Researchers at University of California, San Francisco and Imperial College London have shown that a single dose of psilocybin, the psychedelic compound found in magic mushrooms, causes likely anatomical brain changes that last for up to a month after the experience.

The study, involving healthy volunteers who had never taken a psychedelic, links temporary shifts in brain “entropy”—which is the diversity of neural activity occurring in the brain—to insight. This suggests the psychedelic trip itself is important to the drug’s longer term therapeutic effects.

The researchers found that a high dose of psilocybin led to increased entropy in the minutes and hours after taking the drug. The degree of entropy predicted how much insight, or emotional self-awareness, the participants felt the next day; and this, in turn, forecasted improvements in their sense of wellbeing a month later.

The findings may help to explain psilocybin’s therapeutic effects on conditions such as depression, anxiety, and addiction. “Psychedelic means ‘psyche-revealing,’ or making the psyche visible,” said senior author Robin Carhart-Harris, PhD, the Ralph Metzner distinguished professor of neurology at UCSF. “Our data shows that such experiences of psychological insight relate to an entropic quality of brain activity and how both are involved in causing subsequent improvements in mental health. It suggests that the trip—and its correlates in the brain—is a key component of how psychedelic therapy works.”  Carhart-Harris is senior and corresponding author of the team’s published paper in Nature Communications, titled “Human brain changes after first psilocybin use.”

“Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is largely unknown,” the authors wrote. Psilocybin is the precursor of the compound psilocin, a serotonin receptor agonist. “Converging evidence supports a role for serotonin 2A receptor  (5-HT2AR) agonism in eliciting the characteristic brain and subjective effects of this and related psychedelics in humans,” the team continued.

For their newly reported study, Carhart-Harris and colleagues carried out an exploratory, placebo-controlled, within-patient study in 28 psychedelic-naïve participants who each received a single, high-dose (25 mg) of psilocybin. The researchers used an assortment of brain imaging and brain measurement techniques, some of which were carried out during the peak of the psychedelic experience, as well as before and one-month after drug administration. “This was an exploratory, hypothesis-generating mechanistic study in healthy volunteers,” the authors noted. None of the 28 people in the study had a diagnosed mental health condition, which gave the scientists greater freedom to do more testing.

In the first part of the experiment the subjects were given a 1 mg dose of psilocybin, which the researchers regarded as a placebo, and were then monitored with EEG, which records brain activity from electrodes on the scalp.  Over the next few weeks, the researchers measured their subjects’ psychological insight, wellbeing, and cognitive ability. They examined brain activity with functional MRI (fMRI) and brain connectivity with diffusion tensor imaging (DTI).

One month after the placebo, the subjects were given 25 mg of psilocybin, a dose capable of eliciting a strong psychedelic trip. During the experience, researchers again measured the subjects’ brain activity with EEG, and in the following weeks they repeated the same tests they had given after the 1 mg dose.

This enabled the scientists to compare the effects of the psychedelic trip on the brain and mind to the effects of the placebo. “The multimodal neuroimaging design allowed us to observe changes in brain function and (potential) anatomy from 1-h (EEG) to 1-month (DTI) after high-dose psilocybin,” they explained.

The investigators found that within 60 minutes of taking the 25 mg dose of psilocybin, EEG revealed higher entropy, suggesting that the brain was processing a richer body of information under the psychedelic. A month later, the researchers looked at their subjects’ brains using DTI, which measures the diffusion of water along neural tracts in the brain, and found that they were denser and had more integrity. This is the opposite of what happens in aging, which makes these tracts more diffuse.

The researchers cautioned that more work needs to be done to better understand the meaning of this finding, but the result is a never-before-seen sign of how psychedelics can change the brain. ”The inclusion of DTI enabled us to test for long-term changes in the integrity of white matter tracts post psilocybin,” the authors stated. “Results revealed decreased axial diffusivity in prefrontal-subcortical tracts 1-month post 25mg psilocybin.”

The day after the 25 mg dose, all but one of the 28 subjects rated the trip as the “single most” unusual state of consciousness they had ever experienced. The remaining person rated it as among their top five. The study participants said they had experienced more psychological insight after taking the 25 mg of psilocybin than they had after the 1 mg placebo.  The subjects also reported increased wellbeing two and four weeks after the study. This was measured from responses to statements such as, “I’ve been feeling optimistic about the future,” and “I’ve been dealing with problems well.”

As the scientists noted in their paper, “A predictive relationship was also found between brain entropy and longer-term mental-health changes—namely, improved wellbeing. Improved wellbeing could be predicted directly from acute increases in brain entropy as early as 1-h post dosing.”

A month after the study the study individuals also scored better on a test of cognitive flexibility.  “Psilocybin seems to loosen up stereotyped patterns of brain activity and give people the ability to revise entrenched patterns of thought,” said first author Taylor Lyons, PhD, a research associate at Imperial College London. “The fact that these changes track with insight and improved well‑being is especially exciting.”

The scientists found that the subjects who had experienced the largest increases in brain entropy in the minutes to hours after taking psilocybin were the most likely to have increased insight the next day and increased wellbeing a month later. The researchers concluded that improved wellbeing was driven by the experience of insight.

The authors suggest that the study findings could improve treatment for people with mental illness using psilocybin, for example, by ensuring that the right dosage is used to produce the right amount of brain entropy to promote insight. “We already knew psilocybin could be helpful for treating mental illness,” Carhart-Harris said. “But now we have a much better understanding of how.”

In their paper the team concluded, “The present multi-modal neuroimaging study in healthy participants sheds light on the brain effects of first-time high-dose psychedelic use and the therapeutic action of psilocybin-therapy, suggesting that therapeutically relevant changes—i.e., improved wellbeing—can be forecast via an acute human brain action, i.e., an entropic brain effect, that is well-known to relate to the psychedelic experience … Results support a role for psychological insight in mediating the causal association between the entropic brain effect and potentially enduring improvements in wellbeing.”

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