A newly reported study suggests that fear and the immune system are connected in previously unknown ways. Results from the preclinical research, headed by scientists at Mass General Brigham, showed that interactions between immune and brain cells drive fear responses, and suggest that treatment with psychedelics such as 3,4-methylenedioxymethamphetamine (MDMA), or psilocybin, may reverse these effects.
Collective findings from the study, including work in mouse models and in human tissues, indicated that the immune system can influence stress and fear behaviors by changing how brain cells communicate. Headed by Michael Wheeler, PhD, at the Gene Lay Institute of Immunology and Inflammation, and the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, the investigators further showed that psychedelic treatments could target these neuroimmune interactions and reduce stress-induced fear in preclinical models. They found similar results in human tissue samples.
“Our study underscores how psychedelics can do more than just change perception; they can help dial down inflammation and reset brain-immune interactions,” said Wheeler. “This could reshape how we think about treatment for inflammatory disorders and conditions like anxiety and depression.” Wheeler is corresponding author of the team’s published paper in Nature, titled “Psychedelic control of neuroimmune interactions governing fear,” in which the researchers stated, “Together with validation in clinical samples, these data suggest that psychedelics can be used to target neuroimmune interactions relevant to neuropsychiatric disorders and potentially other inflammatory diseases.”
Prior research has shown immune signaling can drive the development of neuropsychiatric diseases such as major depressive disorder, the authors wrote. “Neuroimmune interactions—signals transmitted between immune and brain cells—regulate many aspects of tissue physiology, including responses to psychological stress, which can predispose individuals to develop neuropsychiatric diseases.” However, the team further stated that the ways specific immune mechanisms can also affect behaviors due to chronic stress or MDD remained unclear. “… although immunotherapies that target peripheral signals induced by psychological stress may be a viable therapeutic area in neuropsychiatric disorders such as MDD,” the team continued, “many relationships between behavioral changes and immunoregulatory mechanisms in the brain remain to be defined.”
For their reported study, the team studied a mouse model of chronic stress. Results from initial tests with the animals showed that in response to chronic stress, plasma levels of corticosterone and certain cytokines and a chemokine were increased. “These results implicate potential links among chronic stress, peripheral inflammatory responses, fear behavior, and neuroimmune interactions,” they reported. Subsequent studies found 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, their research showed that 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. “… we use a combination of genomic and behavioural screens to show that astrocytes in the amygdala limit stress-induced fear behavior through epidermal growth factor receptor (EGFR),” they explained. “… we uncovered a psychedelic-sensitive neuroimmune signaling axis tuned by the recruitment of inflammatory monocytes to the brain meninges, which influences astrocyte–neuron responses in the amygdala and fear behavior.”
The investigators also reported that treating stressed mice with psilocybin and MDMA prevented monocytes from accumulating in the brain and lowered fear behaviors. “By using a phenotypic screen of shared properties among two clinically relevant psychedelics, analogous to studies of social behavior, we found that both psilocybin and MDMA similarly influence immune-cell abundance in tissues,” the authors stated. The resulting data, the scientists continued, “… point to potential direct and indirect mechanisms by which psychedelics influence physiological responses to chronic stress and neuroimmune interactions.”
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. These results, they reported, “… suggest that the neuroimmune mechanisms we initially defined in mice may be relevant in humans and in MDD.”
The authors noted that further experiments are needed to understand exactly how psychedelics affect immune cells and brain communication. “Further research is needed to establish causal cellular and molecular mechanisms by which psychedelics influence tissue physiology more generally, which may reveal psychedelic-responsive pathways with therapeutic applications in unanticipated disorders, including in inflammatory diseases,” they stated. 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.”
In their report, the team concluded, “This study defined mechanisms of astrocyte–neuron crosstalk in the amygdala and their potential regulation by peripheral immune cells in chronic stress and possibly MDD. Together, our results highlight the therapeutic potential of targeting immune mechanisms in neuropsychiatric disorders.”