Why are some mushroom trips anxiety inducing? Scientists have a new clue

By Claudia Lopez-Lloreda

Psychedelics are typically associated with Burning Man, or maybe Brad Pitt’s character in Once Upon a Time in Hollywood smoking an acid-laced cigarette. But for Natasha Mason, they mean running programs on a computer while a study subject trips on psilocybin, the active compound in magic mushrooms.


A participant lies in the scanner after taking psilocybin or the placebo control. Credit: Robert Funke

Mason, a neuroscientist at the University of Maastricht, wanted to understand why psilocybin makes some feel blissfully at one with the universe while others have anxiety-inducing trips. So, she took a trip into their brains using MRI and showed that one important molecule predicted how people responded, a finding that could help psychedelics on the road of becoming a routine therapy for psychiatric disorders.

Researchers have long suspected that glutamate, a chemical that neurons use to communicate, could be linked to how people experience a mushroom trip. Studies pointed to this molecule as an important driver of behavioral changes since it increases in the brain with psilocybin administration. However, that research was limited to animal studies. The recent study, led by Mason and her advisor Johannes Ramaekers, was the first to show glutamate changes in humans.

Their work is part of a psychedelic renaissance, in which scientists are exploring how the drugs could be used as treatments for psychiatric conditions. In order to make, say, psilocybin a useful, widespread treatment, researchers are looking into why individuals’ experiences with the drug can vary.

Specifically, Mason and Ramaekers wanted to see the relationship between glutamate and specific responses to psychedelics, such as ego death. Ego death, also called ego dissolution, is a distortion of the sense of self in response to psychedelics. Some experience it positively, as being connected to the world around them. For others, it’s a bad experience, marked by anxiety, a sense of losing control, and feeling like a puppet.

In a double-blind trial, researchers administered psilocybin or a placebo to 60 participants and measured the changes in glutamate levels across different areas of the brains. Participants spent hours in different scanners, which some of them described as rocket ships, while imaging instruments watched the changing molecules in their brains.

Once they were out of the intimidating MRI machines, participants continued their trip in peace. “They have an area for them that is comfortable, which includes a couch and some flowers to make it just a bit more friendly,” says Mason. In this comfortable space, participants assessed their experience and answered one important question: did they have a good trip or a bad trip?


The “safe space” where participants go to finish their trip. Credit: Natasha Mason

When the researchers looked at the data, they saw that area-specific changes of glutamate predicted how participants would answer that question. A glutamate increase in the medial prefrontal cortex predicted a negative ego dissolution experience, while a glutamate decrease in the hippocampus predicted a positive experience. “It shows the complexity of what substances do in one brain area, and [how] the response of the brain might be different in another,” says Katrin Preller, group leader at the University of Zurich who studies brain activity in response to psychedelics and was not involved in the study.

The authors speculate that hippocampal changes may explain one aspect of ego dissolution. The hippocampus is where autobiographical information lives. Less glutamate in this area could mean that people lose access to it during a mushroom trip and ‘lose themselves’ as a consequence. For some, this loss might produce an anxiety response to mushrooms.

Although Mason and Ramaekers looked for changes in glutamate within the first few hours of psilocybin administration, increases in glutamate could also be behind why some people feel better after treatment. Activation of glutamate pathways enhances the birth of new neurons and is a key player of brain plasticity, the process by which we learn new things. Therefore, increases in glutamate with psilocybin treatment could explain why psychedelics help people feel better in the weeks and even months after treatment. The ability to “encode new perspectives would be something that you could build on in the long term,” says Mason.

A better understanding of individual responses could eventually help doctors evaluate which patients would benefit from psychedelic treatment since ego dissolution has been proposed as an indicator of therapeutic success of psychedelics, says Ramaekers. Prior studies found that the quality of ego dissolution was strongly associated with reduction of clinical symptoms, such as depression, in psychiatric patients.

Mason believes psychedelics hold promise for many, specifically for people who have exhausted their options, such as those with treatment-resistant depression. But there is a long road ahead to establish psychedelics as treatment, says Preller. “We need to understand the mechanisms, we need to be convincing.”

Claudia Lopez Lloreda is a freelance science writer and neuroscience Ph.D. student at the University of Pennsylvania. She writes for the UPenn weekly neuroscience blog PennNeuroKnow. Follow her on Twitter @claulopezneuro or e-mail her at clopezlloreda@gmail.com.

This story was produced as part of NASW's David Perlman Summer Mentoring Program, which was launched in 2020 by our Education Committee. Lopez-Lloreda was mentored by Shannon Palus.


Claudia Lopez-Lloreda
Sep. 16, 2020