Researchers Uncover How Psilocybin Works in the Brain

Psilocybin, the “magic” component of magic mushrooms, works by scrambling one’s sense of space, time, and self. Obviously, it can be a surreal experience.

Advocates argue that these psychedelic experiences – or trips – can ease mental distress in a controlled environment. And a growing body of research backs this up. As a result, an increasing number of researchers insist that understanding how psilocybin influences the brain could make the most of its therapeutic potential.

Visualizing Psilocybin’s Impact

In a new paper published in the journal Nature, researchers with the Washington University School of Medicine in St. Louis reveal that psilocybin temporarily disrupts a critical network of brain areas responsible for reflective thinking, such as daydreaming and remembering. And its this interference that explains the drug’s mind-bending effects and paves the way for developing therapies for mental disorders such as depression and post-traumatic stress disorder.

“There’s a massive effect initially, and when it’s gone, a pinpoint effect remains,” WashU professor of neurology and co-senior author Nico U. F. Dosenbach, MD, PhD, explained in a press release. “That’s exactly what you’d want to see for a potential medicine. You wouldn’t want people’s brain networks to be obliterated for days, but you also wouldn’t want everything to snap back to the way it was immediately. You want an effect that lasts long enough to make a difference.”

The study plots a potential path forward for evaluating the effects of psychoactive drugs on brain function, which could accelerate psychiatric drug development.

Psilocybin first showed promise as a depression treatment back in the late 1950s and early 1960s. However, a series of restrictive federal drug policies prevented further research. Regulators have been backing off more recently, reigniting interest – and investment.

“These days, we know a lot about the psychological effects and the molecular/cellular effects of psilocybin,” psychiatry instructor and first author Joshua S. Siegel, MD, PhD, said. “But we don’t know much about what happens at the level that connects the two — the level of functional brain networks.”

Methodology

To bridge this knowledge gap, Siegel assembled a team including Dosenbach, a brain imaging expert, and co-senior author Ginger E. Nicol, associate professor of psychiatry experienced in clinical trials with controlled substances. The team devised a way to track psilocybin’s effect on functional brain networks and related changes with subjective experiences.

The study involved seven healthy adults who took either a high dose of psilocybin or methylphenidate (generic Ritalin). Given the risk of a “bad trip,” the researchers monitored each participant closely throughout the experiment. Monitors also offered preparation, guidance, and post-experiment support. Each participant underwent an average of 18 functional MRI brain scans before, during, and up to three weeks after their psilocybin experiences. Four participants returned six months later to repeat the experiment.

Effects of a Brain Reset Lingered

The researchers observed that psilocybin induced profound yet temporary changes in the brain’s functional networks. Notably, they found that the drug “desynchronized” the brain’s default mode network. Although the network re-established itself post-trip, small differences persisted for weeks after the original dose. The default mode network remained stable in those who received methylphenidate.

“The idea is that you’re taking this system fundamental to the brain’s ability to think about the self in relation to the world and temporarily desynchronizing it,” Siegel said. “In the short term, this creates a psychedelic experience. The longer-term consequence is that it makes the brain more flexible and potentially more able to come into a healthier state.”

Throughout the experiment, the participants rated their feelings of transcendence, connectedness, and awe using the validated Mystical Experience Questionnaire. The magnitude of changes in functional networks aligned with the intensity of each participant’s subjective experience.

“We obtained precise data on the drug’s effects in each individual,” Nicol said. “This is a step toward precision clinical trials. In psychiatry, we often don’t know who should get a particular medicine and how much or how often. As a result, we prescribe one medicine after another, adjusting dosages until something works. This approach in clinical trials can identify who benefits and make better use of the medicines we have.”

Nicol, Siegel, and Dosenbach caution against self-medicating with psilocybin. The FDA still hasn’t approved these drugs for any treatment. And taking it without professional supervision carries medical and legal risks.

Further Reading

Psilocybin and the Development of Serotonin Toxicity

Psychedelic Microdosing and Mental Health

Medical Uses and Adverse Effects of Psilocybin