What to Know About Psilocybin Therapy for Mental Health

The last few years have seen an increase in attention to the study of psychedelics for issues such as treatment-resistant depression, anxiety, and post-traumatic stress disorder, though they remain illegal at the federal level. As Schedule 1 drugs, psychedelics are typically subject to the most strict laws governing their use—which makes studying them very, very expensive.

Last summer, the U.S. Food and Drug Administration (FDA) reviewed the first application for psychedelic therapy, looking at whether MDMA, commonly known as ecstasy or molly, could treat post-traumatic stress disorder (PTSD). The agency rejected the application, citing flawed data and the need for more research. More recently, however, the U.S. federal government reversed course, saying it wants to speed up the approval for the therapeutic use of these drugs.

Of the psychedelics that have been rigorously studied, psilocybin—the active ingredient found in so-called magic mushrooms—leads the pack. Studies have shown its promise to treat some of the most challenging mental health conditions, including depression, PTSD, obsessive compulsive disorder (OCD), and substance use disorder. Still, regulatory hurdles remain and researchers are divided: skeptics argue there is not yet enough evidence and supporters worry that regulatory and funding obstacles are delaying a medicine that could treat people desperate for help.

To break down what we know, what we don’t, and where the psychedelics field is headed, we spoke with Professor David Nutt, a top psychedelics researcher at Imperial College London and a fellow at the Atria Research and Global Health Institute. “It’s a time of great turbulence and we’re trying to navigate through it,” Professor Nutt says, “but there are exciting things happening.”

How psilocybin works

Researchers are still studying the mechanisms. Right now, the prevailing theory is that the drug works primarily by increasing neuroplasticity, so the brain can form new connections and learn more easily. This happens because the psychedelic compound activates serotonin 5-HT2A receptors in the brain, which are critical for thinking and reasoning. “These receptors are responsible for a lot of what makes us human,” Nutt explains.

Nutt offers a helpful analogy to explain how psilocybin can enhance neuroplasticity: People with depression or trauma are often caught in ruminative cycles, as though their brains are stuck in deep ruts they can’t escape. “When you’re in a rut, you’re making the rut deeper and you can’t get out,” he says. “Psychedelics are like a new blizzard that blows in and fills in all those nasty, rutted thoughts so you can make new paths.”

Researchers think there is something else at play, too. The trip itself—where people might have a transcendental or out-of-body experience—appears to be a critical part of the benefit, according to Nutt. The trips can help individuals reframe events from their past or change the way they see themselves. “The idea that you can be outside yourself and look in and see yourself differently—those conceptual transformations are what predict good outcomes,” Nutt says.

What else psilocybin might treat

While the evidence is strongest for depression, researchers are also exploring psilocybin’s potential to treat a number of other conditions, including PTSD, anxiety associated with life-threatening illnesses, substance use disorder, gambling addiction, anorexia nervosa, and OCD—the latter two of which Professor Nutt’s team is investigating with early positive results.

Clinical trials most commonly administer one or two psilocybin doses of 25-30 mg spaced one to two weeks apart with psychological support, and the benefits last for weeks and up to 6-12 months.

Nutt has also been exploring different dosing depending on the condition treated. For instance, when working with patients who have OCD, he learned that the lack of control that comes with a larger dose would not be beneficial. This prompted him to develop a scale of four dosing levels:

• Macro dose: 25 mg of psilocybin — This induces a psychedelic trip and is the dose studied in most research.
• Midi dose: 10 mg — This won’t induce a trip but may offer therapeutic benefits for some conditions. This is the amount Professor Nutt has used in his study of OCD.
• Mini dose: 1–5 mg — This will make people feel different, often more social or creative, and will not have psychedelic effects.
• Micro dose: 1 mg — This dose may feel like nothing or may feel similar to a mini dose; it has become popular recreationally but its regulatory status remains the same—which is to say in most places, it is illegal to do this.

Understanding more about detailed dosing will be helpful as researchers explore who can benefit most from psychedelics—and at what dose.

Who should be careful

Research has shown that psilocybin is fairly safe when used in controlled medical settings. Experts say that anyone with a personal or immediate family history of psychotic disorders such as schizophrenia should avoid it, as there is evidence psychedelic experiences could trigger or exacerbate such conditions. People with severe epilepsy, those taking lithium, and people on certain other psychotropic medications should also steer clear.

Nutt notes, however, that just because something is safe it doesn’t mean the experience is easy. “People sometimes think they’re just having fun, but we should say quite clearly: the trips are challenging,” he says. “What the trip does is it takes you to the places that your brain has been avoiding going to and helps you process those thoughts or memories.” He compares the experience to exposure therapy or even surgery—neither of which would be described as fun but which can be therapeutic when done properly.

Research has shown that negative effects during a trip—most commonly anxiety, confusion, nausea, and headaches—are temporary and do not reduce the psilocybin’s benefits. In fact, some research shows that a difficult trip was positively associated with “enduring increases in well-being.” For all these reasons, Nutt emphasizes that psilocybin for therapeutic purposes should be taken in medical settings with a trained therapist.

What’s next for psychedelics

There’s a large number of people who could potentially benefit if psychedelic drug research moves forward. About 1 in 8 Americans age 12 and older have depression, according to the Centers for Disease Control and Prevention, and at least 30% of those people do not respond to existing treatments.

In June, Compass Pathways released new findings from the first-ever phase 3 trial of synthetic psilocybin, a major milestone for psychedelic researchers and advocates. The study found a single dose of the drug reduced depression symptoms by a clinically meaningful 3.6 points on the Montgomery-Åsberg Depression Rating Scale compared to a placebo, and had no major safety issues. However, the results disappointed investors, who were hoping to see a more robust improvement in the study participants. Since psychedelic research is so costly, researchers expressed concern that the reaction to the results could set the field back and make it harder to fund future studies.

Professor Nutt sees pockets of hope in parts of the world where decriminalization and compassionate-use approval are experimenting with safe avenues for medical access to psilocybin. “We’re beginning to see countries coming to the decision that psychedelics are medicines,” he says.

New Zealand, for instance, announced earlier this summer it would allow trained psychiatrists to prescribe psilocybin for treatment-resistant depression, and Germany recently became the first European Union country to allow psilocybin to be used in some strict circumstances as part of a compassionate-use program. They join Australia, Canada, and Switzerland, which have similar programs in place.

In the U.S., Oregon and Colorado have created legal frameworks to allow psilocybin for therapeutic use, and New Mexico passed a similar law this spring.

Researchers still have many questions to explore, including learning more about how exactly psilocybin works, who it’s best for, and how often people should take it. Answering these questions will require more clinical trials with larger numbers of participants.

While regulatory uncertainty remains in the U.S., Professor Nutt is encouraged by the momentum in other countries and the real-world and clinical trial evidence they are producing. “These are powerful treatments that can work where other treatments have failed,” he says. “It’s only right that they should be available somehow. Over time, this will increase acceptance more broadly.”

This article is part of Atria’s Future of Health newsletter. Subscribe here.