The drugs disrupted communication between the brain and immune system to lower stress in mice.
From depression to post-traumatic stress disorder, psychedelic drugs combined with therapy might ease symptoms. Once a counterculture outcast, these drugs are undergoing a renaissance in medicine for their ability to rapidly alter the brain’s networks and improve mental health.
But they don’t only work on the brain.
A study in Nature this week found that psilocybin, the active ingredient in magic mushrooms, and MDMA, commonly known as ecstasy, alter the immune system to reduce fear in mice.
“Our study underscores how psychedelics can do more than just change perception; they can help dial down inflammation and reset brain-immune interactions,” said study author Michael Wheeler at Brigham and Women’s Hospital in a press release. “This could reshape how we think about treatment for inflammatory disorders and conditions like anxiety and depression.”
Stress affects the entire body. After analyzing multiple brain cell types and the spleen—which produces immune cells—the team found a delicate, fear-controlling chemical balance between two types of brain cells and a type of immune cell. Stress tipped the balance toward anxiety. Psychedelics acted on the immune cells to restore the balance.
“These brain cells communicate with immune cells…[that] are outside the brain in blood vessels,” wrote Yun Chen and Marco Colonna at the Washington University School of Medicine, who were not involved in the work. “This discovery might lead to innovative strategies for treating chronic stress.”
Brain on Fire
Depression, chronic stress, and the immune system are intricately linked. Changes in the brain send body-wide signals that raise cortisone levels and result in a constant state of fight-or-flight.
The brain also spews out a chemical soup that triggers inflammation and forms neurotoxins.
These conditions decrease serotonin, the “happy” molecule depleted in depression, that psychedelic drugs such as psilocybin and MDMA amp up. This has led to clinical trials investigating whether they might reverse symptoms under guidance and with therapy.
Neurons aren’t the only brain cells involved in cognition and emotions. Astrocytes also play a role. These star-shaped cells don’t generate electrical signals like neurons and are often dubbed “supporting cells.” But they’re quite the chatterboxes and communicate with neurons—and change their activity—as well as other cells using specific molecular signals.
Prior studies have found some astrocytes collaborate with neurons to store emotional memories. Others disrupt fearful memories. This suggests “astrocytes directly regulate fear-associated memory,” wrote Chen and Colonna.
In addition, immune cells communicate with the brain during stress.
Scientists have discovered this signaling can influence depression and other mental health conditions. A study in the 90s, for example, found people with depression have altered monocyte counts—a type of white blood cell usually known for fighting off infections or cleaning up dead cells—suggesting that monocytes may somehow play a role in the disorder.
A Golden Triangle
The new study more carefully teased apart the cellular roles in stress-caused fear. The researchers first sequestered a group of mice inside a tube for six hours a day. Mice like small spaces, but they also like to roam free. After 18 days, the rodents were stressed out.
Challenged with two fear-related tests, they showed far more signs of fear than peers who had lounged for the entire duration. One test, for example, induced the mouse-equivalent of a fear of heights. Compared to mice in the control group, the stressed mice’s cortisone levels spiked much higher, along with higher levels of myriad other inflammatory molecules in the blood.
Because astrocytes, the supporting brain cells, could play a role in this response, the team looked for gene changes in stressed-out mice compared to their happy-go-lucky peers. A unique population of cells based in the amygdala—an almond-shaped region deep in the brain that processes fear, stress, and other emotions—stood out.
The researchers next created gene-edited mice with lower levels of an anti-inflammatory protein (EGFR) in astrocytes. Compared to their peers, these mice had more severe brain inflammation after stress, showcasing the role astrocytes play in brain health. The team found similar results in donated brain tissue from people with either depression or those without the condition. Like the gene-edited mice, EGFR levels were lower in astrocytes in people with depression.
The team also found a small number of monocytes grouped around the brain’s outer wrapping, or meninges. Monocytes move from the spleen to the meninges during stress. Once there, the immune cells pumped out inflammatory molecules, which the astrocytes received and passed on as an “emergency” signal to neurons, boosting the fear response.
The three-part connection is a “striking discovery,” wrote Chen and Colonna.
Here Is My Mind
Lack of serotonin, a chemical in the brain, influences both stress and immune cell health. Two psychedelic drugs, psilocybin and MDMA, can increase serotonin levels.
In the next test, the team gave stressed-out mice a dose of psilocybin or MDMA that roughly corresponded to doses used in people in clinical trials. The mice didn’t show obvious signs of being “high” such as neck twitching. After the dose, their monocytes no longer raged towards the brain’s outer shell. The meninges also pumped out fewer inflammatory molecules. When challenged with the same fear tests, the mice were far less scared even after stress. Their astrocyte and neuron function reverted nearly to normal.
“Together, our results highlight the therapeutic potential of targeting immune mechanisms in neuropsychiatric disorders,” wrote the authors.
Previous studies have mapped the roles of astrocytes, neurons, and the immune system individually. Although the new study integrates those findings into a “unified framework,” wrote Chen and Colonna, there’s much more to explore.
The brain’s own immune cells, microglia, are involved in inflammation and Alzheimer’s disease. How they participate in this neuroimmune communication remains a mystery. And does this three-way crosstalk also regulate short-term stress, such as multitasking while making dinner?
Perhaps more importantly, the results show that psychedelics don’t just affect the mind—they also tinker with the immune system.
“We’re not saying that psychedelics are a cure-all for inflammatory diseases or any other health condition,” Wheeler said. “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.”
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* This article was originally published at Singularity Hub
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