Magic Mushrooms Might Be the New Anti-Depressants

One of the hardest feelings to carry as a psychiatrist is helplessness. As a trainee in the early 2010s, I felt it often. Patients came through our clinic and, no matter what we prescribed, they simply did not get better. I still think of one woman in her forties—a teacher and a mother of two—who had cycled through more antidepressants than she could name and two full courses of therapy. She described an ordinary day as “wading through wet concrete.” What surprised me then, and what now occupies much of my career, is how common her story is. Depression is the most widespread mental illness in the world, but around a third of patients do not respond to the treatments we have, whether that’s psychotherapy or SSRIs. We call this treatment-resistant depression. It is profoundly disabling, and an estimated 700,000 Canadians live with it. We still don’t fully understand why some people don’t respond to treatment. The answer may lie in misdiagnosis, in an underlying biological abnormality or even in genetics. Most likely, it’s a combination of several factors.

In 2016, while I was working in London, England, a new approach emerged that seemed capable of changing the landscape of depression treatment. A group of U.K. scientists had studied the effects of psilocybin—the active compound in magic mushrooms—in people with treatment-resistant depression. One week after the psilocybin dosing, eight of the 12 participants met the criteria for complete remission; they’d fully recovered from their depressive symptoms. Three months after the trial ended, five remained well. The results captivated me and many others within my field. This was not simply another drug. It was a treatment that combined biology with psychology, and even something close to spirituality. After the study, interest in psychedelics’ medical potential took off, eventually reaching Toronto, where I returned to build a program of research in psilocybin therapy.

In the decade since that London study, several trials have shown that psilocybin reduces depressive symptoms in a subgroup of people with treatment-resistant depression—though we still don’t know why. The leading explanation is psilocybin’s effect on neuroplasticity, or the brain’s capacity to change its structure and function in response to experience. Our brains form new neural pathways throughout life; this is how we learn and acquire new skills. Psilocybin seems to accelerate that process, prompting the brain to restructure existing pathways and build new ones. Some scientists believe even a single dose can jolt a person out of entrenched negative thought patterns and, in a sense, “rewire” the brain for the better. Others argue that the experience—the “trip”—lets patients reach memories or feelings buried in the subconscious, which they can work through in talk therapy. Either way, many of the people we’ve treated in Toronto through our clinical trials program seemed to undergo something transformational, and for some the effects lasted remarkably long. Our studies are designed to interrogate some key questions in psychedelic research: does every patient need the trip to benefit, and how much psychotherapy does psilocybin really require to work?

Psychedelics have been used as part of spiritual healing ceremonies across cultures for hundreds, if not thousands, of years. In the mid–20th century there was extensive research on psychedelic therapy, much of it in the United States, where psychedelics were tested for potential therapeutic benefits in mental illness and addiction. The early results were promising, but those studies lacked the guardrails that protect scientific quality and patient safety in modern clinical trials. The research was halted abruptly when the Nixon administration raised alarms about rising recreational use, much of it tied to anti-war activism. In 1971, psychedelics were classified as controlled substances under the UN Convention on Psychotropic Substances. Three years later, Canada banned psilocybin.

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Today we find ourselves in a psychedelic renaissance, spurred by the preliminary studies of the mid-2000s and by the urgent need for new approaches to mental illness. Toronto’s Centre for Addiction and Mental Health, or CAMH, and the University Health Network, or UHN, where I work as a senior scientist and psychiatrist, are at the forefront of psychedelic research in Canada. In 2022, CAMH received the first-ever federal grant to study the therapeutic effects of psilocybin. That same year, I was part of a group of researchers worldwide that published a study of the drug’s efficacy for treatment-resistant depression, spanning 22 sites across 10 countries. It was the largest study of its kind, and it showed that a single 25-milligram dose of psilocybin produced a 50 per cent reduction in depressive symptoms for nearly 40 per cent of participants. Thirty-five per cent of participants went into remission.

The Canadian government is beginning to recognize both how urgently we need new options for treatment-resistant depression and the promise psychedelics may hold. Roughly three million Canadians experience depression each year, and more than one in 10 will be diagnosed at some point in their lives. And scientists are not the only ones paying attention—psilocybin is making its way into our culture, too. This month, the Royal Ontario Museum opened an exhibition on the cultural impact of psychedelics, aimed at broadening the conversation and exploring how they’ve been used through history. I served as a consultant on the exhibition, advising on the science: what we know, and how we have arrived at the current moment in clinical research.

But how should we regulate access to these drug? Illegal magic mushroom dispensaries have opened in dozens of Canadian cities. Last year, the former commissioner of the Ontario Provincial Police told CTV News he believes magic mushrooms will “go the way of marijuana in terms of legality.” There is no doubt that many people are already seeking them out to cope with mental-health issues. If we can establish that psilocybin is safe and effective, it will be important that the right structures exist so that those who could genuinely benefit can access it safely. Treating depression with psilocybin is nothing like prescribing an SSRI. It’s far more specialized and resource-intensive, requiring safety monitoring and psychological support. For that reason, I’d like to see it delivered in specialist centres like CAMH or UHN—though I worry it could end up within reach only of those who can afford private, fee-for-service clinics.

Beneath the hype lies a harder truth: psilocybin is not a cure-all for depression. Current evidence suggests that up to 60 per cent of people with treatment-resistant depression do not improve after psilocybin therapy, and more recent trials have struggled to replicate the large antidepressant effects reported early on. A mind-altering substance like psilocybin can also place people at serious risk of deterioration, particularly if they have a a personal or family history of a severe mental illness such as schizophrenia or psychosis. That’s why we exclude patients with that history from our trials. There is also the possibility of a bad trip, which makes specialized monitoring essential. At CAMH, we’re developing public education about these risks. If we ever reach a point where psilocybin therapy can be prescribed, it would almost certainly be reserved for cases where other treatments have failed or been poorly tolerated.

In Canada, physicians can already apply to use psychedelic therapy through Health Canada’s Special Access Program, which governs access to controlled substances for patients with serious or life-threatening conditions that don’t respond to other evidence-based treatments. In the United States, the Food and Drug Administration designated psilocybin a breakthrough therapy for major depression back in 2019. Its safety and efficacy are now being tested in large phase 3 trials—the final stage before which it will be submitted to the FDA for approval. If it is, Canada and other jurisdictions may follow, and psilocybin therapy could expand into clinical practice.

Treatment-resistant depression is an urgent public health problem in Canada. It’s associated with disability, intense reliance on the health-care system, and, at its worst, suicide. And yet I’ve also seen what is possible when a treatment finally works. One man we treated had spent years convinced he would never feel anything but “a kind of grey flatness”; weeks after his psilocybin sessions, he told me he had laughed with his daughter for the first time in longer than he could remember. Watching someone come back to their own life like that, after so many failed attempts, is the closest thing I know to hope in this work.

Ishrat Husain is a senior scientist for mental health at the Centre for Addiction and Mental Health and University Hospital Network, and an associate professor of psychiatry at the University of Toronto.

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