Why psychedelics hold promise for treating anxiety, depression

The researchers who conducted the animal study demonstrated a reduction in anxiety-like symptoms due to the complex interaction between the psychedelic drug, the receptors, and the specific neurons in a specific location of the brain.

How the drug works and challenges the team faced

Serotonin is a chemical messenger that transmits signals between nerve cells and influences mood, emotions, sleep, and appetite. Serotonergic psychedelics are a class of substances that primarily affect the brain’s serotonin system by acting on serotonin receptors—proteins that help transmit signals when serotonin binds to them. One of the most significant receptors is the 5-HT2A receptor. Common examples of serotonergic psychedelics include LSD (lysergic acid diethylamide) and psilocybin, found in magic mushrooms.

In their research, the team used the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI), a substance commonly employed in medical research. The brain consists of interconnected regions, each responsible for specific functions, such as controlling emotions, memory, and thought processes. One critical area involved in emotional regulation is the ventral hippocampus (vHpc). This region contains various types of brain cells, including parvalbumin (PV)-positive interneurons, which help regulate signals related to anxiety and stress.

These cells have little locks on their surface — the 5-HT2A receptors. When DOI was administered, the researchers found that it specifically targeted “fast-firing” PV-positive interneurons. The drug also unlocked these receptors, thereby boosting the activity of these PV-positive neurons, making them fire more rapidly. This sent calming signals to other parts of the brain, effectively quieting the overactive circuits associated with anxiety. The result was a reduction in anxiety-like symptoms due to the complex interaction between the drug, the receptors, and the specific neurons in the ventral hippocampus.

However, discovering the exact location in the brain, as well as the group of neurons within the location, took almost a decade. “When a drug is consumed, it travels throughout the body. Our goal was to pinpoint exactly where this psychedelic works. To illustrate this, let’s imagine the brain as a country. The brain is a complex structure, and after examining various regions, we discovered that it was the ventral hippocampus in this case. Identifying this region of the brain took us around three years because we had to deliver the drug to different areas of the brain to determine where it was working,” Vaidya explains.

The next step was to identify the exact location within the ventral hippocampus where the drug was working. “Once we knew the location in the brain, we had to determine which exact cells are firing—because there are millions of cells—it helps to know which neurons are being activated by the drug. The Cornell team collaborated with us in identifying that,” Vaidya says.

“Ultimately, we now precisely identified that population of neurons in a particular part of the brain where the drug works, specifically its ability to reduce anxiety. This took us five years. Once this discovery was made, we began experimenting with the receptors on the neurons, removing them, putting them back, and genetically manipulating them to see what effect this would have on anxiety. It was a team effort,” Vaidya says.

Why is this significant?

Vaidya highlights that the findings will aid in the future development of drugs for anxiety. “You don’t want all the effects of psychedelic drugs; you only want the reduction in anxiety, not the hallucinations. To be able to tease a specific pathway, you first need to understand how the drug works. Once you know the pathway, you can design drugs inspired by psychedelics that alleviate anxiety without producing psychedelic effects. This understanding has been one of the significant contributions of this study. It’s crucial because dissecting how these drugs function enables the development of more effective therapies for anxiety disorders,” Vaidya says.

Second, Vaidya emphasises that these findings will provide greater insights for clinical researchers studying psychedelics. “Clinical researchers working with humans who are taking the active ingredient of magic mushrooms, which is a drug called psilocybin, can image the brain to see which parts are activated after a patient is given psilocybin. Our research has established a landmark, especially in examining the effects on anxiety. Without this research, you would be working in the dark, needing to explore the entire brain. However, this work directs you toward specific areas of interest in the human brain. But human studies are essential; it’s a natural next step.” Vaidya says.

Thirdly, Vaidya emphasises that the study’s findings can assist researchers in targeting other brain receptors. “For instance, if we block the receptor in the area we identified, the drug’s effect on anxiety disappears, but its other effects remain. It’s like solving a puzzle—you now know which piece is responsible for one effect, while other pieces handle the rest. We’ve also discovered that hallucinations aren’t generated in this part of the brain; they originate in a different circuit. While the exact circuit remains unclear, we’re certain it’s not in this region,” Vaidya explains.