cognitive dysfunction.

Ketamine’s hallucinogenic and dissociative effects depend on the dosage. It’s given to depressed patients in very low doses, so the side effects – including dizziness and a sense of dissociation – are mild and short-lived, Blier said. He has not seen any long-term side effects yet.

But its benefits don’t last. For some people, the effects last a few days; others can go weeks without needing another infusion. Blier said a major hurdle is determining how frequently and how long people need to take it to maintain the benefits.

“That’s the downside of ketamine right now, but we’re learning to tame it,” he said.

From anesthetic to depression treatment

The first experiments with ketamine and depressed patients came out of a collaboration, more than 15 years ago, between John Krystal at the Yale School of Medicine and Dennis Charney, now dean of the Icahn School of Medicine at Mount Sinai.

In the 1990s, the two were separately examining different chemical messengers in the brain, trying to understand their roles in depression and schizophrenia. When they began bringing their research together, Krystal said in an e-mail, they “were turning the prevailing hypothesis about the biology of depression on its head.”

At the time, depression was believed to be caused by low levels of monoamine neurotransmitters such as serotonin and norepinephrine. But the two suspected another system might be the primary culprit. What if, they reasoned, depression was a problem in the signalling of the neurotransmitter glutamate?

The researchers were aware that drugs like ketamine, which blocked the NMDA glutamate receptor, could have antidepressant properties in animals, Krystal said. But they were taken aback by ketamine’s robust effects on depressed patients.

“What we saw was, to us, remarkable,” he recalled.

Antidepressants typically take weeks to have an effect. But Krystal and Charney found patients reported feeling a little better the same day they were given ketamine. By the next morning, they no longer had clinically significant depression symptoms, Krystal said. They had essentially gone into remission.

The discovery has since paved the way for not only further experimentation with ketamine but also the development of other drugs that target the signalling of glutamate. The Dublin-based pharmaceutical company Allergan, for example, is testing a drug called rapastinel, which acts on the same receptor complex as ketamine but doesn’t appear to share the hallucinogenic side effects.

Meanwhile, Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, is conducting a global, multisite, phase III trial of esketamine, a ketamine-based drug that is delivered intranasally. Last August, the U.S. Food and Drug Administration granted esketamine a breakthrough therapy designation to expedite its development. If the drug receives the regulatory agency’s approval, it will be one of the first new approaches for treating major depressive disorder in 50 years, Janssen noted in a news release. Esketamine is currently being tested in Vancouver, Calgary, Toronto, Ottawa, Kingston and Montreal.

The unknowns

The promise of ketamine – the ability to rapidly treat depression and suicidal ideation – represents psychiatry’s jackpot, said Ian Dawe, chair of the Ontario Hospital Association task force on suicide prevention standards.

“Everybody wants that,” he said. “My God, if we can actually produce outcomes for these severely depressed folks within hours to days, that’s an entirely different ball game for mental health. That would be extraordinary.”

Dawe, who is not involved in the ketamine or esketamine trials, said the research on ketamine is intriguing and he can imagine a future where it, or a variation of it, could become a frontline treatment for depression. But, he emphasized, “we’re not there yet.”

Researchers still need to determine the technical aspects of how it’s administered, he said, noting there seems to be a very fine line between producing a sense of restoration and the unwanted effects of ketamine, such as hallucinations.

Raising further caution, an editorial published last year in the British Journal of Psychiatry Open noted that some experts still question whether ketamine produces a genuine antidepressant response or merely a brief euphoric effect. The authors also said more research needs to be done to establish any adverse effects from long-term use.

DIY ketamine

Some people looking for immediate relief, however, aren’t waiting. The Internet forum Reddit contains multiple posts from people seeking advice on how to treat themselves with ketamine or sharing their own do-it-yourself experiences.

Meanwhile, the site Howtousepsychedelics.org, launched in 2013, provides step-by-step guides on dosing and administering various substances, including ketamine. The site, created by a group of friends in their 20s and 30s of various non-medical occupations, aims to provide information “so that people in need can safely treat themselves,” explained a co-founder, who declined to be named, in an e-mail.

Ketamine is just one of several mind-altering drugs, including lysergic acid diethylamide (LSD), psilocyn and psilocybin, and MDMA, commonly known as ecstasy, that scientists have begun to examine with renewed interest in the past decade. These psychedelic drugs were previously relegated to the fringes of mainstream science, after researchers such as neuroscientist John Lilly and psychologist Timothy Leary documented their own self-experiments in the 1960s. Lately, these drugs have been given a closer, sober look as potential treatments for depression, anxiety, post-traumatic stress disorder and drug and alcohol addiction.

Beyond the laboratory setting, “micro-dosing,” the practice of taking small amounts of psychedelic drugs, has become a trend among individuals seeking to boost their creativity, focus and mental health. Writer Ayelet Waldman, for instance, documented her experience with tiny doses of LSD in her new book released last month, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life.

Depending on local laws, those who treat themselves obtain the drugs in various ways, from prescriptions to buying them on the black market and ordering them online with the digital currency bitcoin, the co-founder of Howtousepsychedelics.org said.

There’s no shortage of people interested in self-treatment. Her website records some 80,000 unique visitors a month and receives many inquiries from Canada, the co-founder said.

“We don’t recommend that anyone breaks the law,” the co-founder said. “The only advice we give is to make sure that you are 100 per cent confident in your source, to test the medicines and to start with tiny amounts.”

While the interest in self-treatment points to the desperation that depression sufferers feel, Blier strongly advises against using ketamine without medical supervision. He’s also less enthusiastic about the research on other psychedelics, citing concerns about controlling the purity of the substances and the possibility of long-term effects, such as the neurotoxic effects of MDMA.

While ketamine has been used safely in hospitals for decades, he said, the way it’s administered makes a big difference – and self-treatment is risky. Since the drug is metabolized quickly, one would need a large oral dose for it to take effect, he said, but taking large doses could pose a risk of bladder obstruction. Administering it intravenously, on the other hand, requires a lower dose, but without the supervision of medical professionals, it poses the risk of infection.

“If you do the ketamine yourself, where are you going to get it? And what is the purity of that stuff? Is it going to be cut with whatever? That’s the scary part,” Blier said.

John understands how unbearable depression can be. He suffered bouts for 14 years. Over time, the bouts became longer and stronger, while the recovery periods became shorter and less frequent, until he was experiencing “just one big down.” Even so, he wouldn’t dare taking ketamine on his own.

Crediting the drug for saving his life, he said he hopes it will be made available to him and other sufferers when they need it.

“In my case, it had benefits that exceeded my expectations,” he said. At last, it allowed him to feel at peace.

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Follow on Twitter: @wencyleung

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