Psilocybin generates psychedelic experience by disrupting brain network

Neurologist takes high-dose psilocybin, and scans his brain as it rewires itself
In a striking blend of self-experimentation and neuroscience, Washington University neurologist Nico Dosenbach volunteered as both researcher and subject in a study of psilocybin, the active compound in “magic mushrooms.”

Study advances efforts to harness drug’s mind-altering power to treat mental illness.
As part of a small trial with seven adults, Dosenbach received either a high 25-milligram dose of psilocybin or a placebo-like dose of the stimulant Ritalin, then repeatedly underwent MRI scans—around 18 times before, during, and up to three weeks after dosing. Blinded at first to which drug he had taken, he reported a vivid shift in consciousness, describing his thoughts as “computer thoughts” and recognizing this as an altered but not frightening state. The work, published in Nature, aimed to understand how psychedelics can so powerfully distort perceptions of self, time, and space while also showing promise as psychiatric treatments.
The scans revealed that psilocybin temporarily “desynchronizes” the brain’s default mode network, a key system involved in self-referential thinking, daydreaming, and autobiographical memory. According to lead author Joshu Siegel, this short-term disruption appears to produce the psychedelic experience while also boosting longer-term brain plasticity, potentially making neural networks more flexible and less locked into rigid, negative thought patterns. Subtle changes in connectivity persisted for weeks—a profile Dosenbach described as ideal for a medicine: a strong but transient acute effect followed by a smaller, enduring shift rather than prolonged disruption. While the findings offer a hopeful glimpse into how psilocybin might help people break maladaptive mental habits, the researchers emphasize that such interventions should occur in controlled, professional settings, not through self-medication.
References (APA style)
Landymore, F. (2024, July 20). Scientist takes high dose of psilocybin, clambers into MRI machine to scan his own brain. Futurism.
Washington University School of Medicine in St. Louis. (2024). Mushrooms generate psychedelic experience by disrupting brain network [Press release].

People who consume psilocybin-containing mushrooms — otherwise known as magic mushrooms — typically undergo a surreal experience in which their sense of space, time and self is distorted. Advocates have long argued that, under the right conditions, psychedelic experiences can alleviate mental distress, and a smattering of scientific studies suggests they may be right. Understanding precisely how the drug affects the brain will help scientists and doctors harness its therapeutic potential.

In a new study, researchers at Washington University School of Medicine in St. Louis report that psilocybin, the active compound in magic mushrooms, temporarily scrambles a critical network of brain areas involved in introspective thinking such as daydreaming and remembering. The findings provide a neurobiological explanation for the drug’s mind-bending effects and lay some of the groundwork for the development of psilocybin-based therapies for mental illnesses such as depression and post-traumatic stress disorder.

“There’s a massive effect initially, and when it’s gone, a pinpoint effect remains,” said co-senior author Nico U. F. Dosenbach, MD, PhD, a professor of neurology. “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, available July 17 in Nature, creates a road map other scientists can follow to evaluate the effects of psychoactive drugs on brain function, potentially accelerating drug development efforts for any number of psychiatric illnesses.

Psilocybin showed promise as a treatment for depression in the 1950s and ‘60s, but restrictive federal drug policy in subsequent decades quashed nearly all further research. In recent years, though, regulations have loosened, and interest in the field has been revived.

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

To fill that gap, Siegel pulled together a team including Dosenbach, who is an expert in brain imaging, and co-senior author Ginger E. Nicol, MD, an associate professor of psychiatry who has experience running clinical trials with controlled substances. Together, they devised a way to visualize the impact of psilocybin on individual participants’ functional brain networks – neural communication pathways that connect different brain regions – and to correlate changes in these networks with subjective experiences.

