This is your brain on psilocybin

(CNN) — As he began the brain scan, neurologist Dr. Nico Dosenbach wasn’t sure if he’d been given a psychedelic or a placebo as part of a new clinical trial that would capture how the brain works on psilocybin, the main psychoactive ingredient in magic mushrooms.

Suddenly he felt a faster heartbeat, a flush of energy and a change in vision. It wasn’t until his brain morphed into a computer, however, that he knew for sure he was on a psychedelic trip.

“Until it kicks in, nobody in the trial knew if they had taken psilocybin or Ritalin (the stimulant methylphenidate), which was picked to be a placebo because it’s also arousing, like drinking a coffee or two,” said Dosenbach, a professor of neurology at Washington University School of Medicine in St. Louis.

“But then I was like, no, this is not placebo,” Dosenbach said. “I was the computer tablet, and my thoughts were like computer thoughts, which of course makes no sense. I was aware this was not normal, but it wasn’t frightening.”

Dosenbach is the co-senior author of a very small, pilot study that conducted up to 30 functional magnetic resonance imaging (fMRI) scans of healthy participants’ brains before, during and three weeks after a psychedelic trip on psilocybin.

“We found that psilocybin desynchronizes the brain,” said co-senior author Ginger Nicol of the study published Wednesday in the journal Nature.

“When psilocybin is on board, the brain is disconnecting from its typical pathways and reconnecting to different parts of the brain,” said Nicol, an associate professor of psychiatry at Washington University School of Medicine in St. Louis.

These new pathways may be responsible for the success of some psychedelics in treating mental health disorders such as depression and anxiety. Also known as shrooms, psilocybin is illegal according to federal law, although in 2020 Oregon became the first US state to legalize psilocybin for personal use for those age 21 and older.

However, the US Food and Drug Administration has allowed psilocybin to be treated as a breakthrough medicine, a process that fast-tracks the development and review of promising drugs.

Greater access to the sense of self

The new study’s scans highlighted an increase in connections to the anterior hippocampus, responsible for emotional memory, perception and imagination, Nicol said.

Parts of the default mode network, which impacts a person’s sense of self, time and space, also lit up on the scans. Antidepressants also target the default mode network, trying to interrupt the “negative thought loop, or stuck thinking that can occur with depression,” Nicol said.

“A lot of antidepressants do work on the default mode network connecting to other parts of the brain, just a lot more slowly than psychedelics do,” she said.

Small clinical trials have shown that one or two doses of psilocybin can make dramatic and long-lasting changes in people who have treatment-resistant major depressive disorder, which typically does not respond to traditional antidepressants.

Psilocybin is also showing promise in combating cluster headaches, anxiety, anorexia nervosa, obsessive-compulsive disorder and various forms of substance abuse.

Typically, clinical trials use trained psychotherapists who sit with the person during the psychedelic trip. In many trials, the therapist meets with the person in the weeks before and after the event to help guide and integrate any insights from the experience.

The new study uses multiple brain scans to illustrate how psilocybin may make connections in the brain more malleable, thus helping people overcome “rigid maladaptive patterns” of thought and behavior, said Dr. Petros Petridis, a professor of psychiatry at the NYU Langone Center for Psychedelic Medicine in New York City. He was not connected to the study.

“Psilocybin could open the door to change, allowing the therapist to lead the patient through,” Petridis wrote in a review published with the study.

“Ultimately, however, large clinical trials with diverse patient populations and factorial study designs (which enable more than one intervention to be evaluated simultaneously) will be needed to examine the efficacy of psychedelics such as psilocybin and the role of talk therapy in treatment,” he added.

‘No words, just the feeling’

The study was extremely small, with only seven volunteers. Each person ingested either 25 milligrams of pharmaceutical-grade psilocybin or a 40 milligram dose of methylphenidate, a stimulant often prescribed for attention deficit hyperactivity disorder, or ADHD. Some participants returned for a second dose of psilocybin 6 months to 12 months later.

All of the participants in the study had prior experience with psychedelics or “mystical experiences,” loosely defined as an altered state of consciousness.

At the peak of his trip, Dosenbach began to feel as though he was present in the minds of people he knew, experiencing their thoughts as his own.

“I was in the brain of famous neuroscientists, including my most senior colleague that I work with, and literally surfing the brain waves,” he said.

“Science doesn’t fully understand the brain yet, but I felt as if I suddenly knew exactly how the brain works. Yet if you were to ask me how it worked, I would have no words, just the feeling.”

Each of the participants had different experiences, with only one not entering a state of mysticism, Dosenbach said.

“My sense of self stretched like I was the universe,” he said. “Other people reported they saw God, and if I was very religious, I could see that, but for me it was more like ‘Oh, I’m the universe.’

“And then it disappeared in what I think psychiatrists call ego death,” he said. “Simultaneously with that I lost my sense of place, and time stopped. It felt like I was literally there for days and then weeks figuring things out.”

One man was able to pinpoint the specific time during the fMRI scan that he had his most vivid mystical experience, Nicol said.

“He felt the light of God was shining on him,” she said. “We were able to actually go to that spot on the scan and pinpoint when he felt that — it happened at the peak of desynchronization (from the brain’s typical pathways).”

A window for change

Scans showed that in the days after the psilocybin trip, most brain networks returned to normal. However, connections between the default mode network and the anterior hippocampus persisted for up to three weeks, Nicol said.

It’s possible that this lingering effect could explain part of the therapeutic impact of psilocybin, she added.

“There’s a massive effect initially, and when it’s gone, a pinpoint effect remains,” Dosenbach said. “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,” he said. “You want an effect that lasts long enough to make a difference.”

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