In particular, the substance – which occurs naturally in magic mushrooms – has shown remarkable promise as a treatment for severe depression. And as we learn more about psilocybin’s effects and mechanisms of action, researchers are becoming increasingly interested in its potential to alleviate a host of other mental health conditions, from eating disorders to addiction.

Hasn’t psilocybin been proven to work already?

Psilocybin’s turnaround in fortunes began in 2016, when a feasibility study demonstrating the drug’s ability to produce rapid, lasting improvements in patients with treatment-resistant depression made global headlines. Led by researchers from Imperial College London and King’s College London, the study’s findings have since been replicated and expanded on by dozens of other trials conducted at the likes of Johns Hopkins University, New York University, and numerous other prestigious institutions around the world.

“The thing is, the studies done by us at Imperial and other similar academic groups, they don’t really count, in the sense that they are not what is going to be filed to the regulatory body who’s going to decide whether [psilocybin] is going to be approved and licensed,” says Dr David Erritzoe, a co-author of the groundbreaking 2016 paper. “So even though there already is quite a lot of evidence [for the drug’s efficacy], those trials that we do are not strong and big enough or done in the way that regulatory bodies need to see before they make a decision,” he tells IFLScience.

In other words, no amount of independent, so-called investigator-led studies will ever constitute proof that psilocybin helps to treat depression or result in the drug being approved for medical use. That objective can only be achieved by massive, multi-phase industry trials, which tend to be colossally expensive and therefore unachievable without sponsorship from big pharmaceutical companies.

At present, a firm called Compass Pathways is bankrolling a series of clinical trials using synthetic psilocybin, and is quite far along the conveyor belt towards regulatory approval. A Phase II trial involving 233 participants was completed in 2022, with results showing a significant and durable improvement in patients’ depression scores after psilocybin treatment.

Two Phase III trials – which represent the final round of research before a regulatory submission package can be sent to the FDA – are now underway, and are expected to be completed in 2026. The larger of the two is being conducted partially at King’s College London, where the research is being led by Dr James Rucker – who also happened to be a co-author of that game-changing 2016 study.

“The Compass study is taking place in over 100 sites worldwide,” he tells IFLScience. “The logistics of it are eye watering, and I think the total number of participants recruited will be over 500. And that is for a protocol that runs over a year, so, if you like, it’s like 500 years of patient follow up.” With costs running into the hundreds of millions of dollars, this type of exercise could never be orchestrated using public grants, which is why academia-led trials are never likely to unlock major policy shifts.

So what’s the point of all those smaller studies?

When you’re investing that amount of dosh in a clinical trial, you understandably want to be pretty sure it’s going to pay off, which is why studies like the Compass one generally don’t get started unless someone else has already paved the way by demonstrating the efficacy of a drug. 

“If you think about our first depression trial we did at Imperial with psilocybin, that was the first in the world with any psychedelic for depression in 50 years,” says Erritzoe. “We did it before any of the companies [like Compass] even existed.”

“Trials like ours, when they’re early on for a new indication with a psychedelic therapy, then they serve as proof of concept, in order to see, is there any signal here? Does it look promising? Did it look safe?” he explains. “So we played a massive role in inspiring them to pursue it and actually go out and raise the investments to do it in the industry version.”

With budget always a major concern, industry trials typically don’t bother looking beyond their primary outcome, which in this case is focused on whether or not psilocybin treatment leads to clinical improvements in depressed patients. “They don’t need to understand the mechanisms,” says Erritzoe. “They don’t therefore need to apply brain imaging and all that to try and understand more about how it works. So we try to close questions that industry will not be closing.”

It is therefore thanks to these smaller, investigator-led brain imaging studies that we have started to build an idea of how psilocybin works its magic. For instance, we know that the compound binds to serotonin 2A receptors in the brain, which then causes a massive increase in neural activity. This, in turn, leads to an “entropic” brain state whereby the distinctions between different brain networks dissolve into a sea of random communication. 