The team recruited seven healthy adults to take a high dose of psilocybin or methylphenidate, the generic form of Ritalin, under controlled conditions. Because psychedelic trips carry the risk of users having negative or scary experiences, a pair of trained experts stayed with each participant throughout the experience. The experts helped prepare the participants for what they were likely to experience, provided guidance and support during each experiment, and helped the volunteers process what had occurred afterward. Each participant underwent an average of 18 functional MRI brain scans in the days to weeks before, during and up to three weeks after their experiences with psilocybin. Four participants returned six months later to repeat the experiment.

Psilocybin caused profound and widespread — yet not permanent — changes to the brain’s functional networks. In particular, it desynchronized the default mode network, an interconnected set of brain areas that, ordinarily, are simultaneously active when the brain is not working on anything in particular. After falling out of sync, the network re-established itself when the acute effects of the drug wore off, but small differences from pre-psilocybin scans persisted for weeks. The default mode network remained stable in people who received methylphenidate.

“The idea is that you’re taking this system that’s fundamental to the brain’s ability to think about the self in relation to the world, and you’re totally desynchronizing it temporarily,” 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.”

more info https://medicine.washu.edu/news/mushrooms-generate-psychedelic-experience-by-disrupting-brain-network

“There’s a massive effect initially, and when it’s gone, a pinpoint effect remains,” said co-senior author Nico U. F. Dosenbach, MD, PhD, a professor of neurology. “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, available July 17 in Nature, creates a road map other scientists can follow to evaluate the effects of psychoactive drugs on brain function, potentially accelerating drug development efforts for any number of psychiatric illnesses.

Psilocybin showed promise as a treatment for depression in the 1950s and ’60s, but restrictive federal drug policy in subsequent decades quashed nearly all further research. In recent years, though, regulations have loosened, and interest in the field has been revived.

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

To fill that gap, Siegel pulled together a team including Dosenbach, who is an expert in brain imaging, and co-senior author Ginger E. Nicol, MD, an associate professor of psychiatry who has experience running clinical trials with controlled substances. Together, they devised a way to visualize the impact of psilocybin on individual participants’ functional brain networks — neural communication pathways that connect different brain regions — and to correlate changes in these networks with subjective experiences.

The team recruited seven healthy adults to take a high dose of psilocybin or methylphenidate, the generic form of Ritalin, under controlled conditions. Because psychedelic trips carry the risk of users having negative or scary experiences, a pair of trained experts stayed with each participant throughout the experience. The experts helped prepare the participants for what they were likely to experience, provided guidance and support during each experiment, and helped the volunteers process what had occurred afterward. Each participant underwent an average of 18 functional MRI brain scans in the days to weeks before, during and up to three weeks after their experiences with psilocybin. Four participants returned six months later to repeat the experiment.

Source https://www.sciencedaily.com/releases/2024/07/240717120949.htm

The psychedelic dimension

To examine the latent dimensions of brain network changes we performed multidimensional scaling (MDS) on the parcellated FC matrices from every fMRI scan³⁸. MDS is blind to session labels (for example, drug, participant). Yet, dimension 1, which explained the largest amount of variability, separated psilocybin from other scans (Fig. 2a), apart from one session during which the participant (P5R) had emesis 30 minutes after taking psilocybin (dark red dots on the left of Fig. 2a). The higher score on dimension 1 associated with psilocybin, corresponded to reduced segregation between the DMN and other networks (fronto-parietal⁴⁹, dorsal attention⁵⁰, salience⁵¹ and action-mode^52,53) that are typically anticorrelated with it⁵⁴ (Fig. 2b and Extended Data Fig. 5). To determine whether this reflects a common effect of psilocybin that generalizes across datasets and psychedelics, we calculated dimension 1 scores for extant datasets from participants receiving intravenous (i.v.) psilocybin⁵⁵ and lysergic acid diethylamide (LSD)⁵⁶. Psychedelic treatment increased dimension 1 in nearly every participant in the psilocybin and LSD datasets (Fig. 2c), suggesting that this is a common effect across psychedelic drugs and individuals.