Psychedelics give the brain flexibility to enter a healthier state

A new study led by the Washington University School of Medicine in St. Louis has shown how psilocybin, the psychedelic compound in magic mushrooms, affects the brain. 

“A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials,” wrote the study authors.

In animal models, psilocybin induces neuroplasticity in cortex and hippocampus. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics.

Psychedelics “dissolve” a key brain network 

The researchers discovered that psilocybin temporarily disrupts the default mode network, a crucial brain area involved in introspective thinking, such as daydreaming and remembering. 

This desynchronization leads to the characteristic psychedelic experience and could explain psilocybin’s potential to treat mental illnesses like depression and PTSD.

“There’s a massive effect initially, and when it’s gone, a pinpoint effect remains,” said so-senior author Dr. Nico U. F. Dosenbach of WUSTL. “That’s exactly what you’d want to see for a potential medicine.”

Dosenbach went on to explain that “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.”

Psychedelics and brain activity

The experts utilized functional MRI scans to observe the brain activity of seven healthy adults before, during, and after consuming psilocybin or methylphenidate. The researchers aimed to correlate changes in brain networks with subjective experiences.

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

Psilocybin caused profound but temporary changes in the brain’s functional networks, particularly the default mode network.

After the acute effects of the drug wore off, small differences from pre-psilocybin scans persisted for weeks.

“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,” explained Dr. Siegel. 

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.

Changes in functional networks 

During the experience, participants rated their feelings of transcendence, connectedness, and awe using the validated Mystical Experience Questionnaire.

The changes in functional networks corresponded with the intensity of each participant’s subjective experience.

“We were able to get very precise data on the effects of the drug in each individual,” said co-senior author Dr. Ginger E. Nicol. 

“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. By using this approach in clinical trials, we can identify the factors that determine who benefits and who doesn’t, and make better use of the medicines we have.”

However, the researchers caution against self-medicating with psilocybin, which is not FDA-approved and carries risks if taken without professional supervision.

Understanding the effects of psilocybin 

“The dramatic departure from typical synchronized patterns of co-activity may be key to understanding the acute effects of psilocybin and also its persistent neurotrophic effects,” wrote the researchers.

Changes in resting activity are linked to shifts in glutamate-dependent signaling during psilocybin exposure.

This phenomenon, shared by ketamine and psychedelics, engages homeostatic plasticity mechanisms, a neurobiological response to large deviations in typical network activity patterns.

Psychedelics rapidly induce synaptogenesis in the hippocampus and cortex, effects that seem to be necessary for rapid antidepressant-like effects in animal models.

However, understanding the underpinnings of the behavioral effects of psychedelics requires human studies.

Advances in precision functional mapping and individual-level characterization enabled us to identify desynchronization of resting-state fMRI signals, connect these changes with subjective psychedelic effects and localize these changes to depression-relevant circuits (DMN, hippocampus).

These analyses rely on precise characterization of an individuals’ baseline brain organization (for example, individual definition of brain areas, networks and day-to-day variability) to understand how that organization is altered by an intervention.

The study is published in the journal Nature.

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