Researchers at the University of Zurich in Switzerland and at Yale have pinpointed the receptor in the brain that makes someone’s reaction to the popular hallucinogenic drug LSD so profound.

The team used brain imaging technology to evaluate participants’ reactions to LSD and to a combination of LSD and ketanserin, a drug that prevents the receptor serotonin 2A from attaching to the molecules of LSD. The results were surprising. According to co-author Joshua Burt GRD ’20, giving patients ketanserin before administering LSD greatly diminished the effects of the hallucinogens.

The finding, published in the journal eLife on Oct. 25, definitively links serotonin 2A to “tripping” caused by LSD and is a major step in using psychedelics to treat disorders such as depression and schizophrenia.

“Hopefully, someday we’ll really be able to understand the mechanisms by which these drugs work and understand the mechanisms by which psychiatric disorders emerge and then merge the two together to develop smarter treatments for these disorders,” Burt said.

According to the study, a total of 24 subjects between the ages of 20 and 34 were randomly given either a placebo, a dose of LSD or a dose of LSD and ketanserin. In addition to undergoing an MRI scan, the participants also filled out post-surveys about their experiences. Using brain scans of the subjects and their responses to the survey, the researchers found a strong similarity between the experiences of the placebo group and of the group given both LSD and ketanserin. This result, the researchers concluded, demonstrated that serotonin 2A is the major contributor to LSD’s psychedelic effects.

By establishing the link between serotonin 2A and “tripping,” Katrin Preller, the first author and visiting professor at Yale, said that psychedelics could be solutions for people who have psychological disorders caused by the serotonin 2A receptor.

However, Preller said, not all patients with psychiatric disorders respond to medication the same way. Using brain scans can help clinicians predict who will be affected by psychedelics in a positive way.

“We hope that by using this technology … we’ll be able to increase personalized medicine to predict who will respond to which medication,” she said.

According to Burt, the study’s trials were conducted in Switzerland because less government regulation surrounds the psychedelic drug. In the United States, LSD, which is illegal to buy, possess, manufacture or distribute without a license, is a Title I substance — the same classification as heroin and ecstasy — making it difficult to perform studies involving the drug. However, more studies on the topic could change the government’s position, he said.

“There’s a renewed interest in the potential therapeutic benefits of psychedelics like LSD, so we’re really starting to see a lot more of this type of research emerge in the U.S,” Burt said.

The results of the study also have important implications for computational neuroscience — the focus of the lab of John Murray ’06 GRD ’13, a study co-author and professor of psychiatry, neuroscience and physics at the School    of Medicine. Models can simulate the human brain’s reaction to psychedelics and other brain-altering drugs without actually running human trials.

Burt, a member of the Murray Lab, likened using brain models to the field of astronomy.

“You can’t really go in and change things out in space that are millions and billions of light years away, so you create a computer simulation, like a little toy model, and you can change that in whatever way you want,” Burt said. “Whatever happens helps you understand more about how the thing actually works.”

According to Preller, there are still unanswered questions associated with the study. She suggested that further research should focus on determining whether the subjects’ responses would change with a higher dose of LSD or ketanserin or whether the results of this study could be replicated with other psychedelic drugs such as magic mushrooms or ecstasy.

“There are still many open questions to be answered,” Preller said, “because pharmacology is not that simple, especially when it comes to dose-dependent responses.”

LSD’s psychedelic properties were first discovered in 1943 by Swiss scientist Albert Hofmann.

Matt Kristoffersen | matt.kristoffersen@yale.edu .