Psychedelics Disrupt Brain-Immune Signals That Promote Fear, Study Suggests

Could the benefits of psychedelics go beyond the brain and impact the immune system? New research suggests an unexpected potential advantage of psychedelics is emerging.

Fear and the immune system could be connected in unexpected ways. Researchers at Mass General Brigham, in affiliation with Harvard Medical School, found that the immune system influences stress and fear behaviors by altering how brain cells communicate. Using preclinical models and human tissue samples, they also found that psychedelics could target these neuroimmune interactions, disrupting them to reduce stress-induced fear. The findings were published April 23 in Nature.

The amygdala, known as the brain’s fear center, processes threats. Some fears—like the fight-or-flight response—are essential for survival. Others pile up and become overwhelming. Researchers believe psychedelics such as MDMA and psilocybin may interrupt unhelpful neuroimmune signals when anxiety, depression, and conditions occur.

Michael Wheeler, a founding member of the Mass General Brigham health care system, is based at the Gene Lay Institute of Immunology and Inflammation and the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital in Boston.

“Our research shows that psychedelics don’t just have powerful effects on the brain’s ability to adapt and change, they also seem to rebalance the way the brain interacts with the body,” Wheeler said in an exclusive statement. “We found that by limiting the brain’s exposure to fear-promoting signals from nearby immune cells, psychedelics might help keep the immune system in check, offering unexpected benefits beyond cognitive effects.”

The study provides insight into the mechanisms at play when psychedelics interact with both the brain and the body, shedding light on their expanding potential in therapeutic settings.

Exploring the Brain-Immune System Connection and Psychedelics

Research in the past has shown immune signals can promote the development of neuropsychiatric conditions such as major depressive disorder (MDD). Looking ahead, psychedelics may provide useful tools in controlling these signals.

In experiments with mouse models under chronic stress, researchers observed increased signaling in the amygdala that amplified fear behaviors, triggered inflammatory responses, and activated fear-promoting neurons. They also found that during chronic stress, inflammatory immune cells called monocytes migrated from other parts of the body to the brain. When stressed mice were given psilocybin and MDMA, monocyte accumulation in the brain was reduced, and fear behaviors decreased.

“We’re especially excited to keep exploring how the immune system factors into psychedelic therapy, both in humans and in mice, and to see whether psychedelics could also have potential as treatments for other inflammatory diseases,” Wheeler wrote.

They also found similar signals 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 pave the way for treatments for neuropsychiatric disorders.

Wheeler is also collaborating with Massachusetts General Hospital Center for the Neuroscience of Psychedelics on a clinical trial of people with depression who are being treated with psychedelic, examining their tissue samples.

Wheeler and colleagues expressed interest in further examining the effects of psychedelics on people with depression and inflammatory diseases. Mass General Brigham, one of the nation’s leading biomedical research organizations, operates across several Harvard Medical School hospitals.

Recent strides have been made in demonstrating the therapeutic effects of psychedelics like MDMA. The FDA initially acknowledged MDMA’s therapeutic potential for PTSD, but ultimately rejected a new drug application, submitted by Lykos Therapeutics (formerly MAPS Public Benefit Corporation). Amid the psychedelic renaissance in medicine, research is leading to potential benefits from psilocybin for treatment-resistant depression, MDD, and addiction.