Psilocybin and MDMA: Psychedelics Can Rewire the Brain Against Fear

Researchers have discovered that the immune system can influence fear and stress by affecting how brain cells communicate. In situations of prolonged stress, immune cells invade the brain and increase fear. In the study, psychedelic drugs such as psilocybin and MDMA were able to reverse this effect, reducing fear and inflammation in the brain. This paves the way for new ways to treat anxiety and depression.

In recent years, researchers have discovered that the immune system and the brain are much more connected than previously thought. A recent study published in the journal Nature showed that these interactions between immune cells and brain cells can directly influence how we respond to stress and fear, and that this could have important implications for diseases such as depression, PTSD, and anxiety.

The main focus of the study was a region of the brain called the amygdala, which is known for its role in processing emotions such as fear and anxiety.

The scientists discovered that certain brain cells called astrocytes, which normally help maintain a stable brain environment, can also control the intensity of fear caused by stress.

This control is done through a receptor called EGFR, which acts as a type of “brake” to limit the exaggerated activation of the fear system in the brain.

When this “brake” does not work properly, as happens in situations of chronic stress, a chain reaction occurs: the production of inflammatory substances increases, communication between brain cells changes, and fearful behavior intensifies.

This exaggerated response also attracts the body’s defense cells, called monocytes, to the meninges (the membranes that surround the brain). This accumulation of immune cells can further worsen stress-related symptoms.

Neurons marked in green and Astrocytes in red

But the study also brought an exciting discovery: psychedelic drugs, such as psilocybin (found in hallucinogenic mushrooms) and MDMA (popularly known as ecstasy), were able to reverse these effects in animal models.

When administered, these compounds prevented monocytes from accumulating in the brain and reduced fear-related behaviors.

This indicates that psychedelics have the potential not only to alter perception, but also to “reset” communication between the immune system and the brain, helping to reduce inflammation and emotional symptoms.

Furthermore, the researchers compared their results with human brain tissue and databases of patients with depression, and found similar signs of inflammation and over-activation of the immune system.

This supports the idea that the same mechanisms may be at work in people with psychiatric disorders.

In short, this study shows that fear and anxiety are not just "in the head", but are also linked to the activity of the immune system.

More importantly, it offers a new treatment option for disorders such as depression and post-traumatic stress disorder, with the controlled use of psychedelics that can restore the balance between the brain and the immune system.

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Psychedelic control of neuroimmune interactions governing fear 

Elizabeth N. Chung, Jinsu Lee, Carolina M. Polonio, Joshua Choi, Camilo Faust Akl, Michael Kilian, Wiebke M. Weiß, Georgia Gunner, Mingyu Ye, Tae Hyun Heo, Sienna S. Drake, Liu Yang, Catarina R. G. L. d’Eca, Joon-Hyuk Lee, Liwen Deng, Daniel Farrenkopf, Anton M. Schüle, Hong-Gyun Lee, Oreoluwa Afolabi, Sharmin Ghaznavi, Stelios M. Smirnakis, Isaac M. Chiu, Vijay K. Kuchroo, Francisco J. Quintana and Michael A. Wheeler, 

Nature. 23 April 2025

DOI: 10.1038/s41586-025-08880-9

Abstract:

Neuroimmune interactions—signals transmitted between immune and brain cells—regulate many aspects of tissue physiology1, including responses to psychological stress2,3,4,5, which can predispose individuals to develop neuropsychiatric diseases6,7,8,9. Still, the interactions between haematopoietic and brain-resident cells that influence complex behaviours are poorly understood. Here, we use a combination of genomic and behavioural screens to show that astrocytes in the amygdala limit stress-induced fear behaviour through epidermal growth factor receptor (EGFR). Mechanistically, EGFR expression in amygdala astrocytes inhibits a stress-induced, pro-inflammatory signal-transduction cascade that facilitates neuron–glial crosstalk and stress-induced fear behaviour through the orphan nuclear receptor NR2F2 in amygdala neurons. In turn, decreased EGFR signalling and fear behaviour are associated with the recruitment of meningeal monocytes during chronic stress. This set of neuroimmune interactions is therapeutically targetable through the administration of psychedelic compounds, which reversed the accumulation of monocytes in the brain meninges along with fear behaviour. 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.