This effect is particularly pronounced within the so-called default mode network, which, according to one study, “is thought to create our sense of space, time and self”. As this brain network melts away, reality begins to shift and warp, often culminating in an archetypal psychedelic “ego death” experience. This, in turn, has been linked to something that researchers call “oceanic boundlessness”, whereby trippers start to unshackle themselves from their rigid thought patterns and perceive an underlying oneness with the cosmos.

Follow-up brain scans have shown that even after the acute effects of psilocybin have worn off, this desynchronization of brain networks persists for several weeks. Researchers think this neural rewiring may generate more flexible cognition in people with depression and other mental health disorders, thus enabling them to break out of their habitual negative thought patterns.

By illuminating the mechanisms behind psilocybin’s effects, then, these studies embolden industry sponsors by confirming that the drug really does work on the root cause of depression. “It adds to the validity of this actually being a real thing, and not just one big placebo,” says Erritzoe.

[Psilocybin] increases the sense of connectedness to others and to the world and to the universe and so on.

Dr David Erritzoe

“And another thing we did in our depression trial that industry wouldn’t do was to compare psilocybin to a standard treatment, which for depression is SSRI [selective serotonin reuptake inhibitor].” This aspect of the research was crucial, as it demonstrated that the psychedelic doesn’t treat depression in the same way as SSRIs, thus confirming psilocybin as a genuine alternative for those who don’t respond to conventional antidepressants.

“Psilocybin increases the global functional connectivity in the brain, and that is not the case for SSRI,” says Erritzoe. Moreover, studies have shown that while SSRIs dampen emotional responses to negative stimuli, psilocybin may actually amplify this response, thus helping patients engage with their feelings rather than avoid them.

“So it breaks patterns,” explains Erritzoe. “It increases the sense of connectedness to others and to the world and to the universe and so on, and to nature. All those things we see more pronounced when we compare [psilocybin] one-to-one with SSRI.” 

This perception of infinite oneness has even been linked to reductions in the fear of death, resulting in improvements in depression and anxiety symptoms in cancer patients. That’s certainly not something you’d expect from SSRIs.

Where do we go next?

As we await the outcome of the Compass clinical trials and regulatory approval process, academic researchers are already looking beyond depression at other potential targets for psilocybin treatment. Preclinical work on rodents indicates that the drug helps to treat animal models of anorexia and obsessive-compulsive disorder (OCD), with initial studies suggesting that these improvements may be linked to increases in cognitive flexibility. Buoyed by these findings, researchers at Imperial have announced plans to conduct human trials for these conditions.

“In a lot of mental health conditions there’s some degree of being trapped, of being stuck in a state that is difficult to break out of,” says Erritzoe. “And so anything that can break those patterns, give a great degree of flexibility and new connectivity in the brain… then you have a recipe for something that really could be used across indications.”

In the context of the existing body of research on psilocybin, it’s particularly important to note that SSRIs are the standard pharmacological treatment for eating disorders, OCD, and even PTSD. Just as psilocybin offers an alternative pathway towards healing depression, therefore, the data provided by previous brain imaging studies implies that the psychedelic drug may be worth a shot when it comes to treating these conditions too.

Psychedelics make you sensitive to context, so you can’t just administer them in A&E.

Dr James Rucker

Of course, each of these treatments may need to go through its own industry trial before being approved, and the likelihood of psilocybin being medicalized for mental health conditions will hinge on the success of the Compass Pathways depression trial. Yet with a showdown with the FDA potentially on the horizon, Rucker says “it’s important to understand that once you get regulatory approval for a treatment or for a drug, that’s just the first stage, and what happens after that is the drugs and treatments find their place in wider medical practice… And with psychedelics, I couldn’t call that one. They’re not easy to implement.”

Even if the regulatory bodies give psilocybin the green light, then, learning how to incorporate psychedelic trips into the mainstream medical system is sure to be a massive challenge. As Rucker says, “they’re just different paradigms.”

“Psychedelics make you sensitive to context, so you can’t just administer them in A&E. It’s not going to work. It’s going to be appalling, in fact,” he continues. “You have to have the right expertise and the right infrastructure. And I would say that at the moment that doesn’t really exist.”