Psychedelic drugs work by interfering with nerve cells to improve mental health

Psychedelics go below the surface of the cell to exert their potentially therapeutic effects.

These drugs show promise in clinical trials as treatments for mental disorders (SN: 12/3/21). Now, let us know how. These substances can get inside nerve cells in the cortex — the region of the brain important for consciousness — to tell neurons to grow, researchers report on Dec. 17. Science.

Several mental health conditions, including depression and post-traumatic stress disorder, are linked to chronic stress, which causes neurons in the cortex to shrink over time. Scientists have long believed that repairing cells could provide therapeutic benefits, such as reduced anxiety and improved mood.

Psychedelics — including psilocin, which comes from magic mushrooms and LSD — do this by stimulating the growth of nerve cell branches that receive information, called dendrites (SN: 11/17/20). Positive behavior could explain the results of drug research. But how it triggers cell growth has been a mystery.

It was already known that certain psychedelic neurons activate certain proteins that receive signals and send messages to the cells. This protein, called the 5-HT2A receptor, is also activated by serotonin, a chemical produced by the body and involved in the mind. But a 2018 study determined that serotonin does not make these neurons grow. That finding is “really leaving us scratching our heads,” says neuroscientist David Olson, director of the Psychedelic and Neurotherapeutic Institute at the University of California, Davis.

To figure out why these two types of chemicals affect neurons differently, Olson and colleagues tested some substances to change how well the receptor acted. Instead, they were trained to turn neurons into growth. Instead, the team noticed that “fatty” substances, such as LSD, easily pass through the outer layers of fat cells resulting in branched neurons.

polar chemicals like serotonin, which are unevenly distributed as electrical charges and therefore cannot enter the cells, did not induce growth. Furthermore, experiments have shown that most cortical neurons’ 5-HT2A receptors are located inside the cell, not on the surface where scientists have studied them the most.

But once serotonin gained access to the interior of cortical neurons – through gates artificially added to the cell’s surface – it also led to growth. They also induce antidepressant-like effects in mice. A day after receiving serotonin, the animals whose brain cells contained unnatural points did not swim as quickly as normal rats. In this experiment, the longer the mice tread water, the more effective the antidepressant is predicted to be, showing that within access to 5-HT2A receptors is the key to possible therapeutic effects.

“It seems to overturn a lot of what we think is true about how these drugs work,” said neuroscientist Alex Kwan of Cornell University, who was not involved in the study. “Everyone, even he, thought so” [psychedelics] it deals with receptors that are on the cell surface. “

That’s where most of the receptors for that function like 5-HT2A are found, says biochemist Javier González-Maeso at Virginia State University in Richmond, who also wasn’t involved in the work.

Because serotonin cannot reach 5-HT2A receptors within typical cortical neurons, Olson proposes that the receptors respond to different chemicals made by the body. “If it’s there, it’s got to be a function,” he said. DMT, for example, is a naturally occurring psychedelic made by plants and animals, including humans, and can affect the inner cell.

Kwan disagrees. “It’s interesting what psychedelics can do in them, but I don’t know if the brain necessarily needs to use them when it’s performing its normal function.” Instead, it suggests that there is an internal reserve pool of receptors, ready to replace those that are degraded on the cell surface.

Either way, understanding the cellular mechanisms behind psychedelics’ potential therapeutic effects could help scientists develop safer and more effective treatments for treating mental disorders.

“Eventually, I hope this leads to better drugs,” Olson said.