High hopes: Why psychedelics (in very small doses) could revolutionize the way we treat mental illness

An ounce of prevention is worth a pound of cure, the old saying goes. But when it comes to psychedelic drugs, how much — or how little — is necessary to achieve genuine medical benefit? Many have attempted to answer that question. (You might recall the vogue for microdosing LSD, psilocybin and MDMA a few years back.) There has been little scientific research, however, to quantify and calibrate psychedelics for medical use.
Starting this fall, two Toronto-based startups, Diamond Therapeutics and GoodCap Pharmaceuticals, are working to change that. Both companies are poised to test new drugs that use sub-perceptual amounts of psilocybin (the active ingredient in magic mushrooms) on humans in clinical trials. If those trials are successful, and Health Canada grants regulatory approval, these companies will transform psychedelics into medications that doctors can prescribe to patients. Although we’re still likely years away from medical mushrooms being a reality, they could revolutionize the way we treat mental illness.   
Scientists have been considering the therapeutic possibilities of psychedelics, increasingly looking at them to treat anxiety, depression and addiction. The majority of studies have focused on the high doses typically ingested for recreational or medical purposes, or during spiritual rituals. Such doses can famously trigger a host of highly dramatic mind-altering effects, and it was believed that those effects were unavoidable in the pursuit of health benefits. About a decade ago, however, a handful of researchers began questioning that belief, exploring the therapeutic potential of even very small doses of psychedelics.
Judy Blumstock, a Toronto health science executive, was intrigued by this shift. After cannabis was legalized in 2018, which helped lessen the stigma surrounding previously prohibited drugs, she founded Diamond Therapeutics to explore the possibilities of psychedelics. The name was a nod to the Beatles classic, “Lucy in the Sky with Diamonds.” John Lennon famously denied the song was a reference to LSD, and Blumstock’s company has a similar relationship to psychedelics. While it’s currently developing a psilocybin-based treatment for anxiety, it’s working only with sub-perceptual doses that have none of the disorientation synonymous with the substance. No light shows, no flights of philosophical fancy, no tangerine trees or marmalade skies. “We’re trying to unlock the power of psychedelics without the psychedelic trip,” Blumstock says.
For Blumstock and others, this is key to avoiding the challenges that have prevented the wider adoption of psychedelics in medicine. A psychedelic trip can be physically and psychically disorienting, unpleasant, even frightening. These experiences can be expensive and are almost always time-consuming. When taken in a clinical setting, high doses are also usually combined with psychotherapy. Trying to disentangle the positive effects of the psychedelic substance from the positive effects of that therapy remains very difficult. Plus, psychedelics are all technically illegal, currently available to patients only in very specific circumstances through Health Canada’s Special Access Program. Commercially produced, sub-perceptual doses that don’t alter a patient’s behaviour would likely not be burdened by these restrictions. Microdosing could ultimately allow psychedelics to be used at a much greater scale by a broader group of people, in a safe, sustainable and commercially viable manner.
There has never been greater demand for such treatment. The Canadian mental health crisis worsens every year: according to the Centre for Addiction and Mental Health, more than 6.7 million people are affected, and half of all Canadians experience some form of mental illness before the age of 40. The medications currently used to treat those illnesses are also insufficient; SSRIs, the most commonly prescribed antidepressants, don’t work for 30 per cent of the people who take them.
In 2019, Blumstock received a grant from the Ontario Brain Institute to investigate the effects of sub-perceptual doses of psilocybin and ketamine on animals. Emboldened by the findings — the drugs improved attention and motivation in rats — in 2021, Diamond conducted a phase one clinical trial to assess safety and tolerability, the world’s first systematic study of very low doses of psilocybin in humans. A phase two trial, scheduled to start later this year, will last 12 to 18 months.
“The need for drugs for mental health is at crisis level, and has been for some time,” Blumstock says. “We’re trying as hard as we can to get something over the finish line that can be really helpful.”
GoodCap is also racing toward that finish line. Darryl Hudson, a molecular biologist and co-founder of the Toronto company, spent years studying medical cannabis and runs psilocybin therapy retreats in the Caribbean. His interest in microdosing began after working with military veterans suffering from PTSD. Perturbed by the side effects of high psilocybin doses, some of those vets began experimenting with lower doses on their own — and getting results. Researchers know that psilocybin interacts with serotonin receptors in the brain — this is the mechanism Diamond’s investigating — but when Hudson began exploring the molecular pathway of the drug, he soon learned that psilocybin is also a potent anti-inflammatory.
Research indicates that inflammatory cytokines (proteins that have an effect on the immune system), are at the root of PTSD symptoms: When a person experiences a traumatic or stressful event, their body triggers cortisol and adrenalin production, which increases the presence of these proteins. While levels usually return to normal, repeated stress or trauma can leave people stuck in an inflammatory state. Hudson has treated such patients with very small amounts of psilocybin — the lowest amount required to see a positive medical result without experiencing any intoxication. And they’ve had what he describes as “miraculous” results. While the treatment may not address the underlying trauma, it can alleviate a lot of its symptoms, allowing people to do simple things they were previously unable to accomplish, he says, like shop for groceries or pick up their kids from school. “It gives them another good day,” Hudson says. “And if you’re just having bad days, a good day is an amazing thing.”     
GoodCap is currently raising money to start phase one of a human clinical trial next year. If all goes well, Hudson expects to have a psilocybin-based pharmaceutical that doctors will be able to prescribe in five to seven years.
Diamond is on a similar schedule. “I think when we look back in 10, 20 years,” says Blumstock, “we’ll see that there are many new drugs on the market that came out of this initial enthusiasm for psychedelics.”
GoodCap and Diamond — not to mention, their investors — are betting a lot on this enthusiasm. But even more skeptical researchers are hopeful. Norman Farb, a psychology professor at the University of Toronto, recently helped lead the development of a Health Canada-approved trial exploring microdosing psilocybin for the Canadian Centre for Psychedelic Science. While trials are continuing, Farb says that initial analysis of the participants, all of whom had treatment-resistant depression, showed reduced depressive symptoms whether they took the psilocybin or a placebo. “If you give people a reason to believe that change is possible,” he says, “they start looking for it themselves in the world.”
But Farb is also familiar with the ways high doses of psychedelics have been shown to affect the chemistry of the brain. He remains open to the possibilities of microdosing that Diamond and GoodCap tout, and looks forward to the results of their trials. “More research is needed to make sure the benefits outweigh the risks. There’s no therapy or drug that helps everyone, but if you really want to help people, you give them options,” he says. “I do believe that there will be some people who can benefit from psychedelics for whom other standard therapies have not worked.”
Diamond and GoodCap are arguing for the same thing. “I’m a big believer in high-dose therapies,” Hudson says. “I just don’t think they’re for everyone. And I don’t think they’re accessible enough to address the dire need. We have to get better tools in the tool box.”
Jason McBride writes about technology for MaRS. Torstar, the parent company of the Toronto Star, has partnered with MaRS to highlight innovation in Canadian companies.