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Yale researchers found that a single dose of the naturally occurring psychedelic compound psilocybin can cause structural changes in the brain that counteract symptoms of depression.

In a paper published in the journal Neuron on Aug. 18, researchers at the Yale School of Medicine presented evidence that administering this drug to mice resulted in an approximately 10 percent increase in neuron size and density in the frontal cortex of the brain. Led by postdoctoral associate Lingxiao Shao and associate professor of psychiatry and neuroscience Alex Kwan, the team found that this “structural remodeling” occurred within 24 hours of the drug administration and persisted for one month, indicating that psilocybin made long-lasting changes in the brain.

“Psilocybin is fascinating because it has an incredibly short half-life, which means that it gets out of the body quickly and yet has long-lasting behavioral effects,” Kwan said. “We’ve seen that psilocybin can be effective in treating depression and other neuropsychiatric disorders. In this study, we wanted to investigate this mystery by observing individual connections in the mouse brain.”

Psilocybin is a naturally occurring substance that is produced by a species of fungi — thus the nickname “magic mushrooms.” Part of a larger category of psychedelics called classic psychedelics, which includes LSD and mescaline, psilocybin works by stimulating serotonin 2A receptors in the brain, according to the paper.

Effects of the drug include visual hallucinations, distortions of reality, euphoria and what some call “spiritual experiences.” However, Kwan and his team are more interested in how the human brain functions after the effects of the drug have already worn off. Psilocybin and other classic psychedelic drugs have long been recognized for their potential as therapeutic drugs to treat disorders like depression, obsessive-compulsive disorder, anxiety and post-traumatic stress disorder.

“I was inspired by Dr. Ronald Duman, who studied ketamine’s effect on [neuron] spine density,” Kwan said. “However, we chose to use psilocybin because it is so well-studied clinically. There is currently a large phase two clinical trial investigating the effects of psilocybin on major depressive disorder.”

However, psychedelic research was not always so popular. Although research into psilocybin and other related drugs began in the 1950s and ’60s, the federal government’s war on drugs during the 1970s stigmatized psychedelic drugs and made them illegal. The federal government declared them Schedule I drugs, meaning that they have a high potential for abuse and no accepted medical use.

However, Kwan and other researchers interested in psychedelics have worked to revive the psychedelic research field, even in the face of tight regulations.

“There are certain risks with a high dosage psychedelic experience, for example increases in heart rate and the possibility of precipitating psychotic episodes, particularly in those predisposed to them,” Albert Garcia-Romeu, assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, said. “However, we take the proper screenings and precautions so that the dosage sessions are safe for participants.”

In this study, Kwan and his team sought to use a mouse model to better understand the changes the human brain undergoes during psychedelic experiences.

Manoj Doss, postdoctoral research fellow at the Johns Hopkins Center for Psychedelic and Consciousness Research, commended the large sample size of 82 mice and the roughly equal distribution between male and female mice in the study — something that Doss said is often overlooked in psychedelic research.

“In this study, the male mouse brains experienced a smaller effect from the dose of psilocybin,” Doss said. “This may point to some heterogeneity or variability in terms of how psilocybin and other psychedelics affect the brain and create long-lasting changes.”

In the future, Kwan and his team hope to investigate the exact mechanisms by which psilocybin increases neuron size and density. Kwan also hopes that this research will help identify new compounds that may have even better properties than psilocybin in treating neuropsychiatric disorders.

Director of Policy and Advocacy at the Multidisciplinary Association for Psychedelic Studies Natalie Ginsberg ’11 expressed her excitement about where the field of psychedelic research is headed.

“This is totally changing the approach to therapy for PTSD and other mental illnesses,” Ginsberg said. “Psychedelics can also greatly impact people’s connections to nature and to each other. We also hope to see psychedelics decriminalized, making them more safe and accessible to those who can be healed by them.”

Psilocybin was classified as a Schedule I drug by the United States in 1970.

VERONICA LEE
Veronica Lee covers breakthrough research for SciTech. She is a sophomore in Branford College majoring in molecular, cellular, and developmental biology.