Psychedelics show hopeful rewiring immune response to fear

New research at Harvard Medical School reveals how compounds such as psilocybin and MDMA affect brain cell and immune system activity, opening the door to potential treatments for anxiety and inflammatory conditions.

Harvard Medical School scientists have discovered the unexpected connection between psychedelic drugs and the immune system, which can change our understanding of how these substances can alleviate fear and anxiety. This pioneering study published in nature shows that psychedelic drugs like psilocybin not only directly affect brain cells, but also interrupt the inflammatory process associated with chronic stress.

“We found that astrocytes in the amygdala use a specific receptor called EGFR to limit the fear caused by stress,” explains Dr. Michael Wheeler, assistant professor at Harvard Medical School and an investigator at Brigham and Women’s Hospital.

“When chronic stress disrupts this signaling, it causes a cascade involving brain resident cells and immune cells, ultimately increasing fear behavior. What’s fascinating is that psychedelic compounds can turn the whole process.”

This study provides compelling evidence that inflammatory monocytes, an immune cell, have been recruited to the protective membrane of the brain (meninges) during chronic stress, where they release inflammatory molecules that affect fear responses. It is worth noting that treatment with psilocybin or MDMA reduces the accumulation of this immune cell and reduces fear behavior in mice.

This study represents a significant shift in our understanding of mental illness. For decades, scientists have focused almost on neurotransmitters when developing treatments for anxiety and depression. Wheeler’s findings suggest that immune dysfunction may be an equally important factor in these diseases.

The team’s work involves multiple methods (from detailed genetic analysis to behavioral testing) that enable astrocytes (astrocytes) to regulate communication between neurons and immune cells. When this communication is disrupted by chronic stress, it leads to an enhanced fear response, which can be reversed by psychedelic therapy.

The researchers observed similar patterns in brain samples from patients with major depression (MDD), suggesting that these findings may translate into human conditions. Brain tissue from MDD patients showed the same astrocyte signaling in long-term stress mice.

Dr. Wheeler’s journey to this discovery began with an unexpected place – the Baltimore City Public Defender Office. “I feel that the actions of the people we defend are inseparable from their environment, including physical or emotional abuse that they cannot control, that I am so desperate to understand the inner work of their minds,” he explained.

This experience inspired his interest in how environmental factors transform neurobiology, ultimately leading him to join a bold interdisciplinary leap through an immunology laboratory without background in the field. “One of the most intimidating choices I made was joining an immunologist’s lab after my approximately election,” Dr. Wheeler noted. “I was only trained in neuroscience at that time, so when I looked at Francisco’s paper on dendritic cells and T cells, I was nervous about what I was in.”

This study has profound implications for not only treating mental illness, but also potentially inflammatory conditions. If psychedelic drugs can regulate immune responses through their effects on the brain, they may be beneficial for a wider range of diseases than previously thought.

Going forward, Dr. Wheeler envisions a fundamental shift close to neuropsychiatric disorders: “I am excited to identify brain-body communication circulation as a fundamental feature of physiology. Usually, we consider mental illness based on their behavioral symptoms. However, we may rely on their behavioral symptoms by focusing on the psychobiology of the brain.”

This work also emphasizes the importance of collaborative, interdisciplinary research. Wheeler attributes his success to bringing together a variety of scientific backgrounds to solve complex problems. “My favorite part is bringing people into the lab and entering our team with a completely different scientific (and personal) background to get everyone working together,” he said. “This helps cross-pollinate between ideas that only happens at the organizational level.”

Although these findings are promising, further research is needed to determine how psychedelic drugs affect specific immune cell types and whether these mechanisms are completely transformed into humans. Clinical trials of psychedelic drugs that study the psychotic and inflammatory components of diseases may provide valuable insights in the coming years.