MDMA and Psilocybin May Reversibly Impact Fear and Stress Responses

Mass General Brigham researchers found that interactions between immune and brain cells drive fear responses, but treatment with psychedelics like MDMA and psilocybin may reverse these effects.

A new study suggests that fear and the immune system are connected in previously unknown ways. Researchers at Mass General Brigham found that the immune system can influence stress and fear behaviors by changing how brain cells communicate. The investigators further showed that psychedelic treatments could target these neuroimmune interactions and reduce stress-induced fear in preclinical models and found similar results in human tissue samples. Results are published in Nature.

“Our study underscores how psychedelics can do more than just change perception; they can help dial down inflammation and reset brain-immune interactions,” said corresponding author Michael Wheeler, PhD, of the Gene Lay Institute of Immunology and Inflammation as well as the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital (BWH), a founding member of the Mass General Brigham healthcare system. “This could reshape how we think about treatment for inflammatory disorders and conditions like anxiety and depression.”

Prior research has shown immune signaling can drive the development of neuropsychiatric diseases such as major depressive disorder (MDD). However, the ways that specific immune mechanisms can also affect behaviors due to chronic stress or MDD remained unclear.

Using a mouse model of chronic stress, the researchers determined that increased crosstalk between cells in the amygdala, or the brain’s fear center, boosted fear behaviors, elevated inflammatory signaling, and activated fear-promoting amygdala neurons.

Furthermore, inflammatory immune cells called monocytes migrated from other parts of the body to the brain meninges during chronic stress. The research team demonstrated that artificially manipulating these cells impacted fear behaviors. Treating stressed mice with psilocybin and MDMA prevented monocytes from accumulating in the brain and lowered fear behaviors.

The investigators found similar signals of response to stress in human brain cells and in gene expression datasets from patients with MDD, suggesting that the same interactions between the immune system and the brain may play a role in neuropsychiatric disorders in humans. The authors note that further experiments are needed to understand exactly how psychedelics affect immune cells and brain communication.

Next steps include examining the long-term effects of psychedelic treatment on patients with MDD or inflammatory diseases. Wheeler is currently collaborating with investigators from the Massachusetts General Hospital Center for the Neuroscience of Psychedelics on a clinical trial of patients with depression who are being treated with psychedelics and will examine their tissue samples.

“We’re not saying that psychedelics are a cure-all for inflammatory diseases or any other health condition,” said Wheeler. “But we do see evidence that psychedelics have some tissue-specific benefits and that learning more about them could open up entirely new possibilities for treatments.”

Reference: Chung EN, Lee J, Polonio CM, et al. Psychedelic control of neuroimmune interactions governing fear. Nature. 2025. doi: 10.1038/s41586-025-08880-9

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